Autoimmune Diseases

Within the last decade, almost 3000 articles have been published on the role of diet in the prevention and management of dermatologic conditions. Patients are increasingly interested in—and employing—dietary modifications that may influence skin appearance and aid in the treatment of cutaneous disease.¹ It is essential that dermatologists are familiar with existing evidence on the role of diet in dermatology to counsel patients appropriately. Herein, we discuss the compositions of several popular diets and their proposed utility for dermatologic purposes. We highlight the limited literature that exists surrounding this topic and emphasize the need for future, well-designed clinical trials that study the impact of diet on skin disease.

Ketogenic Diet

The ketogenic diet has a macronutrient profile composed of high fat, low to moderate protein, and very low carbohydrates. Nutritional ketosis occurs as the body begins to use free fatty acids (via beta oxidation) as the primary metabolite driving cellular metabolism. It has been suggested that the ketogenic diet may impart beneficial effects on skin disease; however, limited literature exists on the role of nutritional ketosis in the treatment of dermatologic conditions.

Mechanistically, the ketogenic diet decreases the secretion of insulin and insulinlike growth factor 1, resulting in a reduction of circulating androgens and increased activity of the retinoid X receptor.² In acne vulgaris, it has been suggested that the ketogenic diet may be beneficial in decreasing androgen-induced sebum production and the overproliferation of keratinocytes.^2-7 The ketogenic diet is one of the most rapidly effective dietary strategies for normalizing both insulin and androgens, thus it may theoretically be useful for other metabolic and hormone-dependent skin diseases, such as hidradenitis suppurativa.^8,9

The cutaneous manifestations associated with chronic hyperinsulinemia and hyperglycemia are numerous and include acanthosis nigricans, acrochordons, diabetic dermopathy, scleredema diabeticorum, bullosis diabeticorum, keratosis pilaris, and generalized granuloma annulare. There also is an increased risk for bacterial and fungal skin infections associated with hyperglycemic states.¹⁰ The ketogenic diet is an effective nonpharmacologic tool for normalizing serum insulin and glucose levels in most patients and may have utility in the aforementioned conditions.^11,12 In addition to improving insulin sensitivity, it has been used as a dietary strategy for weight loss.^11-15 Because obesity and metabolic syndrome are highly correlated with common skin conditions such as psoriasis, hidradenitis suppurativa, and androgenetic alopecia, there may be a role for employing the ketogenic diet in these patient populations.^16,17

Although robust clinical studies on ketogenic diets in skin disease are lacking, a recent single-arm, open-label clinical trial observed benefit in all 37 drug-naïve, overweight patients with chronic plaque psoriasis who underwent a ketogenic weight loss protocol. Significant reductions in psoriasis area and severity index (PASI) score and dermatology life quality index score were reported (P<.001).¹⁸ Another study of 30 patients with psoriasis found that a 4-week, low-calorie, ketogenic diet resulted in 50% improvement of PASI scores, 10% weight loss, and a reduction in the proinflammatory cytokines IL-1β and IL-2.¹⁹ Despite these results, it is a challenge to tease out if the specific dietary intervention or its associated weight loss was the main driver in these reported improvements in skin disease.

There is mixed evidence on the anti-inflammatory nature of the ketogenic diet, likely due to wide variation in the composition of foods included in individual diets. In many instances, the ketogenic diet is thought to possess considerable antioxidant and anti-inflammatory capabilities. Ketones are known activators of the nuclear factor erythroid 2–related factor 2 pathway, which upregulates the production of glutathione, a major endogenous intracellular antioxidant.²⁰ Additionally, dietary compounds from foods that are encouraged while on the ketogenic diet, such as sulforaphane from broccoli, also are independent activators of nuclear factor erythroid 2–related factor 2.²¹ Ketones are efficiently utilized by mitochondria, which also may result in the decreased production of reactive oxygen species and lower oxidative stress.²² Moreover, the ketone body β-hydroxybutyrate has demonstrated the ability to reduce proinflammatory IL-1β levels via suppression of nucleotide-binding domain-like receptor protein 3 inflammasome activity.^23,24 The activity of IL-1β is known to be elevated in many dermatologic conditions, including juvenile idiopathic arthritis, relapsing polychondritis, Schnitzler syndrome, hidradenitis suppurativa, Behçet disease, and other autoinflammatory syndromes.²⁵ Ketones also have been shown to inhibit the nuclear factor–κB proinflammatory signaling pathway.^22,26,27 Overexpression of IL-1β and aberrant activation of nuclear factor–κB are implicated in a variety of inflammatory, autoimmune, and oncologic cutaneous pathologies. The ketogenic diet may prove to be an effective adjunctive treatment for dermatologists to consider in select patient populations.^23,24,28-30

For patients with keratinocyte carcinomas, the ketogenic diet may offer the aforementioned anti-inflammatory and antioxidant effects, as well as suppression of the mechanistic target of rapamycin, a major regulator of cell metabolism and proliferation.^31,32 Inhibition of mechanistic target of rapamycin activity has been shown to slow tumor growth and reduce the development of squamous cell carcinoma.^25,33,34 The ketogenic diet also may exploit the preferential utilization of glucose exhibited by many types of cancer cells, thereby “starving” the tumor of its primary fuel source.^35,36 In vitro and animal studies in a variety of cancer types have demonstrated that a ketogenic metabolic state—achieved through the ketogenic diet or fasting—can sensitize tumor cells to chemotherapy and radiation while conferring a protective effect to normal cells.^37-40 This recently described phenomenon is known as differential stress resistance, but it has not been studied in keratinocyte malignancies or melanoma to date. Importantly, some basal cell carcinomas and BRAF V600E–mutated melanomas have worsened while on the ketogenic diet, suggesting more data is needed before it can be recommended for all cancer patients.^41,42 Furthermore, other skin conditions such as prurigo pigmentosa have been associated with initiation of the ketogenic diet.⁴³

Low FODMAP Diet

Fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) are short-chain carbohydrates that are poorly absorbed, osmotically active, and rapidly fermented by intestinal bacteria.⁴⁴ The low FODMAP diet has been shown to be efficacious for treatment of irritable bowel syndrome, small intestinal bacterial overgrowth (SIBO), and some cases of inflammatory bowel disease (IBD).^44-49 A low FODMAP diet may have potential implications for several dermatologic conditions.

Rosacea has been associated with various gastrointestinal tract disorders including irritable bowel syndrome, SIBO, and IBD.^50-54 A single study found that patients with rosacea had a 13-fold increased risk for SIBO.^55,56 Treatment of 40 patients with SIBO using rifaximin resulted in complete resolution of rosacea in all patients, with no relapse after a 3-year follow-up period.⁵⁵ Psoriasis also has been associated with SIBO and IBD.^57,58 One small study found that eradication of SIBO in psoriatic patients resulted in improved PASI scores and colorimetric values.⁵⁹

Although the long-term health consequences of the low FODMAP diet are unknown, further research on such dietary interventions for inflammatory skin conditions is warranted given the mounting evidence of a gut-skin connection and the role of the intestinal microbiome in skin health.^50,51

Gluten-Free Diet

Gluten is a protein found in a variety of grains. Although the role of gluten in the pathogenesis of celiac disease and dermatitis herpetiformis is indisputable, the deleterious effects of gluten outside of the context of these diseases remain controversial. There may be a compelling case for eliminating gluten in psoriasis patients with seropositivity for celiac disease. A recent systematic review found a 2.2-fold increased risk for celiac disease in psoriasis patients.⁶⁰ Antigliadin antibody titers also were found to be positively correlated with psoriatic disease severity.⁶¹ In addition, one open-label study found a reduction in PASI scores in 73% of patients with antigliadin antibodies after 3 months on a gluten-free diet compared to those without antibodies; however, the study only included 22 patients.⁶² Several other small studies have yielded similar results^63,64; however, antigliadin antibodies are neither the most sensitive nor specific markers of celiac disease, and additional testing should be completed in any patient who may carry this diagnosis. A survey study by the National Psoriasis Foundation found that the dietary change associated with the greatest skin improvement was removal of gluten and nightshade vegetables in approximately 50% of the 1200 psoriasis patients that responded.⁶⁵ Case reports of various dermatologic conditions including sarcoidosis, vitiligo, alopecia areata, lichen planus, dermatomyositis, pyoderma gangrenosum, erythema nodosum, leukocytoclastic vasculitis, linear IgA bullous dermatosis, and aphthous ulcerations have reportedly improved with a gluten-free diet; however, this should not be used as primary therapy in patients without celiac disease.^66-71 Because gluten-free diets can be expensive and challenging to follow, a formal assessment for celiac disease should be considered before recommendation of this dietary intervention.

Low Histamine Diet

Histamine is a biogenic amine produced by the decarboxylation of the amino acid histidine.⁷² It is found in several foods in varying amounts. Because bacteria can convert histidine into histamine, many fermented and aged foods such as kimchi, sauerkraut, cheese, and red wine contain high levels of histamine. Individuals who have decreased activity of diamine oxidase (DAO), an enzyme that degrades histamine, may be more susceptible to histamine intolerance.⁷² The symptoms of histamine intolerance are numerous and include gastrointestinal tract distress, rhinorrhea and nasal congestion, headache, urticaria, flushing, and pruritus. Histamine intolerance can mimic an IgE-mediated food allergy; however, allergy testing is negative in these patients. Unfortunately, there is no laboratory test for histamine intolerance; a double-blind, placebo-controlled food challenge is considered the gold-standard test.⁷²

As it pertains to dermatology, a low histamine diet may play a role in the treatment of certain patients with atopic dermatitis and chronic spontaneous urticaria. One study reported that 17 of 54 (31.5%) atopic patients had higher basal levels of serum histamine compared to controls.⁷³ Another study found that a histamine-free diet led to improvement in both histamine intolerance symptoms and atopic dermatitis disease severity (SCORing atopic dermatitis) in patients with low DAO activity.⁷⁴ In chronic spontaneous urticaria, a recent systematic review found that in 223 patients placed on a low histamine diet for 3 to 4 weeks, 12% and 44% achieved complete and partial remission, respectively.⁷⁵ Although treatment response based on a patient’s DAO activity level has not been correlated, a diet low in histamine may prove useful for patients with persistent atopic dermatitis and chronic spontaneous urticaria who have negative food allergy tests and report exacerbation of symptoms after ingestion of histamine-rich foods.^76,77

Mediterranean Diet

The Mediterranean diet has been touted as one of the healthiest diets to date, and large randomized clinical trials have demonstrated its effectiveness in weight loss, improving insulin sensitivity, and reducing inflammatory cytokine profiles.^78,79 A major criticism of the Mediterranean diet is that it has considerable ambiguity and lacks a precise definition due to the variability of what is consumed in different Mediterranean regions. Generally, the diet emphasizes high consumption of colorful fruits and vegetables, aromatic herbs and spices, olive oil, nuts, and seafood, as well as modest amounts of dairy, eggs, and red meat.⁸⁰ The anti-inflammatory effects of this diet largely have been attributed to its abundance of polyphenols, carotenoids, monounsaturated fatty acids, and omega-3 polyunsaturated fatty acids (PUFAs).^80,81 Examples of polyphenols include resveratrol in red grapes, quercetin in apples and red onions, and curcumin in turmeric, while examples of carotenoids include lycopene in tomatoes and zeaxanthin in dark leafy greens. Oleic acid is a monounsaturated fatty acid present in high concentrations in olive oil, while eicosapentaenoic acid and docosahexaenoic acid are omega-3 PUFAs predominantly found in fish.⁸²

