The Diagnosis: Extragenital Lichen Sclerosus Et Atrophicus 

Histopathologic evaluation revealed hyperkeratosis, follicular plugging, epidermal atrophy, and homogenization of papillary dermal collagen with an underlying lymphocytic infiltrate (Figure 1). Direct immunofluorescence of a plaque with a superimposed bulla was negative for deposition of C3, IgG, IgA, IgM, or fibrinogen. Accordingly, clinicopathologic correlation supported a diagnosis of extragenital lichen sclerosus et atrophicus (LSA). Of note, the patient's history of genital irritation was due to genital LSA that preceded the extragenital manifestations. 

Lichen sclerosus et atrophicus is an inflammatory dermatosis that typically presents as atrophic white papules of the anogenital area that coalesce into pruritic plaques; the exact etiology remains to be elucidated, yet various circulating autoantibodies have been identified, suggesting a role for autoimmunity.^1,2 Lichen sclerosus et atrophicus is more common in women than in men, with a bimodal peak in the age of onset affecting postmenopausal and prepubertal populations.¹ In women, affected areas include the labia minora and majora, clitoris, perineum, and perianal skin; LSA spares the mucosal surfaces of the vagina and cervix.² In men, uncircumscribed genital skin more commonly is affected. Involvement is localized to the foreskin and glans with occasional urethral involvement.²  

In contrast, extragenital LSA tends to present as asymptomatic papules and plaques that develop atrophy with time, involving the back, shoulders, neck, chest, thighs, axillae, and flexural wrists^2,3; an erythematous rim often is present,⁴ and hyperkeratosis with follicular plugging may be prominent.⁵ Our patient's case emphasizes the predilection of plaques for the chest and intermammary skin (Figure 2A). Approximately 15% of LSA cases have extragenital involvement, and extragenital-limited disease accounts for roughly 5% of cases.^6,7 Unlike genital LSA, extragenital disease has not been associated with an increased risk for squamous cell carcinoma.¹ Bullae formation within plaques of genital or extragenital LSA has been reported^3,8 and is exemplified in our patient (Figure 2B). Intralesional bullae formation likely is due to a combination of internal and external factors, mainly the inability to withstand shear forces due to an atrophic epidermis with basal vacuolar injury overlying an edematous papillary dermis with altered collagen.⁸ Dermatoscopic findings may aid in recognizing extragenital LSA9,¹⁰; our patient's plaques demonstrated the characteristic findings of comedolike openings, structureless white areas, and pink borders (Figure 3). 

The clinical differential diagnosis for well-demarcated, pink, scaly plaques is broad. Nummular eczema usually presents as coin-shaped eczematous plaques on the dorsal aspects of the hands or lower extremities, and histology shows epidermal spongiosis.¹¹ Nummular eczema may be considered due to the striking round morphology of various plaques, yet our patient's presentation was better served by a consideration of several papulosquamous disorders. 

Lichen planus (LP) presents as intensely pruritic, violaceous, polygonal, flat-topped papules with overlying reticular white lines, or Wickham striae, that favor the flexural wrists, lower back, and lower extremities. Lichen planus also may have oral and genital mucosal involvement. Similar to LSA, LP is more common in women and preferentially affects the postmenopausal population.¹² Additionally, hypertrophic LP may obscure Wickham striae and mimic extragenital LSA; distinguishing features of hypertrophic LP are intense pruritus and a predilection for the shins. Histology is defined by orthohyperkeratosis, hypergranulosis, sawtooth acanthosis, and vacuolar degeneration of the basal layer with Civatte bodies or dyskeratotic basal keratinocytes overlying a characteristic bandlike infiltrate of lymphocytes.¹² 

Lichen simplex chronicus (LSC) is characterized by intense pruritus and presents as hyperkeratotic plaques with a predilection for accessible regions such as the posterior neck and extremities.¹³ The striking annular demarcation of this case makes LSC unlikely. Comparable to LSA and LP, LSC also may present with both genital and extragenital findings. Histology of LSC is characterized by irregular acanthosis or thickening of the epidermis with vertical streaking of collagen and vascular bundles of the papillary dermis.¹³ 

Subacute cutaneous lupus erythematosus (SCLE) is important to consider for a new papulosquamous eruption with a predilection for the sun-exposed skin of a middle-aged woman. The presence of papules on the volar wrist and history of genital irritation, however, make this entity less likely. Similar to LSA, histologic examination of SCLE reveals epidermal atrophy, basal layer degeneration, and papillary dermal edema with lymphocytic inflammation. However, SCLE lacks the band of inflammation underlying pale homogenized papillary dermal collagen, the most distinguishing feature of LSA; instead, SCLE shows superficial and deep perivascular and periadnexal lymphocytes and mucin in the dermis.¹⁴ 

Lichen sclerosus et atrophicus may be chronic and progressive in nature or cycle through remissions and relapses.² Treatment is not curative, and management is directed to alleviating symptoms and preventing the progression of disease. First-line management of extragenital LSA is potent topical steroids.¹ Adjuvant topical calcineurin inhibitors may be used as steroid-sparing agents.² Phototherapy is a second-line therapy and even narrowband UVB phototherapy has demonstrated efficacy in managing extragenital LSA.^15,16 Our patient was started on mometasone ointment and calcipotriene cream with slight improvement after a 6-month trial. Ongoing management is focused on optimizing application of topical therapies.  

The Diagnosis: Extragenital Lichen Sclerosus Et Atrophicus 

Histopathologic evaluation revealed hyperkeratosis, follicular plugging, epidermal atrophy, and homogenization of papillary dermal collagen with an underlying lymphocytic infiltrate (Figure 1). Direct immunofluorescence of a plaque with a superimposed bulla was negative for deposition of C3, IgG, IgA, IgM, or fibrinogen. Accordingly, clinicopathologic correlation supported a diagnosis of extragenital lichen sclerosus et atrophicus (LSA). Of note, the patient's history of genital irritation was due to genital LSA that preceded the extragenital manifestations. 

Lichen sclerosus et atrophicus is an inflammatory dermatosis that typically presents as atrophic white papules of the anogenital area that coalesce into pruritic plaques; the exact etiology remains to be elucidated, yet various circulating autoantibodies have been identified, suggesting a role for autoimmunity.^1,2 Lichen sclerosus et atrophicus is more common in women than in men, with a bimodal peak in the age of onset affecting postmenopausal and prepubertal populations.¹ In women, affected areas include the labia minora and majora, clitoris, perineum, and perianal skin; LSA spares the mucosal surfaces of the vagina and cervix.² In men, uncircumscribed genital skin more commonly is affected. Involvement is localized to the foreskin and glans with occasional urethral involvement.²  

In contrast, extragenital LSA tends to present as asymptomatic papules and plaques that develop atrophy with time, involving the back, shoulders, neck, chest, thighs, axillae, and flexural wrists^2,3; an erythematous rim often is present,⁴ and hyperkeratosis with follicular plugging may be prominent.⁵ Our patient's case emphasizes the predilection of plaques for the chest and intermammary skin (Figure 2A). Approximately 15% of LSA cases have extragenital involvement, and extragenital-limited disease accounts for roughly 5% of cases.^6,7 Unlike genital LSA, extragenital disease has not been associated with an increased risk for squamous cell carcinoma.¹ Bullae formation within plaques of genital or extragenital LSA has been reported^3,8 and is exemplified in our patient (Figure 2B). Intralesional bullae formation likely is due to a combination of internal and external factors, mainly the inability to withstand shear forces due to an atrophic epidermis with basal vacuolar injury overlying an edematous papillary dermis with altered collagen.⁸ Dermatoscopic findings may aid in recognizing extragenital LSA9,¹⁰; our patient's plaques demonstrated the characteristic findings of comedolike openings, structureless white areas, and pink borders (Figure 3). 

The clinical differential diagnosis for well-demarcated, pink, scaly plaques is broad. Nummular eczema usually presents as coin-shaped eczematous plaques on the dorsal aspects of the hands or lower extremities, and histology shows epidermal spongiosis.¹¹ Nummular eczema may be considered due to the striking round morphology of various plaques, yet our patient's presentation was better served by a consideration of several papulosquamous disorders. 

Lichen planus (LP) presents as intensely pruritic, violaceous, polygonal, flat-topped papules with overlying reticular white lines, or Wickham striae, that favor the flexural wrists, lower back, and lower extremities. Lichen planus also may have oral and genital mucosal involvement. Similar to LSA, LP is more common in women and preferentially affects the postmenopausal population.¹² Additionally, hypertrophic LP may obscure Wickham striae and mimic extragenital LSA; distinguishing features of hypertrophic LP are intense pruritus and a predilection for the shins. Histology is defined by orthohyperkeratosis, hypergranulosis, sawtooth acanthosis, and vacuolar degeneration of the basal layer with Civatte bodies or dyskeratotic basal keratinocytes overlying a characteristic bandlike infiltrate of lymphocytes.¹² 

Lichen simplex chronicus (LSC) is characterized by intense pruritus and presents as hyperkeratotic plaques with a predilection for accessible regions such as the posterior neck and extremities.¹³ The striking annular demarcation of this case makes LSC unlikely. Comparable to LSA and LP, LSC also may present with both genital and extragenital findings. Histology of LSC is characterized by irregular acanthosis or thickening of the epidermis with vertical streaking of collagen and vascular bundles of the papillary dermis.¹³ 

Subacute cutaneous lupus erythematosus (SCLE) is important to consider for a new papulosquamous eruption with a predilection for the sun-exposed skin of a middle-aged woman. The presence of papules on the volar wrist and history of genital irritation, however, make this entity less likely. Similar to LSA, histologic examination of SCLE reveals epidermal atrophy, basal layer degeneration, and papillary dermal edema with lymphocytic inflammation. However, SCLE lacks the band of inflammation underlying pale homogenized papillary dermal collagen, the most distinguishing feature of LSA; instead, SCLE shows superficial and deep perivascular and periadnexal lymphocytes and mucin in the dermis.¹⁴ 

Lichen sclerosus et atrophicus may be chronic and progressive in nature or cycle through remissions and relapses.² Treatment is not curative, and management is directed to alleviating symptoms and preventing the progression of disease. First-line management of extragenital LSA is potent topical steroids.¹ Adjuvant topical calcineurin inhibitors may be used as steroid-sparing agents.² Phototherapy is a second-line therapy and even narrowband UVB phototherapy has demonstrated efficacy in managing extragenital LSA.^15,16 Our patient was started on mometasone ointment and calcipotriene cream with slight improvement after a 6-month trial. Ongoing management is focused on optimizing application of topical therapies.  

The Diagnosis: Extragenital Lichen Sclerosus Et Atrophicus 

Histopathologic evaluation revealed hyperkeratosis, follicular plugging, epidermal atrophy, and homogenization of papillary dermal collagen with an underlying lymphocytic infiltrate (Figure 1). Direct immunofluorescence of a plaque with a superimposed bulla was negative for deposition of C3, IgG, IgA, IgM, or fibrinogen. Accordingly, clinicopathologic correlation supported a diagnosis of extragenital lichen sclerosus et atrophicus (LSA). Of note, the patient's history of genital irritation was due to genital LSA that preceded the extragenital manifestations. 

Lichen sclerosus et atrophicus is an inflammatory dermatosis that typically presents as atrophic white papules of the anogenital area that coalesce into pruritic plaques; the exact etiology remains to be elucidated, yet various circulating autoantibodies have been identified, suggesting a role for autoimmunity.^1,2 Lichen sclerosus et atrophicus is more common in women than in men, with a bimodal peak in the age of onset affecting postmenopausal and prepubertal populations.¹ In women, affected areas include the labia minora and majora, clitoris, perineum, and perianal skin; LSA spares the mucosal surfaces of the vagina and cervix.² In men, uncircumscribed genital skin more commonly is affected. Involvement is localized to the foreskin and glans with occasional urethral involvement.²  

In contrast, extragenital LSA tends to present as asymptomatic papules and plaques that develop atrophy with time, involving the back, shoulders, neck, chest, thighs, axillae, and flexural wrists^2,3; an erythematous rim often is present,⁴ and hyperkeratosis with follicular plugging may be prominent.⁵ Our patient's case emphasizes the predilection of plaques for the chest and intermammary skin (Figure 2A). Approximately 15% of LSA cases have extragenital involvement, and extragenital-limited disease accounts for roughly 5% of cases.^6,7 Unlike genital LSA, extragenital disease has not been associated with an increased risk for squamous cell carcinoma.¹ Bullae formation within plaques of genital or extragenital LSA has been reported^3,8 and is exemplified in our patient (Figure 2B). Intralesional bullae formation likely is due to a combination of internal and external factors, mainly the inability to withstand shear forces due to an atrophic epidermis with basal vacuolar injury overlying an edematous papillary dermis with altered collagen.⁸ Dermatoscopic findings may aid in recognizing extragenital LSA9,¹⁰; our patient's plaques demonstrated the characteristic findings of comedolike openings, structureless white areas, and pink borders (Figure 3). 

The clinical differential diagnosis for well-demarcated, pink, scaly plaques is broad. Nummular eczema usually presents as coin-shaped eczematous plaques on the dorsal aspects of the hands or lower extremities, and histology shows epidermal spongiosis.¹¹ Nummular eczema may be considered due to the striking round morphology of various plaques, yet our patient's presentation was better served by a consideration of several papulosquamous disorders. 

Lichen planus (LP) presents as intensely pruritic, violaceous, polygonal, flat-topped papules with overlying reticular white lines, or Wickham striae, that favor the flexural wrists, lower back, and lower extremities. Lichen planus also may have oral and genital mucosal involvement. Similar to LSA, LP is more common in women and preferentially affects the postmenopausal population.¹² Additionally, hypertrophic LP may obscure Wickham striae and mimic extragenital LSA; distinguishing features of hypertrophic LP are intense pruritus and a predilection for the shins. Histology is defined by orthohyperkeratosis, hypergranulosis, sawtooth acanthosis, and vacuolar degeneration of the basal layer with Civatte bodies or dyskeratotic basal keratinocytes overlying a characteristic bandlike infiltrate of lymphocytes.¹² 

Lichen simplex chronicus (LSC) is characterized by intense pruritus and presents as hyperkeratotic plaques with a predilection for accessible regions such as the posterior neck and extremities.¹³ The striking annular demarcation of this case makes LSC unlikely. Comparable to LSA and LP, LSC also may present with both genital and extragenital findings. Histology of LSC is characterized by irregular acanthosis or thickening of the epidermis with vertical streaking of collagen and vascular bundles of the papillary dermis.¹³ 

Subacute cutaneous lupus erythematosus (SCLE) is important to consider for a new papulosquamous eruption with a predilection for the sun-exposed skin of a middle-aged woman. The presence of papules on the volar wrist and history of genital irritation, however, make this entity less likely. Similar to LSA, histologic examination of SCLE reveals epidermal atrophy, basal layer degeneration, and papillary dermal edema with lymphocytic inflammation. However, SCLE lacks the band of inflammation underlying pale homogenized papillary dermal collagen, the most distinguishing feature of LSA; instead, SCLE shows superficial and deep perivascular and periadnexal lymphocytes and mucin in the dermis.¹⁴ 

Lichen sclerosus et atrophicus may be chronic and progressive in nature or cycle through remissions and relapses.² Treatment is not curative, and management is directed to alleviating symptoms and preventing the progression of disease. First-line management of extragenital LSA is potent topical steroids.¹ Adjuvant topical calcineurin inhibitors may be used as steroid-sparing agents.² Phototherapy is a second-line therapy and even narrowband UVB phototherapy has demonstrated efficacy in managing extragenital LSA.^15,16 Our patient was started on mometasone ointment and calcipotriene cream with slight improvement after a 6-month trial. Ongoing management is focused on optimizing application of topical therapies.  

A large, retrospective study shows how germline genetic testing has evolved over time in women with breast or ovarian cancer and reveals a path forward for testing these patients.

Investigators found racial and ethnic disparities in genetic testing as well as “persistent underuse” of testing in patients with ovarian cancer.

The team also discovered that most pathogenic variant (PV) results were in 20 genes associated with breast and/or ovarian cancer, and testing other genes largely revealed variants of uncertain significance (VUS).

Allison W. Kurian, MD, of Stanford (Calif.) University, and colleagues recounted these findings in the Journal of Clinical Oncology.

Because of improvements in sequencing technology, competition among commercial purveyors, and declining cost, genetic testing has been increasingly available to clinicians for patient management and cancer prevention (JAMA. 2015 Sep 8;314[10]:997-8). Although germline testing can guide therapy for several solid tumors, there is little research about how often and how well it is used in practice.

For their study, Dr. Kurian and colleagues used a SEER Genetic Testing Linkage Demonstration Project in a population-based assessment of testing for cancer risk. The investigators analyzed 7-year trends in testing among all women diagnosed with breast or ovarian cancer in Georgia or California from 2013 to 2017, reviewing testing patterns and result interpretation from 2012 to 2019.

Before analyzing the data, the investigators made the following hypotheses:

• Multigene panels (MGP) would entirely replace testing for BRCA1/2 only.
• Testing underutilization in patients with ovarian cancer would improve over time.
• More patients would be tested at lower levels of pretest risk for PVs.
• Sociodemographic differences in testing trends would not be observed.
• Detection of PVs and VUS would increase.
• Racial and ethnic disparities in rates of VUS would diminish.

Study conduct

The investigators examined genetic tests performed from 2012 through the beginning of 2019 at major commercial laboratories and linked that information with data in the SEER registries in Georgia and California on all breast and ovarian cancer patients diagnosed between 2013 and 2017. There were few criteria for exclusion.

Genetic testing results were categorized as identifying a PV or likely PV, VUS, or benign or likely benign mutation by American College of Medical Genetics criteria. When a patient had genetic testing on more than one occasion, the most recent test was used.

If a PV was identified, the types of PVs were grouped according to the level of evidence that supported pathogenicity into the following categories:

• BRCA1 or BRCA2 mutations.
• PVs in other genes designated by the National Comprehensive Cancer Network as associated with breast or ovarian cancer (e.g., ATM, BARD1, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, NF1, PALB2, MS2, PTEN, RAD51C, RAD51D, STK11, and TP53).
• PVs in other actionable genes (e.g., APC, BMPR1A, MEN1, MUTYH, NF2, RB1, RET, SDHAF2, SDHB, SDHC, SDHD, SMAD4, TSC1, TSC2, and VHL).
• Any other tested genes.

The investigators also tabulated instances in which genetic testing identified a VUS in any gene but no PV. If a VUS was identified originally and was reclassified more recently into the “PV/likely PV” or “benign/likely benign” categories, only the resolved categorization was recorded.

The authors evaluated clinical and sociodemographic correlates of testing trends for breast and ovarian cancer, assessing the relationship between race, age, and geographic site in receipt of any test or type of test.

Among laboratories, the investigators examined trends in the number of genes tested, associations with sociodemographic factors, categories of test results, and whether trends differed by race or ethnicity.
 

Findings, by hypothesis

Hypothesis #1: MGP will entirely replace testing for BRCA1/2 only.

About 25% of tested patients with breast cancer diagnosed in early 2013 received MGP, compared with more than 80% of those diagnosed in late 2017.

The trend for ovarian cancer was similar. About 40% of patients diagnosed in early 2013 received MGP, compared with more than 90% diagnosed in late 2017. These trends were similar in California and Georgia.

From 2012 to 2019, there was a consistent upward trend in gene number for patients with breast cancer (mean, 19) or ovarian cancer (mean, 21), from approximately 10 genes to 35 genes.
 

Hypothesis #2: Underutilization of testing in patients with ovarian cancer will improve.

Among the 187,535 patients with breast cancer and the 14,689 patients with ovarian cancer diagnosed in Georgia or California from 2013 through 2017, on average, testing rates increased 2% per year.

In all, 25.2% of breast cancer patients and 34.3% of ovarian cancer patients had genetic testing on one (87.3%) or more (12.7%) occasions.

Prior research suggested that, in 2013 and 2014, 31% of women with ovarian cancer had genetic testing (JAMA Oncol. 2018 Aug 1;4[8]:1066-72/ J Clin Oncol. 2019 May 20;37[15]:1305-15).

The investigators therefore concluded that underutilization of genetic testing in ovarian cancer did not improve substantially during the 7-year interval analyzed.
 

Hypothesis #3: More patients will be tested at lower levels of pretest risk.

These data were more difficult to abstract from the SEER database, but older patients were more likely to be tested in later years.

In patients older than 60 years of age (who accounted for more than 50% of both cancer cohorts), testing rates increased from 11.1% to 14.9% for breast cancer and 25.3% to 31.4% for ovarian cancer. By contrast, patients younger than 45 years of age were less than 15% of the sample and had lower testing rates over time.

There were no substantial changes in testing rates by other clinical variables. Therefore, in concert with the age-related testing trends, it is likely that women were tested for genetic mutations at increasingly lower levels of pretest risk.
 

Hypothesis #4: Sociodemographic differences in testing trends will not be observed.

Among patients with breast cancer, approximately 31% of those who had genetic testing were uninsured, 31% had Medicaid, and 26% had private insurance, Medicare, or other insurance.

For patients with ovarian cancer, approximately 28% were uninsured, 27% had Medicaid, and 39% had private insurance, Medicare, or other insurance.

The authors had previously found that less testing was associated with Black race, greater poverty, and less insurance coverage (J Clin Oncol. 2019 May 20;37[15]:1305-15). However, they noted no changes in testing rates by sociodemographic variables over time.
 

Hypothesis #5: Detection of both PVs and VUS will increase.

The proportion of tested breast cancer patients with PVs in BRCA1/2 decreased from 7.5% to 5.0% (P < .001), whereas PV yield for the two other clinically salient categories (breast or ovarian and other actionable genes) increased.

The proportion of PVs in any breast or ovarian gene increased from 1.3% to 4.6%, and the proportion in any other actionable gene increased from 0.3% to 1.3%.

For breast cancer patients, VUS-only rates increased from 8.5% in early 2013 to 22.4% in late 2017.

For ovarian cancer patients, the yield of PVs in BRCA1/2 decreased from 15.7% to 12.4% (P < .001), whereas the PV yield for breast or ovarian genes increased from 3.9% to 4.3%, and the yield for other actionable genes increased from 0.3% to 2.0%.

In ovarian cancer patients, the PV or VUS-only result rate increased from 30.8% in early 2013 to 43.0% in late 2017, entirely due to the increase in VUS-only rates. VUS were identified in 8.1% of patients diagnosed in early 2013 and increased to 28.3% in patients diagnosed in late 2017.
 

Hypothesis #6: Racial or ethnic disparities in rates of VUS will diminish.

Among patients with breast cancer, racial or ethnic differences in PV rates were small and did not change over time. For patients with ovarian cancer, PV rates across racial or ethnic groups diminished over time.

However, for both breast and ovarian cancer patients, there were large differences in VUS-only rates by race and ethnicity that persisted during the interval studied.

In 2017, for patients with breast cancer, VUS-only rates were substantially higher in Asian (42.4%), Black (36.6%), and Hispanic (27.7%) patients than in non-Hispanic White patients (24.5%, P < .001).

Similar trends were noted for patients with ovarian cancer. VUS-only rates were substantially higher in Asian (47.8%), Black (46.0%), and Hispanic (36.8%) patients than in non-Hispanic White patients (24.6%, P < .001).

Multivariable logistic regressions were performed separately for tested patients with breast cancer and ovarian cancer, and the results showed no significant interaction between race or ethnicity and date. Therefore, there was no significant change in racial or ethnic differences in VUS-only results across the study period.
 

Where these findings leave clinicians in 2021

Among the patients studied, there was:

• Marked expansion in the number of genes sequenced.
• A likely modest trend toward testing patients with lower pretest risk of a PV.
• No sociodemographic differences in testing trends.
• A small increase in PV rates and a substantial increase in VUS-only rates.
• Near-complete replacement of selective testing by MGP.

For patients with breast cancer, the proportion of all PVs that were in BRCA1/2 fell substantially. Adoption of MGP testing doubled the probability of detecting a PV in other tested genes. Most of the increase was in genes with an established breast or ovarian cancer association, with fewer PVs found in other actionable genes and very few PVs in other tested genes.

Contrary to their hypothesis, the authors observed a sustained undertesting of patients with ovarian cancer. Only 34.3% performed versus nearly 100% recommended, with little change since 2014.

This finding is surprising – and tremendously disappointing – since the prevalence of BRCA1/2 PVs is higher in ovarian cancer than in other cancers (Gynecol Oncol. 2017 Nov;147[2]:375-380), and germline-targeted therapy with PARP inhibitors has been approved for use since 2014.

Furthermore, insurance carriers provide coverage for genetic testing in most patients with carcinoma of the ovary, fallopian tube, and/or peritoneum.
 

