Atopic dermatitis (AD), also known as eczema, is a chronic inflammatory skin condition that is well known for its relapsing, pruritic rash in children and adults. Less recognized are its associated conditions—allergic rhinitis, asthma, food allergies, attention-deficit/hyperactivity disorder (ADHD), depression, and anxiety—and its burden on patients and their families. In fact, families that have children with AD report lower overall quality of life than those with otherwise healthy children.¹ Given AD’s prevalence across age groups and its effect on the family, family physicians are uniquely positioned to diagnose, care for, and counsel patients with AD and its associated maladies.

The prevalence and pathogenesis of AD

AD affects up to 20% of children and 5% of adults in the United States.² AD typically manifests before a child reaches age 5 (often in the first 6 months of life), and it is slightly more common in females (1.3:1). A family history of atopy (eczema, asthma, allergic rhinitis) is common. In fact, children with one atopic parent have a 2- to 3-fold increased risk of atopic dermatitis; those with 2 atopic parents have a 3- to 5-fold increased risk.³

The pathophysiology of AD is complex, culminating in impaired barrier function of the skin and transepidermal water loss resulting in dry and inflamed skin. Additionally, alterations in a cell-mediated immune response leading to an immunoglobulin (Ig) E-mediated hypersensitivity is also theorized to play a role in the development of AD.

Signs and symptoms

Signs at birth. Physical signs of atopic dermatitis typically appear between birth and 6 months. In infancy, lesions generally occur on the scalp, face (FIGURES 1A and 1B), neck, and extensor surfaces of the extremities. Lesions are typically papules and vesicles, sometimes accompanied by serous exudate and crusting. Eczematous lesions typically spare the groin and diaper area, and their presence in this area should raise suspicion for an alternative diagnosis.

Beginning at age 2 years, eczematous lesions are more commonly limited to the folds of the flexor surfaces. Instead of the weeping and crusting lesions seen in infancy, eczema in older children manifests as dry, lichenified papules and plaques in areas that are typically affected in adults: the wrist, hands, ankles, and popliteal and antecubital fossa.²

Although lesions in adults are similar to those of childhood, they may manifest in a more localized area (hand or eyelid, for example). As is the case in childhood, the lesions are dry, sometimes lichenified, and found on the flexural surfaces (FIGURES 2A and 2B).²

Symptom triggers are unproven

While anecdotal reports cite various triggers for AD flares, a systematic review found little scientific evidence to substantiate identifiable triggers.⁴ Triggers often cited and studied are foods, dust mite exposure, airborne allergens, detergents, sunlight, fabrics, bacterial infections, and stress. While as many as one-third of people with AD who also have confirmed dust mite allergy report worsening of symptoms when exposed to dust, a Cochrane review of 7 randomized controlled trials totaling 324 adults and children with eczema found that efforts at dust mite mitigation (laundering of bed covers, increased vacuuming, spraying for mites) were not effective in reducing symptoms.⁵

Continue to: How quality of life diminishes with AD

How quality of life diminishes with AD

AD substantially lessens quality of life. For children, the most distressing physical symptoms include itching that inhibits sleep and provokes scratching, pain, and bleeding. Emotional distress can cause irritability, crying, and uncooperativeness with treatments. Parents also report that they frequently restrict their children from activities, such as playing in the heat or swimming, that may lead to worsening of their eczema.⁶

The loss of sleep associated with AD is not completely understood but is likely multifactorial. Pruritus and scratching leading to sleeplessness is the most obvious culprit, but an altered circadian rhythm, immune system response, and changes in skin physiology are also likely factors.⁷ Whatever the cause, sleep disturbance is reported in as many as 60% of patients with AD, and the degree of sleep disturbance is proportional to increases in disease severity and worsening of quality-of-life scores.⁸ Lost sleep is not limited to patients; parents of children with AD also report significant loss of sleep and subsequent decreased work productivity and quality of life.⁹

Children with AD are often the target of bullying.¹⁰ A 2015 survey by the National Eczema Association indicates that 1 in 5 children reported being bullied due to their AD.¹¹

Associated conditions and comorbidities

AD increases patients’ risks for other illnesses, due either to their underlying atopy or to the effects of AD symptoms (TABLE^12-17).

Atopic march

Atopic march—the clinical succession of AD, allergic rhinitis, and asthma—is a well-­established clinical progression. The presence of all 3 conditions appears to be more common in children diagnosed with AD before 2 years of age.¹² Typically, allergic rhinitis manifests at around age 4, and asthma develops between ages 6 and 8. The severity of AD predicts progression. Compared with an 8% chance of asthma developing among the general population, children with mild AD have a 20% to 30% chance of developing asthma, and those with severe AD have about a 70% chance.¹²

Continue to: Food allergies

Patients with AD are at higher risk for food-induced anaphylaxis, with up to one-third of AD patients having an IgE-mediated food allergy.¹³ While it is theorized that the impaired skin barrier of an atopic child may allow for early sensitization and allergy development, a landmark 2015 study demonstrated that early allergen introduction (specifically, peanuts) may serve as a preventive strategy in those at high risk of food allergies.¹⁴ Current guidelines recommend that physicians be aware of the increased possibility of food allergies in those with AD, and consider evaluating a child for milk, egg, peanut, wheat, and soy allergy if the child is younger than 5 years and has eczema that does not resolve with treatment, or has eczema and a history of an allergic reaction to a specific food.¹⁵

Interestingly, despite the strong association between AD and food allergies, it is not clear that food allergies trigger atopic flares; as such, elimination diets are not universally recommended in those without a proven food allergy.

Psychiatric diagnoses

Children with AD have an increased prevalence of several psychiatric conditions, including ADHD, depression, anxiety, conduct disorder, and autism when compared with peers who do not have AD, and the probability correlates with the severity of AD.¹⁶ While there is a clear link—secondary to nocturnal pruritis—between AD and sleep deprivation, it is not clear whether the sleep deprivation leads to an increase in these psychiatric conditions or if AD is an independent risk factor.

Consider recommending bleach baths in cases of moderate-to-severe atopic dermatitis with frequent bacterial infections.

What we do know is that one of the strongest associations between AD and a psychiatric condition is with ADHD, with a recent pooled meta-analysis showing a 46% increase in risk.¹⁷ The incidence of depression among children with AD appears to correlate with the severity of AD symptoms: estimated at 5% with mild AD, 7% with moderate disease, and 14% with severe disease (compared with 3% without AD). Similar incremental increases are seen when correlating AD and anxiety.¹⁶

Nonpharmacologic care

Bathing

Bathing habits are critical to controlling AD. While bathing serves to both hydrate the skin and remove allergens, the water’s evaporation off the skin surface can lead to increased transepidermal water loss. Combining bathing and immediate application of a moisturizer improves skin hydration in patients with AD vs bathing alone.¹⁸ Thus, consensus guidelines recommend once-daily bathing (bath or shower) to remove scale and crust, followed by immediate application of a moisturizing emollient.¹⁹

Continue to: Emollients

Application of moisturizing emollients is the mainstay of nonpharmacologic care of AD, and there is strong evidence that their regimented use reduces disease burden and the need for prescription treatment.¹⁹ Emollient creams and ointments help retain moisture and improve the skin’s barrier. While ointments may provide a better barrier, patients tend to prefer creams as they are less greasy than ointments.

Emollient therapy may also help prevent development of AD, especially in those infants thought to be at high risk with a family history of atopy. In a multinational randomized controlled trial, infants who received daily full-body application of emollient beginning at 3 weeks of life were significantly less likely than controls to develop AD by 6 months.²⁰ While the mechanism of action is not clearly understood, it is believed that early emollient use prevents skin dehydration and maintains the skin’s barrier integrity, thus decreasing allergen epidermal penetration and subsequent inflammation.

Bleach bath

A bleach bath, prepared by adding 1/2 cup of unconcentrated bleach (5.25% sodium hypochlorite) to a standard 40-gallon bathtub, produces a chlorine mixture equivalent to an average swimming pool. Soaking in a bleach bath for 10 minutes once or twice weekly is thought to reduce inflammation and bacteria on the skin, but studies of its efficacy in improving atopic symptoms are mixed.

In a pooled analysis of 5 studies evaluating bleach baths vs standard baths, there was no significant difference in disease severity at 4 weeks.²¹ Thus, while bleach baths were effective in decreasing disease severity, they appeared to be no more effective than a standard water bath.²¹ Bleach baths may be helpful, however, in cases of moderate-to-severe disease with frequent bacterial infections.¹⁹

Pharmacologic therapy

Steroids

For symptoms refractory to nonpharmacologic skin care, topical steroids are the initial pharmacologic treatment for AD.19 Choose steroid potency based on symptom severity and disease location. Low- to medium-potency is appropriate for mild disease, and medium- to high-potency is useful for ­moderate-to-severe symptoms. High-­potency steroids are generally avoided on the face and skin folds; however, they can be used for short periods in these areas to induce remission. They must then be quickly tapered and discontinued.

Continue to: Frequency

Frequency. Topical corticosteroids are typically applied twice daily, although recent studies indicate that once-daily application is just as efficacious.²² In addition to treatment of an acute flare, topical steroids are useful as maintenance therapy for patients with recurrent outbreaks in the same anatomical site. Guidelines suggest once- or twice-weekly application of a medium-potency steroid to prolong time between flares.¹⁹

For children, a practical guide is for caregivers to apply the amount of steroid covering 1 adult fingertip to an area of the child’s skin equal to that of 2 adult palms.²³ Topical steroids are generally well tolerated and have a good safety profile. Adverse effects are proportional to the amount and duration of use and include purpura, telangiectasias, striae, and skin atrophy. The risk of skin atrophy increases with higher potency steroids, occlusion (covering affected area after steroid application), use on thin-skinned areas, and older patient age.²⁴

A Cochrane review found that efforts at dust mite mitigation (laundering of bed covers, increased vacuuming, spraying for mites) were not effective in reducing symptoms of atopic dermatitis.

Reassure patients/parents about the safety of topical steroids, as fears regarding the potential adverse effects can limit compliance. In one study of 200 patients with AD, 72.5% of respondents expressed fear of using steroids on their own skin or that of their child, and 24% admitted being noncompliant with therapy based on these concerns.²⁵

Treating flares. Oral steroids are sometimes needed to abort or control an AD flare in older children and adults. A tapering course of prednisone over 5 to 7 days, transitioning to medium- to high-dose topical steroids, may be needed to achieve symptom control.

Topical calcineurin inhibitors

Topical calcineurin inhibitors, including tacrolimus and pimecrolimus, are generally second-line therapy to topical corticosteroids. However, as nonsteroidal agents, topical calcineurin inhibitors do not cause skin atrophy and can be a first-line option in areas where atrophy is more common (face, eyelids, neck, and skin folds).²⁶

Continue to: A Cochrane review found...

Interestingly, despite the strong association between atopic dermatitis and food allergies, it is not clear that food allergies trigger atopic flares.

A Cochrane review found tacrolimus 0.1% to be better than low‐potency topical corticosteroids on the face and neck areas, while results were equivocal when compared with moderate‐potency topical corticosteroids on the trunk and extremities (no difference based on physician assessment, but marginal benefit favoring tacrolimus based on participant scoring).²⁷ When compared head-to-head, tacrolimus was more effective than pimecrolimus, although tacrolimus has a higher rate of local irritation. The most common adverse effects are stinging and burning at the application site, although these adverse effects generally improve with repeated application.

There have been long-term safety concerns with topical calcineurin inhibitors—chiefly a 2006 Food and Drug Administration (FDA) black box warning regarding a possible link between topical calcineurin inhibitors and cancer. However, while there may be a slight increased risk of lymphoma in AD patients, a recent meta-analysis did not find an association between topical calcineurin inhibitors use and lymphoma.²⁸ Given the initial concern—and pending additional data—the FDA currently recommends reserving topical calcineurin inhibitors for second-line therapy and only for the minimum amount of time to induce improvement. It also recommends avoiding their use in patients younger than 2 years and in those with compromised immune systems.

Cisaborole

Cisaborole, a topical phosphodiesterase 4 (PDE4) inhibitor, received FDA approval in 2016 for mild-to-moderate AD. By inhibiting PDE4, the drug limits inflammation. In a multicenter randomized trial, patients applying cisaborole 2% twice a day noted reductions in pruritus, inflammation, excoriation, and lichenification.²⁹ Adverse effects are minimal and limited to application site irritation.

Systemic treatments

While beyond the care of a family physician, symptoms refractory to conservative, nonpharmacologic measures and combinations of topical pharmaceuticals can be treated with systemic immunomodulators such as cyclosporine, azathioprine, and methotrexate. Phototherapy is also effective in patients with more widespread skin involvement. Dupilumab, an injectable monoclonal antibody that binds to interleukin-4 receptor and inhibits inflammation, is approved to treat moderate-to-severe AD in adults.³⁰

Ineffective therapies: Oral montelukast and probiotics

While oral antihistamines are frequently prescribed and used, there are no studies evaluating the use of antihistamines (H1) as monotherapy for AD.³¹ Nonetheless, while not altering the disease process, the sedative effect of antihistamines may palliate the nocturnal pruritus frequently associated with AD. Although nonsedating antihistamines may still have a role for atopic patients with concurrent seasonal and environmental allergies, there is no evidence to support their use in the treatment of AD.

Continue to: Data are limited...

Data are limited on the effectiveness of leukotriene receptor antagonists for AD, and all studies meeting inclusion for a Cochrane review assessed oral montelukast. The review found no benefit with the use of montelukast 10 mg in terms of severity of disease, pruritus, or need for topical steroids.³²

A practical guide is for caregivers to apply the amount of steroid covering 1 adult fingertip to an area of the child’s skin equal to that of 2 adult palms.

A systematic review investigating the benefit of probiotics for the treatment of AD found no improvement in patient-rated eczema scores for quality of life.³³ Additionally, a review of 11 randomized controlled trials including 596 participants found no evidence to suggest efficacy of fish oil, zinc, selenium, vitamin D, vitamin E, pyridoxine, sea buckthorn oil, hempseed oil, or sunflower oil in the treatment of AD.³⁴

Education can reduce AD severity

Family physicians can be a source of education and support for patients and families of patients with AD. Support programs for adults with AD—including education, relaxation techniques, and cognitive behavioral therapy—have been shown to decrease disease severity.³⁵ Comparable improvement in disease severity has been demonstrated in children with AD when similar education is provided to them and their families.

CORRESPONDENCE
Franklin Berkey, DO, Penn State Health, 1850 East Park Avenue, Suite 207, State College, PA 16803; fberkey@ pennstatehealth.psu.edu.

Atopic dermatitis (AD), also known as eczema, is a chronic inflammatory skin condition that is well known for its relapsing, pruritic rash in children and adults. Less recognized are its associated conditions—allergic rhinitis, asthma, food allergies, attention-deficit/hyperactivity disorder (ADHD), depression, and anxiety—and its burden on patients and their families. In fact, families that have children with AD report lower overall quality of life than those with otherwise healthy children.¹ Given AD’s prevalence across age groups and its effect on the family, family physicians are uniquely positioned to diagnose, care for, and counsel patients with AD and its associated maladies.

The prevalence and pathogenesis of AD

AD affects up to 20% of children and 5% of adults in the United States.² AD typically manifests before a child reaches age 5 (often in the first 6 months of life), and it is slightly more common in females (1.3:1). A family history of atopy (eczema, asthma, allergic rhinitis) is common. In fact, children with one atopic parent have a 2- to 3-fold increased risk of atopic dermatitis; those with 2 atopic parents have a 3- to 5-fold increased risk.³

The pathophysiology of AD is complex, culminating in impaired barrier function of the skin and transepidermal water loss resulting in dry and inflamed skin. Additionally, alterations in a cell-mediated immune response leading to an immunoglobulin (Ig) E-mediated hypersensitivity is also theorized to play a role in the development of AD.

Signs and symptoms

Signs at birth. Physical signs of atopic dermatitis typically appear between birth and 6 months. In infancy, lesions generally occur on the scalp, face (FIGURES 1A and 1B), neck, and extensor surfaces of the extremities. Lesions are typically papules and vesicles, sometimes accompanied by serous exudate and crusting. Eczematous lesions typically spare the groin and diaper area, and their presence in this area should raise suspicion for an alternative diagnosis.

Beginning at age 2 years, eczematous lesions are more commonly limited to the folds of the flexor surfaces. Instead of the weeping and crusting lesions seen in infancy, eczema in older children manifests as dry, lichenified papules and plaques in areas that are typically affected in adults: the wrist, hands, ankles, and popliteal and antecubital fossa.²

Although lesions in adults are similar to those of childhood, they may manifest in a more localized area (hand or eyelid, for example). As is the case in childhood, the lesions are dry, sometimes lichenified, and found on the flexural surfaces (FIGURES 2A and 2B).²

Symptom triggers are unproven

While anecdotal reports cite various triggers for AD flares, a systematic review found little scientific evidence to substantiate identifiable triggers.⁴ Triggers often cited and studied are foods, dust mite exposure, airborne allergens, detergents, sunlight, fabrics, bacterial infections, and stress. While as many as one-third of people with AD who also have confirmed dust mite allergy report worsening of symptoms when exposed to dust, a Cochrane review of 7 randomized controlled trials totaling 324 adults and children with eczema found that efforts at dust mite mitigation (laundering of bed covers, increased vacuuming, spraying for mites) were not effective in reducing symptoms.⁵

Continue to: How quality of life diminishes with AD

How quality of life diminishes with AD

AD substantially lessens quality of life. For children, the most distressing physical symptoms include itching that inhibits sleep and provokes scratching, pain, and bleeding. Emotional distress can cause irritability, crying, and uncooperativeness with treatments. Parents also report that they frequently restrict their children from activities, such as playing in the heat or swimming, that may lead to worsening of their eczema.⁶

The loss of sleep associated with AD is not completely understood but is likely multifactorial. Pruritus and scratching leading to sleeplessness is the most obvious culprit, but an altered circadian rhythm, immune system response, and changes in skin physiology are also likely factors.⁷ Whatever the cause, sleep disturbance is reported in as many as 60% of patients with AD, and the degree of sleep disturbance is proportional to increases in disease severity and worsening of quality-of-life scores.⁸ Lost sleep is not limited to patients; parents of children with AD also report significant loss of sleep and subsequent decreased work productivity and quality of life.⁹

Children with AD are often the target of bullying.¹⁰ A 2015 survey by the National Eczema Association indicates that 1 in 5 children reported being bullied due to their AD.¹¹

Associated conditions and comorbidities

AD increases patients’ risks for other illnesses, due either to their underlying atopy or to the effects of AD symptoms (TABLE^12-17).

Atopic march

Atopic march—the clinical succession of AD, allergic rhinitis, and asthma—is a well-­established clinical progression. The presence of all 3 conditions appears to be more common in children diagnosed with AD before 2 years of age.¹² Typically, allergic rhinitis manifests at around age 4, and asthma develops between ages 6 and 8. The severity of AD predicts progression. Compared with an 8% chance of asthma developing among the general population, children with mild AD have a 20% to 30% chance of developing asthma, and those with severe AD have about a 70% chance.¹²

Continue to: Food allergies

Patients with AD are at higher risk for food-induced anaphylaxis, with up to one-third of AD patients having an IgE-mediated food allergy.¹³ While it is theorized that the impaired skin barrier of an atopic child may allow for early sensitization and allergy development, a landmark 2015 study demonstrated that early allergen introduction (specifically, peanuts) may serve as a preventive strategy in those at high risk of food allergies.¹⁴ Current guidelines recommend that physicians be aware of the increased possibility of food allergies in those with AD, and consider evaluating a child for milk, egg, peanut, wheat, and soy allergy if the child is younger than 5 years and has eczema that does not resolve with treatment, or has eczema and a history of an allergic reaction to a specific food.¹⁵

Interestingly, despite the strong association between AD and food allergies, it is not clear that food allergies trigger atopic flares; as such, elimination diets are not universally recommended in those without a proven food allergy.

Psychiatric diagnoses

Children with AD have an increased prevalence of several psychiatric conditions, including ADHD, depression, anxiety, conduct disorder, and autism when compared with peers who do not have AD, and the probability correlates with the severity of AD.¹⁶ While there is a clear link—secondary to nocturnal pruritis—between AD and sleep deprivation, it is not clear whether the sleep deprivation leads to an increase in these psychiatric conditions or if AD is an independent risk factor.

Consider recommending bleach baths in cases of moderate-to-severe atopic dermatitis with frequent bacterial infections.

What we do know is that one of the strongest associations between AD and a psychiatric condition is with ADHD, with a recent pooled meta-analysis showing a 46% increase in risk.¹⁷ The incidence of depression among children with AD appears to correlate with the severity of AD symptoms: estimated at 5% with mild AD, 7% with moderate disease, and 14% with severe disease (compared with 3% without AD). Similar incremental increases are seen when correlating AD and anxiety.¹⁶

Nonpharmacologic care

Bathing

Bathing habits are critical to controlling AD. While bathing serves to both hydrate the skin and remove allergens, the water’s evaporation off the skin surface can lead to increased transepidermal water loss. Combining bathing and immediate application of a moisturizer improves skin hydration in patients with AD vs bathing alone.¹⁸ Thus, consensus guidelines recommend once-daily bathing (bath or shower) to remove scale and crust, followed by immediate application of a moisturizing emollient.¹⁹

Continue to: Emollients

Application of moisturizing emollients is the mainstay of nonpharmacologic care of AD, and there is strong evidence that their regimented use reduces disease burden and the need for prescription treatment.¹⁹ Emollient creams and ointments help retain moisture and improve the skin’s barrier. While ointments may provide a better barrier, patients tend to prefer creams as they are less greasy than ointments.

Emollient therapy may also help prevent development of AD, especially in those infants thought to be at high risk with a family history of atopy. In a multinational randomized controlled trial, infants who received daily full-body application of emollient beginning at 3 weeks of life were significantly less likely than controls to develop AD by 6 months.²⁰ While the mechanism of action is not clearly understood, it is believed that early emollient use prevents skin dehydration and maintains the skin’s barrier integrity, thus decreasing allergen epidermal penetration and subsequent inflammation.

Bleach bath

A bleach bath, prepared by adding 1/2 cup of unconcentrated bleach (5.25% sodium hypochlorite) to a standard 40-gallon bathtub, produces a chlorine mixture equivalent to an average swimming pool. Soaking in a bleach bath for 10 minutes once or twice weekly is thought to reduce inflammation and bacteria on the skin, but studies of its efficacy in improving atopic symptoms are mixed.

In a pooled analysis of 5 studies evaluating bleach baths vs standard baths, there was no significant difference in disease severity at 4 weeks.²¹ Thus, while bleach baths were effective in decreasing disease severity, they appeared to be no more effective than a standard water bath.²¹ Bleach baths may be helpful, however, in cases of moderate-to-severe disease with frequent bacterial infections.¹⁹

Pharmacologic therapy

Steroids

For symptoms refractory to nonpharmacologic skin care, topical steroids are the initial pharmacologic treatment for AD.19 Choose steroid potency based on symptom severity and disease location. Low- to medium-potency is appropriate for mild disease, and medium- to high-potency is useful for ­moderate-to-severe symptoms. High-­potency steroids are generally avoided on the face and skin folds; however, they can be used for short periods in these areas to induce remission. They must then be quickly tapered and discontinued.

Continue to: Frequency

Frequency. Topical corticosteroids are typically applied twice daily, although recent studies indicate that once-daily application is just as efficacious.²² In addition to treatment of an acute flare, topical steroids are useful as maintenance therapy for patients with recurrent outbreaks in the same anatomical site. Guidelines suggest once- or twice-weekly application of a medium-potency steroid to prolong time between flares.¹⁹

For children, a practical guide is for caregivers to apply the amount of steroid covering 1 adult fingertip to an area of the child’s skin equal to that of 2 adult palms.²³ Topical steroids are generally well tolerated and have a good safety profile. Adverse effects are proportional to the amount and duration of use and include purpura, telangiectasias, striae, and skin atrophy. The risk of skin atrophy increases with higher potency steroids, occlusion (covering affected area after steroid application), use on thin-skinned areas, and older patient age.²⁴

A Cochrane review found that efforts at dust mite mitigation (laundering of bed covers, increased vacuuming, spraying for mites) were not effective in reducing symptoms of atopic dermatitis.

Reassure patients/parents about the safety of topical steroids, as fears regarding the potential adverse effects can limit compliance. In one study of 200 patients with AD, 72.5% of respondents expressed fear of using steroids on their own skin or that of their child, and 24% admitted being noncompliant with therapy based on these concerns.²⁵

Treating flares. Oral steroids are sometimes needed to abort or control an AD flare in older children and adults. A tapering course of prednisone over 5 to 7 days, transitioning to medium- to high-dose topical steroids, may be needed to achieve symptom control.

Topical calcineurin inhibitors

Topical calcineurin inhibitors, including tacrolimus and pimecrolimus, are generally second-line therapy to topical corticosteroids. However, as nonsteroidal agents, topical calcineurin inhibitors do not cause skin atrophy and can be a first-line option in areas where atrophy is more common (face, eyelids, neck, and skin folds).²⁶

Continue to: A Cochrane review found...

Interestingly, despite the strong association between atopic dermatitis and food allergies, it is not clear that food allergies trigger atopic flares.

A Cochrane review found tacrolimus 0.1% to be better than low‐potency topical corticosteroids on the face and neck areas, while results were equivocal when compared with moderate‐potency topical corticosteroids on the trunk and extremities (no difference based on physician assessment, but marginal benefit favoring tacrolimus based on participant scoring).²⁷ When compared head-to-head, tacrolimus was more effective than pimecrolimus, although tacrolimus has a higher rate of local irritation. The most common adverse effects are stinging and burning at the application site, although these adverse effects generally improve with repeated application.

There have been long-term safety concerns with topical calcineurin inhibitors—chiefly a 2006 Food and Drug Administration (FDA) black box warning regarding a possible link between topical calcineurin inhibitors and cancer. However, while there may be a slight increased risk of lymphoma in AD patients, a recent meta-analysis did not find an association between topical calcineurin inhibitors use and lymphoma.²⁸ Given the initial concern—and pending additional data—the FDA currently recommends reserving topical calcineurin inhibitors for second-line therapy and only for the minimum amount of time to induce improvement. It also recommends avoiding their use in patients younger than 2 years and in those with compromised immune systems.

Cisaborole

Cisaborole, a topical phosphodiesterase 4 (PDE4) inhibitor, received FDA approval in 2016 for mild-to-moderate AD. By inhibiting PDE4, the drug limits inflammation. In a multicenter randomized trial, patients applying cisaborole 2% twice a day noted reductions in pruritus, inflammation, excoriation, and lichenification.²⁹ Adverse effects are minimal and limited to application site irritation.

Systemic treatments

While beyond the care of a family physician, symptoms refractory to conservative, nonpharmacologic measures and combinations of topical pharmaceuticals can be treated with systemic immunomodulators such as cyclosporine, azathioprine, and methotrexate. Phototherapy is also effective in patients with more widespread skin involvement. Dupilumab, an injectable monoclonal antibody that binds to interleukin-4 receptor and inhibits inflammation, is approved to treat moderate-to-severe AD in adults.³⁰

Ineffective therapies: Oral montelukast and probiotics

While oral antihistamines are frequently prescribed and used, there are no studies evaluating the use of antihistamines (H1) as monotherapy for AD.³¹ Nonetheless, while not altering the disease process, the sedative effect of antihistamines may palliate the nocturnal pruritus frequently associated with AD. Although nonsedating antihistamines may still have a role for atopic patients with concurrent seasonal and environmental allergies, there is no evidence to support their use in the treatment of AD.

Continue to: Data are limited...

Data are limited on the effectiveness of leukotriene receptor antagonists for AD, and all studies meeting inclusion for a Cochrane review assessed oral montelukast. The review found no benefit with the use of montelukast 10 mg in terms of severity of disease, pruritus, or need for topical steroids.³²

A practical guide is for caregivers to apply the amount of steroid covering 1 adult fingertip to an area of the child’s skin equal to that of 2 adult palms.

A systematic review investigating the benefit of probiotics for the treatment of AD found no improvement in patient-rated eczema scores for quality of life.³³ Additionally, a review of 11 randomized controlled trials including 596 participants found no evidence to suggest efficacy of fish oil, zinc, selenium, vitamin D, vitamin E, pyridoxine, sea buckthorn oil, hempseed oil, or sunflower oil in the treatment of AD.³⁴

Education can reduce AD severity

Family physicians can be a source of education and support for patients and families of patients with AD. Support programs for adults with AD—including education, relaxation techniques, and cognitive behavioral therapy—have been shown to decrease disease severity.³⁵ Comparable improvement in disease severity has been demonstrated in children with AD when similar education is provided to them and their families.

CORRESPONDENCE
Franklin Berkey, DO, Penn State Health, 1850 East Park Avenue, Suite 207, State College, PA 16803; fberkey@ pennstatehealth.psu.edu.

