Clinical Review

Lower urinary tract symptoms (LUTS)are common and tend to increase in frequency with age. Managing LUTS can be complicated, requires an informed discussion between the primary care practitioner (PCP) and patient, and is best achieved by a thorough understanding of the many medical and surgical options available. Over the past 3 decades, medications have become the most common therapy; but recently, newer minimally invasive surgeries have challenged this paradigm. This article provides a comprehensive review for PCPs regarding the evaluation and management of LUTS in men and when to consider a urology referral.

Benign prostatic hyperplasia (BPH) and LUTS are common clinical encounters for most PCPs. About 50% of men will develop LUTS associated with BPH, and symptoms associated with these conditions increase as men age.^1,2 Studies have estimated that 90% of men aged 45 to 80 years demonstrate some symptoms of LUTS.³ Strong genetic influence seems to suggest heritability, but BPH also occurs in sporadic forms and is heavily influenced by androgens.⁴

BPH is a histologic diagnosis, whereas LUTS consists of complex symptomatology related to both static or dynamic components.¹ The enlarged prostate gland obstructs the urethra, simultaneously causing an increase in muscle tone and resistance at the bladder neck and prostatic urethra, leading to increased resistance to urine flow. As a result, there is a thickening of the detrusor muscles in the bladder wall and an overall decreased compliance. Urine becomes stored under increased pressure. These changes result in a weak or intermittent urine stream, incomplete emptying of the bladder, postvoid dribble, hesitancy, and irritative symptoms, such as urgency, frequency, and nocturia.

For many patients, BPH associated with LUTS is a quality of life (QOL) issue. The stigma associated with these symptoms often leads to delays in patients seeking care. Many patients do not seek treatment until symptoms have become so severe that changes in bladder health are often irreversible. Early intervention can dramatically improve a patient’s QOL. Also, early intervention has the potential to reduce overall health care expenditures. BPH-related spending exceeds $1 billion each year in the Medicare program alone.⁵

PCPs are in a unique position to help many patients who present with early-stage LUTS. Given the substantial impact this disease has on QOL, early recognition of symptoms and prompt treatment play a major role. Paramount to this effort is awareness and understanding of various treatments, their advantages, and adverse effects (AEs). This article highlights evidence-based evaluation and treatment of BPH/LUTS for PCPs who treat veterans and recommendations as to when to refer a patient to a urologist.

Evaluation of LUTS and BPH

Evaluation begins with a thorough medical history and physical examination. Particular attention should focus on ruling out other causes of LUTS, such as a urinary tract infection (UTI), acute prostatitis, malignancy, bladder dysfunction, neurogenic bladder, and other obstructive pathology, such as urethral stricture disease. The differential diagnosis of LUTS includes BPH, UTI, bladder neck obstruction, urethral stricture, bladder stones, polydipsia, overactive bladder (OAB), nocturnal polyuria, neurologic disease, genitourinary malignancy, renal failure, and acute/chronic urinary retention.⁶

Relevant medical history influencing urinary symptoms includes diabetes mellitus, underlying neurologic diseases, previous trauma, sexually transmitted infections, and certain medications. Symptom severity may be obtained using a validated questionnaire, such as the International Prostate Symptom Score (IPSS), which also aids clinicians in assessing the impact of LUTS on QOL. Additionally, urinary frequency or volume records (voiding diary) may help establish the severity of the patient’s symptoms and provide insight into other potential causes for LUTS. Patients with BPH often have concurrent erectile dysfunction (ED) or other sexual dysfunction symptoms. Patients should be evaluated for baseline sexual dysfunction before the initiation of treatment as many therapies worsen symptoms of ED or ejaculatory dysfunction.

A comprehensive physical examination with a focus on the genitourinary system should, at minimum, assess for abnormalities of the urethral meatus, prepuce, penis, groin nodes, and prior surgical scars. A digital rectal examination also should be performed. Although controversial, a digital rectal examination for prostate cancer screening may provide a rough estimate of prostate size, help rule out prostatitis, and detect incident prostate nodules. Prostate size does not necessarily correlate well with the degree of urinary obstruction or LUTS but is an important consideration when deciding among different therapies.¹

Laboratory and Adjunctive Tests

A urinalysis with microscopy helps identify other potential causes for urinary symptoms, including infection, proteinuria, or glucosuria. In patients who present with gross or microscopic hematuria, additional consideration should be given to bladder calculi and genitourinary cancer.² When a reversible source for the hematuria is not identified, these patients require referral to a urologist for a hematuria evaluation.

There is some controversy regarding prostate specific antigen (PSA) testing. Most professional organizations advocate for a shared decision-making approach before testing. The American Cancer Society recommends this informed discussion occur between the patient and the PCP for men aged > 50 years at average risk, men aged > 45 years at high risk of developing prostate cancer (African Americans or first-degree relative with early prostate cancer diagnosis), and aged 40 years for men with more than one first-degree relative with an early prostate cancer diagnosis.⁷

Adjunctive tests include postvoid residual (PVR), cystoscopy, uroflowmetry, urodynamics, and transrectal ultrasound. However, these are mostly performed by urologists. In some patients with bladder decompensation after prolonged partial bladder outlet obstruction, urodynamics may be used by urologists to determine whether a patient may benefit from an outlet obstruction procedure. Ordering additional imaging or serum studies for the assessment of LUTS is rarely helpful.

Treatment

Treatment includes management with or without lifestyle modification, medication administration, and surgical therapy. New to this paradigm are in-office minimally invasive surgical options. The goal of treatment is not only to reduce patient symptoms and improve QOL, but also to prevent the secondary sequala of urinary retention, bladder failure, and eventual renal impairment.⁷A basic understanding of these treatments can aid PCPs with appropriate patient counseling and urologic referral.⁸

Lifestyle and Behavior Modification

Behavior modification is the starting point for all patients with LUTS. Lifestyle modifications for LUTS include avoiding substances that exacerbate symptoms, such as α-agonists (decongestants), caffeine, alcohol, spicy/acidic foods, chocolate, and soda. These substances are known to be bladder irritants. Common medications contributing to LUTS include antidepressants, decongestants, antihistamines, bronchodilators, anticholinergics, and sympathomimetics. To decrease nocturia, behavioral modifications include limiting evening fluid intake, timed diuretic administration for patients already on a diuretic, and elevating legs 1 hour before bedtime. Counseling obese patients to lose weight and increasing physical activity have been linked to reduced LUTS.⁹ Other behavioral techniques include double voiding: a technique where patients void normally then change positions and return to void to empty the bladder. Another technique is timed voiding: Many patients have impaired sensation when the bladder is full. These patients are encouraged to void at regular intervals.

Complementary and Alternative Medicine

Multiple nutraceutical compounds claim improved urinary health and symptom reduction. These compounds are marketed to patients with little regulation and oversight since supplements are not regulated or held to the same standard as prescription medications. The most popular nutraceutical for prostate health and LUTS is saw palmetto. Despite its common usage for the treatment of LUTS, little data support saw palmetto health claims. In 2012, a systematic review of 32 randomized trials including 5666 patients compared saw palmetto with a placebo. The study found no difference in urinary symptom scores, urinary flow, or prostate size.^10,11 Other phytotherapy compounds often considered for urinary symptoms include stinging nettle extract and β-sitosterol compounds. The mechanism of action of these agents is unknown and efficacy data are lacking.

Historically, acupuncture and pelvic floor physical therapy have been used successfully for OAB symptoms. A meta-analysis found positive beneficial effects of acupuncture compared with a sham control for short- and medium-term follow-up in both IPSS and urine flow rates in some studies; however, when combining the studies for more statistical power, the benefits were less clear.¹² Physical therapists with specialized training and certification in pelvic health can incorporate certain bladder training techniques. These include voiding positional changes (double voiding and postvoid urethral milking) and timed voiding.^13,14 These interventions often address etiologies of LUTS for which medical therapies are not effective as the sole treatment option.

Medication Management

Medical management includes α-blockers, 5-α-reductase inhibitors (5-α-RIs), antimuscarinic or anticholinergic medicines, β-3 agonists, and phosphodiesterase inhibitors (Table). These medications work independently as well as synergistically. The use of medications to improve symptoms must be balanced against potential AEs and the consequences of a lifetime of drug usage, which can be additive.^15,16

First-line pharmacological therapy for BPH is α-blockers, which work by blocking α1A receptors in the prostate and bladder neck, leading to smooth muscle relaxation, increased diameter of the channel, and improved urinary flow. α-receptors in the bladder neck and prostate are expressed with increased frequency with age and are a potential cause for worsening symptoms as men age. Studies demonstrate that these medications reduce symptoms by 30 to 40% and increase flow rates by 16 to 25%.¹⁷ Commonly prescribed α-blockers include tamsulosin, alfuzosin, silodosin, doxazosin, and terazosin. Doxazosin and terazosin require dose titrations because they may cause significant hypotension. Orthostatic hypotension typically improves with time and is avoided if the patient takes the medication at bedtime. Both doxazosin and terazosin are on the American Geriatric Society’s Beers Criteria list and should be avoided in older patients.¹⁸ Tamsulosin, alfuzosin, and silodosin have a standardized dosing regimen and lower rates of hypotension. Significant AEs include ejaculation dysfunction, nasal congestion, and orthostatic hypotension. Duan and colleagues have linked tamsulosin with dementia. However, this association is not causal and further studies are necessary.^19,20 Patients who have taken these agents also are at risk for intraoperative floppy iris syndrome (IFIS). Permanent visual problems can arise if the intraoperative management is not managed to account for IFIS. These medications have a rapid onset of action and work immediately. However, to reach maximum benefit, patients must take the medication for several weeks. Unfortunately, up to one-third of patients will have no improvement with α-blocker therapy, and many patients will discontinue these medications because of significant AEs.^6,21

5-α-RIs (finasteride and dutasteride) inhibit the conversion of testosterone to more potent dihydrotestosterone. They effectively reduce prostate volume by 25 to 30%.²² The results occur slowly and can take 6 to 12 months to reach the desired outcome. These medications are effective in men with larger prostates and not as effective in men with smaller prostates.²³ These medications can improve urinary flow rates by about 10%, reduce IPSS scores by 20 to 30%, reduce the risk of urinary retention by 50%, and reduce the progression of BPH to the point where surgery is required by 50%.²⁴ Furthermore, 5-α-RIs lower PSA by > 50% after 12 months of treatment.²⁵

A baseline PSA should be established before administration and after 6 months of treatment. Any increase in the PSA even if the level is within normal limits should be evaluated for prostate cancer. Sarkar and colleagues recently published a study evaluating prostate cancer diagnosis in patients treated with 5-α-RI and found there was a delay in diagnosing prostate cancer in this population. Controversy also exists as to the potential of these medications increasing the risk for high-grade prostate cancer, which has led to a US Food and Drug Administration (FDA) warning. AEs include decreased libido (1.5%), ejaculatory dysfunction (3.4%), gynecomastia (1.3%), and/or ED (1.6%).^26-28 A recent study evaluating 5-α-RIs demonstrated about a 2-fold increased risk of depression.²⁹

There are well-established studies that note increased effectiveness when using combined α-blocker therapy with 5-α-RI medications. The Medical Therapy of Prostate Symptoms (MTOPS) and Combination Avodart and Tamsulosin (CombAT) trials showed that the combination of both medications was more effective in improving voiding symptoms and flow rates than either agent alone.^15,16 Combination therapy resulted in a 66% reduction in disease progression, 81% reduction in urinary retention, and a 67% reduction in the need for surgery compared with placebo.

Anticholinergic medication use in BPH with LUTS is well established, and their use is often combined with other therapies. Anticholinergics work by inhibiting muscarinic M3 receptors to reduce detrusor muscle contraction. This effectively decreases bladder contractions and delays the desire to void. Kaplan and colleagues showed that tolterodine significantly improved a patient’s QOL when added to α-blocker therapy.³⁰ Patients reported a positive outcome at 12 weeks, which resulted in a reduction in urgency incontinence, urgency, nocturia, and the overall number of voiding episodes within 24 hours.

β-3 agonists are a class of medications for OAB; mirabegron and vibegron have proven effective in reducing similar symptoms. In phase 3 clinical trials, mirabegron improved urinary incontinence episodes by 50% and reduced the number of voids in 24 hours.³¹ Mirabegron is well tolerated and avoids many common anticholinergic effects.³² Vibegron is the newest medication in the class and could soon become the preferred agent given it does not have cytochrome P450 interactions and does not cause hypertension like mirabegron.³³

Anticholinergics should be used with caution in patients with a history of urinary retention, elevated after-void residual, or other medications with known anticholinergic effects. AEs include sedation, confusion, dry mouth, constipation, and potential falls in older patients.¹⁸ Recent studies have noted an association with dementia in the prolonged use of these medications in older patients and should be used cautiously.²⁰

Phosphodiesterase-5 enzyme inhibitors (PDE-5) are adjunctive medications shown to improve LUTS. This class of medication is prescribed mostly for ED. However, tadalafil 5 mg taken daily also is FDA approved for the treatment of LUTS secondary to BPH given its prolonged half-life. The exact mechanism for improved BPH symptoms is unknown. Possibly the effects are due to an increase mediated by PDE-5 in cyclic guanosine monophosphate (cGMP), which increases smooth muscle relaxation and tissue perfusion of the prostate and bladder.³⁴ There have been limited studies on objective improvement in uroflowmetry parameters compared with other treatments. The daily dosing of tadalafil should not be prescribed in men with a creatinine clearance < 30 mL/min.²⁹ Tadalafil is not considered a first-line agent and is usually reserved for patients who experience ED in addition to BPH. When initiating BPH pharmacologic therapy, the PCP should be aware of adherence and high discontinuation rates.³⁵

Surgical Treatments

Surgical treatments are often delayed out of fear of potential AEs or considered a last resort when symptoms are too severe.³⁶ Early intervention is required to prevent irreversible deleterious changes to detrusor muscle structure and function (Figure). Patients fear urinary incontinence, ED or ejaculatory dysfunction, and anesthesia complications associated with surgical interventions.^6,37 Multiple studies show that patients fare better with early surgical intervention, experiencing improved IPSS scores, urinary flow, and QOL. The following is an overview of the most popular procedures.

Prostatic urethral lift (PUL) using the UroLift System is an FDA-approved, minimally-invasive treatment of LUTS secondary to BPH. This procedure treats prostates < 80 g with an absent median lobe.^6,21,38 Permanent implants are placed per the prostatic urethra to displace obstructing prostate tissue laterally. This opens the urethra directly without cutting, heating, or removing any prostate tissue. This procedure is minimally invasive, often done in the office as an outpatient procedure, and offers better symptom relief than medication with a lower risk profile than transurethral resection of the prostate (TURP).^39,40 The LIFT study was a multicenter, randomized, blinded trial; patients were randomized 2:1 to undergo UroLift or a sham operation. At 3 years, average improvements were statistically significant for total IPSS reduction (41%), QOL improvement (49%), and improved maximum flow rates by (51%).⁴¹ Risk for urinary incontinence is low, and the procedure has been shown to preserve erectile and ejaculatory function. Furthermore, patients report significant improvement in their QOL without the need for medications. Surgical retreatment rates at 5 years are 13.6%, with an additional 10.7% of subjects back on medication therapy with α-blockers or 5-α-RIs.⁴²

Water vapor thermal therapy or Rez¯um uses steam as thermal energy to destroy obstructing prostate tissue and relieve the obstruction.⁴³ The procedure differs from older conductive heat thermotherapies because the steam penetrates prostate zonal anatomy without affecting areas outside the targeted treatment zone. The procedure is done in the office with local anesthesia and provides long-lasting relief of LUTS with minimal risks. Following the procedure, patients require an indwelling urethral catheter for 3 to 7 days, and most patients begin to experience symptom improvement 2 to 4 weeks following the procedure.⁴⁴ The procedure received FDA approval in 2015. Four-year data show significant improvement in maximal flow rate (50%), IPSS (47%), and QOL (43%).⁴⁵ Surgical retreatment rates were 4.4%. Criticisms of this treatment include patient discomfort with the office procedure, the requirement for an indwelling catheter for a short period, and lack of long-term outcomes data. Guidelines support use in prostate volumes > 80 g with or without median lobe anatomy.

TURP is the gold standard to which other treatments are compared.⁴⁶ The surgery is performed in the operating room where urologists use a rigid cystoscope and resection element to effectively carve out and cauterize obstructing prostate tissue. Patients typically recover for a short period with an indwelling urethral catheter that is often removed 12 to 24 hours after surgery. New research points out that despite increasing mean age (55% of patients are aged > 70 years with associated comorbidities), the morbidity of TURP was < 1% and mortality rate of 0 to 0.3%.⁴⁷ Postoperative complications include bleeding that requires a transfusion (3%), retrograde ejaculation (65%), and rare urinary incontinence (2%).⁴⁷ Surgical retreatment rates for patients following a TURP are approximately 13 to 15% at 8 years.³⁴

Laser surgery for BPH includes multiple techniques: photovaporization of the prostate using a Greenlight XPS laser, holmium laser ablation, and holmium laser enucleation (HoLEP). Proponents of these treatments cite lower bleeding risks compared with TURP, but the operation is largely surgeon dependent on the technology chosen. Most studies comparing these technologies with TURP show similar outcomes of IPSS reports, quality of life improvements, and complications.

Patients with extremely large prostates, > 100 g or 4 times the normal size, pose a unique challenge to surgical treatment. Historically, patients were treated with an open simple prostatectomy operation or staged TURP procedures. Today, urologists use newer, safer ways to treat these patients. Both HoLEP and robot-assisted simple prostatectomy work well in relieving urinary symptoms with lower complications compared with older open surgery. Other minimally invasive procedures, such as prostatic artery embolism, have been described for the treatment of BPH specifically in men who may be unfit for surgery.⁴⁸Future treatments are constantly evolving. Many unanswered questions remain about BPH and the role of inflammation, metabolic dysfunction, obesity, and other genetic factors driving BPH and prostate growth. Pharmaceutical opportunities exist in mechanisms aimed to reduce prostate growth, induce cellular apoptosis, as well as other drugs to reduce bladder symptoms. Newer, minimally invasive therapies also will become more readily available, such as Aquablation, which is the first FDA-granted surgical robot for the autonomous removal of prostatic tissue due to BPH.⁴⁹ However, the goal of all future therapies should include the balance of alleviating disruptive symptoms while demonstrating a favorable risk profile. Many men discontinue taking medications, yet few present for surgery. Most concerning is the significant population of men who will develop irreversible bladder dysfunction while waiting for the perfect treatment. There are many opportunities for an effective treatment that is less invasive than surgery, provides durable relief, has minimal AEs, and is affordable.

Conclusions

There is no perfect treatment for patients with LUTS. All interventions have potential AEs and associated complications. Medications are often started as first-line therapy but are often discontinued at the onset of significant AEs. This process is often repeated. Many patients will try different medications without any significant improvement in their symptoms or short-term relief, which results in the gradual progression of the disease.

The PCP plays a significant role in the initial evaluation and management of BPH. These frontline clinicians can recognize patients who may already be experiencing sequela of prolonged bladder outlet obstruction and refer these men to urologists promptly. Counseling patients about their treatment options is an important duty for all PCPs.

A clear understanding of the available treatment options will help PCPs counsel patients appropriately about lifestyle modification, medications, and surgical treatment options for their symptoms. The treatment of this disorder is a rapidly evolving topic with the constant introduction of new technologies and medications, which are certain to continue to play an important role for PCPs and urologists.

Lower urinary tract symptoms (LUTS)are common and tend to increase in frequency with age. Managing LUTS can be complicated, requires an informed discussion between the primary care practitioner (PCP) and patient, and is best achieved by a thorough understanding of the many medical and surgical options available. Over the past 3 decades, medications have become the most common therapy; but recently, newer minimally invasive surgeries have challenged this paradigm. This article provides a comprehensive review for PCPs regarding the evaluation and management of LUTS in men and when to consider a urology referral.

Benign prostatic hyperplasia (BPH) and LUTS are common clinical encounters for most PCPs. About 50% of men will develop LUTS associated with BPH, and symptoms associated with these conditions increase as men age.^1,2 Studies have estimated that 90% of men aged 45 to 80 years demonstrate some symptoms of LUTS.³ Strong genetic influence seems to suggest heritability, but BPH also occurs in sporadic forms and is heavily influenced by androgens.⁴

BPH is a histologic diagnosis, whereas LUTS consists of complex symptomatology related to both static or dynamic components.¹ The enlarged prostate gland obstructs the urethra, simultaneously causing an increase in muscle tone and resistance at the bladder neck and prostatic urethra, leading to increased resistance to urine flow. As a result, there is a thickening of the detrusor muscles in the bladder wall and an overall decreased compliance. Urine becomes stored under increased pressure. These changes result in a weak or intermittent urine stream, incomplete emptying of the bladder, postvoid dribble, hesitancy, and irritative symptoms, such as urgency, frequency, and nocturia.

For many patients, BPH associated with LUTS is a quality of life (QOL) issue. The stigma associated with these symptoms often leads to delays in patients seeking care. Many patients do not seek treatment until symptoms have become so severe that changes in bladder health are often irreversible. Early intervention can dramatically improve a patient’s QOL. Also, early intervention has the potential to reduce overall health care expenditures. BPH-related spending exceeds $1 billion each year in the Medicare program alone.⁵

PCPs are in a unique position to help many patients who present with early-stage LUTS. Given the substantial impact this disease has on QOL, early recognition of symptoms and prompt treatment play a major role. Paramount to this effort is awareness and understanding of various treatments, their advantages, and adverse effects (AEs). This article highlights evidence-based evaluation and treatment of BPH/LUTS for PCPs who treat veterans and recommendations as to when to refer a patient to a urologist.

Evaluation of LUTS and BPH

Evaluation begins with a thorough medical history and physical examination. Particular attention should focus on ruling out other causes of LUTS, such as a urinary tract infection (UTI), acute prostatitis, malignancy, bladder dysfunction, neurogenic bladder, and other obstructive pathology, such as urethral stricture disease. The differential diagnosis of LUTS includes BPH, UTI, bladder neck obstruction, urethral stricture, bladder stones, polydipsia, overactive bladder (OAB), nocturnal polyuria, neurologic disease, genitourinary malignancy, renal failure, and acute/chronic urinary retention.⁶

Relevant medical history influencing urinary symptoms includes diabetes mellitus, underlying neurologic diseases, previous trauma, sexually transmitted infections, and certain medications. Symptom severity may be obtained using a validated questionnaire, such as the International Prostate Symptom Score (IPSS), which also aids clinicians in assessing the impact of LUTS on QOL. Additionally, urinary frequency or volume records (voiding diary) may help establish the severity of the patient’s symptoms and provide insight into other potential causes for LUTS. Patients with BPH often have concurrent erectile dysfunction (ED) or other sexual dysfunction symptoms. Patients should be evaluated for baseline sexual dysfunction before the initiation of treatment as many therapies worsen symptoms of ED or ejaculatory dysfunction.

A comprehensive physical examination with a focus on the genitourinary system should, at minimum, assess for abnormalities of the urethral meatus, prepuce, penis, groin nodes, and prior surgical scars. A digital rectal examination also should be performed. Although controversial, a digital rectal examination for prostate cancer screening may provide a rough estimate of prostate size, help rule out prostatitis, and detect incident prostate nodules. Prostate size does not necessarily correlate well with the degree of urinary obstruction or LUTS but is an important consideration when deciding among different therapies.¹

Laboratory and Adjunctive Tests

A urinalysis with microscopy helps identify other potential causes for urinary symptoms, including infection, proteinuria, or glucosuria. In patients who present with gross or microscopic hematuria, additional consideration should be given to bladder calculi and genitourinary cancer.² When a reversible source for the hematuria is not identified, these patients require referral to a urologist for a hematuria evaluation.

There is some controversy regarding prostate specific antigen (PSA) testing. Most professional organizations advocate for a shared decision-making approach before testing. The American Cancer Society recommends this informed discussion occur between the patient and the PCP for men aged > 50 years at average risk, men aged > 45 years at high risk of developing prostate cancer (African Americans or first-degree relative with early prostate cancer diagnosis), and aged 40 years for men with more than one first-degree relative with an early prostate cancer diagnosis.⁷

Adjunctive tests include postvoid residual (PVR), cystoscopy, uroflowmetry, urodynamics, and transrectal ultrasound. However, these are mostly performed by urologists. In some patients with bladder decompensation after prolonged partial bladder outlet obstruction, urodynamics may be used by urologists to determine whether a patient may benefit from an outlet obstruction procedure. Ordering additional imaging or serum studies for the assessment of LUTS is rarely helpful.

Treatment

Treatment includes management with or without lifestyle modification, medication administration, and surgical therapy. New to this paradigm are in-office minimally invasive surgical options. The goal of treatment is not only to reduce patient symptoms and improve QOL, but also to prevent the secondary sequala of urinary retention, bladder failure, and eventual renal impairment.⁷A basic understanding of these treatments can aid PCPs with appropriate patient counseling and urologic referral.⁸

Lifestyle and Behavior Modification

Behavior modification is the starting point for all patients with LUTS. Lifestyle modifications for LUTS include avoiding substances that exacerbate symptoms, such as α-agonists (decongestants), caffeine, alcohol, spicy/acidic foods, chocolate, and soda. These substances are known to be bladder irritants. Common medications contributing to LUTS include antidepressants, decongestants, antihistamines, bronchodilators, anticholinergics, and sympathomimetics. To decrease nocturia, behavioral modifications include limiting evening fluid intake, timed diuretic administration for patients already on a diuretic, and elevating legs 1 hour before bedtime. Counseling obese patients to lose weight and increasing physical activity have been linked to reduced LUTS.⁹ Other behavioral techniques include double voiding: a technique where patients void normally then change positions and return to void to empty the bladder. Another technique is timed voiding: Many patients have impaired sensation when the bladder is full. These patients are encouraged to void at regular intervals.

Complementary and Alternative Medicine

Multiple nutraceutical compounds claim improved urinary health and symptom reduction. These compounds are marketed to patients with little regulation and oversight since supplements are not regulated or held to the same standard as prescription medications. The most popular nutraceutical for prostate health and LUTS is saw palmetto. Despite its common usage for the treatment of LUTS, little data support saw palmetto health claims. In 2012, a systematic review of 32 randomized trials including 5666 patients compared saw palmetto with a placebo. The study found no difference in urinary symptom scores, urinary flow, or prostate size.^10,11 Other phytotherapy compounds often considered for urinary symptoms include stinging nettle extract and β-sitosterol compounds. The mechanism of action of these agents is unknown and efficacy data are lacking.

Historically, acupuncture and pelvic floor physical therapy have been used successfully for OAB symptoms. A meta-analysis found positive beneficial effects of acupuncture compared with a sham control for short- and medium-term follow-up in both IPSS and urine flow rates in some studies; however, when combining the studies for more statistical power, the benefits were less clear.¹² Physical therapists with specialized training and certification in pelvic health can incorporate certain bladder training techniques. These include voiding positional changes (double voiding and postvoid urethral milking) and timed voiding.^13,14 These interventions often address etiologies of LUTS for which medical therapies are not effective as the sole treatment option.

Medication Management

Medical management includes α-blockers, 5-α-reductase inhibitors (5-α-RIs), antimuscarinic or anticholinergic medicines, β-3 agonists, and phosphodiesterase inhibitors (Table). These medications work independently as well as synergistically. The use of medications to improve symptoms must be balanced against potential AEs and the consequences of a lifetime of drug usage, which can be additive.^15,16

First-line pharmacological therapy for BPH is α-blockers, which work by blocking α1A receptors in the prostate and bladder neck, leading to smooth muscle relaxation, increased diameter of the channel, and improved urinary flow. α-receptors in the bladder neck and prostate are expressed with increased frequency with age and are a potential cause for worsening symptoms as men age. Studies demonstrate that these medications reduce symptoms by 30 to 40% and increase flow rates by 16 to 25%.¹⁷ Commonly prescribed α-blockers include tamsulosin, alfuzosin, silodosin, doxazosin, and terazosin. Doxazosin and terazosin require dose titrations because they may cause significant hypotension. Orthostatic hypotension typically improves with time and is avoided if the patient takes the medication at bedtime. Both doxazosin and terazosin are on the American Geriatric Society’s Beers Criteria list and should be avoided in older patients.¹⁸ Tamsulosin, alfuzosin, and silodosin have a standardized dosing regimen and lower rates of hypotension. Significant AEs include ejaculation dysfunction, nasal congestion, and orthostatic hypotension. Duan and colleagues have linked tamsulosin with dementia. However, this association is not causal and further studies are necessary.^19,20 Patients who have taken these agents also are at risk for intraoperative floppy iris syndrome (IFIS). Permanent visual problems can arise if the intraoperative management is not managed to account for IFIS. These medications have a rapid onset of action and work immediately. However, to reach maximum benefit, patients must take the medication for several weeks. Unfortunately, up to one-third of patients will have no improvement with α-blocker therapy, and many patients will discontinue these medications because of significant AEs.^6,21

5-α-RIs (finasteride and dutasteride) inhibit the conversion of testosterone to more potent dihydrotestosterone. They effectively reduce prostate volume by 25 to 30%.²² The results occur slowly and can take 6 to 12 months to reach the desired outcome. These medications are effective in men with larger prostates and not as effective in men with smaller prostates.²³ These medications can improve urinary flow rates by about 10%, reduce IPSS scores by 20 to 30%, reduce the risk of urinary retention by 50%, and reduce the progression of BPH to the point where surgery is required by 50%.²⁴ Furthermore, 5-α-RIs lower PSA by > 50% after 12 months of treatment.²⁵

A baseline PSA should be established before administration and after 6 months of treatment. Any increase in the PSA even if the level is within normal limits should be evaluated for prostate cancer. Sarkar and colleagues recently published a study evaluating prostate cancer diagnosis in patients treated with 5-α-RI and found there was a delay in diagnosing prostate cancer in this population. Controversy also exists as to the potential of these medications increasing the risk for high-grade prostate cancer, which has led to a US Food and Drug Administration (FDA) warning. AEs include decreased libido (1.5%), ejaculatory dysfunction (3.4%), gynecomastia (1.3%), and/or ED (1.6%).^26-28 A recent study evaluating 5-α-RIs demonstrated about a 2-fold increased risk of depression.²⁹

There are well-established studies that note increased effectiveness when using combined α-blocker therapy with 5-α-RI medications. The Medical Therapy of Prostate Symptoms (MTOPS) and Combination Avodart and Tamsulosin (CombAT) trials showed that the combination of both medications was more effective in improving voiding symptoms and flow rates than either agent alone.^15,16 Combination therapy resulted in a 66% reduction in disease progression, 81% reduction in urinary retention, and a 67% reduction in the need for surgery compared with placebo.

Anticholinergic medication use in BPH with LUTS is well established, and their use is often combined with other therapies. Anticholinergics work by inhibiting muscarinic M3 receptors to reduce detrusor muscle contraction. This effectively decreases bladder contractions and delays the desire to void. Kaplan and colleagues showed that tolterodine significantly improved a patient’s QOL when added to α-blocker therapy.³⁰ Patients reported a positive outcome at 12 weeks, which resulted in a reduction in urgency incontinence, urgency, nocturia, and the overall number of voiding episodes within 24 hours.

β-3 agonists are a class of medications for OAB; mirabegron and vibegron have proven effective in reducing similar symptoms. In phase 3 clinical trials, mirabegron improved urinary incontinence episodes by 50% and reduced the number of voids in 24 hours.³¹ Mirabegron is well tolerated and avoids many common anticholinergic effects.³² Vibegron is the newest medication in the class and could soon become the preferred agent given it does not have cytochrome P450 interactions and does not cause hypertension like mirabegron.³³

Anticholinergics should be used with caution in patients with a history of urinary retention, elevated after-void residual, or other medications with known anticholinergic effects. AEs include sedation, confusion, dry mouth, constipation, and potential falls in older patients.¹⁸ Recent studies have noted an association with dementia in the prolonged use of these medications in older patients and should be used cautiously.²⁰

Phosphodiesterase-5 enzyme inhibitors (PDE-5) are adjunctive medications shown to improve LUTS. This class of medication is prescribed mostly for ED. However, tadalafil 5 mg taken daily also is FDA approved for the treatment of LUTS secondary to BPH given its prolonged half-life. The exact mechanism for improved BPH symptoms is unknown. Possibly the effects are due to an increase mediated by PDE-5 in cyclic guanosine monophosphate (cGMP), which increases smooth muscle relaxation and tissue perfusion of the prostate and bladder.³⁴ There have been limited studies on objective improvement in uroflowmetry parameters compared with other treatments. The daily dosing of tadalafil should not be prescribed in men with a creatinine clearance < 30 mL/min.²⁹ Tadalafil is not considered a first-line agent and is usually reserved for patients who experience ED in addition to BPH. When initiating BPH pharmacologic therapy, the PCP should be aware of adherence and high discontinuation rates.³⁵

Surgical Treatments

Surgical treatments are often delayed out of fear of potential AEs or considered a last resort when symptoms are too severe.³⁶ Early intervention is required to prevent irreversible deleterious changes to detrusor muscle structure and function (Figure). Patients fear urinary incontinence, ED or ejaculatory dysfunction, and anesthesia complications associated with surgical interventions.^6,37 Multiple studies show that patients fare better with early surgical intervention, experiencing improved IPSS scores, urinary flow, and QOL. The following is an overview of the most popular procedures.

Prostatic urethral lift (PUL) using the UroLift System is an FDA-approved, minimally-invasive treatment of LUTS secondary to BPH. This procedure treats prostates < 80 g with an absent median lobe.^6,21,38 Permanent implants are placed per the prostatic urethra to displace obstructing prostate tissue laterally. This opens the urethra directly without cutting, heating, or removing any prostate tissue. This procedure is minimally invasive, often done in the office as an outpatient procedure, and offers better symptom relief than medication with a lower risk profile than transurethral resection of the prostate (TURP).^39,40 The LIFT study was a multicenter, randomized, blinded trial; patients were randomized 2:1 to undergo UroLift or a sham operation. At 3 years, average improvements were statistically significant for total IPSS reduction (41%), QOL improvement (49%), and improved maximum flow rates by (51%).⁴¹ Risk for urinary incontinence is low, and the procedure has been shown to preserve erectile and ejaculatory function. Furthermore, patients report significant improvement in their QOL without the need for medications. Surgical retreatment rates at 5 years are 13.6%, with an additional 10.7% of subjects back on medication therapy with α-blockers or 5-α-RIs.⁴²

Water vapor thermal therapy or Rez¯um uses steam as thermal energy to destroy obstructing prostate tissue and relieve the obstruction.⁴³ The procedure differs from older conductive heat thermotherapies because the steam penetrates prostate zonal anatomy without affecting areas outside the targeted treatment zone. The procedure is done in the office with local anesthesia and provides long-lasting relief of LUTS with minimal risks. Following the procedure, patients require an indwelling urethral catheter for 3 to 7 days, and most patients begin to experience symptom improvement 2 to 4 weeks following the procedure.⁴⁴ The procedure received FDA approval in 2015. Four-year data show significant improvement in maximal flow rate (50%), IPSS (47%), and QOL (43%).⁴⁵ Surgical retreatment rates were 4.4%. Criticisms of this treatment include patient discomfort with the office procedure, the requirement for an indwelling catheter for a short period, and lack of long-term outcomes data. Guidelines support use in prostate volumes > 80 g with or without median lobe anatomy.

TURP is the gold standard to which other treatments are compared.⁴⁶ The surgery is performed in the operating room where urologists use a rigid cystoscope and resection element to effectively carve out and cauterize obstructing prostate tissue. Patients typically recover for a short period with an indwelling urethral catheter that is often removed 12 to 24 hours after surgery. New research points out that despite increasing mean age (55% of patients are aged > 70 years with associated comorbidities), the morbidity of TURP was < 1% and mortality rate of 0 to 0.3%.⁴⁷ Postoperative complications include bleeding that requires a transfusion (3%), retrograde ejaculation (65%), and rare urinary incontinence (2%).⁴⁷ Surgical retreatment rates for patients following a TURP are approximately 13 to 15% at 8 years.³⁴

Laser surgery for BPH includes multiple techniques: photovaporization of the prostate using a Greenlight XPS laser, holmium laser ablation, and holmium laser enucleation (HoLEP). Proponents of these treatments cite lower bleeding risks compared with TURP, but the operation is largely surgeon dependent on the technology chosen. Most studies comparing these technologies with TURP show similar outcomes of IPSS reports, quality of life improvements, and complications.

Patients with extremely large prostates, > 100 g or 4 times the normal size, pose a unique challenge to surgical treatment. Historically, patients were treated with an open simple prostatectomy operation or staged TURP procedures. Today, urologists use newer, safer ways to treat these patients. Both HoLEP and robot-assisted simple prostatectomy work well in relieving urinary symptoms with lower complications compared with older open surgery. Other minimally invasive procedures, such as prostatic artery embolism, have been described for the treatment of BPH specifically in men who may be unfit for surgery.⁴⁸Future treatments are constantly evolving. Many unanswered questions remain about BPH and the role of inflammation, metabolic dysfunction, obesity, and other genetic factors driving BPH and prostate growth. Pharmaceutical opportunities exist in mechanisms aimed to reduce prostate growth, induce cellular apoptosis, as well as other drugs to reduce bladder symptoms. Newer, minimally invasive therapies also will become more readily available, such as Aquablation, which is the first FDA-granted surgical robot for the autonomous removal of prostatic tissue due to BPH.⁴⁹ However, the goal of all future therapies should include the balance of alleviating disruptive symptoms while demonstrating a favorable risk profile. Many men discontinue taking medications, yet few present for surgery. Most concerning is the significant population of men who will develop irreversible bladder dysfunction while waiting for the perfect treatment. There are many opportunities for an effective treatment that is less invasive than surgery, provides durable relief, has minimal AEs, and is affordable.

Conclusions

There is no perfect treatment for patients with LUTS. All interventions have potential AEs and associated complications. Medications are often started as first-line therapy but are often discontinued at the onset of significant AEs. This process is often repeated. Many patients will try different medications without any significant improvement in their symptoms or short-term relief, which results in the gradual progression of the disease.

The PCP plays a significant role in the initial evaluation and management of BPH. These frontline clinicians can recognize patients who may already be experiencing sequela of prolonged bladder outlet obstruction and refer these men to urologists promptly. Counseling patients about their treatment options is an important duty for all PCPs.

A clear understanding of the available treatment options will help PCPs counsel patients appropriately about lifestyle modification, medications, and surgical treatment options for their symptoms. The treatment of this disorder is a rapidly evolving topic with the constant introduction of new technologies and medications, which are certain to continue to play an important role for PCPs and urologists.

Lower urinary tract symptoms (LUTS)are common and tend to increase in frequency with age. Managing LUTS can be complicated, requires an informed discussion between the primary care practitioner (PCP) and patient, and is best achieved by a thorough understanding of the many medical and surgical options available. Over the past 3 decades, medications have become the most common therapy; but recently, newer minimally invasive surgeries have challenged this paradigm. This article provides a comprehensive review for PCPs regarding the evaluation and management of LUTS in men and when to consider a urology referral.