Action plans: Less could be more

During the period analyzed, the increase in VUS-only results dramatically outpaced the increase in PVs.

Since there is a substantially larger volume of clinical genetic testing in non-Hispanic White patients with breast or ovarian cancer, the spectrum of normal variation is less well-defined in other racial or ethnic groups.

The study showed a widening of the “racial-ethnic VUS gap,” with Black and Asian patients having nearly twofold more VUS, although they were not tested for more genes than non-Hispanic White patients.

This is problematic on several levels. Identification of a VUS is challenging for communicating results to and recommending cascade testing for family members.

There is worrisome information regarding overtreatment or counseling of VUS patients about their results. For example, the PROMPT registry showed that 10%-15% of women with PV/VUS in genes not associated with a high risk of ovarian cancer underwent oophorectomy without a clear indication for the procedure.

Although population-based testing might augment the available data on the spectrum of normal variation in racial and ethnic minorities, it would likely exacerbate the proliferation of VUS over PVs.

It is essential to accelerate ongoing approaches to VUS reclassification.

In addition, the authors suggest that it may be time to reverse the trend in increasing the number of genes tested in MGPs. Their rationale is that, in Georgia and California, most PVs among patients with breast and ovarian cancer were identified in 20 genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, NF1, PMS2, PALB2, PTEN, RAD51C, RAD51D, STK11, and TP53).

If the Georgia and California data are representative of a more generalized pattern, a panel of 20 breast cancer– and/or ovarian cancer–associated genes may be ideal for maximizing the yield of clinically relevant PVs and minimizing VUS results for all patients.

Finally, defining the patient, clinician, and health care system factors that impede widespread genetic testing for ovarian cancer patients must be prioritized. As the authors suggest, quality improvement efforts should focus on getting a lot closer to testing rates of 100% for patients with ovarian cancer and building the database that will help sort VUS in minority patients into their proper context of pathogenicity, rather than adding more genes per test.

This research was supported by the National Cancer Institute, the Centers for Disease Control and Prevention, and the California Department of Public Health. The authors disclosed relationships with Myriad Genetics, Ambry Genetics, Color Genomics, GeneDx/BioReference, InVitae, Genentech, Genomic Health, Roche/Genentech, Oncoquest, Tesaro, and Karyopharm Therapeutics.
 

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

A large, retrospective study shows how germline genetic testing has evolved over time in women with breast or ovarian cancer and reveals a path forward for testing these patients.

Investigators found racial and ethnic disparities in genetic testing as well as “persistent underuse” of testing in patients with ovarian cancer.

The team also discovered that most pathogenic variant (PV) results were in 20 genes associated with breast and/or ovarian cancer, and testing other genes largely revealed variants of uncertain significance (VUS).

Allison W. Kurian, MD, of Stanford (Calif.) University, and colleagues recounted these findings in the Journal of Clinical Oncology.

Because of improvements in sequencing technology, competition among commercial purveyors, and declining cost, genetic testing has been increasingly available to clinicians for patient management and cancer prevention (JAMA. 2015 Sep 8;314[10]:997-8). Although germline testing can guide therapy for several solid tumors, there is little research about how often and how well it is used in practice.

For their study, Dr. Kurian and colleagues used a SEER Genetic Testing Linkage Demonstration Project in a population-based assessment of testing for cancer risk. The investigators analyzed 7-year trends in testing among all women diagnosed with breast or ovarian cancer in Georgia or California from 2013 to 2017, reviewing testing patterns and result interpretation from 2012 to 2019.

Before analyzing the data, the investigators made the following hypotheses:

• Multigene panels (MGP) would entirely replace testing for BRCA1/2 only.
• Testing underutilization in patients with ovarian cancer would improve over time.
• More patients would be tested at lower levels of pretest risk for PVs.
• Sociodemographic differences in testing trends would not be observed.
• Detection of PVs and VUS would increase.
• Racial and ethnic disparities in rates of VUS would diminish.

Study conduct

The investigators examined genetic tests performed from 2012 through the beginning of 2019 at major commercial laboratories and linked that information with data in the SEER registries in Georgia and California on all breast and ovarian cancer patients diagnosed between 2013 and 2017. There were few criteria for exclusion.

Genetic testing results were categorized as identifying a PV or likely PV, VUS, or benign or likely benign mutation by American College of Medical Genetics criteria. When a patient had genetic testing on more than one occasion, the most recent test was used.

If a PV was identified, the types of PVs were grouped according to the level of evidence that supported pathogenicity into the following categories:

• BRCA1 or BRCA2 mutations.
• PVs in other genes designated by the National Comprehensive Cancer Network as associated with breast or ovarian cancer (e.g., ATM, BARD1, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, NF1, PALB2, MS2, PTEN, RAD51C, RAD51D, STK11, and TP53).
• PVs in other actionable genes (e.g., APC, BMPR1A, MEN1, MUTYH, NF2, RB1, RET, SDHAF2, SDHB, SDHC, SDHD, SMAD4, TSC1, TSC2, and VHL).
• Any other tested genes.

The investigators also tabulated instances in which genetic testing identified a VUS in any gene but no PV. If a VUS was identified originally and was reclassified more recently into the “PV/likely PV” or “benign/likely benign” categories, only the resolved categorization was recorded.

The authors evaluated clinical and sociodemographic correlates of testing trends for breast and ovarian cancer, assessing the relationship between race, age, and geographic site in receipt of any test or type of test.

Among laboratories, the investigators examined trends in the number of genes tested, associations with sociodemographic factors, categories of test results, and whether trends differed by race or ethnicity.
 

Findings, by hypothesis

Hypothesis #1: MGP will entirely replace testing for BRCA1/2 only.

About 25% of tested patients with breast cancer diagnosed in early 2013 received MGP, compared with more than 80% of those diagnosed in late 2017.

The trend for ovarian cancer was similar. About 40% of patients diagnosed in early 2013 received MGP, compared with more than 90% diagnosed in late 2017. These trends were similar in California and Georgia.

From 2012 to 2019, there was a consistent upward trend in gene number for patients with breast cancer (mean, 19) or ovarian cancer (mean, 21), from approximately 10 genes to 35 genes.
 

Hypothesis #2: Underutilization of testing in patients with ovarian cancer will improve.

Among the 187,535 patients with breast cancer and the 14,689 patients with ovarian cancer diagnosed in Georgia or California from 2013 through 2017, on average, testing rates increased 2% per year.

In all, 25.2% of breast cancer patients and 34.3% of ovarian cancer patients had genetic testing on one (87.3%) or more (12.7%) occasions.

Prior research suggested that, in 2013 and 2014, 31% of women with ovarian cancer had genetic testing (JAMA Oncol. 2018 Aug 1;4[8]:1066-72/ J Clin Oncol. 2019 May 20;37[15]:1305-15).

The investigators therefore concluded that underutilization of genetic testing in ovarian cancer did not improve substantially during the 7-year interval analyzed.
 

Hypothesis #3: More patients will be tested at lower levels of pretest risk.

These data were more difficult to abstract from the SEER database, but older patients were more likely to be tested in later years.

In patients older than 60 years of age (who accounted for more than 50% of both cancer cohorts), testing rates increased from 11.1% to 14.9% for breast cancer and 25.3% to 31.4% for ovarian cancer. By contrast, patients younger than 45 years of age were less than 15% of the sample and had lower testing rates over time.

There were no substantial changes in testing rates by other clinical variables. Therefore, in concert with the age-related testing trends, it is likely that women were tested for genetic mutations at increasingly lower levels of pretest risk.
 

Hypothesis #4: Sociodemographic differences in testing trends will not be observed.

Among patients with breast cancer, approximately 31% of those who had genetic testing were uninsured, 31% had Medicaid, and 26% had private insurance, Medicare, or other insurance.

For patients with ovarian cancer, approximately 28% were uninsured, 27% had Medicaid, and 39% had private insurance, Medicare, or other insurance.

The authors had previously found that less testing was associated with Black race, greater poverty, and less insurance coverage (J Clin Oncol. 2019 May 20;37[15]:1305-15). However, they noted no changes in testing rates by sociodemographic variables over time.
 

Hypothesis #5: Detection of both PVs and VUS will increase.

The proportion of tested breast cancer patients with PVs in BRCA1/2 decreased from 7.5% to 5.0% (P < .001), whereas PV yield for the two other clinically salient categories (breast or ovarian and other actionable genes) increased.

The proportion of PVs in any breast or ovarian gene increased from 1.3% to 4.6%, and the proportion in any other actionable gene increased from 0.3% to 1.3%.

For breast cancer patients, VUS-only rates increased from 8.5% in early 2013 to 22.4% in late 2017.

For ovarian cancer patients, the yield of PVs in BRCA1/2 decreased from 15.7% to 12.4% (P < .001), whereas the PV yield for breast or ovarian genes increased from 3.9% to 4.3%, and the yield for other actionable genes increased from 0.3% to 2.0%.

In ovarian cancer patients, the PV or VUS-only result rate increased from 30.8% in early 2013 to 43.0% in late 2017, entirely due to the increase in VUS-only rates. VUS were identified in 8.1% of patients diagnosed in early 2013 and increased to 28.3% in patients diagnosed in late 2017.
 

Hypothesis #6: Racial or ethnic disparities in rates of VUS will diminish.

Among patients with breast cancer, racial or ethnic differences in PV rates were small and did not change over time. For patients with ovarian cancer, PV rates across racial or ethnic groups diminished over time.

However, for both breast and ovarian cancer patients, there were large differences in VUS-only rates by race and ethnicity that persisted during the interval studied.

In 2017, for patients with breast cancer, VUS-only rates were substantially higher in Asian (42.4%), Black (36.6%), and Hispanic (27.7%) patients than in non-Hispanic White patients (24.5%, P < .001).

Similar trends were noted for patients with ovarian cancer. VUS-only rates were substantially higher in Asian (47.8%), Black (46.0%), and Hispanic (36.8%) patients than in non-Hispanic White patients (24.6%, P < .001).

Multivariable logistic regressions were performed separately for tested patients with breast cancer and ovarian cancer, and the results showed no significant interaction between race or ethnicity and date. Therefore, there was no significant change in racial or ethnic differences in VUS-only results across the study period.
 

Where these findings leave clinicians in 2021

Among the patients studied, there was:

• Marked expansion in the number of genes sequenced.
• A likely modest trend toward testing patients with lower pretest risk of a PV.
• No sociodemographic differences in testing trends.
• A small increase in PV rates and a substantial increase in VUS-only rates.
• Near-complete replacement of selective testing by MGP.

For patients with breast cancer, the proportion of all PVs that were in BRCA1/2 fell substantially. Adoption of MGP testing doubled the probability of detecting a PV in other tested genes. Most of the increase was in genes with an established breast or ovarian cancer association, with fewer PVs found in other actionable genes and very few PVs in other tested genes.

Contrary to their hypothesis, the authors observed a sustained undertesting of patients with ovarian cancer. Only 34.3% performed versus nearly 100% recommended, with little change since 2014.

This finding is surprising – and tremendously disappointing – since the prevalence of BRCA1/2 PVs is higher in ovarian cancer than in other cancers (Gynecol Oncol. 2017 Nov;147[2]:375-380), and germline-targeted therapy with PARP inhibitors has been approved for use since 2014.

Furthermore, insurance carriers provide coverage for genetic testing in most patients with carcinoma of the ovary, fallopian tube, and/or peritoneum.
 

Action plans: Less could be more

During the period analyzed, the increase in VUS-only results dramatically outpaced the increase in PVs.

Since there is a substantially larger volume of clinical genetic testing in non-Hispanic White patients with breast or ovarian cancer, the spectrum of normal variation is less well-defined in other racial or ethnic groups.

The study showed a widening of the “racial-ethnic VUS gap,” with Black and Asian patients having nearly twofold more VUS, although they were not tested for more genes than non-Hispanic White patients.

This is problematic on several levels. Identification of a VUS is challenging for communicating results to and recommending cascade testing for family members.

There is worrisome information regarding overtreatment or counseling of VUS patients about their results. For example, the PROMPT registry showed that 10%-15% of women with PV/VUS in genes not associated with a high risk of ovarian cancer underwent oophorectomy without a clear indication for the procedure.

Although population-based testing might augment the available data on the spectrum of normal variation in racial and ethnic minorities, it would likely exacerbate the proliferation of VUS over PVs.

It is essential to accelerate ongoing approaches to VUS reclassification.

In addition, the authors suggest that it may be time to reverse the trend in increasing the number of genes tested in MGPs. Their rationale is that, in Georgia and California, most PVs among patients with breast and ovarian cancer were identified in 20 genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, NF1, PMS2, PALB2, PTEN, RAD51C, RAD51D, STK11, and TP53).

If the Georgia and California data are representative of a more generalized pattern, a panel of 20 breast cancer– and/or ovarian cancer–associated genes may be ideal for maximizing the yield of clinically relevant PVs and minimizing VUS results for all patients.

Finally, defining the patient, clinician, and health care system factors that impede widespread genetic testing for ovarian cancer patients must be prioritized. As the authors suggest, quality improvement efforts should focus on getting a lot closer to testing rates of 100% for patients with ovarian cancer and building the database that will help sort VUS in minority patients into their proper context of pathogenicity, rather than adding more genes per test.

This research was supported by the National Cancer Institute, the Centers for Disease Control and Prevention, and the California Department of Public Health. The authors disclosed relationships with Myriad Genetics, Ambry Genetics, Color Genomics, GeneDx/BioReference, InVitae, Genentech, Genomic Health, Roche/Genentech, Oncoquest, Tesaro, and Karyopharm Therapeutics.
 

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

A large, retrospective study shows how germline genetic testing has evolved over time in women with breast or ovarian cancer and reveals a path forward for testing these patients.

Investigators found racial and ethnic disparities in genetic testing as well as “persistent underuse” of testing in patients with ovarian cancer.

The team also discovered that most pathogenic variant (PV) results were in 20 genes associated with breast and/or ovarian cancer, and testing other genes largely revealed variants of uncertain significance (VUS).

Allison W. Kurian, MD, of Stanford (Calif.) University, and colleagues recounted these findings in the Journal of Clinical Oncology.

Because of improvements in sequencing technology, competition among commercial purveyors, and declining cost, genetic testing has been increasingly available to clinicians for patient management and cancer prevention (JAMA. 2015 Sep 8;314[10]:997-8). Although germline testing can guide therapy for several solid tumors, there is little research about how often and how well it is used in practice.

For their study, Dr. Kurian and colleagues used a SEER Genetic Testing Linkage Demonstration Project in a population-based assessment of testing for cancer risk. The investigators analyzed 7-year trends in testing among all women diagnosed with breast or ovarian cancer in Georgia or California from 2013 to 2017, reviewing testing patterns and result interpretation from 2012 to 2019.

Before analyzing the data, the investigators made the following hypotheses:

• Multigene panels (MGP) would entirely replace testing for BRCA1/2 only.
• Testing underutilization in patients with ovarian cancer would improve over time.
• More patients would be tested at lower levels of pretest risk for PVs.
• Sociodemographic differences in testing trends would not be observed.
• Detection of PVs and VUS would increase.
• Racial and ethnic disparities in rates of VUS would diminish.

Study conduct

The investigators examined genetic tests performed from 2012 through the beginning of 2019 at major commercial laboratories and linked that information with data in the SEER registries in Georgia and California on all breast and ovarian cancer patients diagnosed between 2013 and 2017. There were few criteria for exclusion.

Genetic testing results were categorized as identifying a PV or likely PV, VUS, or benign or likely benign mutation by American College of Medical Genetics criteria. When a patient had genetic testing on more than one occasion, the most recent test was used.

If a PV was identified, the types of PVs were grouped according to the level of evidence that supported pathogenicity into the following categories:

• BRCA1 or BRCA2 mutations.
• PVs in other genes designated by the National Comprehensive Cancer Network as associated with breast or ovarian cancer (e.g., ATM, BARD1, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, NF1, PALB2, MS2, PTEN, RAD51C, RAD51D, STK11, and TP53).
• PVs in other actionable genes (e.g., APC, BMPR1A, MEN1, MUTYH, NF2, RB1, RET, SDHAF2, SDHB, SDHC, SDHD, SMAD4, TSC1, TSC2, and VHL).
• Any other tested genes.

The investigators also tabulated instances in which genetic testing identified a VUS in any gene but no PV. If a VUS was identified originally and was reclassified more recently into the “PV/likely PV” or “benign/likely benign” categories, only the resolved categorization was recorded.

The authors evaluated clinical and sociodemographic correlates of testing trends for breast and ovarian cancer, assessing the relationship between race, age, and geographic site in receipt of any test or type of test.

Among laboratories, the investigators examined trends in the number of genes tested, associations with sociodemographic factors, categories of test results, and whether trends differed by race or ethnicity.
 

Findings, by hypothesis

Hypothesis #1: MGP will entirely replace testing for BRCA1/2 only.

About 25% of tested patients with breast cancer diagnosed in early 2013 received MGP, compared with more than 80% of those diagnosed in late 2017.

The trend for ovarian cancer was similar. About 40% of patients diagnosed in early 2013 received MGP, compared with more than 90% diagnosed in late 2017. These trends were similar in California and Georgia.

From 2012 to 2019, there was a consistent upward trend in gene number for patients with breast cancer (mean, 19) or ovarian cancer (mean, 21), from approximately 10 genes to 35 genes.
 

Hypothesis #2: Underutilization of testing in patients with ovarian cancer will improve.

Among the 187,535 patients with breast cancer and the 14,689 patients with ovarian cancer diagnosed in Georgia or California from 2013 through 2017, on average, testing rates increased 2% per year.

In all, 25.2% of breast cancer patients and 34.3% of ovarian cancer patients had genetic testing on one (87.3%) or more (12.7%) occasions.

Prior research suggested that, in 2013 and 2014, 31% of women with ovarian cancer had genetic testing (JAMA Oncol. 2018 Aug 1;4[8]:1066-72/ J Clin Oncol. 2019 May 20;37[15]:1305-15).

The investigators therefore concluded that underutilization of genetic testing in ovarian cancer did not improve substantially during the 7-year interval analyzed.
 

Hypothesis #3: More patients will be tested at lower levels of pretest risk.

These data were more difficult to abstract from the SEER database, but older patients were more likely to be tested in later years.

In patients older than 60 years of age (who accounted for more than 50% of both cancer cohorts), testing rates increased from 11.1% to 14.9% for breast cancer and 25.3% to 31.4% for ovarian cancer. By contrast, patients younger than 45 years of age were less than 15% of the sample and had lower testing rates over time.

There were no substantial changes in testing rates by other clinical variables. Therefore, in concert with the age-related testing trends, it is likely that women were tested for genetic mutations at increasingly lower levels of pretest risk.
 

Hypothesis #4: Sociodemographic differences in testing trends will not be observed.

Among patients with breast cancer, approximately 31% of those who had genetic testing were uninsured, 31% had Medicaid, and 26% had private insurance, Medicare, or other insurance.

For patients with ovarian cancer, approximately 28% were uninsured, 27% had Medicaid, and 39% had private insurance, Medicare, or other insurance.

The authors had previously found that less testing was associated with Black race, greater poverty, and less insurance coverage (J Clin Oncol. 2019 May 20;37[15]:1305-15). However, they noted no changes in testing rates by sociodemographic variables over time.
 

Hypothesis #5: Detection of both PVs and VUS will increase.

The proportion of tested breast cancer patients with PVs in BRCA1/2 decreased from 7.5% to 5.0% (P < .001), whereas PV yield for the two other clinically salient categories (breast or ovarian and other actionable genes) increased.

The proportion of PVs in any breast or ovarian gene increased from 1.3% to 4.6%, and the proportion in any other actionable gene increased from 0.3% to 1.3%.

For breast cancer patients, VUS-only rates increased from 8.5% in early 2013 to 22.4% in late 2017.

For ovarian cancer patients, the yield of PVs in BRCA1/2 decreased from 15.7% to 12.4% (P < .001), whereas the PV yield for breast or ovarian genes increased from 3.9% to 4.3%, and the yield for other actionable genes increased from 0.3% to 2.0%.

In ovarian cancer patients, the PV or VUS-only result rate increased from 30.8% in early 2013 to 43.0% in late 2017, entirely due to the increase in VUS-only rates. VUS were identified in 8.1% of patients diagnosed in early 2013 and increased to 28.3% in patients diagnosed in late 2017.
 

Hypothesis #6: Racial or ethnic disparities in rates of VUS will diminish.

Among patients with breast cancer, racial or ethnic differences in PV rates were small and did not change over time. For patients with ovarian cancer, PV rates across racial or ethnic groups diminished over time.

However, for both breast and ovarian cancer patients, there were large differences in VUS-only rates by race and ethnicity that persisted during the interval studied.

In 2017, for patients with breast cancer, VUS-only rates were substantially higher in Asian (42.4%), Black (36.6%), and Hispanic (27.7%) patients than in non-Hispanic White patients (24.5%, P < .001).

Similar trends were noted for patients with ovarian cancer. VUS-only rates were substantially higher in Asian (47.8%), Black (46.0%), and Hispanic (36.8%) patients than in non-Hispanic White patients (24.6%, P < .001).

Multivariable logistic regressions were performed separately for tested patients with breast cancer and ovarian cancer, and the results showed no significant interaction between race or ethnicity and date. Therefore, there was no significant change in racial or ethnic differences in VUS-only results across the study period.
 

Where these findings leave clinicians in 2021

Among the patients studied, there was:

• Marked expansion in the number of genes sequenced.
• A likely modest trend toward testing patients with lower pretest risk of a PV.
• No sociodemographic differences in testing trends.
• A small increase in PV rates and a substantial increase in VUS-only rates.
• Near-complete replacement of selective testing by MGP.

For patients with breast cancer, the proportion of all PVs that were in BRCA1/2 fell substantially. Adoption of MGP testing doubled the probability of detecting a PV in other tested genes. Most of the increase was in genes with an established breast or ovarian cancer association, with fewer PVs found in other actionable genes and very few PVs in other tested genes.

Contrary to their hypothesis, the authors observed a sustained undertesting of patients with ovarian cancer. Only 34.3% performed versus nearly 100% recommended, with little change since 2014.

This finding is surprising – and tremendously disappointing – since the prevalence of BRCA1/2 PVs is higher in ovarian cancer than in other cancers (Gynecol Oncol. 2017 Nov;147[2]:375-380), and germline-targeted therapy with PARP inhibitors has been approved for use since 2014.

Furthermore, insurance carriers provide coverage for genetic testing in most patients with carcinoma of the ovary, fallopian tube, and/or peritoneum.
 

Action plans: Less could be more

During the period analyzed, the increase in VUS-only results dramatically outpaced the increase in PVs.

Since there is a substantially larger volume of clinical genetic testing in non-Hispanic White patients with breast or ovarian cancer, the spectrum of normal variation is less well-defined in other racial or ethnic groups.

The study showed a widening of the “racial-ethnic VUS gap,” with Black and Asian patients having nearly twofold more VUS, although they were not tested for more genes than non-Hispanic White patients.

This is problematic on several levels. Identification of a VUS is challenging for communicating results to and recommending cascade testing for family members.

There is worrisome information regarding overtreatment or counseling of VUS patients about their results. For example, the PROMPT registry showed that 10%-15% of women with PV/VUS in genes not associated with a high risk of ovarian cancer underwent oophorectomy without a clear indication for the procedure.

Although population-based testing might augment the available data on the spectrum of normal variation in racial and ethnic minorities, it would likely exacerbate the proliferation of VUS over PVs.

It is essential to accelerate ongoing approaches to VUS reclassification.

In addition, the authors suggest that it may be time to reverse the trend in increasing the number of genes tested in MGPs. Their rationale is that, in Georgia and California, most PVs among patients with breast and ovarian cancer were identified in 20 genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, NF1, PMS2, PALB2, PTEN, RAD51C, RAD51D, STK11, and TP53).

If the Georgia and California data are representative of a more generalized pattern, a panel of 20 breast cancer– and/or ovarian cancer–associated genes may be ideal for maximizing the yield of clinically relevant PVs and minimizing VUS results for all patients.

Finally, defining the patient, clinician, and health care system factors that impede widespread genetic testing for ovarian cancer patients must be prioritized. As the authors suggest, quality improvement efforts should focus on getting a lot closer to testing rates of 100% for patients with ovarian cancer and building the database that will help sort VUS in minority patients into their proper context of pathogenicity, rather than adding more genes per test.

This research was supported by the National Cancer Institute, the Centers for Disease Control and Prevention, and the California Department of Public Health. The authors disclosed relationships with Myriad Genetics, Ambry Genetics, Color Genomics, GeneDx/BioReference, InVitae, Genentech, Genomic Health, Roche/Genentech, Oncoquest, Tesaro, and Karyopharm Therapeutics.
 