Atopic dermatitis (AD), also known as eczema, is a chronic inflammatory skin condition that is well known for its relapsing, pruritic rash in children and adults. Less recognized are its associated conditions—allergic rhinitis, asthma, food allergies, attention-deficit/hyperactivity disorder (ADHD), depression, and anxiety—and its burden on patients and their families. In fact, families that have children with AD report lower overall quality of life than those with otherwise healthy children.¹ Given AD’s prevalence across age groups and its effect on the family, family physicians are uniquely positioned to diagnose, care for, and counsel patients with AD and its associated maladies.

The prevalence and pathogenesis of AD

AD affects up to 20% of children and 5% of adults in the United States.² AD typically manifests before a child reaches age 5 (often in the first 6 months of life), and it is slightly more common in females (1.3:1). A family history of atopy (eczema, asthma, allergic rhinitis) is common. In fact, children with one atopic parent have a 2- to 3-fold increased risk of atopic dermatitis; those with 2 atopic parents have a 3- to 5-fold increased risk.³

The pathophysiology of AD is complex, culminating in impaired barrier function of the skin and transepidermal water loss resulting in dry and inflamed skin. Additionally, alterations in a cell-mediated immune response leading to an immunoglobulin (Ig) E-mediated hypersensitivity is also theorized to play a role in the development of AD.

Signs and symptoms

Signs at birth. Physical signs of atopic dermatitis typically appear between birth and 6 months. In infancy, lesions generally occur on the scalp, face (FIGURES 1A and 1B), neck, and extensor surfaces of the extremities. Lesions are typically papules and vesicles, sometimes accompanied by serous exudate and crusting. Eczematous lesions typically spare the groin and diaper area, and their presence in this area should raise suspicion for an alternative diagnosis.

Beginning at age 2 years, eczematous lesions are more commonly limited to the folds of the flexor surfaces. Instead of the weeping and crusting lesions seen in infancy, eczema in older children manifests as dry, lichenified papules and plaques in areas that are typically affected in adults: the wrist, hands, ankles, and popliteal and antecubital fossa.²

Although lesions in adults are similar to those of childhood, they may manifest in a more localized area (hand or eyelid, for example). As is the case in childhood, the lesions are dry, sometimes lichenified, and found on the flexural surfaces (FIGURES 2A and 2B).²

Symptom triggers are unproven

While anecdotal reports cite various triggers for AD flares, a systematic review found little scientific evidence to substantiate identifiable triggers.⁴ Triggers often cited and studied are foods, dust mite exposure, airborne allergens, detergents, sunlight, fabrics, bacterial infections, and stress. While as many as one-third of people with AD who also have confirmed dust mite allergy report worsening of symptoms when exposed to dust, a Cochrane review of 7 randomized controlled trials totaling 324 adults and children with eczema found that efforts at dust mite mitigation (laundering of bed covers, increased vacuuming, spraying for mites) were not effective in reducing symptoms.⁵

Continue to: How quality of life diminishes with AD

How quality of life diminishes with AD

AD substantially lessens quality of life. For children, the most distressing physical symptoms include itching that inhibits sleep and provokes scratching, pain, and bleeding. Emotional distress can cause irritability, crying, and uncooperativeness with treatments. Parents also report that they frequently restrict their children from activities, such as playing in the heat or swimming, that may lead to worsening of their eczema.⁶

The loss of sleep associated with AD is not completely understood but is likely multifactorial. Pruritus and scratching leading to sleeplessness is the most obvious culprit, but an altered circadian rhythm, immune system response, and changes in skin physiology are also likely factors.⁷ Whatever the cause, sleep disturbance is reported in as many as 60% of patients with AD, and the degree of sleep disturbance is proportional to increases in disease severity and worsening of quality-of-life scores.⁸ Lost sleep is not limited to patients; parents of children with AD also report significant loss of sleep and subsequent decreased work productivity and quality of life.⁹

Children with AD are often the target of bullying.¹⁰ A 2015 survey by the National Eczema Association indicates that 1 in 5 children reported being bullied due to their AD.¹¹

Associated conditions and comorbidities

AD increases patients’ risks for other illnesses, due either to their underlying atopy or to the effects of AD symptoms (TABLE^12-17).

Atopic march

Atopic march—the clinical succession of AD, allergic rhinitis, and asthma—is a well-­established clinical progression. The presence of all 3 conditions appears to be more common in children diagnosed with AD before 2 years of age.¹² Typically, allergic rhinitis manifests at around age 4, and asthma develops between ages 6 and 8. The severity of AD predicts progression. Compared with an 8% chance of asthma developing among the general population, children with mild AD have a 20% to 30% chance of developing asthma, and those with severe AD have about a 70% chance.¹²

Continue to: Food allergies

Patients with AD are at higher risk for food-induced anaphylaxis, with up to one-third of AD patients having an IgE-mediated food allergy.¹³ While it is theorized that the impaired skin barrier of an atopic child may allow for early sensitization and allergy development, a landmark 2015 study demonstrated that early allergen introduction (specifically, peanuts) may serve as a preventive strategy in those at high risk of food allergies.¹⁴ Current guidelines recommend that physicians be aware of the increased possibility of food allergies in those with AD, and consider evaluating a child for milk, egg, peanut, wheat, and soy allergy if the child is younger than 5 years and has eczema that does not resolve with treatment, or has eczema and a history of an allergic reaction to a specific food.¹⁵

Interestingly, despite the strong association between AD and food allergies, it is not clear that food allergies trigger atopic flares; as such, elimination diets are not universally recommended in those without a proven food allergy.

Psychiatric diagnoses

Children with AD have an increased prevalence of several psychiatric conditions, including ADHD, depression, anxiety, conduct disorder, and autism when compared with peers who do not have AD, and the probability correlates with the severity of AD.¹⁶ While there is a clear link—secondary to nocturnal pruritis—between AD and sleep deprivation, it is not clear whether the sleep deprivation leads to an increase in these psychiatric conditions or if AD is an independent risk factor.

Consider recommending bleach baths in cases of moderate-to-severe atopic dermatitis with frequent bacterial infections.

What we do know is that one of the strongest associations between AD and a psychiatric condition is with ADHD, with a recent pooled meta-analysis showing a 46% increase in risk.¹⁷ The incidence of depression among children with AD appears to correlate with the severity of AD symptoms: estimated at 5% with mild AD, 7% with moderate disease, and 14% with severe disease (compared with 3% without AD). Similar incremental increases are seen when correlating AD and anxiety.¹⁶

Nonpharmacologic care

Bathing

Bathing habits are critical to controlling AD. While bathing serves to both hydrate the skin and remove allergens, the water’s evaporation off the skin surface can lead to increased transepidermal water loss. Combining bathing and immediate application of a moisturizer improves skin hydration in patients with AD vs bathing alone.¹⁸ Thus, consensus guidelines recommend once-daily bathing (bath or shower) to remove scale and crust, followed by immediate application of a moisturizing emollient.¹⁹

Continue to: Emollients

Application of moisturizing emollients is the mainstay of nonpharmacologic care of AD, and there is strong evidence that their regimented use reduces disease burden and the need for prescription treatment.¹⁹ Emollient creams and ointments help retain moisture and improve the skin’s barrier. While ointments may provide a better barrier, patients tend to prefer creams as they are less greasy than ointments.

Emollient therapy may also help prevent development of AD, especially in those infants thought to be at high risk with a family history of atopy. In a multinational randomized controlled trial, infants who received daily full-body application of emollient beginning at 3 weeks of life were significantly less likely than controls to develop AD by 6 months.²⁰ While the mechanism of action is not clearly understood, it is believed that early emollient use prevents skin dehydration and maintains the skin’s barrier integrity, thus decreasing allergen epidermal penetration and subsequent inflammation.

Bleach bath

A bleach bath, prepared by adding 1/2 cup of unconcentrated bleach (5.25% sodium hypochlorite) to a standard 40-gallon bathtub, produces a chlorine mixture equivalent to an average swimming pool. Soaking in a bleach bath for 10 minutes once or twice weekly is thought to reduce inflammation and bacteria on the skin, but studies of its efficacy in improving atopic symptoms are mixed.

In a pooled analysis of 5 studies evaluating bleach baths vs standard baths, there was no significant difference in disease severity at 4 weeks.²¹ Thus, while bleach baths were effective in decreasing disease severity, they appeared to be no more effective than a standard water bath.²¹ Bleach baths may be helpful, however, in cases of moderate-to-severe disease with frequent bacterial infections.¹⁹

Pharmacologic therapy

Steroids

For symptoms refractory to nonpharmacologic skin care, topical steroids are the initial pharmacologic treatment for AD.19 Choose steroid potency based on symptom severity and disease location. Low- to medium-potency is appropriate for mild disease, and medium- to high-potency is useful for ­moderate-to-severe symptoms. High-­potency steroids are generally avoided on the face and skin folds; however, they can be used for short periods in these areas to induce remission. They must then be quickly tapered and discontinued.

Continue to: Frequency

Frequency. Topical corticosteroids are typically applied twice daily, although recent studies indicate that once-daily application is just as efficacious.²² In addition to treatment of an acute flare, topical steroids are useful as maintenance therapy for patients with recurrent outbreaks in the same anatomical site. Guidelines suggest once- or twice-weekly application of a medium-potency steroid to prolong time between flares.¹⁹

For children, a practical guide is for caregivers to apply the amount of steroid covering 1 adult fingertip to an area of the child’s skin equal to that of 2 adult palms.²³ Topical steroids are generally well tolerated and have a good safety profile. Adverse effects are proportional to the amount and duration of use and include purpura, telangiectasias, striae, and skin atrophy. The risk of skin atrophy increases with higher potency steroids, occlusion (covering affected area after steroid application), use on thin-skinned areas, and older patient age.²⁴

A Cochrane review found that efforts at dust mite mitigation (laundering of bed covers, increased vacuuming, spraying for mites) were not effective in reducing symptoms of atopic dermatitis.

Reassure patients/parents about the safety of topical steroids, as fears regarding the potential adverse effects can limit compliance. In one study of 200 patients with AD, 72.5% of respondents expressed fear of using steroids on their own skin or that of their child, and 24% admitted being noncompliant with therapy based on these concerns.²⁵

Treating flares. Oral steroids are sometimes needed to abort or control an AD flare in older children and adults. A tapering course of prednisone over 5 to 7 days, transitioning to medium- to high-dose topical steroids, may be needed to achieve symptom control.

Topical calcineurin inhibitors

Topical calcineurin inhibitors, including tacrolimus and pimecrolimus, are generally second-line therapy to topical corticosteroids. However, as nonsteroidal agents, topical calcineurin inhibitors do not cause skin atrophy and can be a first-line option in areas where atrophy is more common (face, eyelids, neck, and skin folds).²⁶

Continue to: A Cochrane review found...

Interestingly, despite the strong association between atopic dermatitis and food allergies, it is not clear that food allergies trigger atopic flares.

A Cochrane review found tacrolimus 0.1% to be better than low‐potency topical corticosteroids on the face and neck areas, while results were equivocal when compared with moderate‐potency topical corticosteroids on the trunk and extremities (no difference based on physician assessment, but marginal benefit favoring tacrolimus based on participant scoring).²⁷ When compared head-to-head, tacrolimus was more effective than pimecrolimus, although tacrolimus has a higher rate of local irritation. The most common adverse effects are stinging and burning at the application site, although these adverse effects generally improve with repeated application.

There have been long-term safety concerns with topical calcineurin inhibitors—chiefly a 2006 Food and Drug Administration (FDA) black box warning regarding a possible link between topical calcineurin inhibitors and cancer. However, while there may be a slight increased risk of lymphoma in AD patients, a recent meta-analysis did not find an association between topical calcineurin inhibitors use and lymphoma.²⁸ Given the initial concern—and pending additional data—the FDA currently recommends reserving topical calcineurin inhibitors for second-line therapy and only for the minimum amount of time to induce improvement. It also recommends avoiding their use in patients younger than 2 years and in those with compromised immune systems.

Cisaborole

Cisaborole, a topical phosphodiesterase 4 (PDE4) inhibitor, received FDA approval in 2016 for mild-to-moderate AD. By inhibiting PDE4, the drug limits inflammation. In a multicenter randomized trial, patients applying cisaborole 2% twice a day noted reductions in pruritus, inflammation, excoriation, and lichenification.²⁹ Adverse effects are minimal and limited to application site irritation.

Systemic treatments

While beyond the care of a family physician, symptoms refractory to conservative, nonpharmacologic measures and combinations of topical pharmaceuticals can be treated with systemic immunomodulators such as cyclosporine, azathioprine, and methotrexate. Phototherapy is also effective in patients with more widespread skin involvement. Dupilumab, an injectable monoclonal antibody that binds to interleukin-4 receptor and inhibits inflammation, is approved to treat moderate-to-severe AD in adults.³⁰

Ineffective therapies: Oral montelukast and probiotics

While oral antihistamines are frequently prescribed and used, there are no studies evaluating the use of antihistamines (H1) as monotherapy for AD.³¹ Nonetheless, while not altering the disease process, the sedative effect of antihistamines may palliate the nocturnal pruritus frequently associated with AD. Although nonsedating antihistamines may still have a role for atopic patients with concurrent seasonal and environmental allergies, there is no evidence to support their use in the treatment of AD.

Continue to: Data are limited...

Data are limited on the effectiveness of leukotriene receptor antagonists for AD, and all studies meeting inclusion for a Cochrane review assessed oral montelukast. The review found no benefit with the use of montelukast 10 mg in terms of severity of disease, pruritus, or need for topical steroids.³²

A practical guide is for caregivers to apply the amount of steroid covering 1 adult fingertip to an area of the child’s skin equal to that of 2 adult palms.

A systematic review investigating the benefit of probiotics for the treatment of AD found no improvement in patient-rated eczema scores for quality of life.³³ Additionally, a review of 11 randomized controlled trials including 596 participants found no evidence to suggest efficacy of fish oil, zinc, selenium, vitamin D, vitamin E, pyridoxine, sea buckthorn oil, hempseed oil, or sunflower oil in the treatment of AD.³⁴

Education can reduce AD severity

Family physicians can be a source of education and support for patients and families of patients with AD. Support programs for adults with AD—including education, relaxation techniques, and cognitive behavioral therapy—have been shown to decrease disease severity.³⁵ Comparable improvement in disease severity has been demonstrated in children with AD when similar education is provided to them and their families.

CORRESPONDENCE
Franklin Berkey, DO, Penn State Health, 1850 East Park Avenue, Suite 207, State College, PA 16803; fberkey@ pennstatehealth.psu.edu.

Repeated intravenous infusions of ketamine provide rapid relief for patients with posttraumatic stress disorder, new research suggests.

In what investigators are calling the first randomized controlled trial of repeated ketamine administration for chronic PTSD, 30 patients received six infusions of ketamine or midazolam (used as a psychoactive placebo) over 2 consecutive weeks. 

Between baseline and week 2, those receiving ketamine showed significantly greater improvement than those receiving midazolam. Total scores on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) for the first group were almost 12 points lower than the latter group at week 2, meeting the study’s primary outcome measure.

In addition, 67% vs. 20% of the patients, respectively, were considered to be treatment responders; time to loss of response for those in the ketamine group was 28 days.

Although the overall findings were as expected, “what was surprising was how robust the results were,” lead author Adriana Feder, MD, associate professor of psychiatry, Icahn School of Medicine, Mount Sinai, New York, told this news organization.

It was also a bit surprising that, in a study of just 30 participants, “we were able to show such a clear difference” between the two treatment groups, said Dr. Feder, who is also a coinventor on issued patents for the use of ketamine as therapy for PTSD, and codirector of the Ehrenkranz Lab for the Study of Human Resilience at Mount Sinai.

The findings were published online Jan. 5 in the American Journal of Psychiatry.
 

Unmet need

Ketamine is a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist that was first approved by the U.S. Food and Drug Administration for anesthetic use in 1970. It has also been shown to be effective for treatment-resistant depression.

PTSD has a lifetime prevalence of about 6% in the United States. “While trauma-focused psychotherapies have the most empirical support, they are limited by significant rates of nonresponse, partial response, and treatment dropout,” the investigators write. Also, there are “few available pharmacotherapies for PTSD, and their efficacy is insufficient,” they add.  

“There’s a real need for new treatment interventions that are effective for PTSD and also work rapidly, because it can take weeks to months for currently available treatments to work for PTSD,” Dr. Feder said.

The researchers previously conducted a “proof-of-concept” randomized controlled trial of single infusions of ketamine for chronic PTSD. Results published in 2014 in JAMA Psychiatry showed significant reduction in PTSD symptoms 24 hours after infusion.

For the current study, the investigative team wanted to assess whether ketamine was viable as a longer-term treatment.

“We were encouraged by our initial promising findings” of the earlier trial, Dr. Feder said. “We wanted to do the second study to see if ketamine really works for PTSD, to see if we could replicate the rapid improvement and also examine whether a course of six infusions over 2 weeks could maintain the improvement.”

Thirty patients (aged 18-70; mean age, 39 years) with chronic PTSD from civilian or military trauma were enrolled (mean PTSD duration, 15 years).

The most cited primary trauma was sexual assault or molestation (n = 13), followed by physical assault or abuse (n = 8), witnessing a violent assault or death (n = 4), witnessing the 9/11 attacks (n = 3), and combat exposure (n = 2).

During the 2-week treatment phase, half of the patients were randomly assigned to receive six infusions of ketamine hydrochloride at a dose of 0.5 mg/kg (86.7% women; mean CAPS-5 score, 42), while the other half received six infusions of midazolam at a dose of 0.045 mg/kg (66.7% women; mean CAPS-5 score, 40).

In addition to the primary outcome measure of 2-week changes on the CAPS-5, secondary outcomes included score changes on the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Impact of Event Scale-Revised (IES-R).

Treatment response was defined as a 30% or more improvement in symptoms on the CAPS-5. A number of measures were also used to assess potential treatment-related adverse events (AEs).
 

Safe, effective

Results showed significantly lower total CAPS-5 scores for the ketamine group vs. the midazolam group at week 1 (score difference, 8.8 points; P = .03) and at week 2 (score difference, 11.88 points; P = .004).

Those receiving ketamine also showed improvements in three of the four PTSD symptom clusters on the CAPS-5: avoidance (P < .0001), negative mood and cognitions (P = .02), and intrusions (P = .03). The fourth symptom cluster – arousal and reactivity – did not show a significant improvement.

In addition, the ketamine group showed significantly greater improvement scores on the MADRS at both week 1 and week 2.

Treatment response at 2 weeks was achieved by 10 members of the ketamine group and by three members of the midazolam group (P = .03).

Secondary analyses showed rapid improvement in the treatment responders within the ketamine group, with a mean change of 26 points on the total IES-R score between baseline and 24 hours after their first infusion, and a mean change of 13.4 points on the MADRS total past-24-hour score, a 53% improvement on average.

“A response at 2 weeks is very rapid but they got better sometimes within the first day,” Dr. Feder noted.

There were no serious AEs reported. Although some dissociative symptoms occurred during ketamine infusions, with the highest levels reported at the end of the infusion, these symptoms had resolved by the next assessment, conducted 2 hours after infusion.

The most frequently reported AE in the ketamine group, compared with midazolam, after the start of infusions was blurred vision (53% vs. 0%), followed by dizziness (33% vs. 13%), fatigue (33% vs. 87%), headache (27% vs. 13%), and nausea or vomiting (20% vs. 7%).
 

‘Large-magnitude improvement’

The overall findings show that, in this patient population, “repeated intravenous ketamine infusions administered over 2 weeks were associated with a large-magnitude, clinically significant improvement in PTSD symptoms,” the investigators write.

The results “were very satisfying,” added Dr. Feder. “It was heartening also to hear what some of the participants would say. Some told us about how their symptoms and feelings had changed during the course of treatment with ketamine, where they felt stronger and better able to cope with their trauma and memories.”

She noted, however, that this was not a study designed to specifically assess ketamine in treatment-resistant PTSD. “Some patients had had multiple treatments before that hadn’t worked, while others had not received treatment before. Efficacy for treatment-resistant PTSD is an important question for future research,” Dr. Feder said.

Other areas worth future exploration include treatment efficacy in patients with different types of trauma and whether outcomes can last longer in patients receiving ketamine plus psychotherapy treatment, she noted.

“I don’t want to ignore the fact that currently available treatments work for a number of people with chronic PTSD. But because there are many more for whom [the treatments] don’t work, or they’re insufficiently helped by those treatments, this is certainly one potentially very promising approach that can be added” to a clinician’s toolbox, Dr. Feder said.
 

Speaks to clinical utility

Commenting for this news organization, Gerard Sanacora, MD, PhD, professor of psychiatry at Yale University, New Haven, Connecticut, called this a “very solid and well-designed” study.

“It definitely builds on what’s been found in the past, but it’s a critical piece of information speaking to the clinical utility of this treatment for PTSD,” said Dr. Sanacora, who is also director of the Yale Depression Research Program and was not involved with the current research.

He agreed with the investigators that PTSD has long been a condition that is difficult to treat.

“It’s an area that has a great unmet need for treatment options. Beyond that, as ketamine is becoming more widely used, there’s increasing demand for off-label uses. This [study] actually provides some evidence that there may be efficacy there,” Dr. Sanacora said.

Although he cautioned that this was a small study, and thus further research with a larger patient population will be needed, it provides a compelling foundation to build upon.

“This study provides clear evidence to support a larger study to really give a definitive statement on the efficacy and safety of its use for PTSD. I don’t think this is the study that provides that definitive evidence, but it is a very strong indication, and it very strongly supports the initiation of a large study to address that,” said Dr. Sanacora.

He noted that, although he’s used the term “cautious optimism” for studies in the past, he has “real optimism” that ketamine will be effective for PTSD based on the results of this current study.

“We still need some more data to really convince us of that before we can say with any clear statement that it is effective and safe, but I’m very optimistic,” Dr. Sanacora concluded. “I think the data are very strong.”

The study was funded by the Brain and Behavior Research Foundation, Mount Sinai Innovation Partners and the Mount Sinai i3 Accelerator, Gerald and Glenda Greenwald, and the Ehrenkranz Laboratory for Human Resilience. Dr. Feder is a coinventor on issued patents for the use of ketamine as therapy for PTSD. A list of all disclosures for the other study authors are listed in the original article.

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

Repeated intravenous infusions of ketamine provide rapid relief for patients with posttraumatic stress disorder, new research suggests.

In what investigators are calling the first randomized controlled trial of repeated ketamine administration for chronic PTSD, 30 patients received six infusions of ketamine or midazolam (used as a psychoactive placebo) over 2 consecutive weeks. 

Between baseline and week 2, those receiving ketamine showed significantly greater improvement than those receiving midazolam. Total scores on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) for the first group were almost 12 points lower than the latter group at week 2, meeting the study’s primary outcome measure.

In addition, 67% vs. 20% of the patients, respectively, were considered to be treatment responders; time to loss of response for those in the ketamine group was 28 days.

Although the overall findings were as expected, “what was surprising was how robust the results were,” lead author Adriana Feder, MD, associate professor of psychiatry, Icahn School of Medicine, Mount Sinai, New York, told this news organization.

It was also a bit surprising that, in a study of just 30 participants, “we were able to show such a clear difference” between the two treatment groups, said Dr. Feder, who is also a coinventor on issued patents for the use of ketamine as therapy for PTSD, and codirector of the Ehrenkranz Lab for the Study of Human Resilience at Mount Sinai.

The findings were published online Jan. 5 in the American Journal of Psychiatry.
 

Unmet need

Ketamine is a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist that was first approved by the U.S. Food and Drug Administration for anesthetic use in 1970. It has also been shown to be effective for treatment-resistant depression.

PTSD has a lifetime prevalence of about 6% in the United States. “While trauma-focused psychotherapies have the most empirical support, they are limited by significant rates of nonresponse, partial response, and treatment dropout,” the investigators write. Also, there are “few available pharmacotherapies for PTSD, and their efficacy is insufficient,” they add.  

“There’s a real need for new treatment interventions that are effective for PTSD and also work rapidly, because it can take weeks to months for currently available treatments to work for PTSD,” Dr. Feder said.

The researchers previously conducted a “proof-of-concept” randomized controlled trial of single infusions of ketamine for chronic PTSD. Results published in 2014 in JAMA Psychiatry showed significant reduction in PTSD symptoms 24 hours after infusion.

For the current study, the investigative team wanted to assess whether ketamine was viable as a longer-term treatment.

“We were encouraged by our initial promising findings” of the earlier trial, Dr. Feder said. “We wanted to do the second study to see if ketamine really works for PTSD, to see if we could replicate the rapid improvement and also examine whether a course of six infusions over 2 weeks could maintain the improvement.”

Thirty patients (aged 18-70; mean age, 39 years) with chronic PTSD from civilian or military trauma were enrolled (mean PTSD duration, 15 years).

The most cited primary trauma was sexual assault or molestation (n = 13), followed by physical assault or abuse (n = 8), witnessing a violent assault or death (n = 4), witnessing the 9/11 attacks (n = 3), and combat exposure (n = 2).

During the 2-week treatment phase, half of the patients were randomly assigned to receive six infusions of ketamine hydrochloride at a dose of 0.5 mg/kg (86.7% women; mean CAPS-5 score, 42), while the other half received six infusions of midazolam at a dose of 0.045 mg/kg (66.7% women; mean CAPS-5 score, 40).

In addition to the primary outcome measure of 2-week changes on the CAPS-5, secondary outcomes included score changes on the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Impact of Event Scale-Revised (IES-R).

Treatment response was defined as a 30% or more improvement in symptoms on the CAPS-5. A number of measures were also used to assess potential treatment-related adverse events (AEs).
 

Safe, effective

Results showed significantly lower total CAPS-5 scores for the ketamine group vs. the midazolam group at week 1 (score difference, 8.8 points; P = .03) and at week 2 (score difference, 11.88 points; P = .004).

Those receiving ketamine also showed improvements in three of the four PTSD symptom clusters on the CAPS-5: avoidance (P < .0001), negative mood and cognitions (P = .02), and intrusions (P = .03). The fourth symptom cluster – arousal and reactivity – did not show a significant improvement.

In addition, the ketamine group showed significantly greater improvement scores on the MADRS at both week 1 and week 2.

Treatment response at 2 weeks was achieved by 10 members of the ketamine group and by three members of the midazolam group (P = .03).

Secondary analyses showed rapid improvement in the treatment responders within the ketamine group, with a mean change of 26 points on the total IES-R score between baseline and 24 hours after their first infusion, and a mean change of 13.4 points on the MADRS total past-24-hour score, a 53% improvement on average.

“A response at 2 weeks is very rapid but they got better sometimes within the first day,” Dr. Feder noted.

There were no serious AEs reported. Although some dissociative symptoms occurred during ketamine infusions, with the highest levels reported at the end of the infusion, these symptoms had resolved by the next assessment, conducted 2 hours after infusion.

The most frequently reported AE in the ketamine group, compared with midazolam, after the start of infusions was blurred vision (53% vs. 0%), followed by dizziness (33% vs. 13%), fatigue (33% vs. 87%), headache (27% vs. 13%), and nausea or vomiting (20% vs. 7%).
 

‘Large-magnitude improvement’

The overall findings show that, in this patient population, “repeated intravenous ketamine infusions administered over 2 weeks were associated with a large-magnitude, clinically significant improvement in PTSD symptoms,” the investigators write.

The results “were very satisfying,” added Dr. Feder. “It was heartening also to hear what some of the participants would say. Some told us about how their symptoms and feelings had changed during the course of treatment with ketamine, where they felt stronger and better able to cope with their trauma and memories.”

She noted, however, that this was not a study designed to specifically assess ketamine in treatment-resistant PTSD. “Some patients had had multiple treatments before that hadn’t worked, while others had not received treatment before. Efficacy for treatment-resistant PTSD is an important question for future research,” Dr. Feder said.

Other areas worth future exploration include treatment efficacy in patients with different types of trauma and whether outcomes can last longer in patients receiving ketamine plus psychotherapy treatment, she noted.

“I don’t want to ignore the fact that currently available treatments work for a number of people with chronic PTSD. But because there are many more for whom [the treatments] don’t work, or they’re insufficiently helped by those treatments, this is certainly one potentially very promising approach that can be added” to a clinician’s toolbox, Dr. Feder said.
 

Speaks to clinical utility

Commenting for this news organization, Gerard Sanacora, MD, PhD, professor of psychiatry at Yale University, New Haven, Connecticut, called this a “very solid and well-designed” study.

“It definitely builds on what’s been found in the past, but it’s a critical piece of information speaking to the clinical utility of this treatment for PTSD,” said Dr. Sanacora, who is also director of the Yale Depression Research Program and was not involved with the current research.

He agreed with the investigators that PTSD has long been a condition that is difficult to treat.

“It’s an area that has a great unmet need for treatment options. Beyond that, as ketamine is becoming more widely used, there’s increasing demand for off-label uses. This [study] actually provides some evidence that there may be efficacy there,” Dr. Sanacora said.