Benign prostatic hyperplasia (BPH) and LUTS are common clinical encounters for most PCPs. About 50% of men will develop LUTS associated with BPH, and symptoms associated with these conditions increase as men age.^1,2 Studies have estimated that 90% of men aged 45 to 80 years demonstrate some symptoms of LUTS.³ Strong genetic influence seems to suggest heritability, but BPH also occurs in sporadic forms and is heavily influenced by androgens.⁴

BPH is a histologic diagnosis, whereas LUTS consists of complex symptomatology related to both static or dynamic components.¹ The enlarged prostate gland obstructs the urethra, simultaneously causing an increase in muscle tone and resistance at the bladder neck and prostatic urethra, leading to increased resistance to urine flow. As a result, there is a thickening of the detrusor muscles in the bladder wall and an overall decreased compliance. Urine becomes stored under increased pressure. These changes result in a weak or intermittent urine stream, incomplete emptying of the bladder, postvoid dribble, hesitancy, and irritative symptoms, such as urgency, frequency, and nocturia.

For many patients, BPH associated with LUTS is a quality of life (QOL) issue. The stigma associated with these symptoms often leads to delays in patients seeking care. Many patients do not seek treatment until symptoms have become so severe that changes in bladder health are often irreversible. Early intervention can dramatically improve a patient’s QOL. Also, early intervention has the potential to reduce overall health care expenditures. BPH-related spending exceeds $1 billion each year in the Medicare program alone.⁵

PCPs are in a unique position to help many patients who present with early-stage LUTS. Given the substantial impact this disease has on QOL, early recognition of symptoms and prompt treatment play a major role. Paramount to this effort is awareness and understanding of various treatments, their advantages, and adverse effects (AEs). This article highlights evidence-based evaluation and treatment of BPH/LUTS for PCPs who treat veterans and recommendations as to when to refer a patient to a urologist.

Evaluation of LUTS and BPH

Evaluation begins with a thorough medical history and physical examination. Particular attention should focus on ruling out other causes of LUTS, such as a urinary tract infection (UTI), acute prostatitis, malignancy, bladder dysfunction, neurogenic bladder, and other obstructive pathology, such as urethral stricture disease. The differential diagnosis of LUTS includes BPH, UTI, bladder neck obstruction, urethral stricture, bladder stones, polydipsia, overactive bladder (OAB), nocturnal polyuria, neurologic disease, genitourinary malignancy, renal failure, and acute/chronic urinary retention.⁶

Relevant medical history influencing urinary symptoms includes diabetes mellitus, underlying neurologic diseases, previous trauma, sexually transmitted infections, and certain medications. Symptom severity may be obtained using a validated questionnaire, such as the International Prostate Symptom Score (IPSS), which also aids clinicians in assessing the impact of LUTS on QOL. Additionally, urinary frequency or volume records (voiding diary) may help establish the severity of the patient’s symptoms and provide insight into other potential causes for LUTS. Patients with BPH often have concurrent erectile dysfunction (ED) or other sexual dysfunction symptoms. Patients should be evaluated for baseline sexual dysfunction before the initiation of treatment as many therapies worsen symptoms of ED or ejaculatory dysfunction.

A comprehensive physical examination with a focus on the genitourinary system should, at minimum, assess for abnormalities of the urethral meatus, prepuce, penis, groin nodes, and prior surgical scars. A digital rectal examination also should be performed. Although controversial, a digital rectal examination for prostate cancer screening may provide a rough estimate of prostate size, help rule out prostatitis, and detect incident prostate nodules. Prostate size does not necessarily correlate well with the degree of urinary obstruction or LUTS but is an important consideration when deciding among different therapies.¹

Laboratory and Adjunctive Tests

A urinalysis with microscopy helps identify other potential causes for urinary symptoms, including infection, proteinuria, or glucosuria. In patients who present with gross or microscopic hematuria, additional consideration should be given to bladder calculi and genitourinary cancer.² When a reversible source for the hematuria is not identified, these patients require referral to a urologist for a hematuria evaluation.

There is some controversy regarding prostate specific antigen (PSA) testing. Most professional organizations advocate for a shared decision-making approach before testing. The American Cancer Society recommends this informed discussion occur between the patient and the PCP for men aged > 50 years at average risk, men aged > 45 years at high risk of developing prostate cancer (African Americans or first-degree relative with early prostate cancer diagnosis), and aged 40 years for men with more than one first-degree relative with an early prostate cancer diagnosis.⁷

Adjunctive tests include postvoid residual (PVR), cystoscopy, uroflowmetry, urodynamics, and transrectal ultrasound. However, these are mostly performed by urologists. In some patients with bladder decompensation after prolonged partial bladder outlet obstruction, urodynamics may be used by urologists to determine whether a patient may benefit from an outlet obstruction procedure. Ordering additional imaging or serum studies for the assessment of LUTS is rarely helpful.

Treatment

Treatment includes management with or without lifestyle modification, medication administration, and surgical therapy. New to this paradigm are in-office minimally invasive surgical options. The goal of treatment is not only to reduce patient symptoms and improve QOL, but also to prevent the secondary sequala of urinary retention, bladder failure, and eventual renal impairment.⁷A basic understanding of these treatments can aid PCPs with appropriate patient counseling and urologic referral.⁸

Lifestyle and Behavior Modification

Behavior modification is the starting point for all patients with LUTS. Lifestyle modifications for LUTS include avoiding substances that exacerbate symptoms, such as α-agonists (decongestants), caffeine, alcohol, spicy/acidic foods, chocolate, and soda. These substances are known to be bladder irritants. Common medications contributing to LUTS include antidepressants, decongestants, antihistamines, bronchodilators, anticholinergics, and sympathomimetics. To decrease nocturia, behavioral modifications include limiting evening fluid intake, timed diuretic administration for patients already on a diuretic, and elevating legs 1 hour before bedtime. Counseling obese patients to lose weight and increasing physical activity have been linked to reduced LUTS.⁹ Other behavioral techniques include double voiding: a technique where patients void normally then change positions and return to void to empty the bladder. Another technique is timed voiding: Many patients have impaired sensation when the bladder is full. These patients are encouraged to void at regular intervals.

Complementary and Alternative Medicine

Multiple nutraceutical compounds claim improved urinary health and symptom reduction. These compounds are marketed to patients with little regulation and oversight since supplements are not regulated or held to the same standard as prescription medications. The most popular nutraceutical for prostate health and LUTS is saw palmetto. Despite its common usage for the treatment of LUTS, little data support saw palmetto health claims. In 2012, a systematic review of 32 randomized trials including 5666 patients compared saw palmetto with a placebo. The study found no difference in urinary symptom scores, urinary flow, or prostate size.^10,11 Other phytotherapy compounds often considered for urinary symptoms include stinging nettle extract and β-sitosterol compounds. The mechanism of action of these agents is unknown and efficacy data are lacking.

Historically, acupuncture and pelvic floor physical therapy have been used successfully for OAB symptoms. A meta-analysis found positive beneficial effects of acupuncture compared with a sham control for short- and medium-term follow-up in both IPSS and urine flow rates in some studies; however, when combining the studies for more statistical power, the benefits were less clear.¹² Physical therapists with specialized training and certification in pelvic health can incorporate certain bladder training techniques. These include voiding positional changes (double voiding and postvoid urethral milking) and timed voiding.^13,14 These interventions often address etiologies of LUTS for which medical therapies are not effective as the sole treatment option.

Medication Management

Medical management includes α-blockers, 5-α-reductase inhibitors (5-α-RIs), antimuscarinic or anticholinergic medicines, β-3 agonists, and phosphodiesterase inhibitors (Table). These medications work independently as well as synergistically. The use of medications to improve symptoms must be balanced against potential AEs and the consequences of a lifetime of drug usage, which can be additive.^15,16

First-line pharmacological therapy for BPH is α-blockers, which work by blocking α1A receptors in the prostate and bladder neck, leading to smooth muscle relaxation, increased diameter of the channel, and improved urinary flow. α-receptors in the bladder neck and prostate are expressed with increased frequency with age and are a potential cause for worsening symptoms as men age. Studies demonstrate that these medications reduce symptoms by 30 to 40% and increase flow rates by 16 to 25%.¹⁷ Commonly prescribed α-blockers include tamsulosin, alfuzosin, silodosin, doxazosin, and terazosin. Doxazosin and terazosin require dose titrations because they may cause significant hypotension. Orthostatic hypotension typically improves with time and is avoided if the patient takes the medication at bedtime. Both doxazosin and terazosin are on the American Geriatric Society’s Beers Criteria list and should be avoided in older patients.¹⁸ Tamsulosin, alfuzosin, and silodosin have a standardized dosing regimen and lower rates of hypotension. Significant AEs include ejaculation dysfunction, nasal congestion, and orthostatic hypotension. Duan and colleagues have linked tamsulosin with dementia. However, this association is not causal and further studies are necessary.^19,20 Patients who have taken these agents also are at risk for intraoperative floppy iris syndrome (IFIS). Permanent visual problems can arise if the intraoperative management is not managed to account for IFIS. These medications have a rapid onset of action and work immediately. However, to reach maximum benefit, patients must take the medication for several weeks. Unfortunately, up to one-third of patients will have no improvement with α-blocker therapy, and many patients will discontinue these medications because of significant AEs.^6,21

5-α-RIs (finasteride and dutasteride) inhibit the conversion of testosterone to more potent dihydrotestosterone. They effectively reduce prostate volume by 25 to 30%.²² The results occur slowly and can take 6 to 12 months to reach the desired outcome. These medications are effective in men with larger prostates and not as effective in men with smaller prostates.²³ These medications can improve urinary flow rates by about 10%, reduce IPSS scores by 20 to 30%, reduce the risk of urinary retention by 50%, and reduce the progression of BPH to the point where surgery is required by 50%.²⁴ Furthermore, 5-α-RIs lower PSA by > 50% after 12 months of treatment.²⁵

A baseline PSA should be established before administration and after 6 months of treatment. Any increase in the PSA even if the level is within normal limits should be evaluated for prostate cancer. Sarkar and colleagues recently published a study evaluating prostate cancer diagnosis in patients treated with 5-α-RI and found there was a delay in diagnosing prostate cancer in this population. Controversy also exists as to the potential of these medications increasing the risk for high-grade prostate cancer, which has led to a US Food and Drug Administration (FDA) warning. AEs include decreased libido (1.5%), ejaculatory dysfunction (3.4%), gynecomastia (1.3%), and/or ED (1.6%).^26-28 A recent study evaluating 5-α-RIs demonstrated about a 2-fold increased risk of depression.²⁹

There are well-established studies that note increased effectiveness when using combined α-blocker therapy with 5-α-RI medications. The Medical Therapy of Prostate Symptoms (MTOPS) and Combination Avodart and Tamsulosin (CombAT) trials showed that the combination of both medications was more effective in improving voiding symptoms and flow rates than either agent alone.^15,16 Combination therapy resulted in a 66% reduction in disease progression, 81% reduction in urinary retention, and a 67% reduction in the need for surgery compared with placebo.

Anticholinergic medication use in BPH with LUTS is well established, and their use is often combined with other therapies. Anticholinergics work by inhibiting muscarinic M3 receptors to reduce detrusor muscle contraction. This effectively decreases bladder contractions and delays the desire to void. Kaplan and colleagues showed that tolterodine significantly improved a patient’s QOL when added to α-blocker therapy.³⁰ Patients reported a positive outcome at 12 weeks, which resulted in a reduction in urgency incontinence, urgency, nocturia, and the overall number of voiding episodes within 24 hours.

β-3 agonists are a class of medications for OAB; mirabegron and vibegron have proven effective in reducing similar symptoms. In phase 3 clinical trials, mirabegron improved urinary incontinence episodes by 50% and reduced the number of voids in 24 hours.³¹ Mirabegron is well tolerated and avoids many common anticholinergic effects.³² Vibegron is the newest medication in the class and could soon become the preferred agent given it does not have cytochrome P450 interactions and does not cause hypertension like mirabegron.³³

Anticholinergics should be used with caution in patients with a history of urinary retention, elevated after-void residual, or other medications with known anticholinergic effects. AEs include sedation, confusion, dry mouth, constipation, and potential falls in older patients.¹⁸ Recent studies have noted an association with dementia in the prolonged use of these medications in older patients and should be used cautiously.²⁰

Phosphodiesterase-5 enzyme inhibitors (PDE-5) are adjunctive medications shown to improve LUTS. This class of medication is prescribed mostly for ED. However, tadalafil 5 mg taken daily also is FDA approved for the treatment of LUTS secondary to BPH given its prolonged half-life. The exact mechanism for improved BPH symptoms is unknown. Possibly the effects are due to an increase mediated by PDE-5 in cyclic guanosine monophosphate (cGMP), which increases smooth muscle relaxation and tissue perfusion of the prostate and bladder.³⁴ There have been limited studies on objective improvement in uroflowmetry parameters compared with other treatments. The daily dosing of tadalafil should not be prescribed in men with a creatinine clearance < 30 mL/min.²⁹ Tadalafil is not considered a first-line agent and is usually reserved for patients who experience ED in addition to BPH. When initiating BPH pharmacologic therapy, the PCP should be aware of adherence and high discontinuation rates.³⁵

Surgical Treatments

Surgical treatments are often delayed out of fear of potential AEs or considered a last resort when symptoms are too severe.³⁶ Early intervention is required to prevent irreversible deleterious changes to detrusor muscle structure and function (Figure). Patients fear urinary incontinence, ED or ejaculatory dysfunction, and anesthesia complications associated with surgical interventions.^6,37 Multiple studies show that patients fare better with early surgical intervention, experiencing improved IPSS scores, urinary flow, and QOL. The following is an overview of the most popular procedures.

Prostatic urethral lift (PUL) using the UroLift System is an FDA-approved, minimally-invasive treatment of LUTS secondary to BPH. This procedure treats prostates < 80 g with an absent median lobe.^6,21,38 Permanent implants are placed per the prostatic urethra to displace obstructing prostate tissue laterally. This opens the urethra directly without cutting, heating, or removing any prostate tissue. This procedure is minimally invasive, often done in the office as an outpatient procedure, and offers better symptom relief than medication with a lower risk profile than transurethral resection of the prostate (TURP).^39,40 The LIFT study was a multicenter, randomized, blinded trial; patients were randomized 2:1 to undergo UroLift or a sham operation. At 3 years, average improvements were statistically significant for total IPSS reduction (41%), QOL improvement (49%), and improved maximum flow rates by (51%).⁴¹ Risk for urinary incontinence is low, and the procedure has been shown to preserve erectile and ejaculatory function. Furthermore, patients report significant improvement in their QOL without the need for medications. Surgical retreatment rates at 5 years are 13.6%, with an additional 10.7% of subjects back on medication therapy with α-blockers or 5-α-RIs.⁴²

Water vapor thermal therapy or Rez¯um uses steam as thermal energy to destroy obstructing prostate tissue and relieve the obstruction.⁴³ The procedure differs from older conductive heat thermotherapies because the steam penetrates prostate zonal anatomy without affecting areas outside the targeted treatment zone. The procedure is done in the office with local anesthesia and provides long-lasting relief of LUTS with minimal risks. Following the procedure, patients require an indwelling urethral catheter for 3 to 7 days, and most patients begin to experience symptom improvement 2 to 4 weeks following the procedure.⁴⁴ The procedure received FDA approval in 2015. Four-year data show significant improvement in maximal flow rate (50%), IPSS (47%), and QOL (43%).⁴⁵ Surgical retreatment rates were 4.4%. Criticisms of this treatment include patient discomfort with the office procedure, the requirement for an indwelling catheter for a short period, and lack of long-term outcomes data. Guidelines support use in prostate volumes > 80 g with or without median lobe anatomy.

TURP is the gold standard to which other treatments are compared.⁴⁶ The surgery is performed in the operating room where urologists use a rigid cystoscope and resection element to effectively carve out and cauterize obstructing prostate tissue. Patients typically recover for a short period with an indwelling urethral catheter that is often removed 12 to 24 hours after surgery. New research points out that despite increasing mean age (55% of patients are aged > 70 years with associated comorbidities), the morbidity of TURP was < 1% and mortality rate of 0 to 0.3%.⁴⁷ Postoperative complications include bleeding that requires a transfusion (3%), retrograde ejaculation (65%), and rare urinary incontinence (2%).⁴⁷ Surgical retreatment rates for patients following a TURP are approximately 13 to 15% at 8 years.³⁴

Laser surgery for BPH includes multiple techniques: photovaporization of the prostate using a Greenlight XPS laser, holmium laser ablation, and holmium laser enucleation (HoLEP). Proponents of these treatments cite lower bleeding risks compared with TURP, but the operation is largely surgeon dependent on the technology chosen. Most studies comparing these technologies with TURP show similar outcomes of IPSS reports, quality of life improvements, and complications.

Patients with extremely large prostates, > 100 g or 4 times the normal size, pose a unique challenge to surgical treatment. Historically, patients were treated with an open simple prostatectomy operation or staged TURP procedures. Today, urologists use newer, safer ways to treat these patients. Both HoLEP and robot-assisted simple prostatectomy work well in relieving urinary symptoms with lower complications compared with older open surgery. Other minimally invasive procedures, such as prostatic artery embolism, have been described for the treatment of BPH specifically in men who may be unfit for surgery.⁴⁸Future treatments are constantly evolving. Many unanswered questions remain about BPH and the role of inflammation, metabolic dysfunction, obesity, and other genetic factors driving BPH and prostate growth. Pharmaceutical opportunities exist in mechanisms aimed to reduce prostate growth, induce cellular apoptosis, as well as other drugs to reduce bladder symptoms. Newer, minimally invasive therapies also will become more readily available, such as Aquablation, which is the first FDA-granted surgical robot for the autonomous removal of prostatic tissue due to BPH.⁴⁹ However, the goal of all future therapies should include the balance of alleviating disruptive symptoms while demonstrating a favorable risk profile. Many men discontinue taking medications, yet few present for surgery. Most concerning is the significant population of men who will develop irreversible bladder dysfunction while waiting for the perfect treatment. There are many opportunities for an effective treatment that is less invasive than surgery, provides durable relief, has minimal AEs, and is affordable.

Conclusions

There is no perfect treatment for patients with LUTS. All interventions have potential AEs and associated complications. Medications are often started as first-line therapy but are often discontinued at the onset of significant AEs. This process is often repeated. Many patients will try different medications without any significant improvement in their symptoms or short-term relief, which results in the gradual progression of the disease.

The PCP plays a significant role in the initial evaluation and management of BPH. These frontline clinicians can recognize patients who may already be experiencing sequela of prolonged bladder outlet obstruction and refer these men to urologists promptly. Counseling patients about their treatment options is an important duty for all PCPs.

A clear understanding of the available treatment options will help PCPs counsel patients appropriately about lifestyle modification, medications, and surgical treatment options for their symptoms. The treatment of this disorder is a rapidly evolving topic with the constant introduction of new technologies and medications, which are certain to continue to play an important role for PCPs and urologists.

Recently, the National Osteoporosis Foundation (NOF) changed its name to the Bone Health and Osteoporosis Foundation (BHOF). Several years ago, in 2016 at my urging, this column was renamed from “Update on osteoporosis” to “Update on bone health.” I believe we were on the leading edge of this movement. As expressed in last year’s Update, our patients’ bone health must be emphasized more than it has been in the past.¹

Consider that localized breast cancer carries a 5-year survival rate of 99%.² Most of my patients are keenly aware that periodic competent breast imaging is the key to the earliest possible diagnosis. By contrast, in this country a hip fracture carries a mortality in the first year of 21%!³ Furthermore, approximately one-third of women who fracture their hip do not have osteoporosis.⁴ While the risk of hip fracture is greatest in women with osteoporosis, it is not absent in those without the condition. Finally, the role of muscle mass, strength, and performance in bone health is a rapidly emerging topic and one that constitutes the core of this year’s Update.

Muscle mass and strength play key role in bone health

de Villiers TJ, Goldstein SR. Update on bone health: the International Menopause Society white paper 2021. Climacteric. 2021;24:498-504. doi:10.1080/13697137.2021.1950967.

Recently, de Villiers and Goldstein offered an overview of osteoporosis.⁵ What is worthy of reporting here is the role of muscle in bone health.

The bone-muscle relationship

Most clinicians know that osteoporosis and osteopenia are well-defined conditions with known risks associated with fracture. According to a review of PubMed, the first article with the keyword “osteoporosis” was published in 1894; through May 2020, 93,335 articles used that keyword. “Osteoporosis” is derived from the Greek osteon (bone) and poros (little hole). Thus, osteoporosis means “porous bone.”

Sarcopenia is characterized by progressive and generalized loss of skeletal muscle mass, strength, and function, and the condition is associated with a risk of adverse outcomes that include physical disabilities, poor quality of life, and death.^6,7 “Sarcopenia” has its roots in the Greek words sarx (flesh) and penia (loss), and the term was coined in 1989.⁸ A PubMed review that included “sarcopenia” as the keyword revealed that the first article was published in 1993, with 12,068 articles published through May 2020.

Notably, muscle accounts for about 60% of the body’s protein. Muscle mass decreases with age, but younger patients with malnutrition, cachexia, or inflammatory diseases are also prone to decreased muscle mass. While osteoporosis has a well-accepted definition based on dual-energy x-ray absorptiometry (DXA) measurements, sarcopenia has no universally accepted definition, consensus diagnostic criteria, or treatment guidelines. In 2016, however, the International Classification of Diseases, Tenth Revision, Clinical Modification (CD-10-CM) finally recognized sarcopenia as a disease entity.

Currently, the most widely accepted definition comes from the European Working Group on Sarcopenia in Older People, which labeled presarcopenia as low muscle mass without impact on muscle strength or performance; sarcopenia as low muscle mass with either low muscle strength or low physical performance; and severe sarcopenia has all 3 criteria being present.⁹

When osteosarcopenia (osteoporosis or osteopenia combined with sarcopenia) exists, it can result in a threefold increase in risk of falls and a fourfold increase in fracture risk compared with women who have osteopenia or osteoporosis alone.¹⁰

Continue to: Denosumab decreased falls risk, improved sarcopenia measures vs comparator antiresorptives...

Denosumab decreased falls risk, improved sarcopenia measures vs comparator antiresorptives

El Miedany Y, El Gaafary M, Toth M, et al; Egyptian Academy of Bone Health, Metabolic Bone Diseases. Is there a potential dual effect of denosumab for treatment of osteoporosis and sarcopenia? Clin Rheumatol. 2021;40:4225-4232. doi: 10.1007/s10067-021 -05757-w.

Osteosarcopenia, the combination of osteoporosis or osteopenia with sarcopenia, has been shown to increase the overall rate of falls and fracture when compared with fall and fracture rates in women with osteopenia or osteoporosis alone.¹⁰ A study by El Miedany and colleagues examined whether denosumab treatment had a possible dual therapeutic effect on osteoporosis and sarcopenia.¹¹

Study details

The investigators looked at 135 patients diagnosed with postmenopausal osteoporosis and who were prescribed denosumab and compared them with a control group of 272 patients stratified into 2 subgroups: 136 were prescribed alendronate and 136 were prescribed zoledronate.

Assessments were performed for all participants for BMD (DXA), fall risk (falls risk assessment score [FRAS]), fracture risk (FRAX assessment tool), and sarcopenia measures. Reassessments were conducted after 5 years of denosumab or alendronate therapy, 3 years of zoledronate therapy, and 1 year after stopping the osteoporosis therapy.

The FRAS uses the clinical variables of history of falls in the last 12 months, impaired sight, weak hand grip, history of loss of balance in the last 12 months, and slowing of the walking speed/change in gait to yield a percent chance of sustaining a fall.¹² Sarcopenic measures include grip strength, timed up and go (TUG) mobility test, and gait speed. There were no significant demographic differences between the 3 groups.

Denosumab reduced risk of falls and positively affected muscle strength

On completion of the 5-year denosumab therapy, falls risk was significantly decreased (P = .001) and significant improvements were seen in all sarcopenia measures (P = .01). One year after denosumab was discontinued, a significant worsening of both falls risk and sarcopenia measures (P = .01) occurred. This was in contrast to results in both control groups (alendronate and zoledronate), in which there was an improvement, although less robust in gait speed and the TUG test (P = .05) but no improvement in risk of falls. Thus, the results of this study showed that denosumab not only improved bone mass but also reduced falls risk.

Compared with bisphosphonates, denosumab showed the highest significant positive effect on both physical performance and skeletal muscle strength. This is evidenced by improvement of the gait speed, TUG test, and 4-m walk test (P<.001) in the denosumab group versus in the alendronate and zoledronate group (P<.05).

These results agree with the outcomes of the FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis 6 months) trial, which revealed that not only did denosumab treatment reduce the risk of vertebral, nonvertebral, and hip fracture over 36 months, but also that the denosumab-treated group had fewer falls (4.5%) compared with the other groups (5.7%) (P = .02).¹³

Continue to: Estrogen’s role in bone health and its therapeutic potential in osteosarcopenia...

Estrogen’s role in bone health and its therapeutic potential in osteosarcopenia

Mandelli A, Tacconi E, Levinger I, et al. The role of estrogens in osteosarcopenia: from biology to potential dual therapeutic effects. Climacteric. 2021;1-7. doi: 10.1080/13697137.2021.1965118.

Osteosarcopenia is a particular term used to describe the coexistence of 2 pathologies, osteopenia/ osteoporosis and sarcopenia.¹⁴ Sarcopenia is characterized by a loss of muscle mass, strength, and performance. Numerous studies indicate that higher lean body mass is related to increased BMD and reduced fracture risk, especially in postmenopausal women.¹⁵

Menopause, muscle, and estrogen’s physiologic effects

Estrogens play a critical role in maintaining bone and muscle mass in women. Women experience a decline in musculoskeletal quantity and quality at the onset of menopause.¹⁶ Muscle mass and strength decrease rapidly after menopause, which suggests that degradation of muscle protein begins to exert a more significant effect due to a decrease in protein synthesis. Indeed, a reduced response to anabolic stimuli has been shown in postmenopausal women.¹⁷ Normalization of the protein synthesis response after restoring estrogen levels with estrogen therapy supports this hypothesis.¹⁸

In a meta-analysis to identify the role of estrogen therapy on muscle strength, the authors concluded that estrogens benefit muscle strength not by increasing the skeletal mass but by improving muscle quality and its ability to generate force.¹⁹ In addition, however, it has been demonstrated that exercise prevents and delays the onset of osteosarcopenia.²⁰

When should bone mass be measured in premenopausal women?

Conradie M, de Villiers T. Premenopausal osteoporosis. Climacteric. 2021:1-14. doi: 10.1080/13697137 .2021.1926974.

Most women’s clinicians are somewhat well acquainted with the increasing importance of preventing, diagnosing, and treating postmenopausal osteoporosis, which predisposes to fragility fracture and the morbidity and even mortality that brings. Increasingly, some younger women are asking for and receiving both bone mass measurements that may be inappropriately ordered and/or wrongly interpreted. Conradie and de Villiers provided an overview of premenopausal osteoporosis, containing important facts that all clinicians who care for women should be aware of.²¹

Indications for testing

BMD testing is only indicated in younger women in settings in which the result may influence management decisions, such as:

• a history of fragility fracture
• diseases associated with low bone mass, such as anorexia nervosa, hypogonadism, hyperparathyroidism, hyperthyroidism, celiac disease, irritable bowel disease, rheumatoid arthritis, lupus, renal disease, Marfan syndrome
• medications, such as glucocorticoids, aromatase inhibitors, premenopausal tamoxifen, excess thyroid hormone replacement, progesterone contraception
• excessive alcohol consumption, heavy smoking, vitamin D deficiency, calcium deficiency, occasionally veganism or vegetarianism.

BMD interpretation in premenopausal women does not use the T-scores developed for postmenopausal women in which standard deviations (SD) from the mean for a young reference population are employed. In that population, the normal range is up to -1.0 SD; osteopenia > -1.0 < -2.5 SD; and osteoporosis > -2.5 SD. Instead, in premenopausal patients, Z-scores, which compare the measured bone mass to an age- and gender-matched cohort, are employed. Z-scores > 2 SD below the matched population should be used rather than the T-scores that are already familiar to most clinicians.

Up to 90% of these premenopausal women with such skeletal fragility will display the secondary causes described above. ●

Recently, the National Osteoporosis Foundation (NOF) changed its name to the Bone Health and Osteoporosis Foundation (BHOF). Several years ago, in 2016 at my urging, this column was renamed from “Update on osteoporosis” to “Update on bone health.” I believe we were on the leading edge of this movement. As expressed in last year’s Update, our patients’ bone health must be emphasized more than it has been in the past.¹

Consider that localized breast cancer carries a 5-year survival rate of 99%.² Most of my patients are keenly aware that periodic competent breast imaging is the key to the earliest possible diagnosis. By contrast, in this country a hip fracture carries a mortality in the first year of 21%!³ Furthermore, approximately one-third of women who fracture their hip do not have osteoporosis.⁴ While the risk of hip fracture is greatest in women with osteoporosis, it is not absent in those without the condition. Finally, the role of muscle mass, strength, and performance in bone health is a rapidly emerging topic and one that constitutes the core of this year’s Update.

Muscle mass and strength play key role in bone health

de Villiers TJ, Goldstein SR. Update on bone health: the International Menopause Society white paper 2021. Climacteric. 2021;24:498-504. doi:10.1080/13697137.2021.1950967.

Recently, de Villiers and Goldstein offered an overview of osteoporosis.⁵ What is worthy of reporting here is the role of muscle in bone health.

The bone-muscle relationship

Most clinicians know that osteoporosis and osteopenia are well-defined conditions with known risks associated with fracture. According to a review of PubMed, the first article with the keyword “osteoporosis” was published in 1894; through May 2020, 93,335 articles used that keyword. “Osteoporosis” is derived from the Greek osteon (bone) and poros (little hole). Thus, osteoporosis means “porous bone.”

Sarcopenia is characterized by progressive and generalized loss of skeletal muscle mass, strength, and function, and the condition is associated with a risk of adverse outcomes that include physical disabilities, poor quality of life, and death.^6,7 “Sarcopenia” has its roots in the Greek words sarx (flesh) and penia (loss), and the term was coined in 1989.⁸ A PubMed review that included “sarcopenia” as the keyword revealed that the first article was published in 1993, with 12,068 articles published through May 2020.

Notably, muscle accounts for about 60% of the body’s protein. Muscle mass decreases with age, but younger patients with malnutrition, cachexia, or inflammatory diseases are also prone to decreased muscle mass. While osteoporosis has a well-accepted definition based on dual-energy x-ray absorptiometry (DXA) measurements, sarcopenia has no universally accepted definition, consensus diagnostic criteria, or treatment guidelines. In 2016, however, the International Classification of Diseases, Tenth Revision, Clinical Modification (CD-10-CM) finally recognized sarcopenia as a disease entity.

Currently, the most widely accepted definition comes from the European Working Group on Sarcopenia in Older People, which labeled presarcopenia as low muscle mass without impact on muscle strength or performance; sarcopenia as low muscle mass with either low muscle strength or low physical performance; and severe sarcopenia has all 3 criteria being present.⁹

When osteosarcopenia (osteoporosis or osteopenia combined with sarcopenia) exists, it can result in a threefold increase in risk of falls and a fourfold increase in fracture risk compared with women who have osteopenia or osteoporosis alone.¹⁰

Continue to: Denosumab decreased falls risk, improved sarcopenia measures vs comparator antiresorptives...

Denosumab decreased falls risk, improved sarcopenia measures vs comparator antiresorptives

El Miedany Y, El Gaafary M, Toth M, et al; Egyptian Academy of Bone Health, Metabolic Bone Diseases. Is there a potential dual effect of denosumab for treatment of osteoporosis and sarcopenia? Clin Rheumatol. 2021;40:4225-4232. doi: 10.1007/s10067-021 -05757-w.

Osteosarcopenia, the combination of osteoporosis or osteopenia with sarcopenia, has been shown to increase the overall rate of falls and fracture when compared with fall and fracture rates in women with osteopenia or osteoporosis alone.¹⁰ A study by El Miedany and colleagues examined whether denosumab treatment had a possible dual therapeutic effect on osteoporosis and sarcopenia.¹¹

Study details

The investigators looked at 135 patients diagnosed with postmenopausal osteoporosis and who were prescribed denosumab and compared them with a control group of 272 patients stratified into 2 subgroups: 136 were prescribed alendronate and 136 were prescribed zoledronate.

Assessments were performed for all participants for BMD (DXA), fall risk (falls risk assessment score [FRAS]), fracture risk (FRAX assessment tool), and sarcopenia measures. Reassessments were conducted after 5 years of denosumab or alendronate therapy, 3 years of zoledronate therapy, and 1 year after stopping the osteoporosis therapy.

The FRAS uses the clinical variables of history of falls in the last 12 months, impaired sight, weak hand grip, history of loss of balance in the last 12 months, and slowing of the walking speed/change in gait to yield a percent chance of sustaining a fall.¹² Sarcopenic measures include grip strength, timed up and go (TUG) mobility test, and gait speed. There were no significant demographic differences between the 3 groups.

Denosumab reduced risk of falls and positively affected muscle strength

On completion of the 5-year denosumab therapy, falls risk was significantly decreased (P = .001) and significant improvements were seen in all sarcopenia measures (P = .01). One year after denosumab was discontinued, a significant worsening of both falls risk and sarcopenia measures (P = .01) occurred. This was in contrast to results in both control groups (alendronate and zoledronate), in which there was an improvement, although less robust in gait speed and the TUG test (P = .05) but no improvement in risk of falls. Thus, the results of this study showed that denosumab not only improved bone mass but also reduced falls risk.

Compared with bisphosphonates, denosumab showed the highest significant positive effect on both physical performance and skeletal muscle strength. This is evidenced by improvement of the gait speed, TUG test, and 4-m walk test (P<.001) in the denosumab group versus in the alendronate and zoledronate group (P<.05).

These results agree with the outcomes of the FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis 6 months) trial, which revealed that not only did denosumab treatment reduce the risk of vertebral, nonvertebral, and hip fracture over 36 months, but also that the denosumab-treated group had fewer falls (4.5%) compared with the other groups (5.7%) (P = .02).¹³

Continue to: Estrogen’s role in bone health and its therapeutic potential in osteosarcopenia...

Estrogen’s role in bone health and its therapeutic potential in osteosarcopenia

Mandelli A, Tacconi E, Levinger I, et al. The role of estrogens in osteosarcopenia: from biology to potential dual therapeutic effects. Climacteric. 2021;1-7. doi: 10.1080/13697137.2021.1965118.

Osteosarcopenia is a particular term used to describe the coexistence of 2 pathologies, osteopenia/ osteoporosis and sarcopenia.¹⁴ Sarcopenia is characterized by a loss of muscle mass, strength, and performance. Numerous studies indicate that higher lean body mass is related to increased BMD and reduced fracture risk, especially in postmenopausal women.¹⁵

Menopause, muscle, and estrogen’s physiologic effects

Estrogens play a critical role in maintaining bone and muscle mass in women. Women experience a decline in musculoskeletal quantity and quality at the onset of menopause.¹⁶ Muscle mass and strength decrease rapidly after menopause, which suggests that degradation of muscle protein begins to exert a more significant effect due to a decrease in protein synthesis. Indeed, a reduced response to anabolic stimuli has been shown in postmenopausal women.¹⁷ Normalization of the protein synthesis response after restoring estrogen levels with estrogen therapy supports this hypothesis.¹⁸

In a meta-analysis to identify the role of estrogen therapy on muscle strength, the authors concluded that estrogens benefit muscle strength not by increasing the skeletal mass but by improving muscle quality and its ability to generate force.¹⁹ In addition, however, it has been demonstrated that exercise prevents and delays the onset of osteosarcopenia.²⁰

When should bone mass be measured in premenopausal women?

Conradie M, de Villiers T. Premenopausal osteoporosis. Climacteric. 2021:1-14. doi: 10.1080/13697137 .2021.1926974.

Most women’s clinicians are somewhat well acquainted with the increasing importance of preventing, diagnosing, and treating postmenopausal osteoporosis, which predisposes to fragility fracture and the morbidity and even mortality that brings. Increasingly, some younger women are asking for and receiving both bone mass measurements that may be inappropriately ordered and/or wrongly interpreted. Conradie and de Villiers provided an overview of premenopausal osteoporosis, containing important facts that all clinicians who care for women should be aware of.²¹

Indications for testing

BMD testing is only indicated in younger women in settings in which the result may influence management decisions, such as:

• a history of fragility fracture
• diseases associated with low bone mass, such as anorexia nervosa, hypogonadism, hyperparathyroidism, hyperthyroidism, celiac disease, irritable bowel disease, rheumatoid arthritis, lupus, renal disease, Marfan syndrome
• medications, such as glucocorticoids, aromatase inhibitors, premenopausal tamoxifen, excess thyroid hormone replacement, progesterone contraception
• excessive alcohol consumption, heavy smoking, vitamin D deficiency, calcium deficiency, occasionally veganism or vegetarianism.

BMD interpretation in premenopausal women does not use the T-scores developed for postmenopausal women in which standard deviations (SD) from the mean for a young reference population are employed. In that population, the normal range is up to -1.0 SD; osteopenia > -1.0 < -2.5 SD; and osteoporosis > -2.5 SD. Instead, in premenopausal patients, Z-scores, which compare the measured bone mass to an age- and gender-matched cohort, are employed. Z-scores > 2 SD below the matched population should be used rather than the T-scores that are already familiar to most clinicians.

Up to 90% of these premenopausal women with such skeletal fragility will display the secondary causes described above. ●

Recently, the National Osteoporosis Foundation (NOF) changed its name to the Bone Health and Osteoporosis Foundation (BHOF). Several years ago, in 2016 at my urging, this column was renamed from “Update on osteoporosis” to “Update on bone health.” I believe we were on the leading edge of this movement. As expressed in last year’s Update, our patients’ bone health must be emphasized more than it has been in the past.¹

Consider that localized breast cancer carries a 5-year survival rate of 99%.² Most of my patients are keenly aware that periodic competent breast imaging is the key to the earliest possible diagnosis. By contrast, in this country a hip fracture carries a mortality in the first year of 21%!³ Furthermore, approximately one-third of women who fracture their hip do not have osteoporosis.⁴ While the risk of hip fracture is greatest in women with osteoporosis, it is not absent in those without the condition. Finally, the role of muscle mass, strength, and performance in bone health is a rapidly emerging topic and one that constitutes the core of this year’s Update.

Muscle mass and strength play key role in bone health

de Villiers TJ, Goldstein SR. Update on bone health: the International Menopause Society white paper 2021. Climacteric. 2021;24:498-504. doi:10.1080/13697137.2021.1950967.

Recently, de Villiers and Goldstein offered an overview of osteoporosis.⁵ What is worthy of reporting here is the role of muscle in bone health.

The bone-muscle relationship

Most clinicians know that osteoporosis and osteopenia are well-defined conditions with known risks associated with fracture. According to a review of PubMed, the first article with the keyword “osteoporosis” was published in 1894; through May 2020, 93,335 articles used that keyword. “Osteoporosis” is derived from the Greek osteon (bone) and poros (little hole). Thus, osteoporosis means “porous bone.”

Sarcopenia is characterized by progressive and generalized loss of skeletal muscle mass, strength, and function, and the condition is associated with a risk of adverse outcomes that include physical disabilities, poor quality of life, and death.^6,7 “Sarcopenia” has its roots in the Greek words sarx (flesh) and penia (loss), and the term was coined in 1989.⁸ A PubMed review that included “sarcopenia” as the keyword revealed that the first article was published in 1993, with 12,068 articles published through May 2020.