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Like other people, patients with multiple sclerosis (MS) who become infected with COVID-19 face worse outcomes if they’re older and more disabled, a biostatistician told neurologists. With the exception of anti-CD20s, registries also suggest that disease-modifying therapies (DMTs) don’t cause higher degrees of severity.

“It’s good news since it’s important for patients to stay on these treatments,” said Amber Salter, PhD, MPH, an assistant professor at Washington University, St. Louis, in a follow-up interview following her presentation at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

Dr. Salter reported on the findings of several MS/COVID-19 registries from around the world, including the COViMS Registry, which is supported by the Consortium of MS Centers, the MS Society of Canada, and the National MS Society. It tracks patients who developed COVID-19 while also having MS, neuromyelitis optica, or MOG antibody disease.

The registry began collecting data in April 2020 and is ongoing. As of Jan. 29, 2021, 2,059 patients had been tracked; 85% of cases were confirmed by laboratory tests. Nearly all patients (97%) were from the United States, with about 21% from New York state. Nearly 76% were female, the average age was 48. About 70% were non-Hispanic White, 18% were African American; 83% had relapsing remitting MS, and 17% had progressive MS.

“We found that 11.5% of MS patients were reported being hospitalized, while 4.2% were admitted to the ICU or ventilated and 3% had died,” Dr. Salter said. Not surprisingly, the death rate was highest (21%) in patients aged 75 years or older, compared with 11% of those aged 65-74 years. Those with more severe cases – those who were nonambulatory – had a death rate of 18%, compared with 0.6% of those who were fully ambulatory and 4% of those who walked with assistance.

“A lot of the risks [for COVID-19 severity] we see in the general population are risks in the MS population,” Dr. Salter said.

Dr. Salter also summarized the results of other international registries. After adjustment, a registry in Italy linked the anti-CD20 drugs ocrelizumab or rituximab (odds ratio, 2.37, P = .015) and recent use of methylprednisolone (OR, 5.2; P = .001) to more severe courses of COVID-19, compared with other DMTs. And a global data-sharing project linked anti-CD20s to more severe outcomes, compared with other DMTs (hospitalization, adjusted prevalence ratio, 1.49; ICU admission, aPR, 2.55; and ventilation, aPR, 3.05).

In an interview, neurologist Lauren Gluck, MD, of Albert Einstein College of Medicine and Montefiore Medical Center, both in New York, cautioned that prescribing anti-CD20s now “requires a more complex informed consent process with patients and outlining of risk as well as strategies to minimize contracting the infection.”

Moving forward, she advised colleagues to “keep treating MS with DMTs. Preventing MS attacks will help keep patients out of the hospital and limit need for high-dose steroids.” And she cautioned that “avoiding action due to inaccurate fear of DMTs and COVID-19 may put your patients at unnecessary risk of relapses and accumulated disability. Educate your patients on the reality of the COVID19 pandemic, their personal risk of exposure, and strategies to minimize their risk.”

Fortunately, vaccinations offer protection against COVID-19 in patients with MS, although patients are clearly concerned about potential risks. “A frequent concern is whether the vaccines are safe for MS patients in general and if they could incite MS relapses,” neurologist Hesham Abboud, MD, PhD, of University Hospitals of Cleveland and Case Western Reserve University, said in an interview. “The American Academy of Neurology guidelines have not found a connection between vaccination and MS relapses. Having COVID-19 infection can trigger MS relapses, so clearly the benefit from the vaccine outweighs any potential risks. Obviously, it is not advisable to take any vaccine during an active relapse, but vaccines are safe otherwise when given during remission.”

Dr. Salter and Dr. Gluck reported no relevant disclosures. Dr. Abboud reports consulting fees from Biogen, Genentech, Bristol-Myers Squibb, Alexion, and Viela Bio. He receives research support from Novartis, Bristol-Myers Squibb, Genentech, and Sanofi-Genzyme.


 

Like other people, patients with multiple sclerosis (MS) who become infected with COVID-19 face worse outcomes if they’re older and more disabled, a biostatistician told neurologists. With the exception of anti-CD20s, registries also suggest that disease-modifying therapies (DMTs) don’t cause higher degrees of severity.

“It’s good news since it’s important for patients to stay on these treatments,” said Amber Salter, PhD, MPH, an assistant professor at Washington University, St. Louis, in a follow-up interview following her presentation at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

Dr. Salter reported on the findings of several MS/COVID-19 registries from around the world, including the COViMS Registry, which is supported by the Consortium of MS Centers, the MS Society of Canada, and the National MS Society. It tracks patients who developed COVID-19 while also having MS, neuromyelitis optica, or MOG antibody disease.

The registry began collecting data in April 2020 and is ongoing. As of Jan. 29, 2021, 2,059 patients had been tracked; 85% of cases were confirmed by laboratory tests. Nearly all patients (97%) were from the United States, with about 21% from New York state. Nearly 76% were female, the average age was 48. About 70% were non-Hispanic White, 18% were African American; 83% had relapsing remitting MS, and 17% had progressive MS.

“We found that 11.5% of MS patients were reported being hospitalized, while 4.2% were admitted to the ICU or ventilated and 3% had died,” Dr. Salter said. Not surprisingly, the death rate was highest (21%) in patients aged 75 years or older, compared with 11% of those aged 65-74 years. Those with more severe cases – those who were nonambulatory – had a death rate of 18%, compared with 0.6% of those who were fully ambulatory and 4% of those who walked with assistance.

“A lot of the risks [for COVID-19 severity] we see in the general population are risks in the MS population,” Dr. Salter said.

Dr. Salter also summarized the results of other international registries. After adjustment, a registry in Italy linked the anti-CD20 drugs ocrelizumab or rituximab (odds ratio, 2.37, P = .015) and recent use of methylprednisolone (OR, 5.2; P = .001) to more severe courses of COVID-19, compared with other DMTs. And a global data-sharing project linked anti-CD20s to more severe outcomes, compared with other DMTs (hospitalization, adjusted prevalence ratio, 1.49; ICU admission, aPR, 2.55; and ventilation, aPR, 3.05).

In an interview, neurologist Lauren Gluck, MD, of Albert Einstein College of Medicine and Montefiore Medical Center, both in New York, cautioned that prescribing anti-CD20s now “requires a more complex informed consent process with patients and outlining of risk as well as strategies to minimize contracting the infection.”

Moving forward, she advised colleagues to “keep treating MS with DMTs. Preventing MS attacks will help keep patients out of the hospital and limit need for high-dose steroids.” And she cautioned that “avoiding action due to inaccurate fear of DMTs and COVID-19 may put your patients at unnecessary risk of relapses and accumulated disability. Educate your patients on the reality of the COVID19 pandemic, their personal risk of exposure, and strategies to minimize their risk.”

Fortunately, vaccinations offer protection against COVID-19 in patients with MS, although patients are clearly concerned about potential risks. “A frequent concern is whether the vaccines are safe for MS patients in general and if they could incite MS relapses,” neurologist Hesham Abboud, MD, PhD, of University Hospitals of Cleveland and Case Western Reserve University, said in an interview. “The American Academy of Neurology guidelines have not found a connection between vaccination and MS relapses. Having COVID-19 infection can trigger MS relapses, so clearly the benefit from the vaccine outweighs any potential risks. Obviously, it is not advisable to take any vaccine during an active relapse, but vaccines are safe otherwise when given during remission.”

Dr. Salter and Dr. Gluck reported no relevant disclosures. Dr. Abboud reports consulting fees from Biogen, Genentech, Bristol-Myers Squibb, Alexion, and Viela Bio. He receives research support from Novartis, Bristol-Myers Squibb, Genentech, and Sanofi-Genzyme.


 

Like other people, patients with multiple sclerosis (MS) who become infected with COVID-19 face worse outcomes if they’re older and more disabled, a biostatistician told neurologists. With the exception of anti-CD20s, registries also suggest that disease-modifying therapies (DMTs) don’t cause higher degrees of severity.

“It’s good news since it’s important for patients to stay on these treatments,” said Amber Salter, PhD, MPH, an assistant professor at Washington University, St. Louis, in a follow-up interview following her presentation at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

Dr. Salter reported on the findings of several MS/COVID-19 registries from around the world, including the COViMS Registry, which is supported by the Consortium of MS Centers, the MS Society of Canada, and the National MS Society. It tracks patients who developed COVID-19 while also having MS, neuromyelitis optica, or MOG antibody disease.

The registry began collecting data in April 2020 and is ongoing. As of Jan. 29, 2021, 2,059 patients had been tracked; 85% of cases were confirmed by laboratory tests. Nearly all patients (97%) were from the United States, with about 21% from New York state. Nearly 76% were female, the average age was 48. About 70% were non-Hispanic White, 18% were African American; 83% had relapsing remitting MS, and 17% had progressive MS.

“We found that 11.5% of MS patients were reported being hospitalized, while 4.2% were admitted to the ICU or ventilated and 3% had died,” Dr. Salter said. Not surprisingly, the death rate was highest (21%) in patients aged 75 years or older, compared with 11% of those aged 65-74 years. Those with more severe cases – those who were nonambulatory – had a death rate of 18%, compared with 0.6% of those who were fully ambulatory and 4% of those who walked with assistance.

“A lot of the risks [for COVID-19 severity] we see in the general population are risks in the MS population,” Dr. Salter said.

Dr. Salter also summarized the results of other international registries. After adjustment, a registry in Italy linked the anti-CD20 drugs ocrelizumab or rituximab (odds ratio, 2.37, P = .015) and recent use of methylprednisolone (OR, 5.2; P = .001) to more severe courses of COVID-19, compared with other DMTs. And a global data-sharing project linked anti-CD20s to more severe outcomes, compared with other DMTs (hospitalization, adjusted prevalence ratio, 1.49; ICU admission, aPR, 2.55; and ventilation, aPR, 3.05).

In an interview, neurologist Lauren Gluck, MD, of Albert Einstein College of Medicine and Montefiore Medical Center, both in New York, cautioned that prescribing anti-CD20s now “requires a more complex informed consent process with patients and outlining of risk as well as strategies to minimize contracting the infection.”

Moving forward, she advised colleagues to “keep treating MS with DMTs. Preventing MS attacks will help keep patients out of the hospital and limit need for high-dose steroids.” And she cautioned that “avoiding action due to inaccurate fear of DMTs and COVID-19 may put your patients at unnecessary risk of relapses and accumulated disability. Educate your patients on the reality of the COVID19 pandemic, their personal risk of exposure, and strategies to minimize their risk.”

Fortunately, vaccinations offer protection against COVID-19 in patients with MS, although patients are clearly concerned about potential risks. “A frequent concern is whether the vaccines are safe for MS patients in general and if they could incite MS relapses,” neurologist Hesham Abboud, MD, PhD, of University Hospitals of Cleveland and Case Western Reserve University, said in an interview. “The American Academy of Neurology guidelines have not found a connection between vaccination and MS relapses. Having COVID-19 infection can trigger MS relapses, so clearly the benefit from the vaccine outweighs any potential risks. Obviously, it is not advisable to take any vaccine during an active relapse, but vaccines are safe otherwise when given during remission.”

Dr. Salter and Dr. Gluck reported no relevant disclosures. Dr. Abboud reports consulting fees from Biogen, Genentech, Bristol-Myers Squibb, Alexion, and Viela Bio. He receives research support from Novartis, Bristol-Myers Squibb, Genentech, and Sanofi-Genzyme.


 

The Food and Drug Administration has approved subcutaneously-injected tocilizumab (Actemra) to reduce the rate of pulmonary function decline in systemic sclerosis–associated interstitial lung disease (SSc-ILD) patients, according to a press release from manufacturer Genentech.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

Tocilizumab is the first biologic to be approved by the agency for adults with SSc-ILD, a rare and potentially life-threatening condition that may affect up to 80% of SSc patients and lead to lung inflammation and scarring.

The approval was based primarily on data from a phase 3 randomized, double-blind, placebo-controlled clinical trial (the focuSSced trial) that included 212 adults with SSc. Although that study failed to meet its primary endpoint of change from baseline to 48 weeks in the modified Rodnan Skin Score, the researchers observed a significantly reduced lung function decline as measured by forced vital capacity (FVC) and percent predicted forced vital capacity (ppFVC) among tocilizumab-treated patients, compared with those who received placebo. A total of 68 patients (65%) in the tocilizumab group and 68 patients (64%) in the placebo group had SSc-ILD at baseline.

In a subgroup analysis, patients taking tocilizumab had a smaller decline in mean ppFVC, compared with placebo patients (0.07% vs. –6.4%; mean difference, 6.47%), and a smaller decline in FVC (mean change –14 mL vs. –255 mL with placebo; mean difference, 241 mL).

The mean change from baseline to week 48 in modified Rodnan Skin Score was –5.88 for patients on tocilizumab and –3.77 with placebo.

Safety data were similar between tocilizumab and placebo groups through 48 weeks, and similar for patients with and without SSc-ILD. In general, tocilizumab side effects include increased susceptibility to infections, and serious side effects may include stomach tears, hepatotoxicity, and increased risk of cancer and hepatitis B, according to the prescribing information. However, the most common side effects are upper respiratory tract infections, headache, hypertension, and injection-site reactions.

Tocilizumab, an interleukin-6 receptor antagonist, is already approved for the treatment of adult patients with moderately to severely active rheumatoid arthritis, as well as for adult patients with giant cell arteritis; patients aged 2 years and older with active polyarticular juvenile idiopathic arthritis or active systemic juvenile idiopathic arthritis; and adults and pediatric patients 2 years of age and older with chimeric antigen receptor T-cell–induced severe or life-threatening cytokine release syndrome.

Prescribing information is available here.

The Food and Drug Administration has approved subcutaneously-injected tocilizumab (Actemra) to reduce the rate of pulmonary function decline in systemic sclerosis–associated interstitial lung disease (SSc-ILD) patients, according to a press release from manufacturer Genentech.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

Tocilizumab is the first biologic to be approved by the agency for adults with SSc-ILD, a rare and potentially life-threatening condition that may affect up to 80% of SSc patients and lead to lung inflammation and scarring.

The approval was based primarily on data from a phase 3 randomized, double-blind, placebo-controlled clinical trial (the focuSSced trial) that included 212 adults with SSc. Although that study failed to meet its primary endpoint of change from baseline to 48 weeks in the modified Rodnan Skin Score, the researchers observed a significantly reduced lung function decline as measured by forced vital capacity (FVC) and percent predicted forced vital capacity (ppFVC) among tocilizumab-treated patients, compared with those who received placebo. A total of 68 patients (65%) in the tocilizumab group and 68 patients (64%) in the placebo group had SSc-ILD at baseline.

In a subgroup analysis, patients taking tocilizumab had a smaller decline in mean ppFVC, compared with placebo patients (0.07% vs. –6.4%; mean difference, 6.47%), and a smaller decline in FVC (mean change –14 mL vs. –255 mL with placebo; mean difference, 241 mL).

The mean change from baseline to week 48 in modified Rodnan Skin Score was –5.88 for patients on tocilizumab and –3.77 with placebo.

Safety data were similar between tocilizumab and placebo groups through 48 weeks, and similar for patients with and without SSc-ILD. In general, tocilizumab side effects include increased susceptibility to infections, and serious side effects may include stomach tears, hepatotoxicity, and increased risk of cancer and hepatitis B, according to the prescribing information. However, the most common side effects are upper respiratory tract infections, headache, hypertension, and injection-site reactions.

Tocilizumab, an interleukin-6 receptor antagonist, is already approved for the treatment of adult patients with moderately to severely active rheumatoid arthritis, as well as for adult patients with giant cell arteritis; patients aged 2 years and older with active polyarticular juvenile idiopathic arthritis or active systemic juvenile idiopathic arthritis; and adults and pediatric patients 2 years of age and older with chimeric antigen receptor T-cell–induced severe or life-threatening cytokine release syndrome.

Prescribing information is available here.

The Food and Drug Administration has approved subcutaneously-injected tocilizumab (Actemra) to reduce the rate of pulmonary function decline in systemic sclerosis–associated interstitial lung disease (SSc-ILD) patients, according to a press release from manufacturer Genentech.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

Tocilizumab is the first biologic to be approved by the agency for adults with SSc-ILD, a rare and potentially life-threatening condition that may affect up to 80% of SSc patients and lead to lung inflammation and scarring.

The approval was based primarily on data from a phase 3 randomized, double-blind, placebo-controlled clinical trial (the focuSSced trial) that included 212 adults with SSc. Although that study failed to meet its primary endpoint of change from baseline to 48 weeks in the modified Rodnan Skin Score, the researchers observed a significantly reduced lung function decline as measured by forced vital capacity (FVC) and percent predicted forced vital capacity (ppFVC) among tocilizumab-treated patients, compared with those who received placebo. A total of 68 patients (65%) in the tocilizumab group and 68 patients (64%) in the placebo group had SSc-ILD at baseline.

In a subgroup analysis, patients taking tocilizumab had a smaller decline in mean ppFVC, compared with placebo patients (0.07% vs. –6.4%; mean difference, 6.47%), and a smaller decline in FVC (mean change –14 mL vs. –255 mL with placebo; mean difference, 241 mL).

The mean change from baseline to week 48 in modified Rodnan Skin Score was –5.88 for patients on tocilizumab and –3.77 with placebo.

Safety data were similar between tocilizumab and placebo groups through 48 weeks, and similar for patients with and without SSc-ILD. In general, tocilizumab side effects include increased susceptibility to infections, and serious side effects may include stomach tears, hepatotoxicity, and increased risk of cancer and hepatitis B, according to the prescribing information. However, the most common side effects are upper respiratory tract infections, headache, hypertension, and injection-site reactions.

Tocilizumab, an interleukin-6 receptor antagonist, is already approved for the treatment of adult patients with moderately to severely active rheumatoid arthritis, as well as for adult patients with giant cell arteritis; patients aged 2 years and older with active polyarticular juvenile idiopathic arthritis or active systemic juvenile idiopathic arthritis; and adults and pediatric patients 2 years of age and older with chimeric antigen receptor T-cell–induced severe or life-threatening cytokine release syndrome.

Prescribing information is available here.

It’s now confirmed: What you eat does affect your risk of developing colorectal cancer (CRC).

An umbrella review of studies and meta-analyses found “convincing evidence of an association between a lower CRC risk and higher intakes of dietary fiber, dietary calcium, and yogurt and lower intakes of alcohol and red meat.”

However, more research is needed to address the link between CRC and other foods, including dairy products, whole grains, processed meat, and specific dietary patterns, the authors conclude.

“We can say that the existing recommendations for diet in the primary prevention of colorectal cancer is confirmed,” said lead author Nathorn Chaiyakunapruk, PharmD, PhD, professor of pharmacology at the University of Utah, Salt Lake City.

“It makes sense to encourage healthy diet, including those rich in fruits, vegetables, grains, and low-fat dairy, and reducing red meat and alcohol intake,” he said in an interview. “However, some of them may not yet have convincing evidence to fully support the claim.”

Other lifestyle factors, including excess weight and physical inactivity, also play a role in cancer risk. Dr. Chaiyakunapruk pointed out that their review was focused only on diet and that they had set out to confirm factors for which there was strong and convincing evidence.

The review was published online in JAMA Network Open.

The umbrella review of 45 meta-analyses found 109 associations. Overall, 35 of these 109 associations (32.1%) were nominally statistically significant, as determined on the basis of random-effects meta-analysis models, the researchers explained.

Convincing evidence was found for an increase in the risk for CRC with higher versus lower red meat consumption and with heavy alcohol intake (defined as more than four drinks per day, compared with no drinks per day or occasional drinks).

In addition, convincing evidence was found for three inverse associations: a decrease in the risk for CRC was associated with higher versus lower intake of total dietary fiber, calcium, and yogurt.

The researchers noted that, although not completely convincing, there was highly suggestive evidence for another association: a link between diet and CRC incidence. A higher intake of total dairy products (e.g., milk, cheese, and yogurt) was associated with significant risk reduction, in comparison with lower intake. A moderate intake of alcohol (from one to three drinks but not more than four per day) was associated with an increase in incidence in comparison with no drinks or an occasional drink.

Evidence suggested a reduced risk in association with several lifestyle behaviors, including adherence to a Mediterranean diet, a healthy diet, a pesco-vegetarian or semivegetarian diet, and the intake of whole grains, nonfermented milk, and supplemental calcium.

The evidence suggested that adherence to a Western diet and intake of processed meat were associated with an increased risk for CRC.

There was weak or no evidence for the remaining associations.
 

Existing cancer prevention guidelines

The findings support the existing cancer prevention dietary guidance and recommendations from the American Institute for Cancer Research, commented the institute’s director of nutrition programs, Sheena Swanner Patel, MS, RDN. The study confirms that dietary factors play a strong role in lowering CRC risk.

“AICR’s report found strong evidence for whole grains, foods containing dietary fiber, dairy products, and calcium supplements decreasing risk for colorectal cancer,” she said. “Specifically, eating 90 g or three servings of whole grains per day is associated with a 17% decrease in colorectal cancer risk.”

Ms. Patel added that the AICR’s report also suggested there was strong evidence that eating large amounts of red and processed meat, drinking alcohol excessively, and carrying extra body weight increased the risk for CRC.

Many previous studies have suggested a link between diet and CRC risk. One recent study suggested that, among all cancers, CRC has the highest proportion of diet-related cases (38.3%). The next highest were cancers of the mouth, pharynx, and larynx, for which almost 26% of cases were linked to diet, followed by endometrial cancer, postmenopausal breast cancer, and cancers of the kidney, stomach, liver, pancreas, and esophagus.

Neither Dr. Chaiyakunapruk and coauthors nor Ms. Patel disclosed any relevant financial relationships.

A version of this article first appeared on Medscape.com.

It’s now confirmed: What you eat does affect your risk of developing colorectal cancer (CRC).

An umbrella review of studies and meta-analyses found “convincing evidence of an association between a lower CRC risk and higher intakes of dietary fiber, dietary calcium, and yogurt and lower intakes of alcohol and red meat.”

However, more research is needed to address the link between CRC and other foods, including dairy products, whole grains, processed meat, and specific dietary patterns, the authors conclude.

“We can say that the existing recommendations for diet in the primary prevention of colorectal cancer is confirmed,” said lead author Nathorn Chaiyakunapruk, PharmD, PhD, professor of pharmacology at the University of Utah, Salt Lake City.

“It makes sense to encourage healthy diet, including those rich in fruits, vegetables, grains, and low-fat dairy, and reducing red meat and alcohol intake,” he said in an interview. “However, some of them may not yet have convincing evidence to fully support the claim.”

Other lifestyle factors, including excess weight and physical inactivity, also play a role in cancer risk. Dr. Chaiyakunapruk pointed out that their review was focused only on diet and that they had set out to confirm factors for which there was strong and convincing evidence.

The review was published online in JAMA Network Open.

The umbrella review of 45 meta-analyses found 109 associations. Overall, 35 of these 109 associations (32.1%) were nominally statistically significant, as determined on the basis of random-effects meta-analysis models, the researchers explained.

Convincing evidence was found for an increase in the risk for CRC with higher versus lower red meat consumption and with heavy alcohol intake (defined as more than four drinks per day, compared with no drinks per day or occasional drinks).

In addition, convincing evidence was found for three inverse associations: a decrease in the risk for CRC was associated with higher versus lower intake of total dietary fiber, calcium, and yogurt.

The researchers noted that, although not completely convincing, there was highly suggestive evidence for another association: a link between diet and CRC incidence. A higher intake of total dairy products (e.g., milk, cheese, and yogurt) was associated with significant risk reduction, in comparison with lower intake. A moderate intake of alcohol (from one to three drinks but not more than four per day) was associated with an increase in incidence in comparison with no drinks or an occasional drink.

Evidence suggested a reduced risk in association with several lifestyle behaviors, including adherence to a Mediterranean diet, a healthy diet, a pesco-vegetarian or semivegetarian diet, and the intake of whole grains, nonfermented milk, and supplemental calcium.

The evidence suggested that adherence to a Western diet and intake of processed meat were associated with an increased risk for CRC.

There was weak or no evidence for the remaining associations.
 

Existing cancer prevention guidelines

The findings support the existing cancer prevention dietary guidance and recommendations from the American Institute for Cancer Research, commented the institute’s director of nutrition programs, Sheena Swanner Patel, MS, RDN. The study confirms that dietary factors play a strong role in lowering CRC risk.

“AICR’s report found strong evidence for whole grains, foods containing dietary fiber, dairy products, and calcium supplements decreasing risk for colorectal cancer,” she said. “Specifically, eating 90 g or three servings of whole grains per day is associated with a 17% decrease in colorectal cancer risk.”