Although he cautioned that this was a small study, and thus further research with a larger patient population will be needed, it provides a compelling foundation to build upon.

“This study provides clear evidence to support a larger study to really give a definitive statement on the efficacy and safety of its use for PTSD. I don’t think this is the study that provides that definitive evidence, but it is a very strong indication, and it very strongly supports the initiation of a large study to address that,” said Dr. Sanacora.

He noted that, although he’s used the term “cautious optimism” for studies in the past, he has “real optimism” that ketamine will be effective for PTSD based on the results of this current study.

“We still need some more data to really convince us of that before we can say with any clear statement that it is effective and safe, but I’m very optimistic,” Dr. Sanacora concluded. “I think the data are very strong.”

The study was funded by the Brain and Behavior Research Foundation, Mount Sinai Innovation Partners and the Mount Sinai i3 Accelerator, Gerald and Glenda Greenwald, and the Ehrenkranz Laboratory for Human Resilience. Dr. Feder is a coinventor on issued patents for the use of ketamine as therapy for PTSD. A list of all disclosures for the other study authors are listed in the original article.

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

Repeated intravenous infusions of ketamine provide rapid relief for patients with posttraumatic stress disorder, new research suggests.

In what investigators are calling the first randomized controlled trial of repeated ketamine administration for chronic PTSD, 30 patients received six infusions of ketamine or midazolam (used as a psychoactive placebo) over 2 consecutive weeks. 

Between baseline and week 2, those receiving ketamine showed significantly greater improvement than those receiving midazolam. Total scores on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) for the first group were almost 12 points lower than the latter group at week 2, meeting the study’s primary outcome measure.

In addition, 67% vs. 20% of the patients, respectively, were considered to be treatment responders; time to loss of response for those in the ketamine group was 28 days.

Although the overall findings were as expected, “what was surprising was how robust the results were,” lead author Adriana Feder, MD, associate professor of psychiatry, Icahn School of Medicine, Mount Sinai, New York, told this news organization.

It was also a bit surprising that, in a study of just 30 participants, “we were able to show such a clear difference” between the two treatment groups, said Dr. Feder, who is also a coinventor on issued patents for the use of ketamine as therapy for PTSD, and codirector of the Ehrenkranz Lab for the Study of Human Resilience at Mount Sinai.

The findings were published online Jan. 5 in the American Journal of Psychiatry.
 

Unmet need

Ketamine is a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist that was first approved by the U.S. Food and Drug Administration for anesthetic use in 1970. It has also been shown to be effective for treatment-resistant depression.

PTSD has a lifetime prevalence of about 6% in the United States. “While trauma-focused psychotherapies have the most empirical support, they are limited by significant rates of nonresponse, partial response, and treatment dropout,” the investigators write. Also, there are “few available pharmacotherapies for PTSD, and their efficacy is insufficient,” they add.  

“There’s a real need for new treatment interventions that are effective for PTSD and also work rapidly, because it can take weeks to months for currently available treatments to work for PTSD,” Dr. Feder said.

The researchers previously conducted a “proof-of-concept” randomized controlled trial of single infusions of ketamine for chronic PTSD. Results published in 2014 in JAMA Psychiatry showed significant reduction in PTSD symptoms 24 hours after infusion.

For the current study, the investigative team wanted to assess whether ketamine was viable as a longer-term treatment.

“We were encouraged by our initial promising findings” of the earlier trial, Dr. Feder said. “We wanted to do the second study to see if ketamine really works for PTSD, to see if we could replicate the rapid improvement and also examine whether a course of six infusions over 2 weeks could maintain the improvement.”

Thirty patients (aged 18-70; mean age, 39 years) with chronic PTSD from civilian or military trauma were enrolled (mean PTSD duration, 15 years).

The most cited primary trauma was sexual assault or molestation (n = 13), followed by physical assault or abuse (n = 8), witnessing a violent assault or death (n = 4), witnessing the 9/11 attacks (n = 3), and combat exposure (n = 2).

During the 2-week treatment phase, half of the patients were randomly assigned to receive six infusions of ketamine hydrochloride at a dose of 0.5 mg/kg (86.7% women; mean CAPS-5 score, 42), while the other half received six infusions of midazolam at a dose of 0.045 mg/kg (66.7% women; mean CAPS-5 score, 40).

In addition to the primary outcome measure of 2-week changes on the CAPS-5, secondary outcomes included score changes on the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Impact of Event Scale-Revised (IES-R).

Treatment response was defined as a 30% or more improvement in symptoms on the CAPS-5. A number of measures were also used to assess potential treatment-related adverse events (AEs).
 

Safe, effective

Results showed significantly lower total CAPS-5 scores for the ketamine group vs. the midazolam group at week 1 (score difference, 8.8 points; P = .03) and at week 2 (score difference, 11.88 points; P = .004).

Those receiving ketamine also showed improvements in three of the four PTSD symptom clusters on the CAPS-5: avoidance (P < .0001), negative mood and cognitions (P = .02), and intrusions (P = .03). The fourth symptom cluster – arousal and reactivity – did not show a significant improvement.

In addition, the ketamine group showed significantly greater improvement scores on the MADRS at both week 1 and week 2.

Treatment response at 2 weeks was achieved by 10 members of the ketamine group and by three members of the midazolam group (P = .03).

Secondary analyses showed rapid improvement in the treatment responders within the ketamine group, with a mean change of 26 points on the total IES-R score between baseline and 24 hours after their first infusion, and a mean change of 13.4 points on the MADRS total past-24-hour score, a 53% improvement on average.

“A response at 2 weeks is very rapid but they got better sometimes within the first day,” Dr. Feder noted.

There were no serious AEs reported. Although some dissociative symptoms occurred during ketamine infusions, with the highest levels reported at the end of the infusion, these symptoms had resolved by the next assessment, conducted 2 hours after infusion.

The most frequently reported AE in the ketamine group, compared with midazolam, after the start of infusions was blurred vision (53% vs. 0%), followed by dizziness (33% vs. 13%), fatigue (33% vs. 87%), headache (27% vs. 13%), and nausea or vomiting (20% vs. 7%).
 

‘Large-magnitude improvement’

The overall findings show that, in this patient population, “repeated intravenous ketamine infusions administered over 2 weeks were associated with a large-magnitude, clinically significant improvement in PTSD symptoms,” the investigators write.

The results “were very satisfying,” added Dr. Feder. “It was heartening also to hear what some of the participants would say. Some told us about how their symptoms and feelings had changed during the course of treatment with ketamine, where they felt stronger and better able to cope with their trauma and memories.”

She noted, however, that this was not a study designed to specifically assess ketamine in treatment-resistant PTSD. “Some patients had had multiple treatments before that hadn’t worked, while others had not received treatment before. Efficacy for treatment-resistant PTSD is an important question for future research,” Dr. Feder said.

Other areas worth future exploration include treatment efficacy in patients with different types of trauma and whether outcomes can last longer in patients receiving ketamine plus psychotherapy treatment, she noted.

“I don’t want to ignore the fact that currently available treatments work for a number of people with chronic PTSD. But because there are many more for whom [the treatments] don’t work, or they’re insufficiently helped by those treatments, this is certainly one potentially very promising approach that can be added” to a clinician’s toolbox, Dr. Feder said.
 

Speaks to clinical utility

Commenting for this news organization, Gerard Sanacora, MD, PhD, professor of psychiatry at Yale University, New Haven, Connecticut, called this a “very solid and well-designed” study.

“It definitely builds on what’s been found in the past, but it’s a critical piece of information speaking to the clinical utility of this treatment for PTSD,” said Dr. Sanacora, who is also director of the Yale Depression Research Program and was not involved with the current research.

He agreed with the investigators that PTSD has long been a condition that is difficult to treat.

“It’s an area that has a great unmet need for treatment options. Beyond that, as ketamine is becoming more widely used, there’s increasing demand for off-label uses. This [study] actually provides some evidence that there may be efficacy there,” Dr. Sanacora said.

Although he cautioned that this was a small study, and thus further research with a larger patient population will be needed, it provides a compelling foundation to build upon.

“This study provides clear evidence to support a larger study to really give a definitive statement on the efficacy and safety of its use for PTSD. I don’t think this is the study that provides that definitive evidence, but it is a very strong indication, and it very strongly supports the initiation of a large study to address that,” said Dr. Sanacora.

He noted that, although he’s used the term “cautious optimism” for studies in the past, he has “real optimism” that ketamine will be effective for PTSD based on the results of this current study.

“We still need some more data to really convince us of that before we can say with any clear statement that it is effective and safe, but I’m very optimistic,” Dr. Sanacora concluded. “I think the data are very strong.”

The study was funded by the Brain and Behavior Research Foundation, Mount Sinai Innovation Partners and the Mount Sinai i3 Accelerator, Gerald and Glenda Greenwald, and the Ehrenkranz Laboratory for Human Resilience. Dr. Feder is a coinventor on issued patents for the use of ketamine as therapy for PTSD. A list of all disclosures for the other study authors are listed in the original article.

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

Chronic kidney disease (CKD) is a significant comorbidity of diabetes mellitus. The Kidney Disease Outcomes Quality Initiative (KDOQI) of the National Kidney Foundation defines CKD as the presence of kidney damage or decreased kidney function for ≥ 3 months. CKD caused by diabetes is called diabetic kidney disease (DKD), which is 1 of 3 principal microvascular complications of diabetes. DKD can progress to end-stage renal disease (ESRD), requiring kidney replacement therapy, and is the leading cause of CKD and ESRD in the United States.^1-3 Studies have also shown that, particularly in patients with diabetes, CKD considerably increases the risk of cardiovascular events, which often occur prior to ESRD.^1,4

This article provides the latest recommendations for evaluating and managing DKD to help you prevent or slow its progression.

Defining and categorizing diabetic kidney disease

CKD is defined as persistently elevated excretion of urinary albumin (albuminuria) and decreased estimated glomerular filtration rate (eGFR), or as the presence of signs of progressive kidney damage.^5,6 DKD, also known as diabetic nephropathy, is CKD attributed to long-term diabetes. A patient’s eGFR is the established basis for assignment to a stage (1, 2, 3a, 3b, 4, or 5) of CKD (TABLE 1⁷) and, along with the category of albuminuria (A1, A2, or A3), can indicate prognosis.

Taking its toll in diabetes

As many as 40% of patients with diabetes develop DKD.^8-10 Most studies of DKD have been conducted in patients with type 1 diabetes (T1D), because the time of clinical onset is typically known.

Type 1 diabetes. DKD usually occurs 10 to 15 years, or later, after the onset of diabetes.⁶ As many as 30% of people with T1D have albuminuria approximately 15 years after onset of diabetes; almost one-half of those develop DKD.^5,11 After approximately 22.5 years without albuminuria, patients with T1D have approximately a 1% annual risk of DKD.¹²

Type 2 diabetes (T2D). DKD is often present at diagnosis, likely due to a delay in diagnosis and briefer clinical exposure, compared to T1D. Albuminuria has been reported in as many as 40% of patients with T2D approximately 10 years after onset of diabetes.^12,13

Multiple risk factors with no standout “predictor”

Genetic susceptibility, ethnicity, glycemic control, smoking, blood pressure (BP), and the eGFR have been identified as risk factors for renal involvement in diabetes; obesity, oral contraceptives, and age can also contribute. Although each risk factor increases the risk of DKD, no single factor is adequately predictive. Moderately increased albuminuria, the earliest sign of DKD, is associated with progressive nephropathy.¹²

Continue to: How great is the risk?

How great is the risk? From disease onset to proteinuria and from proteinuria to ESRD, the risk of DKD in T1D and T2D is similar. With appropriate treatment, albuminuria can regress, and the risk of ESRD can be < 20% at 10 years in T1D.¹² As in T1D, good glycemic control might result in regression of albuminuria in T2D.¹⁴

As many as 30% of people with T1D have albuminuria approximately 15 years after onset of diabetes; almost one-half of those develop DKD.

For unknown reasons, the degree of albuminuria can exist independent of the progression of DKD. Factors responsible for a progressive decline in eGFR in DKD without albuminuria are unknown.^12,15

Patient evaluation with an eye toward comorbidities

A comprehensive initial medical evaluation for DKD includes a review of microvascular complications; visits to specialists; lifestyle and behavior patterns (eg, diet, sleep, substance use, and social support); and medication adherence, adverse drug effects, and alternative medicines. Although DKD is often a clinical diagnosis, it can be ruled in by persistent albuminuria or decreased eGFR, or both, in established diabetes or diabetic retinopathy when other causes are unlikely (see “Recommended DKD screening protocol,” below).

Screening for mental health conditions and barriers to self-management is also key.⁶

Comorbidities, of course, can complicate disease management in patients with diabetes.^16-20 Providers and patients therefore need to be aware of potential diabetic comorbidities. For example, DKD and even moderately increased albuminuria significantly increase the risk of cardiovascular disease (CVD).¹² Other possible comorbidities include (but are not limited to) nonalcoholic steatohepatitis, fracture, hearing impairment, cancer (eg, liver, pancreas, endometrium, colon, rectum, breast, and bladder), pancreatitis, hypogonadism, obstructive sleep apnea, periodontal disease, anxiety, depression, and eating disorders.⁶

Continue to: Recommended DKD screening protocol

In all cases of T2D, in cases of T1D of ≥ 5 years’ duration, and in patients with diabetes and comorbid hypertension, perform annual screening for albuminuria, an elevated creatinine level, and a decline in eGFR.

Screen for potential comorbidities of DKD: For example, the risk of cardiovascular disease is significantly elevated in even moderately increased albuminuria.

To confirm the diagnosis of DKD, at least 2 of 3 urine specimens must demonstrate an elevated urinary albumin:creatinine ratio (UACR) over a 3- to 6-month period.²¹ Apart from renal damage, exercise within 24 hours before specimen collection, infection, fever, congestive heart failure, hyperglycemia, menstruation, and hypertension can elevate the UACR.⁶

Levels of the UACR are established as follows²²:

• Normal UACR is defined as < 30 milligrams of albumin per gram of creatinine (expressed as “mg/g”).
• Increased urinary albumin excretion is defined as ≥ 30 mg/g.
• Moderately increased albuminuria, a predictor of potential nephropathy, is the excretion of 30 to 300 mg/g.
• Severely increased albuminuria is excretion > 300 mg/g; it is often followed by a gradual decline in eGFR that, without treatment, eventually leads to ESRD.

The rate of decline in eGFR once albuminuria is severely increased is equivalent in T1D and T2D.¹² Without intervention, the time from severely increased albuminuria to ESRD in T1D and T2D averages approximately 6 or 7 years.

Clinical features

DKD is typically a clinical diagnosis seen in patients with longstanding diabetes, albuminuria, retinopathy, or a reduced eGFR in the absence of another primary cause of kidney damage. In patients with T1D and DKD, signs of retinopathy and neuropathy are almost always present at diagnosis, unless a diagnosis is made early in the course of diabetes.¹² Therefore, the presence of retinopathy suggests that diabetes is the likely cause of CKD.

Continue to: The presence of microvascular disease...

The presence of microvascular disease in patients with T2D and DKD is less predictable.¹² In T2D patients who do not have retinopathy, consider causes of CKD other than DKD. Features suggesting that the cause of CKD is an underlying condition other than diabetes are rapidly increasing albuminuria or decreasing eGFR; urinary sediment comprising red blood cells or white blood cells; and nephrotic syndrome.⁶

As the prevalence of diabetes increases, it has become more common to diagnose DKD by eGFR without albuminuria—underscoring the importance of routine monitoring of eGFR in patients with diabetes.⁶

Sources of expert guidance. The Chronic Kidney Disease Epidemiology Collaboration equation²³ is preferred for calculating eGFR from serum creatinine: An eGFR < 60 mL/min/1.73 m² is considered abnormal.^3,12 At these rates, the prevalence of complications related to CKD rises and screening for complications becomes necessary.

A more comprehensive classification of the stages of CKD, incorporating albuminuria and progression of CKD, has been recommended by Kidney Disease: Improving Global Outcomes (KDIGO).⁷ Because eGFR and excretion of albumin vary, abnormal test results need to be verified over time to stage the degree of CKD.^3,12 Kidney damage often manifests as albuminuria, but also as hematuria, other types of abnormal urinary sediment, radiographic abnormalities, and other abnormal presentations.

Management

Nutritional factors

Excessive protein intake has been shown to increase albuminuria, worsen renal function, and increase CVD mortality in DKD.^24-26 Therefore, daily dietary protein intake of 0.8 g/kg body weight is recommended for patients who are not on dialysis.³ Patients on dialysis might require higher protein intake to preserve muscle mass caused by protein-energy wasting, which is common in dialysis patients.⁶

Continue to: Low sodium intake

Low sodium intake in CKD patients has been shown to decrease BP and thus slow the progression of renal disease and lower the risk of CVD. The recommended dietary sodium intake in CKD patients is 1500-3000 mg/d.³

Low potassium intake. Hyperkalemia is a serious complication of CKD. A low-potassium diet is recommended in ESRD patients who have a potassium level > 5.5 mEq/L.⁶

Blood pressure

Preventing and treating hypertension is critical to slowing the progression of CKD and reducing cardiovascular risk. BP should be measured at every clinic visit. Aside from lifestyle changes, medication might be needed to reach target BP.

The American Diabetes Association recommends a BP goal of ≤ 140/90 mm Hg for hypertensive patients with diabetes, although they do state that a lower BP target (≤ 130/80 mm Hg) might be more appropriate for patients with DKD.²⁷

The American College of Cardiology recommends that hypertensive patients with CKD have a BP target of ≤ 130/80 mm Hg.²⁸

Continue to: ACE inhibitors and ARBs

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) have renoprotective benefits. These agents are recommended as first-line medications for patients with diabetes, hypertension, and an eGFR < 60 mL/min/1.73 m² and a UACR > 300 mg/g.^29-31 Evidence also supports their use when the UACR is 30 to 299 mg/g.

Studies have shown that, in patients with DKD, ACE inhibitors and ARBs can slow the progression of renal disease.^29,30,32 There is no difference between ACE inhibitors and ARBs in their effectiveness for preventing progression of DKD.⁶ There is no added benefit in combining an ACE inhibitor and an ARB³³; notably, combination ACE inhibitor and ARB therapy can increase the risk of adverse events, such as hyperkalemia and acute kidney injury, especially in patients with DKD.³³

There is no evidence for starting an ACE inhibitor or ARB to prevent CKD in patients with diabetes who are not hypertensive.⁵

ACE inhibitors and ARBs should be used with caution in women of childbearing age, who should use a reliable form of contraception if taking one of these drugs.

Diuretics. Thiazide-type and loop diuretics might potentiate the positive effects of ACE inhibitors and ARBs. KDOQI guidelines recommend that, in patients who require a second agent to control BP, a diuretic should be considered in combination with an ACE inhibitor or an ARB.²⁰ A loop diuretic is preferred if the eGFR is < 30 mL/min/1.73 m².

Continue to: Nondihydropyridine calcium-channel blockers

Nondihydropyridine calcium-channel blockers (CCBs), such as diltiazem and verapamil, have been shown to be more effective then dihydrophyridine CCBs, such as amlodipine and nifedipine, in slowing the progression of renal disease because of their antiproteinuric effects. However, the antiproteinuric effects of nondihydropyridine CCBs are not as strong as those of ACE inhibitors or ARBs, and these drugs do not appear to potentiate the effects of an ACE inhibitor or ARB when used in combination.²⁰

Confirmation of suspected DKD requires an elevated albumin:creatinine ratio in at least 2 of 3 urine specimens over a 3- to 6-month period.

Nondihydropyridine CCBs might be a reasonable alternative in patients who cannot tolerate an ACE inhibitor or an ARB.

Mineralocorticoid receptor antagonists in combination with an ACE inhibitor or ARB have been demonstrated to reduce albuminuria in short-term studies.^34,35

Glycemic levels

Studies conducted in patients with T1D, and others in patients with T2D, have shown that tight glycemic control can delay the onset and slow the progression of albuminuria and a decline in the eGFR.^10,36-39 The target glycated hemoglobin (A1C) should be < 7% to prevent or slow progression of DKD.⁴⁰ However, patients with DKD have an increased risk of hypoglycemic events and increased mortality with more intensive glycemic control.^40,41 Given those findings, some patients with DKD and significant comorbidities, ESRD, or limited life expectancy might need to have an A1C target set at 8%.^6,42

Adjustments to antidiabetes medications in DKD

In patients with stages 3 to 5 DKD, several common antidiabetic medications might need to be adjusted or discontinued because they decrease creatinine clearance.

Continue to: First-generation sulfonylureas

First-generation sulfonylureas should be avoided in DKD. Glipizide and gliclazide are preferred among second-generation sulfonylureas because they do not increase the risk of hypoglycemia in DKD patients, although patients taking these medications still require close monitoring of their blood glucose level.²⁰

Metformin. In 2016, recommendations changed for the use of metformin in patients with DKD: The eGFR, not the serum creatinine level, should guide treatment.⁴³ Metformin can be used safely in patients with (1) an eGFR of < 60 mL/min/1.73 m² and (2) an eGFR of 30 mL/min/1.73 m² with close monitoring. Metformin should not be initiated if the eGFR is < 45 mL/min/1.73 m².⁴³ 

Antidiabetes medications with direct effect on the kidney

Several antidiabetes medications have a direct effect on the kidney apart from their effect on the blood glucose level.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce albuminuria and slow the decrease of eGFR independent of glycemic control. In addition, SGLT2 inhibitors have also been shown to have cardiovascular benefits in patients with DKD.^44,45 

Glucagon-like peptide 1 (GLP-1) receptor agonists have been shown to delay and decrease the progression of DKD.^46-48 Also, similar to what is seen with SGLT2 inhibitors, GLP-1 agonists have demonstrable cardiovascular benefit in patients with DKD.^46,48

Continue to: Dyslipidemia and DKD

Because the risk of CVD is increased in patients with DKD, addressing other modifiable risk factors, including dyslipidemia, is recommended in these patients. Patients with diabetes and stages 1 to 4 DKD should be treated with a high-intensity statin or a combination of a statin and ezetimibe.^49,50

Tight glycemic control in T1D and T2D can delay the onset, and slow the progression, of albuminuria and a decline in the eGFR.

If a patient is taking a statin and starting dialysis, it’s important to discuss with him or her whether to continue the statin, based on perceived benefits and risks. It is not recommended that statins be initiated in patients on dialysis unless there is a specific cardiovascular indication for doing so. Risk reduction with a statin has been shown to be significantly less in dialysis patients than in patients who are not being treated with dialysis.⁴⁹

Complications of CKD

Anemia is a common complication of CKD. KDIGO recommends measuring the ­hemoglobin concentration annually in DKD stage 3 patients without anemia; at least every 6 months in stage 4 patients; and at least every 3 months in stage 5. DKD patients with anemia should have additional laboratory testing: the absolute reticulocyte count, serum ferritin, serum transferrin saturation, vitamin B12, and folate.⁵¹

Mineral and bone disorder should be screened for in patients with DKD. TABLE 2⁵² outlines when clinical laboratory tests should be ordered to assess for mineral bone disease.

When to refer to a nephrologist

Refer patients with stage 4 or 5 CKD (eGFR, ≤ 30 mL/min/1.73 m²) to a nephrologist for discussion of kidney replacement therapy.⁶ Patients with stage 3a CKD and severely increased albuminuria or with stage 3b CKD and moderately or severely increased albuminuria should also be referred to a nephrologist for intervention to delay disease progression.

Continue to: Identifying the need for early referral...

Nutritional control is important in DKD: A lowsodium diet can slow progression of DKD, and a low-potassium diet can prevent hyperkalemia in end-stage renal disease.

Identifying the need for early referral to a nephrologist has been shown to reduce the cost, and improve the quality, of care.⁵³ Other indications for earlier referral include uncertainty about the etiology of renal disease, persistent or severe albuminuria, persistent hematuria, a rapid decline in eGFR, and acute kidney injury. Additionally, referral at an earlier stage of DKD might be needed to assist with complications associated with DKD, such as anemia, secondary hyperparathyroidism, mineral and bone disorder, resistant hypertension, fluid overload, and electrolyte disturbances.⁶

ACKNOWLEDGEMENT
The authors thank Colleen Colbert, PhD, and Iqbal Ahmad, PhD, for their review and critique of the manuscript of this article. They also thank Christopher Babiuch, MD, for his guidance in the preparation of the manuscript.

CORRESPONDENCE
Faraz Ahmad, MD, MPH, Care Point East Family Medicine, 543 Taylor Avenue, 2nd floor, Columbus, OH 43203; faraz. [email protected].

Chronic kidney disease (CKD) is a significant comorbidity of diabetes mellitus. The Kidney Disease Outcomes Quality Initiative (KDOQI) of the National Kidney Foundation defines CKD as the presence of kidney damage or decreased kidney function for ≥ 3 months. CKD caused by diabetes is called diabetic kidney disease (DKD), which is 1 of 3 principal microvascular complications of diabetes. DKD can progress to end-stage renal disease (ESRD), requiring kidney replacement therapy, and is the leading cause of CKD and ESRD in the United States.^1-3 Studies have also shown that, particularly in patients with diabetes, CKD considerably increases the risk of cardiovascular events, which often occur prior to ESRD.^1,4

This article provides the latest recommendations for evaluating and managing DKD to help you prevent or slow its progression.

Defining and categorizing diabetic kidney disease

CKD is defined as persistently elevated excretion of urinary albumin (albuminuria) and decreased estimated glomerular filtration rate (eGFR), or as the presence of signs of progressive kidney damage.^5,6 DKD, also known as diabetic nephropathy, is CKD attributed to long-term diabetes. A patient’s eGFR is the established basis for assignment to a stage (1, 2, 3a, 3b, 4, or 5) of CKD (TABLE 1⁷) and, along with the category of albuminuria (A1, A2, or A3), can indicate prognosis.

Taking its toll in diabetes

As many as 40% of patients with diabetes develop DKD.^8-10 Most studies of DKD have been conducted in patients with type 1 diabetes (T1D), because the time of clinical onset is typically known.

Type 1 diabetes. DKD usually occurs 10 to 15 years, or later, after the onset of diabetes.⁶ As many as 30% of people with T1D have albuminuria approximately 15 years after onset of diabetes; almost one-half of those develop DKD.^5,11 After approximately 22.5 years without albuminuria, patients with T1D have approximately a 1% annual risk of DKD.¹²

Type 2 diabetes (T2D). DKD is often present at diagnosis, likely due to a delay in diagnosis and briefer clinical exposure, compared to T1D. Albuminuria has been reported in as many as 40% of patients with T2D approximately 10 years after onset of diabetes.^12,13

Multiple risk factors with no standout “predictor”

Genetic susceptibility, ethnicity, glycemic control, smoking, blood pressure (BP), and the eGFR have been identified as risk factors for renal involvement in diabetes; obesity, oral contraceptives, and age can also contribute. Although each risk factor increases the risk of DKD, no single factor is adequately predictive. Moderately increased albuminuria, the earliest sign of DKD, is associated with progressive nephropathy.¹²

Continue to: How great is the risk?

How great is the risk? From disease onset to proteinuria and from proteinuria to ESRD, the risk of DKD in T1D and T2D is similar. With appropriate treatment, albuminuria can regress, and the risk of ESRD can be < 20% at 10 years in T1D.¹² As in T1D, good glycemic control might result in regression of albuminuria in T2D.¹⁴

As many as 30% of people with T1D have albuminuria approximately 15 years after onset of diabetes; almost one-half of those develop DKD.

For unknown reasons, the degree of albuminuria can exist independent of the progression of DKD. Factors responsible for a progressive decline in eGFR in DKD without albuminuria are unknown.^12,15

Patient evaluation with an eye toward comorbidities

A comprehensive initial medical evaluation for DKD includes a review of microvascular complications; visits to specialists; lifestyle and behavior patterns (eg, diet, sleep, substance use, and social support); and medication adherence, adverse drug effects, and alternative medicines. Although DKD is often a clinical diagnosis, it can be ruled in by persistent albuminuria or decreased eGFR, or both, in established diabetes or diabetic retinopathy when other causes are unlikely (see “Recommended DKD screening protocol,” below).

Screening for mental health conditions and barriers to self-management is also key.⁶

Comorbidities, of course, can complicate disease management in patients with diabetes.^16-20 Providers and patients therefore need to be aware of potential diabetic comorbidities. For example, DKD and even moderately increased albuminuria significantly increase the risk of cardiovascular disease (CVD).¹² Other possible comorbidities include (but are not limited to) nonalcoholic steatohepatitis, fracture, hearing impairment, cancer (eg, liver, pancreas, endometrium, colon, rectum, breast, and bladder), pancreatitis, hypogonadism, obstructive sleep apnea, periodontal disease, anxiety, depression, and eating disorders.⁶

Continue to: Recommended DKD screening protocol

In all cases of T2D, in cases of T1D of ≥ 5 years’ duration, and in patients with diabetes and comorbid hypertension, perform annual screening for albuminuria, an elevated creatinine level, and a decline in eGFR.