Unfortunately, rigorous clinical trials regarding the Mediterranean diet as it pertains to dermatology have not been undertaken. Numerous observational studies in patients with psoriasis have suggested that close adherence to the Mediterranean diet was associated with improvement in PASI scores.^83-86 The National Psoriasis Foundation now recommends a trial of the Mediterranean diet in some patients with psoriasis, emphasizing increased dietary intake of olive oil, fish, and vegetables.⁸⁷ Adherence to a Mediterranean diet also has been inversely correlated to the severity of acne vulgaris and hidradenitis suppurativa^88,89; however, these studies failed to account for the multifactorial risk factors associated with these conditions. Mediterranean diets also may impart a chemopreventive effect, supported by a number of in vivo and in vitro studies demonstrating the inhibition and/or reversal of cutaneous DNA damage induced by UV radiation through supplementation with various phytonutrients and omega-3 PUFAs.^81,90-92 Although small case-control studies have found a decreased risk of basal cell carcinoma in those who closely adhered to a Mediterranean diet, more rigorous clinical research is needed.⁹³

Whole-Food, Plant-Based Diet

A whole-food, plant-based (WFPB) diet is another popular dietary approach that consists of eating fruits, vegetables, legumes, nuts, seeds, and grains in their whole natural form.⁹⁴ This diet discourages all animal products, including red meat, seafood, dairy, and eggs. It is similar to a vegan diet except that it eliminates all highly refined carbohydrates, vegetable oils, and other processed foods.⁹⁴ Randomized clinical studies have demonstrated the WFPB diet to be effective in the treatment of obesity and metabolic syndrome.^95,96

A WFPB diet has been shown to increase the antioxidant capacity of cells, lengthen telomeres, and reduce formation of advanced glycation end products.^94,97,98 These benefits may help combat accelerated skin aging, including increased skin permeability, reduced elasticity and hydration, decreased angiogenesis, impaired immune function, and decreased vitamin D synthesis. Accelerated skin aging can result in delayed wound healing and susceptibility to skin tears and ecchymoses and also may promote the development of cutaneous malignancies.⁹⁹ There remains a lack of clinical data studying a properly formulated WFPB diet in the dermatologic setting.

Paleolithic Diet

The paleolithic (Paleo) diet is an increasingly popular way of eating that attempts to mirror what our ancestors may have consumed between 10,000 and 2.5 million years ago.¹⁰⁰ It is similar to the Mediterranean diet but excludes grains, dairy, legumes, and nightshade vegetables. It also calls for elimination of highly processed sugars and oils as well as chemical food additives and preservatives. There is a strict variation of the diet for individuals with autoimmune disease that also excludes eggs, nuts, and seeds, as these can be inflammatory or immunogenic in some patients.^100-106 Other variations of the diet exist, including the ketogenic Paleo diet, pegan (Paleo vegan) diet, and lacto-Paleo diet.¹⁰⁰ An often cited criticism of the Paleo diet is the low intake of calcium and risk for osteoporosis; however, consumption of calcium-rich foods or a calcium supplement can address this concern.¹⁰⁷

Although small clinical studies have found the Paleo diet to be beneficial for various autoimmune diseases, clinical data evaluating the utility of the diet for cutaneous disease is lacking.^108,109 Numerous randomized trials have demonstrated the Paleo diet to be effective for weight loss and improving insulin sensitivity and lipid levels.^110-116 Thus, the Paleo diet may theoretically serve as a viable adjunct dietary approach to the treatment of cutaneous diseases associated with obesity and metabolic derangement.¹¹⁷

Carnivore Diet

Arguably the most controversial and radical diet is the carnivore diet. As the name implies, the carnivore diet is based on consuming solely animal products. A properly structured carnivore diet emphasizes a “nose-to-tail” eating approach where all parts of the animal including the muscle meats, organs, and fat are consumed. Proponents of the diet cite anthropologic evidence from fossil-stable carbon-13/carbon-12 isotope analyses, craniodental features, and numerous other adaptations that indicate increased consumption of meat during human evolution.^118-122 Notably, many early humans ate a carnivore diet, but life span was very short at this time, suggesting the diet may not be as beneficial as has been suggested.

Despite the abundance of anecdotal evidence supporting its use for a variety of chronic conditions, including cutaneous autoimmune disease, there is a virtual absence of high-quality research on the carnivore diet.^123-125

The purported benefits of the carnivore diet may be attributed to the consumption of organ meats that contain highly bioavailable essential vitamins and minerals, such as iron, zinc, copper, selenium, thiamine, niacin, folate, vitamin B₆, vitamin B₁₂, vitamin A, vitamin D, vitamin K, and choline.^126-128 Other dietary compounds that have demonstrated benefit for skin health and are predominantly found in animal foods include carnosine, carnitine, creatine, taurine, coenzyme Q10, and collagen.^129-134 Nevertheless, there is no data to recommend the elimination of antioxidant- and micronutrient-dense plant-based foods. Rigorous clinical research evaluating the efficacy and safety of the carnivore diet in dermatologic patients is needed. A carnivore diet should not be undertaken without the assistance of a dietician who can ensure adequate micronutrient and macronutrient support.

Final Thoughts

The adjunctive role of diet in the treatment of skin disease is expanding and becoming more widely accepted among dermatologists. Unfortunately, there remains a lack of randomized controlled trials confirming the efficacy of various dietary interventions in the dermatologic setting. Although evidence-based dietary recommendations currently are limited, it is important for dermatologists to be aware of the varied and nuanced dietary interventions employed by patients.

Ultimately, dietary recommendations must be personalized, considering a patient’s comorbidities, personal beliefs and preferences, and nutrigenetics. The emerging field of dermatonutrigenomics—the study of how dietary compounds interact with one’s genes to influence skin health—may allow for precise dietary recommendations to be made in dermatologic practice. Direct-to-consumer genetic tests targeted toward dermatology patients are already on the market, but their clinical utility awaits validation.¹ Because nutritional science is a constantly evolving field, becoming familiar with these popular diets will serve both dermatologists and their patients well.

Within the last decade, almost 3000 articles have been published on the role of diet in the prevention and management of dermatologic conditions. Patients are increasingly interested in—and employing—dietary modifications that may influence skin appearance and aid in the treatment of cutaneous disease.¹ It is essential that dermatologists are familiar with existing evidence on the role of diet in dermatology to counsel patients appropriately. Herein, we discuss the compositions of several popular diets and their proposed utility for dermatologic purposes. We highlight the limited literature that exists surrounding this topic and emphasize the need for future, well-designed clinical trials that study the impact of diet on skin disease.

Ketogenic Diet

The ketogenic diet has a macronutrient profile composed of high fat, low to moderate protein, and very low carbohydrates. Nutritional ketosis occurs as the body begins to use free fatty acids (via beta oxidation) as the primary metabolite driving cellular metabolism. It has been suggested that the ketogenic diet may impart beneficial effects on skin disease; however, limited literature exists on the role of nutritional ketosis in the treatment of dermatologic conditions.

Mechanistically, the ketogenic diet decreases the secretion of insulin and insulinlike growth factor 1, resulting in a reduction of circulating androgens and increased activity of the retinoid X receptor.² In acne vulgaris, it has been suggested that the ketogenic diet may be beneficial in decreasing androgen-induced sebum production and the overproliferation of keratinocytes.^2-7 The ketogenic diet is one of the most rapidly effective dietary strategies for normalizing both insulin and androgens, thus it may theoretically be useful for other metabolic and hormone-dependent skin diseases, such as hidradenitis suppurativa.^8,9

The cutaneous manifestations associated with chronic hyperinsulinemia and hyperglycemia are numerous and include acanthosis nigricans, acrochordons, diabetic dermopathy, scleredema diabeticorum, bullosis diabeticorum, keratosis pilaris, and generalized granuloma annulare. There also is an increased risk for bacterial and fungal skin infections associated with hyperglycemic states.¹⁰ The ketogenic diet is an effective nonpharmacologic tool for normalizing serum insulin and glucose levels in most patients and may have utility in the aforementioned conditions.^11,12 In addition to improving insulin sensitivity, it has been used as a dietary strategy for weight loss.^11-15 Because obesity and metabolic syndrome are highly correlated with common skin conditions such as psoriasis, hidradenitis suppurativa, and androgenetic alopecia, there may be a role for employing the ketogenic diet in these patient populations.^16,17

Although robust clinical studies on ketogenic diets in skin disease are lacking, a recent single-arm, open-label clinical trial observed benefit in all 37 drug-naïve, overweight patients with chronic plaque psoriasis who underwent a ketogenic weight loss protocol. Significant reductions in psoriasis area and severity index (PASI) score and dermatology life quality index score were reported (P<.001).¹⁸ Another study of 30 patients with psoriasis found that a 4-week, low-calorie, ketogenic diet resulted in 50% improvement of PASI scores, 10% weight loss, and a reduction in the proinflammatory cytokines IL-1β and IL-2.¹⁹ Despite these results, it is a challenge to tease out if the specific dietary intervention or its associated weight loss was the main driver in these reported improvements in skin disease.

There is mixed evidence on the anti-inflammatory nature of the ketogenic diet, likely due to wide variation in the composition of foods included in individual diets. In many instances, the ketogenic diet is thought to possess considerable antioxidant and anti-inflammatory capabilities. Ketones are known activators of the nuclear factor erythroid 2–related factor 2 pathway, which upregulates the production of glutathione, a major endogenous intracellular antioxidant.²⁰ Additionally, dietary compounds from foods that are encouraged while on the ketogenic diet, such as sulforaphane from broccoli, also are independent activators of nuclear factor erythroid 2–related factor 2.²¹ Ketones are efficiently utilized by mitochondria, which also may result in the decreased production of reactive oxygen species and lower oxidative stress.²² Moreover, the ketone body β-hydroxybutyrate has demonstrated the ability to reduce proinflammatory IL-1β levels via suppression of nucleotide-binding domain-like receptor protein 3 inflammasome activity.^23,24 The activity of IL-1β is known to be elevated in many dermatologic conditions, including juvenile idiopathic arthritis, relapsing polychondritis, Schnitzler syndrome, hidradenitis suppurativa, Behçet disease, and other autoinflammatory syndromes.²⁵ Ketones also have been shown to inhibit the nuclear factor–κB proinflammatory signaling pathway.^22,26,27 Overexpression of IL-1β and aberrant activation of nuclear factor–κB are implicated in a variety of inflammatory, autoimmune, and oncologic cutaneous pathologies. The ketogenic diet may prove to be an effective adjunctive treatment for dermatologists to consider in select patient populations.^23,24,28-30

For patients with keratinocyte carcinomas, the ketogenic diet may offer the aforementioned anti-inflammatory and antioxidant effects, as well as suppression of the mechanistic target of rapamycin, a major regulator of cell metabolism and proliferation.^31,32 Inhibition of mechanistic target of rapamycin activity has been shown to slow tumor growth and reduce the development of squamous cell carcinoma.^25,33,34 The ketogenic diet also may exploit the preferential utilization of glucose exhibited by many types of cancer cells, thereby “starving” the tumor of its primary fuel source.^35,36 In vitro and animal studies in a variety of cancer types have demonstrated that a ketogenic metabolic state—achieved through the ketogenic diet or fasting—can sensitize tumor cells to chemotherapy and radiation while conferring a protective effect to normal cells.^37-40 This recently described phenomenon is known as differential stress resistance, but it has not been studied in keratinocyte malignancies or melanoma to date. Importantly, some basal cell carcinomas and BRAF V600E–mutated melanomas have worsened while on the ketogenic diet, suggesting more data is needed before it can be recommended for all cancer patients.^41,42 Furthermore, other skin conditions such as prurigo pigmentosa have been associated with initiation of the ketogenic diet.⁴³

Low FODMAP Diet

Fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) are short-chain carbohydrates that are poorly absorbed, osmotically active, and rapidly fermented by intestinal bacteria.⁴⁴ The low FODMAP diet has been shown to be efficacious for treatment of irritable bowel syndrome, small intestinal bacterial overgrowth (SIBO), and some cases of inflammatory bowel disease (IBD).^44-49 A low FODMAP diet may have potential implications for several dermatologic conditions.