Ms. Patel added that the AICR’s report also suggested there was strong evidence that eating large amounts of red and processed meat, drinking alcohol excessively, and carrying extra body weight increased the risk for CRC.

Many previous studies have suggested a link between diet and CRC risk. One recent study suggested that, among all cancers, CRC has the highest proportion of diet-related cases (38.3%). The next highest were cancers of the mouth, pharynx, and larynx, for which almost 26% of cases were linked to diet, followed by endometrial cancer, postmenopausal breast cancer, and cancers of the kidney, stomach, liver, pancreas, and esophagus.

Neither Dr. Chaiyakunapruk and coauthors nor Ms. Patel disclosed any relevant financial relationships.

A version of this article first appeared on Medscape.com.

It’s now confirmed: What you eat does affect your risk of developing colorectal cancer (CRC).

An umbrella review of studies and meta-analyses found “convincing evidence of an association between a lower CRC risk and higher intakes of dietary fiber, dietary calcium, and yogurt and lower intakes of alcohol and red meat.”

However, more research is needed to address the link between CRC and other foods, including dairy products, whole grains, processed meat, and specific dietary patterns, the authors conclude.

“We can say that the existing recommendations for diet in the primary prevention of colorectal cancer is confirmed,” said lead author Nathorn Chaiyakunapruk, PharmD, PhD, professor of pharmacology at the University of Utah, Salt Lake City.

“It makes sense to encourage healthy diet, including those rich in fruits, vegetables, grains, and low-fat dairy, and reducing red meat and alcohol intake,” he said in an interview. “However, some of them may not yet have convincing evidence to fully support the claim.”

Other lifestyle factors, including excess weight and physical inactivity, also play a role in cancer risk. Dr. Chaiyakunapruk pointed out that their review was focused only on diet and that they had set out to confirm factors for which there was strong and convincing evidence.

The review was published online in JAMA Network Open.

The umbrella review of 45 meta-analyses found 109 associations. Overall, 35 of these 109 associations (32.1%) were nominally statistically significant, as determined on the basis of random-effects meta-analysis models, the researchers explained.

Convincing evidence was found for an increase in the risk for CRC with higher versus lower red meat consumption and with heavy alcohol intake (defined as more than four drinks per day, compared with no drinks per day or occasional drinks).

In addition, convincing evidence was found for three inverse associations: a decrease in the risk for CRC was associated with higher versus lower intake of total dietary fiber, calcium, and yogurt.

The researchers noted that, although not completely convincing, there was highly suggestive evidence for another association: a link between diet and CRC incidence. A higher intake of total dairy products (e.g., milk, cheese, and yogurt) was associated with significant risk reduction, in comparison with lower intake. A moderate intake of alcohol (from one to three drinks but not more than four per day) was associated with an increase in incidence in comparison with no drinks or an occasional drink.

Evidence suggested a reduced risk in association with several lifestyle behaviors, including adherence to a Mediterranean diet, a healthy diet, a pesco-vegetarian or semivegetarian diet, and the intake of whole grains, nonfermented milk, and supplemental calcium.

The evidence suggested that adherence to a Western diet and intake of processed meat were associated with an increased risk for CRC.

There was weak or no evidence for the remaining associations.
 

Existing cancer prevention guidelines

The findings support the existing cancer prevention dietary guidance and recommendations from the American Institute for Cancer Research, commented the institute’s director of nutrition programs, Sheena Swanner Patel, MS, RDN. The study confirms that dietary factors play a strong role in lowering CRC risk.

“AICR’s report found strong evidence for whole grains, foods containing dietary fiber, dairy products, and calcium supplements decreasing risk for colorectal cancer,” she said. “Specifically, eating 90 g or three servings of whole grains per day is associated with a 17% decrease in colorectal cancer risk.”

Ms. Patel added that the AICR’s report also suggested there was strong evidence that eating large amounts of red and processed meat, drinking alcohol excessively, and carrying extra body weight increased the risk for CRC.

Many previous studies have suggested a link between diet and CRC risk. One recent study suggested that, among all cancers, CRC has the highest proportion of diet-related cases (38.3%). The next highest were cancers of the mouth, pharynx, and larynx, for which almost 26% of cases were linked to diet, followed by endometrial cancer, postmenopausal breast cancer, and cancers of the kidney, stomach, liver, pancreas, and esophagus.

Neither Dr. Chaiyakunapruk and coauthors nor Ms. Patel disclosed any relevant financial relationships.

A version of this article first appeared on Medscape.com.

Atopic dermatitis (AD) is associated with lower patient satisfaction scores in adults, suggesting there are unmet needs in clinical AD management.

Satisfaction scores were higher when specialists prescribed systemic therapy, but were lower when nonspecialists prescribed systemic therapy and when specialists prescribed only topical therapy.

©aniaostudio/Thinkstock.com

Recognizing that treatment regimens are complex and used differently by provider type, the researchers examined interactions between specialists (dermatologists and allergists) and treatment type. “Previous studies found dermatologists treat more severe, chronic AD,” Mr. Cheng said. “We found here that there was lower satisfaction among those treated with topical therapy and by specialists, which may reflect inadequate disease control. We also found lower satisfaction among those treated with systemic therapy by primary care physicians. This may reflect that these patients are not achieving optimal therapy. We found that satisfaction was highest among those treated with systemic therapy and by dermatologists and allergists.”

Socioeconomic, racial/ethnic, and health care disparities were observed in terms of satisfaction among this cohort. The following characteristics were significantly associated with lower patient satisfaction, compared with the general cohort of adults with AD: poor to low income (aOR, –1.82; P less than .0001), multiracial/other race (aOR, –2.34; P = .0001), Hispanic ethnicity (aOR, –1.40; P = .007), and having no insurance coverage (aOR, –4.53; P less than .0001).

“Moreover, those with multimorbidity had even lower satisfaction,” Mr. Cheng said. “In previous studies, AD has been linked with many other comorbidities. This may reflect that these patients are not being adequately managed overall. So, there’s a need here for multidisciplinary care to ensure that all of these comorbidities and the full spectrum of symptoms are being managed adequately.”

He concluded that future research is needed to determine strategies to optimize patient satisfaction in adults with AD.

“I’m not sure how much more provocative you can get in terms of data,” added Dr. Silverberg, director of clinical research and contact dermatitis at George Washington University, Washington. “It’s really eye-opening. I think many clinicians may feel like they’re doing a perfect job in managing this disease. These data suggest that at least at the national level that may not be the case.”

Mr. Cheng reported having no financial disclosures. Dr. Silverberg reported that he is a consultant to and/or an advisory board member for several pharmaceutical companies. He is also a speaker for Regeneron and Sanofi and has received a grant from Galderma.

[email protected]

Atopic dermatitis (AD) is associated with lower patient satisfaction scores in adults, suggesting there are unmet needs in clinical AD management.

Satisfaction scores were higher when specialists prescribed systemic therapy, but were lower when nonspecialists prescribed systemic therapy and when specialists prescribed only topical therapy.

©aniaostudio/Thinkstock.com

Recognizing that treatment regimens are complex and used differently by provider type, the researchers examined interactions between specialists (dermatologists and allergists) and treatment type. “Previous studies found dermatologists treat more severe, chronic AD,” Mr. Cheng said. “We found here that there was lower satisfaction among those treated with topical therapy and by specialists, which may reflect inadequate disease control. We also found lower satisfaction among those treated with systemic therapy by primary care physicians. This may reflect that these patients are not achieving optimal therapy. We found that satisfaction was highest among those treated with systemic therapy and by dermatologists and allergists.”

Socioeconomic, racial/ethnic, and health care disparities were observed in terms of satisfaction among this cohort. The following characteristics were significantly associated with lower patient satisfaction, compared with the general cohort of adults with AD: poor to low income (aOR, –1.82; P less than .0001), multiracial/other race (aOR, –2.34; P = .0001), Hispanic ethnicity (aOR, –1.40; P = .007), and having no insurance coverage (aOR, –4.53; P less than .0001).

“Moreover, those with multimorbidity had even lower satisfaction,” Mr. Cheng said. “In previous studies, AD has been linked with many other comorbidities. This may reflect that these patients are not being adequately managed overall. So, there’s a need here for multidisciplinary care to ensure that all of these comorbidities and the full spectrum of symptoms are being managed adequately.”

He concluded that future research is needed to determine strategies to optimize patient satisfaction in adults with AD.

“I’m not sure how much more provocative you can get in terms of data,” added Dr. Silverberg, director of clinical research and contact dermatitis at George Washington University, Washington. “It’s really eye-opening. I think many clinicians may feel like they’re doing a perfect job in managing this disease. These data suggest that at least at the national level that may not be the case.”

Mr. Cheng reported having no financial disclosures. Dr. Silverberg reported that he is a consultant to and/or an advisory board member for several pharmaceutical companies. He is also a speaker for Regeneron and Sanofi and has received a grant from Galderma.

[email protected]

Atopic dermatitis (AD) is associated with lower patient satisfaction scores in adults, suggesting there are unmet needs in clinical AD management.

Satisfaction scores were higher when specialists prescribed systemic therapy, but were lower when nonspecialists prescribed systemic therapy and when specialists prescribed only topical therapy.

©aniaostudio/Thinkstock.com

Recognizing that treatment regimens are complex and used differently by provider type, the researchers examined interactions between specialists (dermatologists and allergists) and treatment type. “Previous studies found dermatologists treat more severe, chronic AD,” Mr. Cheng said. “We found here that there was lower satisfaction among those treated with topical therapy and by specialists, which may reflect inadequate disease control. We also found lower satisfaction among those treated with systemic therapy by primary care physicians. This may reflect that these patients are not achieving optimal therapy. We found that satisfaction was highest among those treated with systemic therapy and by dermatologists and allergists.”

Socioeconomic, racial/ethnic, and health care disparities were observed in terms of satisfaction among this cohort. The following characteristics were significantly associated with lower patient satisfaction, compared with the general cohort of adults with AD: poor to low income (aOR, –1.82; P less than .0001), multiracial/other race (aOR, –2.34; P = .0001), Hispanic ethnicity (aOR, –1.40; P = .007), and having no insurance coverage (aOR, –4.53; P less than .0001).

“Moreover, those with multimorbidity had even lower satisfaction,” Mr. Cheng said. “In previous studies, AD has been linked with many other comorbidities. This may reflect that these patients are not being adequately managed overall. So, there’s a need here for multidisciplinary care to ensure that all of these comorbidities and the full spectrum of symptoms are being managed adequately.”

He concluded that future research is needed to determine strategies to optimize patient satisfaction in adults with AD.

“I’m not sure how much more provocative you can get in terms of data,” added Dr. Silverberg, director of clinical research and contact dermatitis at George Washington University, Washington. “It’s really eye-opening. I think many clinicians may feel like they’re doing a perfect job in managing this disease. These data suggest that at least at the national level that may not be the case.”

Mr. Cheng reported having no financial disclosures. Dr. Silverberg reported that he is a consultant to and/or an advisory board member for several pharmaceutical companies. He is also a speaker for Regeneron and Sanofi and has received a grant from Galderma.

[email protected]

A new report by the Veterans Healthcare Policy Institute (VHPI) documents how elements included in many bills passed on Capitol Hill have failed to improve the efficacy of mental health services for our nation’s former service members.¹ The authors argue that while these efforts may be well intended, they often compound problems by squandering precious financial resources and stretching an already overtaxed workforce. Clearly, there are shortcomings in the US Department of Veterans Affairs (VA), our nation’s largest integrated health care system, but rather than bash the VA, as the media and Congress tend to favor, let’s learn from its successes as we improve its services.

To do this we must avoid several policy pitfalls. Consider, for example, the VA MISSION Act (38 USC § 1703), which aimed to increase veteran access to quality health care outside the VA system. Studies confirmed that private sector mental health providers are not ready to deliver veteran-specific mental health care.^2,3 Indeed, a RAND report found that psychotherapists in the private sector were unlikely to have the requisite skills necessary to deliver high-quality mental health care to service members or veterans.⁴

The MISSION Act meant to fix this clinical deficit by directing that competency standards be set for non-VA mental health providers who treat veterans for posttraumatic stress disorder (PTSD), traumatic brain injury, and military sexual trauma. But to date, no minimum competency standards have been set for non-VA mental health providers who treat veterans’ common psychological conditions. A license is all they need.

Legislation like the MISSION Act and the newly passed Commander John Scott Hannon Act (38 USC § 101) also assume that veterans who are suicidal or have mental health problems and don’t go to the VA will seek care from private sector providers. Nothing is further from the truth. Many veterans are deeply resistant to seeking mental health care no matter where that care is delivered.^4,5 Sometimes veterans believe that mental health problems are a sign of weakness and are loathe to seek help.

To address this issue, the VA pioneered models of integrated mental health and primary care services.⁶ This means that if a veteran goes to an outpatient primary care clinic at a VA medical facility or community-based outpatient clinic and discusses a mental health or substance abuse problem, the veteran can get immediate care with a mental health provider without making a separate mental health appointment. In addition, the VA already provides routine, annual screening for PTSD and sexual assault as well as depression and substance abuse at all its primary care clinics nationwide. Thanks to comprehensive screening (at a level unknown in most other health care systems) even if a veteran doesn’t spontaneously report a trauma history or mental health distress, VA is able to identify the problem and offer help right in the primary care clinic. This one-stop shopping reduces the shame and stigma of having to make an appointment with a mental health provider, allows treatment to begin immediately, and reduces no shows at follow-up appointments.

Other health care systems are trying to copy the VA model of integrated primary and mental health care, but given our fragmented insurance system, it’s not easy to replicate.⁷ According to Suzanne Gordon coauthor of the VHPI study, “This VA innovation encourages veterans, socialized by the military to conceal serious mental health problems, to get immediate help. So do many other VA programs, like peer support groups and networks. Legislation needs to strengthen, not weaken, such programs that are almost impossible to reproduce in the private sector.” Outside of VA, mental health challenges faced by veterans likely go undetected, and many veterans will not receive the care that might change, or even save, their lives.

VA best practices include an unprecedented national training initiative on 16 evidence-based psychotherapies that has been in operation for more than a decade.⁸ These high-quality treatments target debilitating conditions such as depression, PTSD, substance use disorders, insomnia, and chronic pain.^9-13 More than 12,700 VA mental health providers have received training in these evidence-based psychotherapies.

“There is no way that non-VA health care systems can ever duplicate the quality of training and supervision that has now been provided, nationally, to VA mental health professionals,” Josef Ruzek, PhD, former Director of the VA National Center for PTSD Dissemination and Training Division told me in a phone conversation (January 14, 2021). “Their program of training and implementation in the very best treatments for veteran mental health conditions stands as an international model of a complex, well-executed, large-scale program to improve mental health service delivery and improve the outcomes of treatment.”

The VA not only paid for the training of these mental health providers, but also contributed substantial efforts to assist in the implementation and sustainability of such practices. These include policy changes mandating their availability at all VA facilities, designation of local evidence-based coordinators at each medical center, and even a nationwide PTSD mentoring program to help PTSD clinic managers make organizational changes and to guide the efforts of any VA clinician seeking advice on how to engage and work with a veteran living with PTSD.¹⁴ All these incredible dissemination and implementation endeavors have resulted in a substantial overall decrease in mental health symptoms and substance misuse behaviors and increase in functional outcomes, like improvement in relationship functioning and increase in quality of life for many veterans.

As a trauma psychologist and former VA employee, I urge lawmakers to assure that veterans are not sent to private sector providers who don’t understand their unique needs and aren’t trained to serve them well, and to similarly assure that systems of care are carefully designed to meet the specific needs of veterans.

A new report by the Veterans Healthcare Policy Institute (VHPI) documents how elements included in many bills passed on Capitol Hill have failed to improve the efficacy of mental health services for our nation’s former service members.¹ The authors argue that while these efforts may be well intended, they often compound problems by squandering precious financial resources and stretching an already overtaxed workforce. Clearly, there are shortcomings in the US Department of Veterans Affairs (VA), our nation’s largest integrated health care system, but rather than bash the VA, as the media and Congress tend to favor, let’s learn from its successes as we improve its services.

To do this we must avoid several policy pitfalls. Consider, for example, the VA MISSION Act (38 USC § 1703), which aimed to increase veteran access to quality health care outside the VA system. Studies confirmed that private sector mental health providers are not ready to deliver veteran-specific mental health care.^2,3 Indeed, a RAND report found that psychotherapists in the private sector were unlikely to have the requisite skills necessary to deliver high-quality mental health care to service members or veterans.⁴

The MISSION Act meant to fix this clinical deficit by directing that competency standards be set for non-VA mental health providers who treat veterans for posttraumatic stress disorder (PTSD), traumatic brain injury, and military sexual trauma. But to date, no minimum competency standards have been set for non-VA mental health providers who treat veterans’ common psychological conditions. A license is all they need.

Legislation like the MISSION Act and the newly passed Commander John Scott Hannon Act (38 USC § 101) also assume that veterans who are suicidal or have mental health problems and don’t go to the VA will seek care from private sector providers. Nothing is further from the truth. Many veterans are deeply resistant to seeking mental health care no matter where that care is delivered.^4,5 Sometimes veterans believe that mental health problems are a sign of weakness and are loathe to seek help.

To address this issue, the VA pioneered models of integrated mental health and primary care services.⁶ This means that if a veteran goes to an outpatient primary care clinic at a VA medical facility or community-based outpatient clinic and discusses a mental health or substance abuse problem, the veteran can get immediate care with a mental health provider without making a separate mental health appointment. In addition, the VA already provides routine, annual screening for PTSD and sexual assault as well as depression and substance abuse at all its primary care clinics nationwide. Thanks to comprehensive screening (at a level unknown in most other health care systems) even if a veteran doesn’t spontaneously report a trauma history or mental health distress, VA is able to identify the problem and offer help right in the primary care clinic. This one-stop shopping reduces the shame and stigma of having to make an appointment with a mental health provider, allows treatment to begin immediately, and reduces no shows at follow-up appointments.

Other health care systems are trying to copy the VA model of integrated primary and mental health care, but given our fragmented insurance system, it’s not easy to replicate.⁷ According to Suzanne Gordon coauthor of the VHPI study, “This VA innovation encourages veterans, socialized by the military to conceal serious mental health problems, to get immediate help. So do many other VA programs, like peer support groups and networks. Legislation needs to strengthen, not weaken, such programs that are almost impossible to reproduce in the private sector.” Outside of VA, mental health challenges faced by veterans likely go undetected, and many veterans will not receive the care that might change, or even save, their lives.

VA best practices include an unprecedented national training initiative on 16 evidence-based psychotherapies that has been in operation for more than a decade.⁸ These high-quality treatments target debilitating conditions such as depression, PTSD, substance use disorders, insomnia, and chronic pain.^9-13 More than 12,700 VA mental health providers have received training in these evidence-based psychotherapies.

“There is no way that non-VA health care systems can ever duplicate the quality of training and supervision that has now been provided, nationally, to VA mental health professionals,” Josef Ruzek, PhD, former Director of the VA National Center for PTSD Dissemination and Training Division told me in a phone conversation (January 14, 2021). “Their program of training and implementation in the very best treatments for veteran mental health conditions stands as an international model of a complex, well-executed, large-scale program to improve mental health service delivery and improve the outcomes of treatment.”

The VA not only paid for the training of these mental health providers, but also contributed substantial efforts to assist in the implementation and sustainability of such practices. These include policy changes mandating their availability at all VA facilities, designation of local evidence-based coordinators at each medical center, and even a nationwide PTSD mentoring program to help PTSD clinic managers make organizational changes and to guide the efforts of any VA clinician seeking advice on how to engage and work with a veteran living with PTSD.¹⁴ All these incredible dissemination and implementation endeavors have resulted in a substantial overall decrease in mental health symptoms and substance misuse behaviors and increase in functional outcomes, like improvement in relationship functioning and increase in quality of life for many veterans.

As a trauma psychologist and former VA employee, I urge lawmakers to assure that veterans are not sent to private sector providers who don’t understand their unique needs and aren’t trained to serve them well, and to similarly assure that systems of care are carefully designed to meet the specific needs of veterans.

A new report by the Veterans Healthcare Policy Institute (VHPI) documents how elements included in many bills passed on Capitol Hill have failed to improve the efficacy of mental health services for our nation’s former service members.¹ The authors argue that while these efforts may be well intended, they often compound problems by squandering precious financial resources and stretching an already overtaxed workforce. Clearly, there are shortcomings in the US Department of Veterans Affairs (VA), our nation’s largest integrated health care system, but rather than bash the VA, as the media and Congress tend to favor, let’s learn from its successes as we improve its services.

To do this we must avoid several policy pitfalls. Consider, for example, the VA MISSION Act (38 USC § 1703), which aimed to increase veteran access to quality health care outside the VA system. Studies confirmed that private sector mental health providers are not ready to deliver veteran-specific mental health care.^2,3 Indeed, a RAND report found that psychotherapists in the private sector were unlikely to have the requisite skills necessary to deliver high-quality mental health care to service members or veterans.⁴

The MISSION Act meant to fix this clinical deficit by directing that competency standards be set for non-VA mental health providers who treat veterans for posttraumatic stress disorder (PTSD), traumatic brain injury, and military sexual trauma. But to date, no minimum competency standards have been set for non-VA mental health providers who treat veterans’ common psychological conditions. A license is all they need.

Legislation like the MISSION Act and the newly passed Commander John Scott Hannon Act (38 USC § 101) also assume that veterans who are suicidal or have mental health problems and don’t go to the VA will seek care from private sector providers. Nothing is further from the truth. Many veterans are deeply resistant to seeking mental health care no matter where that care is delivered.^4,5 Sometimes veterans believe that mental health problems are a sign of weakness and are loathe to seek help.

To address this issue, the VA pioneered models of integrated mental health and primary care services.⁶ This means that if a veteran goes to an outpatient primary care clinic at a VA medical facility or community-based outpatient clinic and discusses a mental health or substance abuse problem, the veteran can get immediate care with a mental health provider without making a separate mental health appointment. In addition, the VA already provides routine, annual screening for PTSD and sexual assault as well as depression and substance abuse at all its primary care clinics nationwide. Thanks to comprehensive screening (at a level unknown in most other health care systems) even if a veteran doesn’t spontaneously report a trauma history or mental health distress, VA is able to identify the problem and offer help right in the primary care clinic. This one-stop shopping reduces the shame and stigma of having to make an appointment with a mental health provider, allows treatment to begin immediately, and reduces no shows at follow-up appointments.

Other health care systems are trying to copy the VA model of integrated primary and mental health care, but given our fragmented insurance system, it’s not easy to replicate.⁷ According to Suzanne Gordon coauthor of the VHPI study, “This VA innovation encourages veterans, socialized by the military to conceal serious mental health problems, to get immediate help. So do many other VA programs, like peer support groups and networks. Legislation needs to strengthen, not weaken, such programs that are almost impossible to reproduce in the private sector.” Outside of VA, mental health challenges faced by veterans likely go undetected, and many veterans will not receive the care that might change, or even save, their lives.

VA best practices include an unprecedented national training initiative on 16 evidence-based psychotherapies that has been in operation for more than a decade.⁸ These high-quality treatments target debilitating conditions such as depression, PTSD, substance use disorders, insomnia, and chronic pain.^9-13 More than 12,700 VA mental health providers have received training in these evidence-based psychotherapies.

“There is no way that non-VA health care systems can ever duplicate the quality of training and supervision that has now been provided, nationally, to VA mental health professionals,” Josef Ruzek, PhD, former Director of the VA National Center for PTSD Dissemination and Training Division told me in a phone conversation (January 14, 2021). “Their program of training and implementation in the very best treatments for veteran mental health conditions stands as an international model of a complex, well-executed, large-scale program to improve mental health service delivery and improve the outcomes of treatment.”

The VA not only paid for the training of these mental health providers, but also contributed substantial efforts to assist in the implementation and sustainability of such practices. These include policy changes mandating their availability at all VA facilities, designation of local evidence-based coordinators at each medical center, and even a nationwide PTSD mentoring program to help PTSD clinic managers make organizational changes and to guide the efforts of any VA clinician seeking advice on how to engage and work with a veteran living with PTSD.¹⁴ All these incredible dissemination and implementation endeavors have resulted in a substantial overall decrease in mental health symptoms and substance misuse behaviors and increase in functional outcomes, like improvement in relationship functioning and increase in quality of life for many veterans.

As a trauma psychologist and former VA employee, I urge lawmakers to assure that veterans are not sent to private sector providers who don’t understand their unique needs and aren’t trained to serve them well, and to similarly assure that systems of care are carefully designed to meet the specific needs of veterans.