Screen for potential comorbidities of DKD: For example, the risk of cardiovascular disease is significantly elevated in even moderately increased albuminuria.

To confirm the diagnosis of DKD, at least 2 of 3 urine specimens must demonstrate an elevated urinary albumin:creatinine ratio (UACR) over a 3- to 6-month period.²¹ Apart from renal damage, exercise within 24 hours before specimen collection, infection, fever, congestive heart failure, hyperglycemia, menstruation, and hypertension can elevate the UACR.⁶

Levels of the UACR are established as follows²²:

• Normal UACR is defined as < 30 milligrams of albumin per gram of creatinine (expressed as “mg/g”).
• Increased urinary albumin excretion is defined as ≥ 30 mg/g.
• Moderately increased albuminuria, a predictor of potential nephropathy, is the excretion of 30 to 300 mg/g.
• Severely increased albuminuria is excretion > 300 mg/g; it is often followed by a gradual decline in eGFR that, without treatment, eventually leads to ESRD.

The rate of decline in eGFR once albuminuria is severely increased is equivalent in T1D and T2D.¹² Without intervention, the time from severely increased albuminuria to ESRD in T1D and T2D averages approximately 6 or 7 years.

Clinical features

DKD is typically a clinical diagnosis seen in patients with longstanding diabetes, albuminuria, retinopathy, or a reduced eGFR in the absence of another primary cause of kidney damage. In patients with T1D and DKD, signs of retinopathy and neuropathy are almost always present at diagnosis, unless a diagnosis is made early in the course of diabetes.¹² Therefore, the presence of retinopathy suggests that diabetes is the likely cause of CKD.

Continue to: The presence of microvascular disease...

The presence of microvascular disease in patients with T2D and DKD is less predictable.¹² In T2D patients who do not have retinopathy, consider causes of CKD other than DKD. Features suggesting that the cause of CKD is an underlying condition other than diabetes are rapidly increasing albuminuria or decreasing eGFR; urinary sediment comprising red blood cells or white blood cells; and nephrotic syndrome.⁶

As the prevalence of diabetes increases, it has become more common to diagnose DKD by eGFR without albuminuria—underscoring the importance of routine monitoring of eGFR in patients with diabetes.⁶

Sources of expert guidance. The Chronic Kidney Disease Epidemiology Collaboration equation²³ is preferred for calculating eGFR from serum creatinine: An eGFR < 60 mL/min/1.73 m² is considered abnormal.^3,12 At these rates, the prevalence of complications related to CKD rises and screening for complications becomes necessary.

A more comprehensive classification of the stages of CKD, incorporating albuminuria and progression of CKD, has been recommended by Kidney Disease: Improving Global Outcomes (KDIGO).⁷ Because eGFR and excretion of albumin vary, abnormal test results need to be verified over time to stage the degree of CKD.^3,12 Kidney damage often manifests as albuminuria, but also as hematuria, other types of abnormal urinary sediment, radiographic abnormalities, and other abnormal presentations.

Management

Nutritional factors

Excessive protein intake has been shown to increase albuminuria, worsen renal function, and increase CVD mortality in DKD.^24-26 Therefore, daily dietary protein intake of 0.8 g/kg body weight is recommended for patients who are not on dialysis.³ Patients on dialysis might require higher protein intake to preserve muscle mass caused by protein-energy wasting, which is common in dialysis patients.⁶

Continue to: Low sodium intake

Low sodium intake in CKD patients has been shown to decrease BP and thus slow the progression of renal disease and lower the risk of CVD. The recommended dietary sodium intake in CKD patients is 1500-3000 mg/d.³

Low potassium intake. Hyperkalemia is a serious complication of CKD. A low-potassium diet is recommended in ESRD patients who have a potassium level > 5.5 mEq/L.⁶

Blood pressure

Preventing and treating hypertension is critical to slowing the progression of CKD and reducing cardiovascular risk. BP should be measured at every clinic visit. Aside from lifestyle changes, medication might be needed to reach target BP.

The American Diabetes Association recommends a BP goal of ≤ 140/90 mm Hg for hypertensive patients with diabetes, although they do state that a lower BP target (≤ 130/80 mm Hg) might be more appropriate for patients with DKD.²⁷

The American College of Cardiology recommends that hypertensive patients with CKD have a BP target of ≤ 130/80 mm Hg.²⁸

Continue to: ACE inhibitors and ARBs

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) have renoprotective benefits. These agents are recommended as first-line medications for patients with diabetes, hypertension, and an eGFR < 60 mL/min/1.73 m² and a UACR > 300 mg/g.^29-31 Evidence also supports their use when the UACR is 30 to 299 mg/g.

Studies have shown that, in patients with DKD, ACE inhibitors and ARBs can slow the progression of renal disease.^29,30,32 There is no difference between ACE inhibitors and ARBs in their effectiveness for preventing progression of DKD.⁶ There is no added benefit in combining an ACE inhibitor and an ARB³³; notably, combination ACE inhibitor and ARB therapy can increase the risk of adverse events, such as hyperkalemia and acute kidney injury, especially in patients with DKD.³³

There is no evidence for starting an ACE inhibitor or ARB to prevent CKD in patients with diabetes who are not hypertensive.⁵

ACE inhibitors and ARBs should be used with caution in women of childbearing age, who should use a reliable form of contraception if taking one of these drugs.

Diuretics. Thiazide-type and loop diuretics might potentiate the positive effects of ACE inhibitors and ARBs. KDOQI guidelines recommend that, in patients who require a second agent to control BP, a diuretic should be considered in combination with an ACE inhibitor or an ARB.²⁰ A loop diuretic is preferred if the eGFR is < 30 mL/min/1.73 m².

Continue to: Nondihydropyridine calcium-channel blockers

Nondihydropyridine calcium-channel blockers (CCBs), such as diltiazem and verapamil, have been shown to be more effective then dihydrophyridine CCBs, such as amlodipine and nifedipine, in slowing the progression of renal disease because of their antiproteinuric effects. However, the antiproteinuric effects of nondihydropyridine CCBs are not as strong as those of ACE inhibitors or ARBs, and these drugs do not appear to potentiate the effects of an ACE inhibitor or ARB when used in combination.²⁰

Confirmation of suspected DKD requires an elevated albumin:creatinine ratio in at least 2 of 3 urine specimens over a 3- to 6-month period.

Nondihydropyridine CCBs might be a reasonable alternative in patients who cannot tolerate an ACE inhibitor or an ARB.

Mineralocorticoid receptor antagonists in combination with an ACE inhibitor or ARB have been demonstrated to reduce albuminuria in short-term studies.^34,35

Glycemic levels

Studies conducted in patients with T1D, and others in patients with T2D, have shown that tight glycemic control can delay the onset and slow the progression of albuminuria and a decline in the eGFR.^10,36-39 The target glycated hemoglobin (A1C) should be < 7% to prevent or slow progression of DKD.⁴⁰ However, patients with DKD have an increased risk of hypoglycemic events and increased mortality with more intensive glycemic control.^40,41 Given those findings, some patients with DKD and significant comorbidities, ESRD, or limited life expectancy might need to have an A1C target set at 8%.^6,42

Adjustments to antidiabetes medications in DKD

In patients with stages 3 to 5 DKD, several common antidiabetic medications might need to be adjusted or discontinued because they decrease creatinine clearance.

Continue to: First-generation sulfonylureas

First-generation sulfonylureas should be avoided in DKD. Glipizide and gliclazide are preferred among second-generation sulfonylureas because they do not increase the risk of hypoglycemia in DKD patients, although patients taking these medications still require close monitoring of their blood glucose level.²⁰

Metformin. In 2016, recommendations changed for the use of metformin in patients with DKD: The eGFR, not the serum creatinine level, should guide treatment.⁴³ Metformin can be used safely in patients with (1) an eGFR of < 60 mL/min/1.73 m² and (2) an eGFR of 30 mL/min/1.73 m² with close monitoring. Metformin should not be initiated if the eGFR is < 45 mL/min/1.73 m².⁴³ 

Antidiabetes medications with direct effect on the kidney

Several antidiabetes medications have a direct effect on the kidney apart from their effect on the blood glucose level.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce albuminuria and slow the decrease of eGFR independent of glycemic control. In addition, SGLT2 inhibitors have also been shown to have cardiovascular benefits in patients with DKD.^44,45 

Glucagon-like peptide 1 (GLP-1) receptor agonists have been shown to delay and decrease the progression of DKD.^46-48 Also, similar to what is seen with SGLT2 inhibitors, GLP-1 agonists have demonstrable cardiovascular benefit in patients with DKD.^46,48

Continue to: Dyslipidemia and DKD

Because the risk of CVD is increased in patients with DKD, addressing other modifiable risk factors, including dyslipidemia, is recommended in these patients. Patients with diabetes and stages 1 to 4 DKD should be treated with a high-intensity statin or a combination of a statin and ezetimibe.^49,50

Tight glycemic control in T1D and T2D can delay the onset, and slow the progression, of albuminuria and a decline in the eGFR.

If a patient is taking a statin and starting dialysis, it’s important to discuss with him or her whether to continue the statin, based on perceived benefits and risks. It is not recommended that statins be initiated in patients on dialysis unless there is a specific cardiovascular indication for doing so. Risk reduction with a statin has been shown to be significantly less in dialysis patients than in patients who are not being treated with dialysis.⁴⁹

Complications of CKD

Anemia is a common complication of CKD. KDIGO recommends measuring the ­hemoglobin concentration annually in DKD stage 3 patients without anemia; at least every 6 months in stage 4 patients; and at least every 3 months in stage 5. DKD patients with anemia should have additional laboratory testing: the absolute reticulocyte count, serum ferritin, serum transferrin saturation, vitamin B12, and folate.⁵¹

Mineral and bone disorder should be screened for in patients with DKD. TABLE 2⁵² outlines when clinical laboratory tests should be ordered to assess for mineral bone disease.

When to refer to a nephrologist

Refer patients with stage 4 or 5 CKD (eGFR, ≤ 30 mL/min/1.73 m²) to a nephrologist for discussion of kidney replacement therapy.⁶ Patients with stage 3a CKD and severely increased albuminuria or with stage 3b CKD and moderately or severely increased albuminuria should also be referred to a nephrologist for intervention to delay disease progression.

Continue to: Identifying the need for early referral...

Nutritional control is important in DKD: A lowsodium diet can slow progression of DKD, and a low-potassium diet can prevent hyperkalemia in end-stage renal disease.

Identifying the need for early referral to a nephrologist has been shown to reduce the cost, and improve the quality, of care.⁵³ Other indications for earlier referral include uncertainty about the etiology of renal disease, persistent or severe albuminuria, persistent hematuria, a rapid decline in eGFR, and acute kidney injury. Additionally, referral at an earlier stage of DKD might be needed to assist with complications associated with DKD, such as anemia, secondary hyperparathyroidism, mineral and bone disorder, resistant hypertension, fluid overload, and electrolyte disturbances.⁶

ACKNOWLEDGEMENT
The authors thank Colleen Colbert, PhD, and Iqbal Ahmad, PhD, for their review and critique of the manuscript of this article. They also thank Christopher Babiuch, MD, for his guidance in the preparation of the manuscript.

CORRESPONDENCE
Faraz Ahmad, MD, MPH, Care Point East Family Medicine, 543 Taylor Avenue, 2nd floor, Columbus, OH 43203; faraz. [email protected].

Chronic kidney disease (CKD) is a significant comorbidity of diabetes mellitus. The Kidney Disease Outcomes Quality Initiative (KDOQI) of the National Kidney Foundation defines CKD as the presence of kidney damage or decreased kidney function for ≥ 3 months. CKD caused by diabetes is called diabetic kidney disease (DKD), which is 1 of 3 principal microvascular complications of diabetes. DKD can progress to end-stage renal disease (ESRD), requiring kidney replacement therapy, and is the leading cause of CKD and ESRD in the United States.^1-3 Studies have also shown that, particularly in patients with diabetes, CKD considerably increases the risk of cardiovascular events, which often occur prior to ESRD.^1,4

This article provides the latest recommendations for evaluating and managing DKD to help you prevent or slow its progression.

Defining and categorizing diabetic kidney disease

CKD is defined as persistently elevated excretion of urinary albumin (albuminuria) and decreased estimated glomerular filtration rate (eGFR), or as the presence of signs of progressive kidney damage.^5,6 DKD, also known as diabetic nephropathy, is CKD attributed to long-term diabetes. A patient’s eGFR is the established basis for assignment to a stage (1, 2, 3a, 3b, 4, or 5) of CKD (TABLE 1⁷) and, along with the category of albuminuria (A1, A2, or A3), can indicate prognosis.

Taking its toll in diabetes

As many as 40% of patients with diabetes develop DKD.^8-10 Most studies of DKD have been conducted in patients with type 1 diabetes (T1D), because the time of clinical onset is typically known.

Type 1 diabetes. DKD usually occurs 10 to 15 years, or later, after the onset of diabetes.⁶ As many as 30% of people with T1D have albuminuria approximately 15 years after onset of diabetes; almost one-half of those develop DKD.^5,11 After approximately 22.5 years without albuminuria, patients with T1D have approximately a 1% annual risk of DKD.¹²

Type 2 diabetes (T2D). DKD is often present at diagnosis, likely due to a delay in diagnosis and briefer clinical exposure, compared to T1D. Albuminuria has been reported in as many as 40% of patients with T2D approximately 10 years after onset of diabetes.^12,13

Multiple risk factors with no standout “predictor”

Genetic susceptibility, ethnicity, glycemic control, smoking, blood pressure (BP), and the eGFR have been identified as risk factors for renal involvement in diabetes; obesity, oral contraceptives, and age can also contribute. Although each risk factor increases the risk of DKD, no single factor is adequately predictive. Moderately increased albuminuria, the earliest sign of DKD, is associated with progressive nephropathy.¹²

Continue to: How great is the risk?

How great is the risk? From disease onset to proteinuria and from proteinuria to ESRD, the risk of DKD in T1D and T2D is similar. With appropriate treatment, albuminuria can regress, and the risk of ESRD can be < 20% at 10 years in T1D.¹² As in T1D, good glycemic control might result in regression of albuminuria in T2D.¹⁴

As many as 30% of people with T1D have albuminuria approximately 15 years after onset of diabetes; almost one-half of those develop DKD.

For unknown reasons, the degree of albuminuria can exist independent of the progression of DKD. Factors responsible for a progressive decline in eGFR in DKD without albuminuria are unknown.^12,15

Patient evaluation with an eye toward comorbidities

A comprehensive initial medical evaluation for DKD includes a review of microvascular complications; visits to specialists; lifestyle and behavior patterns (eg, diet, sleep, substance use, and social support); and medication adherence, adverse drug effects, and alternative medicines. Although DKD is often a clinical diagnosis, it can be ruled in by persistent albuminuria or decreased eGFR, or both, in established diabetes or diabetic retinopathy when other causes are unlikely (see “Recommended DKD screening protocol,” below).

Screening for mental health conditions and barriers to self-management is also key.⁶

Comorbidities, of course, can complicate disease management in patients with diabetes.^16-20 Providers and patients therefore need to be aware of potential diabetic comorbidities. For example, DKD and even moderately increased albuminuria significantly increase the risk of cardiovascular disease (CVD).¹² Other possible comorbidities include (but are not limited to) nonalcoholic steatohepatitis, fracture, hearing impairment, cancer (eg, liver, pancreas, endometrium, colon, rectum, breast, and bladder), pancreatitis, hypogonadism, obstructive sleep apnea, periodontal disease, anxiety, depression, and eating disorders.⁶

Continue to: Recommended DKD screening protocol

In all cases of T2D, in cases of T1D of ≥ 5 years’ duration, and in patients with diabetes and comorbid hypertension, perform annual screening for albuminuria, an elevated creatinine level, and a decline in eGFR.

Screen for potential comorbidities of DKD: For example, the risk of cardiovascular disease is significantly elevated in even moderately increased albuminuria.

To confirm the diagnosis of DKD, at least 2 of 3 urine specimens must demonstrate an elevated urinary albumin:creatinine ratio (UACR) over a 3- to 6-month period.²¹ Apart from renal damage, exercise within 24 hours before specimen collection, infection, fever, congestive heart failure, hyperglycemia, menstruation, and hypertension can elevate the UACR.⁶

Levels of the UACR are established as follows²²:

• Normal UACR is defined as < 30 milligrams of albumin per gram of creatinine (expressed as “mg/g”).
• Increased urinary albumin excretion is defined as ≥ 30 mg/g.
• Moderately increased albuminuria, a predictor of potential nephropathy, is the excretion of 30 to 300 mg/g.
• Severely increased albuminuria is excretion > 300 mg/g; it is often followed by a gradual decline in eGFR that, without treatment, eventually leads to ESRD.

The rate of decline in eGFR once albuminuria is severely increased is equivalent in T1D and T2D.¹² Without intervention, the time from severely increased albuminuria to ESRD in T1D and T2D averages approximately 6 or 7 years.

Clinical features

DKD is typically a clinical diagnosis seen in patients with longstanding diabetes, albuminuria, retinopathy, or a reduced eGFR in the absence of another primary cause of kidney damage. In patients with T1D and DKD, signs of retinopathy and neuropathy are almost always present at diagnosis, unless a diagnosis is made early in the course of diabetes.¹² Therefore, the presence of retinopathy suggests that diabetes is the likely cause of CKD.

Continue to: The presence of microvascular disease...

The presence of microvascular disease in patients with T2D and DKD is less predictable.¹² In T2D patients who do not have retinopathy, consider causes of CKD other than DKD. Features suggesting that the cause of CKD is an underlying condition other than diabetes are rapidly increasing albuminuria or decreasing eGFR; urinary sediment comprising red blood cells or white blood cells; and nephrotic syndrome.⁶

As the prevalence of diabetes increases, it has become more common to diagnose DKD by eGFR without albuminuria—underscoring the importance of routine monitoring of eGFR in patients with diabetes.⁶

Sources of expert guidance. The Chronic Kidney Disease Epidemiology Collaboration equation²³ is preferred for calculating eGFR from serum creatinine: An eGFR < 60 mL/min/1.73 m² is considered abnormal.^3,12 At these rates, the prevalence of complications related to CKD rises and screening for complications becomes necessary.

A more comprehensive classification of the stages of CKD, incorporating albuminuria and progression of CKD, has been recommended by Kidney Disease: Improving Global Outcomes (KDIGO).⁷ Because eGFR and excretion of albumin vary, abnormal test results need to be verified over time to stage the degree of CKD.^3,12 Kidney damage often manifests as albuminuria, but also as hematuria, other types of abnormal urinary sediment, radiographic abnormalities, and other abnormal presentations.

Management

Nutritional factors

Excessive protein intake has been shown to increase albuminuria, worsen renal function, and increase CVD mortality in DKD.^24-26 Therefore, daily dietary protein intake of 0.8 g/kg body weight is recommended for patients who are not on dialysis.³ Patients on dialysis might require higher protein intake to preserve muscle mass caused by protein-energy wasting, which is common in dialysis patients.⁶

Continue to: Low sodium intake

Low sodium intake in CKD patients has been shown to decrease BP and thus slow the progression of renal disease and lower the risk of CVD. The recommended dietary sodium intake in CKD patients is 1500-3000 mg/d.³

Low potassium intake. Hyperkalemia is a serious complication of CKD. A low-potassium diet is recommended in ESRD patients who have a potassium level > 5.5 mEq/L.⁶

Blood pressure

Preventing and treating hypertension is critical to slowing the progression of CKD and reducing cardiovascular risk. BP should be measured at every clinic visit. Aside from lifestyle changes, medication might be needed to reach target BP.

The American Diabetes Association recommends a BP goal of ≤ 140/90 mm Hg for hypertensive patients with diabetes, although they do state that a lower BP target (≤ 130/80 mm Hg) might be more appropriate for patients with DKD.²⁷

The American College of Cardiology recommends that hypertensive patients with CKD have a BP target of ≤ 130/80 mm Hg.²⁸

Continue to: ACE inhibitors and ARBs

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) have renoprotective benefits. These agents are recommended as first-line medications for patients with diabetes, hypertension, and an eGFR < 60 mL/min/1.73 m² and a UACR > 300 mg/g.^29-31 Evidence also supports their use when the UACR is 30 to 299 mg/g.

Studies have shown that, in patients with DKD, ACE inhibitors and ARBs can slow the progression of renal disease.^29,30,32 There is no difference between ACE inhibitors and ARBs in their effectiveness for preventing progression of DKD.⁶ There is no added benefit in combining an ACE inhibitor and an ARB³³; notably, combination ACE inhibitor and ARB therapy can increase the risk of adverse events, such as hyperkalemia and acute kidney injury, especially in patients with DKD.³³

There is no evidence for starting an ACE inhibitor or ARB to prevent CKD in patients with diabetes who are not hypertensive.⁵

ACE inhibitors and ARBs should be used with caution in women of childbearing age, who should use a reliable form of contraception if taking one of these drugs.

Diuretics. Thiazide-type and loop diuretics might potentiate the positive effects of ACE inhibitors and ARBs. KDOQI guidelines recommend that, in patients who require a second agent to control BP, a diuretic should be considered in combination with an ACE inhibitor or an ARB.²⁰ A loop diuretic is preferred if the eGFR is < 30 mL/min/1.73 m².

Continue to: Nondihydropyridine calcium-channel blockers

Nondihydropyridine calcium-channel blockers (CCBs), such as diltiazem and verapamil, have been shown to be more effective then dihydrophyridine CCBs, such as amlodipine and nifedipine, in slowing the progression of renal disease because of their antiproteinuric effects. However, the antiproteinuric effects of nondihydropyridine CCBs are not as strong as those of ACE inhibitors or ARBs, and these drugs do not appear to potentiate the effects of an ACE inhibitor or ARB when used in combination.²⁰

Confirmation of suspected DKD requires an elevated albumin:creatinine ratio in at least 2 of 3 urine specimens over a 3- to 6-month period.

Nondihydropyridine CCBs might be a reasonable alternative in patients who cannot tolerate an ACE inhibitor or an ARB.

Mineralocorticoid receptor antagonists in combination with an ACE inhibitor or ARB have been demonstrated to reduce albuminuria in short-term studies.^34,35

Glycemic levels

Studies conducted in patients with T1D, and others in patients with T2D, have shown that tight glycemic control can delay the onset and slow the progression of albuminuria and a decline in the eGFR.^10,36-39 The target glycated hemoglobin (A1C) should be < 7% to prevent or slow progression of DKD.⁴⁰ However, patients with DKD have an increased risk of hypoglycemic events and increased mortality with more intensive glycemic control.^40,41 Given those findings, some patients with DKD and significant comorbidities, ESRD, or limited life expectancy might need to have an A1C target set at 8%.^6,42

Adjustments to antidiabetes medications in DKD

In patients with stages 3 to 5 DKD, several common antidiabetic medications might need to be adjusted or discontinued because they decrease creatinine clearance.

Continue to: First-generation sulfonylureas

First-generation sulfonylureas should be avoided in DKD. Glipizide and gliclazide are preferred among second-generation sulfonylureas because they do not increase the risk of hypoglycemia in DKD patients, although patients taking these medications still require close monitoring of their blood glucose level.²⁰

Metformin. In 2016, recommendations changed for the use of metformin in patients with DKD: The eGFR, not the serum creatinine level, should guide treatment.⁴³ Metformin can be used safely in patients with (1) an eGFR of < 60 mL/min/1.73 m² and (2) an eGFR of 30 mL/min/1.73 m² with close monitoring. Metformin should not be initiated if the eGFR is < 45 mL/min/1.73 m².⁴³ 

Antidiabetes medications with direct effect on the kidney

Several antidiabetes medications have a direct effect on the kidney apart from their effect on the blood glucose level.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce albuminuria and slow the decrease of eGFR independent of glycemic control. In addition, SGLT2 inhibitors have also been shown to have cardiovascular benefits in patients with DKD.^44,45 

Glucagon-like peptide 1 (GLP-1) receptor agonists have been shown to delay and decrease the progression of DKD.^46-48 Also, similar to what is seen with SGLT2 inhibitors, GLP-1 agonists have demonstrable cardiovascular benefit in patients with DKD.^46,48

Continue to: Dyslipidemia and DKD

Because the risk of CVD is increased in patients with DKD, addressing other modifiable risk factors, including dyslipidemia, is recommended in these patients. Patients with diabetes and stages 1 to 4 DKD should be treated with a high-intensity statin or a combination of a statin and ezetimibe.^49,50

Tight glycemic control in T1D and T2D can delay the onset, and slow the progression, of albuminuria and a decline in the eGFR.

If a patient is taking a statin and starting dialysis, it’s important to discuss with him or her whether to continue the statin, based on perceived benefits and risks. It is not recommended that statins be initiated in patients on dialysis unless there is a specific cardiovascular indication for doing so. Risk reduction with a statin has been shown to be significantly less in dialysis patients than in patients who are not being treated with dialysis.⁴⁹

Complications of CKD

Anemia is a common complication of CKD. KDIGO recommends measuring the ­hemoglobin concentration annually in DKD stage 3 patients without anemia; at least every 6 months in stage 4 patients; and at least every 3 months in stage 5. DKD patients with anemia should have additional laboratory testing: the absolute reticulocyte count, serum ferritin, serum transferrin saturation, vitamin B12, and folate.⁵¹

Mineral and bone disorder should be screened for in patients with DKD. TABLE 2⁵² outlines when clinical laboratory tests should be ordered to assess for mineral bone disease.

When to refer to a nephrologist

Refer patients with stage 4 or 5 CKD (eGFR, ≤ 30 mL/min/1.73 m²) to a nephrologist for discussion of kidney replacement therapy.⁶ Patients with stage 3a CKD and severely increased albuminuria or with stage 3b CKD and moderately or severely increased albuminuria should also be referred to a nephrologist for intervention to delay disease progression.

Continue to: Identifying the need for early referral...

Nutritional control is important in DKD: A lowsodium diet can slow progression of DKD, and a low-potassium diet can prevent hyperkalemia in end-stage renal disease.

Identifying the need for early referral to a nephrologist has been shown to reduce the cost, and improve the quality, of care.⁵³ Other indications for earlier referral include uncertainty about the etiology of renal disease, persistent or severe albuminuria, persistent hematuria, a rapid decline in eGFR, and acute kidney injury. Additionally, referral at an earlier stage of DKD might be needed to assist with complications associated with DKD, such as anemia, secondary hyperparathyroidism, mineral and bone disorder, resistant hypertension, fluid overload, and electrolyte disturbances.⁶

ACKNOWLEDGEMENT
The authors thank Colleen Colbert, PhD, and Iqbal Ahmad, PhD, for their review and critique of the manuscript of this article. They also thank Christopher Babiuch, MD, for his guidance in the preparation of the manuscript.

CORRESPONDENCE
Faraz Ahmad, MD, MPH, Care Point East Family Medicine, 543 Taylor Avenue, 2nd floor, Columbus, OH 43203; faraz. [email protected].

Primary care physicians (PCPs) generate only a small part of the $75 billion to $100 billion wasted every year on low-value care, according to a brief report published online Jan. 18 in Annals of Internal Medicine.

However, one expert said there are better ways to curb low-value care than focusing on which specialties are guilty of the practice.

Analyzing a 20% random sample of Medicare Part B claims, Aaron Baum, PhD, with the Icahn School of Medicine at Mount Sinai, New York, and colleagues found that the services primary care physicians performed or ordered made up on average 8.3% of the low-value care their patients received (interquartile range, 3.9%-15.1%; 95th percentile, 35.6%) and their referrals made up 15.4% (IQR, 6.3%-26.4%; 95th percentile, 44.6%).

By specialty, cardiology had the worst record with 27% of all spending on low-value services ($1.8 billion) attributed to that specialty. Yet, of the 25 highest-spending specialties in the report, 12 of them were associated with 1% or less than 1% each of all low-value spending, indicating the waste was widely distributed.

Dr. Baum said in an interview that though there are some PCPs guilty of high spending on low-value services, overall, most primary care physicians’ low-value services add up to only 0.3% of Part B spending. He noted that Part B spending is about one-third of all Medicare spending.

Primary care is often thought to be at the core of care management and spending and PCPs are often seen as the gatekeepers, but this analysis suggests that efforts to make big differences in curtailing low-value spending might be more effective elsewhere.

“There’s only so much spending you can reduce by changing primary care physicians’ services that they directly perform,” Dr. Baum said.
 

Low-value care is costly, can be harmful

Mark Fendrick, MD, director of the University of Michigan’s Center for Value-Based Insurance Design in Ann Arbor, said in an interview that the report adds confirmation to previous research that has consistently shown low-value care is “extremely common, very costly, and provided by primary care providers and specialists alike.” He noted that it can also be harmful.

“The math is simple,” he said. “If we want to improve coverage and lower patient costs for essential services like visits, diagnostic tests, and drugs, we have to reduce spending on those services that do not make Americans any healthier.”

The study ranked 31 clinical services judged to be low value by physician societies, Medicare and clinical guidelines, and their use among beneficiaries enrolled between 2007 and 2014. Here’s how the top six low-value services compare.