Notably, muscle accounts for about 60% of the body’s protein. Muscle mass decreases with age, but younger patients with malnutrition, cachexia, or inflammatory diseases are also prone to decreased muscle mass. While osteoporosis has a well-accepted definition based on dual-energy x-ray absorptiometry (DXA) measurements, sarcopenia has no universally accepted definition, consensus diagnostic criteria, or treatment guidelines. In 2016, however, the International Classification of Diseases, Tenth Revision, Clinical Modification (CD-10-CM) finally recognized sarcopenia as a disease entity.

Currently, the most widely accepted definition comes from the European Working Group on Sarcopenia in Older People, which labeled presarcopenia as low muscle mass without impact on muscle strength or performance; sarcopenia as low muscle mass with either low muscle strength or low physical performance; and severe sarcopenia has all 3 criteria being present.⁹

When osteosarcopenia (osteoporosis or osteopenia combined with sarcopenia) exists, it can result in a threefold increase in risk of falls and a fourfold increase in fracture risk compared with women who have osteopenia or osteoporosis alone.¹⁰

Continue to: Denosumab decreased falls risk, improved sarcopenia measures vs comparator antiresorptives...

Denosumab decreased falls risk, improved sarcopenia measures vs comparator antiresorptives

El Miedany Y, El Gaafary M, Toth M, et al; Egyptian Academy of Bone Health, Metabolic Bone Diseases. Is there a potential dual effect of denosumab for treatment of osteoporosis and sarcopenia? Clin Rheumatol. 2021;40:4225-4232. doi: 10.1007/s10067-021 -05757-w.

Osteosarcopenia, the combination of osteoporosis or osteopenia with sarcopenia, has been shown to increase the overall rate of falls and fracture when compared with fall and fracture rates in women with osteopenia or osteoporosis alone.¹⁰ A study by El Miedany and colleagues examined whether denosumab treatment had a possible dual therapeutic effect on osteoporosis and sarcopenia.¹¹

Study details

The investigators looked at 135 patients diagnosed with postmenopausal osteoporosis and who were prescribed denosumab and compared them with a control group of 272 patients stratified into 2 subgroups: 136 were prescribed alendronate and 136 were prescribed zoledronate.

Assessments were performed for all participants for BMD (DXA), fall risk (falls risk assessment score [FRAS]), fracture risk (FRAX assessment tool), and sarcopenia measures. Reassessments were conducted after 5 years of denosumab or alendronate therapy, 3 years of zoledronate therapy, and 1 year after stopping the osteoporosis therapy.

The FRAS uses the clinical variables of history of falls in the last 12 months, impaired sight, weak hand grip, history of loss of balance in the last 12 months, and slowing of the walking speed/change in gait to yield a percent chance of sustaining a fall.¹² Sarcopenic measures include grip strength, timed up and go (TUG) mobility test, and gait speed. There were no significant demographic differences between the 3 groups.

Denosumab reduced risk of falls and positively affected muscle strength

On completion of the 5-year denosumab therapy, falls risk was significantly decreased (P = .001) and significant improvements were seen in all sarcopenia measures (P = .01). One year after denosumab was discontinued, a significant worsening of both falls risk and sarcopenia measures (P = .01) occurred. This was in contrast to results in both control groups (alendronate and zoledronate), in which there was an improvement, although less robust in gait speed and the TUG test (P = .05) but no improvement in risk of falls. Thus, the results of this study showed that denosumab not only improved bone mass but also reduced falls risk.

Compared with bisphosphonates, denosumab showed the highest significant positive effect on both physical performance and skeletal muscle strength. This is evidenced by improvement of the gait speed, TUG test, and 4-m walk test (P<.001) in the denosumab group versus in the alendronate and zoledronate group (P<.05).

These results agree with the outcomes of the FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis 6 months) trial, which revealed that not only did denosumab treatment reduce the risk of vertebral, nonvertebral, and hip fracture over 36 months, but also that the denosumab-treated group had fewer falls (4.5%) compared with the other groups (5.7%) (P = .02).¹³

Continue to: Estrogen’s role in bone health and its therapeutic potential in osteosarcopenia...

Estrogen’s role in bone health and its therapeutic potential in osteosarcopenia

Mandelli A, Tacconi E, Levinger I, et al. The role of estrogens in osteosarcopenia: from biology to potential dual therapeutic effects. Climacteric. 2021;1-7. doi: 10.1080/13697137.2021.1965118.

Osteosarcopenia is a particular term used to describe the coexistence of 2 pathologies, osteopenia/ osteoporosis and sarcopenia.¹⁴ Sarcopenia is characterized by a loss of muscle mass, strength, and performance. Numerous studies indicate that higher lean body mass is related to increased BMD and reduced fracture risk, especially in postmenopausal women.¹⁵

Menopause, muscle, and estrogen’s physiologic effects

Estrogens play a critical role in maintaining bone and muscle mass in women. Women experience a decline in musculoskeletal quantity and quality at the onset of menopause.¹⁶ Muscle mass and strength decrease rapidly after menopause, which suggests that degradation of muscle protein begins to exert a more significant effect due to a decrease in protein synthesis. Indeed, a reduced response to anabolic stimuli has been shown in postmenopausal women.¹⁷ Normalization of the protein synthesis response after restoring estrogen levels with estrogen therapy supports this hypothesis.¹⁸

In a meta-analysis to identify the role of estrogen therapy on muscle strength, the authors concluded that estrogens benefit muscle strength not by increasing the skeletal mass but by improving muscle quality and its ability to generate force.¹⁹ In addition, however, it has been demonstrated that exercise prevents and delays the onset of osteosarcopenia.²⁰

When should bone mass be measured in premenopausal women?

Conradie M, de Villiers T. Premenopausal osteoporosis. Climacteric. 2021:1-14. doi: 10.1080/13697137 .2021.1926974.

Most women’s clinicians are somewhat well acquainted with the increasing importance of preventing, diagnosing, and treating postmenopausal osteoporosis, which predisposes to fragility fracture and the morbidity and even mortality that brings. Increasingly, some younger women are asking for and receiving both bone mass measurements that may be inappropriately ordered and/or wrongly interpreted. Conradie and de Villiers provided an overview of premenopausal osteoporosis, containing important facts that all clinicians who care for women should be aware of.²¹

Indications for testing

BMD testing is only indicated in younger women in settings in which the result may influence management decisions, such as:

• a history of fragility fracture
• diseases associated with low bone mass, such as anorexia nervosa, hypogonadism, hyperparathyroidism, hyperthyroidism, celiac disease, irritable bowel disease, rheumatoid arthritis, lupus, renal disease, Marfan syndrome
• medications, such as glucocorticoids, aromatase inhibitors, premenopausal tamoxifen, excess thyroid hormone replacement, progesterone contraception
• excessive alcohol consumption, heavy smoking, vitamin D deficiency, calcium deficiency, occasionally veganism or vegetarianism.

BMD interpretation in premenopausal women does not use the T-scores developed for postmenopausal women in which standard deviations (SD) from the mean for a young reference population are employed. In that population, the normal range is up to -1.0 SD; osteopenia > -1.0 < -2.5 SD; and osteoporosis > -2.5 SD. Instead, in premenopausal patients, Z-scores, which compare the measured bone mass to an age- and gender-matched cohort, are employed. Z-scores > 2 SD below the matched population should be used rather than the T-scores that are already familiar to most clinicians.

Up to 90% of these premenopausal women with such skeletal fragility will display the secondary causes described above. ●

In her presentation at The North American Menopause Society (NAMS) 2021 annual meeting (September 22–25, 2021, in Washington, DC), Dr. Holly J. Pederson offered her expert perspectives on breast cancer prevention in at-risk women in “Chemoprevention for risk reduction: Women’s health clinicians have a role.” OBG Management talked with Dr. Pederson after the meeting to explore key points of the presentation.

Which patients would benefit from chemoprevention?

OBG Management: In your NAMS 2021 presentation on chemoprevention for cancer risk reduction, you make the point that for certain women, preventive medication can decrease the risk of breast cancer but is vastly underutilized. Which women specifically would benefit most from breast cancer risk-reducing medication?

Holly J. Pederson, MD: Obviously, women with significant family history are at risk. And approximately 10% of biopsies that are done for other reasons incidentally show atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS)—which are not precancers or cancers but are markers for the development of the disease—and they markedly increase risk. Atypical hyperplasia confers a 30% risk for developing breast cancer over the next 25 years, and LCIS is associated with up to a 2% per year risk. In this setting, preventive medication has been shown to cut risk by 56% to 86%; this is a targeted population that is often overlooked.

Mathematical risk models can be used to assess risk by assessing women’s risk factors. The United States Preventive Services Task Force (USPSTF) has set forth a threshold at which they believe the benefits outweigh the risks of preventive medications. That threshold is 3% or greater over the next 5 years using the Gail breast cancer risk assessment tool.¹ The American Society of Clinical Oncology (ASCO) uses the Tyrer-Cuzick breast cancer risk evaluation model with a threshold of 5% over the next 10 years.² In general, those are the situations in which chemoprevention is a no-brainer.

Certain genetic mutations also predispose to estrogen-sensitive breast cancer. While preventive medications specifically have not been studied in large groups of gene carriers, chemoprevention makes sense because these medications prevent estrogen-sensitive breast cancers that those patients are prone to. Examples would be patients with ATM and CHEK2 gene mutations, which are very common, and patients with BRCA2 and even BRCA1 variants in the postmenopausal years. Those are the big targets.

Risk assessment models

OBG Management: Do you have a preferred breast cancer risk assessment model that you use in your practice?

Dr. Pederson: Yes, I almost exclusively use the Tyrer-Cuzick risk model, version 8, which incorporates breast density. This model is intimidating to some practitioners initially, but once you get used to it, you can complete it very quickly.

The Gail model is very limited. It assesses only first-degree relatives, so you don’t get the paternal information at all, and you don’t use age at diagnosis, family structure, genetic testing, results of breast density, or body mass index (BMI). There are many limitations of the Gail model, but most people use it because it is so easy and they are familiar with it.

Possibly the best model is the CanRisk tool, which incorporates the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA), but it takes too much time to use in clinic; it’s too complicated. The Tyrer-Cuzick model is easy to use once you get used to it.

OBG Management: When would results of the Tyrer-Cuzick assessment necessitate referral to a specialist?

Dr. Pederson: Risk doesn’t always need to be formally calculated, which can be time-consuming. It’s one of those situations where most practitioners know it when they see it. Benign atypical biopsies, a strong family history, or, obviously, the presence of a genetic mutation are huge red flags.

If a practitioner has a nearby high-risk center where they can refer patients, that can be so useful, even for a one-time consultation to guide management. For example, with the virtual world now, I do a lot of consultations for patients and outline a plan, and then the referring practitioner can carry out the plan with confidence and then send the patient back periodically. There are so many more options now that previously did not exist for the busy ObGyn or primary care provider to rely on.

Continue to: Chemoprevention uptake in at-risk women...

OBG Management: How does the risk assessment result influence the uptake of chemoprevention? Are more women willing to take preventive medication?

Dr. Pederson: We really never practice medicine using numbers. We use clinical judgment, and we use relationships with patients in terms of developing confidence and trust. I think that the uptake that we exhibit in our center probably is more based on the patients’ perception that we are confident in our recommendations. I think that many practitioners simply are not comfortable with explaining medications, explaining and managing adverse effects, and using alternative medications. While the modeling helps, I think the personal expertise really makes the difference.

Going forward, the addition of the polygenic risk score to the mathematical risk models is going to make a big difference. Right now, the mathematical risk model is simply that: it takes the traditional risk factors that a patient has and spits out a number. But adding the patient’s genomic data—that is, a weighted summation of SNPs, or single nucleotide polymorphisms, now numbering over 300 for breast cancer—can explain more about their personalized risk, which is going to be more powerful in influencing a woman to take medication or not to take medication, in my opinion. Knowing their actual genomic risk will be a big step forward in individualized risk stratification and increased medication uptake as well as vigilance with high risk screening and attention to diet, exercise, and drinking alcohol in moderation.

OBG Management: What drugs can be used for breast cancer preventive therapy, and how do you select a drug based on patient factors?

Dr. Pederson: The only drug that can be used in the premenopausal setting is tamoxifen (TABLE 1). Women can’t take it if they are pregnant, planning to become pregnant, or if they don’t use a reliable form of birth control because it is teratogenic. Women also cannot take tamoxifen if they have had a history of blood clots, stroke, or transient ischemic attack; if they are on warfarin or estrogen preparations; or if they have had atypical endometrial biopsies or endometrial cancer. Those are the absolute contraindications for tamoxifen use.

Tamoxifen is generally very well tolerated in most women; some women experience hot flashes and night sweats that often will subside (or become tolerable) over the first 90 days. In addition, some women experience vaginal discharge rather than dryness, but it is not as bothersome to patients as dryness can be.

Tamoxifen can be used in the pre- or postmenopausal setting. In healthy premenopausal women, there’s no increased risk of the serious adverse effects that are seen with tamoxifen use in postmenopausal women, such as the 1% risk of blood clots and the 1% risk of endometrial cancer.

In postmenopausal women who still have their uterus, I’ll preferentially use raloxifene over tamoxifen. If they don’t have their uterus, tamoxifen is slightly more effective than the raloxifene, and I’ll use that.

Tamoxifen and raloxifene are both selective estrogen receptor modulators, or SERMs, which means that they stimulate receptors in some tissues, like bone, keeping bones strong, and block the receptors in other tissues, like the breast, reducing risk. And so you get kind of a two-for-one in terms of breast cancer risk reduction and osteoporosis prevention.

Another class of preventive drugs is the aromatase inhibitors (AIs). They block the enzyme aromatase, which converts androgens to estrogens peripherally; that is, the androgens that are produced primarily in the adrenal gland, but in part in postmenopausal ovaries.

In general, AIs are less well tolerated. There are generally more hot flashes and night sweats, and more vaginal dryness than with the SERMs. Anastrozole use is associated with arthralgias; and with exemestane use, there can be some hair loss (TABLE 2). Relative contraindications to SERMs become more important in the postmenopausal setting because of the increased frequency of both blood clots and uterine cancer in the postmenopausal years. I won’t give it to smokers. I won’t give tamoxifen to smokers in the premenopausal period either. With obese women, care must be taken because of the risk of blood clots with the SERMS, so then I’ll resort to the AIs. In the postmenopausal setting, you have to think a lot harder about the choices you use for preventive medication. Preferentially, I’ll use the SERMS if possible as they have fewer adverse effects.

OBG Management: What is the general duration of treatment with these risk-reducing drugs?

Dr. Pederson: All of them are recommended to be given for 5 years, but the MAP.3 trial, which studied exemestane compared with placebo, showed a 65% risk reduction with 3 years of therapy.³ So occasionally, we’ll use 3 years of therapy. Why the treatment recommendation is universally 5 years is unclear, given that the trial with that particular drug was done in 3 years. And with low-dose tamoxifen, the recommended duration is 3 years. That study was done in Italy with 5 mg daily for 3 years.⁴ In the United States we use 10 mg every other day for 3 years because the 5-mg tablet is not available here.

Continue to: Counseling points...

OBG Management: How do you counsel patients about the adverse effects of preventive medications, and how can they be managed?

Dr. Pederson: Patients’ fears about adverse effects are often worse than the adverse effects themselves. Women will fester over, Should I take it? Should I take it possibly for years? And then they take the medication and they tell me, “I don’t even notice that I’m taking it, and I know I’m being proactive.” The majority of patients who take these medications don’t have a lot of significant adverse effects.

Severe hot flashes can be managed in a number of ways, primarily and most effectively with certain antidepressants. Oxybutynin use is another good way to manage vasomotor symptoms. Sometimes we use local vaginal estrogen if a patient has vaginal dryness. In general, however, I would say at least 80% of my patients who take preventive medications do not require management of adverse side effects, that they are tolerable.

I counsel women this way, “Don’t think of this as a 5-year course of medication. Think of it as a 90-day trial, and let’s see how you do. If you hate it, then we don’t do it.” They often are pleasantly surprised that the medication is much easier to tolerate than they thought it would be.

OBG Management: What role does lifestyle modification play in conjunction with chemoprevention?

Dr. Pederson: It would be neat if a trial would directly compare lifestyle interventions with medications, because probably lifestyle change is as effective as medication is—but we don’t know that and probably will never have that data. We do know that alcohol consumption, every drink per day, increases risk by 10%. We know that obesity is responsible for 30% of breast cancers in this country, and that hormone replacement probably is overrated as a significant risk factor. Updated data from the Women’s Health Initiative study suggest that hormone replacement may actually reduce both breast cancer and cardiovascular risk in women in their 50s, but that’s in average-risk women and not in high-risk women, so we can’t generalize. We do recommend lifestyle measures including weight loss, exercise, and limiting alcohol consumption for all of our patients and certainly for our high-risk patients.

The only 2 things a woman can do to reduce the risk of triple negative breast cancer are to achieve and maintain ideal body weight and to breastfeed. The medications that I have mentioned don’t reduce the risk of triple negative breast cancer. Staying thin and breastfeeding do. It’s a problem in this country because at least 35% of all women and 58% of Black women are obese in America, and Black women tend to be prone to triple-negative breast cancer. That’s a real public health issue that we need to address. If we were going to focus on one thing, it would be focusing on obesity in terms of risk reduction.

Final thoughts

OBG Management: Would you like to add any other points about chemoprevention?

Dr. Pederson: I would like to direct attention to the American Heart Association scientific statement published at the end of 2020 that reported that hormone replacement in average-risk women reduced both cardiovascular events and overall mortality in women in their 50s by 30%.⁵ While that’s not directly related to what we are talking about, we need to weigh the pros and cons of estrogen versus estrogen blockade in women in terms of breast cancer risk management discussions. Part of shared decision making now needs to include cardiovascular risk factors and how estrogen is going to play into that.

In women with atypical hyperplasia or LCIS, they may benefit from the preventive medications we discussed. But in women with family history or in women with genetic mutations who have not had benign atypical biopsies, they may choose to consider estrogen during their 50s and perhaps take tamoxifen either beforehand or raloxifene afterward.

We need to look at patients holistically and consider all their risk factors together. We can’t look at one dimension alone.

OBG Management: Thank you for sharing your insights, Dr. Pederson. ●

In her presentation at The North American Menopause Society (NAMS) 2021 annual meeting (September 22–25, 2021, in Washington, DC), Dr. Holly J. Pederson offered her expert perspectives on breast cancer prevention in at-risk women in “Chemoprevention for risk reduction: Women’s health clinicians have a role.” OBG Management talked with Dr. Pederson after the meeting to explore key points of the presentation.

Which patients would benefit from chemoprevention?

OBG Management: In your NAMS 2021 presentation on chemoprevention for cancer risk reduction, you make the point that for certain women, preventive medication can decrease the risk of breast cancer but is vastly underutilized. Which women specifically would benefit most from breast cancer risk-reducing medication?

Holly J. Pederson, MD: Obviously, women with significant family history are at risk. And approximately 10% of biopsies that are done for other reasons incidentally show atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS)—which are not precancers or cancers but are markers for the development of the disease—and they markedly increase risk. Atypical hyperplasia confers a 30% risk for developing breast cancer over the next 25 years, and LCIS is associated with up to a 2% per year risk. In this setting, preventive medication has been shown to cut risk by 56% to 86%; this is a targeted population that is often overlooked.

Mathematical risk models can be used to assess risk by assessing women’s risk factors. The United States Preventive Services Task Force (USPSTF) has set forth a threshold at which they believe the benefits outweigh the risks of preventive medications. That threshold is 3% or greater over the next 5 years using the Gail breast cancer risk assessment tool.¹ The American Society of Clinical Oncology (ASCO) uses the Tyrer-Cuzick breast cancer risk evaluation model with a threshold of 5% over the next 10 years.² In general, those are the situations in which chemoprevention is a no-brainer.

Certain genetic mutations also predispose to estrogen-sensitive breast cancer. While preventive medications specifically have not been studied in large groups of gene carriers, chemoprevention makes sense because these medications prevent estrogen-sensitive breast cancers that those patients are prone to. Examples would be patients with ATM and CHEK2 gene mutations, which are very common, and patients with BRCA2 and even BRCA1 variants in the postmenopausal years. Those are the big targets.

Risk assessment models

OBG Management: Do you have a preferred breast cancer risk assessment model that you use in your practice?

Dr. Pederson: Yes, I almost exclusively use the Tyrer-Cuzick risk model, version 8, which incorporates breast density. This model is intimidating to some practitioners initially, but once you get used to it, you can complete it very quickly.

The Gail model is very limited. It assesses only first-degree relatives, so you don’t get the paternal information at all, and you don’t use age at diagnosis, family structure, genetic testing, results of breast density, or body mass index (BMI). There are many limitations of the Gail model, but most people use it because it is so easy and they are familiar with it.

Possibly the best model is the CanRisk tool, which incorporates the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA), but it takes too much time to use in clinic; it’s too complicated. The Tyrer-Cuzick model is easy to use once you get used to it.

OBG Management: When would results of the Tyrer-Cuzick assessment necessitate referral to a specialist?

Dr. Pederson: Risk doesn’t always need to be formally calculated, which can be time-consuming. It’s one of those situations where most practitioners know it when they see it. Benign atypical biopsies, a strong family history, or, obviously, the presence of a genetic mutation are huge red flags.

If a practitioner has a nearby high-risk center where they can refer patients, that can be so useful, even for a one-time consultation to guide management. For example, with the virtual world now, I do a lot of consultations for patients and outline a plan, and then the referring practitioner can carry out the plan with confidence and then send the patient back periodically. There are so many more options now that previously did not exist for the busy ObGyn or primary care provider to rely on.

Continue to: Chemoprevention uptake in at-risk women...

OBG Management: How does the risk assessment result influence the uptake of chemoprevention? Are more women willing to take preventive medication?

Dr. Pederson: We really never practice medicine using numbers. We use clinical judgment, and we use relationships with patients in terms of developing confidence and trust. I think that the uptake that we exhibit in our center probably is more based on the patients’ perception that we are confident in our recommendations. I think that many practitioners simply are not comfortable with explaining medications, explaining and managing adverse effects, and using alternative medications. While the modeling helps, I think the personal expertise really makes the difference.

Going forward, the addition of the polygenic risk score to the mathematical risk models is going to make a big difference. Right now, the mathematical risk model is simply that: it takes the traditional risk factors that a patient has and spits out a number. But adding the patient’s genomic data—that is, a weighted summation of SNPs, or single nucleotide polymorphisms, now numbering over 300 for breast cancer—can explain more about their personalized risk, which is going to be more powerful in influencing a woman to take medication or not to take medication, in my opinion. Knowing their actual genomic risk will be a big step forward in individualized risk stratification and increased medication uptake as well as vigilance with high risk screening and attention to diet, exercise, and drinking alcohol in moderation.

OBG Management: What drugs can be used for breast cancer preventive therapy, and how do you select a drug based on patient factors?

Dr. Pederson: The only drug that can be used in the premenopausal setting is tamoxifen (TABLE 1). Women can’t take it if they are pregnant, planning to become pregnant, or if they don’t use a reliable form of birth control because it is teratogenic. Women also cannot take tamoxifen if they have had a history of blood clots, stroke, or transient ischemic attack; if they are on warfarin or estrogen preparations; or if they have had atypical endometrial biopsies or endometrial cancer. Those are the absolute contraindications for tamoxifen use.

Tamoxifen is generally very well tolerated in most women; some women experience hot flashes and night sweats that often will subside (or become tolerable) over the first 90 days. In addition, some women experience vaginal discharge rather than dryness, but it is not as bothersome to patients as dryness can be.

Tamoxifen can be used in the pre- or postmenopausal setting. In healthy premenopausal women, there’s no increased risk of the serious adverse effects that are seen with tamoxifen use in postmenopausal women, such as the 1% risk of blood clots and the 1% risk of endometrial cancer.

In postmenopausal women who still have their uterus, I’ll preferentially use raloxifene over tamoxifen. If they don’t have their uterus, tamoxifen is slightly more effective than the raloxifene, and I’ll use that.

Tamoxifen and raloxifene are both selective estrogen receptor modulators, or SERMs, which means that they stimulate receptors in some tissues, like bone, keeping bones strong, and block the receptors in other tissues, like the breast, reducing risk. And so you get kind of a two-for-one in terms of breast cancer risk reduction and osteoporosis prevention.

Another class of preventive drugs is the aromatase inhibitors (AIs). They block the enzyme aromatase, which converts androgens to estrogens peripherally; that is, the androgens that are produced primarily in the adrenal gland, but in part in postmenopausal ovaries.

In general, AIs are less well tolerated. There are generally more hot flashes and night sweats, and more vaginal dryness than with the SERMs. Anastrozole use is associated with arthralgias; and with exemestane use, there can be some hair loss (TABLE 2). Relative contraindications to SERMs become more important in the postmenopausal setting because of the increased frequency of both blood clots and uterine cancer in the postmenopausal years. I won’t give it to smokers. I won’t give tamoxifen to smokers in the premenopausal period either. With obese women, care must be taken because of the risk of blood clots with the SERMS, so then I’ll resort to the AIs. In the postmenopausal setting, you have to think a lot harder about the choices you use for preventive medication. Preferentially, I’ll use the SERMS if possible as they have fewer adverse effects.

OBG Management: What is the general duration of treatment with these risk-reducing drugs?

Dr. Pederson: All of them are recommended to be given for 5 years, but the MAP.3 trial, which studied exemestane compared with placebo, showed a 65% risk reduction with 3 years of therapy.³ So occasionally, we’ll use 3 years of therapy. Why the treatment recommendation is universally 5 years is unclear, given that the trial with that particular drug was done in 3 years. And with low-dose tamoxifen, the recommended duration is 3 years. That study was done in Italy with 5 mg daily for 3 years.⁴ In the United States we use 10 mg every other day for 3 years because the 5-mg tablet is not available here.

Continue to: Counseling points...

OBG Management: How do you counsel patients about the adverse effects of preventive medications, and how can they be managed?

Dr. Pederson: Patients’ fears about adverse effects are often worse than the adverse effects themselves. Women will fester over, Should I take it? Should I take it possibly for years? And then they take the medication and they tell me, “I don’t even notice that I’m taking it, and I know I’m being proactive.” The majority of patients who take these medications don’t have a lot of significant adverse effects.

Severe hot flashes can be managed in a number of ways, primarily and most effectively with certain antidepressants. Oxybutynin use is another good way to manage vasomotor symptoms. Sometimes we use local vaginal estrogen if a patient has vaginal dryness. In general, however, I would say at least 80% of my patients who take preventive medications do not require management of adverse side effects, that they are tolerable.

I counsel women this way, “Don’t think of this as a 5-year course of medication. Think of it as a 90-day trial, and let’s see how you do. If you hate it, then we don’t do it.” They often are pleasantly surprised that the medication is much easier to tolerate than they thought it would be.

OBG Management: What role does lifestyle modification play in conjunction with chemoprevention?

Dr. Pederson: It would be neat if a trial would directly compare lifestyle interventions with medications, because probably lifestyle change is as effective as medication is—but we don’t know that and probably will never have that data. We do know that alcohol consumption, every drink per day, increases risk by 10%. We know that obesity is responsible for 30% of breast cancers in this country, and that hormone replacement probably is overrated as a significant risk factor. Updated data from the Women’s Health Initiative study suggest that hormone replacement may actually reduce both breast cancer and cardiovascular risk in women in their 50s, but that’s in average-risk women and not in high-risk women, so we can’t generalize. We do recommend lifestyle measures including weight loss, exercise, and limiting alcohol consumption for all of our patients and certainly for our high-risk patients.

The only 2 things a woman can do to reduce the risk of triple negative breast cancer are to achieve and maintain ideal body weight and to breastfeed. The medications that I have mentioned don’t reduce the risk of triple negative breast cancer. Staying thin and breastfeeding do. It’s a problem in this country because at least 35% of all women and 58% of Black women are obese in America, and Black women tend to be prone to triple-negative breast cancer. That’s a real public health issue that we need to address. If we were going to focus on one thing, it would be focusing on obesity in terms of risk reduction.

Final thoughts

OBG Management: Would you like to add any other points about chemoprevention?

Dr. Pederson: I would like to direct attention to the American Heart Association scientific statement published at the end of 2020 that reported that hormone replacement in average-risk women reduced both cardiovascular events and overall mortality in women in their 50s by 30%.⁵ While that’s not directly related to what we are talking about, we need to weigh the pros and cons of estrogen versus estrogen blockade in women in terms of breast cancer risk management discussions. Part of shared decision making now needs to include cardiovascular risk factors and how estrogen is going to play into that.

In women with atypical hyperplasia or LCIS, they may benefit from the preventive medications we discussed. But in women with family history or in women with genetic mutations who have not had benign atypical biopsies, they may choose to consider estrogen during their 50s and perhaps take tamoxifen either beforehand or raloxifene afterward.

We need to look at patients holistically and consider all their risk factors together. We can’t look at one dimension alone.

OBG Management: Thank you for sharing your insights, Dr. Pederson. ●

In her presentation at The North American Menopause Society (NAMS) 2021 annual meeting (September 22–25, 2021, in Washington, DC), Dr. Holly J. Pederson offered her expert perspectives on breast cancer prevention in at-risk women in “Chemoprevention for risk reduction: Women’s health clinicians have a role.” OBG Management talked with Dr. Pederson after the meeting to explore key points of the presentation.

Which patients would benefit from chemoprevention?

OBG Management: In your NAMS 2021 presentation on chemoprevention for cancer risk reduction, you make the point that for certain women, preventive medication can decrease the risk of breast cancer but is vastly underutilized. Which women specifically would benefit most from breast cancer risk-reducing medication?

Holly J. Pederson, MD: Obviously, women with significant family history are at risk. And approximately 10% of biopsies that are done for other reasons incidentally show atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS)—which are not precancers or cancers but are markers for the development of the disease—and they markedly increase risk. Atypical hyperplasia confers a 30% risk for developing breast cancer over the next 25 years, and LCIS is associated with up to a 2% per year risk. In this setting, preventive medication has been shown to cut risk by 56% to 86%; this is a targeted population that is often overlooked.

Mathematical risk models can be used to assess risk by assessing women’s risk factors. The United States Preventive Services Task Force (USPSTF) has set forth a threshold at which they believe the benefits outweigh the risks of preventive medications. That threshold is 3% or greater over the next 5 years using the Gail breast cancer risk assessment tool.¹ The American Society of Clinical Oncology (ASCO) uses the Tyrer-Cuzick breast cancer risk evaluation model with a threshold of 5% over the next 10 years.² In general, those are the situations in which chemoprevention is a no-brainer.

Certain genetic mutations also predispose to estrogen-sensitive breast cancer. While preventive medications specifically have not been studied in large groups of gene carriers, chemoprevention makes sense because these medications prevent estrogen-sensitive breast cancers that those patients are prone to. Examples would be patients with ATM and CHEK2 gene mutations, which are very common, and patients with BRCA2 and even BRCA1 variants in the postmenopausal years. Those are the big targets.

Risk assessment models

OBG Management: Do you have a preferred breast cancer risk assessment model that you use in your practice?

Dr. Pederson: Yes, I almost exclusively use the Tyrer-Cuzick risk model, version 8, which incorporates breast density. This model is intimidating to some practitioners initially, but once you get used to it, you can complete it very quickly.

The Gail model is very limited. It assesses only first-degree relatives, so you don’t get the paternal information at all, and you don’t use age at diagnosis, family structure, genetic testing, results of breast density, or body mass index (BMI). There are many limitations of the Gail model, but most people use it because it is so easy and they are familiar with it.

Possibly the best model is the CanRisk tool, which incorporates the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA), but it takes too much time to use in clinic; it’s too complicated. The Tyrer-Cuzick model is easy to use once you get used to it.

OBG Management: When would results of the Tyrer-Cuzick assessment necessitate referral to a specialist?

Dr. Pederson: Risk doesn’t always need to be formally calculated, which can be time-consuming. It’s one of those situations where most practitioners know it when they see it. Benign atypical biopsies, a strong family history, or, obviously, the presence of a genetic mutation are huge red flags.

If a practitioner has a nearby high-risk center where they can refer patients, that can be so useful, even for a one-time consultation to guide management. For example, with the virtual world now, I do a lot of consultations for patients and outline a plan, and then the referring practitioner can carry out the plan with confidence and then send the patient back periodically. There are so many more options now that previously did not exist for the busy ObGyn or primary care provider to rely on.

Continue to: Chemoprevention uptake in at-risk women...

OBG Management: How does the risk assessment result influence the uptake of chemoprevention? Are more women willing to take preventive medication?

Dr. Pederson: We really never practice medicine using numbers. We use clinical judgment, and we use relationships with patients in terms of developing confidence and trust. I think that the uptake that we exhibit in our center probably is more based on the patients’ perception that we are confident in our recommendations. I think that many practitioners simply are not comfortable with explaining medications, explaining and managing adverse effects, and using alternative medications. While the modeling helps, I think the personal expertise really makes the difference.

Going forward, the addition of the polygenic risk score to the mathematical risk models is going to make a big difference. Right now, the mathematical risk model is simply that: it takes the traditional risk factors that a patient has and spits out a number. But adding the patient’s genomic data—that is, a weighted summation of SNPs, or single nucleotide polymorphisms, now numbering over 300 for breast cancer—can explain more about their personalized risk, which is going to be more powerful in influencing a woman to take medication or not to take medication, in my opinion. Knowing their actual genomic risk will be a big step forward in individualized risk stratification and increased medication uptake as well as vigilance with high risk screening and attention to diet, exercise, and drinking alcohol in moderation.

OBG Management: What drugs can be used for breast cancer preventive therapy, and how do you select a drug based on patient factors?

Dr. Pederson: The only drug that can be used in the premenopausal setting is tamoxifen (TABLE 1). Women can’t take it if they are pregnant, planning to become pregnant, or if they don’t use a reliable form of birth control because it is teratogenic. Women also cannot take tamoxifen if they have had a history of blood clots, stroke, or transient ischemic attack; if they are on warfarin or estrogen preparations; or if they have had atypical endometrial biopsies or endometrial cancer. Those are the absolute contraindications for tamoxifen use.

Tamoxifen is generally very well tolerated in most women; some women experience hot flashes and night sweats that often will subside (or become tolerable) over the first 90 days. In addition, some women experience vaginal discharge rather than dryness, but it is not as bothersome to patients as dryness can be.

Tamoxifen can be used in the pre- or postmenopausal setting. In healthy premenopausal women, there’s no increased risk of the serious adverse effects that are seen with tamoxifen use in postmenopausal women, such as the 1% risk of blood clots and the 1% risk of endometrial cancer.

In postmenopausal women who still have their uterus, I’ll preferentially use raloxifene over tamoxifen. If they don’t have their uterus, tamoxifen is slightly more effective than the raloxifene, and I’ll use that.

Tamoxifen and raloxifene are both selective estrogen receptor modulators, or SERMs, which means that they stimulate receptors in some tissues, like bone, keeping bones strong, and block the receptors in other tissues, like the breast, reducing risk. And so you get kind of a two-for-one in terms of breast cancer risk reduction and osteoporosis prevention.

Another class of preventive drugs is the aromatase inhibitors (AIs). They block the enzyme aromatase, which converts androgens to estrogens peripherally; that is, the androgens that are produced primarily in the adrenal gland, but in part in postmenopausal ovaries.

In general, AIs are less well tolerated. There are generally more hot flashes and night sweats, and more vaginal dryness than with the SERMs. Anastrozole use is associated with arthralgias; and with exemestane use, there can be some hair loss (TABLE 2). Relative contraindications to SERMs become more important in the postmenopausal setting because of the increased frequency of both blood clots and uterine cancer in the postmenopausal years. I won’t give it to smokers. I won’t give tamoxifen to smokers in the premenopausal period either. With obese women, care must be taken because of the risk of blood clots with the SERMS, so then I’ll resort to the AIs. In the postmenopausal setting, you have to think a lot harder about the choices you use for preventive medication. Preferentially, I’ll use the SERMS if possible as they have fewer adverse effects.

OBG Management: What is the general duration of treatment with these risk-reducing drugs?

Dr. Pederson: All of them are recommended to be given for 5 years, but the MAP.3 trial, which studied exemestane compared with placebo, showed a 65% risk reduction with 3 years of therapy.³ So occasionally, we’ll use 3 years of therapy. Why the treatment recommendation is universally 5 years is unclear, given that the trial with that particular drug was done in 3 years. And with low-dose tamoxifen, the recommended duration is 3 years. That study was done in Italy with 5 mg daily for 3 years.⁴ In the United States we use 10 mg every other day for 3 years because the 5-mg tablet is not available here.

Continue to: Counseling points...

OBG Management: How do you counsel patients about the adverse effects of preventive medications, and how can they be managed?

Dr. Pederson: Patients’ fears about adverse effects are often worse than the adverse effects themselves. Women will fester over, Should I take it? Should I take it possibly for years? And then they take the medication and they tell me, “I don’t even notice that I’m taking it, and I know I’m being proactive.” The majority of patients who take these medications don’t have a lot of significant adverse effects.

Severe hot flashes can be managed in a number of ways, primarily and most effectively with certain antidepressants. Oxybutynin use is another good way to manage vasomotor symptoms. Sometimes we use local vaginal estrogen if a patient has vaginal dryness. In general, however, I would say at least 80% of my patients who take preventive medications do not require management of adverse side effects, that they are tolerable.

I counsel women this way, “Don’t think of this as a 5-year course of medication. Think of it as a 90-day trial, and let’s see how you do. If you hate it, then we don’t do it.” They often are pleasantly surprised that the medication is much easier to tolerate than they thought it would be.

OBG Management: What role does lifestyle modification play in conjunction with chemoprevention?

Dr. Pederson: It would be neat if a trial would directly compare lifestyle interventions with medications, because probably lifestyle change is as effective as medication is—but we don’t know that and probably will never have that data. We do know that alcohol consumption, every drink per day, increases risk by 10%. We know that obesity is responsible for 30% of breast cancers in this country, and that hormone replacement probably is overrated as a significant risk factor. Updated data from the Women’s Health Initiative study suggest that hormone replacement may actually reduce both breast cancer and cardiovascular risk in women in their 50s, but that’s in average-risk women and not in high-risk women, so we can’t generalize. We do recommend lifestyle measures including weight loss, exercise, and limiting alcohol consumption for all of our patients and certainly for our high-risk patients.

The only 2 things a woman can do to reduce the risk of triple negative breast cancer are to achieve and maintain ideal body weight and to breastfeed. The medications that I have mentioned don’t reduce the risk of triple negative breast cancer. Staying thin and breastfeeding do. It’s a problem in this country because at least 35% of all women and 58% of Black women are obese in America, and Black women tend to be prone to triple-negative breast cancer. That’s a real public health issue that we need to address. If we were going to focus on one thing, it would be focusing on obesity in terms of risk reduction.

Final thoughts

OBG Management: Would you like to add any other points about chemoprevention?

Dr. Pederson: I would like to direct attention to the American Heart Association scientific statement published at the end of 2020 that reported that hormone replacement in average-risk women reduced both cardiovascular events and overall mortality in women in their 50s by 30%.⁵ While that’s not directly related to what we are talking about, we need to weigh the pros and cons of estrogen versus estrogen blockade in women in terms of breast cancer risk management discussions. Part of shared decision making now needs to include cardiovascular risk factors and how estrogen is going to play into that.