Adolescents are an increasingly diverse population reflecting changes in the racial, ethnic, and geopolitical milieus of the United States. The World Health Organization classifies adolescence as ages 10 to 19 years.¹ However, given the complexity of adolescent development physically, behaviorally, emotionally, and socially, others propose that adolescence may extend to age 24.²

Recognizing the specific challenges adolescents face is key to providing comprehensive longitudinal health care. Moreover, creating an environment of trust helps to ensure open 2-way communication that can facilitate anticipatory guidance.

Our review focuses on common adolescent issues, including injury from vehicles and firearms, tobacco and substance misuse, obesity, behavioral health, sexual health, and social media use. We discuss current trends and recommend strategies to maximize health and wellness.

Start by framing the visit

Confidentiality

Laws governing confidentiality in adolescent health care vary by state. Be aware of the laws pertaining to your practice setting. In addition, health care facilities may have their own policies regarding consent and confidentiality in adolescent care. Discuss confidentiality with both an adolescent and the parent/guardian at the initial visit. And, to help avoid potential misunderstandings, let them know in advance what will (and will not) be divulged.

The American Academy of Pediatrics has developed a useful tip sheet regarding confidentiality laws (www.aap.org/en-us/advocacy-and-policy/aap-health-initiatives/healthy-foster-care-america/Documents/Confidentiality_Laws.pdf). Examples of required (conditional) disclosure include abuse and suicidal or homicidal ideations. Patients should understand that sexually transmitted infections (STIs) are reportable to public health authorities and that potentially injurious behaviors to self or others (eg, excessive drinking prior to driving) may also warrant disclosure(TABLE 1³).

Privacy and general visit structure

Create a safe atmosphere where adolescents can discuss personal issues without fear of repercussion or judgment. While parents may prefer to be present during the visit, allowing for time to visit independently with an adolescent offers the opportunity to reinforce issues of privacy and confidentiality. Also discuss your office policies regarding electronic communication, phone communication, and relaying test results.

A useful paradigm for organizing a visit for routine adolescent care is to use an expanded version of the HEADSS mnemonic (TABLE 2^4,5), which includes questions about an adolescent’s Home, Education, Activities, Drug and alcohol use, Sexual behavior, Suicidality and depression, and other topics. Other validated screening tools include RAAPS (Rapid Adolescent Prevention Screening)⁶ (www.possibilitiesforchange.com/raaps/); the Guidelines for Adolescent Preventive Services⁷; and the Bright Futures recommendations for preventive care from the American Academy of Pediatrics.⁸ Below, we consider important topics addressed with the HEADSS approach.

Continue to: Injury from vehicles and firearms

Motor vehicle accidents and firearm wounds are the 2 leading causes of adolescent injury. In 2016, of the more than 20,000 deaths in children and adolescents (ages 1-19 years), 20% were due to motor vehicle accidents (4074) and 15% were a result of firearm-­related injuries (3143). Among firearm-­related deaths, 60% were homicides, 35% were suicides, and 4% were due to accidental discharge.⁹ The rate of firearm-related deaths among American teens is 36 times greater than that of any other developed nation.⁹ Currently, 1 of every 3 US households with children younger than 18 has a firearm. Data suggest that in 43% of these households, the firearm is loaded and kept in an unlocked location.¹⁰

To aid anticipatory guidance, ask adolescents about firearm and seat belt use, drinking and driving, and suicidal thoughts (TABLE 2^4,5). Advise them to always wear seat belts whether driving or riding as a passenger. They should never drink and drive (or get in a car with someone who has been drinking). Advise parents that if firearms are present in the household, they should be kept in a secure, locked location. Weapons should be separated from ammunition and safety mechanisms should be engaged on all devices.

Tobacco and substance misuse

Tobacco use, the leading preventable cause of death in the United States,¹¹ is responsible for more deaths than alcohol, motor vehicle accidents, suicides, homicides, and HIV disease combined.¹² Most tobacco-associated mortality occurs in individuals who began smoking before the age of 18.¹² Individuals who start smoking early are also more likely to continue smoking through adulthood.

Encouragingly, tobacco use has declined significantly among adolescents over the past several decades. Roughly 1 in 25 high school seniors reports daily tobacco use.¹³ Adolescent smoking behaviors are also changing dramatically with the increasing popularity of electronic cigarettes (“vaping”). Currently, more adolescents vape than smoke cigarettes.¹³ Vaping has additional health risks including toxic lung injury.

Multiple resources can help combat tobacco and nicotine use in adolescents. The US Preventive Services Task Force recommends that primary care clinicians intervene through education or brief counselling to prevent initiation of tobacco use in school-aged children and adolescents.¹⁴ Ask teens about tobacco and electronic cigarette use and encourage them to quit when use is acknowledged. Other helpful office-based tools are the “Quit Line” 800-QUIT-NOW and texting “Quit” to 47848. Smokefree teen (https://teen.smokefree.gov/) is a website that reviews the risks of tobacco and nicotine use and provides age-appropriate cessation tools and tips (including a smartphone app and a live-chat feature). Other useful information is available in a report from the Surgeon General on preventing tobacco use among young adults.¹⁵

Continue to: Alcohol use

Alcohol use. Three in 5 high school students report ever having used alcohol.¹³ As with tobacco, adolescent alcohol use has declined over the past decade. However, binge drinking (≥ 5 drinks on 1 occasion for males; ≥ 4 drinks on 1 occasion for females) remains a common high-risk behavior among adolescents (particularly college students). Based on the Monitoring the Future Survey, 1 in 6 high school seniors reported binge drinking in the past 2 weeks.¹³ While historically more common among males, rates of binge drinking are now basically similar between male and female adolescents.¹³

While historically more common among males, rates of binge drinking are now basically similar between male and female adolescents.

The National Institute on Alcohol Abuse and Alcoholism has a screening and intervention guide specifically for adolescents.¹⁶A 2-question screening tool asking about personal use of alcohol and use of alcohol by friends is followed by a risk assessment with recommendations to advise young patients not to drink and to assist them with appropriate intervention and follow-up (https://pubs.niaaa.nih.gov/publications/Practitioner/YouthGuide/YouthGuidePocket.pdf).

Illicit drug use. Half of adolescents report using an illicit drug by their senior year in high school.¹³ Marijuana is the most commonly used substance, and laws governing its use are rapidly changing across the United States. Marijuana is illegal in 10 states and legal in 10 states (and the District of Columbia). The remaining states have varying policies on the medical use of marijuana and the decriminalization of marijuana. In addition, cannabinoid (CBD) products are increasingly available. Frequent cannabis use in adolescence has an adverse impact on general executive function (compared with adult users) and learning.¹⁷ Marijuana may serve as a gateway drug in the abuse of other substances,¹⁸ and its use should be strongly discouraged in adolescents.

Of note, there has been a sharp rise in the illicit use of prescription drugs, particularly opioids, creating a public health emergency across the United States.¹⁹ In 2015, more than 4000 young people, ages 15 to 24, died from a drug-related overdose (> 50% of these attributable to opioids).²⁰ Adolescents with a history of substance abuse and behavioral illness are at particular risk. Many adolescents who misuse opioids and other prescription drugs obtain them from friends and relatives.²¹

The Substance Abuse and Mental Health Services Administration (SAMHSA) recommends universal screening of adolescents for substance abuse. This screening should be accompanied by a brief intervention to prevent, mitigate, or eliminate substance use, or a referral to appropriate treatment sources. This process of screening, brief intervention, and referral to treatment (SBIRT) is recommended as part of routine health care.²²

Continue to: Obesity and physical activity

Obesity and physical activity

The percentage of overweight and obese adolescents in the United States has more than tripled over the past 40 years,²³ and 1 in 5 US adolescents is obese.²³ Obese teens are at higher risk for multiple chronic diseases, including type 2 diabetes, sleep apnea, and heart disease.²⁴ They are also more likely to be bullied and to have poor self-esteem.²⁵ Only 1 in 5 American high school students engages in 60 or more minutes of moderate-to-­vigorous physical activity on 5 or more days per week.²⁶

Regular physical activity is, of course, beneficial for cardiorespiratory fitness, bone health, weight control, and improved indices of behavioral health.²⁶ Adolescents who are physically active consistently demonstrate better school attendance and grades.¹⁷ Higher levels of physical fitness are also associated with improved overall cognitive performance.²⁴

General recommendations. The Department of Health and Human Services recommends that adolescents get at least 60 minutes of mostly moderate physical activity every day.²⁶ Encourage adolescents to engage in vigorous physical activity (heavy breathing, sweating) at least 3 days a week. As part of their physical activity patterns, adolescents should also engage in muscle-­strengthening and bone-strengthening activities on at least 3 days per week.

Behavioral health

As young people develop their sense of personal identity, they also strive for independence. It can be difficult, at times, to differentiate normal adolescent rebellion from true mental illness. An estimated 17% to 19% of adolescents meet criteria for mental illness, and about 7% have a severe psychiatric disorder.²⁷ Only one-third of adolescents with mental illness receive any mental health services.²⁸

Depression. The 1-year incidence of major depression in adolescents is 3% to 4%, and the lifetime prevalence of depressive symptoms is 25% in all high school students.²⁷ Risk factors include ethnic minority status, poor self-esteem, poor health, recent personal crisis, insomnia, and alcohol/­substance abuse. Depression in adolescent girls is correlated with becoming sexually active at a younger age, failure to use contraception, having an STI, and suicide attempts. Depressed boys are more likely to have unprotected intercourse and participate in physical fights.²⁹ Depressed teens have a 2- to 3-fold greater risk for behavioral disorders, anxiety, and attention-deficit/hyperactivity disorder (ADHD).³⁰

Continue to: Suicide

Suicide. Among individuals 15 to 29 years of age, suicide is the second leading cause of death globally, with an annual incidence of 11 to 15 per 100,000.³¹ Suicide attempts are 10 to 20 times more common than completed suicide.³¹ Males are more likely than females to die by suicide,³² and boys with a history of attempted suicide have a 30-fold increased risk of subsequent successful suicide.³¹ Hanging, drug poisoning, and firearms (particularly for males) are the most common means of suicide in adolescents. More than half of adolescents dying by suicide have coexisting depression.³¹

Adolescents prefer that providers address sexual health and are more likely to respond if asked directly about sexual behaviors.

Characteristics associated with suicidal behaviors in adolescents include impulsivity, poor problem-solving skills, and dichotomous thinking.³¹ There may be a genetic component as well. In 1 of 5 teenage suicides, a precipitating life event such as the break-up of a relationship, cyber-bullying, or peer rejection is felt to contribute.³¹

ADHD. The prevalence of ADHD is 7% to 9% in US school-aged children.³³ Boys more commonly exhibit hyperactive behaviors, while girls have more inattention. Hyperactivity often diminishes in teens, but inattention and impulsivity persist. Sequelae of ADHD include high-risk sexual behaviors, motor vehicle accidents, incarceration, and substance abuse.³⁴ Poor self-esteem, suicidal ideation, smoking, and obesity are also increased.³⁴ ADHD often persists into adulthood, with implications for social relationships and job performance.³⁴

Eating disorders. The distribution of eating disorders is now known to increasingly include more minorities and males, the latter representing 5% to 10% of cases.³⁵ Eating disorders show a strong genetic tendency and appear to be accelerated by puberty. The most common eating disorder (diagnosed in 0.8%-14% of teens) is eating disorder not otherwise specified (NOS).³⁵ Anorexia nervosa is diagnosed in 0.5% of adolescent girls, and bulimia nervosa in 1% to 2%—particularly among athletes and performers.³⁵ Unanticipated loss of weight, amenorrhea, excessive concern about weight, and deceleration in height/weight curves are potential indicators of an eating disorder. When identified, eating disorders are best managed by a trusted family physician, acting as a coordinator of a multidisciplinary team.

Sexual health

Girls begin to menstruate at an average age of 12, and it takes about 4 years for them to reach reproductive maturity.³⁶ Puberty has been documented to start at younger ages over the past 30 years, likely due to an increase in average body mass index and a decrease in levels of physical activity.³⁷ Girls with early maturation are often insecure and self-conscious, with higher levels of psychological distress.³⁸ In boys, the average age for spermarche (first ejaculation) is 13.³⁹ Boys who mature early tend to be taller, be more confident, and express a good body image.⁴⁰ Those who have early puberty are more likely to be sexually active or participate in high-risk behaviors.⁴¹

Continue to: Pregnancy and contraception

Over the past several decades, more US teens have been abstaining from sexual intercourse or have been using effective forms of birth control, particularly condoms and long-acting reversible contraceptives (LARCs).⁴² Teenage birth rates in girls ages 15 to 19 have declined significantly since the 1980s.⁴² Despite this, the teenage birth rate in the United States remains higher than in other industrialized nations, and most teen pregnancies are unintended.⁴³ Disparities in teenage birth rates also persist across racial and socioeconomic lines.⁴⁴

Restricting computer use to an area with parental supervision or installing monitoring programs does not seem to exert any protective influence on cyber-bullying or unsolicited stranger contact.

There are numerous interventions to reduce teen pregnancy, including sex education, contraceptive counseling, the use of mobile apps that track a user’s monthly fertility cycle or issue reminders to take oral contraceptives,⁴⁵ and the liberal distribution of contraceptives and condoms. The Contraceptive CHOICE Project shows that providing free (or low-cost) LARCs influences young women to choose these as their preferred contraceptive method.⁴⁶ Other programs specifically empower girls to convince partners to use condoms and to resist unwanted sexual advances or intimate partner violence.

Adolescents prefer to have their health care providers address the topic of sexual health. Teens are more likely to share information with providers if asked directly about sexual behaviors.⁴⁷TABLE 2^4,5 offers tips for anticipatory guidance and potential ways to frame questions with adolescents in this context. State laws vary with regard to the ability of minors to seek contraception, pregnancy testing, or care/screening for STIs without parental consent. Contraceptive counseling combined with effective screening decrease the incidence of STIs and pelvic inflammatory disease for sexually active teens.⁴⁸

Sexually transmitted infections

Young adolescents often have a limited ability to imagine consequences related to specific actions. In general, there is also an increased desire to engage in experimental behaviors as an expression of developing autonomy, which may expose them to STIs. About half of all STIs contracted in the United States occur in individuals 15 to 24 years of age.⁴⁹ Girls are at particular risk for the sequelae of these infections, including cervical dysplasia and infertility. Many teens erroneously believe that sexual activities other than intercourse decrease their risk of contracting an STI.⁵⁰

Human papillomavirus (HPV) infection is the most common STI in adolescence.⁵¹ In most cases, HPV is transient and asymptomatic. Oncogenic strains may cause cervical cancer or cancers of the anogenital or oropharyngeal systems. Due to viral latency, it is not recommended to perform HPV typing in men or in women younger than 30 years of age; however, Pap tests are recommended every 3 years for women ages 21 to 29. Primary care providers are pivotal in the public health struggle to prevent HPV infection.

Continue to: Universal immunization of all children...

Universal immunization of all children older than 11 years of age against HPV is strongly advised as part of routine well-child care. Emphasize the proven role of HPV vaccination in preventing cervical⁵² and oropharyngeal⁵³ cancers. And be prepared to address concerns raised by parents in the context of vaccine safety and the initiation of sexual behaviors (www.cdc.gov/hpv/hcp/answering-questions.html).

Chlamydia is the second most common STI in the United States, usually occurring in individuals younger than 24.⁵⁴ The CDC estimates that more than 3 million new chlamydial infections occur yearly. These infections are often asymptomatic, particularly in females, but may cause urethritis, cervicitis, epididymitis, proctitis, or pelvic inflammatory disease. Indolent chlamydial infection is the leading cause of tubal infertility in women.⁵⁴ Routine annual screening for chlamydia is recommended for all sexually active females ≤ 25 years (and for older women with specific risks).⁵⁵ Annual screening is also recommended for men who have sex with men (MSM).⁵⁵

Chlamydial infection may be diagnosed with first-catch urine sampling (men or women), urethral swab (men), endocervical swab (women), or self-collected vaginal swab. Nucleic acid amplification testing is the most sensitive test that is widely available.⁵⁶ First-line treatment includes either azithromycin (1 g orally, single dose) or doxycycline (100 mg orally, twice daily for 7 days).⁵⁶

Gonorrhea. In 2018, there were more than 500,000 annual cases of gonorrhea, with the majority occurring in those between 15 and 24 years of age.⁵⁷ Gonorrhea may increase rates of HIV infection transmission up to 5-fold.⁵⁷ As more adolescents practice oral sex, cases of pharyngeal gonorrhea (and oropharyngeal HPV) have increased. Symptoms of urethritis occur more frequently in men. Screening is recommended for all sexually active women younger than 25.⁵⁶ Importantly, the organism Neisseria gonorrhoeae has developed significant antibiotic resistance over the past decade. The CDC currently recommends dual therapy for the treatment of gonorrhea using 250 mg of intramuscular ceftriaxone and 1 g of oral azithromycin.⁵⁶

Syphilis. Rates of syphilis are increasing among individuals ages 15 to 24.⁵¹ Screening is particularly recommended for MSM and individuals infected with HIV. Benzathine penicillin G, 50,000 U/kg IM, remains the treatment of choice.⁵⁶

Continue to: HIV

HIV. Globally, HIV impacts young people disproportionately. HIV infection also facilitates infection with other STIs. In the United States, the highest burden of HIV infection is borne by young MSM, with prevalence among those 18 to 24 years old varying between 26% to 30% (black) and 3% to 5.5% (non-Hispanic white).⁵¹ The use of emtricitabine/tenofovir disoproxil fumarate for pre-exposure prophylaxis (PrEP) has recently been approved for the prevention of HIV. PrEP reduces risk by up to 92% for MSM and transgender women.⁵⁸

Sexual identity

One in 10 high school students self-identifies as “nonheterosexual,” and 1 in 15 reports same-sex sexual contact.⁵⁹ The term LGBTQ+ includes the communities of lesbian, gay, bisexual, transgender, transsexual, queer, questioning, intersex, and asexual individuals. Developing a safe sense of sexual identity is fundamental to adolescent psychological development, and many adolescents struggle to develop a positive sexual identity. Suicide rates and self-harm behaviors among ­LGBTQ+ adolescents can be 4 times higher than among their heterosexual peers.⁶⁰ Rates of mood disorders, substance abuse, and high-risk sexual behaviors are also increased in the LGBTQ+ population.⁶¹

Suicide rates and self-harm behaviors among LGBTQ+ adolescents can be 4 times higher than among their heterosexual peers.

The LGBTQ+ community often seeks health care advice and affirmation from primary care providers. Resources to enhance this care are available at www.lgbthealtheducation.org.

Social media

Adolescents today have more media exposure than any prior generation, with smartphone and computer use increasing exponentially. Most (95%) teens have access to a smartphone,⁶² 45% describe themselves as constantly connected to the Internet, and 14% feel that social media is “addictive.”⁶² Most manage their social media portfolio on multiple sites. Patterns of adolescents' online activities show that boys prefer online gaming, while girls tend to spend more time on social networking.⁶²

Whether extensive media use is psychologically beneficial or deleterious has been widely debated. Increased time online correlates with decreased levels of physical activity.⁶³ And sleep disturbances have been associated with excessive screen time and the presence of mobile devices in the bedroom.⁶⁴ The use of social media prior to bedtime also has an adverse impact on academic performance—particularly for girls. This adverse impact on academics persists after correcting for daytime sleepiness, body mass index, and number of hours spent on homework.⁶⁴

Continue to: Due to growing concerns...

Due to growing concerns about the risks of social media in children and adolescents, the American Academy of Pediatrics has developed the Family Media Plan (www.healthychildren.org/English/media/Pages/default.aspx). Some specific questions that providers may ask are outlined in TABLE 3.⁶⁴ The Family Media Plan can provide age-specific guidelines to assist parents or caregivers in answering these questions.

Cyber-bullying. One in 3 adolescents (primarily female) has been a victim of cyber-bullying.⁶⁵ Sadly, 1 in 5 teens has received some form of electronic sexual solicitation.⁶⁶ The likelihood of unsolicited stranger contact correlates with teens’ online habits and the amount of information disclosed. Predictors include female sex, visiting chat rooms, posting photos, and disclosing personal information. Restricting computer use to an area with parental supervision or installing monitoring programs does not seem to exert any protective influence on cyber-bullying or unsolicited stranger contact.⁶⁵ While 63% of cyber-bullying victims feel upset, embarrassed, or stressed by these contacts,⁶⁶ few events are actually reported. To address this, some states have adopted laws adding cyber-bullying to school disciplinary codes.

Adolescents rarely disclose bullying to parents or other adults, fearing restriction of Internet access, and many of them think that adults may downplay the seriousness of the events.

Negative health impacts associated with cyber-bullying include anxiety, sadness, and greater difficulty in concentrating on school work.⁶⁵ Victims of bullying are more likely to have school disciplinary actions and depression and to be truant or to carry weapons to school.⁶⁶ Cyber-bullying is uniquely destructive due to its ubiquitous presence. A sense of relative anonymity online may encourage perpetrators to act more cruelly, with less concern for punishment.

Young people are also more likely to share passwords as a sign of friendship. This may result in others assuming their identity online. Adolescents rarely disclose bullying to parents or other adults, fearing restriction of Internet access, and many of them think that adults may downplay the seriousness of the events.⁶⁶

CORRESPONDENCE
Mark B. Stephens, MD, Penn State Health Medical Group, 1850 East Park Avenue, State College, PA 16803; [email protected].

Adolescents are an increasingly diverse population reflecting changes in the racial, ethnic, and geopolitical milieus of the United States. The World Health Organization classifies adolescence as ages 10 to 19 years.¹ However, given the complexity of adolescent development physically, behaviorally, emotionally, and socially, others propose that adolescence may extend to age 24.²

Recognizing the specific challenges adolescents face is key to providing comprehensive longitudinal health care. Moreover, creating an environment of trust helps to ensure open 2-way communication that can facilitate anticipatory guidance.

Our review focuses on common adolescent issues, including injury from vehicles and firearms, tobacco and substance misuse, obesity, behavioral health, sexual health, and social media use. We discuss current trends and recommend strategies to maximize health and wellness.

Start by framing the visit

Confidentiality

Laws governing confidentiality in adolescent health care vary by state. Be aware of the laws pertaining to your practice setting. In addition, health care facilities may have their own policies regarding consent and confidentiality in adolescent care. Discuss confidentiality with both an adolescent and the parent/guardian at the initial visit. And, to help avoid potential misunderstandings, let them know in advance what will (and will not) be divulged.

The American Academy of Pediatrics has developed a useful tip sheet regarding confidentiality laws (www.aap.org/en-us/advocacy-and-policy/aap-health-initiatives/healthy-foster-care-america/Documents/Confidentiality_Laws.pdf). Examples of required (conditional) disclosure include abuse and suicidal or homicidal ideations. Patients should understand that sexually transmitted infections (STIs) are reportable to public health authorities and that potentially injurious behaviors to self or others (eg, excessive drinking prior to driving) may also warrant disclosure(TABLE 1³).

Privacy and general visit structure

Create a safe atmosphere where adolescents can discuss personal issues without fear of repercussion or judgment. While parents may prefer to be present during the visit, allowing for time to visit independently with an adolescent offers the opportunity to reinforce issues of privacy and confidentiality. Also discuss your office policies regarding electronic communication, phone communication, and relaying test results.

A useful paradigm for organizing a visit for routine adolescent care is to use an expanded version of the HEADSS mnemonic (TABLE 2^4,5), which includes questions about an adolescent’s Home, Education, Activities, Drug and alcohol use, Sexual behavior, Suicidality and depression, and other topics. Other validated screening tools include RAAPS (Rapid Adolescent Prevention Screening)⁶ (www.possibilitiesforchange.com/raaps/); the Guidelines for Adolescent Preventive Services⁷; and the Bright Futures recommendations for preventive care from the American Academy of Pediatrics.⁸ Below, we consider important topics addressed with the HEADSS approach.

Continue to: Injury from vehicles and firearms

Motor vehicle accidents and firearm wounds are the 2 leading causes of adolescent injury. In 2016, of the more than 20,000 deaths in children and adolescents (ages 1-19 years), 20% were due to motor vehicle accidents (4074) and 15% were a result of firearm-­related injuries (3143). Among firearm-­related deaths, 60% were homicides, 35% were suicides, and 4% were due to accidental discharge.⁹ The rate of firearm-related deaths among American teens is 36 times greater than that of any other developed nation.⁹ Currently, 1 of every 3 US households with children younger than 18 has a firearm. Data suggest that in 43% of these households, the firearm is loaded and kept in an unlocked location.¹⁰

To aid anticipatory guidance, ask adolescents about firearm and seat belt use, drinking and driving, and suicidal thoughts (TABLE 2^4,5). Advise them to always wear seat belts whether driving or riding as a passenger. They should never drink and drive (or get in a car with someone who has been drinking). Advise parents that if firearms are present in the household, they should be kept in a secure, locked location. Weapons should be separated from ammunition and safety mechanisms should be engaged on all devices.