Rosacea has been associated with various gastrointestinal tract disorders including irritable bowel syndrome, SIBO, and IBD.^50-54 A single study found that patients with rosacea had a 13-fold increased risk for SIBO.^55,56 Treatment of 40 patients with SIBO using rifaximin resulted in complete resolution of rosacea in all patients, with no relapse after a 3-year follow-up period.⁵⁵ Psoriasis also has been associated with SIBO and IBD.^57,58 One small study found that eradication of SIBO in psoriatic patients resulted in improved PASI scores and colorimetric values.⁵⁹

Although the long-term health consequences of the low FODMAP diet are unknown, further research on such dietary interventions for inflammatory skin conditions is warranted given the mounting evidence of a gut-skin connection and the role of the intestinal microbiome in skin health.^50,51

Gluten-Free Diet

Gluten is a protein found in a variety of grains. Although the role of gluten in the pathogenesis of celiac disease and dermatitis herpetiformis is indisputable, the deleterious effects of gluten outside of the context of these diseases remain controversial. There may be a compelling case for eliminating gluten in psoriasis patients with seropositivity for celiac disease. A recent systematic review found a 2.2-fold increased risk for celiac disease in psoriasis patients.⁶⁰ Antigliadin antibody titers also were found to be positively correlated with psoriatic disease severity.⁶¹ In addition, one open-label study found a reduction in PASI scores in 73% of patients with antigliadin antibodies after 3 months on a gluten-free diet compared to those without antibodies; however, the study only included 22 patients.⁶² Several other small studies have yielded similar results^63,64; however, antigliadin antibodies are neither the most sensitive nor specific markers of celiac disease, and additional testing should be completed in any patient who may carry this diagnosis. A survey study by the National Psoriasis Foundation found that the dietary change associated with the greatest skin improvement was removal of gluten and nightshade vegetables in approximately 50% of the 1200 psoriasis patients that responded.⁶⁵ Case reports of various dermatologic conditions including sarcoidosis, vitiligo, alopecia areata, lichen planus, dermatomyositis, pyoderma gangrenosum, erythema nodosum, leukocytoclastic vasculitis, linear IgA bullous dermatosis, and aphthous ulcerations have reportedly improved with a gluten-free diet; however, this should not be used as primary therapy in patients without celiac disease.^66-71 Because gluten-free diets can be expensive and challenging to follow, a formal assessment for celiac disease should be considered before recommendation of this dietary intervention.

Low Histamine Diet

Histamine is a biogenic amine produced by the decarboxylation of the amino acid histidine.⁷² It is found in several foods in varying amounts. Because bacteria can convert histidine into histamine, many fermented and aged foods such as kimchi, sauerkraut, cheese, and red wine contain high levels of histamine. Individuals who have decreased activity of diamine oxidase (DAO), an enzyme that degrades histamine, may be more susceptible to histamine intolerance.⁷² The symptoms of histamine intolerance are numerous and include gastrointestinal tract distress, rhinorrhea and nasal congestion, headache, urticaria, flushing, and pruritus. Histamine intolerance can mimic an IgE-mediated food allergy; however, allergy testing is negative in these patients. Unfortunately, there is no laboratory test for histamine intolerance; a double-blind, placebo-controlled food challenge is considered the gold-standard test.⁷²

As it pertains to dermatology, a low histamine diet may play a role in the treatment of certain patients with atopic dermatitis and chronic spontaneous urticaria. One study reported that 17 of 54 (31.5%) atopic patients had higher basal levels of serum histamine compared to controls.⁷³ Another study found that a histamine-free diet led to improvement in both histamine intolerance symptoms and atopic dermatitis disease severity (SCORing atopic dermatitis) in patients with low DAO activity.⁷⁴ In chronic spontaneous urticaria, a recent systematic review found that in 223 patients placed on a low histamine diet for 3 to 4 weeks, 12% and 44% achieved complete and partial remission, respectively.⁷⁵ Although treatment response based on a patient’s DAO activity level has not been correlated, a diet low in histamine may prove useful for patients with persistent atopic dermatitis and chronic spontaneous urticaria who have negative food allergy tests and report exacerbation of symptoms after ingestion of histamine-rich foods.^76,77

Mediterranean Diet

The Mediterranean diet has been touted as one of the healthiest diets to date, and large randomized clinical trials have demonstrated its effectiveness in weight loss, improving insulin sensitivity, and reducing inflammatory cytokine profiles.^78,79 A major criticism of the Mediterranean diet is that it has considerable ambiguity and lacks a precise definition due to the variability of what is consumed in different Mediterranean regions. Generally, the diet emphasizes high consumption of colorful fruits and vegetables, aromatic herbs and spices, olive oil, nuts, and seafood, as well as modest amounts of dairy, eggs, and red meat.⁸⁰ The anti-inflammatory effects of this diet largely have been attributed to its abundance of polyphenols, carotenoids, monounsaturated fatty acids, and omega-3 polyunsaturated fatty acids (PUFAs).^80,81 Examples of polyphenols include resveratrol in red grapes, quercetin in apples and red onions, and curcumin in turmeric, while examples of carotenoids include lycopene in tomatoes and zeaxanthin in dark leafy greens. Oleic acid is a monounsaturated fatty acid present in high concentrations in olive oil, while eicosapentaenoic acid and docosahexaenoic acid are omega-3 PUFAs predominantly found in fish.⁸²

Unfortunately, rigorous clinical trials regarding the Mediterranean diet as it pertains to dermatology have not been undertaken. Numerous observational studies in patients with psoriasis have suggested that close adherence to the Mediterranean diet was associated with improvement in PASI scores.^83-86 The National Psoriasis Foundation now recommends a trial of the Mediterranean diet in some patients with psoriasis, emphasizing increased dietary intake of olive oil, fish, and vegetables.⁸⁷ Adherence to a Mediterranean diet also has been inversely correlated to the severity of acne vulgaris and hidradenitis suppurativa^88,89; however, these studies failed to account for the multifactorial risk factors associated with these conditions. Mediterranean diets also may impart a chemopreventive effect, supported by a number of in vivo and in vitro studies demonstrating the inhibition and/or reversal of cutaneous DNA damage induced by UV radiation through supplementation with various phytonutrients and omega-3 PUFAs.^81,90-92 Although small case-control studies have found a decreased risk of basal cell carcinoma in those who closely adhered to a Mediterranean diet, more rigorous clinical research is needed.⁹³

Whole-Food, Plant-Based Diet

A whole-food, plant-based (WFPB) diet is another popular dietary approach that consists of eating fruits, vegetables, legumes, nuts, seeds, and grains in their whole natural form.⁹⁴ This diet discourages all animal products, including red meat, seafood, dairy, and eggs. It is similar to a vegan diet except that it eliminates all highly refined carbohydrates, vegetable oils, and other processed foods.⁹⁴ Randomized clinical studies have demonstrated the WFPB diet to be effective in the treatment of obesity and metabolic syndrome.^95,96

A WFPB diet has been shown to increase the antioxidant capacity of cells, lengthen telomeres, and reduce formation of advanced glycation end products.^94,97,98 These benefits may help combat accelerated skin aging, including increased skin permeability, reduced elasticity and hydration, decreased angiogenesis, impaired immune function, and decreased vitamin D synthesis. Accelerated skin aging can result in delayed wound healing and susceptibility to skin tears and ecchymoses and also may promote the development of cutaneous malignancies.⁹⁹ There remains a lack of clinical data studying a properly formulated WFPB diet in the dermatologic setting.

Paleolithic Diet

The paleolithic (Paleo) diet is an increasingly popular way of eating that attempts to mirror what our ancestors may have consumed between 10,000 and 2.5 million years ago.¹⁰⁰ It is similar to the Mediterranean diet but excludes grains, dairy, legumes, and nightshade vegetables. It also calls for elimination of highly processed sugars and oils as well as chemical food additives and preservatives. There is a strict variation of the diet for individuals with autoimmune disease that also excludes eggs, nuts, and seeds, as these can be inflammatory or immunogenic in some patients.^100-106 Other variations of the diet exist, including the ketogenic Paleo diet, pegan (Paleo vegan) diet, and lacto-Paleo diet.¹⁰⁰ An often cited criticism of the Paleo diet is the low intake of calcium and risk for osteoporosis; however, consumption of calcium-rich foods or a calcium supplement can address this concern.¹⁰⁷

Although small clinical studies have found the Paleo diet to be beneficial for various autoimmune diseases, clinical data evaluating the utility of the diet for cutaneous disease is lacking.^108,109 Numerous randomized trials have demonstrated the Paleo diet to be effective for weight loss and improving insulin sensitivity and lipid levels.^110-116 Thus, the Paleo diet may theoretically serve as a viable adjunct dietary approach to the treatment of cutaneous diseases associated with obesity and metabolic derangement.¹¹⁷

Carnivore Diet

Arguably the most controversial and radical diet is the carnivore diet. As the name implies, the carnivore diet is based on consuming solely animal products. A properly structured carnivore diet emphasizes a “nose-to-tail” eating approach where all parts of the animal including the muscle meats, organs, and fat are consumed. Proponents of the diet cite anthropologic evidence from fossil-stable carbon-13/carbon-12 isotope analyses, craniodental features, and numerous other adaptations that indicate increased consumption of meat during human evolution.^118-122 Notably, many early humans ate a carnivore diet, but life span was very short at this time, suggesting the diet may not be as beneficial as has been suggested.

Despite the abundance of anecdotal evidence supporting its use for a variety of chronic conditions, including cutaneous autoimmune disease, there is a virtual absence of high-quality research on the carnivore diet.^123-125

The purported benefits of the carnivore diet may be attributed to the consumption of organ meats that contain highly bioavailable essential vitamins and minerals, such as iron, zinc, copper, selenium, thiamine, niacin, folate, vitamin B₆, vitamin B₁₂, vitamin A, vitamin D, vitamin K, and choline.^126-128 Other dietary compounds that have demonstrated benefit for skin health and are predominantly found in animal foods include carnosine, carnitine, creatine, taurine, coenzyme Q10, and collagen.^129-134 Nevertheless, there is no data to recommend the elimination of antioxidant- and micronutrient-dense plant-based foods. Rigorous clinical research evaluating the efficacy and safety of the carnivore diet in dermatologic patients is needed. A carnivore diet should not be undertaken without the assistance of a dietician who can ensure adequate micronutrient and macronutrient support.

Final Thoughts

The adjunctive role of diet in the treatment of skin disease is expanding and becoming more widely accepted among dermatologists. Unfortunately, there remains a lack of randomized controlled trials confirming the efficacy of various dietary interventions in the dermatologic setting. Although evidence-based dietary recommendations currently are limited, it is important for dermatologists to be aware of the varied and nuanced dietary interventions employed by patients.

Ultimately, dietary recommendations must be personalized, considering a patient’s comorbidities, personal beliefs and preferences, and nutrigenetics. The emerging field of dermatonutrigenomics—the study of how dietary compounds interact with one’s genes to influence skin health—may allow for precise dietary recommendations to be made in dermatologic practice. Direct-to-consumer genetic tests targeted toward dermatology patients are already on the market, but their clinical utility awaits validation.¹ Because nutritional science is a constantly evolving field, becoming familiar with these popular diets will serve both dermatologists and their patients well.