In women with atypical hyperplasia or LCIS, they may benefit from the preventive medications we discussed. But in women with family history or in women with genetic mutations who have not had benign atypical biopsies, they may choose to consider estrogen during their 50s and perhaps take tamoxifen either beforehand or raloxifene afterward.

We need to look at patients holistically and consider all their risk factors together. We can’t look at one dimension alone.

OBG Management: Thank you for sharing your insights, Dr. Pederson. ●

CASE Woman with BRCA2 mutation

An 80-year-old woman presents for evaluation of newly diagnosed metastatic pancreatic adenocarcinoma. Her medical history is notable for breast cancer. Genetic testing of pancreatic tumor tissue detected a pathogenic variant in BRCA2. Family history revealed a history of melanoma as well as bladder, prostate, breast, and colon cancer. The patient subsequently underwent germline genetic testing with an 86-gene panel and a pathogenic mutation in BRCA2 was identified.

Watch a video of this patient and her clinician, Dr. Andrea Hagemann: https://www.youtube.com/watch?v=0x1jUG2u51c&t=21s.

Methods of genetic testing

It is estimated that 1 in 300 to 1 in 500 women in the United States carry a deleterious mutation in BRCA1 or BRCA2. This equates to between 250,000 and 415,000 women who are at high risk for breast and ovarian cancer.¹ Looking at all women with cancer, 20% with ovarian,² 10% with breast,³ 2% to 3% with endometrial,⁴ and 5% with colon cancer⁵ will have a germline mutation predisposing them to cancer. Identification of germline or somatic (tumor) mutations now inform treatment for patients with cancer. An equally important goal of germline genetic testing is cancer prevention. Cancer prevention strategies include risk-based screening for breast, colon, melanoma, and pancreatic cancer and prophylactic surgeries to reduce the risk of breast and ovarian cancer based on mutation type. Evidence-based screening guidelines by mutation type and absolute risk of associated cancers can be found on the National Comprehensive Cancer Network (NCCN).^6,7

Multiple strategies have been proposed to identify patients for germline genetic testing. Patients can be identified based on a detailed multigenerational family history. This strategy requires clinicians or genetic counselors to take and update family histories, to recognize when a patient requires referral for testing, and for such testing to be completed. Even then the generation of a detailed pedigree is not very sensitive or specific. Population-based screening for high-penetrance breast and ovarian cancer susceptibility genes, regardless of family history, also has been proposed.⁸ Such a strategy has become increasingly realistic with decreasing cost and increasing availability of genetic testing. However, it would require increased genetic counseling resources to feasibly and equitably reach the target population and to explain the results to those patients and their relatives.

An alternative is to test the enriched population of family members of a patient with cancer who has been found to carry a pathogenic variant in a clinically relevant cancer susceptibility gene. This type of testing is termed cascade genetic testing. Cascade testing in first-degree family members carries a 50% probability of detecting the same pathogenic mutation. A related testing model is traceback testing where genetic testing is performed on pathology or tumor registry specimens from deceased patients with cancer.⁹ This genetic testing information is then provided to the family. Traceback models of genetic testing are an active area of research but can introduce ethical dilemmas. The more widely accepted cascade testing starts with the testing of a living patient affected with cancer. A recent article demonstrated the feasibility of a cascade testing model. Using a multiple linear regression model, the authors determined that all carriers of pathogenic mutations in 18 clinically relevant cancer susceptibility genes in the United States could be identified in 9.9 years if there was a 70% cascade testing rate of first-, second- and third-degree relatives, compared to 59.5 years with no cascade testing.¹⁰

Gaps in practice

Identification of mutation carriers, either through screening triggered by family history or through testing of patients affected with cancer, represents a gap between guidelines and clinical practice. Current NCCN guidelines outline genetic testing criteria for hereditary breast and ovarian cancer syndrome and for hereditary colorectal cancer. Despite well-established criteria, a survey in the United States revealed that only 19% of primary care providers were able to accurately assess family history for BRCA1 and 2 testing.¹¹ Looking at patients who meet criteria for testing for Lynch syndrome, only 1 in 4 individuals have undergone genetic testing.¹² Among patients diagnosed with breast and ovarian cancer, current NCCN guidelines recommend germline genetic testing for all patients with epithelial ovarian cancer; emerging evidence suggests all patients with breast cancer should be offered germline genetic testing.^7,13 Large population-based studies have repeatedly demonstrated that testing rates fall short of this goal, with only 10% to 30% of patients undergoing genetic testing.^9,14

Among families with a known hereditary mutation, rates of cascade genetic testing are also low, ranging from 17% to 50%.^15-18 Evidence-based management guidelines, for both hereditary breast and ovarian cancer as well as Lynch syndrome, have been shown to reduce mortality.^19,20 Failure to identify patients who carry these genetic mutations equates to increased mortality for our patients.

Barriers to cascade genetic testing

Cascade genetic testing ideally would be performed on entire families. Actual practice is far from ideal, and barriers to cascade testing exist. Barriers encompass resistance on the part of the family and provider as well as environmental or system factors.

Family factors

Because of privacy laws, the responsibility of disclosure of genetic testing results to family members falls primarily to the patient. Proband education is critical to ensure disclosure amongst family members. Family dynamics and geographic distribution of family members can further complicate disclosure. Following disclosure, family member gender, education, and demographics as well as personal views, attitudes, and emotions affect whether a family member decides to undergo testing.²¹ Furthermore, insurance status and awareness of and access to specialty-specific care for the proband’s family members may influence cascade genetic testing rates.

Provider factors

Provider factors that affect cascade genetic testing include awareness of testing guidelines, interpretation of genetic testing results, and education and knowledge of specific mutations. For instance, providers must recognize that cascade testing is not appropriate for variants of uncertain significance. This can lead to unnecessary surveillance testing and prophylactic surgeries. Providers, however, must continue to follow patients and periodically update testing results as variants may be reclassified over time. Additionally, providers must be knowledgeable about the complex and nuanced nature of the screening guidelines for each mutation. The NCCN provides detailed recommendations by mutation.⁷ Patients may benefit from care with cancer specialists who are aware of the guidelines, particularly for moderate-penetrance genes like BRIP1 and PALB2, as discussions about the timing of risk-reducing surgery are more nuanced in this population. Finally, which providers are responsible for facilitating cascade testing may be unclear; oncologists and genetic counselors not primarily treating probands’ relatives may assume the proper information has been passed along to family members without a practical means to follow up, and primary care providers may assume it is being taken care of by the oncology provider.

Continue to: Environmental or system factors...

Environmental or system factors

Accessibility of genetic counseling and testing is a common barrier to cascade testing. Family members may be geographically remote and connecting them to counseling and testing can be challenging. Working with local genetic counselors can facilitate this process. Insurance coverage of testing is a common perceived barrier; however, many testing companies now provide cascade testing free of charge if within a certain window from the initial test. Despite this, patients often site cost as a barrier to undergoing testing. Concerns about insurance coverage are common after a positive result. The Genetic Information Nondiscrimination Act of 2008 prohibits discrimination against employees or insurance applicants because of genetic information. Life insurance or long-term care policies, however, can incorporate genetic testing information into policy rates, so patients should be recommended to consider purchasing life insurance prior to undergoing genetic testing. This is especially important if the person considering testing has not yet been diagnosed with cancer.

Implications of a positive result

Family members who receive a positive test result should be referred for genetic counseling and to the appropriate specialists for evidence-based screening and discussion for risk-reducing surgery (FIGURE).⁷ For mutations associated with hereditary breast and ovarian cancer, referral to breast and gynecologic surgeons with expertise in risk reducing surgery is critical as the risk of diagnosing an occult malignancy is approximately 1%.²² Surgical technique with a 2-cm margin on the infundibulopelvic ligament and pathologic evaluation with sectioning and extensive examination of the fimbriated end of the tubes (SEE-Fim technique) is recommended for mutation carriers. Additionally, evidence has emerged suggesting an increased risk of uterine serous cancer in BRCA1 carriers necessitating a discussion about risk-reducing hysterectomy in these patients.²³ Following risk reducing surgery, surgical menopause can have significant impacts on patients’ health and well-being. Treatment options including hormone replacement therapy can be considered.²⁴ To minimize recovery time burdens for patients, combination surgeries with breast, plastic, and gynecology specialties can be offered.

Patient resources: decision aids, websites

As genetic testing becomes more accessible and people are tested at younger ages, studies examining the balance of risk reduction and quality of life (QOL) are increasingly important. Fertility concerns, effects of early menopause, and the interrelatedness between decisions for breast and gynecologic risk reduction should all be considered in the counseling for surgical risk reduction. Patient decision aids can help mutation carriers navigate the complex information and decisions.²⁵ Websites specifically designed by advocacy groups can be useful adjuncts to in-office counseling (Facing Our Risk Empowered, FORCE; Facingourrisk.org).

Family letters

The American College of Obstetricians and Gynecologists recommends an ObGyn have a letter or documentation stating that the patient’s relative has a specific mutation before initiating cascade testing for an at-risk family member. The indicated test (such as BRCA1) should be ordered only after the patient has been counseled about potential outcomes and has expressly decided to be tested.²⁶ Letters, such as the example given in the American College of Obstetricians and Gynecologists practice bulletin,²⁶ are a key component of communication between oncology providers, probands, family members, and their primary care providers. ObGyn providers should work together with genetic counselors and gynecologic oncologists to determine the most efficient strategies in their communities.

Technology

Access to genetic testing and genetic counseling has been improved with the rise in telemedicine. Geographically remote patients can now access genetic counseling through medical center–based counselors as well as company-provided genetic counseling over the phone. Patients also can submit samples remotely without needing to be tested in a doctor’s office.

Databases from cancer centers that detail cascade genetic testing rates. As the preventive impact of cascade genetic testing becomes clearer, strategies to have recurrent discussions with cancer patients regarding their family members’ risk should be implemented. It is still unclear which providers—genetic counselors, gynecologic oncologists, medical oncologists, breast surgeons, ObGyns, to name a few—are primarily responsible for remembering to have these follow-up discussions, and despite advances, the burden still rests on the cancer patient themselves. Databases with automated follow-up surveys done every 6 to 12 months could provide some aid to busy providers in this regard.

Emerging research

If gynecologic risk-reducing surgery is chosen, clinical trial involvement should be encouraged. The Women Choosing Surgical Prevention (NCT02760849) in the United States and the TUBA study (NCT02321228) in the Netherlands were designed to compare menopause-related QOL between standard risk-reducing salpingo-oophorectomy (RRSO) and the innovative risk-reducing salpingectomy with delayed oophorectomy for mutation carriers. Results from the nonrandomized controlled TUBA trial suggest that patients have better menopause-related QOL after risk-reducing salpingectomy than after RRSO, regardless of hormone replacement therapy.²⁷ International collaboration is continuing to better understand oncologic safety. In the United States, the SOROCk trial (NCT04251052) is a noninferiority surgical choice study underway for BRCA1 mutation carriers aged 35 to 50, powered to determine oncologic outcome differences in addition to QOL outcomes between RRSO and delayed oophorectomy arms.

Returning to the case

The patient and her family underwent genetic counseling. The patient’s 2 daughters, each in their 50s, underwent cascade genetic testing and were found to carry the same pathogenic mutation in BRCA2. After counseling from both breast and gynecologic surgeons, they both elected to undergo risk reducing bilateral salpingo-oophorectomy with hysterectomy. Both now complete regular screening for breast cancer and melanoma with plans to start screening for pancreatic cancer. Both are currently cancer free.

Summary

Cascade genetic testing is an efficient strategy to identify mutation carriers for hereditary breast and ovarian cancer syndrome. Implementation of the best patient-centric care will require continued collaboration and communication across and within disciplines. ●

CASE Woman with BRCA2 mutation

An 80-year-old woman presents for evaluation of newly diagnosed metastatic pancreatic adenocarcinoma. Her medical history is notable for breast cancer. Genetic testing of pancreatic tumor tissue detected a pathogenic variant in BRCA2. Family history revealed a history of melanoma as well as bladder, prostate, breast, and colon cancer. The patient subsequently underwent germline genetic testing with an 86-gene panel and a pathogenic mutation in BRCA2 was identified.

Watch a video of this patient and her clinician, Dr. Andrea Hagemann: https://www.youtube.com/watch?v=0x1jUG2u51c&t=21s.

Methods of genetic testing

It is estimated that 1 in 300 to 1 in 500 women in the United States carry a deleterious mutation in BRCA1 or BRCA2. This equates to between 250,000 and 415,000 women who are at high risk for breast and ovarian cancer.¹ Looking at all women with cancer, 20% with ovarian,² 10% with breast,³ 2% to 3% with endometrial,⁴ and 5% with colon cancer⁵ will have a germline mutation predisposing them to cancer. Identification of germline or somatic (tumor) mutations now inform treatment for patients with cancer. An equally important goal of germline genetic testing is cancer prevention. Cancer prevention strategies include risk-based screening for breast, colon, melanoma, and pancreatic cancer and prophylactic surgeries to reduce the risk of breast and ovarian cancer based on mutation type. Evidence-based screening guidelines by mutation type and absolute risk of associated cancers can be found on the National Comprehensive Cancer Network (NCCN).^6,7

Multiple strategies have been proposed to identify patients for germline genetic testing. Patients can be identified based on a detailed multigenerational family history. This strategy requires clinicians or genetic counselors to take and update family histories, to recognize when a patient requires referral for testing, and for such testing to be completed. Even then the generation of a detailed pedigree is not very sensitive or specific. Population-based screening for high-penetrance breast and ovarian cancer susceptibility genes, regardless of family history, also has been proposed.⁸ Such a strategy has become increasingly realistic with decreasing cost and increasing availability of genetic testing. However, it would require increased genetic counseling resources to feasibly and equitably reach the target population and to explain the results to those patients and their relatives.

An alternative is to test the enriched population of family members of a patient with cancer who has been found to carry a pathogenic variant in a clinically relevant cancer susceptibility gene. This type of testing is termed cascade genetic testing. Cascade testing in first-degree family members carries a 50% probability of detecting the same pathogenic mutation. A related testing model is traceback testing where genetic testing is performed on pathology or tumor registry specimens from deceased patients with cancer.⁹ This genetic testing information is then provided to the family. Traceback models of genetic testing are an active area of research but can introduce ethical dilemmas. The more widely accepted cascade testing starts with the testing of a living patient affected with cancer. A recent article demonstrated the feasibility of a cascade testing model. Using a multiple linear regression model, the authors determined that all carriers of pathogenic mutations in 18 clinically relevant cancer susceptibility genes in the United States could be identified in 9.9 years if there was a 70% cascade testing rate of first-, second- and third-degree relatives, compared to 59.5 years with no cascade testing.¹⁰

Gaps in practice

Identification of mutation carriers, either through screening triggered by family history or through testing of patients affected with cancer, represents a gap between guidelines and clinical practice. Current NCCN guidelines outline genetic testing criteria for hereditary breast and ovarian cancer syndrome and for hereditary colorectal cancer. Despite well-established criteria, a survey in the United States revealed that only 19% of primary care providers were able to accurately assess family history for BRCA1 and 2 testing.¹¹ Looking at patients who meet criteria for testing for Lynch syndrome, only 1 in 4 individuals have undergone genetic testing.¹² Among patients diagnosed with breast and ovarian cancer, current NCCN guidelines recommend germline genetic testing for all patients with epithelial ovarian cancer; emerging evidence suggests all patients with breast cancer should be offered germline genetic testing.^7,13 Large population-based studies have repeatedly demonstrated that testing rates fall short of this goal, with only 10% to 30% of patients undergoing genetic testing.^9,14

Among families with a known hereditary mutation, rates of cascade genetic testing are also low, ranging from 17% to 50%.^15-18 Evidence-based management guidelines, for both hereditary breast and ovarian cancer as well as Lynch syndrome, have been shown to reduce mortality.^19,20 Failure to identify patients who carry these genetic mutations equates to increased mortality for our patients.

Barriers to cascade genetic testing

Cascade genetic testing ideally would be performed on entire families. Actual practice is far from ideal, and barriers to cascade testing exist. Barriers encompass resistance on the part of the family and provider as well as environmental or system factors.

Family factors

Because of privacy laws, the responsibility of disclosure of genetic testing results to family members falls primarily to the patient. Proband education is critical to ensure disclosure amongst family members. Family dynamics and geographic distribution of family members can further complicate disclosure. Following disclosure, family member gender, education, and demographics as well as personal views, attitudes, and emotions affect whether a family member decides to undergo testing.²¹ Furthermore, insurance status and awareness of and access to specialty-specific care for the proband’s family members may influence cascade genetic testing rates.

Provider factors

Provider factors that affect cascade genetic testing include awareness of testing guidelines, interpretation of genetic testing results, and education and knowledge of specific mutations. For instance, providers must recognize that cascade testing is not appropriate for variants of uncertain significance. This can lead to unnecessary surveillance testing and prophylactic surgeries. Providers, however, must continue to follow patients and periodically update testing results as variants may be reclassified over time. Additionally, providers must be knowledgeable about the complex and nuanced nature of the screening guidelines for each mutation. The NCCN provides detailed recommendations by mutation.⁷ Patients may benefit from care with cancer specialists who are aware of the guidelines, particularly for moderate-penetrance genes like BRIP1 and PALB2, as discussions about the timing of risk-reducing surgery are more nuanced in this population. Finally, which providers are responsible for facilitating cascade testing may be unclear; oncologists and genetic counselors not primarily treating probands’ relatives may assume the proper information has been passed along to family members without a practical means to follow up, and primary care providers may assume it is being taken care of by the oncology provider.

Continue to: Environmental or system factors...

Environmental or system factors

Accessibility of genetic counseling and testing is a common barrier to cascade testing. Family members may be geographically remote and connecting them to counseling and testing can be challenging. Working with local genetic counselors can facilitate this process. Insurance coverage of testing is a common perceived barrier; however, many testing companies now provide cascade testing free of charge if within a certain window from the initial test. Despite this, patients often site cost as a barrier to undergoing testing. Concerns about insurance coverage are common after a positive result. The Genetic Information Nondiscrimination Act of 2008 prohibits discrimination against employees or insurance applicants because of genetic information. Life insurance or long-term care policies, however, can incorporate genetic testing information into policy rates, so patients should be recommended to consider purchasing life insurance prior to undergoing genetic testing. This is especially important if the person considering testing has not yet been diagnosed with cancer.

Implications of a positive result

Family members who receive a positive test result should be referred for genetic counseling and to the appropriate specialists for evidence-based screening and discussion for risk-reducing surgery (FIGURE).⁷ For mutations associated with hereditary breast and ovarian cancer, referral to breast and gynecologic surgeons with expertise in risk reducing surgery is critical as the risk of diagnosing an occult malignancy is approximately 1%.²² Surgical technique with a 2-cm margin on the infundibulopelvic ligament and pathologic evaluation with sectioning and extensive examination of the fimbriated end of the tubes (SEE-Fim technique) is recommended for mutation carriers. Additionally, evidence has emerged suggesting an increased risk of uterine serous cancer in BRCA1 carriers necessitating a discussion about risk-reducing hysterectomy in these patients.²³ Following risk reducing surgery, surgical menopause can have significant impacts on patients’ health and well-being. Treatment options including hormone replacement therapy can be considered.²⁴ To minimize recovery time burdens for patients, combination surgeries with breast, plastic, and gynecology specialties can be offered.

Patient resources: decision aids, websites

As genetic testing becomes more accessible and people are tested at younger ages, studies examining the balance of risk reduction and quality of life (QOL) are increasingly important. Fertility concerns, effects of early menopause, and the interrelatedness between decisions for breast and gynecologic risk reduction should all be considered in the counseling for surgical risk reduction. Patient decision aids can help mutation carriers navigate the complex information and decisions.²⁵ Websites specifically designed by advocacy groups can be useful adjuncts to in-office counseling (Facing Our Risk Empowered, FORCE; Facingourrisk.org).

Family letters

The American College of Obstetricians and Gynecologists recommends an ObGyn have a letter or documentation stating that the patient’s relative has a specific mutation before initiating cascade testing for an at-risk family member. The indicated test (such as BRCA1) should be ordered only after the patient has been counseled about potential outcomes and has expressly decided to be tested.²⁶ Letters, such as the example given in the American College of Obstetricians and Gynecologists practice bulletin,²⁶ are a key component of communication between oncology providers, probands, family members, and their primary care providers. ObGyn providers should work together with genetic counselors and gynecologic oncologists to determine the most efficient strategies in their communities.

Technology

Access to genetic testing and genetic counseling has been improved with the rise in telemedicine. Geographically remote patients can now access genetic counseling through medical center–based counselors as well as company-provided genetic counseling over the phone. Patients also can submit samples remotely without needing to be tested in a doctor’s office.

Databases from cancer centers that detail cascade genetic testing rates. As the preventive impact of cascade genetic testing becomes clearer, strategies to have recurrent discussions with cancer patients regarding their family members’ risk should be implemented. It is still unclear which providers—genetic counselors, gynecologic oncologists, medical oncologists, breast surgeons, ObGyns, to name a few—are primarily responsible for remembering to have these follow-up discussions, and despite advances, the burden still rests on the cancer patient themselves. Databases with automated follow-up surveys done every 6 to 12 months could provide some aid to busy providers in this regard.

Emerging research

If gynecologic risk-reducing surgery is chosen, clinical trial involvement should be encouraged. The Women Choosing Surgical Prevention (NCT02760849) in the United States and the TUBA study (NCT02321228) in the Netherlands were designed to compare menopause-related QOL between standard risk-reducing salpingo-oophorectomy (RRSO) and the innovative risk-reducing salpingectomy with delayed oophorectomy for mutation carriers. Results from the nonrandomized controlled TUBA trial suggest that patients have better menopause-related QOL after risk-reducing salpingectomy than after RRSO, regardless of hormone replacement therapy.²⁷ International collaboration is continuing to better understand oncologic safety. In the United States, the SOROCk trial (NCT04251052) is a noninferiority surgical choice study underway for BRCA1 mutation carriers aged 35 to 50, powered to determine oncologic outcome differences in addition to QOL outcomes between RRSO and delayed oophorectomy arms.

Returning to the case

The patient and her family underwent genetic counseling. The patient’s 2 daughters, each in their 50s, underwent cascade genetic testing and were found to carry the same pathogenic mutation in BRCA2. After counseling from both breast and gynecologic surgeons, they both elected to undergo risk reducing bilateral salpingo-oophorectomy with hysterectomy. Both now complete regular screening for breast cancer and melanoma with plans to start screening for pancreatic cancer. Both are currently cancer free.

Summary

Cascade genetic testing is an efficient strategy to identify mutation carriers for hereditary breast and ovarian cancer syndrome. Implementation of the best patient-centric care will require continued collaboration and communication across and within disciplines. ●

CASE Woman with BRCA2 mutation

An 80-year-old woman presents for evaluation of newly diagnosed metastatic pancreatic adenocarcinoma. Her medical history is notable for breast cancer. Genetic testing of pancreatic tumor tissue detected a pathogenic variant in BRCA2. Family history revealed a history of melanoma as well as bladder, prostate, breast, and colon cancer. The patient subsequently underwent germline genetic testing with an 86-gene panel and a pathogenic mutation in BRCA2 was identified.

Watch a video of this patient and her clinician, Dr. Andrea Hagemann: https://www.youtube.com/watch?v=0x1jUG2u51c&t=21s.

Methods of genetic testing

It is estimated that 1 in 300 to 1 in 500 women in the United States carry a deleterious mutation in BRCA1 or BRCA2. This equates to between 250,000 and 415,000 women who are at high risk for breast and ovarian cancer.¹ Looking at all women with cancer, 20% with ovarian,² 10% with breast,³ 2% to 3% with endometrial,⁴ and 5% with colon cancer⁵ will have a germline mutation predisposing them to cancer. Identification of germline or somatic (tumor) mutations now inform treatment for patients with cancer. An equally important goal of germline genetic testing is cancer prevention. Cancer prevention strategies include risk-based screening for breast, colon, melanoma, and pancreatic cancer and prophylactic surgeries to reduce the risk of breast and ovarian cancer based on mutation type. Evidence-based screening guidelines by mutation type and absolute risk of associated cancers can be found on the National Comprehensive Cancer Network (NCCN).^6,7

Multiple strategies have been proposed to identify patients for germline genetic testing. Patients can be identified based on a detailed multigenerational family history. This strategy requires clinicians or genetic counselors to take and update family histories, to recognize when a patient requires referral for testing, and for such testing to be completed. Even then the generation of a detailed pedigree is not very sensitive or specific. Population-based screening for high-penetrance breast and ovarian cancer susceptibility genes, regardless of family history, also has been proposed.⁸ Such a strategy has become increasingly realistic with decreasing cost and increasing availability of genetic testing. However, it would require increased genetic counseling resources to feasibly and equitably reach the target population and to explain the results to those patients and their relatives.

An alternative is to test the enriched population of family members of a patient with cancer who has been found to carry a pathogenic variant in a clinically relevant cancer susceptibility gene. This type of testing is termed cascade genetic testing. Cascade testing in first-degree family members carries a 50% probability of detecting the same pathogenic mutation. A related testing model is traceback testing where genetic testing is performed on pathology or tumor registry specimens from deceased patients with cancer.⁹ This genetic testing information is then provided to the family. Traceback models of genetic testing are an active area of research but can introduce ethical dilemmas. The more widely accepted cascade testing starts with the testing of a living patient affected with cancer. A recent article demonstrated the feasibility of a cascade testing model. Using a multiple linear regression model, the authors determined that all carriers of pathogenic mutations in 18 clinically relevant cancer susceptibility genes in the United States could be identified in 9.9 years if there was a 70% cascade testing rate of first-, second- and third-degree relatives, compared to 59.5 years with no cascade testing.¹⁰

Gaps in practice

Identification of mutation carriers, either through screening triggered by family history or through testing of patients affected with cancer, represents a gap between guidelines and clinical practice. Current NCCN guidelines outline genetic testing criteria for hereditary breast and ovarian cancer syndrome and for hereditary colorectal cancer. Despite well-established criteria, a survey in the United States revealed that only 19% of primary care providers were able to accurately assess family history for BRCA1 and 2 testing.¹¹ Looking at patients who meet criteria for testing for Lynch syndrome, only 1 in 4 individuals have undergone genetic testing.¹² Among patients diagnosed with breast and ovarian cancer, current NCCN guidelines recommend germline genetic testing for all patients with epithelial ovarian cancer; emerging evidence suggests all patients with breast cancer should be offered germline genetic testing.^7,13 Large population-based studies have repeatedly demonstrated that testing rates fall short of this goal, with only 10% to 30% of patients undergoing genetic testing.^9,14

Among families with a known hereditary mutation, rates of cascade genetic testing are also low, ranging from 17% to 50%.^15-18 Evidence-based management guidelines, for both hereditary breast and ovarian cancer as well as Lynch syndrome, have been shown to reduce mortality.^19,20 Failure to identify patients who carry these genetic mutations equates to increased mortality for our patients.

Barriers to cascade genetic testing

Cascade genetic testing ideally would be performed on entire families. Actual practice is far from ideal, and barriers to cascade testing exist. Barriers encompass resistance on the part of the family and provider as well as environmental or system factors.

Family factors

Because of privacy laws, the responsibility of disclosure of genetic testing results to family members falls primarily to the patient. Proband education is critical to ensure disclosure amongst family members. Family dynamics and geographic distribution of family members can further complicate disclosure. Following disclosure, family member gender, education, and demographics as well as personal views, attitudes, and emotions affect whether a family member decides to undergo testing.²¹ Furthermore, insurance status and awareness of and access to specialty-specific care for the proband’s family members may influence cascade genetic testing rates.

Provider factors

Provider factors that affect cascade genetic testing include awareness of testing guidelines, interpretation of genetic testing results, and education and knowledge of specific mutations. For instance, providers must recognize that cascade testing is not appropriate for variants of uncertain significance. This can lead to unnecessary surveillance testing and prophylactic surgeries. Providers, however, must continue to follow patients and periodically update testing results as variants may be reclassified over time. Additionally, providers must be knowledgeable about the complex and nuanced nature of the screening guidelines for each mutation. The NCCN provides detailed recommendations by mutation.⁷ Patients may benefit from care with cancer specialists who are aware of the guidelines, particularly for moderate-penetrance genes like BRIP1 and PALB2, as discussions about the timing of risk-reducing surgery are more nuanced in this population. Finally, which providers are responsible for facilitating cascade testing may be unclear; oncologists and genetic counselors not primarily treating probands’ relatives may assume the proper information has been passed along to family members without a practical means to follow up, and primary care providers may assume it is being taken care of by the oncology provider.

Continue to: Environmental or system factors...

Environmental or system factors

Accessibility of genetic counseling and testing is a common barrier to cascade testing. Family members may be geographically remote and connecting them to counseling and testing can be challenging. Working with local genetic counselors can facilitate this process. Insurance coverage of testing is a common perceived barrier; however, many testing companies now provide cascade testing free of charge if within a certain window from the initial test. Despite this, patients often site cost as a barrier to undergoing testing. Concerns about insurance coverage are common after a positive result. The Genetic Information Nondiscrimination Act of 2008 prohibits discrimination against employees or insurance applicants because of genetic information. Life insurance or long-term care policies, however, can incorporate genetic testing information into policy rates, so patients should be recommended to consider purchasing life insurance prior to undergoing genetic testing. This is especially important if the person considering testing has not yet been diagnosed with cancer.

Implications of a positive result

Family members who receive a positive test result should be referred for genetic counseling and to the appropriate specialists for evidence-based screening and discussion for risk-reducing surgery (FIGURE).⁷ For mutations associated with hereditary breast and ovarian cancer, referral to breast and gynecologic surgeons with expertise in risk reducing surgery is critical as the risk of diagnosing an occult malignancy is approximately 1%.²² Surgical technique with a 2-cm margin on the infundibulopelvic ligament and pathologic evaluation with sectioning and extensive examination of the fimbriated end of the tubes (SEE-Fim technique) is recommended for mutation carriers. Additionally, evidence has emerged suggesting an increased risk of uterine serous cancer in BRCA1 carriers necessitating a discussion about risk-reducing hysterectomy in these patients.²³ Following risk reducing surgery, surgical menopause can have significant impacts on patients’ health and well-being. Treatment options including hormone replacement therapy can be considered.²⁴ To minimize recovery time burdens for patients, combination surgeries with breast, plastic, and gynecology specialties can be offered.

Patient resources: decision aids, websites

As genetic testing becomes more accessible and people are tested at younger ages, studies examining the balance of risk reduction and quality of life (QOL) are increasingly important. Fertility concerns, effects of early menopause, and the interrelatedness between decisions for breast and gynecologic risk reduction should all be considered in the counseling for surgical risk reduction. Patient decision aids can help mutation carriers navigate the complex information and decisions.²⁵ Websites specifically designed by advocacy groups can be useful adjuncts to in-office counseling (Facing Our Risk Empowered, FORCE; Facingourrisk.org).

Family letters

The American College of Obstetricians and Gynecologists recommends an ObGyn have a letter or documentation stating that the patient’s relative has a specific mutation before initiating cascade testing for an at-risk family member. The indicated test (such as BRCA1) should be ordered only after the patient has been counseled about potential outcomes and has expressly decided to be tested.²⁶ Letters, such as the example given in the American College of Obstetricians and Gynecologists practice bulletin,²⁶ are a key component of communication between oncology providers, probands, family members, and their primary care providers. ObGyn providers should work together with genetic counselors and gynecologic oncologists to determine the most efficient strategies in their communities.

Technology

Access to genetic testing and genetic counseling has been improved with the rise in telemedicine. Geographically remote patients can now access genetic counseling through medical center–based counselors as well as company-provided genetic counseling over the phone. Patients also can submit samples remotely without needing to be tested in a doctor’s office.

Databases from cancer centers that detail cascade genetic testing rates. As the preventive impact of cascade genetic testing becomes clearer, strategies to have recurrent discussions with cancer patients regarding their family members’ risk should be implemented. It is still unclear which providers—genetic counselors, gynecologic oncologists, medical oncologists, breast surgeons, ObGyns, to name a few—are primarily responsible for remembering to have these follow-up discussions, and despite advances, the burden still rests on the cancer patient themselves. Databases with automated follow-up surveys done every 6 to 12 months could provide some aid to busy providers in this regard.

Emerging research

If gynecologic risk-reducing surgery is chosen, clinical trial involvement should be encouraged. The Women Choosing Surgical Prevention (NCT02760849) in the United States and the TUBA study (NCT02321228) in the Netherlands were designed to compare menopause-related QOL between standard risk-reducing salpingo-oophorectomy (RRSO) and the innovative risk-reducing salpingectomy with delayed oophorectomy for mutation carriers. Results from the nonrandomized controlled TUBA trial suggest that patients have better menopause-related QOL after risk-reducing salpingectomy than after RRSO, regardless of hormone replacement therapy.²⁷ International collaboration is continuing to better understand oncologic safety. In the United States, the SOROCk trial (NCT04251052) is a noninferiority surgical choice study underway for BRCA1 mutation carriers aged 35 to 50, powered to determine oncologic outcome differences in addition to QOL outcomes between RRSO and delayed oophorectomy arms.

Returning to the case

The patient and her family underwent genetic counseling. The patient’s 2 daughters, each in their 50s, underwent cascade genetic testing and were found to carry the same pathogenic mutation in BRCA2. After counseling from both breast and gynecologic surgeons, they both elected to undergo risk reducing bilateral salpingo-oophorectomy with hysterectomy. Both now complete regular screening for breast cancer and melanoma with plans to start screening for pancreatic cancer. Both are currently cancer free.

Summary

Cascade genetic testing is an efficient strategy to identify mutation carriers for hereditary breast and ovarian cancer syndrome. Implementation of the best patient-centric care will require continued collaboration and communication across and within disciplines. ●

From Pacific Lutheran School of Nursing, Tacoma, WA.

Objective: This quality improvement project aimed to enhance The Olympia Free Clinic’s (TOFC) data availability using International Classification of Diseases (ICD) code entry into the electronic health record (EHR). Prior to this project, TOFC lacked quality diagnosis data. This project strived to answer questions like “How many TOFC patients have diabetes?”

Methods: A new system was implemented for inputting ICD codes into Practice Fusion, the clinic’s EHR. During the initial phase, TOFC’s 21 volunteer providers entered the codes associated with the appropriate diagnosis for each of 157 encounters using a simplified map of options, including a map of the 20 most common diagnoses and a more comprehensive 60-code map.

Results: An EHR report found that 128 new diagnoses were entered during project implementation, hypertension being the most common diagnosis, followed by depression, then posttraumatic stress disorder.

Conclusion: The knowledge of patient diagnoses enabled the clinic to make more-informed decisions.

Keywords: free clinic, data, quality improvement, electronic health record, International Classification of Diseases

Data creates a starting point, a goal, background, understanding of needs and context, and allows for tracking and improvement over time. This quality improvement (QI) project for The Olympia Free Clinic (TOFC) implemented a new system for tracking patient diagnoses. The 21 primary TOFC providers were encouraged to input mapped International Statistical Classification of Diseases and Related Health Problems (ICD) codes into the electronic health record (EHR). The clinic’s providers consisted of mostly retired, but some actively practicing, medical doctors, doctors of osteopathy, nurse practitioners, physician assistants, and psychiatrists.

Previous to this project, the clinic lacked any concrete data on patient demographics or diagnoses. For example, the clinic was unable to accurately answer the National Association of Free and Charitable Clinics’ questions about how many patients TOFC providers saw with diabetes, hypertension, asthma, and hyperlipidemia.¹ Additionally, the needs of the clinic and its population were based on educated guesses.

Purpose

The project enlisted 21 volunteer providers to record diagnoses through ICD codes on the approximately 2000 active patients between March 22, 2021, and June 15, 2021. Tracking patient diagnoses improves clinic data, outcomes, and decision-making. By working on data improvement, the clinic can better understand its patient population and their needs, enhance clinical care, create better outcomes, make informed decisions, and raise eligibility for grants. The clinic was at a turning point as they reevaluated their mission statement and decided whether they would continue to focus on acute ailments or expand to formally manage chronic diseases as well. This decision needed to be made with knowledge, understanding, and context, which diagnosis data can provide. For example, the knowledge that the clinic’s 3 most common diagnoses are chronic conditions demonstrated that an official shift in their mission may have been warranted.

Literature Review

QI projects are effective and common in the free clinic setting.^2-4 To the author’s knowledge, no literature to date shows the implementation of a system to better track diagnoses using a free clinic’s EHR with ICD codes.

Data bring value to clinics in many ways. It can also lead to more informed and better distribution of resources, such as preventative health and social services, patient education, and medical inventory.⁴

The focus of the US health care system is shifting to a value-based system under the Patient Protection and Affordable Care Act.⁵ Outcome measurements and improvement play a key role in this.⁶ Without knowing diagnoses, we cannot effectively track outcomes and have no data on which to base improvements. Insurance and reimbursement requirements typically hold health care facilities accountable for making these outcomes and improvements a reality.^5,6 Free clinics, however, lack these motivations, which explains why a free clinic may be deficient in data and tracking methods. Tracking diagnosis codes will, going forward, allow TOFC to see outcomes and trends over time, track the effectiveness of the treatments, and change course if need be.⁶

TOFC fully implemented the EHR in 2018, giving the clinic better capabilities for pulling reports and tracking data. Although there were growing pains, many TOFC providers were already familiar with ICD codes, which, along with an EHR, provide a system to easily retrieve, store, and analyze diagnoses for evidence-based and informed decision-making.⁷ This made using ICD codes and the EHR an obvious choice to track patient diagnoses. However, most of the providers were not putting them in ICD codes before this project was implemented. Instead, diagnoses were typed in the notes and, therefore, not easy to generate in a report without having to open each chart for each individual encounter and combing through the notes. To make matters worse, providers were never trained on how to enter the codes in the EHR, and most providers saw no reason to, because the clinic does not bill for services.

Methods

A needs assessment determined that TOFC lacked data. This QI project used a combination of primary and secondary continuous quality improvement data.⁸ The primary data came from pulling the reports on Practice Fusion to see how many times each diagnosis code was put in during the implementation phase of this project. Secondary data came from interviewing the providers and asking whether they put in the diagnosis codes.

ICD diagnosis entry

Practice Fusion is the EHR TOFC uses and was therefore the platform for this QI project. Two ICD maps were created, which incorporated both International Classification of Diseases, Ninth Revision (ICD-9) and International Classification of Diseases, Tenth Revision (ICD-10) codes. There are tens of thousands of ICD codes in existence, but because TOFC is a free clinic that does not bill or receive reimbursement, the codes did not need to be as specific as they do in a paid clinic. Therefore, the maps put all the variations of each disease into a single category. For example, every patient with diabetes would receive the same ICD code regardless of whether their diabetes was controlled, uncontrolled, or any other variation. The goal of simplifying the codes was to improve compliance with ICD code entry and make reports easier to generate. The maps allowed the options to be simplified and, therefore, more user friendly for both the providers and the data collectors pulling reports. As some ICD-9 codes were already being used, these codes were incorporated so providers could keep using what they were already familiar with. To create the map, generic ICD codes were selected to represent each disease.