Tobacco and substance misuse

Tobacco use, the leading preventable cause of death in the United States,¹¹ is responsible for more deaths than alcohol, motor vehicle accidents, suicides, homicides, and HIV disease combined.¹² Most tobacco-associated mortality occurs in individuals who began smoking before the age of 18.¹² Individuals who start smoking early are also more likely to continue smoking through adulthood.

Encouragingly, tobacco use has declined significantly among adolescents over the past several decades. Roughly 1 in 25 high school seniors reports daily tobacco use.¹³ Adolescent smoking behaviors are also changing dramatically with the increasing popularity of electronic cigarettes (“vaping”). Currently, more adolescents vape than smoke cigarettes.¹³ Vaping has additional health risks including toxic lung injury.

Multiple resources can help combat tobacco and nicotine use in adolescents. The US Preventive Services Task Force recommends that primary care clinicians intervene through education or brief counselling to prevent initiation of tobacco use in school-aged children and adolescents.¹⁴ Ask teens about tobacco and electronic cigarette use and encourage them to quit when use is acknowledged. Other helpful office-based tools are the “Quit Line” 800-QUIT-NOW and texting “Quit” to 47848. Smokefree teen (https://teen.smokefree.gov/) is a website that reviews the risks of tobacco and nicotine use and provides age-appropriate cessation tools and tips (including a smartphone app and a live-chat feature). Other useful information is available in a report from the Surgeon General on preventing tobacco use among young adults.¹⁵

Continue to: Alcohol use

Alcohol use. Three in 5 high school students report ever having used alcohol.¹³ As with tobacco, adolescent alcohol use has declined over the past decade. However, binge drinking (≥ 5 drinks on 1 occasion for males; ≥ 4 drinks on 1 occasion for females) remains a common high-risk behavior among adolescents (particularly college students). Based on the Monitoring the Future Survey, 1 in 6 high school seniors reported binge drinking in the past 2 weeks.¹³ While historically more common among males, rates of binge drinking are now basically similar between male and female adolescents.¹³

While historically more common among males, rates of binge drinking are now basically similar between male and female adolescents.

The National Institute on Alcohol Abuse and Alcoholism has a screening and intervention guide specifically for adolescents.¹⁶A 2-question screening tool asking about personal use of alcohol and use of alcohol by friends is followed by a risk assessment with recommendations to advise young patients not to drink and to assist them with appropriate intervention and follow-up (https://pubs.niaaa.nih.gov/publications/Practitioner/YouthGuide/YouthGuidePocket.pdf).

Illicit drug use. Half of adolescents report using an illicit drug by their senior year in high school.¹³ Marijuana is the most commonly used substance, and laws governing its use are rapidly changing across the United States. Marijuana is illegal in 10 states and legal in 10 states (and the District of Columbia). The remaining states have varying policies on the medical use of marijuana and the decriminalization of marijuana. In addition, cannabinoid (CBD) products are increasingly available. Frequent cannabis use in adolescence has an adverse impact on general executive function (compared with adult users) and learning.¹⁷ Marijuana may serve as a gateway drug in the abuse of other substances,¹⁸ and its use should be strongly discouraged in adolescents.

Of note, there has been a sharp rise in the illicit use of prescription drugs, particularly opioids, creating a public health emergency across the United States.¹⁹ In 2015, more than 4000 young people, ages 15 to 24, died from a drug-related overdose (> 50% of these attributable to opioids).²⁰ Adolescents with a history of substance abuse and behavioral illness are at particular risk. Many adolescents who misuse opioids and other prescription drugs obtain them from friends and relatives.²¹

The Substance Abuse and Mental Health Services Administration (SAMHSA) recommends universal screening of adolescents for substance abuse. This screening should be accompanied by a brief intervention to prevent, mitigate, or eliminate substance use, or a referral to appropriate treatment sources. This process of screening, brief intervention, and referral to treatment (SBIRT) is recommended as part of routine health care.²²

Continue to: Obesity and physical activity

Obesity and physical activity

The percentage of overweight and obese adolescents in the United States has more than tripled over the past 40 years,²³ and 1 in 5 US adolescents is obese.²³ Obese teens are at higher risk for multiple chronic diseases, including type 2 diabetes, sleep apnea, and heart disease.²⁴ They are also more likely to be bullied and to have poor self-esteem.²⁵ Only 1 in 5 American high school students engages in 60 or more minutes of moderate-to-­vigorous physical activity on 5 or more days per week.²⁶

Regular physical activity is, of course, beneficial for cardiorespiratory fitness, bone health, weight control, and improved indices of behavioral health.²⁶ Adolescents who are physically active consistently demonstrate better school attendance and grades.¹⁷ Higher levels of physical fitness are also associated with improved overall cognitive performance.²⁴

General recommendations. The Department of Health and Human Services recommends that adolescents get at least 60 minutes of mostly moderate physical activity every day.²⁶ Encourage adolescents to engage in vigorous physical activity (heavy breathing, sweating) at least 3 days a week. As part of their physical activity patterns, adolescents should also engage in muscle-­strengthening and bone-strengthening activities on at least 3 days per week.

Behavioral health

As young people develop their sense of personal identity, they also strive for independence. It can be difficult, at times, to differentiate normal adolescent rebellion from true mental illness. An estimated 17% to 19% of adolescents meet criteria for mental illness, and about 7% have a severe psychiatric disorder.²⁷ Only one-third of adolescents with mental illness receive any mental health services.²⁸

Depression. The 1-year incidence of major depression in adolescents is 3% to 4%, and the lifetime prevalence of depressive symptoms is 25% in all high school students.²⁷ Risk factors include ethnic minority status, poor self-esteem, poor health, recent personal crisis, insomnia, and alcohol/­substance abuse. Depression in adolescent girls is correlated with becoming sexually active at a younger age, failure to use contraception, having an STI, and suicide attempts. Depressed boys are more likely to have unprotected intercourse and participate in physical fights.²⁹ Depressed teens have a 2- to 3-fold greater risk for behavioral disorders, anxiety, and attention-deficit/hyperactivity disorder (ADHD).³⁰

Continue to: Suicide

Suicide. Among individuals 15 to 29 years of age, suicide is the second leading cause of death globally, with an annual incidence of 11 to 15 per 100,000.³¹ Suicide attempts are 10 to 20 times more common than completed suicide.³¹ Males are more likely than females to die by suicide,³² and boys with a history of attempted suicide have a 30-fold increased risk of subsequent successful suicide.³¹ Hanging, drug poisoning, and firearms (particularly for males) are the most common means of suicide in adolescents. More than half of adolescents dying by suicide have coexisting depression.³¹

Adolescents prefer that providers address sexual health and are more likely to respond if asked directly about sexual behaviors.

Characteristics associated with suicidal behaviors in adolescents include impulsivity, poor problem-solving skills, and dichotomous thinking.³¹ There may be a genetic component as well. In 1 of 5 teenage suicides, a precipitating life event such as the break-up of a relationship, cyber-bullying, or peer rejection is felt to contribute.³¹

ADHD. The prevalence of ADHD is 7% to 9% in US school-aged children.³³ Boys more commonly exhibit hyperactive behaviors, while girls have more inattention. Hyperactivity often diminishes in teens, but inattention and impulsivity persist. Sequelae of ADHD include high-risk sexual behaviors, motor vehicle accidents, incarceration, and substance abuse.³⁴ Poor self-esteem, suicidal ideation, smoking, and obesity are also increased.³⁴ ADHD often persists into adulthood, with implications for social relationships and job performance.³⁴

Eating disorders. The distribution of eating disorders is now known to increasingly include more minorities and males, the latter representing 5% to 10% of cases.³⁵ Eating disorders show a strong genetic tendency and appear to be accelerated by puberty. The most common eating disorder (diagnosed in 0.8%-14% of teens) is eating disorder not otherwise specified (NOS).³⁵ Anorexia nervosa is diagnosed in 0.5% of adolescent girls, and bulimia nervosa in 1% to 2%—particularly among athletes and performers.³⁵ Unanticipated loss of weight, amenorrhea, excessive concern about weight, and deceleration in height/weight curves are potential indicators of an eating disorder. When identified, eating disorders are best managed by a trusted family physician, acting as a coordinator of a multidisciplinary team.

Sexual health

Girls begin to menstruate at an average age of 12, and it takes about 4 years for them to reach reproductive maturity.³⁶ Puberty has been documented to start at younger ages over the past 30 years, likely due to an increase in average body mass index and a decrease in levels of physical activity.³⁷ Girls with early maturation are often insecure and self-conscious, with higher levels of psychological distress.³⁸ In boys, the average age for spermarche (first ejaculation) is 13.³⁹ Boys who mature early tend to be taller, be more confident, and express a good body image.⁴⁰ Those who have early puberty are more likely to be sexually active or participate in high-risk behaviors.⁴¹

Continue to: Pregnancy and contraception

Over the past several decades, more US teens have been abstaining from sexual intercourse or have been using effective forms of birth control, particularly condoms and long-acting reversible contraceptives (LARCs).⁴² Teenage birth rates in girls ages 15 to 19 have declined significantly since the 1980s.⁴² Despite this, the teenage birth rate in the United States remains higher than in other industrialized nations, and most teen pregnancies are unintended.⁴³ Disparities in teenage birth rates also persist across racial and socioeconomic lines.⁴⁴

Restricting computer use to an area with parental supervision or installing monitoring programs does not seem to exert any protective influence on cyber-bullying or unsolicited stranger contact.

There are numerous interventions to reduce teen pregnancy, including sex education, contraceptive counseling, the use of mobile apps that track a user’s monthly fertility cycle or issue reminders to take oral contraceptives,⁴⁵ and the liberal distribution of contraceptives and condoms. The Contraceptive CHOICE Project shows that providing free (or low-cost) LARCs influences young women to choose these as their preferred contraceptive method.⁴⁶ Other programs specifically empower girls to convince partners to use condoms and to resist unwanted sexual advances or intimate partner violence.

Adolescents prefer to have their health care providers address the topic of sexual health. Teens are more likely to share information with providers if asked directly about sexual behaviors.⁴⁷TABLE 2^4,5 offers tips for anticipatory guidance and potential ways to frame questions with adolescents in this context. State laws vary with regard to the ability of minors to seek contraception, pregnancy testing, or care/screening for STIs without parental consent. Contraceptive counseling combined with effective screening decrease the incidence of STIs and pelvic inflammatory disease for sexually active teens.⁴⁸

Sexually transmitted infections

Young adolescents often have a limited ability to imagine consequences related to specific actions. In general, there is also an increased desire to engage in experimental behaviors as an expression of developing autonomy, which may expose them to STIs. About half of all STIs contracted in the United States occur in individuals 15 to 24 years of age.⁴⁹ Girls are at particular risk for the sequelae of these infections, including cervical dysplasia and infertility. Many teens erroneously believe that sexual activities other than intercourse decrease their risk of contracting an STI.⁵⁰

Human papillomavirus (HPV) infection is the most common STI in adolescence.⁵¹ In most cases, HPV is transient and asymptomatic. Oncogenic strains may cause cervical cancer or cancers of the anogenital or oropharyngeal systems. Due to viral latency, it is not recommended to perform HPV typing in men or in women younger than 30 years of age; however, Pap tests are recommended every 3 years for women ages 21 to 29. Primary care providers are pivotal in the public health struggle to prevent HPV infection.

Continue to: Universal immunization of all children...

Universal immunization of all children older than 11 years of age against HPV is strongly advised as part of routine well-child care. Emphasize the proven role of HPV vaccination in preventing cervical⁵² and oropharyngeal⁵³ cancers. And be prepared to address concerns raised by parents in the context of vaccine safety and the initiation of sexual behaviors (www.cdc.gov/hpv/hcp/answering-questions.html).

Chlamydia is the second most common STI in the United States, usually occurring in individuals younger than 24.⁵⁴ The CDC estimates that more than 3 million new chlamydial infections occur yearly. These infections are often asymptomatic, particularly in females, but may cause urethritis, cervicitis, epididymitis, proctitis, or pelvic inflammatory disease. Indolent chlamydial infection is the leading cause of tubal infertility in women.⁵⁴ Routine annual screening for chlamydia is recommended for all sexually active females ≤ 25 years (and for older women with specific risks).⁵⁵ Annual screening is also recommended for men who have sex with men (MSM).⁵⁵

Chlamydial infection may be diagnosed with first-catch urine sampling (men or women), urethral swab (men), endocervical swab (women), or self-collected vaginal swab. Nucleic acid amplification testing is the most sensitive test that is widely available.⁵⁶ First-line treatment includes either azithromycin (1 g orally, single dose) or doxycycline (100 mg orally, twice daily for 7 days).⁵⁶

Gonorrhea. In 2018, there were more than 500,000 annual cases of gonorrhea, with the majority occurring in those between 15 and 24 years of age.⁵⁷ Gonorrhea may increase rates of HIV infection transmission up to 5-fold.⁵⁷ As more adolescents practice oral sex, cases of pharyngeal gonorrhea (and oropharyngeal HPV) have increased. Symptoms of urethritis occur more frequently in men. Screening is recommended for all sexually active women younger than 25.⁵⁶ Importantly, the organism Neisseria gonorrhoeae has developed significant antibiotic resistance over the past decade. The CDC currently recommends dual therapy for the treatment of gonorrhea using 250 mg of intramuscular ceftriaxone and 1 g of oral azithromycin.⁵⁶

Syphilis. Rates of syphilis are increasing among individuals ages 15 to 24.⁵¹ Screening is particularly recommended for MSM and individuals infected with HIV. Benzathine penicillin G, 50,000 U/kg IM, remains the treatment of choice.⁵⁶

Continue to: HIV

HIV. Globally, HIV impacts young people disproportionately. HIV infection also facilitates infection with other STIs. In the United States, the highest burden of HIV infection is borne by young MSM, with prevalence among those 18 to 24 years old varying between 26% to 30% (black) and 3% to 5.5% (non-Hispanic white).⁵¹ The use of emtricitabine/tenofovir disoproxil fumarate for pre-exposure prophylaxis (PrEP) has recently been approved for the prevention of HIV. PrEP reduces risk by up to 92% for MSM and transgender women.⁵⁸

Sexual identity

One in 10 high school students self-identifies as “nonheterosexual,” and 1 in 15 reports same-sex sexual contact.⁵⁹ The term LGBTQ+ includes the communities of lesbian, gay, bisexual, transgender, transsexual, queer, questioning, intersex, and asexual individuals. Developing a safe sense of sexual identity is fundamental to adolescent psychological development, and many adolescents struggle to develop a positive sexual identity. Suicide rates and self-harm behaviors among ­LGBTQ+ adolescents can be 4 times higher than among their heterosexual peers.⁶⁰ Rates of mood disorders, substance abuse, and high-risk sexual behaviors are also increased in the LGBTQ+ population.⁶¹

Suicide rates and self-harm behaviors among LGBTQ+ adolescents can be 4 times higher than among their heterosexual peers.

The LGBTQ+ community often seeks health care advice and affirmation from primary care providers. Resources to enhance this care are available at www.lgbthealtheducation.org.

Social media

Adolescents today have more media exposure than any prior generation, with smartphone and computer use increasing exponentially. Most (95%) teens have access to a smartphone,⁶² 45% describe themselves as constantly connected to the Internet, and 14% feel that social media is “addictive.”⁶² Most manage their social media portfolio on multiple sites. Patterns of adolescents' online activities show that boys prefer online gaming, while girls tend to spend more time on social networking.⁶²

Whether extensive media use is psychologically beneficial or deleterious has been widely debated. Increased time online correlates with decreased levels of physical activity.⁶³ And sleep disturbances have been associated with excessive screen time and the presence of mobile devices in the bedroom.⁶⁴ The use of social media prior to bedtime also has an adverse impact on academic performance—particularly for girls. This adverse impact on academics persists after correcting for daytime sleepiness, body mass index, and number of hours spent on homework.⁶⁴

Continue to: Due to growing concerns...

Due to growing concerns about the risks of social media in children and adolescents, the American Academy of Pediatrics has developed the Family Media Plan (www.healthychildren.org/English/media/Pages/default.aspx). Some specific questions that providers may ask are outlined in TABLE 3.⁶⁴ The Family Media Plan can provide age-specific guidelines to assist parents or caregivers in answering these questions.

Cyber-bullying. One in 3 adolescents (primarily female) has been a victim of cyber-bullying.⁶⁵ Sadly, 1 in 5 teens has received some form of electronic sexual solicitation.⁶⁶ The likelihood of unsolicited stranger contact correlates with teens’ online habits and the amount of information disclosed. Predictors include female sex, visiting chat rooms, posting photos, and disclosing personal information. Restricting computer use to an area with parental supervision or installing monitoring programs does not seem to exert any protective influence on cyber-bullying or unsolicited stranger contact.⁶⁵ While 63% of cyber-bullying victims feel upset, embarrassed, or stressed by these contacts,⁶⁶ few events are actually reported. To address this, some states have adopted laws adding cyber-bullying to school disciplinary codes.

Adolescents rarely disclose bullying to parents or other adults, fearing restriction of Internet access, and many of them think that adults may downplay the seriousness of the events.

Negative health impacts associated with cyber-bullying include anxiety, sadness, and greater difficulty in concentrating on school work.⁶⁵ Victims of bullying are more likely to have school disciplinary actions and depression and to be truant or to carry weapons to school.⁶⁶ Cyber-bullying is uniquely destructive due to its ubiquitous presence. A sense of relative anonymity online may encourage perpetrators to act more cruelly, with less concern for punishment.

Young people are also more likely to share passwords as a sign of friendship. This may result in others assuming their identity online. Adolescents rarely disclose bullying to parents or other adults, fearing restriction of Internet access, and many of them think that adults may downplay the seriousness of the events.⁶⁶

CORRESPONDENCE
Mark B. Stephens, MD, Penn State Health Medical Group, 1850 East Park Avenue, State College, PA 16803; [email protected].

Adolescents are an increasingly diverse population reflecting changes in the racial, ethnic, and geopolitical milieus of the United States. The World Health Organization classifies adolescence as ages 10 to 19 years.¹ However, given the complexity of adolescent development physically, behaviorally, emotionally, and socially, others propose that adolescence may extend to age 24.²

Recognizing the specific challenges adolescents face is key to providing comprehensive longitudinal health care. Moreover, creating an environment of trust helps to ensure open 2-way communication that can facilitate anticipatory guidance.

Our review focuses on common adolescent issues, including injury from vehicles and firearms, tobacco and substance misuse, obesity, behavioral health, sexual health, and social media use. We discuss current trends and recommend strategies to maximize health and wellness.

Start by framing the visit

Confidentiality

Laws governing confidentiality in adolescent health care vary by state. Be aware of the laws pertaining to your practice setting. In addition, health care facilities may have their own policies regarding consent and confidentiality in adolescent care. Discuss confidentiality with both an adolescent and the parent/guardian at the initial visit. And, to help avoid potential misunderstandings, let them know in advance what will (and will not) be divulged.

The American Academy of Pediatrics has developed a useful tip sheet regarding confidentiality laws (www.aap.org/en-us/advocacy-and-policy/aap-health-initiatives/healthy-foster-care-america/Documents/Confidentiality_Laws.pdf). Examples of required (conditional) disclosure include abuse and suicidal or homicidal ideations. Patients should understand that sexually transmitted infections (STIs) are reportable to public health authorities and that potentially injurious behaviors to self or others (eg, excessive drinking prior to driving) may also warrant disclosure(TABLE 1³).

Privacy and general visit structure

Create a safe atmosphere where adolescents can discuss personal issues without fear of repercussion or judgment. While parents may prefer to be present during the visit, allowing for time to visit independently with an adolescent offers the opportunity to reinforce issues of privacy and confidentiality. Also discuss your office policies regarding electronic communication, phone communication, and relaying test results.

A useful paradigm for organizing a visit for routine adolescent care is to use an expanded version of the HEADSS mnemonic (TABLE 2^4,5), which includes questions about an adolescent’s Home, Education, Activities, Drug and alcohol use, Sexual behavior, Suicidality and depression, and other topics. Other validated screening tools include RAAPS (Rapid Adolescent Prevention Screening)⁶ (www.possibilitiesforchange.com/raaps/); the Guidelines for Adolescent Preventive Services⁷; and the Bright Futures recommendations for preventive care from the American Academy of Pediatrics.⁸ Below, we consider important topics addressed with the HEADSS approach.

Continue to: Injury from vehicles and firearms

Motor vehicle accidents and firearm wounds are the 2 leading causes of adolescent injury. In 2016, of the more than 20,000 deaths in children and adolescents (ages 1-19 years), 20% were due to motor vehicle accidents (4074) and 15% were a result of firearm-­related injuries (3143). Among firearm-­related deaths, 60% were homicides, 35% were suicides, and 4% were due to accidental discharge.⁹ The rate of firearm-related deaths among American teens is 36 times greater than that of any other developed nation.⁹ Currently, 1 of every 3 US households with children younger than 18 has a firearm. Data suggest that in 43% of these households, the firearm is loaded and kept in an unlocked location.¹⁰

To aid anticipatory guidance, ask adolescents about firearm and seat belt use, drinking and driving, and suicidal thoughts (TABLE 2^4,5). Advise them to always wear seat belts whether driving or riding as a passenger. They should never drink and drive (or get in a car with someone who has been drinking). Advise parents that if firearms are present in the household, they should be kept in a secure, locked location. Weapons should be separated from ammunition and safety mechanisms should be engaged on all devices.

Tobacco and substance misuse

Tobacco use, the leading preventable cause of death in the United States,¹¹ is responsible for more deaths than alcohol, motor vehicle accidents, suicides, homicides, and HIV disease combined.¹² Most tobacco-associated mortality occurs in individuals who began smoking before the age of 18.¹² Individuals who start smoking early are also more likely to continue smoking through adulthood.

Encouragingly, tobacco use has declined significantly among adolescents over the past several decades. Roughly 1 in 25 high school seniors reports daily tobacco use.¹³ Adolescent smoking behaviors are also changing dramatically with the increasing popularity of electronic cigarettes (“vaping”). Currently, more adolescents vape than smoke cigarettes.¹³ Vaping has additional health risks including toxic lung injury.

Multiple resources can help combat tobacco and nicotine use in adolescents. The US Preventive Services Task Force recommends that primary care clinicians intervene through education or brief counselling to prevent initiation of tobacco use in school-aged children and adolescents.¹⁴ Ask teens about tobacco and electronic cigarette use and encourage them to quit when use is acknowledged. Other helpful office-based tools are the “Quit Line” 800-QUIT-NOW and texting “Quit” to 47848. Smokefree teen (https://teen.smokefree.gov/) is a website that reviews the risks of tobacco and nicotine use and provides age-appropriate cessation tools and tips (including a smartphone app and a live-chat feature). Other useful information is available in a report from the Surgeon General on preventing tobacco use among young adults.¹⁵

Continue to: Alcohol use

Alcohol use. Three in 5 high school students report ever having used alcohol.¹³ As with tobacco, adolescent alcohol use has declined over the past decade. However, binge drinking (≥ 5 drinks on 1 occasion for males; ≥ 4 drinks on 1 occasion for females) remains a common high-risk behavior among adolescents (particularly college students). Based on the Monitoring the Future Survey, 1 in 6 high school seniors reported binge drinking in the past 2 weeks.¹³ While historically more common among males, rates of binge drinking are now basically similar between male and female adolescents.¹³

While historically more common among males, rates of binge drinking are now basically similar between male and female adolescents.

The National Institute on Alcohol Abuse and Alcoholism has a screening and intervention guide specifically for adolescents.¹⁶A 2-question screening tool asking about personal use of alcohol and use of alcohol by friends is followed by a risk assessment with recommendations to advise young patients not to drink and to assist them with appropriate intervention and follow-up (https://pubs.niaaa.nih.gov/publications/Practitioner/YouthGuide/YouthGuidePocket.pdf).

Illicit drug use. Half of adolescents report using an illicit drug by their senior year in high school.¹³ Marijuana is the most commonly used substance, and laws governing its use are rapidly changing across the United States. Marijuana is illegal in 10 states and legal in 10 states (and the District of Columbia). The remaining states have varying policies on the medical use of marijuana and the decriminalization of marijuana. In addition, cannabinoid (CBD) products are increasingly available. Frequent cannabis use in adolescence has an adverse impact on general executive function (compared with adult users) and learning.¹⁷ Marijuana may serve as a gateway drug in the abuse of other substances,¹⁸ and its use should be strongly discouraged in adolescents.