Within the last decade, almost 3000 articles have been published on the role of diet in the prevention and management of dermatologic conditions. Patients are increasingly interested in—and employing—dietary modifications that may influence skin appearance and aid in the treatment of cutaneous disease.¹ It is essential that dermatologists are familiar with existing evidence on the role of diet in dermatology to counsel patients appropriately. Herein, we discuss the compositions of several popular diets and their proposed utility for dermatologic purposes. We highlight the limited literature that exists surrounding this topic and emphasize the need for future, well-designed clinical trials that study the impact of diet on skin disease.

Ketogenic Diet

The ketogenic diet has a macronutrient profile composed of high fat, low to moderate protein, and very low carbohydrates. Nutritional ketosis occurs as the body begins to use free fatty acids (via beta oxidation) as the primary metabolite driving cellular metabolism. It has been suggested that the ketogenic diet may impart beneficial effects on skin disease; however, limited literature exists on the role of nutritional ketosis in the treatment of dermatologic conditions.

Mechanistically, the ketogenic diet decreases the secretion of insulin and insulinlike growth factor 1, resulting in a reduction of circulating androgens and increased activity of the retinoid X receptor.² In acne vulgaris, it has been suggested that the ketogenic diet may be beneficial in decreasing androgen-induced sebum production and the overproliferation of keratinocytes.^2-7 The ketogenic diet is one of the most rapidly effective dietary strategies for normalizing both insulin and androgens, thus it may theoretically be useful for other metabolic and hormone-dependent skin diseases, such as hidradenitis suppurativa.^8,9

The cutaneous manifestations associated with chronic hyperinsulinemia and hyperglycemia are numerous and include acanthosis nigricans, acrochordons, diabetic dermopathy, scleredema diabeticorum, bullosis diabeticorum, keratosis pilaris, and generalized granuloma annulare. There also is an increased risk for bacterial and fungal skin infections associated with hyperglycemic states.¹⁰ The ketogenic diet is an effective nonpharmacologic tool for normalizing serum insulin and glucose levels in most patients and may have utility in the aforementioned conditions.^11,12 In addition to improving insulin sensitivity, it has been used as a dietary strategy for weight loss.^11-15 Because obesity and metabolic syndrome are highly correlated with common skin conditions such as psoriasis, hidradenitis suppurativa, and androgenetic alopecia, there may be a role for employing the ketogenic diet in these patient populations.^16,17

Although robust clinical studies on ketogenic diets in skin disease are lacking, a recent single-arm, open-label clinical trial observed benefit in all 37 drug-naïve, overweight patients with chronic plaque psoriasis who underwent a ketogenic weight loss protocol. Significant reductions in psoriasis area and severity index (PASI) score and dermatology life quality index score were reported (P<.001).¹⁸ Another study of 30 patients with psoriasis found that a 4-week, low-calorie, ketogenic diet resulted in 50% improvement of PASI scores, 10% weight loss, and a reduction in the proinflammatory cytokines IL-1β and IL-2.¹⁹ Despite these results, it is a challenge to tease out if the specific dietary intervention or its associated weight loss was the main driver in these reported improvements in skin disease.

There is mixed evidence on the anti-inflammatory nature of the ketogenic diet, likely due to wide variation in the composition of foods included in individual diets. In many instances, the ketogenic diet is thought to possess considerable antioxidant and anti-inflammatory capabilities. Ketones are known activators of the nuclear factor erythroid 2–related factor 2 pathway, which upregulates the production of glutathione, a major endogenous intracellular antioxidant.²⁰ Additionally, dietary compounds from foods that are encouraged while on the ketogenic diet, such as sulforaphane from broccoli, also are independent activators of nuclear factor erythroid 2–related factor 2.²¹ Ketones are efficiently utilized by mitochondria, which also may result in the decreased production of reactive oxygen species and lower oxidative stress.²² Moreover, the ketone body β-hydroxybutyrate has demonstrated the ability to reduce proinflammatory IL-1β levels via suppression of nucleotide-binding domain-like receptor protein 3 inflammasome activity.^23,24 The activity of IL-1β is known to be elevated in many dermatologic conditions, including juvenile idiopathic arthritis, relapsing polychondritis, Schnitzler syndrome, hidradenitis suppurativa, Behçet disease, and other autoinflammatory syndromes.²⁵ Ketones also have been shown to inhibit the nuclear factor–κB proinflammatory signaling pathway.^22,26,27 Overexpression of IL-1β and aberrant activation of nuclear factor–κB are implicated in a variety of inflammatory, autoimmune, and oncologic cutaneous pathologies. The ketogenic diet may prove to be an effective adjunctive treatment for dermatologists to consider in select patient populations.^23,24,28-30

For patients with keratinocyte carcinomas, the ketogenic diet may offer the aforementioned anti-inflammatory and antioxidant effects, as well as suppression of the mechanistic target of rapamycin, a major regulator of cell metabolism and proliferation.^31,32 Inhibition of mechanistic target of rapamycin activity has been shown to slow tumor growth and reduce the development of squamous cell carcinoma.^25,33,34 The ketogenic diet also may exploit the preferential utilization of glucose exhibited by many types of cancer cells, thereby “starving” the tumor of its primary fuel source.^35,36 In vitro and animal studies in a variety of cancer types have demonstrated that a ketogenic metabolic state—achieved through the ketogenic diet or fasting—can sensitize tumor cells to chemotherapy and radiation while conferring a protective effect to normal cells.^37-40 This recently described phenomenon is known as differential stress resistance, but it has not been studied in keratinocyte malignancies or melanoma to date. Importantly, some basal cell carcinomas and BRAF V600E–mutated melanomas have worsened while on the ketogenic diet, suggesting more data is needed before it can be recommended for all cancer patients.^41,42 Furthermore, other skin conditions such as prurigo pigmentosa have been associated with initiation of the ketogenic diet.⁴³

Low FODMAP Diet

Fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) are short-chain carbohydrates that are poorly absorbed, osmotically active, and rapidly fermented by intestinal bacteria.⁴⁴ The low FODMAP diet has been shown to be efficacious for treatment of irritable bowel syndrome, small intestinal bacterial overgrowth (SIBO), and some cases of inflammatory bowel disease (IBD).^44-49 A low FODMAP diet may have potential implications for several dermatologic conditions.

Rosacea has been associated with various gastrointestinal tract disorders including irritable bowel syndrome, SIBO, and IBD.^50-54 A single study found that patients with rosacea had a 13-fold increased risk for SIBO.^55,56 Treatment of 40 patients with SIBO using rifaximin resulted in complete resolution of rosacea in all patients, with no relapse after a 3-year follow-up period.⁵⁵ Psoriasis also has been associated with SIBO and IBD.^57,58 One small study found that eradication of SIBO in psoriatic patients resulted in improved PASI scores and colorimetric values.⁵⁹

Although the long-term health consequences of the low FODMAP diet are unknown, further research on such dietary interventions for inflammatory skin conditions is warranted given the mounting evidence of a gut-skin connection and the role of the intestinal microbiome in skin health.^50,51

Gluten-Free Diet

Gluten is a protein found in a variety of grains. Although the role of gluten in the pathogenesis of celiac disease and dermatitis herpetiformis is indisputable, the deleterious effects of gluten outside of the context of these diseases remain controversial. There may be a compelling case for eliminating gluten in psoriasis patients with seropositivity for celiac disease. A recent systematic review found a 2.2-fold increased risk for celiac disease in psoriasis patients.⁶⁰ Antigliadin antibody titers also were found to be positively correlated with psoriatic disease severity.⁶¹ In addition, one open-label study found a reduction in PASI scores in 73% of patients with antigliadin antibodies after 3 months on a gluten-free diet compared to those without antibodies; however, the study only included 22 patients.⁶² Several other small studies have yielded similar results^63,64; however, antigliadin antibodies are neither the most sensitive nor specific markers of celiac disease, and additional testing should be completed in any patient who may carry this diagnosis. A survey study by the National Psoriasis Foundation found that the dietary change associated with the greatest skin improvement was removal of gluten and nightshade vegetables in approximately 50% of the 1200 psoriasis patients that responded.⁶⁵ Case reports of various dermatologic conditions including sarcoidosis, vitiligo, alopecia areata, lichen planus, dermatomyositis, pyoderma gangrenosum, erythema nodosum, leukocytoclastic vasculitis, linear IgA bullous dermatosis, and aphthous ulcerations have reportedly improved with a gluten-free diet; however, this should not be used as primary therapy in patients without celiac disease.^66-71 Because gluten-free diets can be expensive and challenging to follow, a formal assessment for celiac disease should be considered before recommendation of this dietary intervention.

Low Histamine Diet

Histamine is a biogenic amine produced by the decarboxylation of the amino acid histidine.⁷² It is found in several foods in varying amounts. Because bacteria can convert histidine into histamine, many fermented and aged foods such as kimchi, sauerkraut, cheese, and red wine contain high levels of histamine. Individuals who have decreased activity of diamine oxidase (DAO), an enzyme that degrades histamine, may be more susceptible to histamine intolerance.⁷² The symptoms of histamine intolerance are numerous and include gastrointestinal tract distress, rhinorrhea and nasal congestion, headache, urticaria, flushing, and pruritus. Histamine intolerance can mimic an IgE-mediated food allergy; however, allergy testing is negative in these patients. Unfortunately, there is no laboratory test for histamine intolerance; a double-blind, placebo-controlled food challenge is considered the gold-standard test.⁷²

As it pertains to dermatology, a low histamine diet may play a role in the treatment of certain patients with atopic dermatitis and chronic spontaneous urticaria. One study reported that 17 of 54 (31.5%) atopic patients had higher basal levels of serum histamine compared to controls.⁷³ Another study found that a histamine-free diet led to improvement in both histamine intolerance symptoms and atopic dermatitis disease severity (SCORing atopic dermatitis) in patients with low DAO activity.⁷⁴ In chronic spontaneous urticaria, a recent systematic review found that in 223 patients placed on a low histamine diet for 3 to 4 weeks, 12% and 44% achieved complete and partial remission, respectively.⁷⁵ Although treatment response based on a patient’s DAO activity level has not been correlated, a diet low in histamine may prove useful for patients with persistent atopic dermatitis and chronic spontaneous urticaria who have negative food allergy tests and report exacerbation of symptoms after ingestion of histamine-rich foods.^76,77

Mediterranean Diet

The Mediterranean diet has been touted as one of the healthiest diets to date, and large randomized clinical trials have demonstrated its effectiveness in weight loss, improving insulin sensitivity, and reducing inflammatory cytokine profiles.^78,79 A major criticism of the Mediterranean diet is that it has considerable ambiguity and lacks a precise definition due to the variability of what is consumed in different Mediterranean regions. Generally, the diet emphasizes high consumption of colorful fruits and vegetables, aromatic herbs and spices, olive oil, nuts, and seafood, as well as modest amounts of dairy, eggs, and red meat.⁸⁰ The anti-inflammatory effects of this diet largely have been attributed to its abundance of polyphenols, carotenoids, monounsaturated fatty acids, and omega-3 polyunsaturated fatty acids (PUFAs).^80,81 Examples of polyphenols include resveratrol in red grapes, quercetin in apples and red onions, and curcumin in turmeric, while examples of carotenoids include lycopene in tomatoes and zeaxanthin in dark leafy greens. Oleic acid is a monounsaturated fatty acid present in high concentrations in olive oil, while eicosapentaenoic acid and docosahexaenoic acid are omega-3 PUFAs predominantly found in fish.⁸²