An initial survey was conducted prior to implementation with 10 providers, 2 nurses, and 2 staff members, asking which diagnoses they thought were seen most often in the clinic. Based off those answers, a map was created with the 20 most commonly used ICD codes, which can be seen in the Table. A more comprehensive map was also created, with 61 encompassing diagnoses.

Surveys

Surveys were conducted after the project was completed with willing and available providers and staff members in order to assess the utility of the project as well as to ensure future improvements and sustainability of the system.

Provider surveys

Do you currently input mapped ICD-10 codes when you chart for each encounter?

Yes No

If yes, do you intend to continue inputting the ICD codes in your encounters in the future?

Yes No

If no to either question above, please explain:

Do you have any recommendations for making it easier to input ICD codes or another way to track patients’ diagnoses?

Staff surveys

Is this data helpful for your role?

Yes No

If yes, how will you use this data?

Results

During the implementation phase, hypertension was the most common diagnosis seen at TOFC, accounting for 35 of 131 (27%) top 20 diagnoses entered. Depression was second, accounting for about 20% of diagnoses. Posttraumatic stress disorder was the third most common, making up 18% of diagnoses. There were 157 encounters during the implementation phase and 128 ICD diagnoses entered into the chart during this time period, suggesting that most encounters had a corresponding diagnosis code entered. See the Table for more details.

Provider surveys

Six providers answered the survey questions. Four answered “yes” to both questions and 2 answered “no” to both questions. Reasons cited for why they did not input the ICD codes included not remembering to enter the codes or not remembering how to enter the codes. Recommendations for making it easier included incorporating the diagnosis in the assessment section of the EHR instead of standing alone as its own section, replacing ICD-9 codes with ICD-10 codes on the maps, making more specific codes for options, like typing more mental health diagnoses, and implementing more training on how to enter the codes.

Staff surveys

Three of 4 staff members responded to the survey. All 3 indicated that the data collected from this project assisted in their role. Stated uses for this data included grant applications and funding; community education, such as presentations and outreach; program development and monitoring; quality improvement; supply purchasing (eg, medications in stock to treat most commonly seen conditions), scheduling clinics and providers; allocating resources and supplies; and accepting or rejecting medical supply donations.

Discussion

Before this project, 668 of the top 20 most common diagnosis codes were entered from when TOFC introduced use of the EHR in the clinic in 2017, until the beginning of the implementation phase of this project in March 2021. During the 3 months of the implementation phase, 131 diagnoses were entered, representing almost 20% of the amount that were entered in 3 and a half years. Pulling the reports for these 20 diagnoses took less than 1 hour. During the needs assessment phase of this project, diagnoses for 3 months were extracted from the EHR by combing through provider notes and extracting the data from the notes—a process that took 11 hours.

Knowledge of diagnoses and the reasons for clinic attendance help the clinic make decisions about staffing, resources, and services. The TOFC board of directors used this data to assist with the decision of whether or not to change the clinic’s mission to include primary care as an official clinic function. The original purpose of the clinic was to address acute issues for people who lacked the resources for medical care. For example, a homeless person with an abscess could come to the clinic and have the abscess drained and treated. The results of this project illustrate that, in reality, most of the diagnoses actually seen in the clinic are more chronic in nature and require consistent, ongoing care. For instance, the project identified 52 clinic patients receiving consistent diabetic care. This type of data can help the clinic determine whether it should accept diabetes-associated donations and whether it needs to recruit a volunteer diabetes educator. Generally, this data can help guide other decisions as well, like what medications should be kept in the pharmacy, whether there are certain specialists the clinic should seek to partner with, and whether the clinic should embark on any particular education campaigns. By inputting ICD codes, diagnosis data are easily obtained to assist with future decisions.

A limitation of this project was that the reports could only be pulled within a certain time frame if the start date of the diagnosis was specified. As most providers did not indicate a start date with their entered diagnosis code, the only way to compare the before and after was to count the total before and the total after the implementation time frame. In other words, comparison reports could not be pulled retroactively, so some data on the less common diagnosis codes are missing from this paper, as reports for the comprehensive map were not pulled ahead of time. Providers may have omitted the start date when entering the diagnosis codes because many of these patients had their diagnoses for years—seeing different providers each time—so starting the diagnosis at that particular encounter did not make sense. Additionally, during training, although how to enter the start date was demonstrated, the emphasis and priority was placed on actually entering the ICD code, in an effort to keep the process simple and increase participation.

Conclusion

Evidence-based care and informed decision-making require data. In a free clinic, this can be difficult to obtain due to limited staffing and the absence of billing and insurance requirements. ICD codes and EHRs are powerful tools to collect data and information about clinic needs. This project improved TOFC’s knowledge about what kind of patients and diagnoses they see.

Corresponding author: Sarah M. Shanahan, MSN, RN, Pacific Lutheran University School of Nursing, Ramstad, Room 214, Tacoma, WA 98447; [email protected].

Financial disclosures: None.

From Pacific Lutheran School of Nursing, Tacoma, WA.

Objective: This quality improvement project aimed to enhance The Olympia Free Clinic’s (TOFC) data availability using International Classification of Diseases (ICD) code entry into the electronic health record (EHR). Prior to this project, TOFC lacked quality diagnosis data. This project strived to answer questions like “How many TOFC patients have diabetes?”

Methods: A new system was implemented for inputting ICD codes into Practice Fusion, the clinic’s EHR. During the initial phase, TOFC’s 21 volunteer providers entered the codes associated with the appropriate diagnosis for each of 157 encounters using a simplified map of options, including a map of the 20 most common diagnoses and a more comprehensive 60-code map.

Results: An EHR report found that 128 new diagnoses were entered during project implementation, hypertension being the most common diagnosis, followed by depression, then posttraumatic stress disorder.

Conclusion: The knowledge of patient diagnoses enabled the clinic to make more-informed decisions.

Keywords: free clinic, data, quality improvement, electronic health record, International Classification of Diseases

Data creates a starting point, a goal, background, understanding of needs and context, and allows for tracking and improvement over time. This quality improvement (QI) project for The Olympia Free Clinic (TOFC) implemented a new system for tracking patient diagnoses. The 21 primary TOFC providers were encouraged to input mapped International Statistical Classification of Diseases and Related Health Problems (ICD) codes into the electronic health record (EHR). The clinic’s providers consisted of mostly retired, but some actively practicing, medical doctors, doctors of osteopathy, nurse practitioners, physician assistants, and psychiatrists.

Previous to this project, the clinic lacked any concrete data on patient demographics or diagnoses. For example, the clinic was unable to accurately answer the National Association of Free and Charitable Clinics’ questions about how many patients TOFC providers saw with diabetes, hypertension, asthma, and hyperlipidemia.¹ Additionally, the needs of the clinic and its population were based on educated guesses.

Purpose

The project enlisted 21 volunteer providers to record diagnoses through ICD codes on the approximately 2000 active patients between March 22, 2021, and June 15, 2021. Tracking patient diagnoses improves clinic data, outcomes, and decision-making. By working on data improvement, the clinic can better understand its patient population and their needs, enhance clinical care, create better outcomes, make informed decisions, and raise eligibility for grants. The clinic was at a turning point as they reevaluated their mission statement and decided whether they would continue to focus on acute ailments or expand to formally manage chronic diseases as well. This decision needed to be made with knowledge, understanding, and context, which diagnosis data can provide. For example, the knowledge that the clinic’s 3 most common diagnoses are chronic conditions demonstrated that an official shift in their mission may have been warranted.

Literature Review

QI projects are effective and common in the free clinic setting.^2-4 To the author’s knowledge, no literature to date shows the implementation of a system to better track diagnoses using a free clinic’s EHR with ICD codes.

Data bring value to clinics in many ways. It can also lead to more informed and better distribution of resources, such as preventative health and social services, patient education, and medical inventory.⁴

The focus of the US health care system is shifting to a value-based system under the Patient Protection and Affordable Care Act.⁵ Outcome measurements and improvement play a key role in this.⁶ Without knowing diagnoses, we cannot effectively track outcomes and have no data on which to base improvements. Insurance and reimbursement requirements typically hold health care facilities accountable for making these outcomes and improvements a reality.^5,6 Free clinics, however, lack these motivations, which explains why a free clinic may be deficient in data and tracking methods. Tracking diagnosis codes will, going forward, allow TOFC to see outcomes and trends over time, track the effectiveness of the treatments, and change course if need be.⁶

TOFC fully implemented the EHR in 2018, giving the clinic better capabilities for pulling reports and tracking data. Although there were growing pains, many TOFC providers were already familiar with ICD codes, which, along with an EHR, provide a system to easily retrieve, store, and analyze diagnoses for evidence-based and informed decision-making.⁷ This made using ICD codes and the EHR an obvious choice to track patient diagnoses. However, most of the providers were not putting them in ICD codes before this project was implemented. Instead, diagnoses were typed in the notes and, therefore, not easy to generate in a report without having to open each chart for each individual encounter and combing through the notes. To make matters worse, providers were never trained on how to enter the codes in the EHR, and most providers saw no reason to, because the clinic does not bill for services.

Methods

A needs assessment determined that TOFC lacked data. This QI project used a combination of primary and secondary continuous quality improvement data.⁸ The primary data came from pulling the reports on Practice Fusion to see how many times each diagnosis code was put in during the implementation phase of this project. Secondary data came from interviewing the providers and asking whether they put in the diagnosis codes.

ICD diagnosis entry

Practice Fusion is the EHR TOFC uses and was therefore the platform for this QI project. Two ICD maps were created, which incorporated both International Classification of Diseases, Ninth Revision (ICD-9) and International Classification of Diseases, Tenth Revision (ICD-10) codes. There are tens of thousands of ICD codes in existence, but because TOFC is a free clinic that does not bill or receive reimbursement, the codes did not need to be as specific as they do in a paid clinic. Therefore, the maps put all the variations of each disease into a single category. For example, every patient with diabetes would receive the same ICD code regardless of whether their diabetes was controlled, uncontrolled, or any other variation. The goal of simplifying the codes was to improve compliance with ICD code entry and make reports easier to generate. The maps allowed the options to be simplified and, therefore, more user friendly for both the providers and the data collectors pulling reports. As some ICD-9 codes were already being used, these codes were incorporated so providers could keep using what they were already familiar with. To create the map, generic ICD codes were selected to represent each disease.

An initial survey was conducted prior to implementation with 10 providers, 2 nurses, and 2 staff members, asking which diagnoses they thought were seen most often in the clinic. Based off those answers, a map was created with the 20 most commonly used ICD codes, which can be seen in the Table. A more comprehensive map was also created, with 61 encompassing diagnoses.

Surveys

Surveys were conducted after the project was completed with willing and available providers and staff members in order to assess the utility of the project as well as to ensure future improvements and sustainability of the system.

Provider surveys

Do you currently input mapped ICD-10 codes when you chart for each encounter?

Yes No

If yes, do you intend to continue inputting the ICD codes in your encounters in the future?

Yes No

If no to either question above, please explain:

Do you have any recommendations for making it easier to input ICD codes or another way to track patients’ diagnoses?

Staff surveys

Is this data helpful for your role?

Yes No

If yes, how will you use this data?

Results

During the implementation phase, hypertension was the most common diagnosis seen at TOFC, accounting for 35 of 131 (27%) top 20 diagnoses entered. Depression was second, accounting for about 20% of diagnoses. Posttraumatic stress disorder was the third most common, making up 18% of diagnoses. There were 157 encounters during the implementation phase and 128 ICD diagnoses entered into the chart during this time period, suggesting that most encounters had a corresponding diagnosis code entered. See the Table for more details.

Provider surveys

Six providers answered the survey questions. Four answered “yes” to both questions and 2 answered “no” to both questions. Reasons cited for why they did not input the ICD codes included not remembering to enter the codes or not remembering how to enter the codes. Recommendations for making it easier included incorporating the diagnosis in the assessment section of the EHR instead of standing alone as its own section, replacing ICD-9 codes with ICD-10 codes on the maps, making more specific codes for options, like typing more mental health diagnoses, and implementing more training on how to enter the codes.

Staff surveys

Three of 4 staff members responded to the survey. All 3 indicated that the data collected from this project assisted in their role. Stated uses for this data included grant applications and funding; community education, such as presentations and outreach; program development and monitoring; quality improvement; supply purchasing (eg, medications in stock to treat most commonly seen conditions), scheduling clinics and providers; allocating resources and supplies; and accepting or rejecting medical supply donations.

Discussion

Before this project, 668 of the top 20 most common diagnosis codes were entered from when TOFC introduced use of the EHR in the clinic in 2017, until the beginning of the implementation phase of this project in March 2021. During the 3 months of the implementation phase, 131 diagnoses were entered, representing almost 20% of the amount that were entered in 3 and a half years. Pulling the reports for these 20 diagnoses took less than 1 hour. During the needs assessment phase of this project, diagnoses for 3 months were extracted from the EHR by combing through provider notes and extracting the data from the notes—a process that took 11 hours.

Knowledge of diagnoses and the reasons for clinic attendance help the clinic make decisions about staffing, resources, and services. The TOFC board of directors used this data to assist with the decision of whether or not to change the clinic’s mission to include primary care as an official clinic function. The original purpose of the clinic was to address acute issues for people who lacked the resources for medical care. For example, a homeless person with an abscess could come to the clinic and have the abscess drained and treated. The results of this project illustrate that, in reality, most of the diagnoses actually seen in the clinic are more chronic in nature and require consistent, ongoing care. For instance, the project identified 52 clinic patients receiving consistent diabetic care. This type of data can help the clinic determine whether it should accept diabetes-associated donations and whether it needs to recruit a volunteer diabetes educator. Generally, this data can help guide other decisions as well, like what medications should be kept in the pharmacy, whether there are certain specialists the clinic should seek to partner with, and whether the clinic should embark on any particular education campaigns. By inputting ICD codes, diagnosis data are easily obtained to assist with future decisions.

A limitation of this project was that the reports could only be pulled within a certain time frame if the start date of the diagnosis was specified. As most providers did not indicate a start date with their entered diagnosis code, the only way to compare the before and after was to count the total before and the total after the implementation time frame. In other words, comparison reports could not be pulled retroactively, so some data on the less common diagnosis codes are missing from this paper, as reports for the comprehensive map were not pulled ahead of time. Providers may have omitted the start date when entering the diagnosis codes because many of these patients had their diagnoses for years—seeing different providers each time—so starting the diagnosis at that particular encounter did not make sense. Additionally, during training, although how to enter the start date was demonstrated, the emphasis and priority was placed on actually entering the ICD code, in an effort to keep the process simple and increase participation.

Conclusion

Evidence-based care and informed decision-making require data. In a free clinic, this can be difficult to obtain due to limited staffing and the absence of billing and insurance requirements. ICD codes and EHRs are powerful tools to collect data and information about clinic needs. This project improved TOFC’s knowledge about what kind of patients and diagnoses they see.

Corresponding author: Sarah M. Shanahan, MSN, RN, Pacific Lutheran University School of Nursing, Ramstad, Room 214, Tacoma, WA 98447; [email protected].

Financial disclosures: None.

From Pacific Lutheran School of Nursing, Tacoma, WA.

Objective: This quality improvement project aimed to enhance The Olympia Free Clinic’s (TOFC) data availability using International Classification of Diseases (ICD) code entry into the electronic health record (EHR). Prior to this project, TOFC lacked quality diagnosis data. This project strived to answer questions like “How many TOFC patients have diabetes?”

Methods: A new system was implemented for inputting ICD codes into Practice Fusion, the clinic’s EHR. During the initial phase, TOFC’s 21 volunteer providers entered the codes associated with the appropriate diagnosis for each of 157 encounters using a simplified map of options, including a map of the 20 most common diagnoses and a more comprehensive 60-code map.

Results: An EHR report found that 128 new diagnoses were entered during project implementation, hypertension being the most common diagnosis, followed by depression, then posttraumatic stress disorder.

Conclusion: The knowledge of patient diagnoses enabled the clinic to make more-informed decisions.

Keywords: free clinic, data, quality improvement, electronic health record, International Classification of Diseases

Data creates a starting point, a goal, background, understanding of needs and context, and allows for tracking and improvement over time. This quality improvement (QI) project for The Olympia Free Clinic (TOFC) implemented a new system for tracking patient diagnoses. The 21 primary TOFC providers were encouraged to input mapped International Statistical Classification of Diseases and Related Health Problems (ICD) codes into the electronic health record (EHR). The clinic’s providers consisted of mostly retired, but some actively practicing, medical doctors, doctors of osteopathy, nurse practitioners, physician assistants, and psychiatrists.

Previous to this project, the clinic lacked any concrete data on patient demographics or diagnoses. For example, the clinic was unable to accurately answer the National Association of Free and Charitable Clinics’ questions about how many patients TOFC providers saw with diabetes, hypertension, asthma, and hyperlipidemia.¹ Additionally, the needs of the clinic and its population were based on educated guesses.

Purpose

The project enlisted 21 volunteer providers to record diagnoses through ICD codes on the approximately 2000 active patients between March 22, 2021, and June 15, 2021. Tracking patient diagnoses improves clinic data, outcomes, and decision-making. By working on data improvement, the clinic can better understand its patient population and their needs, enhance clinical care, create better outcomes, make informed decisions, and raise eligibility for grants. The clinic was at a turning point as they reevaluated their mission statement and decided whether they would continue to focus on acute ailments or expand to formally manage chronic diseases as well. This decision needed to be made with knowledge, understanding, and context, which diagnosis data can provide. For example, the knowledge that the clinic’s 3 most common diagnoses are chronic conditions demonstrated that an official shift in their mission may have been warranted.

Literature Review

QI projects are effective and common in the free clinic setting.^2-4 To the author’s knowledge, no literature to date shows the implementation of a system to better track diagnoses using a free clinic’s EHR with ICD codes.

Data bring value to clinics in many ways. It can also lead to more informed and better distribution of resources, such as preventative health and social services, patient education, and medical inventory.⁴

The focus of the US health care system is shifting to a value-based system under the Patient Protection and Affordable Care Act.⁵ Outcome measurements and improvement play a key role in this.⁶ Without knowing diagnoses, we cannot effectively track outcomes and have no data on which to base improvements. Insurance and reimbursement requirements typically hold health care facilities accountable for making these outcomes and improvements a reality.^5,6 Free clinics, however, lack these motivations, which explains why a free clinic may be deficient in data and tracking methods. Tracking diagnosis codes will, going forward, allow TOFC to see outcomes and trends over time, track the effectiveness of the treatments, and change course if need be.⁶

TOFC fully implemented the EHR in 2018, giving the clinic better capabilities for pulling reports and tracking data. Although there were growing pains, many TOFC providers were already familiar with ICD codes, which, along with an EHR, provide a system to easily retrieve, store, and analyze diagnoses for evidence-based and informed decision-making.⁷ This made using ICD codes and the EHR an obvious choice to track patient diagnoses. However, most of the providers were not putting them in ICD codes before this project was implemented. Instead, diagnoses were typed in the notes and, therefore, not easy to generate in a report without having to open each chart for each individual encounter and combing through the notes. To make matters worse, providers were never trained on how to enter the codes in the EHR, and most providers saw no reason to, because the clinic does not bill for services.

Methods

A needs assessment determined that TOFC lacked data. This QI project used a combination of primary and secondary continuous quality improvement data.⁸ The primary data came from pulling the reports on Practice Fusion to see how many times each diagnosis code was put in during the implementation phase of this project. Secondary data came from interviewing the providers and asking whether they put in the diagnosis codes.

ICD diagnosis entry

Practice Fusion is the EHR TOFC uses and was therefore the platform for this QI project. Two ICD maps were created, which incorporated both International Classification of Diseases, Ninth Revision (ICD-9) and International Classification of Diseases, Tenth Revision (ICD-10) codes. There are tens of thousands of ICD codes in existence, but because TOFC is a free clinic that does not bill or receive reimbursement, the codes did not need to be as specific as they do in a paid clinic. Therefore, the maps put all the variations of each disease into a single category. For example, every patient with diabetes would receive the same ICD code regardless of whether their diabetes was controlled, uncontrolled, or any other variation. The goal of simplifying the codes was to improve compliance with ICD code entry and make reports easier to generate. The maps allowed the options to be simplified and, therefore, more user friendly for both the providers and the data collectors pulling reports. As some ICD-9 codes were already being used, these codes were incorporated so providers could keep using what they were already familiar with. To create the map, generic ICD codes were selected to represent each disease.

An initial survey was conducted prior to implementation with 10 providers, 2 nurses, and 2 staff members, asking which diagnoses they thought were seen most often in the clinic. Based off those answers, a map was created with the 20 most commonly used ICD codes, which can be seen in the Table. A more comprehensive map was also created, with 61 encompassing diagnoses.

Surveys

Surveys were conducted after the project was completed with willing and available providers and staff members in order to assess the utility of the project as well as to ensure future improvements and sustainability of the system.

Provider surveys

Do you currently input mapped ICD-10 codes when you chart for each encounter?

Yes No

If yes, do you intend to continue inputting the ICD codes in your encounters in the future?

Yes No

If no to either question above, please explain:

Do you have any recommendations for making it easier to input ICD codes or another way to track patients’ diagnoses?

Staff surveys

Is this data helpful for your role?

Yes No

If yes, how will you use this data?

Results

During the implementation phase, hypertension was the most common diagnosis seen at TOFC, accounting for 35 of 131 (27%) top 20 diagnoses entered. Depression was second, accounting for about 20% of diagnoses. Posttraumatic stress disorder was the third most common, making up 18% of diagnoses. There were 157 encounters during the implementation phase and 128 ICD diagnoses entered into the chart during this time period, suggesting that most encounters had a corresponding diagnosis code entered. See the Table for more details.

Provider surveys

Six providers answered the survey questions. Four answered “yes” to both questions and 2 answered “no” to both questions. Reasons cited for why they did not input the ICD codes included not remembering to enter the codes or not remembering how to enter the codes. Recommendations for making it easier included incorporating the diagnosis in the assessment section of the EHR instead of standing alone as its own section, replacing ICD-9 codes with ICD-10 codes on the maps, making more specific codes for options, like typing more mental health diagnoses, and implementing more training on how to enter the codes.

Staff surveys

Three of 4 staff members responded to the survey. All 3 indicated that the data collected from this project assisted in their role. Stated uses for this data included grant applications and funding; community education, such as presentations and outreach; program development and monitoring; quality improvement; supply purchasing (eg, medications in stock to treat most commonly seen conditions), scheduling clinics and providers; allocating resources and supplies; and accepting or rejecting medical supply donations.

Discussion

Before this project, 668 of the top 20 most common diagnosis codes were entered from when TOFC introduced use of the EHR in the clinic in 2017, until the beginning of the implementation phase of this project in March 2021. During the 3 months of the implementation phase, 131 diagnoses were entered, representing almost 20% of the amount that were entered in 3 and a half years. Pulling the reports for these 20 diagnoses took less than 1 hour. During the needs assessment phase of this project, diagnoses for 3 months were extracted from the EHR by combing through provider notes and extracting the data from the notes—a process that took 11 hours.

Knowledge of diagnoses and the reasons for clinic attendance help the clinic make decisions about staffing, resources, and services. The TOFC board of directors used this data to assist with the decision of whether or not to change the clinic’s mission to include primary care as an official clinic function. The original purpose of the clinic was to address acute issues for people who lacked the resources for medical care. For example, a homeless person with an abscess could come to the clinic and have the abscess drained and treated. The results of this project illustrate that, in reality, most of the diagnoses actually seen in the clinic are more chronic in nature and require consistent, ongoing care. For instance, the project identified 52 clinic patients receiving consistent diabetic care. This type of data can help the clinic determine whether it should accept diabetes-associated donations and whether it needs to recruit a volunteer diabetes educator. Generally, this data can help guide other decisions as well, like what medications should be kept in the pharmacy, whether there are certain specialists the clinic should seek to partner with, and whether the clinic should embark on any particular education campaigns. By inputting ICD codes, diagnosis data are easily obtained to assist with future decisions.

A limitation of this project was that the reports could only be pulled within a certain time frame if the start date of the diagnosis was specified. As most providers did not indicate a start date with their entered diagnosis code, the only way to compare the before and after was to count the total before and the total after the implementation time frame. In other words, comparison reports could not be pulled retroactively, so some data on the less common diagnosis codes are missing from this paper, as reports for the comprehensive map were not pulled ahead of time. Providers may have omitted the start date when entering the diagnosis codes because many of these patients had their diagnoses for years—seeing different providers each time—so starting the diagnosis at that particular encounter did not make sense. Additionally, during training, although how to enter the start date was demonstrated, the emphasis and priority was placed on actually entering the ICD code, in an effort to keep the process simple and increase participation.

Conclusion

Evidence-based care and informed decision-making require data. In a free clinic, this can be difficult to obtain due to limited staffing and the absence of billing and insurance requirements. ICD codes and EHRs are powerful tools to collect data and information about clinic needs. This project improved TOFC’s knowledge about what kind of patients and diagnoses they see.

Corresponding author: Sarah M. Shanahan, MSN, RN, Pacific Lutheran University School of Nursing, Ramstad, Room 214, Tacoma, WA 98447; [email protected].

Financial disclosures: None.

Uterine leiomyomas affect 70% to 80% of reproductive-age women. Interventions for symptomatic patients include myomectomy, hysterectomy, uterine artery embolization (UAE), and radiofrequency ablation (RFA). Several RFA devices exist on the market. One such device is the sonography-guided transcervical ablation of uterine fibroids (Sonata), which is unique in its transcervical approach that allows for incisionless treatment.¹ It can be used to treat fibroids classified as FIGO 1-6 with a radius up to 5 cm.¹ Postablative therapy outcomes at 1 and 2 years have been promising for total volume reduction (mean maximal volume reduction, 63.8%) and improvement in symptoms, including quality-of-life measures and amount of bleeding (95% reported reduction).^2,3

In our practice, we find this tool most helpful for medium-sized (3–5 cm) intramural fibroids and large type 2 fibroids.

In the accompanying video, we illustrate the steps for use of transcervical ultrasonographic RFA with Sonata treatment and demonstrate its impact on the uterus during simultaneous laparoscopy. We present a patient who underwent Sonata treatment for a 4-cm intramural fibroid and simultaneous laparoscopic myomectomy for a 4-cm pedunculated fibroid. This allowed for the unique ability to view the external effect on the uterus during Sonata use. We review the key surgical steps with this approach, including:

1. cervical dilation
2. introduction of the Sonata system
3. sonographic identification of the target fibroid
4. adjust size and shape of Smart Guide overlays
5. deploy the introducer
6. safety rotation check
7. deploy the needle electrodes
8. initiate RFA
9. withdraw needle electrodes and introducer.

RFA with Sonata treatment is a simple, minimally invasive therapeutic option for fibroids.

We hope that you find this video useful to your clinical practice.

>>DR. ARNOLD P. ADVINCULA AND COLLEAGUES

Vidyard Video

Uterine leiomyomas affect 70% to 80% of reproductive-age women. Interventions for symptomatic patients include myomectomy, hysterectomy, uterine artery embolization (UAE), and radiofrequency ablation (RFA). Several RFA devices exist on the market. One such device is the sonography-guided transcervical ablation of uterine fibroids (Sonata), which is unique in its transcervical approach that allows for incisionless treatment.¹ It can be used to treat fibroids classified as FIGO 1-6 with a radius up to 5 cm.¹ Postablative therapy outcomes at 1 and 2 years have been promising for total volume reduction (mean maximal volume reduction, 63.8%) and improvement in symptoms, including quality-of-life measures and amount of bleeding (95% reported reduction).^2,3

In our practice, we find this tool most helpful for medium-sized (3–5 cm) intramural fibroids and large type 2 fibroids.

In the accompanying video, we illustrate the steps for use of transcervical ultrasonographic RFA with Sonata treatment and demonstrate its impact on the uterus during simultaneous laparoscopy. We present a patient who underwent Sonata treatment for a 4-cm intramural fibroid and simultaneous laparoscopic myomectomy for a 4-cm pedunculated fibroid. This allowed for the unique ability to view the external effect on the uterus during Sonata use. We review the key surgical steps with this approach, including:

1. cervical dilation
2. introduction of the Sonata system
3. sonographic identification of the target fibroid
4. adjust size and shape of Smart Guide overlays
5. deploy the introducer
6. safety rotation check
7. deploy the needle electrodes
8. initiate RFA
9. withdraw needle electrodes and introducer.

RFA with Sonata treatment is a simple, minimally invasive therapeutic option for fibroids.

We hope that you find this video useful to your clinical practice.

>>DR. ARNOLD P. ADVINCULA AND COLLEAGUES

Vidyard Video

Uterine leiomyomas affect 70% to 80% of reproductive-age women. Interventions for symptomatic patients include myomectomy, hysterectomy, uterine artery embolization (UAE), and radiofrequency ablation (RFA). Several RFA devices exist on the market. One such device is the sonography-guided transcervical ablation of uterine fibroids (Sonata), which is unique in its transcervical approach that allows for incisionless treatment.¹ It can be used to treat fibroids classified as FIGO 1-6 with a radius up to 5 cm.¹ Postablative therapy outcomes at 1 and 2 years have been promising for total volume reduction (mean maximal volume reduction, 63.8%) and improvement in symptoms, including quality-of-life measures and amount of bleeding (95% reported reduction).^2,3

In our practice, we find this tool most helpful for medium-sized (3–5 cm) intramural fibroids and large type 2 fibroids.

In the accompanying video, we illustrate the steps for use of transcervical ultrasonographic RFA with Sonata treatment and demonstrate its impact on the uterus during simultaneous laparoscopy. We present a patient who underwent Sonata treatment for a 4-cm intramural fibroid and simultaneous laparoscopic myomectomy for a 4-cm pedunculated fibroid. This allowed for the unique ability to view the external effect on the uterus during Sonata use. We review the key surgical steps with this approach, including:

1. cervical dilation
2. introduction of the Sonata system
3. sonographic identification of the target fibroid
4. adjust size and shape of Smart Guide overlays
5. deploy the introducer
6. safety rotation check
7. deploy the needle electrodes
8. initiate RFA
9. withdraw needle electrodes and introducer.

RFA with Sonata treatment is a simple, minimally invasive therapeutic option for fibroids.

We hope that you find this video useful to your clinical practice.

>>DR. ARNOLD P. ADVINCULA AND COLLEAGUES

Vidyard Video

Hidradenitis suppurativa (HS) is a chronic inflammatory, androgen gland disorder characterized by recurrent rupture of the hair follicles with a vigorous inflammatory response. This response results in abscess formation and development of draining sinus tracts and hypertrophic fibrous scars.^1,2 Pain, discomfort, and odorous discharge from the recalcitrant lesions have a profound impact on patient quality of life.^3,4

The morbidity and disease burden associated with HS are particularly underestimated, as patients frequently report debilitating pain that often is overlooked.^5,6 Additionally, the quality and intensity of perceived pain are compounded by frequently associated depression and anxiety.^7-9 Pain has been reported by patients with HS to be the highest cause of morbidity, despite the disfiguring nature of the disease and its associated psychosocial distress.^7,10 Nonetheless, HS lacks an accepted pain management algorithm similar to those that have been developed for the treatment of other acute or chronic pain disorders, such as back pain and sickle cell disease.^4,11-13

Given the lack of formal studies regarding pain management in patients with HS, clinicians are limited to general pain guidelines, expert opinion, small trials, and patient preference.³ Furthermore, effective pain management in HS necessitates the treatment of both chronic pain affecting daily function and acute pain present during disease flares, surgical interventions, and dressing changes.³ The result is a wide array of strategies used for HS-associated pain.^3,4

Epidemiology and Pathophysiology

Hidradenitis suppurativa historically has been an overlooked and underdiagnosed disease, which limits epidemiology data.⁵ Current estimates are that HS affects approximately 1% of the general population; however, prevalence rates range from 0.03% to 4.1%.^14-16

The exact etiology of HS remains unclear, but it is thought that genetic factors, immune dysregulation, and environmental/behavioral influences all contribute to its pathophysiology.^1,17 Up to 40% of patients with HS report a positive family history of the disease.^18-20 Hidradenitis suppurativa has been associated with other inflammatory disease states, such as inflammatory bowel disease, spondyloarthropathies, and pyoderma gangrenosum.^16,21,22

It is thought that HS is the result of some defect in keratin clearance that leads to follicular hyperkeratinization and occlusion.¹ Resultant rupture of pilosebaceous units and spillage of contents (including keratin and bacteria) into the surrounding dermis triggers a vigorous inflammatory response. Sinus tracts and fistulas become the targets of bacterial colonization, biofilm formation, and secondary infection. The result is suppuration and extension of the lesions as well as sustained chronic inflammation.^23,24

Although the etiology of HS is complex, several modifiable risk factors for the disease have been identified, most prominently cigarette smoking and obesity. Approximately 70% of patients with HS smoke cigarettes.^2,15,25,26 Obesity has a well-known association with HS, and it is possible that weight reduction lowers disease severity.^27-30

Clinical Presentation and Diagnosis

Establishing a diagnosis of HS necessitates recognition of disease morphology, topography, and chronicity. Hidradenitis suppurativa most commonly occurs in the axillae, inguinal and anogenital region, perineal region, and inframammary region.^5,31 A typical history involves a prolonged disease course with recurrent lesions and intermittent periods of improvement or remission. Primary lesions are deep, inflamed, painful, and sterile. Ultimately, these lesions rupture and track subcutaneously.^15,25 Intercommunicating sinus tracts form from multiple recurrent nodules in close proximity and may ultimately lead to fibrotic scarring and local architectural distortion.³² The Hurley staging system helps to guide treatment interventions based on disease severity. Approach to pain management is discussed below.

Pain Management in HS: General Principles

Pain management is complex for clinicians, as there are limited studies from which to draw treatment recommendations. Incomplete understanding of the etiology and pathophysiology of the disease contributes to the lack of established management guidelines.

A PubMed search of articles indexed for MEDLINE using the terms hidradenitis, suppurativa, pain, and management revealed 61 different results dating back to 1980, 52 of which had been published in the last 5 years. When the word acute was added to the search, there were only 6 results identified. These results clearly reflect a better understanding of HS-mediated pain as well as clinical unmet needs and evolving strategies in pain management therapeutics. However, many of these studies reflect therapies focused on the mediation or modulation of HS pathogenesis rather than potential pain management therapies.

In addition, the heterogenous nature of the pain experience in HS poses a challenge for clinicians. Patients may experience multiple pain types concurrently, including inflammatory, noninflammatory, nociceptive, neuropathic, and ischemic, as well as pain related to arthritis.^3,33,34 Pain perception is further complicated by the observation that patients with HS have high rates of psychiatric comorbidities such as depression and anxiety, both of which profoundly alter perception of both the strength and quality of pain.^7,8,22,35 A suggested algorithm for treatment of pain in HS is described in the eTable.³⁶

Chronicity is a hallmark of HS. Patients experience a prolonged disease course involving acute painful exacerbations superimposed on chronic pain that affects all aspects of daily life. Changes in self-perception, daily living activities, mood state, physical functioning, and physical comfort frequently are reported to have a major impact on quality of life.^1,3,37

In 2018, Thorlacius et al³⁸ created a multistakeholder consensus on a core outcome set of domains detailing what to measure in clinical trials for HS. The authors hoped that the routine adoption of these core domains would promote the collection of consistent and relevant information, bolster the strength of evidence synthesis, and minimize the risk for outcome reporting bias among studies.³⁸ It is important to ascertain the patient’s description of his/her pain to distinguish between stimulus-dependent nociceptive pain vs spontaneous neuropathic pain.^3,7,10 The most common pain descriptors used by patients are “shooting,” “itchy,” “blinding,” “cutting,” and “exhausting.”¹⁰ In addition to obtaining descriptive factors, it is important for the clinician to obtain information on the timing of the pain, whether or not the pain is relieved with spontaneous or surgical drainage, and if the patient is experiencing chronic background pain secondary to scarring or skin contraction.³ With the routine utilization of a consistent set of core domains, advances in our understanding of the different elements of HS pain, and increased provider awareness of the disease, the future of pain management in patients with HS seems promising.

Acute and Perioperative Pain Management

Acute Pain Management—The pain in HS can range from mild to excruciating.^3,7 The difference between acute and chronic pain in this condition may be hard to delineate, as patients may have intense acute flares on top of a baseline level of chronic pain.^3,7,14 These factors, in combination with various pain types of differing etiologies, make the treatment of HS-associated pain a therapeutic challenge.

The first-line treatments for acute pain in HS are oral acetaminophen, oral nonsteroidal anti-inflammatory drugs (NSAIDs), and topical analgesics.³ These treatment modalities are especially helpful for nociceptive pain, which often is described as having an aching or tender quality.³ Topical treatment for acute pain episodes includes diclofenac gel and liposomal lidocaine cream.³⁹ Topical lidocaine in particular has the benefit of being rapid acting, and its effect can last 1 to 2 hours. Ketamine has been anecdotally used as a topical treatment. Treatment options for neuropathic pain include topical amitriptyline, gabapentin, and pregabalin.³⁹ Dressings and ice packs may be used in cases of mild acute pain, depending on patient preference.³

First-line therapies may not provide adequate pain control in many patients.^3,40,41 Should the first-line treatments fail, oral opiates can be considered as a treatment option, especially if the patient has a history of recurrent pain unresponsive to milder methods of pain control.^3,40,41 However, prudence should be exercised, as patients with HS have a higher risk for opioid abuse, and referral to a pain specialist is advisable.⁴⁰ Generally, use of opioids should be limited to the smallest period of time possible.^40,41 Codeine can be used as a first opioid option, with hydromorphone available as an alternative.⁴¹

Pain caused by inflamed abscesses and nodules can be treated with either intralesional corticosteroids or incision and drainage. Intralesional triamcinolone has been found to cause substantial pain relief within 1 day of injection in patients with HS.^3,42

Prompt discussion about the remitting course of HS will prepare patients for flares. Although the therapies discussed here aim to reduce the clinical severity and inflammation associated with HS, achieving pain-free remission can be challenging. Barriers to developing a long-term treatment regimen include intolerable side effects or simply nonresponsive disease.^36,43

Management of Perioperative Pain—Medical treatment of HS often yields only transient or mild results. Hurley stage II or III lesions typically require surgical removal of affected tissues.^32,44-46 Surgery may dramatically reduce the primary disease burden and provide substantial pain relief.^3,4,44 Complete resection of the affected tissue by wide excision is the most common surgical procedure used.^46-48 However, various tissue-sparing techniques, such as skin-tissue-sparing excision with electrosurgical peeling, also have been utilized. Tissue-sparing surgical techniques may lead to shorter healing times and less postoperative pain.⁴⁸

There currently is little guidance available on the perioperative management of pain as it relates to surgical procedures for HS. The pain experienced from surgery varies based on the area and location of affected tissue; extent of disease; surgical technique used; and whether primary closure, closure by secondary intention, or skin grafting is utilized.^47,49 Medical treatment aimed at reducing inflammation prior to surgical intervention may improve postoperative pain and complications.

The use of general vs local anesthesia during surgery depends on the extent of the disease and the amount of tissue being removed; however, the use of local anesthesia has been associated with a higher recurrence of disease, possibly owing to less aggressive tissue removal.⁵⁰ Intraoperatively, the injection of 0.5% bupivacaine around the wound edges may lead to less postoperative pain.^3,48 Postoperative pain usually is managed with acetaminophen and NSAIDs.⁴⁸ In cases of severe postoperative pain, short- and long-acting opioid oxycodone preparations may be used. The combination of diclofenac and tramadol also has been used postoperatively.³ Patients who do not undergo extensive surgery often can leave the hospital the same day.