Dr. Fendrick said a weakness of the paper is the years of the data (2007-2014). Some of the criteria around low-value care have changed since then. The age that a prostate-specific antigen test becomes low-value is now 70 years, for instance, instead of 75. He added that some of the figures attributed to non-PCP providers appear out of date.

Dr. Fendrick said, “I understand that there are Medicare patients who end up at a gastroenterologist or surgeon’s office to get colorectal cancer screening, but it would be very hard for me to believe that half of stress tests and over half of colon cancer screening over [age] 85 [years] and half of PSA for people over 75 did not have some type of referring clinicians involved. I certainly don’t think that would be the case in 2020-2021.”

Dr. Baum said those years were the latest years available for the data points needed for this analysis, but he and his colleagues were working to update the data for future publication.

Dr. Fendrick said not much has changed in recent years in terms of waste on low-value care, even with campaigns such as Choosing Wisely dedicated to identifying low-value services or procedures in each specialty.

“I believe there’s not a particular group of clinicians one way or the other who are actually doing any better now than they were 7 years ago,” he said. He would rather focus less on which specialties are associated with the most low-value care and more on the underlying policies that encourage low-value care.

“If you’re going to get paid for doing a stress test and get paid nothing or significantly less if you don’t, the incentives are in the wrong direction,” he said.

Dr. Fendrick said the pandemic era provides an opportunity to eliminate low-value care because use of those services has dropped drastically as resources have been diverted to COVID-19 patients and many services have been delayed or canceled.

He said he has been pushing an approach that providers should be paid more after the pandemic “to do the things we want them to do.”

As an example, he said, instead of paying $886 million on colonoscopies for people over the age of 85, “why don’t we put a policy in place that would make it better for patients by lowering cost sharing and better for providers by paying them more to do the service on the people who need it as opposed to the people who don’t?”

The research was funded by the American Board of Family Medicine Foundation. Dr. Baum and a coauthor reported receiving personal fees from American Board of Family Medicine Foundation during the conduct of the study. Another coauthor reported receiving personal fees from Collective Health, HealthRight 360, PLOS Medicine, and the New England Journal of Medicine, outside the submitted work. Dr. Fendrick disclosed no relevant financial relationships.

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

Primary care physicians (PCPs) generate only a small part of the $75 billion to $100 billion wasted every year on low-value care, according to a brief report published online Jan. 18 in Annals of Internal Medicine.

However, one expert said there are better ways to curb low-value care than focusing on which specialties are guilty of the practice.

Analyzing a 20% random sample of Medicare Part B claims, Aaron Baum, PhD, with the Icahn School of Medicine at Mount Sinai, New York, and colleagues found that the services primary care physicians performed or ordered made up on average 8.3% of the low-value care their patients received (interquartile range, 3.9%-15.1%; 95th percentile, 35.6%) and their referrals made up 15.4% (IQR, 6.3%-26.4%; 95th percentile, 44.6%).

By specialty, cardiology had the worst record with 27% of all spending on low-value services ($1.8 billion) attributed to that specialty. Yet, of the 25 highest-spending specialties in the report, 12 of them were associated with 1% or less than 1% each of all low-value spending, indicating the waste was widely distributed.

Dr. Baum said in an interview that though there are some PCPs guilty of high spending on low-value services, overall, most primary care physicians’ low-value services add up to only 0.3% of Part B spending. He noted that Part B spending is about one-third of all Medicare spending.

Primary care is often thought to be at the core of care management and spending and PCPs are often seen as the gatekeepers, but this analysis suggests that efforts to make big differences in curtailing low-value spending might be more effective elsewhere.

“There’s only so much spending you can reduce by changing primary care physicians’ services that they directly perform,” Dr. Baum said.
 

Low-value care is costly, can be harmful

Mark Fendrick, MD, director of the University of Michigan’s Center for Value-Based Insurance Design in Ann Arbor, said in an interview that the report adds confirmation to previous research that has consistently shown low-value care is “extremely common, very costly, and provided by primary care providers and specialists alike.” He noted that it can also be harmful.

“The math is simple,” he said. “If we want to improve coverage and lower patient costs for essential services like visits, diagnostic tests, and drugs, we have to reduce spending on those services that do not make Americans any healthier.”

The study ranked 31 clinical services judged to be low value by physician societies, Medicare and clinical guidelines, and their use among beneficiaries enrolled between 2007 and 2014. Here’s how the top six low-value services compare.

Dr. Fendrick said a weakness of the paper is the years of the data (2007-2014). Some of the criteria around low-value care have changed since then. The age that a prostate-specific antigen test becomes low-value is now 70 years, for instance, instead of 75. He added that some of the figures attributed to non-PCP providers appear out of date.

Dr. Fendrick said, “I understand that there are Medicare patients who end up at a gastroenterologist or surgeon’s office to get colorectal cancer screening, but it would be very hard for me to believe that half of stress tests and over half of colon cancer screening over [age] 85 [years] and half of PSA for people over 75 did not have some type of referring clinicians involved. I certainly don’t think that would be the case in 2020-2021.”

Dr. Baum said those years were the latest years available for the data points needed for this analysis, but he and his colleagues were working to update the data for future publication.

Dr. Fendrick said not much has changed in recent years in terms of waste on low-value care, even with campaigns such as Choosing Wisely dedicated to identifying low-value services or procedures in each specialty.

“I believe there’s not a particular group of clinicians one way or the other who are actually doing any better now than they were 7 years ago,” he said. He would rather focus less on which specialties are associated with the most low-value care and more on the underlying policies that encourage low-value care.

“If you’re going to get paid for doing a stress test and get paid nothing or significantly less if you don’t, the incentives are in the wrong direction,” he said.

Dr. Fendrick said the pandemic era provides an opportunity to eliminate low-value care because use of those services has dropped drastically as resources have been diverted to COVID-19 patients and many services have been delayed or canceled.

He said he has been pushing an approach that providers should be paid more after the pandemic “to do the things we want them to do.”

As an example, he said, instead of paying $886 million on colonoscopies for people over the age of 85, “why don’t we put a policy in place that would make it better for patients by lowering cost sharing and better for providers by paying them more to do the service on the people who need it as opposed to the people who don’t?”

The research was funded by the American Board of Family Medicine Foundation. Dr. Baum and a coauthor reported receiving personal fees from American Board of Family Medicine Foundation during the conduct of the study. Another coauthor reported receiving personal fees from Collective Health, HealthRight 360, PLOS Medicine, and the New England Journal of Medicine, outside the submitted work. Dr. Fendrick disclosed no relevant financial relationships.

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

Primary care physicians (PCPs) generate only a small part of the $75 billion to $100 billion wasted every year on low-value care, according to a brief report published online Jan. 18 in Annals of Internal Medicine.

However, one expert said there are better ways to curb low-value care than focusing on which specialties are guilty of the practice.

Analyzing a 20% random sample of Medicare Part B claims, Aaron Baum, PhD, with the Icahn School of Medicine at Mount Sinai, New York, and colleagues found that the services primary care physicians performed or ordered made up on average 8.3% of the low-value care their patients received (interquartile range, 3.9%-15.1%; 95th percentile, 35.6%) and their referrals made up 15.4% (IQR, 6.3%-26.4%; 95th percentile, 44.6%).

By specialty, cardiology had the worst record with 27% of all spending on low-value services ($1.8 billion) attributed to that specialty. Yet, of the 25 highest-spending specialties in the report, 12 of them were associated with 1% or less than 1% each of all low-value spending, indicating the waste was widely distributed.

Dr. Baum said in an interview that though there are some PCPs guilty of high spending on low-value services, overall, most primary care physicians’ low-value services add up to only 0.3% of Part B spending. He noted that Part B spending is about one-third of all Medicare spending.

Primary care is often thought to be at the core of care management and spending and PCPs are often seen as the gatekeepers, but this analysis suggests that efforts to make big differences in curtailing low-value spending might be more effective elsewhere.

“There’s only so much spending you can reduce by changing primary care physicians’ services that they directly perform,” Dr. Baum said.
 

Low-value care is costly, can be harmful

Mark Fendrick, MD, director of the University of Michigan’s Center for Value-Based Insurance Design in Ann Arbor, said in an interview that the report adds confirmation to previous research that has consistently shown low-value care is “extremely common, very costly, and provided by primary care providers and specialists alike.” He noted that it can also be harmful.

“The math is simple,” he said. “If we want to improve coverage and lower patient costs for essential services like visits, diagnostic tests, and drugs, we have to reduce spending on those services that do not make Americans any healthier.”

The study ranked 31 clinical services judged to be low value by physician societies, Medicare and clinical guidelines, and their use among beneficiaries enrolled between 2007 and 2014. Here’s how the top six low-value services compare.

Dr. Fendrick said a weakness of the paper is the years of the data (2007-2014). Some of the criteria around low-value care have changed since then. The age that a prostate-specific antigen test becomes low-value is now 70 years, for instance, instead of 75. He added that some of the figures attributed to non-PCP providers appear out of date.

Dr. Fendrick said, “I understand that there are Medicare patients who end up at a gastroenterologist or surgeon’s office to get colorectal cancer screening, but it would be very hard for me to believe that half of stress tests and over half of colon cancer screening over [age] 85 [years] and half of PSA for people over 75 did not have some type of referring clinicians involved. I certainly don’t think that would be the case in 2020-2021.”

Dr. Baum said those years were the latest years available for the data points needed for this analysis, but he and his colleagues were working to update the data for future publication.

Dr. Fendrick said not much has changed in recent years in terms of waste on low-value care, even with campaigns such as Choosing Wisely dedicated to identifying low-value services or procedures in each specialty.

“I believe there’s not a particular group of clinicians one way or the other who are actually doing any better now than they were 7 years ago,” he said. He would rather focus less on which specialties are associated with the most low-value care and more on the underlying policies that encourage low-value care.

“If you’re going to get paid for doing a stress test and get paid nothing or significantly less if you don’t, the incentives are in the wrong direction,” he said.

Dr. Fendrick said the pandemic era provides an opportunity to eliminate low-value care because use of those services has dropped drastically as resources have been diverted to COVID-19 patients and many services have been delayed or canceled.

He said he has been pushing an approach that providers should be paid more after the pandemic “to do the things we want them to do.”

As an example, he said, instead of paying $886 million on colonoscopies for people over the age of 85, “why don’t we put a policy in place that would make it better for patients by lowering cost sharing and better for providers by paying them more to do the service on the people who need it as opposed to the people who don’t?”

The research was funded by the American Board of Family Medicine Foundation. Dr. Baum and a coauthor reported receiving personal fees from American Board of Family Medicine Foundation during the conduct of the study. Another coauthor reported receiving personal fees from Collective Health, HealthRight 360, PLOS Medicine, and the New England Journal of Medicine, outside the submitted work. Dr. Fendrick disclosed no relevant financial relationships.

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

Medication overuse headache (MOH), a secondary headache diagnosis, is a prevalent phenomenon that complicates headache diagnosis and treatment, increases the cost of care, and reduces quality of life. Effective abortive medication is essential for the headache sufferer; when an abortive is used too frequently, however, headache frequency increases—potentially beginning a cycle in which the patient then takes more medication to abort the headache. Over time, the patient suffers from an ever-­increasing number of headaches, takes even more abortive medication, and so on. In the presence of MOH, there is a reduction in pain response to preventive and abortive treatments; when medication overuse is eliminated, pain response improves.¹

Although MOH is well recognized among headache specialists, the condition is often overlooked in primary care. Since headache is a top complaint in primary care, however, and prevention is a major goal in family medicine, the opportunity for you to recognize, treat, and prevent MOH is significant. In fact, a randomized controlled trial showed that brief patient education about headache care and MOH provided by a primary care physician can lead to a significant reduction in headache frequency among patients with MOH.²

Although medication overuse headache is well recognized among headache specialists, the condition is often overlooked in primary care.

This article reviews the recognition and diagnosis of MOH, based on historical features and current criteria; addresses risk factors for abortive medication overuse and how to withdraw an offending agent; and explores the value of bridging and preventive therapies to reduce the overall frequency of headache.

IMAGE © ROY SCOTT

What defines MOH?

Typically, MOH is a chronification of a primary headache disorder. However, in patients with a history of migraine who are undergoing treatment for another chronic pain condition with an opioid or other analgesic, MOH can be induced.³ An increase in the frequency of headache raises the specter of a concomitant increase in the level of disability⁴; psychiatric comorbidity⁵; and more headache days, with time lost from school and work.

The Migraine Disability Assessment (MIDAS) questionnaire, a validated instrument that helps the provider (1) measure the impact that headache has on a patient’s life and (2) follow treatment progress, also provides information to employers and insurance companies on treatment coverage and the need for work modification. The MIDAS score is 3 times higher in patients with MOH than in patients with episodic migraine.^6,7

The annual associated cost per person of MOH has been estimated at $4000, resulting in billions of dollars in associated costs⁸; most of these costs are related to absenteeism and disability. After detoxification for MOH, annual outpatient medication costs are reduced by approximately 24%.⁹

Efforts to solve a common problem create another

Headache affects nearly 50% of the general population worldwide,¹⁰ accounting for about 4% of primary care visits¹¹ and approximately 20% of outpatient neurology consultations.¹² Although inpatient stays for headache are approximately half the duration of the overall average hospital stay, headache accounts for 3% of admissions.¹³ According to the Global Burden of Disease study, tension-type headache, migraine, and MOH are the 3 most common headache disorders.¹⁰ Headache is the second leading cause of disability among people 15 to 49 years of age.¹⁰

Continue to: The prevalence of MOH...

The prevalence of MOH in the general population is 2%.^7,14,15 A population-based study showed that the rate of progression from episodic headache (< 15 d/mo) to chronic headache (≥ 15 d/mo) in the general population is 2.5% per year¹⁶; however, progression to chronic headache is 14% per year in patients with medication overuse. One-third of the general population with chronic migraine overuses symptomatic medication; in US headache clinics, roughly one-half of patients with chronic headache overuse acute medication.⁶

Definitions and diagnosis

MOH is a secondary headache diagnosis in the third edition of the International Classification of Headache Disorders (ICHD-3) (TABLE 1),¹⁷ which lists diagnostic criteria for recognized headache disorders.

Terminology. MOH has also been called rebound headache, drug-induced headache, and transformed migraine, but these terms are outdated and are not formal diagnoses. Patients sometimes refer to substance-withdrawal headaches (not discussed in this article) as rebound headaches, so clarity is important when discussing headache with patients: namely, that MOH is an exacerbation of an existing headache condition caused by overuse of abortive headache medications, including analgesics, combination analgesics, triptans, barbiturates, and opioids.

The time it takes to develop medication overuse headache is shortest with triptans, followed by ergots, then analgesics.

MOH was recognized in the early 1950s and fully differentiated as a diagnosis in 2005 in the second edition of the ICHD. The disorder is subcategorized by offending abortive agent (TABLE 2¹⁷) because the frequency of analgesic use required to develop MOH differs by agent.

Risk factors for MOH and chronification of a primary headache ­disorder. There are several risk factors for developing MOH, and others that contribute to increasing headache frequency in general (TABLE 3^5,14,18-23). Some risk factors are common to each. All are important to address because some are modifiable.

Continue to: Pathophysiology

Pathophysiology. The pathophysiology and psychology behind MOH are largely unknown. Physiologic changes in pain processing and functional imaging changes have been demonstrated in patients with MOH, both of which are reversible upon withdrawal of medication.²³ Genetic factors and changes in hormone and neurotransmitter levels are found in MOH patients; this is not the case in patients who have an episodic headache pattern only.²⁴

Presentation. Diagnostic criteria for MOH do not include clinical characteristics. Typically, the phenotype of MOH in a given patient is similar to the underlying primary headache²⁵—although this principle can be complicated to tease out because these medications can suppress some symptoms. Diagnosis of a primary headache disorder should be documented along with the diagnosis of MOH.

Medication overuse can exist without MOH: Not every patient who frequently uses an abortive medication develops MOH.

Treatment is multifaceted—and can become complex

Mainstays of treatment of MOH are education about the disorder and detoxification from the overused agent, although specific treatments can differ depending on the agent involved, the frequency and duration of its use, and a patient’s behavioral patterns and psychiatric comorbidities. Often, a daily medication to prevent headache is considered upon, or after, withdrawal of the offending agent. The timing of introducing a preventive might impact its effectiveness. Some refractory cases require more intensive therapy, including hospitalization at a specialized tertiary center.

But before we look at detoxification from an overused agent, it’s important to review one of the best strategies of all in combatting MOH.

Continue to: First and best strategy

Select an appropriate abortive to reduce the risk of MOH. With regard to specific acute headache medications, some nuances other than type of headache should be considered. Nonsteroidal anti-inflammatory drugs (NSAIDs) are recommended as abortive therapy by the American Headache Society for their efficacy, favorable adverse effect profile, and low cost. NSAIDs are protective against development of MOH if a patient’s baseline headache frequency is < 10/mo; at a frequency of 10 to 14 d/mo, however, the risk of MOH increases when using an NSAID.⁶ A similar effect has been seen with triptans.¹⁶ Longer-acting NSAIDs, such as nabumetone and naproxen, have been proposed as less likely to cause MOH, and are even used as bridging therapy sometimes (as long as neither of these was the overused medication).²⁶

The time it takes to develop MOH is shortest with triptans, followed by ergots, then analgesics.²⁷

Prospective cohort studies^6,16 have shown that barbiturates and opioids are more likely to induce MOH; for that reason, agents in these analgesic classes are almost universally avoided unless no other medically acceptable options exist. Using barbiturate-containing compounds or opioids > 4 d/mo exponentially increases the likelihood of MOH.

Promising preclinical data demonstrate that the gepant, or small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist, class of medications used as abortive therapy does not induce medication overuse cutaneous allodynia.²⁸

Provide education. Primary prevention of MOH involves (1) increasing patients’ awareness of how to take medications appropriately and (2) restricting intake of over-the-counter abortive medications. Often, the expert recommendation is to limit abortives to approximately 2 d/wk because more frequent use places patients at risk of further increased use and subsequent MOH.

Continue to: A randomized controlled trial in Norway...

A randomized controlled trial in Norway compared outcomes in 2 groups of patients with MOH: One group was given advice on the disorder by a physician; the other group was not provided with advice. In the “business-as-usual” group, there was no significant improvement; however, when general practitioners provided simple advice (lasting roughly 9 minutes) about reducing abortive medication use to a safe level and cautioned patients that they would be “feeling worse before feeling better,” headache days were reduced by approximately 8 per month and medication days, by 16 per month.²

A subsequent, long-term follow-up study²⁹ of patients from the Norway trial² who had been given advice and education showed a relapse rate (ie, into overuse of headache medication) of only 8% and sustained reduction of headache days and medication use at 16 months.

Offer support and other nondrug interventions. A recent review of 3 studies²³ recommended that extra support for patients from a headache nurse, close follow-up, keeping an electronic diary that provides feedback, and undertaking a short course of psychotherapy can reduce medication overuse and prevent relapse.

If MOH develops, initiate withdrawal, introduce a preventive

Withdraw overused medication. Most current evidence suggests that withdrawal of the offending agent is the most effective factor in reducing headache days and improving quality of life. A randomized controlled trial compared the effects of (1) complete and immediate withdrawal of an abortive medication with (2) reducing its use (ie, limiting intake to 2 d/wk), on headache frequency, disability, and quality of life.³⁰ There was a reduction of headache days in both groups; however, reduction was much greater at 2 months in the complete withdrawal group than in the restricted intake group (respectively, a 41% and a 26% reduction in headache days per month). This effect was sustained at 6 and 12 months in both groups. The study confirmed the results of earlier research^2,15: Abrupt withdrawal leads to reversion to an episodic pattern at 2 to 6 months in approximately 40% to 60% of patients.

More studies are needed to determine the most appropriate treatment course for MOH; however, complete withdrawal of the causative drug is the most important intervention.

Continue to: Consider withdrawal plus preventive treatment

Consider withdrawal plus preventive treatment. Use of sodium valproate, in addition to medication overuse detoxification, led to a significant reduction in headache days and improvement in quality of life at 12 weeks but no difference after 24 weeks, compared with detoxification alone in a randomized, double-blind, placebo-controlled study.³¹

A study of 61 patients showed a larger reduction (by 7.2 d/mo) in headache frequency with any preventive medication in addition to medication withdrawal, compared to withdrawal alone (by 4.1 d/mo) after 3 months; however, the relative benefit was gone at 6 months.³²

A study of 98 patients compared immediate and delayed initiation of preventive medication upon withdrawal of overused abortive medication.³³ Response was defined as a > 50% reduction in headache frequency and was similar in both groups; results showed a 28% response with immediate initiation of a preventive; a 23% response with delayed (ie, 2 months after withdrawal) initiation; and a 48% response in both groups at 12 months.

Collectively, these studies suggest that adding a preventive medication at the time of withdrawal has the potential to reduce headache frequency more quickly than withdrawal alone. However, after 3 to 6 months, the outcome of reduced headache frequency is the same whether or not a preventive medication is used—as long as the offending agent has been withdrawn.

Do preventives work without withdrawing overused medication? Patients with MOH often show little or no improvement with addition of a preventive medication only; their response to a preventive improves after withdrawal of the overused medication. Patients without previous headache improvement after addition of a preventive, who also did not improve 2 months after withdrawal, then demonstrated an overall reduction in headache by 26% when a preventive was reintroduced after withdrawal.²

Continue to: The research evidence for preventives

The research evidence for preventives. Medications for headache prevention have not been extensively evaluated specifically for treating MOH. Here is what’s known:

• Flunarizine, amitriptyline, and beta-blockers usually are ineffective for MOH.²⁴
• Results for topiramate are mixed: A small, double-blind, placebo-controlled chronic migraine study in Europe showed that, in a subgroup of patients with MOH, topiramate led to a small but significant reduction (3.5 d/mo) in headache frequency, compared to placebo.²⁷ A similar study done in the United States did not show a significant difference between the active-treatment and placebo groups.³⁴
• Findings regarding onabotulinumtoxinA are intriguing: In a posthoc analysis of onabotulinumtoxinA to treat chronic migraine, patients with MOH who did not undergo detoxification had an 8 d/mo greater reduction in headache, compared to placebo.³⁵ However, when compared to placebo in conjunction with detoxification, onabotulinumtoxinA demonstrated no benefit.³⁶
• Newer CGRP antagonist and CGRP receptor antagonist monoclonal antibodies are successful preventive medications that have demonstrated a reduction in acute medication use days per month and headache days per month³⁷; these compounds have not been compared to withdrawal alone.

Reducing the severity and duration of withdrawal symptoms

Withdrawal from overused abortive headache medications can lead to worsening headache, nausea, vomiting, hypotension, tachycardia, sleep disturbances, restlessness, anxiety, and nervousness. Symptoms usually last 2 to 10 days but can persist for as long as 4 weeks; duration of withdrawal symptoms varies with the medication that is being overused. In patients who have used a triptan, for example, mean duration of withdrawal is 4.1 days; ergotamine, 6.7 days; and NSAIDs, 9.5 days.²³ Tapered withdrawal is sometimes recommended with opioids and barbiturates to reduce withdrawal symptoms. It is unclear whether starting a preventive medication during withdrawal assists in reducing withdrawal symptoms.³⁸

Bridging therapy to reduce symptoms of withdrawal is often provided despite debatable utility. Available evidence does not favor one agent or method but suggests some strategies that could be helpful:

• A prednisone taper has a potential role during the first 6 days of withdrawal by reducing rebound headache and withdrawal symptoms³⁹; however, oral prednisolone has been shown to have no benefit.⁴⁰
• Alone, IV methylprednisolone seems not to be of benefit; however, in a retrospective study of 94 patients, IV methylprednisolone plus diazepam for 5 days led to a significant reduction in headache frequency and drug consumption that was sustained after 3 months.⁴¹
• Celecoxib was compared to prednisone over a 20-day course: a celecoxib dosage of 400 mg/d for the first 5 days, tapered by 100 mg every 5 days, and an oral prednisone dosage of 75 mg/d for the first 5 days, then tapered every 5 days. Patients taking celecoxib had lower headache intensity but there was no difference in headache frequency and acute medication intake between the groups.⁴²

Other strategies. Using antiemetics and NSAIDs to reduce withdrawal symptoms is widely practiced, but no placebo-­controlled trials have been conducted to support this strategy.

Reduce the risk of medication overuse headache by selecting an appropriate abortive; NSAIDs are recommended for their efficacy, favorable adverse effect profile, and low cost.

Patients in withdrawal might be more likely to benefit from inpatient care if they have a severe comorbidity, such as opioid or barbiturate use; failure to respond to, tolerate, or adhere to treatment; or relapse after withdrawal.³⁸

Continue to: Cognitive behavioral therapy...

Cognitive behavioral therapy, exercise, a headache diary, and biofeedback should be considered in every patient’s treatment strategy because a multidisciplinary approach increases adherence and leads to improvement in headache frequency and a decrease in disability and medication use.⁴³

Predictors of Tx success

A prospective cohort study determined that the rate of MOH relapse is 31% at 6 months, 41% at 1 year, and 45% at 4 years, with the highest risk of relapse during the first year.⁴⁴ Looking at the correlation between type of medication overused and relapse rate, the research indicates that

• triptans have the lowest risk of relapse,⁴⁴
• simple analgesics have a higher risk of relapse than triptans,^22,44 and
• opioids have the highest risk of relapse.²²

Where the data don’t agree. Data on combination analgesics and on ergots are conflicting.²² In addition, data on whether the primary type of headache predicts relapse rate conflict; however, migraine might predict a better outcome than tension-type headache.²²

To recap and expand: Management pearls

The major goals of headache management generally are to rule out secondary headache, reach a correct diagnosis, reduce overall headache frequency, and provide effective abortive medication. A large component of reducing headache frequency is addressing and treating medication overuse.

Seek to understand the nature of the patient’s headache disorder. Components of the history are key in identifying the underlying headache diagnosis and ruling out other, more concerning secondary headache diagnoses. The ICHD-3 is an excellent resource for treating headache disorders because the classification lists specific diagnostic criteria for all recognized headache diagnoses.

Continue to: Medication withdrawal...

Medication withdrawal—with or without preventive medication—should reduce the frequency of MOH in 2 or 3 months. If headache does not become less frequent, however, the headache diagnosis might need to be reconsidered. Minimizing the use of abortive medication is generally recommended, but reduction or withdrawal of these medications does not guarantee that patients will revert to an episodic pattern of headache.

Inpatient care of withdrawal might be beneficial when a patient has a severe comorbidity; does not respond to, tolerate, or adhere to treatment; or relapses after withdrawal.

Treating withdrawal symptoms is a reasonable approach in some patients, but evidence does not support routinely providing bridging therapy.

Apply preventives carefully. Abortive medication withdrawal should generally be completed before initiating preventive medication; however, over the short term, starting preventive therapy while withdrawing the overused medication could assist in reducing headache frequency rapidly. This strategy can put patients at risk of medication adverse effects and using the medications longer than necessary, yet might be reasonable in certain patients, given their comorbidities, risk of relapse, and physician and patient preference. A preventive medication for an individual patient should generally be chosen in line with recommendations of the American Academy of Neurology⁴⁵ and on the basis of the history and comorbidities.

Provide education, which is essential to lowering barriers to success. Patients with MOH must be counseled to understand that (1) a headache treatment that is supposed to be making them feel better is, in fact, making them feel worse and (2) they will get worse before they get better. Many patients are afraid to be without medication to use as needed. It is helpful to educate them on the different types of treatments (abortive, preventive); how MOH interferes with headache prophylaxis and medication efficacy; how MOH alters brain function (ie, aforementioned physiologic changes in pain processing and functional imaging changes²³); and that such change is reversible when medication is withdrawn.

ACKNOWLEDGEMENT
The author thanks Jeffrey Curtis, MD, MPH, for his support and editing assistance with the manuscript.

CORRESPONDENCE
Allison Crain, MD, 2927 N 7th Avenue, Phoenix, AZ 85013; [email protected].

Medication overuse headache (MOH), a secondary headache diagnosis, is a prevalent phenomenon that complicates headache diagnosis and treatment, increases the cost of care, and reduces quality of life. Effective abortive medication is essential for the headache sufferer; when an abortive is used too frequently, however, headache frequency increases—potentially beginning a cycle in which the patient then takes more medication to abort the headache. Over time, the patient suffers from an ever-­increasing number of headaches, takes even more abortive medication, and so on. In the presence of MOH, there is a reduction in pain response to preventive and abortive treatments; when medication overuse is eliminated, pain response improves.¹

Although MOH is well recognized among headache specialists, the condition is often overlooked in primary care. Since headache is a top complaint in primary care, however, and prevention is a major goal in family medicine, the opportunity for you to recognize, treat, and prevent MOH is significant. In fact, a randomized controlled trial showed that brief patient education about headache care and MOH provided by a primary care physician can lead to a significant reduction in headache frequency among patients with MOH.²

Although medication overuse headache is well recognized among headache specialists, the condition is often overlooked in primary care.