Unfortunately, rigorous clinical trials regarding the Mediterranean diet as it pertains to dermatology have not been undertaken. Numerous observational studies in patients with psoriasis have suggested that close adherence to the Mediterranean diet was associated with improvement in PASI scores.^83-86 The National Psoriasis Foundation now recommends a trial of the Mediterranean diet in some patients with psoriasis, emphasizing increased dietary intake of olive oil, fish, and vegetables.⁸⁷ Adherence to a Mediterranean diet also has been inversely correlated to the severity of acne vulgaris and hidradenitis suppurativa^88,89; however, these studies failed to account for the multifactorial risk factors associated with these conditions. Mediterranean diets also may impart a chemopreventive effect, supported by a number of in vivo and in vitro studies demonstrating the inhibition and/or reversal of cutaneous DNA damage induced by UV radiation through supplementation with various phytonutrients and omega-3 PUFAs.^81,90-92 Although small case-control studies have found a decreased risk of basal cell carcinoma in those who closely adhered to a Mediterranean diet, more rigorous clinical research is needed.⁹³

Whole-Food, Plant-Based Diet

A whole-food, plant-based (WFPB) diet is another popular dietary approach that consists of eating fruits, vegetables, legumes, nuts, seeds, and grains in their whole natural form.⁹⁴ This diet discourages all animal products, including red meat, seafood, dairy, and eggs. It is similar to a vegan diet except that it eliminates all highly refined carbohydrates, vegetable oils, and other processed foods.⁹⁴ Randomized clinical studies have demonstrated the WFPB diet to be effective in the treatment of obesity and metabolic syndrome.^95,96

A WFPB diet has been shown to increase the antioxidant capacity of cells, lengthen telomeres, and reduce formation of advanced glycation end products.^94,97,98 These benefits may help combat accelerated skin aging, including increased skin permeability, reduced elasticity and hydration, decreased angiogenesis, impaired immune function, and decreased vitamin D synthesis. Accelerated skin aging can result in delayed wound healing and susceptibility to skin tears and ecchymoses and also may promote the development of cutaneous malignancies.⁹⁹ There remains a lack of clinical data studying a properly formulated WFPB diet in the dermatologic setting.

Paleolithic Diet

The paleolithic (Paleo) diet is an increasingly popular way of eating that attempts to mirror what our ancestors may have consumed between 10,000 and 2.5 million years ago.¹⁰⁰ It is similar to the Mediterranean diet but excludes grains, dairy, legumes, and nightshade vegetables. It also calls for elimination of highly processed sugars and oils as well as chemical food additives and preservatives. There is a strict variation of the diet for individuals with autoimmune disease that also excludes eggs, nuts, and seeds, as these can be inflammatory or immunogenic in some patients.^100-106 Other variations of the diet exist, including the ketogenic Paleo diet, pegan (Paleo vegan) diet, and lacto-Paleo diet.¹⁰⁰ An often cited criticism of the Paleo diet is the low intake of calcium and risk for osteoporosis; however, consumption of calcium-rich foods or a calcium supplement can address this concern.¹⁰⁷

Although small clinical studies have found the Paleo diet to be beneficial for various autoimmune diseases, clinical data evaluating the utility of the diet for cutaneous disease is lacking.^108,109 Numerous randomized trials have demonstrated the Paleo diet to be effective for weight loss and improving insulin sensitivity and lipid levels.^110-116 Thus, the Paleo diet may theoretically serve as a viable adjunct dietary approach to the treatment of cutaneous diseases associated with obesity and metabolic derangement.¹¹⁷

Carnivore Diet

Arguably the most controversial and radical diet is the carnivore diet. As the name implies, the carnivore diet is based on consuming solely animal products. A properly structured carnivore diet emphasizes a “nose-to-tail” eating approach where all parts of the animal including the muscle meats, organs, and fat are consumed. Proponents of the diet cite anthropologic evidence from fossil-stable carbon-13/carbon-12 isotope analyses, craniodental features, and numerous other adaptations that indicate increased consumption of meat during human evolution.^118-122 Notably, many early humans ate a carnivore diet, but life span was very short at this time, suggesting the diet may not be as beneficial as has been suggested.

Despite the abundance of anecdotal evidence supporting its use for a variety of chronic conditions, including cutaneous autoimmune disease, there is a virtual absence of high-quality research on the carnivore diet.^123-125

The purported benefits of the carnivore diet may be attributed to the consumption of organ meats that contain highly bioavailable essential vitamins and minerals, such as iron, zinc, copper, selenium, thiamine, niacin, folate, vitamin B₆, vitamin B₁₂, vitamin A, vitamin D, vitamin K, and choline.^126-128 Other dietary compounds that have demonstrated benefit for skin health and are predominantly found in animal foods include carnosine, carnitine, creatine, taurine, coenzyme Q10, and collagen.^129-134 Nevertheless, there is no data to recommend the elimination of antioxidant- and micronutrient-dense plant-based foods. Rigorous clinical research evaluating the efficacy and safety of the carnivore diet in dermatologic patients is needed. A carnivore diet should not be undertaken without the assistance of a dietician who can ensure adequate micronutrient and macronutrient support.

Final Thoughts

The adjunctive role of diet in the treatment of skin disease is expanding and becoming more widely accepted among dermatologists. Unfortunately, there remains a lack of randomized controlled trials confirming the efficacy of various dietary interventions in the dermatologic setting. Although evidence-based dietary recommendations currently are limited, it is important for dermatologists to be aware of the varied and nuanced dietary interventions employed by patients.

Ultimately, dietary recommendations must be personalized, considering a patient’s comorbidities, personal beliefs and preferences, and nutrigenetics. The emerging field of dermatonutrigenomics—the study of how dietary compounds interact with one’s genes to influence skin health—may allow for precise dietary recommendations to be made in dermatologic practice. Direct-to-consumer genetic tests targeted toward dermatology patients are already on the market, but their clinical utility awaits validation.¹ Because nutritional science is a constantly evolving field, becoming familiar with these popular diets will serve both dermatologists and their patients well.

Using belimumab after rituximab to treat patients with systemic lupus erythematosus (SLE) refractory to conventional therapy not only significantly decreased levels of serum IgG anti-dsDNA antibody levels but also prolonged the time before severe flares of disease occurred in the phase 2b BEAT-LUPUS (Belimumab after B cell depletion in SLE) study.

The trial’s primary outcome of serum IgG anti-dsDNA antibody levels showed a decline from a geometric mean of 162 IU/mL at baseline to 69 IU/mL at 24 weeks and 47 IU/mL at 1 year in patients treated with belimumab (Benlysta) after rituximab (Rituxan and biosimilars). These reductions were significantly lower than the values seen in the placebo after rituximab arm (a respective 121 IU/mL, 99 IU/mL, and 103 IU/mL; P < .001).

Just 3 patients who received belimumab versus 10 who received placebo after rituximab experienced a severe BILAG (British Isles Lupus Assessment Group) index A flare by the end of the study at 52 weeks. The hazard ratio (HR) for the flare reduction was 0.27 (P = .03), indicating a 73% reduction.

The use of belimumab rather than a placebo also led to a small reduction in total serum IgG, and significantly suppressed B-cell repopulation (P = .03).

These results need confirming in a larger, phase 3 trial, the trial’s principal investigator, Michael Ehrenstein, PhD, said at the annual European Congress of Rheumatology. They are “clearly encouraging” and “support the hypothesis that BAFF [B-cell–activating factor] can drive flares after rituximab,” he said.

Although B-cell depletion with rituximab is recommended by national and international guidelines to treat some patients with SLE who are refractory to conventional therapy, its use is not licensed.

“Certainly, rituximab is a controversial drug in lupus,” Dr. Ehrenstein, a consultant rheumatologist based at University College London, said in an interview. Although there is real-world evidence from registries and open-label studies suggesting that it is widely used and effective in some patients, the randomized, controlled trials conducted with rituximab about 10 years ago failed to meet their primary endpoints.

“A lot has been written about why that was, but probably the biggest reason was the high dose of steroids in both groups,” Dr. Ehrenstein said. To try to avoid muddying the waters of the BEAT-LUPUS trial findings, the maximum dose of prednisolone allowed to be used as background therapy was 20 mg/day. The trial’s investigators were also encouraged to reduce the baseline steroid dose to at least 50% by the trial’s 6-month halfway point.

“We tried to reflect what was going on in the U.K.,” Dr. Ehrenstein said, noting that the inspiration for the trial was a patient who had received sequential rituximab treatment. Although she got better with each cycle of rituximab, when her disease flared it would be worse than the time before, with increasingly higher anti-dsDNA levels recorded. The reason for this seemed to be because of increasing BAFF levels, and so the hypothesis was that if rituximab was associated with increased BAFF levels, then co-targeting BAFF with belimumab should be able to prevent those flares from happening.

The BEAT-LUPUS trial has been a huge collaborative effort and was conducted across 16 U.K. centers. From initial funding to the data analysis, it has taken 6 years to complete and was made possible by a unique partnership between Versus Arthritis, University College London Hospitals Biomedical Research Center, the National Institute for Health Research UK Musculoskeletal Translational Research Collaboration, and GlaxoSmithKline (GSK). GSK provided belimumab free of charge, as well as additional funding, but had no role in the design of the study and will not have any role going forward.

From an initial 172 patients assessed for eligibility, 52 patients were finally enrolled into the trial and received rituximab as two infusions given 2 weeks apart. Patients were then randomized in a double-blind manner to receive either belimumab (n = 26) or placebo (n = 26) 4-8 weeks after their first dose of rituximab. The intention-to-treat population consisted of 43 patients.

The use of belimumab after rituximab did not increase the risk for infection – serious or otherwise – or adverse effects, Dr. Ehrenstein reported. Serious adverse events were reported in six (23%) patients in each arm, and serious infections were seen in two (8%) of the belimumab- and four (15%) of the placebo-treated patients.

“I think the take-home message is that it seems that belimumab can reduce the number of severe flares that occur after rituximab therapy,” Dr. Ehrenstein said. “It’s promising, but not definitive,” he added. The next step is of course to publish these data and to perform a phase 3 trial.

In the discussion time following the presentation, session moderator Xavier Mariette, MD, PhD, of Bicêtre Hospital, Paris-Saclay University, asked why not give belimumab first before rituximab if using belimumab afterward works?

“Our strategy was driven by the observation that BAFF levels surged after rituximab, and therefore it’s logical to give the belimumab to block that BAFF surge,” he answered.

“Certainly, there are ideas that belimumab releases mature B cells into the circulation and rituximab can target that,” he added. That strategy is under investigation in the BLISS-BELIEVE trial, which should also report by the end of this year. It’s a much larger, phase 3 trial, involving nearly 300 patients and is sponsored by GSK.

“Clearly, this is a combination treatment [but] whether you give one before the other is uncertain,” Dr. Ehrenstein observed.

Another member of the viewing audience asked whether it would have been a fairer comparison if another dose of rituximab had been given to patients at week 24 instead of no treatment. Dr. Ehrenstein noted that it was a “good point” to make, but the investigators mainly wanted to answer whether giving belimumab after rituximab would target BAFF and thereby drop serum anti-dsDNA antibody levels. He said that a full trial of rituximab for patients with SLE, perhaps adding this extra dose, needs to be conducted.

Dr. Ehrenstein disclosed receiving research funding and educational grants from GSK and participating in advisory panels for the company.

Using belimumab after rituximab to treat patients with systemic lupus erythematosus (SLE) refractory to conventional therapy not only significantly decreased levels of serum IgG anti-dsDNA antibody levels but also prolonged the time before severe flares of disease occurred in the phase 2b BEAT-LUPUS (Belimumab after B cell depletion in SLE) study.

The trial’s primary outcome of serum IgG anti-dsDNA antibody levels showed a decline from a geometric mean of 162 IU/mL at baseline to 69 IU/mL at 24 weeks and 47 IU/mL at 1 year in patients treated with belimumab (Benlysta) after rituximab (Rituxan and biosimilars). These reductions were significantly lower than the values seen in the placebo after rituximab arm (a respective 121 IU/mL, 99 IU/mL, and 103 IU/mL; P < .001).