Effective strategies for mitigating HS-associated pain must address the chronic pain component of the disease. Long-term management involves lifestyle modifications and pharmacologic agents.

Chronic Pain Management

Although HS is not a curable disease, there are treatments available to minimize symptoms. Long-term management of HS is essential to minimize the effects of chronic pain and physical scarring associated with inflammation.³¹ In one study from the French Society of Dermatology, pain reported by patients with HS was directly associated with severity and duration of disease, emotional symptoms, and reduced functionality.⁵¹ For these reasons, many treatments for HS target reducing clinical severity and achieving remission, often defined as more than 6 months without any recurrence of lesions.⁵² In addition to lifestyle management, therapies available to manage HS include topical and systemic medications as well as procedures such as surgical excision.^36,43,52,53

Lifestyle Modifications

Regardless of the severity of HS, all patients may benefit from basic education on the pathogenesis of the disease.³⁶ The associations with smoking and obesity have been well documented, and treatment of these comorbid conditions is indicated.^36,43,52 For example, in relation to obesity, the use of metformin is very well tolerated and seems to positively impact HS symptoms.⁴³ Several studies have suggested that weight reduction lowers disease severity.^28-30 Patients should be counseled on the importance of smoking cessation and weight loss.

Finally, the emotional impact of HS is not to be discounted, both the physical and social discomfort as well as the chronicity of the disease and frustration with treatment.⁵¹ Chronic pain has been associated with increased rates of depression, and 43% of patients with HS specifically have been diagnosed with major depressive disorder.⁷ For these reasons, clinician guidance, social support, and websites can improve patient understanding of the disease, adherence to treatment, and comorbid anxiety and depression.⁵²

Topical Therapy

Topical therapy generally is limited to mild disease and is geared at decreasing inflammation or superimposed infection.^36,52 Some of the earliest therapies used were topical antibiotics.⁴³ Topical clindamycin has been shown to be as effective as oral tetracyclines in reducing the number of abscesses, but neither treatment substantially reduces pain associated with smaller nodules.⁵⁴ Intralesional corticosteroids such as triamcinolone acetonide have been shown to decrease both patient-reported pain and physician-assessed severity within 1 to 7 days.⁴² Routine injection, however, is not a feasible means of long-term treatment both because of inconvenience and the potential adverse effects of corticosteroids.^36,52 Both topical clindamycin and intralesional steroids are helpful in reducing inflammation prior to planned surgical intervention.^36,52,53

Newer topical therapies include resorcinol peels and combination antimicrobials, such as 2% triclosan and oral zinc gluconate.^52,53 Data surrounding the use of resorcinol in mild to moderate HS are promising and have shown decreased severity of both new and long-standing nodules. Fifteen-percent resorcinol peels are helpful tools that allow for self-administration by patients during exacerbations to decrease pain and flare duration.^55,56 In a 2016 clinical trial, a combination of oral zinc gluconate with topical triclosan was shown to reduce flare-ups and nodules in mild HS.⁵⁷ Oral zinc alone may have anti-inflammatory properties and generally is well tolerated.^43,53 Topical therapies have a role in reducing HS-associated pain but often are limited to milder disease.

Systemic Agents

Several therapeutic options exist for the treatment of HS; however, a detailed description of their mechanisms and efficacies is beyond the scope of this review, which is focused on pain. Briefly, these systemic agents include antibiotics, retinoids, corticosteroids, antiandrogens, and biologics.^43,52,53

Treatment with antibiotics such as tetracyclines or a combination of clindamycin plus rifampin has been shown to produce complete remission in 60% to 80% of users; however, this treatment requires more than 6 months of antibiotic therapy, which can be difficult to tolerate.^52,53,58 Relapse is common after antibiotic cessation.^2,43,52 Antibiotics have demonstrated efficacy during acute flares and in reducing inflammatory activity prior to surgery.⁵²

Retinoids have been utilized in the treatment of HS because of their action on sebaceous glands and hair follicles.^43,53 Acitretin has been shown to be the most effective oral retinoid available in the United States.⁴³ Unfortunately, many of the studies investigating the use of retinoids for treatment of HS are limited by small sample size.^36,43,52

Because HS is predominantly an inflammatory condition, immunosuppressants have been adapted to manage patients when antibiotics and topicals have failed. Systemic steroids rarely are used for long-term therapy because of the severe side effects and are preferred only for acute management.^36,52 Cyclosporine and dapsone have demonstrated efficacy in treating moderate to severe HS, whereas methotrexate and colchicine have shown little efficacy.⁵² Both cyclosporine and dapsone are difficult to tolerate, require laboratory monitoring, and lead to only conservative improvement rather than remission in most patients.⁴³

Immune dysregulation in HS involves elevated levels of proinflammatory cytokines such as tumor necrosis factor α (TNF-α), which is a key mediator of inflammation and a stimulator of other inflammatory cytokines.^59,60 The first approved biologic treatment of HS was adalimumab, a TNF-α inhibitor, which showed a 50% reduction in total abscess and inflammatory nodule count in 60% of patients with moderate to severe HS.^61-63 Of course, TNF-α inhibitor therapy is not without risks, specifically those of infection.^43,53,61,62 Maintenance therapy may be required if patients relapse.^53,61

Various interleukin inhibitors also have emerged as potential therapies for HS, such as ustekinumab and anakinra.^36,64 Both have been subject to numerous small case trials that have reported improvements in clinical severity and pain; however, both drugs were associated with a fair number of nonresponders.^36,64,65

Surgical Procedures

Although HS lesions may regress on their own in a matter of weeks, surgical drainage allows an acute alleviation of the severe burning pain associated with HS flares.^36,52,53 Because of improved understanding of the disease pathophysiology, recent therapies targeting the hair follicle have been developed and have shown promising results. These therapies include laser- and light-based procedures. Long-pulsed Nd:YAG laser therapy reduces the number of hair follicles and sebaceous glands and has been effective for Hurley stage I or II disease.^{36,43,52,53,66} Photodynamic therapy offers a less-invasive option compared to surgery and laser therapy.^52,53,66 Both Nd:YAG and CO₂ laser therapy offer low recurrence rates (<30%) due to destruction of the apocrine unit.^43,53 Photodynamic therapy for mild disease offers a less-invasive option compared to surgery and laser therapy.⁵³ There is a need for larger randomized controlled trials involving laser, light, and CO₂ therapies.⁶⁶

Conclusion

Hidradenitis suppurativa is a debilitating condition with an underestimated disease burden. Although the pathophysiology of the disease is not completely understood, it is evident that pain is a major cause of morbidity. Patients experience a multitude of acute and chronic pain types: inflammatory, noninflammatory, nociceptive, neuropathic, and ischemic. Pain perception and quality of life are further impacted by psychiatric conditions such as depression and anxiety, both of which are common comorbidities in patients with HS. Several pharmacologic agents have been used to treat HS-associated pain with mixed results. First-line treatment of acute pain episodes includes oral acetaminophen, NSAIDs, and topical analgesics. Management of chronic pain includes utilization of topical agents, systemic agents, and biologics, as well as addressing lifestyle (eg, obesity, smoking status) and psychiatric comorbidities. Although these therapies have roles in HS pain management, the most effective pain remedies developed thus far are limited to surgery and TNF-α inhibitors. Optimization of pain control in patients with HS requires multidisciplinary collaboration among dermatologists, pain specialists, psychiatrists, and other members of the health care team. Further large-scale studies are needed to create an evidence-based treatment algorithm for the management of pain in HS.

Hidradenitis suppurativa (HS) is a chronic inflammatory, androgen gland disorder characterized by recurrent rupture of the hair follicles with a vigorous inflammatory response. This response results in abscess formation and development of draining sinus tracts and hypertrophic fibrous scars.^1,2 Pain, discomfort, and odorous discharge from the recalcitrant lesions have a profound impact on patient quality of life.^3,4

The morbidity and disease burden associated with HS are particularly underestimated, as patients frequently report debilitating pain that often is overlooked.^5,6 Additionally, the quality and intensity of perceived pain are compounded by frequently associated depression and anxiety.^7-9 Pain has been reported by patients with HS to be the highest cause of morbidity, despite the disfiguring nature of the disease and its associated psychosocial distress.^7,10 Nonetheless, HS lacks an accepted pain management algorithm similar to those that have been developed for the treatment of other acute or chronic pain disorders, such as back pain and sickle cell disease.^4,11-13

Given the lack of formal studies regarding pain management in patients with HS, clinicians are limited to general pain guidelines, expert opinion, small trials, and patient preference.³ Furthermore, effective pain management in HS necessitates the treatment of both chronic pain affecting daily function and acute pain present during disease flares, surgical interventions, and dressing changes.³ The result is a wide array of strategies used for HS-associated pain.^3,4

Epidemiology and Pathophysiology

Hidradenitis suppurativa historically has been an overlooked and underdiagnosed disease, which limits epidemiology data.⁵ Current estimates are that HS affects approximately 1% of the general population; however, prevalence rates range from 0.03% to 4.1%.^14-16

The exact etiology of HS remains unclear, but it is thought that genetic factors, immune dysregulation, and environmental/behavioral influences all contribute to its pathophysiology.^1,17 Up to 40% of patients with HS report a positive family history of the disease.^18-20 Hidradenitis suppurativa has been associated with other inflammatory disease states, such as inflammatory bowel disease, spondyloarthropathies, and pyoderma gangrenosum.^16,21,22

It is thought that HS is the result of some defect in keratin clearance that leads to follicular hyperkeratinization and occlusion.¹ Resultant rupture of pilosebaceous units and spillage of contents (including keratin and bacteria) into the surrounding dermis triggers a vigorous inflammatory response. Sinus tracts and fistulas become the targets of bacterial colonization, biofilm formation, and secondary infection. The result is suppuration and extension of the lesions as well as sustained chronic inflammation.^23,24

Although the etiology of HS is complex, several modifiable risk factors for the disease have been identified, most prominently cigarette smoking and obesity. Approximately 70% of patients with HS smoke cigarettes.^2,15,25,26 Obesity has a well-known association with HS, and it is possible that weight reduction lowers disease severity.^27-30

Clinical Presentation and Diagnosis

Establishing a diagnosis of HS necessitates recognition of disease morphology, topography, and chronicity. Hidradenitis suppurativa most commonly occurs in the axillae, inguinal and anogenital region, perineal region, and inframammary region.^5,31 A typical history involves a prolonged disease course with recurrent lesions and intermittent periods of improvement or remission. Primary lesions are deep, inflamed, painful, and sterile. Ultimately, these lesions rupture and track subcutaneously.^15,25 Intercommunicating sinus tracts form from multiple recurrent nodules in close proximity and may ultimately lead to fibrotic scarring and local architectural distortion.³² The Hurley staging system helps to guide treatment interventions based on disease severity. Approach to pain management is discussed below.

Pain Management in HS: General Principles

Pain management is complex for clinicians, as there are limited studies from which to draw treatment recommendations. Incomplete understanding of the etiology and pathophysiology of the disease contributes to the lack of established management guidelines.

A PubMed search of articles indexed for MEDLINE using the terms hidradenitis, suppurativa, pain, and management revealed 61 different results dating back to 1980, 52 of which had been published in the last 5 years. When the word acute was added to the search, there were only 6 results identified. These results clearly reflect a better understanding of HS-mediated pain as well as clinical unmet needs and evolving strategies in pain management therapeutics. However, many of these studies reflect therapies focused on the mediation or modulation of HS pathogenesis rather than potential pain management therapies.

In addition, the heterogenous nature of the pain experience in HS poses a challenge for clinicians. Patients may experience multiple pain types concurrently, including inflammatory, noninflammatory, nociceptive, neuropathic, and ischemic, as well as pain related to arthritis.^3,33,34 Pain perception is further complicated by the observation that patients with HS have high rates of psychiatric comorbidities such as depression and anxiety, both of which profoundly alter perception of both the strength and quality of pain.^7,8,22,35 A suggested algorithm for treatment of pain in HS is described in the eTable.³⁶

Chronicity is a hallmark of HS. Patients experience a prolonged disease course involving acute painful exacerbations superimposed on chronic pain that affects all aspects of daily life. Changes in self-perception, daily living activities, mood state, physical functioning, and physical comfort frequently are reported to have a major impact on quality of life.^1,3,37

In 2018, Thorlacius et al³⁸ created a multistakeholder consensus on a core outcome set of domains detailing what to measure in clinical trials for HS. The authors hoped that the routine adoption of these core domains would promote the collection of consistent and relevant information, bolster the strength of evidence synthesis, and minimize the risk for outcome reporting bias among studies.³⁸ It is important to ascertain the patient’s description of his/her pain to distinguish between stimulus-dependent nociceptive pain vs spontaneous neuropathic pain.^3,7,10 The most common pain descriptors used by patients are “shooting,” “itchy,” “blinding,” “cutting,” and “exhausting.”¹⁰ In addition to obtaining descriptive factors, it is important for the clinician to obtain information on the timing of the pain, whether or not the pain is relieved with spontaneous or surgical drainage, and if the patient is experiencing chronic background pain secondary to scarring or skin contraction.³ With the routine utilization of a consistent set of core domains, advances in our understanding of the different elements of HS pain, and increased provider awareness of the disease, the future of pain management in patients with HS seems promising.

Acute and Perioperative Pain Management

Acute Pain Management—The pain in HS can range from mild to excruciating.^3,7 The difference between acute and chronic pain in this condition may be hard to delineate, as patients may have intense acute flares on top of a baseline level of chronic pain.^3,7,14 These factors, in combination with various pain types of differing etiologies, make the treatment of HS-associated pain a therapeutic challenge.

The first-line treatments for acute pain in HS are oral acetaminophen, oral nonsteroidal anti-inflammatory drugs (NSAIDs), and topical analgesics.³ These treatment modalities are especially helpful for nociceptive pain, which often is described as having an aching or tender quality.³ Topical treatment for acute pain episodes includes diclofenac gel and liposomal lidocaine cream.³⁹ Topical lidocaine in particular has the benefit of being rapid acting, and its effect can last 1 to 2 hours. Ketamine has been anecdotally used as a topical treatment. Treatment options for neuropathic pain include topical amitriptyline, gabapentin, and pregabalin.³⁹ Dressings and ice packs may be used in cases of mild acute pain, depending on patient preference.³

First-line therapies may not provide adequate pain control in many patients.^3,40,41 Should the first-line treatments fail, oral opiates can be considered as a treatment option, especially if the patient has a history of recurrent pain unresponsive to milder methods of pain control.^3,40,41 However, prudence should be exercised, as patients with HS have a higher risk for opioid abuse, and referral to a pain specialist is advisable.⁴⁰ Generally, use of opioids should be limited to the smallest period of time possible.^40,41 Codeine can be used as a first opioid option, with hydromorphone available as an alternative.⁴¹

Pain caused by inflamed abscesses and nodules can be treated with either intralesional corticosteroids or incision and drainage. Intralesional triamcinolone has been found to cause substantial pain relief within 1 day of injection in patients with HS.^3,42

Prompt discussion about the remitting course of HS will prepare patients for flares. Although the therapies discussed here aim to reduce the clinical severity and inflammation associated with HS, achieving pain-free remission can be challenging. Barriers to developing a long-term treatment regimen include intolerable side effects or simply nonresponsive disease.^36,43

Management of Perioperative Pain—Medical treatment of HS often yields only transient or mild results. Hurley stage II or III lesions typically require surgical removal of affected tissues.^32,44-46 Surgery may dramatically reduce the primary disease burden and provide substantial pain relief.^3,4,44 Complete resection of the affected tissue by wide excision is the most common surgical procedure used.^46-48 However, various tissue-sparing techniques, such as skin-tissue-sparing excision with electrosurgical peeling, also have been utilized. Tissue-sparing surgical techniques may lead to shorter healing times and less postoperative pain.⁴⁸

There currently is little guidance available on the perioperative management of pain as it relates to surgical procedures for HS. The pain experienced from surgery varies based on the area and location of affected tissue; extent of disease; surgical technique used; and whether primary closure, closure by secondary intention, or skin grafting is utilized.^47,49 Medical treatment aimed at reducing inflammation prior to surgical intervention may improve postoperative pain and complications.

The use of general vs local anesthesia during surgery depends on the extent of the disease and the amount of tissue being removed; however, the use of local anesthesia has been associated with a higher recurrence of disease, possibly owing to less aggressive tissue removal.⁵⁰ Intraoperatively, the injection of 0.5% bupivacaine around the wound edges may lead to less postoperative pain.^3,48 Postoperative pain usually is managed with acetaminophen and NSAIDs.⁴⁸ In cases of severe postoperative pain, short- and long-acting opioid oxycodone preparations may be used. The combination of diclofenac and tramadol also has been used postoperatively.³ Patients who do not undergo extensive surgery often can leave the hospital the same day.

Effective strategies for mitigating HS-associated pain must address the chronic pain component of the disease. Long-term management involves lifestyle modifications and pharmacologic agents.

Chronic Pain Management

Although HS is not a curable disease, there are treatments available to minimize symptoms. Long-term management of HS is essential to minimize the effects of chronic pain and physical scarring associated with inflammation.³¹ In one study from the French Society of Dermatology, pain reported by patients with HS was directly associated with severity and duration of disease, emotional symptoms, and reduced functionality.⁵¹ For these reasons, many treatments for HS target reducing clinical severity and achieving remission, often defined as more than 6 months without any recurrence of lesions.⁵² In addition to lifestyle management, therapies available to manage HS include topical and systemic medications as well as procedures such as surgical excision.^36,43,52,53

Lifestyle Modifications

Regardless of the severity of HS, all patients may benefit from basic education on the pathogenesis of the disease.³⁶ The associations with smoking and obesity have been well documented, and treatment of these comorbid conditions is indicated.^36,43,52 For example, in relation to obesity, the use of metformin is very well tolerated and seems to positively impact HS symptoms.⁴³ Several studies have suggested that weight reduction lowers disease severity.^28-30 Patients should be counseled on the importance of smoking cessation and weight loss.

Finally, the emotional impact of HS is not to be discounted, both the physical and social discomfort as well as the chronicity of the disease and frustration with treatment.⁵¹ Chronic pain has been associated with increased rates of depression, and 43% of patients with HS specifically have been diagnosed with major depressive disorder.⁷ For these reasons, clinician guidance, social support, and websites can improve patient understanding of the disease, adherence to treatment, and comorbid anxiety and depression.⁵²

Topical Therapy

Topical therapy generally is limited to mild disease and is geared at decreasing inflammation or superimposed infection.^36,52 Some of the earliest therapies used were topical antibiotics.⁴³ Topical clindamycin has been shown to be as effective as oral tetracyclines in reducing the number of abscesses, but neither treatment substantially reduces pain associated with smaller nodules.⁵⁴ Intralesional corticosteroids such as triamcinolone acetonide have been shown to decrease both patient-reported pain and physician-assessed severity within 1 to 7 days.⁴² Routine injection, however, is not a feasible means of long-term treatment both because of inconvenience and the potential adverse effects of corticosteroids.^36,52 Both topical clindamycin and intralesional steroids are helpful in reducing inflammation prior to planned surgical intervention.^36,52,53

Newer topical therapies include resorcinol peels and combination antimicrobials, such as 2% triclosan and oral zinc gluconate.^52,53 Data surrounding the use of resorcinol in mild to moderate HS are promising and have shown decreased severity of both new and long-standing nodules. Fifteen-percent resorcinol peels are helpful tools that allow for self-administration by patients during exacerbations to decrease pain and flare duration.^55,56 In a 2016 clinical trial, a combination of oral zinc gluconate with topical triclosan was shown to reduce flare-ups and nodules in mild HS.⁵⁷ Oral zinc alone may have anti-inflammatory properties and generally is well tolerated.^43,53 Topical therapies have a role in reducing HS-associated pain but often are limited to milder disease.

Systemic Agents

Several therapeutic options exist for the treatment of HS; however, a detailed description of their mechanisms and efficacies is beyond the scope of this review, which is focused on pain. Briefly, these systemic agents include antibiotics, retinoids, corticosteroids, antiandrogens, and biologics.^43,52,53

Treatment with antibiotics such as tetracyclines or a combination of clindamycin plus rifampin has been shown to produce complete remission in 60% to 80% of users; however, this treatment requires more than 6 months of antibiotic therapy, which can be difficult to tolerate.^52,53,58 Relapse is common after antibiotic cessation.^2,43,52 Antibiotics have demonstrated efficacy during acute flares and in reducing inflammatory activity prior to surgery.⁵²

Retinoids have been utilized in the treatment of HS because of their action on sebaceous glands and hair follicles.^43,53 Acitretin has been shown to be the most effective oral retinoid available in the United States.⁴³ Unfortunately, many of the studies investigating the use of retinoids for treatment of HS are limited by small sample size.^36,43,52

Because HS is predominantly an inflammatory condition, immunosuppressants have been adapted to manage patients when antibiotics and topicals have failed. Systemic steroids rarely are used for long-term therapy because of the severe side effects and are preferred only for acute management.^36,52 Cyclosporine and dapsone have demonstrated efficacy in treating moderate to severe HS, whereas methotrexate and colchicine have shown little efficacy.⁵² Both cyclosporine and dapsone are difficult to tolerate, require laboratory monitoring, and lead to only conservative improvement rather than remission in most patients.⁴³

Immune dysregulation in HS involves elevated levels of proinflammatory cytokines such as tumor necrosis factor α (TNF-α), which is a key mediator of inflammation and a stimulator of other inflammatory cytokines.^59,60 The first approved biologic treatment of HS was adalimumab, a TNF-α inhibitor, which showed a 50% reduction in total abscess and inflammatory nodule count in 60% of patients with moderate to severe HS.^61-63 Of course, TNF-α inhibitor therapy is not without risks, specifically those of infection.^43,53,61,62 Maintenance therapy may be required if patients relapse.^53,61

Various interleukin inhibitors also have emerged as potential therapies for HS, such as ustekinumab and anakinra.^36,64 Both have been subject to numerous small case trials that have reported improvements in clinical severity and pain; however, both drugs were associated with a fair number of nonresponders.^36,64,65

Surgical Procedures

Although HS lesions may regress on their own in a matter of weeks, surgical drainage allows an acute alleviation of the severe burning pain associated with HS flares.^36,52,53 Because of improved understanding of the disease pathophysiology, recent therapies targeting the hair follicle have been developed and have shown promising results. These therapies include laser- and light-based procedures. Long-pulsed Nd:YAG laser therapy reduces the number of hair follicles and sebaceous glands and has been effective for Hurley stage I or II disease.^{36,43,52,53,66} Photodynamic therapy offers a less-invasive option compared to surgery and laser therapy.^52,53,66 Both Nd:YAG and CO₂ laser therapy offer low recurrence rates (<30%) due to destruction of the apocrine unit.^43,53 Photodynamic therapy for mild disease offers a less-invasive option compared to surgery and laser therapy.⁵³ There is a need for larger randomized controlled trials involving laser, light, and CO₂ therapies.⁶⁶

Conclusion

Hidradenitis suppurativa is a debilitating condition with an underestimated disease burden. Although the pathophysiology of the disease is not completely understood, it is evident that pain is a major cause of morbidity. Patients experience a multitude of acute and chronic pain types: inflammatory, noninflammatory, nociceptive, neuropathic, and ischemic. Pain perception and quality of life are further impacted by psychiatric conditions such as depression and anxiety, both of which are common comorbidities in patients with HS. Several pharmacologic agents have been used to treat HS-associated pain with mixed results. First-line treatment of acute pain episodes includes oral acetaminophen, NSAIDs, and topical analgesics. Management of chronic pain includes utilization of topical agents, systemic agents, and biologics, as well as addressing lifestyle (eg, obesity, smoking status) and psychiatric comorbidities. Although these therapies have roles in HS pain management, the most effective pain remedies developed thus far are limited to surgery and TNF-α inhibitors. Optimization of pain control in patients with HS requires multidisciplinary collaboration among dermatologists, pain specialists, psychiatrists, and other members of the health care team. Further large-scale studies are needed to create an evidence-based treatment algorithm for the management of pain in HS.

Hidradenitis suppurativa (HS) is a chronic inflammatory, androgen gland disorder characterized by recurrent rupture of the hair follicles with a vigorous inflammatory response. This response results in abscess formation and development of draining sinus tracts and hypertrophic fibrous scars.^1,2 Pain, discomfort, and odorous discharge from the recalcitrant lesions have a profound impact on patient quality of life.^3,4

The morbidity and disease burden associated with HS are particularly underestimated, as patients frequently report debilitating pain that often is overlooked.^5,6 Additionally, the quality and intensity of perceived pain are compounded by frequently associated depression and anxiety.^7-9 Pain has been reported by patients with HS to be the highest cause of morbidity, despite the disfiguring nature of the disease and its associated psychosocial distress.^7,10 Nonetheless, HS lacks an accepted pain management algorithm similar to those that have been developed for the treatment of other acute or chronic pain disorders, such as back pain and sickle cell disease.^4,11-13

Given the lack of formal studies regarding pain management in patients with HS, clinicians are limited to general pain guidelines, expert opinion, small trials, and patient preference.³ Furthermore, effective pain management in HS necessitates the treatment of both chronic pain affecting daily function and acute pain present during disease flares, surgical interventions, and dressing changes.³ The result is a wide array of strategies used for HS-associated pain.^3,4

Epidemiology and Pathophysiology

Hidradenitis suppurativa historically has been an overlooked and underdiagnosed disease, which limits epidemiology data.⁵ Current estimates are that HS affects approximately 1% of the general population; however, prevalence rates range from 0.03% to 4.1%.^14-16

The exact etiology of HS remains unclear, but it is thought that genetic factors, immune dysregulation, and environmental/behavioral influences all contribute to its pathophysiology.^1,17 Up to 40% of patients with HS report a positive family history of the disease.^18-20 Hidradenitis suppurativa has been associated with other inflammatory disease states, such as inflammatory bowel disease, spondyloarthropathies, and pyoderma gangrenosum.^16,21,22

It is thought that HS is the result of some defect in keratin clearance that leads to follicular hyperkeratinization and occlusion.¹ Resultant rupture of pilosebaceous units and spillage of contents (including keratin and bacteria) into the surrounding dermis triggers a vigorous inflammatory response. Sinus tracts and fistulas become the targets of bacterial colonization, biofilm formation, and secondary infection. The result is suppuration and extension of the lesions as well as sustained chronic inflammation.^23,24

Although the etiology of HS is complex, several modifiable risk factors for the disease have been identified, most prominently cigarette smoking and obesity. Approximately 70% of patients with HS smoke cigarettes.^2,15,25,26 Obesity has a well-known association with HS, and it is possible that weight reduction lowers disease severity.^27-30

Clinical Presentation and Diagnosis

Establishing a diagnosis of HS necessitates recognition of disease morphology, topography, and chronicity. Hidradenitis suppurativa most commonly occurs in the axillae, inguinal and anogenital region, perineal region, and inframammary region.^5,31 A typical history involves a prolonged disease course with recurrent lesions and intermittent periods of improvement or remission. Primary lesions are deep, inflamed, painful, and sterile. Ultimately, these lesions rupture and track subcutaneously.^15,25 Intercommunicating sinus tracts form from multiple recurrent nodules in close proximity and may ultimately lead to fibrotic scarring and local architectural distortion.³² The Hurley staging system helps to guide treatment interventions based on disease severity. Approach to pain management is discussed below.

Pain Management in HS: General Principles

Pain management is complex for clinicians, as there are limited studies from which to draw treatment recommendations. Incomplete understanding of the etiology and pathophysiology of the disease contributes to the lack of established management guidelines.

A PubMed search of articles indexed for MEDLINE using the terms hidradenitis, suppurativa, pain, and management revealed 61 different results dating back to 1980, 52 of which had been published in the last 5 years. When the word acute was added to the search, there were only 6 results identified. These results clearly reflect a better understanding of HS-mediated pain as well as clinical unmet needs and evolving strategies in pain management therapeutics. However, many of these studies reflect therapies focused on the mediation or modulation of HS pathogenesis rather than potential pain management therapies.

In addition, the heterogenous nature of the pain experience in HS poses a challenge for clinicians. Patients may experience multiple pain types concurrently, including inflammatory, noninflammatory, nociceptive, neuropathic, and ischemic, as well as pain related to arthritis.^3,33,34 Pain perception is further complicated by the observation that patients with HS have high rates of psychiatric comorbidities such as depression and anxiety, both of which profoundly alter perception of both the strength and quality of pain.^7,8,22,35 A suggested algorithm for treatment of pain in HS is described in the eTable.³⁶

Chronicity is a hallmark of HS. Patients experience a prolonged disease course involving acute painful exacerbations superimposed on chronic pain that affects all aspects of daily life. Changes in self-perception, daily living activities, mood state, physical functioning, and physical comfort frequently are reported to have a major impact on quality of life.^1,3,37

In 2018, Thorlacius et al³⁸ created a multistakeholder consensus on a core outcome set of domains detailing what to measure in clinical trials for HS. The authors hoped that the routine adoption of these core domains would promote the collection of consistent and relevant information, bolster the strength of evidence synthesis, and minimize the risk for outcome reporting bias among studies.³⁸ It is important to ascertain the patient’s description of his/her pain to distinguish between stimulus-dependent nociceptive pain vs spontaneous neuropathic pain.^3,7,10 The most common pain descriptors used by patients are “shooting,” “itchy,” “blinding,” “cutting,” and “exhausting.”¹⁰ In addition to obtaining descriptive factors, it is important for the clinician to obtain information on the timing of the pain, whether or not the pain is relieved with spontaneous or surgical drainage, and if the patient is experiencing chronic background pain secondary to scarring or skin contraction.³ With the routine utilization of a consistent set of core domains, advances in our understanding of the different elements of HS pain, and increased provider awareness of the disease, the future of pain management in patients with HS seems promising.

Acute and Perioperative Pain Management

Acute Pain Management—The pain in HS can range from mild to excruciating.^3,7 The difference between acute and chronic pain in this condition may be hard to delineate, as patients may have intense acute flares on top of a baseline level of chronic pain.^3,7,14 These factors, in combination with various pain types of differing etiologies, make the treatment of HS-associated pain a therapeutic challenge.

The first-line treatments for acute pain in HS are oral acetaminophen, oral nonsteroidal anti-inflammatory drugs (NSAIDs), and topical analgesics.³ These treatment modalities are especially helpful for nociceptive pain, which often is described as having an aching or tender quality.³ Topical treatment for acute pain episodes includes diclofenac gel and liposomal lidocaine cream.³⁹ Topical lidocaine in particular has the benefit of being rapid acting, and its effect can last 1 to 2 hours. Ketamine has been anecdotally used as a topical treatment. Treatment options for neuropathic pain include topical amitriptyline, gabapentin, and pregabalin.³⁹ Dressings and ice packs may be used in cases of mild acute pain, depending on patient preference.³

First-line therapies may not provide adequate pain control in many patients.^3,40,41 Should the first-line treatments fail, oral opiates can be considered as a treatment option, especially if the patient has a history of recurrent pain unresponsive to milder methods of pain control.^3,40,41 However, prudence should be exercised, as patients with HS have a higher risk for opioid abuse, and referral to a pain specialist is advisable.⁴⁰ Generally, use of opioids should be limited to the smallest period of time possible.^40,41 Codeine can be used as a first opioid option, with hydromorphone available as an alternative.⁴¹

Pain caused by inflamed abscesses and nodules can be treated with either intralesional corticosteroids or incision and drainage. Intralesional triamcinolone has been found to cause substantial pain relief within 1 day of injection in patients with HS.^3,42

Prompt discussion about the remitting course of HS will prepare patients for flares. Although the therapies discussed here aim to reduce the clinical severity and inflammation associated with HS, achieving pain-free remission can be challenging. Barriers to developing a long-term treatment regimen include intolerable side effects or simply nonresponsive disease.^36,43

Management of Perioperative Pain—Medical treatment of HS often yields only transient or mild results. Hurley stage II or III lesions typically require surgical removal of affected tissues.^32,44-46 Surgery may dramatically reduce the primary disease burden and provide substantial pain relief.^3,4,44 Complete resection of the affected tissue by wide excision is the most common surgical procedure used.^46-48 However, various tissue-sparing techniques, such as skin-tissue-sparing excision with electrosurgical peeling, also have been utilized. Tissue-sparing surgical techniques may lead to shorter healing times and less postoperative pain.⁴⁸

There currently is little guidance available on the perioperative management of pain as it relates to surgical procedures for HS. The pain experienced from surgery varies based on the area and location of affected tissue; extent of disease; surgical technique used; and whether primary closure, closure by secondary intention, or skin grafting is utilized.^47,49 Medical treatment aimed at reducing inflammation prior to surgical intervention may improve postoperative pain and complications.

The use of general vs local anesthesia during surgery depends on the extent of the disease and the amount of tissue being removed; however, the use of local anesthesia has been associated with a higher recurrence of disease, possibly owing to less aggressive tissue removal.⁵⁰ Intraoperatively, the injection of 0.5% bupivacaine around the wound edges may lead to less postoperative pain.^3,48 Postoperative pain usually is managed with acetaminophen and NSAIDs.⁴⁸ In cases of severe postoperative pain, short- and long-acting opioid oxycodone preparations may be used. The combination of diclofenac and tramadol also has been used postoperatively.³ Patients who do not undergo extensive surgery often can leave the hospital the same day.

Effective strategies for mitigating HS-associated pain must address the chronic pain component of the disease. Long-term management involves lifestyle modifications and pharmacologic agents.

Chronic Pain Management

Although HS is not a curable disease, there are treatments available to minimize symptoms. Long-term management of HS is essential to minimize the effects of chronic pain and physical scarring associated with inflammation.³¹ In one study from the French Society of Dermatology, pain reported by patients with HS was directly associated with severity and duration of disease, emotional symptoms, and reduced functionality.⁵¹ For these reasons, many treatments for HS target reducing clinical severity and achieving remission, often defined as more than 6 months without any recurrence of lesions.⁵² In addition to lifestyle management, therapies available to manage HS include topical and systemic medications as well as procedures such as surgical excision.^36,43,52,53

Lifestyle Modifications

Regardless of the severity of HS, all patients may benefit from basic education on the pathogenesis of the disease.³⁶ The associations with smoking and obesity have been well documented, and treatment of these comorbid conditions is indicated.^36,43,52 For example, in relation to obesity, the use of metformin is very well tolerated and seems to positively impact HS symptoms.⁴³ Several studies have suggested that weight reduction lowers disease severity.^28-30 Patients should be counseled on the importance of smoking cessation and weight loss.

Finally, the emotional impact of HS is not to be discounted, both the physical and social discomfort as well as the chronicity of the disease and frustration with treatment.⁵¹ Chronic pain has been associated with increased rates of depression, and 43% of patients with HS specifically have been diagnosed with major depressive disorder.⁷ For these reasons, clinician guidance, social support, and websites can improve patient understanding of the disease, adherence to treatment, and comorbid anxiety and depression.⁵²

Topical Therapy

Topical therapy generally is limited to mild disease and is geared at decreasing inflammation or superimposed infection.^36,52 Some of the earliest therapies used were topical antibiotics.⁴³ Topical clindamycin has been shown to be as effective as oral tetracyclines in reducing the number of abscesses, but neither treatment substantially reduces pain associated with smaller nodules.⁵⁴ Intralesional corticosteroids such as triamcinolone acetonide have been shown to decrease both patient-reported pain and physician-assessed severity within 1 to 7 days.⁴² Routine injection, however, is not a feasible means of long-term treatment both because of inconvenience and the potential adverse effects of corticosteroids.^36,52 Both topical clindamycin and intralesional steroids are helpful in reducing inflammation prior to planned surgical intervention.^36,52,53

Newer topical therapies include resorcinol peels and combination antimicrobials, such as 2% triclosan and oral zinc gluconate.^52,53 Data surrounding the use of resorcinol in mild to moderate HS are promising and have shown decreased severity of both new and long-standing nodules. Fifteen-percent resorcinol peels are helpful tools that allow for self-administration by patients during exacerbations to decrease pain and flare duration.^55,56 In a 2016 clinical trial, a combination of oral zinc gluconate with topical triclosan was shown to reduce flare-ups and nodules in mild HS.⁵⁷ Oral zinc alone may have anti-inflammatory properties and generally is well tolerated.^43,53 Topical therapies have a role in reducing HS-associated pain but often are limited to milder disease.

Systemic Agents

Several therapeutic options exist for the treatment of HS; however, a detailed description of their mechanisms and efficacies is beyond the scope of this review, which is focused on pain. Briefly, these systemic agents include antibiotics, retinoids, corticosteroids, antiandrogens, and biologics.^43,52,53

Treatment with antibiotics such as tetracyclines or a combination of clindamycin plus rifampin has been shown to produce complete remission in 60% to 80% of users; however, this treatment requires more than 6 months of antibiotic therapy, which can be difficult to tolerate.^52,53,58 Relapse is common after antibiotic cessation.^2,43,52 Antibiotics have demonstrated efficacy during acute flares and in reducing inflammatory activity prior to surgery.⁵²

Retinoids have been utilized in the treatment of HS because of their action on sebaceous glands and hair follicles.^43,53 Acitretin has been shown to be the most effective oral retinoid available in the United States.⁴³ Unfortunately, many of the studies investigating the use of retinoids for treatment of HS are limited by small sample size.^36,43,52

Because HS is predominantly an inflammatory condition, immunosuppressants have been adapted to manage patients when antibiotics and topicals have failed. Systemic steroids rarely are used for long-term therapy because of the severe side effects and are preferred only for acute management.^36,52 Cyclosporine and dapsone have demonstrated efficacy in treating moderate to severe HS, whereas methotrexate and colchicine have shown little efficacy.⁵² Both cyclosporine and dapsone are difficult to tolerate, require laboratory monitoring, and lead to only conservative improvement rather than remission in most patients.⁴³

Immune dysregulation in HS involves elevated levels of proinflammatory cytokines such as tumor necrosis factor α (TNF-α), which is a key mediator of inflammation and a stimulator of other inflammatory cytokines.^59,60 The first approved biologic treatment of HS was adalimumab, a TNF-α inhibitor, which showed a 50% reduction in total abscess and inflammatory nodule count in 60% of patients with moderate to severe HS.^61-63 Of course, TNF-α inhibitor therapy is not without risks, specifically those of infection.^43,53,61,62 Maintenance therapy may be required if patients relapse.^53,61

Various interleukin inhibitors also have emerged as potential therapies for HS, such as ustekinumab and anakinra.^36,64 Both have been subject to numerous small case trials that have reported improvements in clinical severity and pain; however, both drugs were associated with a fair number of nonresponders.^36,64,65

Surgical Procedures

Although HS lesions may regress on their own in a matter of weeks, surgical drainage allows an acute alleviation of the severe burning pain associated with HS flares.^36,52,53 Because of improved understanding of the disease pathophysiology, recent therapies targeting the hair follicle have been developed and have shown promising results. These therapies include laser- and light-based procedures. Long-pulsed Nd:YAG laser therapy reduces the number of hair follicles and sebaceous glands and has been effective for Hurley stage I or II disease.^{36,43,52,53,66} Photodynamic therapy offers a less-invasive option compared to surgery and laser therapy.^52,53,66 Both Nd:YAG and CO₂ laser therapy offer low recurrence rates (<30%) due to destruction of the apocrine unit.^43,53 Photodynamic therapy for mild disease offers a less-invasive option compared to surgery and laser therapy.⁵³ There is a need for larger randomized controlled trials involving laser, light, and CO₂ therapies.⁶⁶

Conclusion

Hidradenitis suppurativa is a debilitating condition with an underestimated disease burden. Although the pathophysiology of the disease is not completely understood, it is evident that pain is a major cause of morbidity. Patients experience a multitude of acute and chronic pain types: inflammatory, noninflammatory, nociceptive, neuropathic, and ischemic. Pain perception and quality of life are further impacted by psychiatric conditions such as depression and anxiety, both of which are common comorbidities in patients with HS. Several pharmacologic agents have been used to treat HS-associated pain with mixed results. First-line treatment of acute pain episodes includes oral acetaminophen, NSAIDs, and topical analgesics. Management of chronic pain includes utilization of topical agents, systemic agents, and biologics, as well as addressing lifestyle (eg, obesity, smoking status) and psychiatric comorbidities. Although these therapies have roles in HS pain management, the most effective pain remedies developed thus far are limited to surgery and TNF-α inhibitors. Optimization of pain control in patients with HS requires multidisciplinary collaboration among dermatologists, pain specialists, psychiatrists, and other members of the health care team. Further large-scale studies are needed to create an evidence-based treatment algorithm for the management of pain in HS.