This article reviews the recognition and diagnosis of MOH, based on historical features and current criteria; addresses risk factors for abortive medication overuse and how to withdraw an offending agent; and explores the value of bridging and preventive therapies to reduce the overall frequency of headache.

IMAGE © ROY SCOTT

What defines MOH?

Typically, MOH is a chronification of a primary headache disorder. However, in patients with a history of migraine who are undergoing treatment for another chronic pain condition with an opioid or other analgesic, MOH can be induced.³ An increase in the frequency of headache raises the specter of a concomitant increase in the level of disability⁴; psychiatric comorbidity⁵; and more headache days, with time lost from school and work.

The Migraine Disability Assessment (MIDAS) questionnaire, a validated instrument that helps the provider (1) measure the impact that headache has on a patient’s life and (2) follow treatment progress, also provides information to employers and insurance companies on treatment coverage and the need for work modification. The MIDAS score is 3 times higher in patients with MOH than in patients with episodic migraine.^6,7

The annual associated cost per person of MOH has been estimated at $4000, resulting in billions of dollars in associated costs⁸; most of these costs are related to absenteeism and disability. After detoxification for MOH, annual outpatient medication costs are reduced by approximately 24%.⁹

Efforts to solve a common problem create another

Headache affects nearly 50% of the general population worldwide,¹⁰ accounting for about 4% of primary care visits¹¹ and approximately 20% of outpatient neurology consultations.¹² Although inpatient stays for headache are approximately half the duration of the overall average hospital stay, headache accounts for 3% of admissions.¹³ According to the Global Burden of Disease study, tension-type headache, migraine, and MOH are the 3 most common headache disorders.¹⁰ Headache is the second leading cause of disability among people 15 to 49 years of age.¹⁰

Continue to: The prevalence of MOH...

The prevalence of MOH in the general population is 2%.^7,14,15 A population-based study showed that the rate of progression from episodic headache (< 15 d/mo) to chronic headache (≥ 15 d/mo) in the general population is 2.5% per year¹⁶; however, progression to chronic headache is 14% per year in patients with medication overuse. One-third of the general population with chronic migraine overuses symptomatic medication; in US headache clinics, roughly one-half of patients with chronic headache overuse acute medication.⁶

Definitions and diagnosis

MOH is a secondary headache diagnosis in the third edition of the International Classification of Headache Disorders (ICHD-3) (TABLE 1),¹⁷ which lists diagnostic criteria for recognized headache disorders.

Terminology. MOH has also been called rebound headache, drug-induced headache, and transformed migraine, but these terms are outdated and are not formal diagnoses. Patients sometimes refer to substance-withdrawal headaches (not discussed in this article) as rebound headaches, so clarity is important when discussing headache with patients: namely, that MOH is an exacerbation of an existing headache condition caused by overuse of abortive headache medications, including analgesics, combination analgesics, triptans, barbiturates, and opioids.

The time it takes to develop medication overuse headache is shortest with triptans, followed by ergots, then analgesics.

MOH was recognized in the early 1950s and fully differentiated as a diagnosis in 2005 in the second edition of the ICHD. The disorder is subcategorized by offending abortive agent (TABLE 2¹⁷) because the frequency of analgesic use required to develop MOH differs by agent.

Risk factors for MOH and chronification of a primary headache ­disorder. There are several risk factors for developing MOH, and others that contribute to increasing headache frequency in general (TABLE 3^5,14,18-23). Some risk factors are common to each. All are important to address because some are modifiable.

Continue to: Pathophysiology

Pathophysiology. The pathophysiology and psychology behind MOH are largely unknown. Physiologic changes in pain processing and functional imaging changes have been demonstrated in patients with MOH, both of which are reversible upon withdrawal of medication.²³ Genetic factors and changes in hormone and neurotransmitter levels are found in MOH patients; this is not the case in patients who have an episodic headache pattern only.²⁴

Presentation. Diagnostic criteria for MOH do not include clinical characteristics. Typically, the phenotype of MOH in a given patient is similar to the underlying primary headache²⁵—although this principle can be complicated to tease out because these medications can suppress some symptoms. Diagnosis of a primary headache disorder should be documented along with the diagnosis of MOH.

Medication overuse can exist without MOH: Not every patient who frequently uses an abortive medication develops MOH.

Treatment is multifaceted—and can become complex

Mainstays of treatment of MOH are education about the disorder and detoxification from the overused agent, although specific treatments can differ depending on the agent involved, the frequency and duration of its use, and a patient’s behavioral patterns and psychiatric comorbidities. Often, a daily medication to prevent headache is considered upon, or after, withdrawal of the offending agent. The timing of introducing a preventive might impact its effectiveness. Some refractory cases require more intensive therapy, including hospitalization at a specialized tertiary center.

But before we look at detoxification from an overused agent, it’s important to review one of the best strategies of all in combatting MOH.

Continue to: First and best strategy

Select an appropriate abortive to reduce the risk of MOH. With regard to specific acute headache medications, some nuances other than type of headache should be considered. Nonsteroidal anti-inflammatory drugs (NSAIDs) are recommended as abortive therapy by the American Headache Society for their efficacy, favorable adverse effect profile, and low cost. NSAIDs are protective against development of MOH if a patient’s baseline headache frequency is < 10/mo; at a frequency of 10 to 14 d/mo, however, the risk of MOH increases when using an NSAID.⁶ A similar effect has been seen with triptans.¹⁶ Longer-acting NSAIDs, such as nabumetone and naproxen, have been proposed as less likely to cause MOH, and are even used as bridging therapy sometimes (as long as neither of these was the overused medication).²⁶

The time it takes to develop MOH is shortest with triptans, followed by ergots, then analgesics.²⁷

Prospective cohort studies^6,16 have shown that barbiturates and opioids are more likely to induce MOH; for that reason, agents in these analgesic classes are almost universally avoided unless no other medically acceptable options exist. Using barbiturate-containing compounds or opioids > 4 d/mo exponentially increases the likelihood of MOH.

Promising preclinical data demonstrate that the gepant, or small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist, class of medications used as abortive therapy does not induce medication overuse cutaneous allodynia.²⁸

Provide education. Primary prevention of MOH involves (1) increasing patients’ awareness of how to take medications appropriately and (2) restricting intake of over-the-counter abortive medications. Often, the expert recommendation is to limit abortives to approximately 2 d/wk because more frequent use places patients at risk of further increased use and subsequent MOH.

Continue to: A randomized controlled trial in Norway...

A randomized controlled trial in Norway compared outcomes in 2 groups of patients with MOH: One group was given advice on the disorder by a physician; the other group was not provided with advice. In the “business-as-usual” group, there was no significant improvement; however, when general practitioners provided simple advice (lasting roughly 9 minutes) about reducing abortive medication use to a safe level and cautioned patients that they would be “feeling worse before feeling better,” headache days were reduced by approximately 8 per month and medication days, by 16 per month.²

A subsequent, long-term follow-up study²⁹ of patients from the Norway trial² who had been given advice and education showed a relapse rate (ie, into overuse of headache medication) of only 8% and sustained reduction of headache days and medication use at 16 months.

Offer support and other nondrug interventions. A recent review of 3 studies²³ recommended that extra support for patients from a headache nurse, close follow-up, keeping an electronic diary that provides feedback, and undertaking a short course of psychotherapy can reduce medication overuse and prevent relapse.

If MOH develops, initiate withdrawal, introduce a preventive

Withdraw overused medication. Most current evidence suggests that withdrawal of the offending agent is the most effective factor in reducing headache days and improving quality of life. A randomized controlled trial compared the effects of (1) complete and immediate withdrawal of an abortive medication with (2) reducing its use (ie, limiting intake to 2 d/wk), on headache frequency, disability, and quality of life.³⁰ There was a reduction of headache days in both groups; however, reduction was much greater at 2 months in the complete withdrawal group than in the restricted intake group (respectively, a 41% and a 26% reduction in headache days per month). This effect was sustained at 6 and 12 months in both groups. The study confirmed the results of earlier research^2,15: Abrupt withdrawal leads to reversion to an episodic pattern at 2 to 6 months in approximately 40% to 60% of patients.

More studies are needed to determine the most appropriate treatment course for MOH; however, complete withdrawal of the causative drug is the most important intervention.

Continue to: Consider withdrawal plus preventive treatment

Consider withdrawal plus preventive treatment. Use of sodium valproate, in addition to medication overuse detoxification, led to a significant reduction in headache days and improvement in quality of life at 12 weeks but no difference after 24 weeks, compared with detoxification alone in a randomized, double-blind, placebo-controlled study.³¹

A study of 61 patients showed a larger reduction (by 7.2 d/mo) in headache frequency with any preventive medication in addition to medication withdrawal, compared to withdrawal alone (by 4.1 d/mo) after 3 months; however, the relative benefit was gone at 6 months.³²

A study of 98 patients compared immediate and delayed initiation of preventive medication upon withdrawal of overused abortive medication.³³ Response was defined as a > 50% reduction in headache frequency and was similar in both groups; results showed a 28% response with immediate initiation of a preventive; a 23% response with delayed (ie, 2 months after withdrawal) initiation; and a 48% response in both groups at 12 months.

Collectively, these studies suggest that adding a preventive medication at the time of withdrawal has the potential to reduce headache frequency more quickly than withdrawal alone. However, after 3 to 6 months, the outcome of reduced headache frequency is the same whether or not a preventive medication is used—as long as the offending agent has been withdrawn.

Do preventives work without withdrawing overused medication? Patients with MOH often show little or no improvement with addition of a preventive medication only; their response to a preventive improves after withdrawal of the overused medication. Patients without previous headache improvement after addition of a preventive, who also did not improve 2 months after withdrawal, then demonstrated an overall reduction in headache by 26% when a preventive was reintroduced after withdrawal.²

Continue to: The research evidence for preventives

The research evidence for preventives. Medications for headache prevention have not been extensively evaluated specifically for treating MOH. Here is what’s known:

• Flunarizine, amitriptyline, and beta-blockers usually are ineffective for MOH.²⁴
• Results for topiramate are mixed: A small, double-blind, placebo-controlled chronic migraine study in Europe showed that, in a subgroup of patients with MOH, topiramate led to a small but significant reduction (3.5 d/mo) in headache frequency, compared to placebo.²⁷ A similar study done in the United States did not show a significant difference between the active-treatment and placebo groups.³⁴
• Findings regarding onabotulinumtoxinA are intriguing: In a posthoc analysis of onabotulinumtoxinA to treat chronic migraine, patients with MOH who did not undergo detoxification had an 8 d/mo greater reduction in headache, compared to placebo.³⁵ However, when compared to placebo in conjunction with detoxification, onabotulinumtoxinA demonstrated no benefit.³⁶
• Newer CGRP antagonist and CGRP receptor antagonist monoclonal antibodies are successful preventive medications that have demonstrated a reduction in acute medication use days per month and headache days per month³⁷; these compounds have not been compared to withdrawal alone.

Reducing the severity and duration of withdrawal symptoms

Withdrawal from overused abortive headache medications can lead to worsening headache, nausea, vomiting, hypotension, tachycardia, sleep disturbances, restlessness, anxiety, and nervousness. Symptoms usually last 2 to 10 days but can persist for as long as 4 weeks; duration of withdrawal symptoms varies with the medication that is being overused. In patients who have used a triptan, for example, mean duration of withdrawal is 4.1 days; ergotamine, 6.7 days; and NSAIDs, 9.5 days.²³ Tapered withdrawal is sometimes recommended with opioids and barbiturates to reduce withdrawal symptoms. It is unclear whether starting a preventive medication during withdrawal assists in reducing withdrawal symptoms.³⁸

Bridging therapy to reduce symptoms of withdrawal is often provided despite debatable utility. Available evidence does not favor one agent or method but suggests some strategies that could be helpful:

• A prednisone taper has a potential role during the first 6 days of withdrawal by reducing rebound headache and withdrawal symptoms³⁹; however, oral prednisolone has been shown to have no benefit.⁴⁰
• Alone, IV methylprednisolone seems not to be of benefit; however, in a retrospective study of 94 patients, IV methylprednisolone plus diazepam for 5 days led to a significant reduction in headache frequency and drug consumption that was sustained after 3 months.⁴¹
• Celecoxib was compared to prednisone over a 20-day course: a celecoxib dosage of 400 mg/d for the first 5 days, tapered by 100 mg every 5 days, and an oral prednisone dosage of 75 mg/d for the first 5 days, then tapered every 5 days. Patients taking celecoxib had lower headache intensity but there was no difference in headache frequency and acute medication intake between the groups.⁴²

Other strategies. Using antiemetics and NSAIDs to reduce withdrawal symptoms is widely practiced, but no placebo-­controlled trials have been conducted to support this strategy.

Reduce the risk of medication overuse headache by selecting an appropriate abortive; NSAIDs are recommended for their efficacy, favorable adverse effect profile, and low cost.

Patients in withdrawal might be more likely to benefit from inpatient care if they have a severe comorbidity, such as opioid or barbiturate use; failure to respond to, tolerate, or adhere to treatment; or relapse after withdrawal.³⁸

Continue to: Cognitive behavioral therapy...

Cognitive behavioral therapy, exercise, a headache diary, and biofeedback should be considered in every patient’s treatment strategy because a multidisciplinary approach increases adherence and leads to improvement in headache frequency and a decrease in disability and medication use.⁴³

Predictors of Tx success

A prospective cohort study determined that the rate of MOH relapse is 31% at 6 months, 41% at 1 year, and 45% at 4 years, with the highest risk of relapse during the first year.⁴⁴ Looking at the correlation between type of medication overused and relapse rate, the research indicates that

• triptans have the lowest risk of relapse,⁴⁴
• simple analgesics have a higher risk of relapse than triptans,^22,44 and
• opioids have the highest risk of relapse.²²

Where the data don’t agree. Data on combination analgesics and on ergots are conflicting.²² In addition, data on whether the primary type of headache predicts relapse rate conflict; however, migraine might predict a better outcome than tension-type headache.²²

To recap and expand: Management pearls

The major goals of headache management generally are to rule out secondary headache, reach a correct diagnosis, reduce overall headache frequency, and provide effective abortive medication. A large component of reducing headache frequency is addressing and treating medication overuse.

Seek to understand the nature of the patient’s headache disorder. Components of the history are key in identifying the underlying headache diagnosis and ruling out other, more concerning secondary headache diagnoses. The ICHD-3 is an excellent resource for treating headache disorders because the classification lists specific diagnostic criteria for all recognized headache diagnoses.

Continue to: Medication withdrawal...

Medication withdrawal—with or without preventive medication—should reduce the frequency of MOH in 2 or 3 months. If headache does not become less frequent, however, the headache diagnosis might need to be reconsidered. Minimizing the use of abortive medication is generally recommended, but reduction or withdrawal of these medications does not guarantee that patients will revert to an episodic pattern of headache.

Inpatient care of withdrawal might be beneficial when a patient has a severe comorbidity; does not respond to, tolerate, or adhere to treatment; or relapses after withdrawal.

Treating withdrawal symptoms is a reasonable approach in some patients, but evidence does not support routinely providing bridging therapy.

Apply preventives carefully. Abortive medication withdrawal should generally be completed before initiating preventive medication; however, over the short term, starting preventive therapy while withdrawing the overused medication could assist in reducing headache frequency rapidly. This strategy can put patients at risk of medication adverse effects and using the medications longer than necessary, yet might be reasonable in certain patients, given their comorbidities, risk of relapse, and physician and patient preference. A preventive medication for an individual patient should generally be chosen in line with recommendations of the American Academy of Neurology⁴⁵ and on the basis of the history and comorbidities.

Provide education, which is essential to lowering barriers to success. Patients with MOH must be counseled to understand that (1) a headache treatment that is supposed to be making them feel better is, in fact, making them feel worse and (2) they will get worse before they get better. Many patients are afraid to be without medication to use as needed. It is helpful to educate them on the different types of treatments (abortive, preventive); how MOH interferes with headache prophylaxis and medication efficacy; how MOH alters brain function (ie, aforementioned physiologic changes in pain processing and functional imaging changes²³); and that such change is reversible when medication is withdrawn.

ACKNOWLEDGEMENT
The author thanks Jeffrey Curtis, MD, MPH, for his support and editing assistance with the manuscript.

CORRESPONDENCE
Allison Crain, MD, 2927 N 7th Avenue, Phoenix, AZ 85013; [email protected].

Medication overuse headache (MOH), a secondary headache diagnosis, is a prevalent phenomenon that complicates headache diagnosis and treatment, increases the cost of care, and reduces quality of life. Effective abortive medication is essential for the headache sufferer; when an abortive is used too frequently, however, headache frequency increases—potentially beginning a cycle in which the patient then takes more medication to abort the headache. Over time, the patient suffers from an ever-­increasing number of headaches, takes even more abortive medication, and so on. In the presence of MOH, there is a reduction in pain response to preventive and abortive treatments; when medication overuse is eliminated, pain response improves.¹

Although MOH is well recognized among headache specialists, the condition is often overlooked in primary care. Since headache is a top complaint in primary care, however, and prevention is a major goal in family medicine, the opportunity for you to recognize, treat, and prevent MOH is significant. In fact, a randomized controlled trial showed that brief patient education about headache care and MOH provided by a primary care physician can lead to a significant reduction in headache frequency among patients with MOH.²

Although medication overuse headache is well recognized among headache specialists, the condition is often overlooked in primary care.

This article reviews the recognition and diagnosis of MOH, based on historical features and current criteria; addresses risk factors for abortive medication overuse and how to withdraw an offending agent; and explores the value of bridging and preventive therapies to reduce the overall frequency of headache.

IMAGE © ROY SCOTT

What defines MOH?

Typically, MOH is a chronification of a primary headache disorder. However, in patients with a history of migraine who are undergoing treatment for another chronic pain condition with an opioid or other analgesic, MOH can be induced.³ An increase in the frequency of headache raises the specter of a concomitant increase in the level of disability⁴; psychiatric comorbidity⁵; and more headache days, with time lost from school and work.

The Migraine Disability Assessment (MIDAS) questionnaire, a validated instrument that helps the provider (1) measure the impact that headache has on a patient’s life and (2) follow treatment progress, also provides information to employers and insurance companies on treatment coverage and the need for work modification. The MIDAS score is 3 times higher in patients with MOH than in patients with episodic migraine.^6,7

The annual associated cost per person of MOH has been estimated at $4000, resulting in billions of dollars in associated costs⁸; most of these costs are related to absenteeism and disability. After detoxification for MOH, annual outpatient medication costs are reduced by approximately 24%.⁹

Efforts to solve a common problem create another

Headache affects nearly 50% of the general population worldwide,¹⁰ accounting for about 4% of primary care visits¹¹ and approximately 20% of outpatient neurology consultations.¹² Although inpatient stays for headache are approximately half the duration of the overall average hospital stay, headache accounts for 3% of admissions.¹³ According to the Global Burden of Disease study, tension-type headache, migraine, and MOH are the 3 most common headache disorders.¹⁰ Headache is the second leading cause of disability among people 15 to 49 years of age.¹⁰

Continue to: The prevalence of MOH...

The prevalence of MOH in the general population is 2%.^7,14,15 A population-based study showed that the rate of progression from episodic headache (< 15 d/mo) to chronic headache (≥ 15 d/mo) in the general population is 2.5% per year¹⁶; however, progression to chronic headache is 14% per year in patients with medication overuse. One-third of the general population with chronic migraine overuses symptomatic medication; in US headache clinics, roughly one-half of patients with chronic headache overuse acute medication.⁶

Definitions and diagnosis

MOH is a secondary headache diagnosis in the third edition of the International Classification of Headache Disorders (ICHD-3) (TABLE 1),¹⁷ which lists diagnostic criteria for recognized headache disorders.

Terminology. MOH has also been called rebound headache, drug-induced headache, and transformed migraine, but these terms are outdated and are not formal diagnoses. Patients sometimes refer to substance-withdrawal headaches (not discussed in this article) as rebound headaches, so clarity is important when discussing headache with patients: namely, that MOH is an exacerbation of an existing headache condition caused by overuse of abortive headache medications, including analgesics, combination analgesics, triptans, barbiturates, and opioids.

The time it takes to develop medication overuse headache is shortest with triptans, followed by ergots, then analgesics.

MOH was recognized in the early 1950s and fully differentiated as a diagnosis in 2005 in the second edition of the ICHD. The disorder is subcategorized by offending abortive agent (TABLE 2¹⁷) because the frequency of analgesic use required to develop MOH differs by agent.

Risk factors for MOH and chronification of a primary headache ­disorder. There are several risk factors for developing MOH, and others that contribute to increasing headache frequency in general (TABLE 3^5,14,18-23). Some risk factors are common to each. All are important to address because some are modifiable.

Continue to: Pathophysiology

Pathophysiology. The pathophysiology and psychology behind MOH are largely unknown. Physiologic changes in pain processing and functional imaging changes have been demonstrated in patients with MOH, both of which are reversible upon withdrawal of medication.²³ Genetic factors and changes in hormone and neurotransmitter levels are found in MOH patients; this is not the case in patients who have an episodic headache pattern only.²⁴

Presentation. Diagnostic criteria for MOH do not include clinical characteristics. Typically, the phenotype of MOH in a given patient is similar to the underlying primary headache²⁵—although this principle can be complicated to tease out because these medications can suppress some symptoms. Diagnosis of a primary headache disorder should be documented along with the diagnosis of MOH.

Medication overuse can exist without MOH: Not every patient who frequently uses an abortive medication develops MOH.

Treatment is multifaceted—and can become complex

Mainstays of treatment of MOH are education about the disorder and detoxification from the overused agent, although specific treatments can differ depending on the agent involved, the frequency and duration of its use, and a patient’s behavioral patterns and psychiatric comorbidities. Often, a daily medication to prevent headache is considered upon, or after, withdrawal of the offending agent. The timing of introducing a preventive might impact its effectiveness. Some refractory cases require more intensive therapy, including hospitalization at a specialized tertiary center.

But before we look at detoxification from an overused agent, it’s important to review one of the best strategies of all in combatting MOH.

Continue to: First and best strategy

Select an appropriate abortive to reduce the risk of MOH. With regard to specific acute headache medications, some nuances other than type of headache should be considered. Nonsteroidal anti-inflammatory drugs (NSAIDs) are recommended as abortive therapy by the American Headache Society for their efficacy, favorable adverse effect profile, and low cost. NSAIDs are protective against development of MOH if a patient’s baseline headache frequency is < 10/mo; at a frequency of 10 to 14 d/mo, however, the risk of MOH increases when using an NSAID.⁶ A similar effect has been seen with triptans.¹⁶ Longer-acting NSAIDs, such as nabumetone and naproxen, have been proposed as less likely to cause MOH, and are even used as bridging therapy sometimes (as long as neither of these was the overused medication).²⁶

The time it takes to develop MOH is shortest with triptans, followed by ergots, then analgesics.²⁷

Prospective cohort studies^6,16 have shown that barbiturates and opioids are more likely to induce MOH; for that reason, agents in these analgesic classes are almost universally avoided unless no other medically acceptable options exist. Using barbiturate-containing compounds or opioids > 4 d/mo exponentially increases the likelihood of MOH.

Promising preclinical data demonstrate that the gepant, or small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist, class of medications used as abortive therapy does not induce medication overuse cutaneous allodynia.²⁸

Provide education. Primary prevention of MOH involves (1) increasing patients’ awareness of how to take medications appropriately and (2) restricting intake of over-the-counter abortive medications. Often, the expert recommendation is to limit abortives to approximately 2 d/wk because more frequent use places patients at risk of further increased use and subsequent MOH.

Continue to: A randomized controlled trial in Norway...

A randomized controlled trial in Norway compared outcomes in 2 groups of patients with MOH: One group was given advice on the disorder by a physician; the other group was not provided with advice. In the “business-as-usual” group, there was no significant improvement; however, when general practitioners provided simple advice (lasting roughly 9 minutes) about reducing abortive medication use to a safe level and cautioned patients that they would be “feeling worse before feeling better,” headache days were reduced by approximately 8 per month and medication days, by 16 per month.²

A subsequent, long-term follow-up study²⁹ of patients from the Norway trial² who had been given advice and education showed a relapse rate (ie, into overuse of headache medication) of only 8% and sustained reduction of headache days and medication use at 16 months.

Offer support and other nondrug interventions. A recent review of 3 studies²³ recommended that extra support for patients from a headache nurse, close follow-up, keeping an electronic diary that provides feedback, and undertaking a short course of psychotherapy can reduce medication overuse and prevent relapse.

If MOH develops, initiate withdrawal, introduce a preventive

Withdraw overused medication. Most current evidence suggests that withdrawal of the offending agent is the most effective factor in reducing headache days and improving quality of life. A randomized controlled trial compared the effects of (1) complete and immediate withdrawal of an abortive medication with (2) reducing its use (ie, limiting intake to 2 d/wk), on headache frequency, disability, and quality of life.³⁰ There was a reduction of headache days in both groups; however, reduction was much greater at 2 months in the complete withdrawal group than in the restricted intake group (respectively, a 41% and a 26% reduction in headache days per month). This effect was sustained at 6 and 12 months in both groups. The study confirmed the results of earlier research^2,15: Abrupt withdrawal leads to reversion to an episodic pattern at 2 to 6 months in approximately 40% to 60% of patients.

More studies are needed to determine the most appropriate treatment course for MOH; however, complete withdrawal of the causative drug is the most important intervention.

Continue to: Consider withdrawal plus preventive treatment

Consider withdrawal plus preventive treatment. Use of sodium valproate, in addition to medication overuse detoxification, led to a significant reduction in headache days and improvement in quality of life at 12 weeks but no difference after 24 weeks, compared with detoxification alone in a randomized, double-blind, placebo-controlled study.³¹

A study of 61 patients showed a larger reduction (by 7.2 d/mo) in headache frequency with any preventive medication in addition to medication withdrawal, compared to withdrawal alone (by 4.1 d/mo) after 3 months; however, the relative benefit was gone at 6 months.³²

A study of 98 patients compared immediate and delayed initiation of preventive medication upon withdrawal of overused abortive medication.³³ Response was defined as a > 50% reduction in headache frequency and was similar in both groups; results showed a 28% response with immediate initiation of a preventive; a 23% response with delayed (ie, 2 months after withdrawal) initiation; and a 48% response in both groups at 12 months.

Collectively, these studies suggest that adding a preventive medication at the time of withdrawal has the potential to reduce headache frequency more quickly than withdrawal alone. However, after 3 to 6 months, the outcome of reduced headache frequency is the same whether or not a preventive medication is used—as long as the offending agent has been withdrawn.

Do preventives work without withdrawing overused medication? Patients with MOH often show little or no improvement with addition of a preventive medication only; their response to a preventive improves after withdrawal of the overused medication. Patients without previous headache improvement after addition of a preventive, who also did not improve 2 months after withdrawal, then demonstrated an overall reduction in headache by 26% when a preventive was reintroduced after withdrawal.²

Continue to: The research evidence for preventives

The research evidence for preventives. Medications for headache prevention have not been extensively evaluated specifically for treating MOH. Here is what’s known:

• Flunarizine, amitriptyline, and beta-blockers usually are ineffective for MOH.²⁴
• Results for topiramate are mixed: A small, double-blind, placebo-controlled chronic migraine study in Europe showed that, in a subgroup of patients with MOH, topiramate led to a small but significant reduction (3.5 d/mo) in headache frequency, compared to placebo.²⁷ A similar study done in the United States did not show a significant difference between the active-treatment and placebo groups.³⁴
• Findings regarding onabotulinumtoxinA are intriguing: In a posthoc analysis of onabotulinumtoxinA to treat chronic migraine, patients with MOH who did not undergo detoxification had an 8 d/mo greater reduction in headache, compared to placebo.³⁵ However, when compared to placebo in conjunction with detoxification, onabotulinumtoxinA demonstrated no benefit.³⁶
• Newer CGRP antagonist and CGRP receptor antagonist monoclonal antibodies are successful preventive medications that have demonstrated a reduction in acute medication use days per month and headache days per month³⁷; these compounds have not been compared to withdrawal alone.