Just 3 patients who received belimumab versus 10 who received placebo after rituximab experienced a severe BILAG (British Isles Lupus Assessment Group) index A flare by the end of the study at 52 weeks. The hazard ratio (HR) for the flare reduction was 0.27 (P = .03), indicating a 73% reduction.

The use of belimumab rather than a placebo also led to a small reduction in total serum IgG, and significantly suppressed B-cell repopulation (P = .03).

These results need confirming in a larger, phase 3 trial, the trial’s principal investigator, Michael Ehrenstein, PhD, said at the annual European Congress of Rheumatology. They are “clearly encouraging” and “support the hypothesis that BAFF [B-cell–activating factor] can drive flares after rituximab,” he said.

Although B-cell depletion with rituximab is recommended by national and international guidelines to treat some patients with SLE who are refractory to conventional therapy, its use is not licensed.

“Certainly, rituximab is a controversial drug in lupus,” Dr. Ehrenstein, a consultant rheumatologist based at University College London, said in an interview. Although there is real-world evidence from registries and open-label studies suggesting that it is widely used and effective in some patients, the randomized, controlled trials conducted with rituximab about 10 years ago failed to meet their primary endpoints.

“A lot has been written about why that was, but probably the biggest reason was the high dose of steroids in both groups,” Dr. Ehrenstein said. To try to avoid muddying the waters of the BEAT-LUPUS trial findings, the maximum dose of prednisolone allowed to be used as background therapy was 20 mg/day. The trial’s investigators were also encouraged to reduce the baseline steroid dose to at least 50% by the trial’s 6-month halfway point.

“We tried to reflect what was going on in the U.K.,” Dr. Ehrenstein said, noting that the inspiration for the trial was a patient who had received sequential rituximab treatment. Although she got better with each cycle of rituximab, when her disease flared it would be worse than the time before, with increasingly higher anti-dsDNA levels recorded. The reason for this seemed to be because of increasing BAFF levels, and so the hypothesis was that if rituximab was associated with increased BAFF levels, then co-targeting BAFF with belimumab should be able to prevent those flares from happening.

The BEAT-LUPUS trial has been a huge collaborative effort and was conducted across 16 U.K. centers. From initial funding to the data analysis, it has taken 6 years to complete and was made possible by a unique partnership between Versus Arthritis, University College London Hospitals Biomedical Research Center, the National Institute for Health Research UK Musculoskeletal Translational Research Collaboration, and GlaxoSmithKline (GSK). GSK provided belimumab free of charge, as well as additional funding, but had no role in the design of the study and will not have any role going forward.

From an initial 172 patients assessed for eligibility, 52 patients were finally enrolled into the trial and received rituximab as two infusions given 2 weeks apart. Patients were then randomized in a double-blind manner to receive either belimumab (n = 26) or placebo (n = 26) 4-8 weeks after their first dose of rituximab. The intention-to-treat population consisted of 43 patients.

The use of belimumab after rituximab did not increase the risk for infection – serious or otherwise – or adverse effects, Dr. Ehrenstein reported. Serious adverse events were reported in six (23%) patients in each arm, and serious infections were seen in two (8%) of the belimumab- and four (15%) of the placebo-treated patients.

“I think the take-home message is that it seems that belimumab can reduce the number of severe flares that occur after rituximab therapy,” Dr. Ehrenstein said. “It’s promising, but not definitive,” he added. The next step is of course to publish these data and to perform a phase 3 trial.

In the discussion time following the presentation, session moderator Xavier Mariette, MD, PhD, of Bicêtre Hospital, Paris-Saclay University, asked why not give belimumab first before rituximab if using belimumab afterward works?

“Our strategy was driven by the observation that BAFF levels surged after rituximab, and therefore it’s logical to give the belimumab to block that BAFF surge,” he answered.

“Certainly, there are ideas that belimumab releases mature B cells into the circulation and rituximab can target that,” he added. That strategy is under investigation in the BLISS-BELIEVE trial, which should also report by the end of this year. It’s a much larger, phase 3 trial, involving nearly 300 patients and is sponsored by GSK.

“Clearly, this is a combination treatment [but] whether you give one before the other is uncertain,” Dr. Ehrenstein observed.

Another member of the viewing audience asked whether it would have been a fairer comparison if another dose of rituximab had been given to patients at week 24 instead of no treatment. Dr. Ehrenstein noted that it was a “good point” to make, but the investigators mainly wanted to answer whether giving belimumab after rituximab would target BAFF and thereby drop serum anti-dsDNA antibody levels. He said that a full trial of rituximab for patients with SLE, perhaps adding this extra dose, needs to be conducted.

Dr. Ehrenstein disclosed receiving research funding and educational grants from GSK and participating in advisory panels for the company.

Using belimumab after rituximab to treat patients with systemic lupus erythematosus (SLE) refractory to conventional therapy not only significantly decreased levels of serum IgG anti-dsDNA antibody levels but also prolonged the time before severe flares of disease occurred in the phase 2b BEAT-LUPUS (Belimumab after B cell depletion in SLE) study.

The trial’s primary outcome of serum IgG anti-dsDNA antibody levels showed a decline from a geometric mean of 162 IU/mL at baseline to 69 IU/mL at 24 weeks and 47 IU/mL at 1 year in patients treated with belimumab (Benlysta) after rituximab (Rituxan and biosimilars). These reductions were significantly lower than the values seen in the placebo after rituximab arm (a respective 121 IU/mL, 99 IU/mL, and 103 IU/mL; P < .001).

Just 3 patients who received belimumab versus 10 who received placebo after rituximab experienced a severe BILAG (British Isles Lupus Assessment Group) index A flare by the end of the study at 52 weeks. The hazard ratio (HR) for the flare reduction was 0.27 (P = .03), indicating a 73% reduction.

The use of belimumab rather than a placebo also led to a small reduction in total serum IgG, and significantly suppressed B-cell repopulation (P = .03).

These results need confirming in a larger, phase 3 trial, the trial’s principal investigator, Michael Ehrenstein, PhD, said at the annual European Congress of Rheumatology. They are “clearly encouraging” and “support the hypothesis that BAFF [B-cell–activating factor] can drive flares after rituximab,” he said.

Although B-cell depletion with rituximab is recommended by national and international guidelines to treat some patients with SLE who are refractory to conventional therapy, its use is not licensed.

“Certainly, rituximab is a controversial drug in lupus,” Dr. Ehrenstein, a consultant rheumatologist based at University College London, said in an interview. Although there is real-world evidence from registries and open-label studies suggesting that it is widely used and effective in some patients, the randomized, controlled trials conducted with rituximab about 10 years ago failed to meet their primary endpoints.

“A lot has been written about why that was, but probably the biggest reason was the high dose of steroids in both groups,” Dr. Ehrenstein said. To try to avoid muddying the waters of the BEAT-LUPUS trial findings, the maximum dose of prednisolone allowed to be used as background therapy was 20 mg/day. The trial’s investigators were also encouraged to reduce the baseline steroid dose to at least 50% by the trial’s 6-month halfway point.

“We tried to reflect what was going on in the U.K.,” Dr. Ehrenstein said, noting that the inspiration for the trial was a patient who had received sequential rituximab treatment. Although she got better with each cycle of rituximab, when her disease flared it would be worse than the time before, with increasingly higher anti-dsDNA levels recorded. The reason for this seemed to be because of increasing BAFF levels, and so the hypothesis was that if rituximab was associated with increased BAFF levels, then co-targeting BAFF with belimumab should be able to prevent those flares from happening.

The BEAT-LUPUS trial has been a huge collaborative effort and was conducted across 16 U.K. centers. From initial funding to the data analysis, it has taken 6 years to complete and was made possible by a unique partnership between Versus Arthritis, University College London Hospitals Biomedical Research Center, the National Institute for Health Research UK Musculoskeletal Translational Research Collaboration, and GlaxoSmithKline (GSK). GSK provided belimumab free of charge, as well as additional funding, but had no role in the design of the study and will not have any role going forward.

From an initial 172 patients assessed for eligibility, 52 patients were finally enrolled into the trial and received rituximab as two infusions given 2 weeks apart. Patients were then randomized in a double-blind manner to receive either belimumab (n = 26) or placebo (n = 26) 4-8 weeks after their first dose of rituximab. The intention-to-treat population consisted of 43 patients.

The use of belimumab after rituximab did not increase the risk for infection – serious or otherwise – or adverse effects, Dr. Ehrenstein reported. Serious adverse events were reported in six (23%) patients in each arm, and serious infections were seen in two (8%) of the belimumab- and four (15%) of the placebo-treated patients.

“I think the take-home message is that it seems that belimumab can reduce the number of severe flares that occur after rituximab therapy,” Dr. Ehrenstein said. “It’s promising, but not definitive,” he added. The next step is of course to publish these data and to perform a phase 3 trial.

In the discussion time following the presentation, session moderator Xavier Mariette, MD, PhD, of Bicêtre Hospital, Paris-Saclay University, asked why not give belimumab first before rituximab if using belimumab afterward works?

“Our strategy was driven by the observation that BAFF levels surged after rituximab, and therefore it’s logical to give the belimumab to block that BAFF surge,” he answered.

“Certainly, there are ideas that belimumab releases mature B cells into the circulation and rituximab can target that,” he added. That strategy is under investigation in the BLISS-BELIEVE trial, which should also report by the end of this year. It’s a much larger, phase 3 trial, involving nearly 300 patients and is sponsored by GSK.

“Clearly, this is a combination treatment [but] whether you give one before the other is uncertain,” Dr. Ehrenstein observed.

Another member of the viewing audience asked whether it would have been a fairer comparison if another dose of rituximab had been given to patients at week 24 instead of no treatment. Dr. Ehrenstein noted that it was a “good point” to make, but the investigators mainly wanted to answer whether giving belimumab after rituximab would target BAFF and thereby drop serum anti-dsDNA antibody levels. He said that a full trial of rituximab for patients with SLE, perhaps adding this extra dose, needs to be conducted.

Dr. Ehrenstein disclosed receiving research funding and educational grants from GSK and participating in advisory panels for the company.

The first multinational, phase 3, placebo-controlled trial conducted with intravenous immunoglobulin therapy (IVIg) for dermatomyositis has confirmed significant efficacy and acceptable safety, according to data presented at the opening plenary abstract session of the annual European Congress of Rheumatology.

At the week 16 evaluation of the trial, called ProDERM, the response rates were 78.7% and 43.8% (P = .0008) for active therapy and placebo, respectively, reported Rohit Aggarwal, MD, medical director of the Arthritis and Autoimmunity Center at the University of Pittsburgh.

ProDERM is a “much-awaited study,” according to session moderator Hendrik Schulze-Koops, MD, PhD, of the division of rheumatology and clinical immunology at Ludwig Maximilian University of Munich (Germany). He was not involved in the study.

“We all have been doing what we have been doing,” Dr. Schulze-Koops said, referring to the use of IVIg for the control of dermatomyositis, “but we had no evidence for support.”

This statement could apply not only to IVIg, which has long been listed among treatment options by the Myositis Association despite the absence of controlled studies, but also to most immunosuppressive therapies and other options used for this challenging disease.

The proprietary IVIg employed in this study, Octagam 10%, has been approved in the United States for the treatment of chronic immune thrombocytopenic purpura. Its manufacturer, Octagam, plans to file a supplemental new drug application with the Food and Drug Administration for the treatment of dermatomyositis. The agent is already approved for dermatomyositis by the European Medicines Agency, according to Dr. Aggarwal.