Of note, there has been a sharp rise in the illicit use of prescription drugs, particularly opioids, creating a public health emergency across the United States.¹⁹ In 2015, more than 4000 young people, ages 15 to 24, died from a drug-related overdose (> 50% of these attributable to opioids).²⁰ Adolescents with a history of substance abuse and behavioral illness are at particular risk. Many adolescents who misuse opioids and other prescription drugs obtain them from friends and relatives.²¹

The Substance Abuse and Mental Health Services Administration (SAMHSA) recommends universal screening of adolescents for substance abuse. This screening should be accompanied by a brief intervention to prevent, mitigate, or eliminate substance use, or a referral to appropriate treatment sources. This process of screening, brief intervention, and referral to treatment (SBIRT) is recommended as part of routine health care.²²

Continue to: Obesity and physical activity

Obesity and physical activity

The percentage of overweight and obese adolescents in the United States has more than tripled over the past 40 years,²³ and 1 in 5 US adolescents is obese.²³ Obese teens are at higher risk for multiple chronic diseases, including type 2 diabetes, sleep apnea, and heart disease.²⁴ They are also more likely to be bullied and to have poor self-esteem.²⁵ Only 1 in 5 American high school students engages in 60 or more minutes of moderate-to-­vigorous physical activity on 5 or more days per week.²⁶

Regular physical activity is, of course, beneficial for cardiorespiratory fitness, bone health, weight control, and improved indices of behavioral health.²⁶ Adolescents who are physically active consistently demonstrate better school attendance and grades.¹⁷ Higher levels of physical fitness are also associated with improved overall cognitive performance.²⁴

General recommendations. The Department of Health and Human Services recommends that adolescents get at least 60 minutes of mostly moderate physical activity every day.²⁶ Encourage adolescents to engage in vigorous physical activity (heavy breathing, sweating) at least 3 days a week. As part of their physical activity patterns, adolescents should also engage in muscle-­strengthening and bone-strengthening activities on at least 3 days per week.

Behavioral health

As young people develop their sense of personal identity, they also strive for independence. It can be difficult, at times, to differentiate normal adolescent rebellion from true mental illness. An estimated 17% to 19% of adolescents meet criteria for mental illness, and about 7% have a severe psychiatric disorder.²⁷ Only one-third of adolescents with mental illness receive any mental health services.²⁸

Depression. The 1-year incidence of major depression in adolescents is 3% to 4%, and the lifetime prevalence of depressive symptoms is 25% in all high school students.²⁷ Risk factors include ethnic minority status, poor self-esteem, poor health, recent personal crisis, insomnia, and alcohol/­substance abuse. Depression in adolescent girls is correlated with becoming sexually active at a younger age, failure to use contraception, having an STI, and suicide attempts. Depressed boys are more likely to have unprotected intercourse and participate in physical fights.²⁹ Depressed teens have a 2- to 3-fold greater risk for behavioral disorders, anxiety, and attention-deficit/hyperactivity disorder (ADHD).³⁰

Continue to: Suicide

Suicide. Among individuals 15 to 29 years of age, suicide is the second leading cause of death globally, with an annual incidence of 11 to 15 per 100,000.³¹ Suicide attempts are 10 to 20 times more common than completed suicide.³¹ Males are more likely than females to die by suicide,³² and boys with a history of attempted suicide have a 30-fold increased risk of subsequent successful suicide.³¹ Hanging, drug poisoning, and firearms (particularly for males) are the most common means of suicide in adolescents. More than half of adolescents dying by suicide have coexisting depression.³¹

Adolescents prefer that providers address sexual health and are more likely to respond if asked directly about sexual behaviors.

Characteristics associated with suicidal behaviors in adolescents include impulsivity, poor problem-solving skills, and dichotomous thinking.³¹ There may be a genetic component as well. In 1 of 5 teenage suicides, a precipitating life event such as the break-up of a relationship, cyber-bullying, or peer rejection is felt to contribute.³¹

ADHD. The prevalence of ADHD is 7% to 9% in US school-aged children.³³ Boys more commonly exhibit hyperactive behaviors, while girls have more inattention. Hyperactivity often diminishes in teens, but inattention and impulsivity persist. Sequelae of ADHD include high-risk sexual behaviors, motor vehicle accidents, incarceration, and substance abuse.³⁴ Poor self-esteem, suicidal ideation, smoking, and obesity are also increased.³⁴ ADHD often persists into adulthood, with implications for social relationships and job performance.³⁴

Eating disorders. The distribution of eating disorders is now known to increasingly include more minorities and males, the latter representing 5% to 10% of cases.³⁵ Eating disorders show a strong genetic tendency and appear to be accelerated by puberty. The most common eating disorder (diagnosed in 0.8%-14% of teens) is eating disorder not otherwise specified (NOS).³⁵ Anorexia nervosa is diagnosed in 0.5% of adolescent girls, and bulimia nervosa in 1% to 2%—particularly among athletes and performers.³⁵ Unanticipated loss of weight, amenorrhea, excessive concern about weight, and deceleration in height/weight curves are potential indicators of an eating disorder. When identified, eating disorders are best managed by a trusted family physician, acting as a coordinator of a multidisciplinary team.

Sexual health

Girls begin to menstruate at an average age of 12, and it takes about 4 years for them to reach reproductive maturity.³⁶ Puberty has been documented to start at younger ages over the past 30 years, likely due to an increase in average body mass index and a decrease in levels of physical activity.³⁷ Girls with early maturation are often insecure and self-conscious, with higher levels of psychological distress.³⁸ In boys, the average age for spermarche (first ejaculation) is 13.³⁹ Boys who mature early tend to be taller, be more confident, and express a good body image.⁴⁰ Those who have early puberty are more likely to be sexually active or participate in high-risk behaviors.⁴¹

Continue to: Pregnancy and contraception

Over the past several decades, more US teens have been abstaining from sexual intercourse or have been using effective forms of birth control, particularly condoms and long-acting reversible contraceptives (LARCs).⁴² Teenage birth rates in girls ages 15 to 19 have declined significantly since the 1980s.⁴² Despite this, the teenage birth rate in the United States remains higher than in other industrialized nations, and most teen pregnancies are unintended.⁴³ Disparities in teenage birth rates also persist across racial and socioeconomic lines.⁴⁴

Restricting computer use to an area with parental supervision or installing monitoring programs does not seem to exert any protective influence on cyber-bullying or unsolicited stranger contact.

There are numerous interventions to reduce teen pregnancy, including sex education, contraceptive counseling, the use of mobile apps that track a user’s monthly fertility cycle or issue reminders to take oral contraceptives,⁴⁵ and the liberal distribution of contraceptives and condoms. The Contraceptive CHOICE Project shows that providing free (or low-cost) LARCs influences young women to choose these as their preferred contraceptive method.⁴⁶ Other programs specifically empower girls to convince partners to use condoms and to resist unwanted sexual advances or intimate partner violence.

Adolescents prefer to have their health care providers address the topic of sexual health. Teens are more likely to share information with providers if asked directly about sexual behaviors.⁴⁷TABLE 2^4,5 offers tips for anticipatory guidance and potential ways to frame questions with adolescents in this context. State laws vary with regard to the ability of minors to seek contraception, pregnancy testing, or care/screening for STIs without parental consent. Contraceptive counseling combined with effective screening decrease the incidence of STIs and pelvic inflammatory disease for sexually active teens.⁴⁸

Sexually transmitted infections

Young adolescents often have a limited ability to imagine consequences related to specific actions. In general, there is also an increased desire to engage in experimental behaviors as an expression of developing autonomy, which may expose them to STIs. About half of all STIs contracted in the United States occur in individuals 15 to 24 years of age.⁴⁹ Girls are at particular risk for the sequelae of these infections, including cervical dysplasia and infertility. Many teens erroneously believe that sexual activities other than intercourse decrease their risk of contracting an STI.⁵⁰

Human papillomavirus (HPV) infection is the most common STI in adolescence.⁵¹ In most cases, HPV is transient and asymptomatic. Oncogenic strains may cause cervical cancer or cancers of the anogenital or oropharyngeal systems. Due to viral latency, it is not recommended to perform HPV typing in men or in women younger than 30 years of age; however, Pap tests are recommended every 3 years for women ages 21 to 29. Primary care providers are pivotal in the public health struggle to prevent HPV infection.

Continue to: Universal immunization of all children...

Universal immunization of all children older than 11 years of age against HPV is strongly advised as part of routine well-child care. Emphasize the proven role of HPV vaccination in preventing cervical⁵² and oropharyngeal⁵³ cancers. And be prepared to address concerns raised by parents in the context of vaccine safety and the initiation of sexual behaviors (www.cdc.gov/hpv/hcp/answering-questions.html).

Chlamydia is the second most common STI in the United States, usually occurring in individuals younger than 24.⁵⁴ The CDC estimates that more than 3 million new chlamydial infections occur yearly. These infections are often asymptomatic, particularly in females, but may cause urethritis, cervicitis, epididymitis, proctitis, or pelvic inflammatory disease. Indolent chlamydial infection is the leading cause of tubal infertility in women.⁵⁴ Routine annual screening for chlamydia is recommended for all sexually active females ≤ 25 years (and for older women with specific risks).⁵⁵ Annual screening is also recommended for men who have sex with men (MSM).⁵⁵

Chlamydial infection may be diagnosed with first-catch urine sampling (men or women), urethral swab (men), endocervical swab (women), or self-collected vaginal swab. Nucleic acid amplification testing is the most sensitive test that is widely available.⁵⁶ First-line treatment includes either azithromycin (1 g orally, single dose) or doxycycline (100 mg orally, twice daily for 7 days).⁵⁶

Gonorrhea. In 2018, there were more than 500,000 annual cases of gonorrhea, with the majority occurring in those between 15 and 24 years of age.⁵⁷ Gonorrhea may increase rates of HIV infection transmission up to 5-fold.⁵⁷ As more adolescents practice oral sex, cases of pharyngeal gonorrhea (and oropharyngeal HPV) have increased. Symptoms of urethritis occur more frequently in men. Screening is recommended for all sexually active women younger than 25.⁵⁶ Importantly, the organism Neisseria gonorrhoeae has developed significant antibiotic resistance over the past decade. The CDC currently recommends dual therapy for the treatment of gonorrhea using 250 mg of intramuscular ceftriaxone and 1 g of oral azithromycin.⁵⁶

Syphilis. Rates of syphilis are increasing among individuals ages 15 to 24.⁵¹ Screening is particularly recommended for MSM and individuals infected with HIV. Benzathine penicillin G, 50,000 U/kg IM, remains the treatment of choice.⁵⁶

Continue to: HIV

HIV. Globally, HIV impacts young people disproportionately. HIV infection also facilitates infection with other STIs. In the United States, the highest burden of HIV infection is borne by young MSM, with prevalence among those 18 to 24 years old varying between 26% to 30% (black) and 3% to 5.5% (non-Hispanic white).⁵¹ The use of emtricitabine/tenofovir disoproxil fumarate for pre-exposure prophylaxis (PrEP) has recently been approved for the prevention of HIV. PrEP reduces risk by up to 92% for MSM and transgender women.⁵⁸

Sexual identity

One in 10 high school students self-identifies as “nonheterosexual,” and 1 in 15 reports same-sex sexual contact.⁵⁹ The term LGBTQ+ includes the communities of lesbian, gay, bisexual, transgender, transsexual, queer, questioning, intersex, and asexual individuals. Developing a safe sense of sexual identity is fundamental to adolescent psychological development, and many adolescents struggle to develop a positive sexual identity. Suicide rates and self-harm behaviors among ­LGBTQ+ adolescents can be 4 times higher than among their heterosexual peers.⁶⁰ Rates of mood disorders, substance abuse, and high-risk sexual behaviors are also increased in the LGBTQ+ population.⁶¹

Suicide rates and self-harm behaviors among LGBTQ+ adolescents can be 4 times higher than among their heterosexual peers.

The LGBTQ+ community often seeks health care advice and affirmation from primary care providers. Resources to enhance this care are available at www.lgbthealtheducation.org.

Social media

Adolescents today have more media exposure than any prior generation, with smartphone and computer use increasing exponentially. Most (95%) teens have access to a smartphone,⁶² 45% describe themselves as constantly connected to the Internet, and 14% feel that social media is “addictive.”⁶² Most manage their social media portfolio on multiple sites. Patterns of adolescents' online activities show that boys prefer online gaming, while girls tend to spend more time on social networking.⁶²

Whether extensive media use is psychologically beneficial or deleterious has been widely debated. Increased time online correlates with decreased levels of physical activity.⁶³ And sleep disturbances have been associated with excessive screen time and the presence of mobile devices in the bedroom.⁶⁴ The use of social media prior to bedtime also has an adverse impact on academic performance—particularly for girls. This adverse impact on academics persists after correcting for daytime sleepiness, body mass index, and number of hours spent on homework.⁶⁴

Continue to: Due to growing concerns...

Due to growing concerns about the risks of social media in children and adolescents, the American Academy of Pediatrics has developed the Family Media Plan (www.healthychildren.org/English/media/Pages/default.aspx). Some specific questions that providers may ask are outlined in TABLE 3.⁶⁴ The Family Media Plan can provide age-specific guidelines to assist parents or caregivers in answering these questions.

Cyber-bullying. One in 3 adolescents (primarily female) has been a victim of cyber-bullying.⁶⁵ Sadly, 1 in 5 teens has received some form of electronic sexual solicitation.⁶⁶ The likelihood of unsolicited stranger contact correlates with teens’ online habits and the amount of information disclosed. Predictors include female sex, visiting chat rooms, posting photos, and disclosing personal information. Restricting computer use to an area with parental supervision or installing monitoring programs does not seem to exert any protective influence on cyber-bullying or unsolicited stranger contact.⁶⁵ While 63% of cyber-bullying victims feel upset, embarrassed, or stressed by these contacts,⁶⁶ few events are actually reported. To address this, some states have adopted laws adding cyber-bullying to school disciplinary codes.

Adolescents rarely disclose bullying to parents or other adults, fearing restriction of Internet access, and many of them think that adults may downplay the seriousness of the events.

Negative health impacts associated with cyber-bullying include anxiety, sadness, and greater difficulty in concentrating on school work.⁶⁵ Victims of bullying are more likely to have school disciplinary actions and depression and to be truant or to carry weapons to school.⁶⁶ Cyber-bullying is uniquely destructive due to its ubiquitous presence. A sense of relative anonymity online may encourage perpetrators to act more cruelly, with less concern for punishment.

Young people are also more likely to share passwords as a sign of friendship. This may result in others assuming their identity online. Adolescents rarely disclose bullying to parents or other adults, fearing restriction of Internet access, and many of them think that adults may downplay the seriousness of the events.⁶⁶

CORRESPONDENCE
Mark B. Stephens, MD, Penn State Health Medical Group, 1850 East Park Avenue, State College, PA 16803; [email protected].

COVID-19 vaccines are considered safe for patients with multiple sclerosis (MS), a neurologist told colleagues, but those who are on disease-modifying therapy (DMT) – or about to begin it – should be cautious about the timing of their shots.

“There’s no reason to think any of the three authorized vaccines are in any way more dangerous in people with MS, or in the context of MS DMTs. It’s only a question of whether certain DMTs will influence the degree of benefit you get from the vaccine,” said Amit Bar-Or, MD, director of the Center for Neuroinflammation and Neurotherapeutics, chief of the multiple sclerosis division, and Melissa and Paul Anderson President’s Distinguished Professor at the University of Pennsylvania, Philadelphia. He spoke at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis, and he also answered questions in a follow-up interview.

“The merits of being protected by the COVID-19 vaccines far outweigh any risks that one would consider associated with vaccines and individuals with MS,” said Dr. Bar-Or. “And there’s reason to think that the RNA vaccines may even be safer than prior, more traditional vaccines. They are nonlive, noninactivated vaccines, and there is no risk in terms of interacting with MS.”

Where do DMTs fit in? In an interview, Hesham Abboud, MD, PhD, of University Hospitals of Cleveland and Case Western Reserve University, also in Cleveland, said there’s reason for caution regarding DMTs that deplete immune cells or entrap them in the lymph nodes. “What is not clearly known is the effect of the fumarates, which do not act through cell depletion but can occasionally deplete immune cells as a side effect. These likely have no negative effect on vaccine efficacy in patients with normal immune cell count but may have a negative effect in those with significant immune cell reduction. Luckily, significant immune cell reduction is rare in patients taking fumarates.”

In addition, he said, “interferons and natalizumab are generally thought to have no impact on vaccine efficacy while glatiramer acetate and teriflunomide are thought to have no or only little impact on vaccines. Most of these concepts are derived from studies of non–COVID-19 vaccines.”

Dr. Bar-Or highlighted specific DMTs. Teriflunomide (Aubagio) “has a relatively mild effect on the immune system and is not thought to be particularly immune suppressive or deplete immune cells,” Dr. Bar-Or said, as shown in a 2015 study he led (Neurol Neuroimmunol Neuroinflamm. 2015 Feb 12;2[2]:e70). In contrast, a 2020 study, also led by Dr. Bar-Or, showed that nonlive vaccinations given after treatment with ocrelizumab (Ocrevus) – an anti-CD20 monoclonal antibody – are “attenuated, compared with untreated or interferon-beta–treated patients, but they can still be expected to be protective.”

Dr. Bar-Or pointed to National MS Society guidelines about the timing of the Pfizer and Moderna mRNA vaccines for patients with MS who are on DMT. In patients with stable MS, the society recommends no adjustments in timing for patients starting or remaining on several DMTs. The list includes teriflunomide, glatiramer acetate (Copaxone), and dimethyl fumarate, among others.

Patients shouldn’t start fingolimod (Gilenya), siponimod (Mayzent), or ozanimod (Zeposia) until 4 weeks or more after their second vaccine dose, the guidelines suggest. Vaccine doses are recommended 3-5 days after the final dose of high-dose steroids. And there are more complicated recommendations regarding a number of other DMTs – ocrelizumab, ofatumumab (Kesimpta), alemtuzumab (Lemtrada), cladribine (Mavenclad), and rituximab (Rituxan).

Dr. Bar-Or cautioned that the guidelines are an imperfect “first pass” and are being updated.

He added that the guidelines are not set in stone: “Scheduling is not always possible in terms of adjusting the vaccine timing. Patients in general are recommended to take the vaccine when it becomes available, as it may be more important for them to get the vaccine than to try to time the vaccine relative to the DMT.”

Guidance regarding the newly authorized Johnson & Johnson vaccine is expected soon, said neurologist Barbara Giesser, MD, of Pacific Neuroscience Institute in Santa Monica, Calif., in an interview. As for her advice to patients, she said that, “in general, I am recommending that patients get [vaccinated] as soon as it is available to them with adjustment of timing of some DMTs as may be appropriate.”

Dr. Bar-Or has received consulting fees and/or grant support from – or participated as a speaker in events sponsored by – Accure, Atara Biotherapeutics, Biogen, Bristol-Myer Squibb/Celgene/Receptos, GlaxoSmithKline, Gossamer, Janssen/Actelion, Medimmune, Merck/EMD Serono, Novartis, Roche/Genentech, and Sanofi-Genzyme. He also receives research funding from various organizations and agencies. Dr. Abboud reported receiving consulting fees from Biogen, Genentech, Bristol-Myer Squibb, Alexion, and Viela Bio. He receives research support from Novartis, Bristol-Myer Squibb, Genentech, and Sanofi-Genzyme. Dr. Giesser reports no disclosures.
 

COVID-19 vaccines are considered safe for patients with multiple sclerosis (MS), a neurologist told colleagues, but those who are on disease-modifying therapy (DMT) – or about to begin it – should be cautious about the timing of their shots.

“There’s no reason to think any of the three authorized vaccines are in any way more dangerous in people with MS, or in the context of MS DMTs. It’s only a question of whether certain DMTs will influence the degree of benefit you get from the vaccine,” said Amit Bar-Or, MD, director of the Center for Neuroinflammation and Neurotherapeutics, chief of the multiple sclerosis division, and Melissa and Paul Anderson President’s Distinguished Professor at the University of Pennsylvania, Philadelphia. He spoke at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis, and he also answered questions in a follow-up interview.

“The merits of being protected by the COVID-19 vaccines far outweigh any risks that one would consider associated with vaccines and individuals with MS,” said Dr. Bar-Or. “And there’s reason to think that the RNA vaccines may even be safer than prior, more traditional vaccines. They are nonlive, noninactivated vaccines, and there is no risk in terms of interacting with MS.”

Where do DMTs fit in? In an interview, Hesham Abboud, MD, PhD, of University Hospitals of Cleveland and Case Western Reserve University, also in Cleveland, said there’s reason for caution regarding DMTs that deplete immune cells or entrap them in the lymph nodes. “What is not clearly known is the effect of the fumarates, which do not act through cell depletion but can occasionally deplete immune cells as a side effect. These likely have no negative effect on vaccine efficacy in patients with normal immune cell count but may have a negative effect in those with significant immune cell reduction. Luckily, significant immune cell reduction is rare in patients taking fumarates.”

In addition, he said, “interferons and natalizumab are generally thought to have no impact on vaccine efficacy while glatiramer acetate and teriflunomide are thought to have no or only little impact on vaccines. Most of these concepts are derived from studies of non–COVID-19 vaccines.”

Dr. Bar-Or highlighted specific DMTs. Teriflunomide (Aubagio) “has a relatively mild effect on the immune system and is not thought to be particularly immune suppressive or deplete immune cells,” Dr. Bar-Or said, as shown in a 2015 study he led (Neurol Neuroimmunol Neuroinflamm. 2015 Feb 12;2[2]:e70). In contrast, a 2020 study, also led by Dr. Bar-Or, showed that nonlive vaccinations given after treatment with ocrelizumab (Ocrevus) – an anti-CD20 monoclonal antibody – are “attenuated, compared with untreated or interferon-beta–treated patients, but they can still be expected to be protective.”

Dr. Bar-Or pointed to National MS Society guidelines about the timing of the Pfizer and Moderna mRNA vaccines for patients with MS who are on DMT. In patients with stable MS, the society recommends no adjustments in timing for patients starting or remaining on several DMTs. The list includes teriflunomide, glatiramer acetate (Copaxone), and dimethyl fumarate, among others.

Patients shouldn’t start fingolimod (Gilenya), siponimod (Mayzent), or ozanimod (Zeposia) until 4 weeks or more after their second vaccine dose, the guidelines suggest. Vaccine doses are recommended 3-5 days after the final dose of high-dose steroids. And there are more complicated recommendations regarding a number of other DMTs – ocrelizumab, ofatumumab (Kesimpta), alemtuzumab (Lemtrada), cladribine (Mavenclad), and rituximab (Rituxan).

Dr. Bar-Or cautioned that the guidelines are an imperfect “first pass” and are being updated.

He added that the guidelines are not set in stone: “Scheduling is not always possible in terms of adjusting the vaccine timing. Patients in general are recommended to take the vaccine when it becomes available, as it may be more important for them to get the vaccine than to try to time the vaccine relative to the DMT.”

Guidance regarding the newly authorized Johnson & Johnson vaccine is expected soon, said neurologist Barbara Giesser, MD, of Pacific Neuroscience Institute in Santa Monica, Calif., in an interview. As for her advice to patients, she said that, “in general, I am recommending that patients get [vaccinated] as soon as it is available to them with adjustment of timing of some DMTs as may be appropriate.”

Dr. Bar-Or has received consulting fees and/or grant support from – or participated as a speaker in events sponsored by – Accure, Atara Biotherapeutics, Biogen, Bristol-Myer Squibb/Celgene/Receptos, GlaxoSmithKline, Gossamer, Janssen/Actelion, Medimmune, Merck/EMD Serono, Novartis, Roche/Genentech, and Sanofi-Genzyme. He also receives research funding from various organizations and agencies. Dr. Abboud reported receiving consulting fees from Biogen, Genentech, Bristol-Myer Squibb, Alexion, and Viela Bio. He receives research support from Novartis, Bristol-Myer Squibb, Genentech, and Sanofi-Genzyme. Dr. Giesser reports no disclosures.
 

COVID-19 vaccines are considered safe for patients with multiple sclerosis (MS), a neurologist told colleagues, but those who are on disease-modifying therapy (DMT) – or about to begin it – should be cautious about the timing of their shots.

“There’s no reason to think any of the three authorized vaccines are in any way more dangerous in people with MS, or in the context of MS DMTs. It’s only a question of whether certain DMTs will influence the degree of benefit you get from the vaccine,” said Amit Bar-Or, MD, director of the Center for Neuroinflammation and Neurotherapeutics, chief of the multiple sclerosis division, and Melissa and Paul Anderson President’s Distinguished Professor at the University of Pennsylvania, Philadelphia. He spoke at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis, and he also answered questions in a follow-up interview.

“The merits of being protected by the COVID-19 vaccines far outweigh any risks that one would consider associated with vaccines and individuals with MS,” said Dr. Bar-Or. “And there’s reason to think that the RNA vaccines may even be safer than prior, more traditional vaccines. They are nonlive, noninactivated vaccines, and there is no risk in terms of interacting with MS.”