Artificial Intelligence (AI) was first described in 1956 and refers to machines having the ability to learn as they receive and process information, resulting in the ability to “think” like humans.¹ AI’s impact in medicine is increasing; currently, at least 29 AI medical devices and algorithms are approved by the US Food and Drug Administration (FDA) in a variety of areas, including radiograph interpretation, managing glucose levels in patients with diabetes mellitus, analyzing electrocardiograms (ECGs), and diagnosing sleep disorders among others.² Significantly, in 2020, the Centers for Medicare and Medicaid Services (CMS) announced the first reimbursement to hospitals for an AI platform, a model for early detection of strokes.³ AI is rapidly becoming an integral part of health care, and its role will only increase in the future (Table).

As knowledge in medicine is expanding exponentially, AI has great potential to assist with handling complex patient care data. The concept of exponential growth is not a natural one. As Bini described, with exponential growth the volume of knowledge amassed over the past 10 years will now occur in perhaps only 1 year.¹ Likewise, equivalent advances over the past year may take just a few months. This phenomenon is partly due to the law of accelerating returns, which states that advances feed on themselves, continually increasing the rate of further advances.⁴ The volume of medical data doubles every 2 to 5 years.⁵ Fortunately, the field of AI is growing exponentially as well and can help health care practitioners (HCPs) keep pace, allowing the continued delivery of effective health care.

In this report, we review common terminology, principles, and general applications of AI, followed by current and potential applications of AI for selected medical specialties. Finally, we discuss AI’s future in health care, along with potential risks and pitfalls.

AI Overview

AI refers to machine programs that can “learn” or think based on past experiences. This functionality contrasts with simple rules-based programming available to health care for years. An example of rules-based programming is the warfarindosing.org website developed by Barnes-Jewish Hospital at Washington University Medical Center, which guides initial warfarin dosing.^6,7 The prescriber inputs detailed patient information, including age, sex, height, weight, tobacco history, medications, laboratory results, and genotype if available. The application then calculates recommended warfarin dosing regimens to avoid over- or underanticoagulation. While the dosing algorithm may be complex, it depends entirely on preprogrammed rules. The program does not learn to reach its conclusions and recommendations from patient data.

In contrast, one of the most common subsets of AI is machine learning (ML). ML describes a program that “learns from experience and improves its performance as it learns.”¹ With ML, the computer is initially provided with a training data set—data with known outcomes or labels. Because the initial data are input from known samples, this type of AI is known as supervised learning.^8-10 As an example, we recently reported using ML to diagnose various types of cancer from pathology slides.¹¹ In one experiment, we captured images of colon adenocarcinoma and normal colon (these 2 groups represent the training data set). Unlike traditional programming, we did not define characteristics that would differentiate colon cancer from normal; rather, the machine learned these characteristics independently by assessing the labeled images provided. A second data set (the validation data set) was used to evaluate the program and fine-tune the ML training model’s parameters. Finally, the program was presented with new images of cancer and normal cases for final assessment of accuracy (test data set). Our program learned to recognize differences from the images provided and was able to differentiate normal and cancer images with > 95% accuracy.

Advances in computer processing have allowed for the development of artificial neural networks (ANNs). While there are several types of ANNs, the most common types used for image classification and segmentation are known as convolutional neural networks (CNNs).^9,12-14 The programs are designed to work similar to the human brain, specifically the visual cortex.^15,16 As data are acquired, they are processed by various layers in the program. Much like neurons in the brain, one layer decides whether to advance information to the next.^13,14 CNNs can be many layers deep, leading to the term deep learning: “computational models that are composed of multiple processing layers to learn representations of data with multiple levels of abstraction.”^1,13,17

ANNs can process larger volumes of data. This advance has led to the development of unstructured or unsupervised learning. With this type of learning, imputing defined features (ie, predetermined answers) of the training data set described above is no longer required.^1,8,10,14 The advantage of unsupervised learning is that the program can be presented raw data and extract meaningful interpretation without human input, often with less bias than may exist with supervised learning.^1,18 If shown enough data, the program can extract relevant features to make conclusions independently without predefined definitions, potentially uncovering markers not previously known. For example, several studies have used unsupervised learning to search patient data to assess readmission risks of patients with congestive heart failure.^10,19,20 AI compiled features independently and not previously defined, predicting patients at greater risk for readmission superior to traditional methods.

Health Care Applications

Image analysis has seen the most AI health care applications.^8,15 AI has shown potential in interpreting many types of medical images, including pathology slides, radiographs of various types, retina and other eye scans, and photographs of skin lesions. Many studies have demonstrated that AI can interpret these images as accurately as or even better than experienced clinicians.^9,13,22-29 Studies have suggested AI interpretation of radiographs may better distinguish patients infected with COVID-19 from other causes of pneumonia, and AI interpretation of pathology slides may detect specific genetic mutations not previously identified without additional molecular tests.^{11,14,23,24,30-32}

The second area in which AI can impact health care is improving workflow and efficiency. AI has improved surgery scheduling, saving significant revenue, and decreased patient wait times for appointments.¹ AI can screen and triage radiographs, allowing attention to be directed to critical patients. This use would be valuable in many busy clinical settings, such as the recent COVID-19 pandemic.^8,23 Similarly, AI can screen retina images to prioritize urgent conditions.²⁵ AI has improved pathologists’ efficiency when used to detect breast metastases.³³ Finally, AI may reduce medical errors, thereby ensuring patient safety.^8,9,34

A third health care benefit of AI is in public health and epidemiology. AI can assist with clinical decision-making and diagnoses in low-income countries and areas with limited health care resources and personnel.^25,29 AI can improve identification of infectious outbreaks, such as tuberculosis, malaria, dengue fever, and influenza.^29,35-40 AI has been used to predict transmission patterns of the Zika virus and the current COVID-19 pandemic.^41,42 Applications can stratify the risk of outbreaks based on multiple factors, including age, income, race, atypical geographic clusters, and seasonal factors like rainfall and temperature.^35,36,38,43 AI has been used to assess morbidity and mortality, such as predicting disease severity with malaria and identifying treatment failures in tuberculosis.²⁹

Finally, AI can dramatically impact health care due to processing large data sets or disconnected volumes of patient information—so-called big data.^44-46 An example is the widespread use of electronic health records (EHRs) such as the Computerized Patient Record System used in Veteran Affairs medical centers (VAMCs). Much of patient information exists in written text: HCP notes, laboratory and radiology reports, medication records, etc. Natural language processing (NLP) allows platforms to sort through extensive volumes of data on complex patients at rates much faster than human capability, which has great potential to assist with diagnosis and treatment decisions.⁹

Medical literature is being produced at rates that exceed our ability to digest. More than 200,000 cancer-related articles were published in 2019 alone.¹⁴ NLP capabilities of AI have the potential to rapidly sort through this extensive medical literature and relate specific verbiage in patient records guiding therapy.⁴⁶ IBM Watson, a supercomputer based on ML and NLP, demonstrates this concept with many potential applications, only some of which relate to health care.^1,9 Watson has an oncology component to assimilate multiple aspects of patient care, including clinical notes, pathology results, radiograph findings, staging, and a tumor’s genetic profile. It coordinates these inputs from the EHR and mines medical literature and research databases to recommend treatment options.^1,46 AI can assess and compile far greater patient data and therapeutic options than would be feasible by individual clinicians, thus providing customized patient care.⁴⁷ Watson has partnered with numerous medical centers, including MD Anderson Cancer Center and Memorial Sloan Kettering Cancer Center, with variable success.^44,47-49 While the full potential of Watson appears not yet realized, these AI-driven approaches will likely play an important role in leveraging the hidden value in the expanding volume of health care information.

Medical Specialty Applications

Radiology

Currently > 70% of FDA-approved AI medical devices are in the field of radiology.² Most radiology departments have used AI-friendly digital imaging for years, such as the picture archiving and communication systems used by numerous health care systems, including VAMCs.^2,15 Gray-scale images common in radiology lend themselves to standardization, although AI is not limited to black-and- white image interpretation.¹⁵

An abundance of literature describes plain radiograph interpretation using AI. One FDA-approved platform improved X-ray diagnosis of wrist fractures when used by emergency medicine clinicians.^2,50 AI has been applied to chest X-ray (CXR) interpretation of many conditions, including pneumonia, tuberculosis, malignant lung lesions, and COVID-19.^{23,25,28,44,51-53} For example, Nam and colleagues suggested AI is better at diagnosing malignant pulmonary nodules from CXRs than are trained radiologists.²⁸

In addition to plain radiographs, AI has been applied to many other imaging technologies, including ultrasounds, positron emission tomography, mammograms, computed tomography (CT), and magnetic resonance imaging (MRI).^{15,26,44,48,54-56} A large study demonstrated that ML platforms significantly reduced the time to diagnose intracranial hemorrhages on CT and identified subtle hemorrhages missed by radiologists.⁵⁵ Other studies have claimed that AI programs may be better than radiologists in detecting cancer in screening mammograms, and 3 FDA-approved devices focus on mammogram interpretation.^2,15,54,57 There is also great interest in MRI applications to detect and predict prognosis for breast cancer based on imaging findings.^21,56

Aside from providing accurate diagnoses, other studies focus on AI radiograph interpretation to assist with patient screening, triage, improving time to final diagnosis, providing a rapid “second opinion,” and even monitoring disease progression and offering insights into prognosis.^{8,21,23,52,55,56,58} These features help in busy urban centers but may play an even greater role in areas with limited access to health care or trained specialists such as radiologists.⁵²

Cardiology

Cardiology has the second highest number of FDA-approved AI applications.² Many cardiology AI platforms involve image analysis, as described in several recent reviews.^45,59,60 AI has been applied to echocardiography to measure ejection fractions, detect valvular disease, and assess heart failure from hypertrophic and restrictive cardiomyopathy and amyloidosis.^45,48,59 Applications for cardiac CT scans and CT angiography have successfully quantified both calcified and noncalcified coronary artery plaques and lumen assessments, assessed myocardial perfusion, and performed coronary artery calcium scoring.^45,59,60 Likewise, AI applications for cardiac MRI have been used to quantitate ejection fraction, large vessel flow assessment, and cardiac scar burden.^45,59

For years ECG devices have provided interpretation with limited accuracy using preprogrammed parameters.⁴⁸ However, the application of AI allows ECG interpretation on par with trained cardiologists. Numerous such AI applications exist, and 2 FDA-approved devices perform ECG interpretation.^2,61-64 One of these devices incorporates an AI-powered stethoscope to detect atrial fibrillation and heart murmurs.⁶⁵

Pathology

The advancement of whole slide imaging, wherein entire slides can be scanned and digitized at high speed and resolution, creates great potential for AI applications in pathology.^{12,24,32,33,66} A landmark study demonstrating the potential of AI for assessing whole slide imaging examined sentinel lymph node metastases in patients with breast cancer.²² Multiple algorithms in the study demonstrated that AI was equivalent or better than pathologists in detecting metastases, especially when the pathologists were time-constrained consistent with a normal working environment. Significantly, the most accurate and efficient diagnoses were achieved when the pathologist and AI interpretations were used together.^22,33

AI has shown promise in diagnosing many other entities, including cancers of the prostate (including Gleason scoring), lung, colon, breast, and skin.^{11,12,24,27,32,67} In addition, AI has shown great potential in scoring biomarkers important for prognosis and treatment, such as immunohistochemistry (IHC) labeling of Ki-67 and PD-L1.³² Pathologists can have difficulty classifying certain tumors or determining the site of origin for metastases, often having to rely on IHC with limited success. The unique features of image analysis with AI have the potential to assist in classifying difficult tumors and identifying sites of origin for metastatic disease based on morphology alone.¹¹

Oncology depends heavily on molecular pathology testing to dictate treatment options and determine prognosis. Preliminary studies suggest that AI interpretation alone has the potential to delineate whether certain molecular mutations are present in tumors from various sites.^11,14,24,32 One study combined histology and genomic results for AI interpretation that improved prognostic predictions.⁶⁸ In addition, AI analysis may have potential in predicting tumor recurrence or prognosis based on cellular features, as demonstrated for lung cancer and melanoma.^67,69,70

Ophthalmology

AI applications for ophthalmology have focused on diabetic retinopathy, age-related macular degeneration, glaucoma, retinopathy of prematurity, age-related and congenital cataracts, and retinal vein occlusion.^71-73 Diabetic retinopathy is a leading cause of blindness and has been studied by numerous platforms with good success, most having used color fundus photography.^71,72 One study showed AI could diagnose diabetic retinopathy and diabetic macular edema with specificities similar to ophthalmologists.⁷⁴ In 2018, the FDA approved the AI platform IDx-DR. This diagnostic system classifies retinal images and recommends referral for patients determined to have “more than mild diabetic retinopathy” and reexamination within a year for other patients.^8,75 Significantly, the platform recommendations do not require confirmation by a clinician.⁸

AI has been applied to other modalities in ophthalmology such as optical coherence tomography (OCT) to diagnose retinal disease and to predict appropriate management of congenital cataracts.^25,73,76 For example, an AI application using OCT has been demonstrated to match or exceed the accuracy of retinal experts in diagnosing and triaging patients with a variety of retinal pathologies, including patients needing urgent referrals.⁷⁷

Dermatology

Multiple studies demonstrate AI performs at least equal to experienced dermatologists in differentiating selected skin lesions.^78-81 For example, Esteva and colleagues demonstrated AI could differentiate keratinocyte carcinomas from benign seborrheic keratoses and malignant melanomas from benign nevi with accuracy equal to 21 board-certified dermatologists.⁷⁸

AI is applicable to various imaging procedures common to dermatology, such as dermoscopy, very high-frequency ultrasound, and reflectance confocal microscopy.⁸² Several studies have demonstrated that AI interpretation compared favorably to dermatologists evaluating dermoscopy to assess melanocytic lesions.^78-81,83

A limitation in these studies is that they differentiate only a few diagnoses.⁸² Furthermore, dermatologists have sensory input such as touch and visual examination under various conditions, something AI has yet to replicate.^15,34,84 Also, most AI devices use no or limited clinical information.⁸¹ Dermatologists can recognize rarer conditions for which AI models may have had limited or no training.³⁴ Nevertheless, a recent study assessed AI for the diagnosis of 134 separate skin disorders with promising results, including providing diagnoses with accuracy comparable to that of dermatologists and providing accurate treatment strategies.⁸⁴ As Topol points out, most skin lesions are diagnosed in the primary care setting where AI can have a greater impact when used in conjunction with the clinical impression, especially where specialists are in limited supply.^48,78

Finally, dermatology lends itself to using portable or smartphone applications (apps) wherein the user can photograph a lesion for analysis by AI algorithms to assess the need for further evaluation or make treatment recommendations.^34,84,85 Although results from currently available apps are not encouraging, they may play a greater role as the technology advances.^34,85

Oncology

Applications of AI in oncology include predicting prognosis for patients with cancer based on histologic and/or genetic information.^14,68,86 Programs can predict the risk of complications before and recurrence risks after surgery for malignancies.^44,87-89 AI can also assist in treatment planning and predict treatment failure with radiation therapy.^90,91

AI has great potential in processing the large volumes of patient data in cancer genomics. Next-generation sequencing has allowed for the identification of millions of DNA sequences in a single tumor to detect genetic anomalies.⁹² Thousands of mutations can be found in individual tumor samples, and processing this information and determining its significance can be beyond human capability.¹⁴ We know little about the effects of various mutation combinations, and most tumors have a heterogeneous molecular profile among different cell populations.^14,93 The presence or absence of various mutations can have diagnostic, prognostic, and therapeutic implications.⁹³ AI has great potential to sort through these complex data and identify actionable findings.

More than 200,000 cancer-related articles were published in 2019, and publications in the field of cancer genomics are increasing exponentially.^14,92,93 Patel and colleagues assessed the utility of IBM Watson for Genomics against results from a molecular tumor board.⁹³ Watson for Genomics identified potentially significant mutations not identified by the tumor board in 32% of patients. Most mutations were related to new clinical trials not yet added to the tumor board watch list, demonstrating the role AI will have in processing the large volume of genetic data required to deliver personalized medicine moving forward.

Gastroenterology

AI has shown promise in predicting risk or outcomes based on clinical parameters in various common gastroenterology problems, including gastric reflux, acute pancreatitis, gastrointestinal bleeding, celiac disease, and inflammatory bowel disease.^94,95 AI endoscopic analysis has demonstrated potential in assessing Barrett’s esophagus, gastric Helicobacter pylori infections, gastric atrophy, and gastric intestinal metaplasia.⁹⁵ Applications have been used to assess esophageal, gastric, and colonic malignancies, including depth of invasion based on endoscopic images.⁹⁵ Finally, studies have evaluated AI to assess small colon polyps during colonoscopy, including differentiating benign and premalignant polyps with success comparable to gastroenterologists.^94,95 AI has been shown to increase the speed and accuracy of gastroenterologists in detecting small polyps during colonoscopy.⁴⁸ In a prospective randomized study, colonoscopies performed using an AI device identified significantly more small adenomatous polyps than colonoscopies without AI.⁹⁶

Neurology

It has been suggested that AI technologies are well suited for application in neurology due to the subtle presentation of many neurologic diseases.¹⁶ Viz LVO, the first CMS-approved AI reimbursement for the diagnosis of strokes, analyzes CTs to detect early ischemic strokes and alerts the medical team, thus shortening time to treatment.^3,97 Many other AI platforms are in use or development that use CT and MRI for the early detection of strokes as well as for treatment and prognosis.^9,97

AI technologies have been applied to neurodegenerative diseases, such as Alzheimer and Parkinson diseases.^16,98 For example, several studies have evaluated patient movements in Parkinson disease for both early diagnosis and to assess response to treatment.⁹⁸ These evaluations included assessment with both external cameras as well as wearable devices and smartphone apps.

Mental Health

Due to the interactive nature of mental health care, the field has been slower to develop AI applications.¹⁸ With heavy reliance on textual information (eg, clinic notes, mood rating scales, and documentation of conversations), successful AI applications in this field will likely rely heavily on NLP.¹⁸ However, studies investigating the application of AI to mental health have also incorporated data such as brain imaging, smartphone monitoring, and social media platforms, such as Facebook and Twitter.^18,103,104

The risk of suicide is higher in veteran patients, and ML algorithms have had limited success in predicting suicide risk in both veteran and nonveteran populations.^104-106 While early models have low positive predictive values and low sensitivities, they still promise to be a useful tool in conjunction with traditional risk assessments.¹⁰⁶ Kessler and colleagues suggest that combining multiple rather than single ML algorithms might lead to greater success.^105,106

AI may assist in diagnosing other mental health disorders, including major depressive disorder, attention deficit hyperactivity disorder (ADHD), schizophrenia, posttraumatic stress disorder, and Alzheimer disease.^103,104,107 These investigations are in the early stages with limited clinical applicability. However, 2 AI applications awaiting FDA approval relate to ADHD and opioid use.² Furthermore, potential exists for AI to not only assist with prevention and diagnosis of ADHD, but also to identify optimal treatment options.^2,103

General and Personalized Medicine

Additional AI applications include diagnosing patients with suspected sepsis, measuring liver iron concentrations, predicting hospital mortality at the time of admission, and more.^2,108,109 AI can guide end-of-life decisions such as resuscitation status or whether to initiate mechanical ventilation.⁴⁸

AI-driven smartphone apps can be beneficial to both patients and clinicians. Examples include predicting nonadherence to anticoagulation therapy, monitoring heart rhythms for atrial fibrillation or signs of hyperkalemia in patients with renal failure, and improving outcomes for patients with diabetes mellitus by decreasing glycemic variability and reducing hypoglycemia.^8,48,110,111 The potential for AI applications to health care and personalized medicine are almost limitless.

Discussion

With ever-increasing expectations for all health care sectors to deliver timely, fiscally-responsible, high-quality health care, AI has the potential to have numerous impacts. AI can improve diagnostic accuracy while limiting errors and impact patient safety such as assisting with prescription delivery.^8,9,34 It can screen and triage patients, alerting clinicians to those needing more urgent evaluation.^8,23,77,97 AI also may increase a clinician’s efficiency and speed to render a diagnosis.^12,13,55,97 AI can provide a rapid second opinion, an ability especially beneficial in underserved areas with shortages of specialists.^{23,25,26,29,34} Similarly, AI may decrease the inter- and intraobserver variability common in many medical specialties.^12,27,45 AI applications can also monitor disease progression, identifying patients at greatest risk, and provide information for prognosis.^21,23,56,58 Finally, as described with applications using IBM Watson, AI can allow for an integrated approach to health care that is currently lacking.

We have described many reports suggesting AI can render diagnoses as well as or better than experienced clinicians, and speculation exists that AI will replace many roles currently performed by health care practitioners.^9,26 However, most studies demonstrate that AI’s diagnostic benefits are best realized when used to supplement a clinician’s impression.^{8,22,30,33,52,54,56,69,84} AI is not likely to replace humans in health care in the foreseeable future. The technology can be likened to the impact of CT scans developed in the 1970s in neurology. Prior to such detailed imaging, neurologists spent extensive time performing detailed physicals to render diagnoses and locate lesions before surgery. There was mistrust of this new technology and concern that CT scans would eliminate the need for neurologists.¹¹² On the contrary, neurology is alive and well, frequently being augmented by the technologies once speculated to replace it.

Commercial AI health care platforms represented a $2 billion industry in 2018 and are growing rapidly each year.^13,32 Many AI products are offered ready for implementation for various tasks, including diagnostics, patient management, and improved efficiency. Others will likely be provided as templates suitable for modification to meet the specific needs of the facility, practice, or specialty for its patient population.

AI Risks and Limitations

AI has several risks and limitations. Although there is progress in explainable AI, at times we still struggle to understand how the output provided by machine learning algorithms was created.^44,48 The many layers associated with deep learning self-determine the criteria to reach its conclusion, and these criteria can continually evolve. The parameters of deep learning are not preprogrammed, and there are too many individual data points to be extrapolated or deconvoluted for evaluation at our current level of knowledge.^26,51 These apparent lack of constraints cause concern for patient safety and suggest that greater validation and continued scrutiny of validity is required.^8,48 Efforts are underway to create explainable AI programs to make their processes more transparent, but such clarification is limited presently.^14,26,48,77

Another challenge of AI is determining the amount of training data required to function optimally. Also, if the output describes multiple variables or diagnoses, are each equally valid?¹¹³ Furthermore, many AI applications look for a specific process, such as cancer diagnoses on CXRs. However, how coexisting conditions like cardiomegaly, emphysema, pneumonia, etc, seen on CXRs will affect the diagnosis needs to be considered.^51,52 Zech and colleagues provide the example that diagnoses for pneumothorax are frequently rendered on CXRs with chest tubes in place.⁵¹ They suggest that CNNs may develop a bias toward diagnosing pneumothorax when chest tubes are present. Many current studies approach an issue in isolation, a situation not realistic in real-world clinical practice.²⁶

Most studies on AI have been retrospective, and frequently data used to train the program are preselected.^13,26 The data are typically validated on available databases rather than actual patients in the clinical setting, limiting confidence in the validity of the AI output when applied to real-world situations. Currently, fewer than 12 prospective trials had been published comparing AI with traditional clinical care.^13,114 Randomized prospective clinical trials are even fewer, with none currently reported from the United States.^13,114 The results from several studies have been shown to diminish when repeated prospectively.¹¹⁴

The FDA has created a new category known as Software as a Medical Device and has a Digital Health Innovation Action Plan to regulate AI platforms. Still, the process of AI regulation is of necessity different from traditional approval processes and is continually evolving.⁸ The FDA approval process cannot account for the fact that the program’s parameters may continually evolve or adapt.²

Guidelines for investigating and reporting AI research with its unique attributes are being developed. Examples include the TRIPOD-ML statement and others.^49,115 In September 2020, 2 publications addressed the paucity of gold-standard randomized clinical trials in clinical AI applications.^116,117 The SPIRIT-AI statement expands on the original SPIRIT statement published in 2013 to guide minimal reporting standards for AI clinical trial protocols to promote transparency of design and methodology.¹¹⁶ Similarly, the CONSORT-AI extension, stemming from the original CONSORT statement in 1996, aims to ensure quality reporting of randomized controlled trials in AI.¹¹⁷

Another risk with AI is that while an individual physician making a mistake may adversely affect 1 patient, a single mistake in an AI algorithm could potentially affect thousands of patients.⁴⁸ Also, AI programs developed for patient populations at a facility may not translate to another. Referred to as overfitting, this phenomenon relates to selection bias in training data sets.^{15,34,49,51,52} Studies have shown that programs that underrepresent certain group characteristics such as age, sex, or race may be less effective when applied to a population in which these characteristics have differing representations.^8,48,49 This problem of underrepresentation has been demonstrated in programs interpreting pathology slides, radiographs, and skin lesions.^15,32,51

Admittedly, most of these challenges are not specific to AI and existed in health care previously. Physicians make mistakes, treatments are sometimes used without adequate prospective studies, and medications are given without understanding their mechanism of action, much like AI-facilitated processes reach a conclusion that cannot be fully explained.⁴⁸

Conclusions

The view that AI will dramatically impact health care in the coming years will likely prove true. However, much work is needed, especially because of the paucity of prospective clinical trials as has been historically required in medical research. Any concern that AI will replace HCPs seems unwarranted. Early studies suggest that even AI programs that appear to exceed human interpretation perform best when working in cooperation with and oversight from clinicians. AI’s greatest potential appears to be its ability to augment care from health professionals, improving efficiency and accuracy, and should be anticipated with enthusiasm as the field moves forward at an exponential rate.

Acknowledgments

The authors thank Makenna G. Thomas for proofreading and review of the manuscript. This material is the result of work supported with resources and the use of facilities at the James A. Haley Veterans’ Hospital. This research has been approved by the James A. Haley Veteran’s Hospital Office of Communications and Media.

Artificial Intelligence (AI) was first described in 1956 and refers to machines having the ability to learn as they receive and process information, resulting in the ability to “think” like humans.¹ AI’s impact in medicine is increasing; currently, at least 29 AI medical devices and algorithms are approved by the US Food and Drug Administration (FDA) in a variety of areas, including radiograph interpretation, managing glucose levels in patients with diabetes mellitus, analyzing electrocardiograms (ECGs), and diagnosing sleep disorders among others.² Significantly, in 2020, the Centers for Medicare and Medicaid Services (CMS) announced the first reimbursement to hospitals for an AI platform, a model for early detection of strokes.³ AI is rapidly becoming an integral part of health care, and its role will only increase in the future (Table).

As knowledge in medicine is expanding exponentially, AI has great potential to assist with handling complex patient care data. The concept of exponential growth is not a natural one. As Bini described, with exponential growth the volume of knowledge amassed over the past 10 years will now occur in perhaps only 1 year.¹ Likewise, equivalent advances over the past year may take just a few months. This phenomenon is partly due to the law of accelerating returns, which states that advances feed on themselves, continually increasing the rate of further advances.⁴ The volume of medical data doubles every 2 to 5 years.⁵ Fortunately, the field of AI is growing exponentially as well and can help health care practitioners (HCPs) keep pace, allowing the continued delivery of effective health care.

In this report, we review common terminology, principles, and general applications of AI, followed by current and potential applications of AI for selected medical specialties. Finally, we discuss AI’s future in health care, along with potential risks and pitfalls.

AI Overview

AI refers to machine programs that can “learn” or think based on past experiences. This functionality contrasts with simple rules-based programming available to health care for years. An example of rules-based programming is the warfarindosing.org website developed by Barnes-Jewish Hospital at Washington University Medical Center, which guides initial warfarin dosing.^6,7 The prescriber inputs detailed patient information, including age, sex, height, weight, tobacco history, medications, laboratory results, and genotype if available. The application then calculates recommended warfarin dosing regimens to avoid over- or underanticoagulation. While the dosing algorithm may be complex, it depends entirely on preprogrammed rules. The program does not learn to reach its conclusions and recommendations from patient data.

In contrast, one of the most common subsets of AI is machine learning (ML). ML describes a program that “learns from experience and improves its performance as it learns.”¹ With ML, the computer is initially provided with a training data set—data with known outcomes or labels. Because the initial data are input from known samples, this type of AI is known as supervised learning.^8-10 As an example, we recently reported using ML to diagnose various types of cancer from pathology slides.¹¹ In one experiment, we captured images of colon adenocarcinoma and normal colon (these 2 groups represent the training data set). Unlike traditional programming, we did not define characteristics that would differentiate colon cancer from normal; rather, the machine learned these characteristics independently by assessing the labeled images provided. A second data set (the validation data set) was used to evaluate the program and fine-tune the ML training model’s parameters. Finally, the program was presented with new images of cancer and normal cases for final assessment of accuracy (test data set). Our program learned to recognize differences from the images provided and was able to differentiate normal and cancer images with > 95% accuracy.

Advances in computer processing have allowed for the development of artificial neural networks (ANNs). While there are several types of ANNs, the most common types used for image classification and segmentation are known as convolutional neural networks (CNNs).^9,12-14 The programs are designed to work similar to the human brain, specifically the visual cortex.^15,16 As data are acquired, they are processed by various layers in the program. Much like neurons in the brain, one layer decides whether to advance information to the next.^13,14 CNNs can be many layers deep, leading to the term deep learning: “computational models that are composed of multiple processing layers to learn representations of data with multiple levels of abstraction.”^1,13,17

ANNs can process larger volumes of data. This advance has led to the development of unstructured or unsupervised learning. With this type of learning, imputing defined features (ie, predetermined answers) of the training data set described above is no longer required.^1,8,10,14 The advantage of unsupervised learning is that the program can be presented raw data and extract meaningful interpretation without human input, often with less bias than may exist with supervised learning.^1,18 If shown enough data, the program can extract relevant features to make conclusions independently without predefined definitions, potentially uncovering markers not previously known. For example, several studies have used unsupervised learning to search patient data to assess readmission risks of patients with congestive heart failure.^10,19,20 AI compiled features independently and not previously defined, predicting patients at greater risk for readmission superior to traditional methods.

Health Care Applications

Image analysis has seen the most AI health care applications.^8,15 AI has shown potential in interpreting many types of medical images, including pathology slides, radiographs of various types, retina and other eye scans, and photographs of skin lesions. Many studies have demonstrated that AI can interpret these images as accurately as or even better than experienced clinicians.^9,13,22-29 Studies have suggested AI interpretation of radiographs may better distinguish patients infected with COVID-19 from other causes of pneumonia, and AI interpretation of pathology slides may detect specific genetic mutations not previously identified without additional molecular tests.^{11,14,23,24,30-32}

The second area in which AI can impact health care is improving workflow and efficiency. AI has improved surgery scheduling, saving significant revenue, and decreased patient wait times for appointments.¹ AI can screen and triage radiographs, allowing attention to be directed to critical patients. This use would be valuable in many busy clinical settings, such as the recent COVID-19 pandemic.^8,23 Similarly, AI can screen retina images to prioritize urgent conditions.²⁵ AI has improved pathologists’ efficiency when used to detect breast metastases.³³ Finally, AI may reduce medical errors, thereby ensuring patient safety.^8,9,34

A third health care benefit of AI is in public health and epidemiology. AI can assist with clinical decision-making and diagnoses in low-income countries and areas with limited health care resources and personnel.^25,29 AI can improve identification of infectious outbreaks, such as tuberculosis, malaria, dengue fever, and influenza.^29,35-40 AI has been used to predict transmission patterns of the Zika virus and the current COVID-19 pandemic.^41,42 Applications can stratify the risk of outbreaks based on multiple factors, including age, income, race, atypical geographic clusters, and seasonal factors like rainfall and temperature.^35,36,38,43 AI has been used to assess morbidity and mortality, such as predicting disease severity with malaria and identifying treatment failures in tuberculosis.²⁹

Finally, AI can dramatically impact health care due to processing large data sets or disconnected volumes of patient information—so-called big data.^44-46 An example is the widespread use of electronic health records (EHRs) such as the Computerized Patient Record System used in Veteran Affairs medical centers (VAMCs). Much of patient information exists in written text: HCP notes, laboratory and radiology reports, medication records, etc. Natural language processing (NLP) allows platforms to sort through extensive volumes of data on complex patients at rates much faster than human capability, which has great potential to assist with diagnosis and treatment decisions.⁹

Medical literature is being produced at rates that exceed our ability to digest. More than 200,000 cancer-related articles were published in 2019 alone.¹⁴ NLP capabilities of AI have the potential to rapidly sort through this extensive medical literature and relate specific verbiage in patient records guiding therapy.⁴⁶ IBM Watson, a supercomputer based on ML and NLP, demonstrates this concept with many potential applications, only some of which relate to health care.^1,9 Watson has an oncology component to assimilate multiple aspects of patient care, including clinical notes, pathology results, radiograph findings, staging, and a tumor’s genetic profile. It coordinates these inputs from the EHR and mines medical literature and research databases to recommend treatment options.^1,46 AI can assess and compile far greater patient data and therapeutic options than would be feasible by individual clinicians, thus providing customized patient care.⁴⁷ Watson has partnered with numerous medical centers, including MD Anderson Cancer Center and Memorial Sloan Kettering Cancer Center, with variable success.^44,47-49 While the full potential of Watson appears not yet realized, these AI-driven approaches will likely play an important role in leveraging the hidden value in the expanding volume of health care information.

Medical Specialty Applications

Radiology

Currently > 70% of FDA-approved AI medical devices are in the field of radiology.² Most radiology departments have used AI-friendly digital imaging for years, such as the picture archiving and communication systems used by numerous health care systems, including VAMCs.^2,15 Gray-scale images common in radiology lend themselves to standardization, although AI is not limited to black-and- white image interpretation.¹⁵

An abundance of literature describes plain radiograph interpretation using AI. One FDA-approved platform improved X-ray diagnosis of wrist fractures when used by emergency medicine clinicians.^2,50 AI has been applied to chest X-ray (CXR) interpretation of many conditions, including pneumonia, tuberculosis, malignant lung lesions, and COVID-19.^{23,25,28,44,51-53} For example, Nam and colleagues suggested AI is better at diagnosing malignant pulmonary nodules from CXRs than are trained radiologists.²⁸

In addition to plain radiographs, AI has been applied to many other imaging technologies, including ultrasounds, positron emission tomography, mammograms, computed tomography (CT), and magnetic resonance imaging (MRI).^{15,26,44,48,54-56} A large study demonstrated that ML platforms significantly reduced the time to diagnose intracranial hemorrhages on CT and identified subtle hemorrhages missed by radiologists.⁵⁵ Other studies have claimed that AI programs may be better than radiologists in detecting cancer in screening mammograms, and 3 FDA-approved devices focus on mammogram interpretation.^2,15,54,57 There is also great interest in MRI applications to detect and predict prognosis for breast cancer based on imaging findings.^21,56

Aside from providing accurate diagnoses, other studies focus on AI radiograph interpretation to assist with patient screening, triage, improving time to final diagnosis, providing a rapid “second opinion,” and even monitoring disease progression and offering insights into prognosis.^{8,21,23,52,55,56,58} These features help in busy urban centers but may play an even greater role in areas with limited access to health care or trained specialists such as radiologists.⁵²

Cardiology

Cardiology has the second highest number of FDA-approved AI applications.² Many cardiology AI platforms involve image analysis, as described in several recent reviews.^45,59,60 AI has been applied to echocardiography to measure ejection fractions, detect valvular disease, and assess heart failure from hypertrophic and restrictive cardiomyopathy and amyloidosis.^45,48,59 Applications for cardiac CT scans and CT angiography have successfully quantified both calcified and noncalcified coronary artery plaques and lumen assessments, assessed myocardial perfusion, and performed coronary artery calcium scoring.^45,59,60 Likewise, AI applications for cardiac MRI have been used to quantitate ejection fraction, large vessel flow assessment, and cardiac scar burden.^45,59

For years ECG devices have provided interpretation with limited accuracy using preprogrammed parameters.⁴⁸ However, the application of AI allows ECG interpretation on par with trained cardiologists. Numerous such AI applications exist, and 2 FDA-approved devices perform ECG interpretation.^2,61-64 One of these devices incorporates an AI-powered stethoscope to detect atrial fibrillation and heart murmurs.⁶⁵

Pathology

The advancement of whole slide imaging, wherein entire slides can be scanned and digitized at high speed and resolution, creates great potential for AI applications in pathology.^{12,24,32,33,66} A landmark study demonstrating the potential of AI for assessing whole slide imaging examined sentinel lymph node metastases in patients with breast cancer.²² Multiple algorithms in the study demonstrated that AI was equivalent or better than pathologists in detecting metastases, especially when the pathologists were time-constrained consistent with a normal working environment. Significantly, the most accurate and efficient diagnoses were achieved when the pathologist and AI interpretations were used together.^22,33

AI has shown promise in diagnosing many other entities, including cancers of the prostate (including Gleason scoring), lung, colon, breast, and skin.^{11,12,24,27,32,67} In addition, AI has shown great potential in scoring biomarkers important for prognosis and treatment, such as immunohistochemistry (IHC) labeling of Ki-67 and PD-L1.³² Pathologists can have difficulty classifying certain tumors or determining the site of origin for metastases, often having to rely on IHC with limited success. The unique features of image analysis with AI have the potential to assist in classifying difficult tumors and identifying sites of origin for metastatic disease based on morphology alone.¹¹

Oncology depends heavily on molecular pathology testing to dictate treatment options and determine prognosis. Preliminary studies suggest that AI interpretation alone has the potential to delineate whether certain molecular mutations are present in tumors from various sites.^11,14,24,32 One study combined histology and genomic results for AI interpretation that improved prognostic predictions.⁶⁸ In addition, AI analysis may have potential in predicting tumor recurrence or prognosis based on cellular features, as demonstrated for lung cancer and melanoma.^67,69,70

Ophthalmology

AI applications for ophthalmology have focused on diabetic retinopathy, age-related macular degeneration, glaucoma, retinopathy of prematurity, age-related and congenital cataracts, and retinal vein occlusion.^71-73 Diabetic retinopathy is a leading cause of blindness and has been studied by numerous platforms with good success, most having used color fundus photography.^71,72 One study showed AI could diagnose diabetic retinopathy and diabetic macular edema with specificities similar to ophthalmologists.⁷⁴ In 2018, the FDA approved the AI platform IDx-DR. This diagnostic system classifies retinal images and recommends referral for patients determined to have “more than mild diabetic retinopathy” and reexamination within a year for other patients.^8,75 Significantly, the platform recommendations do not require confirmation by a clinician.⁸

AI has been applied to other modalities in ophthalmology such as optical coherence tomography (OCT) to diagnose retinal disease and to predict appropriate management of congenital cataracts.^25,73,76 For example, an AI application using OCT has been demonstrated to match or exceed the accuracy of retinal experts in diagnosing and triaging patients with a variety of retinal pathologies, including patients needing urgent referrals.⁷⁷

Dermatology

Multiple studies demonstrate AI performs at least equal to experienced dermatologists in differentiating selected skin lesions.^78-81 For example, Esteva and colleagues demonstrated AI could differentiate keratinocyte carcinomas from benign seborrheic keratoses and malignant melanomas from benign nevi with accuracy equal to 21 board-certified dermatologists.⁷⁸

AI is applicable to various imaging procedures common to dermatology, such as dermoscopy, very high-frequency ultrasound, and reflectance confocal microscopy.⁸² Several studies have demonstrated that AI interpretation compared favorably to dermatologists evaluating dermoscopy to assess melanocytic lesions.^78-81,83

A limitation in these studies is that they differentiate only a few diagnoses.⁸² Furthermore, dermatologists have sensory input such as touch and visual examination under various conditions, something AI has yet to replicate.^15,34,84 Also, most AI devices use no or limited clinical information.⁸¹ Dermatologists can recognize rarer conditions for which AI models may have had limited or no training.³⁴ Nevertheless, a recent study assessed AI for the diagnosis of 134 separate skin disorders with promising results, including providing diagnoses with accuracy comparable to that of dermatologists and providing accurate treatment strategies.⁸⁴ As Topol points out, most skin lesions are diagnosed in the primary care setting where AI can have a greater impact when used in conjunction with the clinical impression, especially where specialists are in limited supply.^48,78

Finally, dermatology lends itself to using portable or smartphone applications (apps) wherein the user can photograph a lesion for analysis by AI algorithms to assess the need for further evaluation or make treatment recommendations.^34,84,85 Although results from currently available apps are not encouraging, they may play a greater role as the technology advances.^34,85

Oncology

Applications of AI in oncology include predicting prognosis for patients with cancer based on histologic and/or genetic information.^14,68,86 Programs can predict the risk of complications before and recurrence risks after surgery for malignancies.^44,87-89 AI can also assist in treatment planning and predict treatment failure with radiation therapy.^90,91

AI has great potential in processing the large volumes of patient data in cancer genomics. Next-generation sequencing has allowed for the identification of millions of DNA sequences in a single tumor to detect genetic anomalies.⁹² Thousands of mutations can be found in individual tumor samples, and processing this information and determining its significance can be beyond human capability.¹⁴ We know little about the effects of various mutation combinations, and most tumors have a heterogeneous molecular profile among different cell populations.^14,93 The presence or absence of various mutations can have diagnostic, prognostic, and therapeutic implications.⁹³ AI has great potential to sort through these complex data and identify actionable findings.