Reducing the severity and duration of withdrawal symptoms

Withdrawal from overused abortive headache medications can lead to worsening headache, nausea, vomiting, hypotension, tachycardia, sleep disturbances, restlessness, anxiety, and nervousness. Symptoms usually last 2 to 10 days but can persist for as long as 4 weeks; duration of withdrawal symptoms varies with the medication that is being overused. In patients who have used a triptan, for example, mean duration of withdrawal is 4.1 days; ergotamine, 6.7 days; and NSAIDs, 9.5 days.²³ Tapered withdrawal is sometimes recommended with opioids and barbiturates to reduce withdrawal symptoms. It is unclear whether starting a preventive medication during withdrawal assists in reducing withdrawal symptoms.³⁸

Bridging therapy to reduce symptoms of withdrawal is often provided despite debatable utility. Available evidence does not favor one agent or method but suggests some strategies that could be helpful:

• A prednisone taper has a potential role during the first 6 days of withdrawal by reducing rebound headache and withdrawal symptoms³⁹; however, oral prednisolone has been shown to have no benefit.⁴⁰
• Alone, IV methylprednisolone seems not to be of benefit; however, in a retrospective study of 94 patients, IV methylprednisolone plus diazepam for 5 days led to a significant reduction in headache frequency and drug consumption that was sustained after 3 months.⁴¹
• Celecoxib was compared to prednisone over a 20-day course: a celecoxib dosage of 400 mg/d for the first 5 days, tapered by 100 mg every 5 days, and an oral prednisone dosage of 75 mg/d for the first 5 days, then tapered every 5 days. Patients taking celecoxib had lower headache intensity but there was no difference in headache frequency and acute medication intake between the groups.⁴²

Other strategies. Using antiemetics and NSAIDs to reduce withdrawal symptoms is widely practiced, but no placebo-­controlled trials have been conducted to support this strategy.

Reduce the risk of medication overuse headache by selecting an appropriate abortive; NSAIDs are recommended for their efficacy, favorable adverse effect profile, and low cost.

Patients in withdrawal might be more likely to benefit from inpatient care if they have a severe comorbidity, such as opioid or barbiturate use; failure to respond to, tolerate, or adhere to treatment; or relapse after withdrawal.³⁸

Continue to: Cognitive behavioral therapy...

Cognitive behavioral therapy, exercise, a headache diary, and biofeedback should be considered in every patient’s treatment strategy because a multidisciplinary approach increases adherence and leads to improvement in headache frequency and a decrease in disability and medication use.⁴³

Predictors of Tx success

A prospective cohort study determined that the rate of MOH relapse is 31% at 6 months, 41% at 1 year, and 45% at 4 years, with the highest risk of relapse during the first year.⁴⁴ Looking at the correlation between type of medication overused and relapse rate, the research indicates that

• triptans have the lowest risk of relapse,⁴⁴
• simple analgesics have a higher risk of relapse than triptans,^22,44 and
• opioids have the highest risk of relapse.²²

Where the data don’t agree. Data on combination analgesics and on ergots are conflicting.²² In addition, data on whether the primary type of headache predicts relapse rate conflict; however, migraine might predict a better outcome than tension-type headache.²²

To recap and expand: Management pearls

The major goals of headache management generally are to rule out secondary headache, reach a correct diagnosis, reduce overall headache frequency, and provide effective abortive medication. A large component of reducing headache frequency is addressing and treating medication overuse.

Seek to understand the nature of the patient’s headache disorder. Components of the history are key in identifying the underlying headache diagnosis and ruling out other, more concerning secondary headache diagnoses. The ICHD-3 is an excellent resource for treating headache disorders because the classification lists specific diagnostic criteria for all recognized headache diagnoses.

Continue to: Medication withdrawal...

Medication withdrawal—with or without preventive medication—should reduce the frequency of MOH in 2 or 3 months. If headache does not become less frequent, however, the headache diagnosis might need to be reconsidered. Minimizing the use of abortive medication is generally recommended, but reduction or withdrawal of these medications does not guarantee that patients will revert to an episodic pattern of headache.

Inpatient care of withdrawal might be beneficial when a patient has a severe comorbidity; does not respond to, tolerate, or adhere to treatment; or relapses after withdrawal.

Treating withdrawal symptoms is a reasonable approach in some patients, but evidence does not support routinely providing bridging therapy.

Apply preventives carefully. Abortive medication withdrawal should generally be completed before initiating preventive medication; however, over the short term, starting preventive therapy while withdrawing the overused medication could assist in reducing headache frequency rapidly. This strategy can put patients at risk of medication adverse effects and using the medications longer than necessary, yet might be reasonable in certain patients, given their comorbidities, risk of relapse, and physician and patient preference. A preventive medication for an individual patient should generally be chosen in line with recommendations of the American Academy of Neurology⁴⁵ and on the basis of the history and comorbidities.

Provide education, which is essential to lowering barriers to success. Patients with MOH must be counseled to understand that (1) a headache treatment that is supposed to be making them feel better is, in fact, making them feel worse and (2) they will get worse before they get better. Many patients are afraid to be without medication to use as needed. It is helpful to educate them on the different types of treatments (abortive, preventive); how MOH interferes with headache prophylaxis and medication efficacy; how MOH alters brain function (ie, aforementioned physiologic changes in pain processing and functional imaging changes²³); and that such change is reversible when medication is withdrawn.

ACKNOWLEDGEMENT
The author thanks Jeffrey Curtis, MD, MPH, for his support and editing assistance with the manuscript.

CORRESPONDENCE
Allison Crain, MD, 2927 N 7th Avenue, Phoenix, AZ 85013; [email protected].

Peripartum maternal oxygen supplementation does not yield a clinically relevant improvement in umbilical artery gas pH or other neonatal outcomes, reported Nandini Raghuraman, MD, MS, of the Washington University School of Medicine, St. Louis, MO, and her associates.

In a meta-analysis of 16 studies identified between Feb. 18 and April 3, 2020, the investigators sought to determine whether maternal oxygen supplementation during delivery leads to improved measures in umbilical artery (UA) gas and neonatal outcomes. Using data from randomized clinical trials, they compared peripartum oxygen supplementation with room air and examined the link between oxygen delivery during regular labor or planned cesarean delivery (CD) with UA gas measures and other neonatal outcomes.

Altogether, 1,078 patients were randomized to the oxygen group or the room air group. UA pH remained similar between the two groups even after the researchers factored in risk of bias, use of low-flow devices, or FIO₂ below 60%, noted the authors. Oxygen supplementation also appeared to reduce rates of UA pH that were less than 7.2 and increase UA PaO₂ relative to room air during scheduled cesarean deliveries, they added.
 

Considerable interstudy heterogeneity was found

Although marginally lower one-minute Apgar scores were observed in infants whose mothers received oxygen during cesarean delivery, the mean difference between oxygen and room air was less than a point and there were no other statistically significant differences in any secondary outcomes, the authors said. Considerable interstudy heterogeneity was noted across most of the study outcomes.

It is important to note that results pooled from all the studies reviewed indicated an increase in UA PaO₂ but no notable differences in UA pH when oxygen was used. Citing multiple studies included in the review, the authors observed that UA PaO₂ is a “poor estimator of neonatal morbidity” because, when evaluated in cord blood gas, it represents dissolved oxygen and is not an accurate indication of how much oxygen is bound to hemoglobin. For this reason, dissolved oxygen content by itself is not an indication of hypoxia or subpar tissue oxygenation.

“Prolonged tissue hypoxia leads to anaerobic metabolism, resulting in decreased pH, which is why UA pH ultimately serves as a better marker for prediction of neonatal morbidity. An intervention that increases the PaO₂ without concomitantly increasing the pH has limited clinical benefit, particularly because hyperoxemia is associated with production of free radicals and oxidative cell damage in adults and neonates,” they explained.
 

With unproven benefits and potential for risk of harm, prolonged oxygen use should be limited

“A large, adequately powered trial is needed to investigate the effect of maternal oxygen supplementation in response to fetal heart rate tracings on short- and long-term neonatal morbidity,” the authors suggested. For the time being, they cautioned limiting prolonged oxygen use since the benefits are unproven and there is a potential risk of harm.

In a separate interview, Iris Krishna, MD, MPH, FACOG, Emory University, Atlanta, noted, “The use of maternal supplemental oxygen with the intent of improving fetal oxygenation is a common clinical practice. Previous studies on maternal oxygen supplementation during labor have yielded conflicting results; however, there is growing literature suggesting that maternal intrapartum supplemental oxygenation may not provide clinically significant benefit and there may even be potential harm to mother and baby.

“Unique to this meta-analysis is evaluation of maternal oxygen supplementation in the presence or absence of labor, hypothesizing that placental oxygen transfer may be affected by regular uterine contractions. The pooled results suggest that the use of maternal supplemental oxygenation does not result in clinically relevant fetal oxygenation in the presence or absence of labor when compared to room air. A limitation of this meta-analysis is that the use of oxygen in response to nonreassuring fetal tracing was not assessed, the most common clinical indication for maternal oxygen supplementation.

“This study further challenges the practice of maternal intrapartum supplemental oxygen and highlights that we have much to learn about the impact of this practice. More research is needed to assess optimal duration of oxygen supplementation, safety and efficacy of oxygen supplementation, appropriate clinical indications for oxygen supplementation, as well as the long-term neonatal outcomes of in utero hyperoxygenation.“

Dr. Raghuraman reported receiving multiple grants and acknowledged multiple funding sources. Her colleagues and Dr. Krishna had no conflicts of interest to report.

Peripartum maternal oxygen supplementation does not yield a clinically relevant improvement in umbilical artery gas pH or other neonatal outcomes, reported Nandini Raghuraman, MD, MS, of the Washington University School of Medicine, St. Louis, MO, and her associates.

In a meta-analysis of 16 studies identified between Feb. 18 and April 3, 2020, the investigators sought to determine whether maternal oxygen supplementation during delivery leads to improved measures in umbilical artery (UA) gas and neonatal outcomes. Using data from randomized clinical trials, they compared peripartum oxygen supplementation with room air and examined the link between oxygen delivery during regular labor or planned cesarean delivery (CD) with UA gas measures and other neonatal outcomes.

Altogether, 1,078 patients were randomized to the oxygen group or the room air group. UA pH remained similar between the two groups even after the researchers factored in risk of bias, use of low-flow devices, or FIO₂ below 60%, noted the authors. Oxygen supplementation also appeared to reduce rates of UA pH that were less than 7.2 and increase UA PaO₂ relative to room air during scheduled cesarean deliveries, they added.
 

Considerable interstudy heterogeneity was found

Although marginally lower one-minute Apgar scores were observed in infants whose mothers received oxygen during cesarean delivery, the mean difference between oxygen and room air was less than a point and there were no other statistically significant differences in any secondary outcomes, the authors said. Considerable interstudy heterogeneity was noted across most of the study outcomes.

It is important to note that results pooled from all the studies reviewed indicated an increase in UA PaO₂ but no notable differences in UA pH when oxygen was used. Citing multiple studies included in the review, the authors observed that UA PaO₂ is a “poor estimator of neonatal morbidity” because, when evaluated in cord blood gas, it represents dissolved oxygen and is not an accurate indication of how much oxygen is bound to hemoglobin. For this reason, dissolved oxygen content by itself is not an indication of hypoxia or subpar tissue oxygenation.

“Prolonged tissue hypoxia leads to anaerobic metabolism, resulting in decreased pH, which is why UA pH ultimately serves as a better marker for prediction of neonatal morbidity. An intervention that increases the PaO₂ without concomitantly increasing the pH has limited clinical benefit, particularly because hyperoxemia is associated with production of free radicals and oxidative cell damage in adults and neonates,” they explained.
 

With unproven benefits and potential for risk of harm, prolonged oxygen use should be limited

“A large, adequately powered trial is needed to investigate the effect of maternal oxygen supplementation in response to fetal heart rate tracings on short- and long-term neonatal morbidity,” the authors suggested. For the time being, they cautioned limiting prolonged oxygen use since the benefits are unproven and there is a potential risk of harm.

In a separate interview, Iris Krishna, MD, MPH, FACOG, Emory University, Atlanta, noted, “The use of maternal supplemental oxygen with the intent of improving fetal oxygenation is a common clinical practice. Previous studies on maternal oxygen supplementation during labor have yielded conflicting results; however, there is growing literature suggesting that maternal intrapartum supplemental oxygenation may not provide clinically significant benefit and there may even be potential harm to mother and baby.

“Unique to this meta-analysis is evaluation of maternal oxygen supplementation in the presence or absence of labor, hypothesizing that placental oxygen transfer may be affected by regular uterine contractions. The pooled results suggest that the use of maternal supplemental oxygenation does not result in clinically relevant fetal oxygenation in the presence or absence of labor when compared to room air. A limitation of this meta-analysis is that the use of oxygen in response to nonreassuring fetal tracing was not assessed, the most common clinical indication for maternal oxygen supplementation.

“This study further challenges the practice of maternal intrapartum supplemental oxygen and highlights that we have much to learn about the impact of this practice. More research is needed to assess optimal duration of oxygen supplementation, safety and efficacy of oxygen supplementation, appropriate clinical indications for oxygen supplementation, as well as the long-term neonatal outcomes of in utero hyperoxygenation.“

Dr. Raghuraman reported receiving multiple grants and acknowledged multiple funding sources. Her colleagues and Dr. Krishna had no conflicts of interest to report.

Peripartum maternal oxygen supplementation does not yield a clinically relevant improvement in umbilical artery gas pH or other neonatal outcomes, reported Nandini Raghuraman, MD, MS, of the Washington University School of Medicine, St. Louis, MO, and her associates.

In a meta-analysis of 16 studies identified between Feb. 18 and April 3, 2020, the investigators sought to determine whether maternal oxygen supplementation during delivery leads to improved measures in umbilical artery (UA) gas and neonatal outcomes. Using data from randomized clinical trials, they compared peripartum oxygen supplementation with room air and examined the link between oxygen delivery during regular labor or planned cesarean delivery (CD) with UA gas measures and other neonatal outcomes.

Altogether, 1,078 patients were randomized to the oxygen group or the room air group. UA pH remained similar between the two groups even after the researchers factored in risk of bias, use of low-flow devices, or FIO₂ below 60%, noted the authors. Oxygen supplementation also appeared to reduce rates of UA pH that were less than 7.2 and increase UA PaO₂ relative to room air during scheduled cesarean deliveries, they added.
 

Considerable interstudy heterogeneity was found

Although marginally lower one-minute Apgar scores were observed in infants whose mothers received oxygen during cesarean delivery, the mean difference between oxygen and room air was less than a point and there were no other statistically significant differences in any secondary outcomes, the authors said. Considerable interstudy heterogeneity was noted across most of the study outcomes.

It is important to note that results pooled from all the studies reviewed indicated an increase in UA PaO₂ but no notable differences in UA pH when oxygen was used. Citing multiple studies included in the review, the authors observed that UA PaO₂ is a “poor estimator of neonatal morbidity” because, when evaluated in cord blood gas, it represents dissolved oxygen and is not an accurate indication of how much oxygen is bound to hemoglobin. For this reason, dissolved oxygen content by itself is not an indication of hypoxia or subpar tissue oxygenation.

“Prolonged tissue hypoxia leads to anaerobic metabolism, resulting in decreased pH, which is why UA pH ultimately serves as a better marker for prediction of neonatal morbidity. An intervention that increases the PaO₂ without concomitantly increasing the pH has limited clinical benefit, particularly because hyperoxemia is associated with production of free radicals and oxidative cell damage in adults and neonates,” they explained.
 

With unproven benefits and potential for risk of harm, prolonged oxygen use should be limited

“A large, adequately powered trial is needed to investigate the effect of maternal oxygen supplementation in response to fetal heart rate tracings on short- and long-term neonatal morbidity,” the authors suggested. For the time being, they cautioned limiting prolonged oxygen use since the benefits are unproven and there is a potential risk of harm.

In a separate interview, Iris Krishna, MD, MPH, FACOG, Emory University, Atlanta, noted, “The use of maternal supplemental oxygen with the intent of improving fetal oxygenation is a common clinical practice. Previous studies on maternal oxygen supplementation during labor have yielded conflicting results; however, there is growing literature suggesting that maternal intrapartum supplemental oxygenation may not provide clinically significant benefit and there may even be potential harm to mother and baby.

“Unique to this meta-analysis is evaluation of maternal oxygen supplementation in the presence or absence of labor, hypothesizing that placental oxygen transfer may be affected by regular uterine contractions. The pooled results suggest that the use of maternal supplemental oxygenation does not result in clinically relevant fetal oxygenation in the presence or absence of labor when compared to room air. A limitation of this meta-analysis is that the use of oxygen in response to nonreassuring fetal tracing was not assessed, the most common clinical indication for maternal oxygen supplementation.

“This study further challenges the practice of maternal intrapartum supplemental oxygen and highlights that we have much to learn about the impact of this practice. More research is needed to assess optimal duration of oxygen supplementation, safety and efficacy of oxygen supplementation, appropriate clinical indications for oxygen supplementation, as well as the long-term neonatal outcomes of in utero hyperoxygenation.“

Dr. Raghuraman reported receiving multiple grants and acknowledged multiple funding sources. Her colleagues and Dr. Krishna had no conflicts of interest to report.

Most patients with active chronic prurigo nodularis are not satisfied with their treatment, according to a large European survey.

The eye-opening results of the 406-patient, 12-country European patient survey indicate “high levels of disbelief in currently available treatment options and an overall dissatisfaction with treatment,” Manuel P. Pereira, MD, PhD, said in presenting the findings at the annual congress of the European Academy of Dermatology and Venereology.
 

Only 5.3% of patients pronounced themselves “very satisfied” with their treatment. Another 28% were “rather satisfied.”

“Remarkably, almost 10% of patients were not being treated for prurigo despite having active disease,” said Dr. Pereira, a dermatologist at the Center for Chronic Pruritus at University Hospital Münster (Germany).

When survey participants were asked to identify their most important unmet treatment needs, 79.5% named improvement of itch, 57.2% sought improvement in skin lesions, and 30.5% wanted better sleep.

The most widely used treatments were emollients, prescribed in 84.5% of patients; topical steroids, in 55.7%; antihistamines, 55.2%; and phototherapy, 42.1%. Far fewer patients were on more potent medications: Cyclosporine, systemic corticosteroids, or other immunosuppressants were prescribed for 21.9% of patients; gabapentin and related compounds in 17%; and topical immunomodulators in 8.6%. Twenty-three percent of patients were on antidepressants.

None of the available treatment options, all of which are off label, received high marks from patients. For example, only 1 in 10 patients on antihistamines during the last 6 months rated the drugs as effective. Topical immunomodulators were deemed effective by 1.1% of patients with active prurigo nodularis; gabapentinoids by 3.1%; phototherapy by 9.9%; and antidepressants were rated as effective for the chronic skin disease by only 2.3% of patients. The top-rated therapies were topical steroids, deemed effective by 12.8% of patients; systemic immunosuppressants, favored by 12.2%; and emollients, deemed effective by 10.5% of patients, even though more than 80% of survey participants were using them.

Dr. Pereira said the survey results highlight a pressing need for guidelines aimed at improving clinical care for patients with chronic prurigo nodularis. The first-ever such guidelines on the diagnosis and management of this debilitating disease, developed by Dr. Pereira and other members of the International Forum for the Study of Itch (IFSI), were recently published in the journal Itch. The new guidelines advocate a multimodal treatment approach incorporating a combination of topical and systemic therapies.

At present, there is no approved treatment for prurigo nodularis. Given the unmet need, however, the pace of research has quickened. Innovative potential treatments in the developmental pipeline include Janus kinase inhibitors, topical phosphodiesterase-4 inhibitors, systemic opioid receptor modulators, and neurokinin-1 receptor antagonists.

The patient survey was funded by the EADV and carried out by the EADV’s Pruritus Task Force as part of the European Prurigo Project. Dr. Pereira reported receiving research funding from the EADV and the German Research Foundation. He is a paid speaker for AbbVie, Galderma, Menlo Therapeutics (now VYNE Therapeutics), Novartis, and Trevi.

[email protected]

Most patients with active chronic prurigo nodularis are not satisfied with their treatment, according to a large European survey.

The eye-opening results of the 406-patient, 12-country European patient survey indicate “high levels of disbelief in currently available treatment options and an overall dissatisfaction with treatment,” Manuel P. Pereira, MD, PhD, said in presenting the findings at the annual congress of the European Academy of Dermatology and Venereology.
 

Only 5.3% of patients pronounced themselves “very satisfied” with their treatment. Another 28% were “rather satisfied.”

“Remarkably, almost 10% of patients were not being treated for prurigo despite having active disease,” said Dr. Pereira, a dermatologist at the Center for Chronic Pruritus at University Hospital Münster (Germany).

When survey participants were asked to identify their most important unmet treatment needs, 79.5% named improvement of itch, 57.2% sought improvement in skin lesions, and 30.5% wanted better sleep.

The most widely used treatments were emollients, prescribed in 84.5% of patients; topical steroids, in 55.7%; antihistamines, 55.2%; and phototherapy, 42.1%. Far fewer patients were on more potent medications: Cyclosporine, systemic corticosteroids, or other immunosuppressants were prescribed for 21.9% of patients; gabapentin and related compounds in 17%; and topical immunomodulators in 8.6%. Twenty-three percent of patients were on antidepressants.

None of the available treatment options, all of which are off label, received high marks from patients. For example, only 1 in 10 patients on antihistamines during the last 6 months rated the drugs as effective. Topical immunomodulators were deemed effective by 1.1% of patients with active prurigo nodularis; gabapentinoids by 3.1%; phototherapy by 9.9%; and antidepressants were rated as effective for the chronic skin disease by only 2.3% of patients. The top-rated therapies were topical steroids, deemed effective by 12.8% of patients; systemic immunosuppressants, favored by 12.2%; and emollients, deemed effective by 10.5% of patients, even though more than 80% of survey participants were using them.

Dr. Pereira said the survey results highlight a pressing need for guidelines aimed at improving clinical care for patients with chronic prurigo nodularis. The first-ever such guidelines on the diagnosis and management of this debilitating disease, developed by Dr. Pereira and other members of the International Forum for the Study of Itch (IFSI), were recently published in the journal Itch. The new guidelines advocate a multimodal treatment approach incorporating a combination of topical and systemic therapies.

At present, there is no approved treatment for prurigo nodularis. Given the unmet need, however, the pace of research has quickened. Innovative potential treatments in the developmental pipeline include Janus kinase inhibitors, topical phosphodiesterase-4 inhibitors, systemic opioid receptor modulators, and neurokinin-1 receptor antagonists.

The patient survey was funded by the EADV and carried out by the EADV’s Pruritus Task Force as part of the European Prurigo Project. Dr. Pereira reported receiving research funding from the EADV and the German Research Foundation. He is a paid speaker for AbbVie, Galderma, Menlo Therapeutics (now VYNE Therapeutics), Novartis, and Trevi.

[email protected]

Most patients with active chronic prurigo nodularis are not satisfied with their treatment, according to a large European survey.

The eye-opening results of the 406-patient, 12-country European patient survey indicate “high levels of disbelief in currently available treatment options and an overall dissatisfaction with treatment,” Manuel P. Pereira, MD, PhD, said in presenting the findings at the annual congress of the European Academy of Dermatology and Venereology.
 

Only 5.3% of patients pronounced themselves “very satisfied” with their treatment. Another 28% were “rather satisfied.”

“Remarkably, almost 10% of patients were not being treated for prurigo despite having active disease,” said Dr. Pereira, a dermatologist at the Center for Chronic Pruritus at University Hospital Münster (Germany).

When survey participants were asked to identify their most important unmet treatment needs, 79.5% named improvement of itch, 57.2% sought improvement in skin lesions, and 30.5% wanted better sleep.

The most widely used treatments were emollients, prescribed in 84.5% of patients; topical steroids, in 55.7%; antihistamines, 55.2%; and phototherapy, 42.1%. Far fewer patients were on more potent medications: Cyclosporine, systemic corticosteroids, or other immunosuppressants were prescribed for 21.9% of patients; gabapentin and related compounds in 17%; and topical immunomodulators in 8.6%. Twenty-three percent of patients were on antidepressants.

None of the available treatment options, all of which are off label, received high marks from patients. For example, only 1 in 10 patients on antihistamines during the last 6 months rated the drugs as effective. Topical immunomodulators were deemed effective by 1.1% of patients with active prurigo nodularis; gabapentinoids by 3.1%; phototherapy by 9.9%; and antidepressants were rated as effective for the chronic skin disease by only 2.3% of patients. The top-rated therapies were topical steroids, deemed effective by 12.8% of patients; systemic immunosuppressants, favored by 12.2%; and emollients, deemed effective by 10.5% of patients, even though more than 80% of survey participants were using them.

Dr. Pereira said the survey results highlight a pressing need for guidelines aimed at improving clinical care for patients with chronic prurigo nodularis. The first-ever such guidelines on the diagnosis and management of this debilitating disease, developed by Dr. Pereira and other members of the International Forum for the Study of Itch (IFSI), were recently published in the journal Itch. The new guidelines advocate a multimodal treatment approach incorporating a combination of topical and systemic therapies.

At present, there is no approved treatment for prurigo nodularis. Given the unmet need, however, the pace of research has quickened. Innovative potential treatments in the developmental pipeline include Janus kinase inhibitors, topical phosphodiesterase-4 inhibitors, systemic opioid receptor modulators, and neurokinin-1 receptor antagonists.

The patient survey was funded by the EADV and carried out by the EADV’s Pruritus Task Force as part of the European Prurigo Project. Dr. Pereira reported receiving research funding from the EADV and the German Research Foundation. He is a paid speaker for AbbVie, Galderma, Menlo Therapeutics (now VYNE Therapeutics), Novartis, and Trevi.

[email protected]

Background: Currently the recommended duration of antibiotic therapy for native joint bacterial arthritis is 3-6 weeks based on expert opinion.

Study design: Prospective, unblinded, randomized, noninferiority.

Setting: Single center in Geneva.

Synopsis: In total, 154 patients were randomized to either 2 weeks or 4 weeks of antibiotic regimen selected in consultation with infectious disease specialists after surgical drainage of native joint bacterial arthritis.

The study population was 38% women with a median age of 51 years. Sites of infection were majority hand and wrist arthritis (64%). The most frequent pathogen was Staphylococcus aureus (31%) with no methicillin-resistant strains. There was a low incidence of patients with bacteremia (4%) and chronic immune compromise (10%). Antibiotic regimen varied with 13 different initial intravenous regimens and 11 different oral regimens.

The primary study outcome was rate of recurrent infection within 2 years, which was low with only one recurrence in the 2-week arm and two recurrences in the 4-week arm. This difference was well within the 10% noninferiority margin selected by the authors.

The study was underpowered for nonhand and nonwrist cases, limiting generalizability.

Bottom line: Consider a shorter duration of antibiotic therapy after surgical drainage for native joint bacterial arthritis of the hand and wrist in an otherwise healthy patient.

Citation: Gjika E et al. Two weeks versus four weeks of antibiotic therapy after surgical drainage for native joint bacterial arthritis: a prospective, randomized, non-inferiority trial. Ann Rheum Dis. 2019 Aug;78(8):1114-21.

Dr. Zarookian is a hospitalist at Maine Medical Center in Portland and Stephens Memorial Hospital in Norway, Maine.

Background: Currently the recommended duration of antibiotic therapy for native joint bacterial arthritis is 3-6 weeks based on expert opinion.

Study design: Prospective, unblinded, randomized, noninferiority.

Setting: Single center in Geneva.

Synopsis: In total, 154 patients were randomized to either 2 weeks or 4 weeks of antibiotic regimen selected in consultation with infectious disease specialists after surgical drainage of native joint bacterial arthritis.

The study population was 38% women with a median age of 51 years. Sites of infection were majority hand and wrist arthritis (64%). The most frequent pathogen was Staphylococcus aureus (31%) with no methicillin-resistant strains. There was a low incidence of patients with bacteremia (4%) and chronic immune compromise (10%). Antibiotic regimen varied with 13 different initial intravenous regimens and 11 different oral regimens.

The primary study outcome was rate of recurrent infection within 2 years, which was low with only one recurrence in the 2-week arm and two recurrences in the 4-week arm. This difference was well within the 10% noninferiority margin selected by the authors.

The study was underpowered for nonhand and nonwrist cases, limiting generalizability.

Bottom line: Consider a shorter duration of antibiotic therapy after surgical drainage for native joint bacterial arthritis of the hand and wrist in an otherwise healthy patient.

Citation: Gjika E et al. Two weeks versus four weeks of antibiotic therapy after surgical drainage for native joint bacterial arthritis: a prospective, randomized, non-inferiority trial. Ann Rheum Dis. 2019 Aug;78(8):1114-21.

Dr. Zarookian is a hospitalist at Maine Medical Center in Portland and Stephens Memorial Hospital in Norway, Maine.

Background: Currently the recommended duration of antibiotic therapy for native joint bacterial arthritis is 3-6 weeks based on expert opinion.

Study design: Prospective, unblinded, randomized, noninferiority.

Setting: Single center in Geneva.

Synopsis: In total, 154 patients were randomized to either 2 weeks or 4 weeks of antibiotic regimen selected in consultation with infectious disease specialists after surgical drainage of native joint bacterial arthritis.

The study population was 38% women with a median age of 51 years. Sites of infection were majority hand and wrist arthritis (64%). The most frequent pathogen was Staphylococcus aureus (31%) with no methicillin-resistant strains. There was a low incidence of patients with bacteremia (4%) and chronic immune compromise (10%). Antibiotic regimen varied with 13 different initial intravenous regimens and 11 different oral regimens.

The primary study outcome was rate of recurrent infection within 2 years, which was low with only one recurrence in the 2-week arm and two recurrences in the 4-week arm. This difference was well within the 10% noninferiority margin selected by the authors.