Where do DMTs fit in? In an interview, Hesham Abboud, MD, PhD, of University Hospitals of Cleveland and Case Western Reserve University, also in Cleveland, said there’s reason for caution regarding DMTs that deplete immune cells or entrap them in the lymph nodes. “What is not clearly known is the effect of the fumarates, which do not act through cell depletion but can occasionally deplete immune cells as a side effect. These likely have no negative effect on vaccine efficacy in patients with normal immune cell count but may have a negative effect in those with significant immune cell reduction. Luckily, significant immune cell reduction is rare in patients taking fumarates.”

In addition, he said, “interferons and natalizumab are generally thought to have no impact on vaccine efficacy while glatiramer acetate and teriflunomide are thought to have no or only little impact on vaccines. Most of these concepts are derived from studies of non–COVID-19 vaccines.”

Dr. Bar-Or highlighted specific DMTs. Teriflunomide (Aubagio) “has a relatively mild effect on the immune system and is not thought to be particularly immune suppressive or deplete immune cells,” Dr. Bar-Or said, as shown in a 2015 study he led (Neurol Neuroimmunol Neuroinflamm. 2015 Feb 12;2[2]:e70). In contrast, a 2020 study, also led by Dr. Bar-Or, showed that nonlive vaccinations given after treatment with ocrelizumab (Ocrevus) – an anti-CD20 monoclonal antibody – are “attenuated, compared with untreated or interferon-beta–treated patients, but they can still be expected to be protective.”

Dr. Bar-Or pointed to National MS Society guidelines about the timing of the Pfizer and Moderna mRNA vaccines for patients with MS who are on DMT. In patients with stable MS, the society recommends no adjustments in timing for patients starting or remaining on several DMTs. The list includes teriflunomide, glatiramer acetate (Copaxone), and dimethyl fumarate, among others.

Patients shouldn’t start fingolimod (Gilenya), siponimod (Mayzent), or ozanimod (Zeposia) until 4 weeks or more after their second vaccine dose, the guidelines suggest. Vaccine doses are recommended 3-5 days after the final dose of high-dose steroids. And there are more complicated recommendations regarding a number of other DMTs – ocrelizumab, ofatumumab (Kesimpta), alemtuzumab (Lemtrada), cladribine (Mavenclad), and rituximab (Rituxan).

Dr. Bar-Or cautioned that the guidelines are an imperfect “first pass” and are being updated.

He added that the guidelines are not set in stone: “Scheduling is not always possible in terms of adjusting the vaccine timing. Patients in general are recommended to take the vaccine when it becomes available, as it may be more important for them to get the vaccine than to try to time the vaccine relative to the DMT.”

Guidance regarding the newly authorized Johnson & Johnson vaccine is expected soon, said neurologist Barbara Giesser, MD, of Pacific Neuroscience Institute in Santa Monica, Calif., in an interview. As for her advice to patients, she said that, “in general, I am recommending that patients get [vaccinated] as soon as it is available to them with adjustment of timing of some DMTs as may be appropriate.”

Dr. Bar-Or has received consulting fees and/or grant support from – or participated as a speaker in events sponsored by – Accure, Atara Biotherapeutics, Biogen, Bristol-Myer Squibb/Celgene/Receptos, GlaxoSmithKline, Gossamer, Janssen/Actelion, Medimmune, Merck/EMD Serono, Novartis, Roche/Genentech, and Sanofi-Genzyme. He also receives research funding from various organizations and agencies. Dr. Abboud reported receiving consulting fees from Biogen, Genentech, Bristol-Myer Squibb, Alexion, and Viela Bio. He receives research support from Novartis, Bristol-Myer Squibb, Genentech, and Sanofi-Genzyme. Dr. Giesser reports no disclosures.
 

ILLUSTRATIVE CASE

A 37-year-old woman with moderate persistent asthma, controlled on the ICS fluticasone (110 μg twice a day) presents to you for an annual exam. She uses her rescue albuterol inhaler a few times per month. Her last exacerbation was 2 years ago. She has never smoked. She is concerned about continuing to take an ICS every day. What alternative regimen would you recommend for this patient?

According to the Centers for Disease Control and Prevention, asthma affected 24.7 million children and adults in the United States in 2018, accounting for 9.8 million physician visits and 1.6 million emergency department (ED) visits.² The National Institutes of Health (NIH) asthma care guidelines, updated in 2020, recommend a SABA prn as step 1 for intermittent asthma, along with nonpharmacologic management.³ Once a patient has persistent asthma, treatment escalation to step 2 calls for use of daily maintenance inhalers as the preferred treatment option.³

However, the 2020 Global Initiative for Asthma (GINA) warns that an as-needed SABA does not protect patients from severe exacerbations, and regular use of a SABA alone (> 3 inhalers/year) can increase the risk of exacerbations.⁴ A meta-analysis and systematic review from 2018 showed that using an ICS/LABA—scheduled and prn for rescue—had lower risk of asthma exacerbations compared with scheduled ICS/LABA with SABA prn for rescue in patients with ­moderate-to-severe persistent asthma.⁵ Interestingly, the updated 2020 NIH guidelines have adopted this strategy. SABA use prn is no longer recommended for rescue in mild and moderate persistent asthma, and the guidelines now suggest that ICS/LABA be used as rescue in addition to daily medication.³

Although evidence has been mounting for adding the as-needed ICS/LABA for rescue in patients on daily medication, the mainstay has been to provide a SABA prn for rescue use.⁵ Confusing matters more, evidence is emerging that as-needed ICS/LABA for rescue alone in certain patients is safe and effective. The randomized controlled Novel START study, an open-label, parallel-group study, compared ICS/LABA prn vs scheduled ICS with SABA prn vs SABA alone prn in adult patients with intermittent or mild persistent asthma.⁶ ICS/LABA prn prevented more exacerbations and provided better daily control than as-needed SABA alone.⁶ In addition, ICS/LABA as needed resulted in fewer severe exacerbations but potentially poorer daily control than ICS with SABA as needed.⁶

The PRACTICAL study investigated treatment of patients with intermittent, mild persistent, and moderate persistent asthma.¹

STUDY SUMMARY

ICS/LABA prn reduced risk of severe exacerbations

The randomized controlled PRACTICAL study was a 52-week, open-label, parallel-group, superiority trial in New Zealand that compared as-needed ICS/LABA (n = 437) to scheduled ICS plus as-needed SABA (n = 448). Patients were 18 to 75 years old, with a diagnosis of asthma. Applying NIH guideline definitions, these patients would fall into intermittent, mild persistent, or moderate persistent asthma categories, and were on either as-needed SABA alone or a scheduled low- to moderate-dose ICS plus an as-needed SABA in the previous 12 weeks.

Patients on an as-needed SABA prerandomization had to have at least 1 of the following: (1) asthma symptoms or need for a SABA at least twice in the past 4 weeks; (2) at least 1 nighttime awakening due to asthma in the past 4 weeks; or (3) a severe exacerbation requiring oral corticosteroids in the past year. Patients on scheduled ICS plus SABA prn prerandomization were required to have either: (1) low or moderate ICS dosing with partly or well-controlled asthma; or (2) if uncontrolled, poor inhaler technique or adherence.

Continue to: Patients in the ICS/LABA group...

Patients in the ICS/LABA group were given budesonide 200 µg/formoterol 6 µg, 1 puff prn, and patients in the ICS plus as-needed SABA group were given budesonide 200 µg, 1 puff twice daily, and terbutaline 250 µg, 2 puffs prn. All patients received an asthma action plan that provided guidance on when to seek medical care if asthma worsened, as well as a log to note urgent medical visits and use of systemic corticosteroids. A subset of patients had adherence and dosing monitored by electronic inhaler usage monitors. Patients were seen at 0, 4, 16, 28, 40, and 52 weeks.

Outcomes. The primary outcome was the number of severe exacerbations per patient per year, defined as treatment with oral corticosteroids for ≥ 3 days or ED visit or hospital admission requiring systemic corticosteroids. Among the secondary outcomes were number of moderate and severe exacerbations per patient per year (defined as an unplanned medical visit: primary care, ED, hospital admission, and any duration of steroids); time to first severe exacerbation; assessment with the Asthma Control Questionnaire (ACQ-5); adverse outcomes; and quantity of ICS used (analysis done only for the subset with electronic inhaler monitoring).

This study represents a compelling, real-world look at emerging asthma recommendations.

ACQ-5 takes the mean of 5 questions assessing asthma control in the previous week, with each question ranging from 0 (no impairment) to 6 (maximum impairment). The statistician was blinded to the primary outcome.

Results. The rate of severe exacerbations per patient per year was 0.119 in the as-needed ICS/LABA group vs 0.172 in the scheduled ICS plus as-needed SABA group (relative rate [RR] = 0.69; 95% confidence interval [CI], 0.48–1.00). Time to first severe asthma exacerbation was longer in the as-needed ICS/LABA group (hazard ratio = 0.60; 95% CI, 0.40–0.91). The rate of moderate and severe exacerbations per patient per year was lower in the as-needed ICS/LABA group: 0.165 vs 0.237 (RR = 0.70; 95% CI, 0.51–0.95).

ACQ-5 scores were similar at all time points (mean difference = 0.07; 95% CI, –0.03 to 0.17). Adverse events were similar between groups (most commonly nasopharyngitis in both groups). Less ICS was used in the ICS/LABA group (difference = –126.5 µg per day; 95% CI, –171.0 to –81.9).

Continue to: WHAT'S NEW

WHAT’S NEW

Study lends support to recent recommendations

This study represents a compelling, real-world look at emerging asthma recommendations. This was the first comprehensive study to show that as-needed ICS/LABA therapy prevents more moderate and severe exacerbations and lengthens the time to first severe exacerbation, compared with scheduled ICS plus SABA prn in intermittent, mild persistent, or moderate persistent asthma. These data have been incorporated into the GINA guidelines, which recommend ICS/LABA prn for step 2.

CAVEATS

Potential bias in study design

The LABA used in this study was formoterol, which has a quicker onset than other LABAs. It is likely that not all LABAs can be used the same way, and both the NIH and GINA guidelines call it out specifically. Additionally, the study’s open-label design can introduce bias but may be the only way to simulate the real-world actions of our patients. Prior studies used placebo inhalers to keep participants and providers blinded but then could not capitalize on the behavior of using only an inhaler prn (as with the ICS/LABA of this study). Finally, there is discordance between the NIH and GINA asthma guidelines on how to use these data.

CHALLENGES TO IMPLEMENTATION

Cost of ICS/LABA may limit its use

Cost is the largest barrier to implementation. Budesonide costs 6 to 10 times more than albuterol per inhaler (retail price of $281-$427 vs $17-$92, respectively).^7,8 However, cost differences are likely negated for patients already on a maintenance inhaler.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 37-year-old woman with moderate persistent asthma, controlled on the ICS fluticasone (110 μg twice a day) presents to you for an annual exam. She uses her rescue albuterol inhaler a few times per month. Her last exacerbation was 2 years ago. She has never smoked. She is concerned about continuing to take an ICS every day. What alternative regimen would you recommend for this patient?

According to the Centers for Disease Control and Prevention, asthma affected 24.7 million children and adults in the United States in 2018, accounting for 9.8 million physician visits and 1.6 million emergency department (ED) visits.² The National Institutes of Health (NIH) asthma care guidelines, updated in 2020, recommend a SABA prn as step 1 for intermittent asthma, along with nonpharmacologic management.³ Once a patient has persistent asthma, treatment escalation to step 2 calls for use of daily maintenance inhalers as the preferred treatment option.³

However, the 2020 Global Initiative for Asthma (GINA) warns that an as-needed SABA does not protect patients from severe exacerbations, and regular use of a SABA alone (> 3 inhalers/year) can increase the risk of exacerbations.⁴ A meta-analysis and systematic review from 2018 showed that using an ICS/LABA—scheduled and prn for rescue—had lower risk of asthma exacerbations compared with scheduled ICS/LABA with SABA prn for rescue in patients with ­moderate-to-severe persistent asthma.⁵ Interestingly, the updated 2020 NIH guidelines have adopted this strategy. SABA use prn is no longer recommended for rescue in mild and moderate persistent asthma, and the guidelines now suggest that ICS/LABA be used as rescue in addition to daily medication.³

Although evidence has been mounting for adding the as-needed ICS/LABA for rescue in patients on daily medication, the mainstay has been to provide a SABA prn for rescue use.⁵ Confusing matters more, evidence is emerging that as-needed ICS/LABA for rescue alone in certain patients is safe and effective. The randomized controlled Novel START study, an open-label, parallel-group study, compared ICS/LABA prn vs scheduled ICS with SABA prn vs SABA alone prn in adult patients with intermittent or mild persistent asthma.⁶ ICS/LABA prn prevented more exacerbations and provided better daily control than as-needed SABA alone.⁶ In addition, ICS/LABA as needed resulted in fewer severe exacerbations but potentially poorer daily control than ICS with SABA as needed.⁶

The PRACTICAL study investigated treatment of patients with intermittent, mild persistent, and moderate persistent asthma.¹

STUDY SUMMARY

ICS/LABA prn reduced risk of severe exacerbations

The randomized controlled PRACTICAL study was a 52-week, open-label, parallel-group, superiority trial in New Zealand that compared as-needed ICS/LABA (n = 437) to scheduled ICS plus as-needed SABA (n = 448). Patients were 18 to 75 years old, with a diagnosis of asthma. Applying NIH guideline definitions, these patients would fall into intermittent, mild persistent, or moderate persistent asthma categories, and were on either as-needed SABA alone or a scheduled low- to moderate-dose ICS plus an as-needed SABA in the previous 12 weeks.

Patients on an as-needed SABA prerandomization had to have at least 1 of the following: (1) asthma symptoms or need for a SABA at least twice in the past 4 weeks; (2) at least 1 nighttime awakening due to asthma in the past 4 weeks; or (3) a severe exacerbation requiring oral corticosteroids in the past year. Patients on scheduled ICS plus SABA prn prerandomization were required to have either: (1) low or moderate ICS dosing with partly or well-controlled asthma; or (2) if uncontrolled, poor inhaler technique or adherence.

Continue to: Patients in the ICS/LABA group...

Patients in the ICS/LABA group were given budesonide 200 µg/formoterol 6 µg, 1 puff prn, and patients in the ICS plus as-needed SABA group were given budesonide 200 µg, 1 puff twice daily, and terbutaline 250 µg, 2 puffs prn. All patients received an asthma action plan that provided guidance on when to seek medical care if asthma worsened, as well as a log to note urgent medical visits and use of systemic corticosteroids. A subset of patients had adherence and dosing monitored by electronic inhaler usage monitors. Patients were seen at 0, 4, 16, 28, 40, and 52 weeks.

Outcomes. The primary outcome was the number of severe exacerbations per patient per year, defined as treatment with oral corticosteroids for ≥ 3 days or ED visit or hospital admission requiring systemic corticosteroids. Among the secondary outcomes were number of moderate and severe exacerbations per patient per year (defined as an unplanned medical visit: primary care, ED, hospital admission, and any duration of steroids); time to first severe exacerbation; assessment with the Asthma Control Questionnaire (ACQ-5); adverse outcomes; and quantity of ICS used (analysis done only for the subset with electronic inhaler monitoring).

This study represents a compelling, real-world look at emerging asthma recommendations.

ACQ-5 takes the mean of 5 questions assessing asthma control in the previous week, with each question ranging from 0 (no impairment) to 6 (maximum impairment). The statistician was blinded to the primary outcome.

Results. The rate of severe exacerbations per patient per year was 0.119 in the as-needed ICS/LABA group vs 0.172 in the scheduled ICS plus as-needed SABA group (relative rate [RR] = 0.69; 95% confidence interval [CI], 0.48–1.00). Time to first severe asthma exacerbation was longer in the as-needed ICS/LABA group (hazard ratio = 0.60; 95% CI, 0.40–0.91). The rate of moderate and severe exacerbations per patient per year was lower in the as-needed ICS/LABA group: 0.165 vs 0.237 (RR = 0.70; 95% CI, 0.51–0.95).

ACQ-5 scores were similar at all time points (mean difference = 0.07; 95% CI, –0.03 to 0.17). Adverse events were similar between groups (most commonly nasopharyngitis in both groups). Less ICS was used in the ICS/LABA group (difference = –126.5 µg per day; 95% CI, –171.0 to –81.9).

Continue to: WHAT'S NEW

WHAT’S NEW

Study lends support to recent recommendations

This study represents a compelling, real-world look at emerging asthma recommendations. This was the first comprehensive study to show that as-needed ICS/LABA therapy prevents more moderate and severe exacerbations and lengthens the time to first severe exacerbation, compared with scheduled ICS plus SABA prn in intermittent, mild persistent, or moderate persistent asthma. These data have been incorporated into the GINA guidelines, which recommend ICS/LABA prn for step 2.

CAVEATS

Potential bias in study design

The LABA used in this study was formoterol, which has a quicker onset than other LABAs. It is likely that not all LABAs can be used the same way, and both the NIH and GINA guidelines call it out specifically. Additionally, the study’s open-label design can introduce bias but may be the only way to simulate the real-world actions of our patients. Prior studies used placebo inhalers to keep participants and providers blinded but then could not capitalize on the behavior of using only an inhaler prn (as with the ICS/LABA of this study). Finally, there is discordance between the NIH and GINA asthma guidelines on how to use these data.

CHALLENGES TO IMPLEMENTATION

Cost of ICS/LABA may limit its use

Cost is the largest barrier to implementation. Budesonide costs 6 to 10 times more than albuterol per inhaler (retail price of $281-$427 vs $17-$92, respectively).^7,8 However, cost differences are likely negated for patients already on a maintenance inhaler.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 37-year-old woman with moderate persistent asthma, controlled on the ICS fluticasone (110 μg twice a day) presents to you for an annual exam. She uses her rescue albuterol inhaler a few times per month. Her last exacerbation was 2 years ago. She has never smoked. She is concerned about continuing to take an ICS every day. What alternative regimen would you recommend for this patient?

According to the Centers for Disease Control and Prevention, asthma affected 24.7 million children and adults in the United States in 2018, accounting for 9.8 million physician visits and 1.6 million emergency department (ED) visits.² The National Institutes of Health (NIH) asthma care guidelines, updated in 2020, recommend a SABA prn as step 1 for intermittent asthma, along with nonpharmacologic management.³ Once a patient has persistent asthma, treatment escalation to step 2 calls for use of daily maintenance inhalers as the preferred treatment option.³

However, the 2020 Global Initiative for Asthma (GINA) warns that an as-needed SABA does not protect patients from severe exacerbations, and regular use of a SABA alone (> 3 inhalers/year) can increase the risk of exacerbations.⁴ A meta-analysis and systematic review from 2018 showed that using an ICS/LABA—scheduled and prn for rescue—had lower risk of asthma exacerbations compared with scheduled ICS/LABA with SABA prn for rescue in patients with ­moderate-to-severe persistent asthma.⁵ Interestingly, the updated 2020 NIH guidelines have adopted this strategy. SABA use prn is no longer recommended for rescue in mild and moderate persistent asthma, and the guidelines now suggest that ICS/LABA be used as rescue in addition to daily medication.³

Although evidence has been mounting for adding the as-needed ICS/LABA for rescue in patients on daily medication, the mainstay has been to provide a SABA prn for rescue use.⁵ Confusing matters more, evidence is emerging that as-needed ICS/LABA for rescue alone in certain patients is safe and effective. The randomized controlled Novel START study, an open-label, parallel-group study, compared ICS/LABA prn vs scheduled ICS with SABA prn vs SABA alone prn in adult patients with intermittent or mild persistent asthma.⁶ ICS/LABA prn prevented more exacerbations and provided better daily control than as-needed SABA alone.⁶ In addition, ICS/LABA as needed resulted in fewer severe exacerbations but potentially poorer daily control than ICS with SABA as needed.⁶

The PRACTICAL study investigated treatment of patients with intermittent, mild persistent, and moderate persistent asthma.¹

STUDY SUMMARY

ICS/LABA prn reduced risk of severe exacerbations

The randomized controlled PRACTICAL study was a 52-week, open-label, parallel-group, superiority trial in New Zealand that compared as-needed ICS/LABA (n = 437) to scheduled ICS plus as-needed SABA (n = 448). Patients were 18 to 75 years old, with a diagnosis of asthma. Applying NIH guideline definitions, these patients would fall into intermittent, mild persistent, or moderate persistent asthma categories, and were on either as-needed SABA alone or a scheduled low- to moderate-dose ICS plus an as-needed SABA in the previous 12 weeks.

Patients on an as-needed SABA prerandomization had to have at least 1 of the following: (1) asthma symptoms or need for a SABA at least twice in the past 4 weeks; (2) at least 1 nighttime awakening due to asthma in the past 4 weeks; or (3) a severe exacerbation requiring oral corticosteroids in the past year. Patients on scheduled ICS plus SABA prn prerandomization were required to have either: (1) low or moderate ICS dosing with partly or well-controlled asthma; or (2) if uncontrolled, poor inhaler technique or adherence.

Continue to: Patients in the ICS/LABA group...

Patients in the ICS/LABA group were given budesonide 200 µg/formoterol 6 µg, 1 puff prn, and patients in the ICS plus as-needed SABA group were given budesonide 200 µg, 1 puff twice daily, and terbutaline 250 µg, 2 puffs prn. All patients received an asthma action plan that provided guidance on when to seek medical care if asthma worsened, as well as a log to note urgent medical visits and use of systemic corticosteroids. A subset of patients had adherence and dosing monitored by electronic inhaler usage monitors. Patients were seen at 0, 4, 16, 28, 40, and 52 weeks.

Outcomes. The primary outcome was the number of severe exacerbations per patient per year, defined as treatment with oral corticosteroids for ≥ 3 days or ED visit or hospital admission requiring systemic corticosteroids. Among the secondary outcomes were number of moderate and severe exacerbations per patient per year (defined as an unplanned medical visit: primary care, ED, hospital admission, and any duration of steroids); time to first severe exacerbation; assessment with the Asthma Control Questionnaire (ACQ-5); adverse outcomes; and quantity of ICS used (analysis done only for the subset with electronic inhaler monitoring).

This study represents a compelling, real-world look at emerging asthma recommendations.

ACQ-5 takes the mean of 5 questions assessing asthma control in the previous week, with each question ranging from 0 (no impairment) to 6 (maximum impairment). The statistician was blinded to the primary outcome.

Results. The rate of severe exacerbations per patient per year was 0.119 in the as-needed ICS/LABA group vs 0.172 in the scheduled ICS plus as-needed SABA group (relative rate [RR] = 0.69; 95% confidence interval [CI], 0.48–1.00). Time to first severe asthma exacerbation was longer in the as-needed ICS/LABA group (hazard ratio = 0.60; 95% CI, 0.40–0.91). The rate of moderate and severe exacerbations per patient per year was lower in the as-needed ICS/LABA group: 0.165 vs 0.237 (RR = 0.70; 95% CI, 0.51–0.95).

ACQ-5 scores were similar at all time points (mean difference = 0.07; 95% CI, –0.03 to 0.17). Adverse events were similar between groups (most commonly nasopharyngitis in both groups). Less ICS was used in the ICS/LABA group (difference = –126.5 µg per day; 95% CI, –171.0 to –81.9).

Continue to: WHAT'S NEW

WHAT’S NEW

Study lends support to recent recommendations

This study represents a compelling, real-world look at emerging asthma recommendations. This was the first comprehensive study to show that as-needed ICS/LABA therapy prevents more moderate and severe exacerbations and lengthens the time to first severe exacerbation, compared with scheduled ICS plus SABA prn in intermittent, mild persistent, or moderate persistent asthma. These data have been incorporated into the GINA guidelines, which recommend ICS/LABA prn for step 2.

CAVEATS

Potential bias in study design

The LABA used in this study was formoterol, which has a quicker onset than other LABAs. It is likely that not all LABAs can be used the same way, and both the NIH and GINA guidelines call it out specifically. Additionally, the study’s open-label design can introduce bias but may be the only way to simulate the real-world actions of our patients. Prior studies used placebo inhalers to keep participants and providers blinded but then could not capitalize on the behavior of using only an inhaler prn (as with the ICS/LABA of this study). Finally, there is discordance between the NIH and GINA asthma guidelines on how to use these data.

CHALLENGES TO IMPLEMENTATION

Cost of ICS/LABA may limit its use

Cost is the largest barrier to implementation. Budesonide costs 6 to 10 times more than albuterol per inhaler (retail price of $281-$427 vs $17-$92, respectively).^7,8 However, cost differences are likely negated for patients already on a maintenance inhaler.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.