Multiple response criteria favor IVIg

In the trial, 95 patients with dermatomyositis were randomized to 2 g/kg of IVIg (Octagam 10%) or placebo administered every 4 weeks. In a subsequent open-label extension study in which patients on placebo were switched to active therapy, the same every-4-week treatment schedule was used. The patients’ mean age was 53; 75% were women, and 92% were White.

The primary endpoint was at least minimal improvement on 2016 ACR/EULAR (American College of Rheumatology/European Alliance of Associations for Rheumatology) myositis response criteria, defined as a 20-point or greater gain in the Total Improvement Score (TIS) and no clinical worsening at two consecutive visits. But IVIg also provided a large relative benefit over placebo using more rigorous definitions of improvement. For moderate improvement, defined as at least a 40-point TIS improvement, there was a 45.2% relative advantage for IVIg over placebo (68.1% vs. 22.9%; P < .0001). For major improvement, defined as at least a 60-point TIS improvement, the relative advantage was 23.6% (31.9% vs. 8.3%; P < .0062).

At 16 weeks, the mean TIS score was more than twice as high in those receiving IVIg than in those randomized to placebo (48.4 vs. 21.6). At that point, an open-label extension was initiated. Those in the IVIg group were permitted to remain on therapy for an additional 24 weeks if they had not worsened in the blinded phase.

The mean TIS score in the IVIg group continued to rise during the extension phase. By 12 weeks in this phase, it reached 54.0. Over the same period, mean TIS scores climbed steeply among the placebo-treated patients who had switched to active therapy, reaching 44.4.

At the end of 24 weeks of the extension trial, when patients initiated on IVIg had been on active therapy for 40 weeks, the mean TIS score advantage of starting on IVIg rather than placebo was relatively modest (55.4 vs. 51.1).
 

Benefit is significant for skin and muscle

Changes in the two major components of dermatomyositis were tracked individually. For skin symptoms, patients were evaluated with the Cutaneous Dermatomyositis Disease Areas and Severity Index (CDASI). For muscle involvement, symptoms were evaluated with the 8-item Manual Muscle Testing (MMT-8) tool.

“The effects of IVIg on the muscle and the skin were both highly statistically significant,” Dr. Aggarwal reported. He said the CDASI score was reduced by almost half at the end of 16 weeks among those treated with IVIg relative to those treated with placebo. Improvement in MMT-8 scores were also clinically as well as statistically significant.

The IVIg therapy was well tolerated. The most common adverse effects in this study, like those reported with IVIg when used to treat other diseases, were headache, pyrexia, and nausea, but Dr. Aggarwal reported that these were generally mild.

Serious adverse events, particularly thromboembolism, did occur over the course of the study, but the rate of events was only slightly higher in the group receiving active therapy (5.8% vs. 4.2%).

Patients who entered the study were permitted to remain on most immunosuppressive therapies, such as methotrexate, mycophenolate, tacrolimus, and glucocorticoids. Dr. Aggarwal said that the majority of patients were taking a glucocorticoid and at least one nonglucocorticoid immunosuppressant.

Effect on associated conditions is planned

The data from this trial have not yet been analyzed for the impact of IVIg on conditions that occur frequently in association with dermatomyositis, such as interstitial lung disease (ILD) and dysphagia, but Dr. Aggarwal reported that there are plans to do so. Although severe ILD was a trial exclusion, the presence of mild to moderate ILD and dysphagia were evaluated at baseline, so the impact of treatment can be assessed.

There are also plans to evaluate how the presence or absence of myositis-specific antibodies, which were also evaluated at baseline, affected response to IVIg.

Dr. Aggarwal has financial relationships with more than 15 pharmaceutical companies, including Octapharma, which provided financial support for this trial. Dr. Schulze-Koops reported no relevant potential conflicts of interest.

The first multinational, phase 3, placebo-controlled trial conducted with intravenous immunoglobulin therapy (IVIg) for dermatomyositis has confirmed significant efficacy and acceptable safety, according to data presented at the opening plenary abstract session of the annual European Congress of Rheumatology.

At the week 16 evaluation of the trial, called ProDERM, the response rates were 78.7% and 43.8% (P = .0008) for active therapy and placebo, respectively, reported Rohit Aggarwal, MD, medical director of the Arthritis and Autoimmunity Center at the University of Pittsburgh.

ProDERM is a “much-awaited study,” according to session moderator Hendrik Schulze-Koops, MD, PhD, of the division of rheumatology and clinical immunology at Ludwig Maximilian University of Munich (Germany). He was not involved in the study.

“We all have been doing what we have been doing,” Dr. Schulze-Koops said, referring to the use of IVIg for the control of dermatomyositis, “but we had no evidence for support.”

This statement could apply not only to IVIg, which has long been listed among treatment options by the Myositis Association despite the absence of controlled studies, but also to most immunosuppressive therapies and other options used for this challenging disease.

The proprietary IVIg employed in this study, Octagam 10%, has been approved in the United States for the treatment of chronic immune thrombocytopenic purpura. Its manufacturer, Octagam, plans to file a supplemental new drug application with the Food and Drug Administration for the treatment of dermatomyositis. The agent is already approved for dermatomyositis by the European Medicines Agency, according to Dr. Aggarwal.

Multiple response criteria favor IVIg

In the trial, 95 patients with dermatomyositis were randomized to 2 g/kg of IVIg (Octagam 10%) or placebo administered every 4 weeks. In a subsequent open-label extension study in which patients on placebo were switched to active therapy, the same every-4-week treatment schedule was used. The patients’ mean age was 53; 75% were women, and 92% were White.

The primary endpoint was at least minimal improvement on 2016 ACR/EULAR (American College of Rheumatology/European Alliance of Associations for Rheumatology) myositis response criteria, defined as a 20-point or greater gain in the Total Improvement Score (TIS) and no clinical worsening at two consecutive visits. But IVIg also provided a large relative benefit over placebo using more rigorous definitions of improvement. For moderate improvement, defined as at least a 40-point TIS improvement, there was a 45.2% relative advantage for IVIg over placebo (68.1% vs. 22.9%; P < .0001). For major improvement, defined as at least a 60-point TIS improvement, the relative advantage was 23.6% (31.9% vs. 8.3%; P < .0062).

At 16 weeks, the mean TIS score was more than twice as high in those receiving IVIg than in those randomized to placebo (48.4 vs. 21.6). At that point, an open-label extension was initiated. Those in the IVIg group were permitted to remain on therapy for an additional 24 weeks if they had not worsened in the blinded phase.

The mean TIS score in the IVIg group continued to rise during the extension phase. By 12 weeks in this phase, it reached 54.0. Over the same period, mean TIS scores climbed steeply among the placebo-treated patients who had switched to active therapy, reaching 44.4.

At the end of 24 weeks of the extension trial, when patients initiated on IVIg had been on active therapy for 40 weeks, the mean TIS score advantage of starting on IVIg rather than placebo was relatively modest (55.4 vs. 51.1).
 

Benefit is significant for skin and muscle

Changes in the two major components of dermatomyositis were tracked individually. For skin symptoms, patients were evaluated with the Cutaneous Dermatomyositis Disease Areas and Severity Index (CDASI). For muscle involvement, symptoms were evaluated with the 8-item Manual Muscle Testing (MMT-8) tool.

“The effects of IVIg on the muscle and the skin were both highly statistically significant,” Dr. Aggarwal reported. He said the CDASI score was reduced by almost half at the end of 16 weeks among those treated with IVIg relative to those treated with placebo. Improvement in MMT-8 scores were also clinically as well as statistically significant.

The IVIg therapy was well tolerated. The most common adverse effects in this study, like those reported with IVIg when used to treat other diseases, were headache, pyrexia, and nausea, but Dr. Aggarwal reported that these were generally mild.

Serious adverse events, particularly thromboembolism, did occur over the course of the study, but the rate of events was only slightly higher in the group receiving active therapy (5.8% vs. 4.2%).

Patients who entered the study were permitted to remain on most immunosuppressive therapies, such as methotrexate, mycophenolate, tacrolimus, and glucocorticoids. Dr. Aggarwal said that the majority of patients were taking a glucocorticoid and at least one nonglucocorticoid immunosuppressant.

Effect on associated conditions is planned

The data from this trial have not yet been analyzed for the impact of IVIg on conditions that occur frequently in association with dermatomyositis, such as interstitial lung disease (ILD) and dysphagia, but Dr. Aggarwal reported that there are plans to do so. Although severe ILD was a trial exclusion, the presence of mild to moderate ILD and dysphagia were evaluated at baseline, so the impact of treatment can be assessed.

There are also plans to evaluate how the presence or absence of myositis-specific antibodies, which were also evaluated at baseline, affected response to IVIg.

Dr. Aggarwal has financial relationships with more than 15 pharmaceutical companies, including Octapharma, which provided financial support for this trial. Dr. Schulze-Koops reported no relevant potential conflicts of interest.

The first multinational, phase 3, placebo-controlled trial conducted with intravenous immunoglobulin therapy (IVIg) for dermatomyositis has confirmed significant efficacy and acceptable safety, according to data presented at the opening plenary abstract session of the annual European Congress of Rheumatology.

At the week 16 evaluation of the trial, called ProDERM, the response rates were 78.7% and 43.8% (P = .0008) for active therapy and placebo, respectively, reported Rohit Aggarwal, MD, medical director of the Arthritis and Autoimmunity Center at the University of Pittsburgh.

ProDERM is a “much-awaited study,” according to session moderator Hendrik Schulze-Koops, MD, PhD, of the division of rheumatology and clinical immunology at Ludwig Maximilian University of Munich (Germany). He was not involved in the study.

“We all have been doing what we have been doing,” Dr. Schulze-Koops said, referring to the use of IVIg for the control of dermatomyositis, “but we had no evidence for support.”

This statement could apply not only to IVIg, which has long been listed among treatment options by the Myositis Association despite the absence of controlled studies, but also to most immunosuppressive therapies and other options used for this challenging disease.

The proprietary IVIg employed in this study, Octagam 10%, has been approved in the United States for the treatment of chronic immune thrombocytopenic purpura. Its manufacturer, Octagam, plans to file a supplemental new drug application with the Food and Drug Administration for the treatment of dermatomyositis. The agent is already approved for dermatomyositis by the European Medicines Agency, according to Dr. Aggarwal.

Multiple response criteria favor IVIg

In the trial, 95 patients with dermatomyositis were randomized to 2 g/kg of IVIg (Octagam 10%) or placebo administered every 4 weeks. In a subsequent open-label extension study in which patients on placebo were switched to active therapy, the same every-4-week treatment schedule was used. The patients’ mean age was 53; 75% were women, and 92% were White.

The primary endpoint was at least minimal improvement on 2016 ACR/EULAR (American College of Rheumatology/European Alliance of Associations for Rheumatology) myositis response criteria, defined as a 20-point or greater gain in the Total Improvement Score (TIS) and no clinical worsening at two consecutive visits. But IVIg also provided a large relative benefit over placebo using more rigorous definitions of improvement. For moderate improvement, defined as at least a 40-point TIS improvement, there was a 45.2% relative advantage for IVIg over placebo (68.1% vs. 22.9%; P < .0001). For major improvement, defined as at least a 60-point TIS improvement, the relative advantage was 23.6% (31.9% vs. 8.3%; P < .0062).

At 16 weeks, the mean TIS score was more than twice as high in those receiving IVIg than in those randomized to placebo (48.4 vs. 21.6). At that point, an open-label extension was initiated. Those in the IVIg group were permitted to remain on therapy for an additional 24 weeks if they had not worsened in the blinded phase.

The mean TIS score in the IVIg group continued to rise during the extension phase. By 12 weeks in this phase, it reached 54.0. Over the same period, mean TIS scores climbed steeply among the placebo-treated patients who had switched to active therapy, reaching 44.4.