More than 200,000 cancer-related articles were published in 2019, and publications in the field of cancer genomics are increasing exponentially.^14,92,93 Patel and colleagues assessed the utility of IBM Watson for Genomics against results from a molecular tumor board.⁹³ Watson for Genomics identified potentially significant mutations not identified by the tumor board in 32% of patients. Most mutations were related to new clinical trials not yet added to the tumor board watch list, demonstrating the role AI will have in processing the large volume of genetic data required to deliver personalized medicine moving forward.

Gastroenterology

AI has shown promise in predicting risk or outcomes based on clinical parameters in various common gastroenterology problems, including gastric reflux, acute pancreatitis, gastrointestinal bleeding, celiac disease, and inflammatory bowel disease.^94,95 AI endoscopic analysis has demonstrated potential in assessing Barrett’s esophagus, gastric Helicobacter pylori infections, gastric atrophy, and gastric intestinal metaplasia.⁹⁵ Applications have been used to assess esophageal, gastric, and colonic malignancies, including depth of invasion based on endoscopic images.⁹⁵ Finally, studies have evaluated AI to assess small colon polyps during colonoscopy, including differentiating benign and premalignant polyps with success comparable to gastroenterologists.^94,95 AI has been shown to increase the speed and accuracy of gastroenterologists in detecting small polyps during colonoscopy.⁴⁸ In a prospective randomized study, colonoscopies performed using an AI device identified significantly more small adenomatous polyps than colonoscopies without AI.⁹⁶

Neurology

It has been suggested that AI technologies are well suited for application in neurology due to the subtle presentation of many neurologic diseases.¹⁶ Viz LVO, the first CMS-approved AI reimbursement for the diagnosis of strokes, analyzes CTs to detect early ischemic strokes and alerts the medical team, thus shortening time to treatment.^3,97 Many other AI platforms are in use or development that use CT and MRI for the early detection of strokes as well as for treatment and prognosis.^9,97

AI technologies have been applied to neurodegenerative diseases, such as Alzheimer and Parkinson diseases.^16,98 For example, several studies have evaluated patient movements in Parkinson disease for both early diagnosis and to assess response to treatment.⁹⁸ These evaluations included assessment with both external cameras as well as wearable devices and smartphone apps.

Mental Health

Due to the interactive nature of mental health care, the field has been slower to develop AI applications.¹⁸ With heavy reliance on textual information (eg, clinic notes, mood rating scales, and documentation of conversations), successful AI applications in this field will likely rely heavily on NLP.¹⁸ However, studies investigating the application of AI to mental health have also incorporated data such as brain imaging, smartphone monitoring, and social media platforms, such as Facebook and Twitter.^18,103,104

The risk of suicide is higher in veteran patients, and ML algorithms have had limited success in predicting suicide risk in both veteran and nonveteran populations.^104-106 While early models have low positive predictive values and low sensitivities, they still promise to be a useful tool in conjunction with traditional risk assessments.¹⁰⁶ Kessler and colleagues suggest that combining multiple rather than single ML algorithms might lead to greater success.^105,106

AI may assist in diagnosing other mental health disorders, including major depressive disorder, attention deficit hyperactivity disorder (ADHD), schizophrenia, posttraumatic stress disorder, and Alzheimer disease.^103,104,107 These investigations are in the early stages with limited clinical applicability. However, 2 AI applications awaiting FDA approval relate to ADHD and opioid use.² Furthermore, potential exists for AI to not only assist with prevention and diagnosis of ADHD, but also to identify optimal treatment options.^2,103

General and Personalized Medicine

Additional AI applications include diagnosing patients with suspected sepsis, measuring liver iron concentrations, predicting hospital mortality at the time of admission, and more.^2,108,109 AI can guide end-of-life decisions such as resuscitation status or whether to initiate mechanical ventilation.⁴⁸

AI-driven smartphone apps can be beneficial to both patients and clinicians. Examples include predicting nonadherence to anticoagulation therapy, monitoring heart rhythms for atrial fibrillation or signs of hyperkalemia in patients with renal failure, and improving outcomes for patients with diabetes mellitus by decreasing glycemic variability and reducing hypoglycemia.^8,48,110,111 The potential for AI applications to health care and personalized medicine are almost limitless.

Discussion

With ever-increasing expectations for all health care sectors to deliver timely, fiscally-responsible, high-quality health care, AI has the potential to have numerous impacts. AI can improve diagnostic accuracy while limiting errors and impact patient safety such as assisting with prescription delivery.^8,9,34 It can screen and triage patients, alerting clinicians to those needing more urgent evaluation.^8,23,77,97 AI also may increase a clinician’s efficiency and speed to render a diagnosis.^12,13,55,97 AI can provide a rapid second opinion, an ability especially beneficial in underserved areas with shortages of specialists.^{23,25,26,29,34} Similarly, AI may decrease the inter- and intraobserver variability common in many medical specialties.^12,27,45 AI applications can also monitor disease progression, identifying patients at greatest risk, and provide information for prognosis.^21,23,56,58 Finally, as described with applications using IBM Watson, AI can allow for an integrated approach to health care that is currently lacking.

We have described many reports suggesting AI can render diagnoses as well as or better than experienced clinicians, and speculation exists that AI will replace many roles currently performed by health care practitioners.^9,26 However, most studies demonstrate that AI’s diagnostic benefits are best realized when used to supplement a clinician’s impression.^{8,22,30,33,52,54,56,69,84} AI is not likely to replace humans in health care in the foreseeable future. The technology can be likened to the impact of CT scans developed in the 1970s in neurology. Prior to such detailed imaging, neurologists spent extensive time performing detailed physicals to render diagnoses and locate lesions before surgery. There was mistrust of this new technology and concern that CT scans would eliminate the need for neurologists.¹¹² On the contrary, neurology is alive and well, frequently being augmented by the technologies once speculated to replace it.

Commercial AI health care platforms represented a $2 billion industry in 2018 and are growing rapidly each year.^13,32 Many AI products are offered ready for implementation for various tasks, including diagnostics, patient management, and improved efficiency. Others will likely be provided as templates suitable for modification to meet the specific needs of the facility, practice, or specialty for its patient population.

AI Risks and Limitations

AI has several risks and limitations. Although there is progress in explainable AI, at times we still struggle to understand how the output provided by machine learning algorithms was created.^44,48 The many layers associated with deep learning self-determine the criteria to reach its conclusion, and these criteria can continually evolve. The parameters of deep learning are not preprogrammed, and there are too many individual data points to be extrapolated or deconvoluted for evaluation at our current level of knowledge.^26,51 These apparent lack of constraints cause concern for patient safety and suggest that greater validation and continued scrutiny of validity is required.^8,48 Efforts are underway to create explainable AI programs to make their processes more transparent, but such clarification is limited presently.^14,26,48,77

Another challenge of AI is determining the amount of training data required to function optimally. Also, if the output describes multiple variables or diagnoses, are each equally valid?¹¹³ Furthermore, many AI applications look for a specific process, such as cancer diagnoses on CXRs. However, how coexisting conditions like cardiomegaly, emphysema, pneumonia, etc, seen on CXRs will affect the diagnosis needs to be considered.^51,52 Zech and colleagues provide the example that diagnoses for pneumothorax are frequently rendered on CXRs with chest tubes in place.⁵¹ They suggest that CNNs may develop a bias toward diagnosing pneumothorax when chest tubes are present. Many current studies approach an issue in isolation, a situation not realistic in real-world clinical practice.²⁶

Most studies on AI have been retrospective, and frequently data used to train the program are preselected.^13,26 The data are typically validated on available databases rather than actual patients in the clinical setting, limiting confidence in the validity of the AI output when applied to real-world situations. Currently, fewer than 12 prospective trials had been published comparing AI with traditional clinical care.^13,114 Randomized prospective clinical trials are even fewer, with none currently reported from the United States.^13,114 The results from several studies have been shown to diminish when repeated prospectively.¹¹⁴

The FDA has created a new category known as Software as a Medical Device and has a Digital Health Innovation Action Plan to regulate AI platforms. Still, the process of AI regulation is of necessity different from traditional approval processes and is continually evolving.⁸ The FDA approval process cannot account for the fact that the program’s parameters may continually evolve or adapt.²

Guidelines for investigating and reporting AI research with its unique attributes are being developed. Examples include the TRIPOD-ML statement and others.^49,115 In September 2020, 2 publications addressed the paucity of gold-standard randomized clinical trials in clinical AI applications.^116,117 The SPIRIT-AI statement expands on the original SPIRIT statement published in 2013 to guide minimal reporting standards for AI clinical trial protocols to promote transparency of design and methodology.¹¹⁶ Similarly, the CONSORT-AI extension, stemming from the original CONSORT statement in 1996, aims to ensure quality reporting of randomized controlled trials in AI.¹¹⁷

Another risk with AI is that while an individual physician making a mistake may adversely affect 1 patient, a single mistake in an AI algorithm could potentially affect thousands of patients.⁴⁸ Also, AI programs developed for patient populations at a facility may not translate to another. Referred to as overfitting, this phenomenon relates to selection bias in training data sets.^{15,34,49,51,52} Studies have shown that programs that underrepresent certain group characteristics such as age, sex, or race may be less effective when applied to a population in which these characteristics have differing representations.^8,48,49 This problem of underrepresentation has been demonstrated in programs interpreting pathology slides, radiographs, and skin lesions.^15,32,51

Admittedly, most of these challenges are not specific to AI and existed in health care previously. Physicians make mistakes, treatments are sometimes used without adequate prospective studies, and medications are given without understanding their mechanism of action, much like AI-facilitated processes reach a conclusion that cannot be fully explained.⁴⁸

Conclusions

The view that AI will dramatically impact health care in the coming years will likely prove true. However, much work is needed, especially because of the paucity of prospective clinical trials as has been historically required in medical research. Any concern that AI will replace HCPs seems unwarranted. Early studies suggest that even AI programs that appear to exceed human interpretation perform best when working in cooperation with and oversight from clinicians. AI’s greatest potential appears to be its ability to augment care from health professionals, improving efficiency and accuracy, and should be anticipated with enthusiasm as the field moves forward at an exponential rate.

Acknowledgments

The authors thank Makenna G. Thomas for proofreading and review of the manuscript. This material is the result of work supported with resources and the use of facilities at the James A. Haley Veterans’ Hospital. This research has been approved by the James A. Haley Veteran’s Hospital Office of Communications and Media.

Artificial Intelligence (AI) was first described in 1956 and refers to machines having the ability to learn as they receive and process information, resulting in the ability to “think” like humans.¹ AI’s impact in medicine is increasing; currently, at least 29 AI medical devices and algorithms are approved by the US Food and Drug Administration (FDA) in a variety of areas, including radiograph interpretation, managing glucose levels in patients with diabetes mellitus, analyzing electrocardiograms (ECGs), and diagnosing sleep disorders among others.² Significantly, in 2020, the Centers for Medicare and Medicaid Services (CMS) announced the first reimbursement to hospitals for an AI platform, a model for early detection of strokes.³ AI is rapidly becoming an integral part of health care, and its role will only increase in the future (Table).

As knowledge in medicine is expanding exponentially, AI has great potential to assist with handling complex patient care data. The concept of exponential growth is not a natural one. As Bini described, with exponential growth the volume of knowledge amassed over the past 10 years will now occur in perhaps only 1 year.¹ Likewise, equivalent advances over the past year may take just a few months. This phenomenon is partly due to the law of accelerating returns, which states that advances feed on themselves, continually increasing the rate of further advances.⁴ The volume of medical data doubles every 2 to 5 years.⁵ Fortunately, the field of AI is growing exponentially as well and can help health care practitioners (HCPs) keep pace, allowing the continued delivery of effective health care.

In this report, we review common terminology, principles, and general applications of AI, followed by current and potential applications of AI for selected medical specialties. Finally, we discuss AI’s future in health care, along with potential risks and pitfalls.

AI Overview

AI refers to machine programs that can “learn” or think based on past experiences. This functionality contrasts with simple rules-based programming available to health care for years. An example of rules-based programming is the warfarindosing.org website developed by Barnes-Jewish Hospital at Washington University Medical Center, which guides initial warfarin dosing.^6,7 The prescriber inputs detailed patient information, including age, sex, height, weight, tobacco history, medications, laboratory results, and genotype if available. The application then calculates recommended warfarin dosing regimens to avoid over- or underanticoagulation. While the dosing algorithm may be complex, it depends entirely on preprogrammed rules. The program does not learn to reach its conclusions and recommendations from patient data.

In contrast, one of the most common subsets of AI is machine learning (ML). ML describes a program that “learns from experience and improves its performance as it learns.”¹ With ML, the computer is initially provided with a training data set—data with known outcomes or labels. Because the initial data are input from known samples, this type of AI is known as supervised learning.^8-10 As an example, we recently reported using ML to diagnose various types of cancer from pathology slides.¹¹ In one experiment, we captured images of colon adenocarcinoma and normal colon (these 2 groups represent the training data set). Unlike traditional programming, we did not define characteristics that would differentiate colon cancer from normal; rather, the machine learned these characteristics independently by assessing the labeled images provided. A second data set (the validation data set) was used to evaluate the program and fine-tune the ML training model’s parameters. Finally, the program was presented with new images of cancer and normal cases for final assessment of accuracy (test data set). Our program learned to recognize differences from the images provided and was able to differentiate normal and cancer images with > 95% accuracy.

Advances in computer processing have allowed for the development of artificial neural networks (ANNs). While there are several types of ANNs, the most common types used for image classification and segmentation are known as convolutional neural networks (CNNs).^9,12-14 The programs are designed to work similar to the human brain, specifically the visual cortex.^15,16 As data are acquired, they are processed by various layers in the program. Much like neurons in the brain, one layer decides whether to advance information to the next.^13,14 CNNs can be many layers deep, leading to the term deep learning: “computational models that are composed of multiple processing layers to learn representations of data with multiple levels of abstraction.”^1,13,17

ANNs can process larger volumes of data. This advance has led to the development of unstructured or unsupervised learning. With this type of learning, imputing defined features (ie, predetermined answers) of the training data set described above is no longer required.^1,8,10,14 The advantage of unsupervised learning is that the program can be presented raw data and extract meaningful interpretation without human input, often with less bias than may exist with supervised learning.^1,18 If shown enough data, the program can extract relevant features to make conclusions independently without predefined definitions, potentially uncovering markers not previously known. For example, several studies have used unsupervised learning to search patient data to assess readmission risks of patients with congestive heart failure.^10,19,20 AI compiled features independently and not previously defined, predicting patients at greater risk for readmission superior to traditional methods.

Health Care Applications

Image analysis has seen the most AI health care applications.^8,15 AI has shown potential in interpreting many types of medical images, including pathology slides, radiographs of various types, retina and other eye scans, and photographs of skin lesions. Many studies have demonstrated that AI can interpret these images as accurately as or even better than experienced clinicians.^9,13,22-29 Studies have suggested AI interpretation of radiographs may better distinguish patients infected with COVID-19 from other causes of pneumonia, and AI interpretation of pathology slides may detect specific genetic mutations not previously identified without additional molecular tests.^{11,14,23,24,30-32}

The second area in which AI can impact health care is improving workflow and efficiency. AI has improved surgery scheduling, saving significant revenue, and decreased patient wait times for appointments.¹ AI can screen and triage radiographs, allowing attention to be directed to critical patients. This use would be valuable in many busy clinical settings, such as the recent COVID-19 pandemic.^8,23 Similarly, AI can screen retina images to prioritize urgent conditions.²⁵ AI has improved pathologists’ efficiency when used to detect breast metastases.³³ Finally, AI may reduce medical errors, thereby ensuring patient safety.^8,9,34

A third health care benefit of AI is in public health and epidemiology. AI can assist with clinical decision-making and diagnoses in low-income countries and areas with limited health care resources and personnel.^25,29 AI can improve identification of infectious outbreaks, such as tuberculosis, malaria, dengue fever, and influenza.^29,35-40 AI has been used to predict transmission patterns of the Zika virus and the current COVID-19 pandemic.^41,42 Applications can stratify the risk of outbreaks based on multiple factors, including age, income, race, atypical geographic clusters, and seasonal factors like rainfall and temperature.^35,36,38,43 AI has been used to assess morbidity and mortality, such as predicting disease severity with malaria and identifying treatment failures in tuberculosis.²⁹

Finally, AI can dramatically impact health care due to processing large data sets or disconnected volumes of patient information—so-called big data.^44-46 An example is the widespread use of electronic health records (EHRs) such as the Computerized Patient Record System used in Veteran Affairs medical centers (VAMCs). Much of patient information exists in written text: HCP notes, laboratory and radiology reports, medication records, etc. Natural language processing (NLP) allows platforms to sort through extensive volumes of data on complex patients at rates much faster than human capability, which has great potential to assist with diagnosis and treatment decisions.⁹

Medical literature is being produced at rates that exceed our ability to digest. More than 200,000 cancer-related articles were published in 2019 alone.¹⁴ NLP capabilities of AI have the potential to rapidly sort through this extensive medical literature and relate specific verbiage in patient records guiding therapy.⁴⁶ IBM Watson, a supercomputer based on ML and NLP, demonstrates this concept with many potential applications, only some of which relate to health care.^1,9 Watson has an oncology component to assimilate multiple aspects of patient care, including clinical notes, pathology results, radiograph findings, staging, and a tumor’s genetic profile. It coordinates these inputs from the EHR and mines medical literature and research databases to recommend treatment options.^1,46 AI can assess and compile far greater patient data and therapeutic options than would be feasible by individual clinicians, thus providing customized patient care.⁴⁷ Watson has partnered with numerous medical centers, including MD Anderson Cancer Center and Memorial Sloan Kettering Cancer Center, with variable success.^44,47-49 While the full potential of Watson appears not yet realized, these AI-driven approaches will likely play an important role in leveraging the hidden value in the expanding volume of health care information.

Medical Specialty Applications

Radiology

Currently > 70% of FDA-approved AI medical devices are in the field of radiology.² Most radiology departments have used AI-friendly digital imaging for years, such as the picture archiving and communication systems used by numerous health care systems, including VAMCs.^2,15 Gray-scale images common in radiology lend themselves to standardization, although AI is not limited to black-and- white image interpretation.¹⁵

An abundance of literature describes plain radiograph interpretation using AI. One FDA-approved platform improved X-ray diagnosis of wrist fractures when used by emergency medicine clinicians.^2,50 AI has been applied to chest X-ray (CXR) interpretation of many conditions, including pneumonia, tuberculosis, malignant lung lesions, and COVID-19.^{23,25,28,44,51-53} For example, Nam and colleagues suggested AI is better at diagnosing malignant pulmonary nodules from CXRs than are trained radiologists.²⁸

In addition to plain radiographs, AI has been applied to many other imaging technologies, including ultrasounds, positron emission tomography, mammograms, computed tomography (CT), and magnetic resonance imaging (MRI).^{15,26,44,48,54-56} A large study demonstrated that ML platforms significantly reduced the time to diagnose intracranial hemorrhages on CT and identified subtle hemorrhages missed by radiologists.⁵⁵ Other studies have claimed that AI programs may be better than radiologists in detecting cancer in screening mammograms, and 3 FDA-approved devices focus on mammogram interpretation.^2,15,54,57 There is also great interest in MRI applications to detect and predict prognosis for breast cancer based on imaging findings.^21,56

Aside from providing accurate diagnoses, other studies focus on AI radiograph interpretation to assist with patient screening, triage, improving time to final diagnosis, providing a rapid “second opinion,” and even monitoring disease progression and offering insights into prognosis.^{8,21,23,52,55,56,58} These features help in busy urban centers but may play an even greater role in areas with limited access to health care or trained specialists such as radiologists.⁵²

Cardiology

Cardiology has the second highest number of FDA-approved AI applications.² Many cardiology AI platforms involve image analysis, as described in several recent reviews.^45,59,60 AI has been applied to echocardiography to measure ejection fractions, detect valvular disease, and assess heart failure from hypertrophic and restrictive cardiomyopathy and amyloidosis.^45,48,59 Applications for cardiac CT scans and CT angiography have successfully quantified both calcified and noncalcified coronary artery plaques and lumen assessments, assessed myocardial perfusion, and performed coronary artery calcium scoring.^45,59,60 Likewise, AI applications for cardiac MRI have been used to quantitate ejection fraction, large vessel flow assessment, and cardiac scar burden.^45,59

For years ECG devices have provided interpretation with limited accuracy using preprogrammed parameters.⁴⁸ However, the application of AI allows ECG interpretation on par with trained cardiologists. Numerous such AI applications exist, and 2 FDA-approved devices perform ECG interpretation.^2,61-64 One of these devices incorporates an AI-powered stethoscope to detect atrial fibrillation and heart murmurs.⁶⁵

Pathology

The advancement of whole slide imaging, wherein entire slides can be scanned and digitized at high speed and resolution, creates great potential for AI applications in pathology.^{12,24,32,33,66} A landmark study demonstrating the potential of AI for assessing whole slide imaging examined sentinel lymph node metastases in patients with breast cancer.²² Multiple algorithms in the study demonstrated that AI was equivalent or better than pathologists in detecting metastases, especially when the pathologists were time-constrained consistent with a normal working environment. Significantly, the most accurate and efficient diagnoses were achieved when the pathologist and AI interpretations were used together.^22,33

AI has shown promise in diagnosing many other entities, including cancers of the prostate (including Gleason scoring), lung, colon, breast, and skin.^{11,12,24,27,32,67} In addition, AI has shown great potential in scoring biomarkers important for prognosis and treatment, such as immunohistochemistry (IHC) labeling of Ki-67 and PD-L1.³² Pathologists can have difficulty classifying certain tumors or determining the site of origin for metastases, often having to rely on IHC with limited success. The unique features of image analysis with AI have the potential to assist in classifying difficult tumors and identifying sites of origin for metastatic disease based on morphology alone.¹¹

Oncology depends heavily on molecular pathology testing to dictate treatment options and determine prognosis. Preliminary studies suggest that AI interpretation alone has the potential to delineate whether certain molecular mutations are present in tumors from various sites.^11,14,24,32 One study combined histology and genomic results for AI interpretation that improved prognostic predictions.⁶⁸ In addition, AI analysis may have potential in predicting tumor recurrence or prognosis based on cellular features, as demonstrated for lung cancer and melanoma.^67,69,70

Ophthalmology

AI applications for ophthalmology have focused on diabetic retinopathy, age-related macular degeneration, glaucoma, retinopathy of prematurity, age-related and congenital cataracts, and retinal vein occlusion.^71-73 Diabetic retinopathy is a leading cause of blindness and has been studied by numerous platforms with good success, most having used color fundus photography.^71,72 One study showed AI could diagnose diabetic retinopathy and diabetic macular edema with specificities similar to ophthalmologists.⁷⁴ In 2018, the FDA approved the AI platform IDx-DR. This diagnostic system classifies retinal images and recommends referral for patients determined to have “more than mild diabetic retinopathy” and reexamination within a year for other patients.^8,75 Significantly, the platform recommendations do not require confirmation by a clinician.⁸

AI has been applied to other modalities in ophthalmology such as optical coherence tomography (OCT) to diagnose retinal disease and to predict appropriate management of congenital cataracts.^25,73,76 For example, an AI application using OCT has been demonstrated to match or exceed the accuracy of retinal experts in diagnosing and triaging patients with a variety of retinal pathologies, including patients needing urgent referrals.⁷⁷

Dermatology

Multiple studies demonstrate AI performs at least equal to experienced dermatologists in differentiating selected skin lesions.^78-81 For example, Esteva and colleagues demonstrated AI could differentiate keratinocyte carcinomas from benign seborrheic keratoses and malignant melanomas from benign nevi with accuracy equal to 21 board-certified dermatologists.⁷⁸

AI is applicable to various imaging procedures common to dermatology, such as dermoscopy, very high-frequency ultrasound, and reflectance confocal microscopy.⁸² Several studies have demonstrated that AI interpretation compared favorably to dermatologists evaluating dermoscopy to assess melanocytic lesions.^78-81,83

A limitation in these studies is that they differentiate only a few diagnoses.⁸² Furthermore, dermatologists have sensory input such as touch and visual examination under various conditions, something AI has yet to replicate.^15,34,84 Also, most AI devices use no or limited clinical information.⁸¹ Dermatologists can recognize rarer conditions for which AI models may have had limited or no training.³⁴ Nevertheless, a recent study assessed AI for the diagnosis of 134 separate skin disorders with promising results, including providing diagnoses with accuracy comparable to that of dermatologists and providing accurate treatment strategies.⁸⁴ As Topol points out, most skin lesions are diagnosed in the primary care setting where AI can have a greater impact when used in conjunction with the clinical impression, especially where specialists are in limited supply.^48,78

Finally, dermatology lends itself to using portable or smartphone applications (apps) wherein the user can photograph a lesion for analysis by AI algorithms to assess the need for further evaluation or make treatment recommendations.^34,84,85 Although results from currently available apps are not encouraging, they may play a greater role as the technology advances.^34,85

Oncology

Applications of AI in oncology include predicting prognosis for patients with cancer based on histologic and/or genetic information.^14,68,86 Programs can predict the risk of complications before and recurrence risks after surgery for malignancies.^44,87-89 AI can also assist in treatment planning and predict treatment failure with radiation therapy.^90,91

AI has great potential in processing the large volumes of patient data in cancer genomics. Next-generation sequencing has allowed for the identification of millions of DNA sequences in a single tumor to detect genetic anomalies.⁹² Thousands of mutations can be found in individual tumor samples, and processing this information and determining its significance can be beyond human capability.¹⁴ We know little about the effects of various mutation combinations, and most tumors have a heterogeneous molecular profile among different cell populations.^14,93 The presence or absence of various mutations can have diagnostic, prognostic, and therapeutic implications.⁹³ AI has great potential to sort through these complex data and identify actionable findings.

More than 200,000 cancer-related articles were published in 2019, and publications in the field of cancer genomics are increasing exponentially.^14,92,93 Patel and colleagues assessed the utility of IBM Watson for Genomics against results from a molecular tumor board.⁹³ Watson for Genomics identified potentially significant mutations not identified by the tumor board in 32% of patients. Most mutations were related to new clinical trials not yet added to the tumor board watch list, demonstrating the role AI will have in processing the large volume of genetic data required to deliver personalized medicine moving forward.

Gastroenterology

AI has shown promise in predicting risk or outcomes based on clinical parameters in various common gastroenterology problems, including gastric reflux, acute pancreatitis, gastrointestinal bleeding, celiac disease, and inflammatory bowel disease.^94,95 AI endoscopic analysis has demonstrated potential in assessing Barrett’s esophagus, gastric Helicobacter pylori infections, gastric atrophy, and gastric intestinal metaplasia.⁹⁵ Applications have been used to assess esophageal, gastric, and colonic malignancies, including depth of invasion based on endoscopic images.⁹⁵ Finally, studies have evaluated AI to assess small colon polyps during colonoscopy, including differentiating benign and premalignant polyps with success comparable to gastroenterologists.^94,95 AI has been shown to increase the speed and accuracy of gastroenterologists in detecting small polyps during colonoscopy.⁴⁸ In a prospective randomized study, colonoscopies performed using an AI device identified significantly more small adenomatous polyps than colonoscopies without AI.⁹⁶

Neurology

It has been suggested that AI technologies are well suited for application in neurology due to the subtle presentation of many neurologic diseases.¹⁶ Viz LVO, the first CMS-approved AI reimbursement for the diagnosis of strokes, analyzes CTs to detect early ischemic strokes and alerts the medical team, thus shortening time to treatment.^3,97 Many other AI platforms are in use or development that use CT and MRI for the early detection of strokes as well as for treatment and prognosis.^9,97

AI technologies have been applied to neurodegenerative diseases, such as Alzheimer and Parkinson diseases.^16,98 For example, several studies have evaluated patient movements in Parkinson disease for both early diagnosis and to assess response to treatment.⁹⁸ These evaluations included assessment with both external cameras as well as wearable devices and smartphone apps.

Mental Health

Due to the interactive nature of mental health care, the field has been slower to develop AI applications.¹⁸ With heavy reliance on textual information (eg, clinic notes, mood rating scales, and documentation of conversations), successful AI applications in this field will likely rely heavily on NLP.¹⁸ However, studies investigating the application of AI to mental health have also incorporated data such as brain imaging, smartphone monitoring, and social media platforms, such as Facebook and Twitter.^18,103,104

The risk of suicide is higher in veteran patients, and ML algorithms have had limited success in predicting suicide risk in both veteran and nonveteran populations.^104-106 While early models have low positive predictive values and low sensitivities, they still promise to be a useful tool in conjunction with traditional risk assessments.¹⁰⁶ Kessler and colleagues suggest that combining multiple rather than single ML algorithms might lead to greater success.^105,106

AI may assist in diagnosing other mental health disorders, including major depressive disorder, attention deficit hyperactivity disorder (ADHD), schizophrenia, posttraumatic stress disorder, and Alzheimer disease.^103,104,107 These investigations are in the early stages with limited clinical applicability. However, 2 AI applications awaiting FDA approval relate to ADHD and opioid use.² Furthermore, potential exists for AI to not only assist with prevention and diagnosis of ADHD, but also to identify optimal treatment options.^2,103

General and Personalized Medicine

Additional AI applications include diagnosing patients with suspected sepsis, measuring liver iron concentrations, predicting hospital mortality at the time of admission, and more.^2,108,109 AI can guide end-of-life decisions such as resuscitation status or whether to initiate mechanical ventilation.⁴⁸

AI-driven smartphone apps can be beneficial to both patients and clinicians. Examples include predicting nonadherence to anticoagulation therapy, monitoring heart rhythms for atrial fibrillation or signs of hyperkalemia in patients with renal failure, and improving outcomes for patients with diabetes mellitus by decreasing glycemic variability and reducing hypoglycemia.^8,48,110,111 The potential for AI applications to health care and personalized medicine are almost limitless.

Discussion

With ever-increasing expectations for all health care sectors to deliver timely, fiscally-responsible, high-quality health care, AI has the potential to have numerous impacts. AI can improve diagnostic accuracy while limiting errors and impact patient safety such as assisting with prescription delivery.^8,9,34 It can screen and triage patients, alerting clinicians to those needing more urgent evaluation.^8,23,77,97 AI also may increase a clinician’s efficiency and speed to render a diagnosis.^12,13,55,97 AI can provide a rapid second opinion, an ability especially beneficial in underserved areas with shortages of specialists.^{23,25,26,29,34} Similarly, AI may decrease the inter- and intraobserver variability common in many medical specialties.^12,27,45 AI applications can also monitor disease progression, identifying patients at greatest risk, and provide information for prognosis.^21,23,56,58 Finally, as described with applications using IBM Watson, AI can allow for an integrated approach to health care that is currently lacking.

We have described many reports suggesting AI can render diagnoses as well as or better than experienced clinicians, and speculation exists that AI will replace many roles currently performed by health care practitioners.^9,26 However, most studies demonstrate that AI’s diagnostic benefits are best realized when used to supplement a clinician’s impression.^{8,22,30,33,52,54,56,69,84} AI is not likely to replace humans in health care in the foreseeable future. The technology can be likened to the impact of CT scans developed in the 1970s in neurology. Prior to such detailed imaging, neurologists spent extensive time performing detailed physicals to render diagnoses and locate lesions before surgery. There was mistrust of this new technology and concern that CT scans would eliminate the need for neurologists.¹¹² On the contrary, neurology is alive and well, frequently being augmented by the technologies once speculated to replace it.

Commercial AI health care platforms represented a $2 billion industry in 2018 and are growing rapidly each year.^13,32 Many AI products are offered ready for implementation for various tasks, including diagnostics, patient management, and improved efficiency. Others will likely be provided as templates suitable for modification to meet the specific needs of the facility, practice, or specialty for its patient population.

AI Risks and Limitations

AI has several risks and limitations. Although there is progress in explainable AI, at times we still struggle to understand how the output provided by machine learning algorithms was created.^44,48 The many layers associated with deep learning self-determine the criteria to reach its conclusion, and these criteria can continually evolve. The parameters of deep learning are not preprogrammed, and there are too many individual data points to be extrapolated or deconvoluted for evaluation at our current level of knowledge.^26,51 These apparent lack of constraints cause concern for patient safety and suggest that greater validation and continued scrutiny of validity is required.^8,48 Efforts are underway to create explainable AI programs to make their processes more transparent, but such clarification is limited presently.^14,26,48,77

Another challenge of AI is determining the amount of training data required to function optimally. Also, if the output describes multiple variables or diagnoses, are each equally valid?¹¹³ Furthermore, many AI applications look for a specific process, such as cancer diagnoses on CXRs. However, how coexisting conditions like cardiomegaly, emphysema, pneumonia, etc, seen on CXRs will affect the diagnosis needs to be considered.^51,52 Zech and colleagues provide the example that diagnoses for pneumothorax are frequently rendered on CXRs with chest tubes in place.⁵¹ They suggest that CNNs may develop a bias toward diagnosing pneumothorax when chest tubes are present. Many current studies approach an issue in isolation, a situation not realistic in real-world clinical practice.²⁶

Most studies on AI have been retrospective, and frequently data used to train the program are preselected.^13,26 The data are typically validated on available databases rather than actual patients in the clinical setting, limiting confidence in the validity of the AI output when applied to real-world situations. Currently, fewer than 12 prospective trials had been published comparing AI with traditional clinical care.^13,114 Randomized prospective clinical trials are even fewer, with none currently reported from the United States.^13,114 The results from several studies have been shown to diminish when repeated prospectively.¹¹⁴

The FDA has created a new category known as Software as a Medical Device and has a Digital Health Innovation Action Plan to regulate AI platforms. Still, the process of AI regulation is of necessity different from traditional approval processes and is continually evolving.⁸ The FDA approval process cannot account for the fact that the program’s parameters may continually evolve or adapt.²

Guidelines for investigating and reporting AI research with its unique attributes are being developed. Examples include the TRIPOD-ML statement and others.^49,115 In September 2020, 2 publications addressed the paucity of gold-standard randomized clinical trials in clinical AI applications.^116,117 The SPIRIT-AI statement expands on the original SPIRIT statement published in 2013 to guide minimal reporting standards for AI clinical trial protocols to promote transparency of design and methodology.¹¹⁶ Similarly, the CONSORT-AI extension, stemming from the original CONSORT statement in 1996, aims to ensure quality reporting of randomized controlled trials in AI.¹¹⁷

Another risk with AI is that while an individual physician making a mistake may adversely affect 1 patient, a single mistake in an AI algorithm could potentially affect thousands of patients.⁴⁸ Also, AI programs developed for patient populations at a facility may not translate to another. Referred to as overfitting, this phenomenon relates to selection bias in training data sets.^{15,34,49,51,52} Studies have shown that programs that underrepresent certain group characteristics such as age, sex, or race may be less effective when applied to a population in which these characteristics have differing representations.^8,48,49 This problem of underrepresentation has been demonstrated in programs interpreting pathology slides, radiographs, and skin lesions.^15,32,51

Admittedly, most of these challenges are not specific to AI and existed in health care previously. Physicians make mistakes, treatments are sometimes used without adequate prospective studies, and medications are given without understanding their mechanism of action, much like AI-facilitated processes reach a conclusion that cannot be fully explained.⁴⁸

Conclusions

The view that AI will dramatically impact health care in the coming years will likely prove true. However, much work is needed, especially because of the paucity of prospective clinical trials as has been historically required in medical research. Any concern that AI will replace HCPs seems unwarranted. Early studies suggest that even AI programs that appear to exceed human interpretation perform best when working in cooperation with and oversight from clinicians. AI’s greatest potential appears to be its ability to augment care from health professionals, improving efficiency and accuracy, and should be anticipated with enthusiasm as the field moves forward at an exponential rate.

Acknowledgments

The authors thank Makenna G. Thomas for proofreading and review of the manuscript. This material is the result of work supported with resources and the use of facilities at the James A. Haley Veterans’ Hospital. This research has been approved by the James A. Haley Veteran’s Hospital Office of Communications and Media.