The study was underpowered for nonhand and nonwrist cases, limiting generalizability.

Bottom line: Consider a shorter duration of antibiotic therapy after surgical drainage for native joint bacterial arthritis of the hand and wrist in an otherwise healthy patient.

Citation: Gjika E et al. Two weeks versus four weeks of antibiotic therapy after surgical drainage for native joint bacterial arthritis: a prospective, randomized, non-inferiority trial. Ann Rheum Dis. 2019 Aug;78(8):1114-21.

Dr. Zarookian is a hospitalist at Maine Medical Center in Portland and Stephens Memorial Hospital in Norway, Maine.

In addition to sharing this handout (see PDF link) with your patients, Dr. Gupta also recommends advising them to watch the video Hand-washing Steps Using the WHO Technique, which is available at https://youtu.be/IisgnbMfKvI

In addition to sharing this handout (see PDF link) with your patients, Dr. Gupta also recommends advising them to watch the video Hand-washing Steps Using the WHO Technique, which is available at https://youtu.be/IisgnbMfKvI

In addition to sharing this handout (see PDF link) with your patients, Dr. Gupta also recommends advising them to watch the video Hand-washing Steps Using the WHO Technique, which is available at https://youtu.be/IisgnbMfKvI

Evidence on emerging treatments for COVID-19 has been incomplete, often disappointing, and rapidly changing. The concept of a practice-changing press release is as novel as the coronavirus. The pandemic has created an interdependent set of inpatient challenges: keeping up with evolving science and operationalizing clinical workflows, technology, and therapeutics to adapt what we are learning. 

At Dell Medical School, we have created a Therapeutics and Informatics Committee to put evidence into practice in real-time, and below is a brief framework of what we have learned to date:

The COVID-19 disease course can be broken down into 3 stages, and workup and interventions should be targeted to those stages.^1–3

Stage 1 is the viral phase following a median 5-day pre-symptomatic phase from exposure; this is indistinguishable from an influenza-like illness with the typical fever, cough, GI symptoms, and the more specific anosmia, ageusia, and orthostasis.

Stage 2 is the pulmonary phase where patients develop COVID-19 pneumonia and will have diffuse chest infiltrates on imaging. This stage usually represents the tail end of the viral phase prior to recovery, but for the ~15% of patients who present to the hospital needing admission because of hypoxemia (the definition of severe COVID-19, typically 5-7 days from symptom onset) this phase is characterized by elevated inflammatory markers and an exuberant host-immune response.

Stage 3 is the dreaded thrombo-inflammatory phase, which is a late manifestation usually >10 days from symptom onset and appears to be independent of viral replication. The morbidity and mortality associated with COVID-19 is likely a result of diffuse microthrombosis, and critical disease should no longer be thought of as a “cytokine storm,” but as life-threatening organ dysfunction caused by a dysregulated host response to infection. Unlike sepsis, the predominant pathology is not vasodilation and shock, but a hypercoagulable state with diffuse endothelial damage.^4,5

Workup on presentation to the hospital should focus on identifying which phase of illness the patient is in, based on timing of symptom onset, inflammatory markers, and end-organ damage. CBC, CMP, D-dimer, troponin, and CRP are likely sufficient baseline labs in addition to a chest X-ray. There are many risk stratification tools, but to date, the 4C Mortality 4C Deterioration Scores are recommended due to their large derivation cohort and reliance on only 8 practical variables.⁶

Remdesivir and convalescent plasma (CVP) disrupt viral replication in stages 1 and 2 of the illness. Remdesivir has shown efficacy reducing hospital length of stay and a small trend towards decreasing mortality, especially if given within 10 days of symptom onset, although its effectiveness in general use is very small, if it exists at all.^7,8 CVP efficacy has been disappointing and should not be the standard of care: multiple RCTs do not show any clinical benefit, although the Mayo Clinic registry data suggests that high-titer CVP given within 3 days from diagnosis decreases mortality compared to low-titer plasma.^9-11 Monoclonal antibodies are theoretically “supercharged” high-titer CVP, but are approved for outpatient use only. Trials for hospitalized patients requiring oxygen were stopped due to futility. By the time the patient is hospitalized, it is probably too late in the disease course for CVP or monoclonal antibodies to be effective.

Dexamethasone is the only treatment with a proven mortality benefit. The RECOVERY trial showed the greatest mortality benefit (number needed to treat [NNT] of 8) in mechanically ventilated patients > 7 days from symptom onset. While there is a benefit to patients requiring any oxygen (NNT of 35), early administration to patients in the viral phase is associated with higher mortality as corticosteroids can reduce viral clearance.¹² Corticosteroids should therefore be targeted to a therapeutic window to reduce the dysregulated host immune response and treat ARDS in phases 2 and 3; earlier is not necessarily better.

Incidence of venous thromboembolism (VTE) increases linearly with disease severity (one metanalysis showing a rate of 24% in the ICU¹³) and autopsy studies demonstrate diffuse microthrombosis even when VTE was not suspected⁵. Observational studies have shown VTE pharmacoprophylaxis reduces mortality, but the optimal agent, timing, and intensity of regimens is not yet clear.^14-15 A recent press release from the NIH reported that full dose prophylactic anticoagulation in moderately ill patients reduced disease progression and trended toward lower mortality. Interestingly, for critically ill patients requiring high-flow nasal cannula (HFNC) or mechanical ventilation, intensified anticoagulation regiments had potential harm, and enrollment was stopped in this cohort.¹⁶ This announcement is a hopeful sign that intensified anticoagulation regimens can prevent thrombo-inflammation, but until the data of multiple ongoing trials is published it remains expert opinion only.

The most important treatment remains delivering oxygen with fidelity, correcting the much-observed “silent” or “happy hypoxemic.”¹⁷ Given the high mortality associated with mechanical ventilation and that hypoxemia can be out of proportion to respiratory distress, arbitrary thresholds should not be used to decide when to intubate and instead should evaluate work of breathing, hypercapnia, mentation, or progression of end-organ damage rather than a single cutoff.¹⁸ High-flow nasal cannula (HFNC) can correct severe hypoxemia in addition to self-proning, and while there is scant outcomes data for this strategy, it has been adopted widely as ICU capacity is strained nationally. A ventilator can add PEEP for alveolar recruitment or perform the work of breathing for a patient, but a patient will receive 100% FiO2 whether it is delivered through the nares on HFNC or 10 inches lower by an endotracheal tube.

In the absence of a single therapeutic cure or breakthrough, caring for a COVID-19 patient requires the hospital system to instead do a thousand things conscientiously and consistently. This is supportive care: most patients will get better with time and attentive evaluation for end-organ complications like myocarditis, encephalopathy, or pressure ulcers. It requires nursing to patient ratios that allows for this type of vigilance, with shared protocols, order sets, and close communication among team members that provides this support. The treatment of COVID-19 continues to evolve, but as we confront rising hospital volumes nationally, it is important to standardize care for patients throughout each of the 3 stages of illness until we find that single breakthrough.

Dr. Brode is a practicing internal medicine physician at Dell Seton Medical Center and assistant professor in the Department of Internal Medicine at Dell Medical School, both in Austin, Texas. He is a clinician educator who emphasizes knowing the patient as a person first, evidence-based diagnosis, and comprehensive care for the patients who are most vulnerable. This article is part of a series originally published in The Hospital Leader, the official blog of SHM.

References

1. Cummings MJ, et al. Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study. The Lancet. 2020 June 6;395(10239):1763-1770. doi:10.1016/S0140-6736(20)31189-2.

2. Oudkerk M, et al. Diagnosis, prevention, and treatment of thromboembolic complications in COVID-19: Report of the National Institute for Public Health of the Netherlands. Radiology. 2020;297(1):E216-E222. doi:10.1148/radiol.2020201629.

3. Siddiqi HK, and Mehra MR. COVID-19 illness in native and immunosuppressed states: A clinical–therapeutic staging proposal. J Heart Lung Transplant. 2020;39:405-407.

4. Connors JM, and Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood. 2020;135:2033-2040.

5. Ackermann M, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med. 2020 July 9;383:120-128. doi:10.1056/NEJMoa2015432.

6. Knight SR, et al. Risk stratification of patients admitted to hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: Development and validation of the 4C Mortality Score. BMJ. 2020;370:m3339. doi:10.1136/bmj.m3339.

7. Beigel JH, et al. Remdesivir for the treatment of Covid-19 – Final report. N Engl J Med. 2020;383:1813-1826. doi:10.1056/NEJMoa2007764.

8. Repurposed antiviral drugs for COVID-19: Interim WHO SOLIDARITY trial results. medRxiv. 2020;10.15.20209817. doi:10.1101/2020.10.15.20209817.

9. Agarwal A, et al. Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial). BMJ. 2020;371:m3939.

10. Simonovich VA, et al. A randomized trial of convalescent plasma in Covid-19 severe pneumonia. N Engl J Med. 2020 Nov 24. doi:10.1056/NEJMoa2031304.

11. Joyner MJ, et al. Convalescent Plasma Antibody Levels and the Risk of Death from Covid-19. N Engl J Med 2021; 384:1015-1027. doi:10.1056/NEJMoa2031893.

12. The RECOVERY Collaborative Group: Dexamethasone in hospitalized patients with Covid-19 – Preliminary report. N Engl J Med. 2020 July 17. doi:10.1056/NEJMoa2021436.

13. Porfidia A, et al. Venous thromboembolism in patients with COVID-19: Systematic review and meta-analysis. Thromb Res. 2020 Dec;196:67-74.

14. Nadkarni GN, et al. Anticoagulation, mortality, bleeding and pathology among patients hospitalized with COVID-19: A single health system study. J Am Coll Cardiol. 2020 Oct 20;76(16):1815-1826. doi:10.1016/j.jacc.2020.08.041.

15. Paranjpe I, et al. Association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with COVID-19. J Am Coll Cardiol. 2020 Jul 7;76(1):122-124. doi:10.1016/j.jacc.2020.05.001.

16. Full-dose blood thinners decreased need for life support and improved outcome in hospitalized COVID-19 patients. National Institutes of Health. Available at https://www.nih.gov/news-events/news-releases/full-dose-blood-thinners-decreased-need-life-support-improved-outcome-hospitalized-covid-19-patients.

17. Tobin MJ, et al. Why COVID-19 silent hypoxemia is baffling to physicians. Am J Respir Crit Care Med. 2020 Aug 1;202(3):356-360. doi:10.1164/rccm.202006-2157CP.

18. Berlin DA, et al. Severe Covid-19. N Engl J Med. 2020;383:2451-2460. doi:10.1056/NEJMcp2009575.

Evidence on emerging treatments for COVID-19 has been incomplete, often disappointing, and rapidly changing. The concept of a practice-changing press release is as novel as the coronavirus. The pandemic has created an interdependent set of inpatient challenges: keeping up with evolving science and operationalizing clinical workflows, technology, and therapeutics to adapt what we are learning. 

At Dell Medical School, we have created a Therapeutics and Informatics Committee to put evidence into practice in real-time, and below is a brief framework of what we have learned to date:

The COVID-19 disease course can be broken down into 3 stages, and workup and interventions should be targeted to those stages.^1–3

Stage 1 is the viral phase following a median 5-day pre-symptomatic phase from exposure; this is indistinguishable from an influenza-like illness with the typical fever, cough, GI symptoms, and the more specific anosmia, ageusia, and orthostasis.

Stage 2 is the pulmonary phase where patients develop COVID-19 pneumonia and will have diffuse chest infiltrates on imaging. This stage usually represents the tail end of the viral phase prior to recovery, but for the ~15% of patients who present to the hospital needing admission because of hypoxemia (the definition of severe COVID-19, typically 5-7 days from symptom onset) this phase is characterized by elevated inflammatory markers and an exuberant host-immune response.

Stage 3 is the dreaded thrombo-inflammatory phase, which is a late manifestation usually >10 days from symptom onset and appears to be independent of viral replication. The morbidity and mortality associated with COVID-19 is likely a result of diffuse microthrombosis, and critical disease should no longer be thought of as a “cytokine storm,” but as life-threatening organ dysfunction caused by a dysregulated host response to infection. Unlike sepsis, the predominant pathology is not vasodilation and shock, but a hypercoagulable state with diffuse endothelial damage.^4,5

Workup on presentation to the hospital should focus on identifying which phase of illness the patient is in, based on timing of symptom onset, inflammatory markers, and end-organ damage. CBC, CMP, D-dimer, troponin, and CRP are likely sufficient baseline labs in addition to a chest X-ray. There are many risk stratification tools, but to date, the 4C Mortality 4C Deterioration Scores are recommended due to their large derivation cohort and reliance on only 8 practical variables.⁶

Remdesivir and convalescent plasma (CVP) disrupt viral replication in stages 1 and 2 of the illness. Remdesivir has shown efficacy reducing hospital length of stay and a small trend towards decreasing mortality, especially if given within 10 days of symptom onset, although its effectiveness in general use is very small, if it exists at all.^7,8 CVP efficacy has been disappointing and should not be the standard of care: multiple RCTs do not show any clinical benefit, although the Mayo Clinic registry data suggests that high-titer CVP given within 3 days from diagnosis decreases mortality compared to low-titer plasma.^9-11 Monoclonal antibodies are theoretically “supercharged” high-titer CVP, but are approved for outpatient use only. Trials for hospitalized patients requiring oxygen were stopped due to futility. By the time the patient is hospitalized, it is probably too late in the disease course for CVP or monoclonal antibodies to be effective.

Dexamethasone is the only treatment with a proven mortality benefit. The RECOVERY trial showed the greatest mortality benefit (number needed to treat [NNT] of 8) in mechanically ventilated patients > 7 days from symptom onset. While there is a benefit to patients requiring any oxygen (NNT of 35), early administration to patients in the viral phase is associated with higher mortality as corticosteroids can reduce viral clearance.¹² Corticosteroids should therefore be targeted to a therapeutic window to reduce the dysregulated host immune response and treat ARDS in phases 2 and 3; earlier is not necessarily better.

Incidence of venous thromboembolism (VTE) increases linearly with disease severity (one metanalysis showing a rate of 24% in the ICU¹³) and autopsy studies demonstrate diffuse microthrombosis even when VTE was not suspected⁵. Observational studies have shown VTE pharmacoprophylaxis reduces mortality, but the optimal agent, timing, and intensity of regimens is not yet clear.^14-15 A recent press release from the NIH reported that full dose prophylactic anticoagulation in moderately ill patients reduced disease progression and trended toward lower mortality. Interestingly, for critically ill patients requiring high-flow nasal cannula (HFNC) or mechanical ventilation, intensified anticoagulation regiments had potential harm, and enrollment was stopped in this cohort.¹⁶ This announcement is a hopeful sign that intensified anticoagulation regimens can prevent thrombo-inflammation, but until the data of multiple ongoing trials is published it remains expert opinion only.

The most important treatment remains delivering oxygen with fidelity, correcting the much-observed “silent” or “happy hypoxemic.”¹⁷ Given the high mortality associated with mechanical ventilation and that hypoxemia can be out of proportion to respiratory distress, arbitrary thresholds should not be used to decide when to intubate and instead should evaluate work of breathing, hypercapnia, mentation, or progression of end-organ damage rather than a single cutoff.¹⁸ High-flow nasal cannula (HFNC) can correct severe hypoxemia in addition to self-proning, and while there is scant outcomes data for this strategy, it has been adopted widely as ICU capacity is strained nationally. A ventilator can add PEEP for alveolar recruitment or perform the work of breathing for a patient, but a patient will receive 100% FiO2 whether it is delivered through the nares on HFNC or 10 inches lower by an endotracheal tube.

In the absence of a single therapeutic cure or breakthrough, caring for a COVID-19 patient requires the hospital system to instead do a thousand things conscientiously and consistently. This is supportive care: most patients will get better with time and attentive evaluation for end-organ complications like myocarditis, encephalopathy, or pressure ulcers. It requires nursing to patient ratios that allows for this type of vigilance, with shared protocols, order sets, and close communication among team members that provides this support. The treatment of COVID-19 continues to evolve, but as we confront rising hospital volumes nationally, it is important to standardize care for patients throughout each of the 3 stages of illness until we find that single breakthrough.

Dr. Brode is a practicing internal medicine physician at Dell Seton Medical Center and assistant professor in the Department of Internal Medicine at Dell Medical School, both in Austin, Texas. He is a clinician educator who emphasizes knowing the patient as a person first, evidence-based diagnosis, and comprehensive care for the patients who are most vulnerable. This article is part of a series originally published in The Hospital Leader, the official blog of SHM.

References

1. Cummings MJ, et al. Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study. The Lancet. 2020 June 6;395(10239):1763-1770. doi:10.1016/S0140-6736(20)31189-2.

2. Oudkerk M, et al. Diagnosis, prevention, and treatment of thromboembolic complications in COVID-19: Report of the National Institute for Public Health of the Netherlands. Radiology. 2020;297(1):E216-E222. doi:10.1148/radiol.2020201629.

3. Siddiqi HK, and Mehra MR. COVID-19 illness in native and immunosuppressed states: A clinical–therapeutic staging proposal. J Heart Lung Transplant. 2020;39:405-407.

4. Connors JM, and Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood. 2020;135:2033-2040.

5. Ackermann M, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med. 2020 July 9;383:120-128. doi:10.1056/NEJMoa2015432.

6. Knight SR, et al. Risk stratification of patients admitted to hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: Development and validation of the 4C Mortality Score. BMJ. 2020;370:m3339. doi:10.1136/bmj.m3339.

7. Beigel JH, et al. Remdesivir for the treatment of Covid-19 – Final report. N Engl J Med. 2020;383:1813-1826. doi:10.1056/NEJMoa2007764.

8. Repurposed antiviral drugs for COVID-19: Interim WHO SOLIDARITY trial results. medRxiv. 2020;10.15.20209817. doi:10.1101/2020.10.15.20209817.

9. Agarwal A, et al. Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial). BMJ. 2020;371:m3939.

10. Simonovich VA, et al. A randomized trial of convalescent plasma in Covid-19 severe pneumonia. N Engl J Med. 2020 Nov 24. doi:10.1056/NEJMoa2031304.

11. Joyner MJ, et al. Convalescent Plasma Antibody Levels and the Risk of Death from Covid-19. N Engl J Med 2021; 384:1015-1027. doi:10.1056/NEJMoa2031893.

12. The RECOVERY Collaborative Group: Dexamethasone in hospitalized patients with Covid-19 – Preliminary report. N Engl J Med. 2020 July 17. doi:10.1056/NEJMoa2021436.

13. Porfidia A, et al. Venous thromboembolism in patients with COVID-19: Systematic review and meta-analysis. Thromb Res. 2020 Dec;196:67-74.

14. Nadkarni GN, et al. Anticoagulation, mortality, bleeding and pathology among patients hospitalized with COVID-19: A single health system study. J Am Coll Cardiol. 2020 Oct 20;76(16):1815-1826. doi:10.1016/j.jacc.2020.08.041.

15. Paranjpe I, et al. Association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with COVID-19. J Am Coll Cardiol. 2020 Jul 7;76(1):122-124. doi:10.1016/j.jacc.2020.05.001.

16. Full-dose blood thinners decreased need for life support and improved outcome in hospitalized COVID-19 patients. National Institutes of Health. Available at https://www.nih.gov/news-events/news-releases/full-dose-blood-thinners-decreased-need-life-support-improved-outcome-hospitalized-covid-19-patients.

17. Tobin MJ, et al. Why COVID-19 silent hypoxemia is baffling to physicians. Am J Respir Crit Care Med. 2020 Aug 1;202(3):356-360. doi:10.1164/rccm.202006-2157CP.

18. Berlin DA, et al. Severe Covid-19. N Engl J Med. 2020;383:2451-2460. doi:10.1056/NEJMcp2009575.

Evidence on emerging treatments for COVID-19 has been incomplete, often disappointing, and rapidly changing. The concept of a practice-changing press release is as novel as the coronavirus. The pandemic has created an interdependent set of inpatient challenges: keeping up with evolving science and operationalizing clinical workflows, technology, and therapeutics to adapt what we are learning. 

At Dell Medical School, we have created a Therapeutics and Informatics Committee to put evidence into practice in real-time, and below is a brief framework of what we have learned to date:

The COVID-19 disease course can be broken down into 3 stages, and workup and interventions should be targeted to those stages.^1–3

Stage 1 is the viral phase following a median 5-day pre-symptomatic phase from exposure; this is indistinguishable from an influenza-like illness with the typical fever, cough, GI symptoms, and the more specific anosmia, ageusia, and orthostasis.

Stage 2 is the pulmonary phase where patients develop COVID-19 pneumonia and will have diffuse chest infiltrates on imaging. This stage usually represents the tail end of the viral phase prior to recovery, but for the ~15% of patients who present to the hospital needing admission because of hypoxemia (the definition of severe COVID-19, typically 5-7 days from symptom onset) this phase is characterized by elevated inflammatory markers and an exuberant host-immune response.

Stage 3 is the dreaded thrombo-inflammatory phase, which is a late manifestation usually >10 days from symptom onset and appears to be independent of viral replication. The morbidity and mortality associated with COVID-19 is likely a result of diffuse microthrombosis, and critical disease should no longer be thought of as a “cytokine storm,” but as life-threatening organ dysfunction caused by a dysregulated host response to infection. Unlike sepsis, the predominant pathology is not vasodilation and shock, but a hypercoagulable state with diffuse endothelial damage.^4,5

Workup on presentation to the hospital should focus on identifying which phase of illness the patient is in, based on timing of symptom onset, inflammatory markers, and end-organ damage. CBC, CMP, D-dimer, troponin, and CRP are likely sufficient baseline labs in addition to a chest X-ray. There are many risk stratification tools, but to date, the 4C Mortality 4C Deterioration Scores are recommended due to their large derivation cohort and reliance on only 8 practical variables.⁶

Remdesivir and convalescent plasma (CVP) disrupt viral replication in stages 1 and 2 of the illness. Remdesivir has shown efficacy reducing hospital length of stay and a small trend towards decreasing mortality, especially if given within 10 days of symptom onset, although its effectiveness in general use is very small, if it exists at all.^7,8 CVP efficacy has been disappointing and should not be the standard of care: multiple RCTs do not show any clinical benefit, although the Mayo Clinic registry data suggests that high-titer CVP given within 3 days from diagnosis decreases mortality compared to low-titer plasma.^9-11 Monoclonal antibodies are theoretically “supercharged” high-titer CVP, but are approved for outpatient use only. Trials for hospitalized patients requiring oxygen were stopped due to futility. By the time the patient is hospitalized, it is probably too late in the disease course for CVP or monoclonal antibodies to be effective.

Dexamethasone is the only treatment with a proven mortality benefit. The RECOVERY trial showed the greatest mortality benefit (number needed to treat [NNT] of 8) in mechanically ventilated patients > 7 days from symptom onset. While there is a benefit to patients requiring any oxygen (NNT of 35), early administration to patients in the viral phase is associated with higher mortality as corticosteroids can reduce viral clearance.¹² Corticosteroids should therefore be targeted to a therapeutic window to reduce the dysregulated host immune response and treat ARDS in phases 2 and 3; earlier is not necessarily better.

Incidence of venous thromboembolism (VTE) increases linearly with disease severity (one metanalysis showing a rate of 24% in the ICU¹³) and autopsy studies demonstrate diffuse microthrombosis even when VTE was not suspected⁵. Observational studies have shown VTE pharmacoprophylaxis reduces mortality, but the optimal agent, timing, and intensity of regimens is not yet clear.^14-15 A recent press release from the NIH reported that full dose prophylactic anticoagulation in moderately ill patients reduced disease progression and trended toward lower mortality. Interestingly, for critically ill patients requiring high-flow nasal cannula (HFNC) or mechanical ventilation, intensified anticoagulation regiments had potential harm, and enrollment was stopped in this cohort.¹⁶ This announcement is a hopeful sign that intensified anticoagulation regimens can prevent thrombo-inflammation, but until the data of multiple ongoing trials is published it remains expert opinion only.

The most important treatment remains delivering oxygen with fidelity, correcting the much-observed “silent” or “happy hypoxemic.”¹⁷ Given the high mortality associated with mechanical ventilation and that hypoxemia can be out of proportion to respiratory distress, arbitrary thresholds should not be used to decide when to intubate and instead should evaluate work of breathing, hypercapnia, mentation, or progression of end-organ damage rather than a single cutoff.¹⁸ High-flow nasal cannula (HFNC) can correct severe hypoxemia in addition to self-proning, and while there is scant outcomes data for this strategy, it has been adopted widely as ICU capacity is strained nationally. A ventilator can add PEEP for alveolar recruitment or perform the work of breathing for a patient, but a patient will receive 100% FiO2 whether it is delivered through the nares on HFNC or 10 inches lower by an endotracheal tube.

In the absence of a single therapeutic cure or breakthrough, caring for a COVID-19 patient requires the hospital system to instead do a thousand things conscientiously and consistently. This is supportive care: most patients will get better with time and attentive evaluation for end-organ complications like myocarditis, encephalopathy, or pressure ulcers. It requires nursing to patient ratios that allows for this type of vigilance, with shared protocols, order sets, and close communication among team members that provides this support. The treatment of COVID-19 continues to evolve, but as we confront rising hospital volumes nationally, it is important to standardize care for patients throughout each of the 3 stages of illness until we find that single breakthrough.

Dr. Brode is a practicing internal medicine physician at Dell Seton Medical Center and assistant professor in the Department of Internal Medicine at Dell Medical School, both in Austin, Texas. He is a clinician educator who emphasizes knowing the patient as a person first, evidence-based diagnosis, and comprehensive care for the patients who are most vulnerable. This article is part of a series originally published in The Hospital Leader, the official blog of SHM.

References

1. Cummings MJ, et al. Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study. The Lancet. 2020 June 6;395(10239):1763-1770. doi:10.1016/S0140-6736(20)31189-2.

2. Oudkerk M, et al. Diagnosis, prevention, and treatment of thromboembolic complications in COVID-19: Report of the National Institute for Public Health of the Netherlands. Radiology. 2020;297(1):E216-E222. doi:10.1148/radiol.2020201629.

3. Siddiqi HK, and Mehra MR. COVID-19 illness in native and immunosuppressed states: A clinical–therapeutic staging proposal. J Heart Lung Transplant. 2020;39:405-407.

4. Connors JM, and Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood. 2020;135:2033-2040.

5. Ackermann M, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med. 2020 July 9;383:120-128. doi:10.1056/NEJMoa2015432.

6. Knight SR, et al. Risk stratification of patients admitted to hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: Development and validation of the 4C Mortality Score. BMJ. 2020;370:m3339. doi:10.1136/bmj.m3339.

7. Beigel JH, et al. Remdesivir for the treatment of Covid-19 – Final report. N Engl J Med. 2020;383:1813-1826. doi:10.1056/NEJMoa2007764.

8. Repurposed antiviral drugs for COVID-19: Interim WHO SOLIDARITY trial results. medRxiv. 2020;10.15.20209817. doi:10.1101/2020.10.15.20209817.

9. Agarwal A, et al. Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial). BMJ. 2020;371:m3939.

10. Simonovich VA, et al. A randomized trial of convalescent plasma in Covid-19 severe pneumonia. N Engl J Med. 2020 Nov 24. doi:10.1056/NEJMoa2031304.

11. Joyner MJ, et al. Convalescent Plasma Antibody Levels and the Risk of Death from Covid-19. N Engl J Med 2021; 384:1015-1027. doi:10.1056/NEJMoa2031893.

12. The RECOVERY Collaborative Group: Dexamethasone in hospitalized patients with Covid-19 – Preliminary report. N Engl J Med. 2020 July 17. doi:10.1056/NEJMoa2021436.

13. Porfidia A, et al. Venous thromboembolism in patients with COVID-19: Systematic review and meta-analysis. Thromb Res. 2020 Dec;196:67-74.

14. Nadkarni GN, et al. Anticoagulation, mortality, bleeding and pathology among patients hospitalized with COVID-19: A single health system study. J Am Coll Cardiol. 2020 Oct 20;76(16):1815-1826. doi:10.1016/j.jacc.2020.08.041.

15. Paranjpe I, et al. Association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with COVID-19. J Am Coll Cardiol. 2020 Jul 7;76(1):122-124. doi:10.1016/j.jacc.2020.05.001.

16. Full-dose blood thinners decreased need for life support and improved outcome in hospitalized COVID-19 patients. National Institutes of Health. Available at https://www.nih.gov/news-events/news-releases/full-dose-blood-thinners-decreased-need-life-support-improved-outcome-hospitalized-covid-19-patients.

17. Tobin MJ, et al. Why COVID-19 silent hypoxemia is baffling to physicians. Am J Respir Crit Care Med. 2020 Aug 1;202(3):356-360. doi:10.1164/rccm.202006-2157CP.

18. Berlin DA, et al. Severe Covid-19. N Engl J Med. 2020;383:2451-2460. doi:10.1056/NEJMcp2009575.