At the end of 24 weeks of the extension trial, when patients initiated on IVIg had been on active therapy for 40 weeks, the mean TIS score advantage of starting on IVIg rather than placebo was relatively modest (55.4 vs. 51.1).
 

Benefit is significant for skin and muscle

Changes in the two major components of dermatomyositis were tracked individually. For skin symptoms, patients were evaluated with the Cutaneous Dermatomyositis Disease Areas and Severity Index (CDASI). For muscle involvement, symptoms were evaluated with the 8-item Manual Muscle Testing (MMT-8) tool.

“The effects of IVIg on the muscle and the skin were both highly statistically significant,” Dr. Aggarwal reported. He said the CDASI score was reduced by almost half at the end of 16 weeks among those treated with IVIg relative to those treated with placebo. Improvement in MMT-8 scores were also clinically as well as statistically significant.

The IVIg therapy was well tolerated. The most common adverse effects in this study, like those reported with IVIg when used to treat other diseases, were headache, pyrexia, and nausea, but Dr. Aggarwal reported that these were generally mild.

Serious adverse events, particularly thromboembolism, did occur over the course of the study, but the rate of events was only slightly higher in the group receiving active therapy (5.8% vs. 4.2%).

Patients who entered the study were permitted to remain on most immunosuppressive therapies, such as methotrexate, mycophenolate, tacrolimus, and glucocorticoids. Dr. Aggarwal said that the majority of patients were taking a glucocorticoid and at least one nonglucocorticoid immunosuppressant.

Effect on associated conditions is planned

The data from this trial have not yet been analyzed for the impact of IVIg on conditions that occur frequently in association with dermatomyositis, such as interstitial lung disease (ILD) and dysphagia, but Dr. Aggarwal reported that there are plans to do so. Although severe ILD was a trial exclusion, the presence of mild to moderate ILD and dysphagia were evaluated at baseline, so the impact of treatment can be assessed.

There are also plans to evaluate how the presence or absence of myositis-specific antibodies, which were also evaluated at baseline, affected response to IVIg.

Dr. Aggarwal has financial relationships with more than 15 pharmaceutical companies, including Octapharma, which provided financial support for this trial. Dr. Schulze-Koops reported no relevant potential conflicts of interest.

Dermatomyositis (DM) is an autoimmune condition characterized by skin and muscle inflammation with an estimated incidence of 9 cases per 1 million people. The incidence of amyopathic DM, which includes antimelanoma differentiation–associated gene 5 (anti-MDA5) DM, is approximately 2 cases per 1 million people.¹ Classic cutaneous manifestations of DM include a heliotrope rash, Gottron papules, and the shawl sign. Features of anti-MDA5 DM include cutaneous ulcerations, most commonly overlying Gottron papules on the elbows and digits, as well as painful palmar macules and papules. We describe 2 patients with anti-MDA5 DM who presented with an ulcerative heliotrope rash. Although heliotrope rash is classic for DM and cutaneous ulcerations are a hallmark of the anti-MDA5 subtype of DM, overlap of these cutaneous manifestations is not commonly reported. Furthermore, ulcerations of the lateral canthi were associated with rapidly progressive interstitial lung disease (ILD).

Case Reports

Patient 1
A woman in her 30s presented with diffuse arthralgias, bilateral eyelid edema, fatigue, and a progressive diffuse exanthem of 3 months’ duration. A review of systems was notable for the absence of myalgias. Physical examination revealed periorbital poikilodermatous patches with erythematous-to-violaceous plaques along the eyelid margins, violaceous papules on the dorsal knuckles, and edematous eroded plaques on the palmar fingertips. The patient was found to have a positive antinuclear antibody titer of 1:320 (reference range, <1:80) with a speckled pattern. A computed tomography (CT) scan of the chest showed patchy bilateral ground-glass opacities that were concerning for ILD. The cutaneous erosions, absence of myalgias, considerable proximal weakness, radiographic evidence of ILD, and positive antinuclear antibody test were clinically suggestive of anti-MDA5 DM. Further workup confirmed this diagnosis with positive reactivity to MDA5 by line immunoassay. The patient was treated with intravenous corticosteroids and was discharged after a 17-day hospitalization; however, she presented 2 months later to outpatient dermatology for progression of the cutaneous ulcerations, at which time an ulcerative heliotrope rash (Figure 1) was identified. Despite compliance with oral corticosteroids (1 mg/kg/d), she was hospitalized 1 month later for progressive respiratory insufficiency. A chest CT showed ground-glass linear opacities centrally located in all lobes of both lungs, consistent with rapidly progressive ILD. Over the course of her 5-day hospitalization, she was treated with corticosteroids, intravenous immunoglobulin (IVIG), and mycophenolate mofetil. The patient responded well to these therapies, leading to resolution of the respiratory symptoms, and she was discharged with plans to continue this regimen as an outpatient.

Patient 2
A woman in her late 30s with a history of known anti-MDA5 DM confirmed by line immunoassay 1 year prior presented to the emergency department with shortness of breath due to progressive ILD and a worsening exanthem. Dermatology was consulted to provide treatment recommendations. The treatment team was concerned for infection or anti-MDA5 DM disease progression. Physical examination revealed an ulcerative heliotrope rash (Figure 2) in addition to cutaneous findings classic for anti-MDA5 DM. Despite interventions, including high-dose corticosteroids, rituximab, IVIG, and plasma exchange, the ILD continued to progress, and the patient and her family elected to de-escalate aggressive medical care and pursue comfort care. The patient later died in in patient hospice.

Comment

Clinical Presentation of Anti-MDA5 DM
Dermatomyositis classically presents with cutaneous manifestations including a heliotropic erythematous rash and Gottron papules as well as accompanying muscle weakness.² However, a subtype known as amyopathic DM, which includes anti-MDA5 DM, usually presents without muscle involvement.³ Clinical muscle weakness has been reported in cases of anti-MDA5 DM, though it is less likely in these patients.⁴ The characteristic cutaneous phenotype of anti-MDA5 DM was described by Fiorentino et al⁵ in 2011 through a seminal retrospective study. Kurtzman and Vleugels⁶ provided validation of the clinical features of anti-MDA5 DM in their 2018 review. The classic cutaneous phenotype of anti-MDA5 DM consists of tender palmar papules and/or skin ulcerations that commonly develop over Gottron papules on the knuckles and digits, lateral nail folds, and elbows.^7-10 A meta-analysis of 1500 patients with anti-MDA5 DM found a statistically significant association with alopecia, Gottron sign or papules, mechanic’s hands, and V rash (P<.05), as well as skin ulcers, panniculitis, arthritis/arthralgia, pneumomediastinum, and rapidly progressive ILD (RP-ILD)(P≤.01).⁴ Rapidly progressive ILD is highly associated with anti-MDA5 DM.^6,11

While a heliotrope rash is classic for DM, and ulcerations are a hallmark of the anti-MDA5 DM subtype, overlap of these cutaneous manifestations is not commonly reported. In both cases presented here, ulcerations of the lateral canthi were associated with progression of ILD.

Diagnosis of Anti-MDA5 DM
Anti-MDA5 DM is defined by the presence of the anti-MDA5 antibody in the serum, named for its reactivity against the RNA helicase encoded by MDA5, within the clinical context of cutaneous signs of DM as described above.¹²

As described by Rider et al,¹³ a thorough laboratory analysis, including complete blood cell count, serum electrolytes, calcium, magnesium, phosphorus, and thyroid-stimulating hormone, is necessary to rule out conditions with similar presentations. Additionally, serum analysis for elevated muscle enzymes (creatinine phosphokinase, aldolase, lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase) is necessary to assess for subclinical muscle involvement. Serologic evidence of myositis usually denotes an alternative diagnosis.¹³ Antinuclear antibodies and myositis-specific antibody positivity are much less frequent in the anti-MDA5 DM subtype than in other forms of DM.⁶

Anti-MDA5 antibody titer, ferritin, and IL-18 can be trended and may be useful in the evaluation of the response to treatment and ILD status in patients with anti-MDA5 DM.^14,15 Elevated alveolar-arterial gradient, serum ferritin, serum chitotriosidase, and serum chitinase-3-like protein 1 (YKL-40) have each been associated with poorer prognosis of anti-MDA5 DM. The aforementioned serologies therefore may be helpful in determination of risk stratification and treatment aggressiveness.^16-19

Because of its strong association with RP-ILD, screening for pulmonary disease is necessary in all patients with confirmed or strongly suspected anti-MDA5 DM. Screening can be performed with pulmonary function testing; however, high-resolution chest CT is the gold standard for diagnosis of ILD.²⁰

Finally, all patients with a new diagnosis of DM should be evaluated for underlying malignancy through cancer screenings, given the propensity for DM to present as a paraneoplastic process.²¹ However, reports have indicated that the anti-MDA5 DM subtype may have a reduced risk for or an inverse relationship with underlying malignancy.⁵

Treatment Options for Anti-MDA5 DM
Early and aggressive therapy should be considered in the treatment of anti-MDA5 DM because of its association with RP-ILD. No treatment protocol is well established; thus, an individualized therapeutic approach may be guided by symptom severity and the clinical, radiographic, or functional evidence of ILD.⁶ High-dose systemic corticosteroids are first line, either in combination with or as a bridge to corticosteroid-sparing agents for immunosuppression. Many steroid-sparing medications have been employed with varying success. Mycophenolate mofetil is a reasonable first-line corticosteroid-sparing immunosuppressant agent, given its added benefit of attenuating ILD progression.⁶ A combination of high-dose corticosteroids, cyclosporine, and cyclophosphamide is utilized by some initially in the treatment of anti-MDA5 with ILD.^22,23 While others have used combinations of these immunomodulatory agents with mycophenolate mofetil, IVIG, rituximab, azathioprine, tofacitinib, and polymyxin B, direct hemoperfusion has been added, leading to successful remission.^23-28

Conclusion

We present 2 patients with anti-MDA5 DM who demonstrated a rare cutaneous manifestation of an ulcerative heliotrope rash. In both cases, this cutaneous finding was associated with the development of RP-ILD. Because of the strong association with and rapid progression of ILD seen in anti-MDA5 DM, early identification and aggressive treatment of this subtype are imperative. The clinician should recognize nonacral locations of cutaneous ulcerations, including an ulcerated heliotrope rash, to optimize diagnosis and management.

Dermatomyositis (DM) is an autoimmune condition characterized by skin and muscle inflammation with an estimated incidence of 9 cases per 1 million people. The incidence of amyopathic DM, which includes antimelanoma differentiation–associated gene 5 (anti-MDA5) DM, is approximately 2 cases per 1 million people.¹ Classic cutaneous manifestations of DM include a heliotrope rash, Gottron papules, and the shawl sign. Features of anti-MDA5 DM include cutaneous ulcerations, most commonly overlying Gottron papules on the elbows and digits, as well as painful palmar macules and papules. We describe 2 patients with anti-MDA5 DM who presented with an ulcerative heliotrope rash. Although heliotrope rash is classic for DM and cutaneous ulcerations are a hallmark of the anti-MDA5 subtype of DM, overlap of these cutaneous manifestations is not commonly reported. Furthermore, ulcerations of the lateral canthi were associated with rapidly progressive interstitial lung disease (ILD).

Case Reports

Patient 1
A woman in her 30s presented with diffuse arthralgias, bilateral eyelid edema, fatigue, and a progressive diffuse exanthem of 3 months’ duration. A review of systems was notable for the absence of myalgias. Physical examination revealed periorbital poikilodermatous patches with erythematous-to-violaceous plaques along the eyelid margins, violaceous papules on the dorsal knuckles, and edematous eroded plaques on the palmar fingertips. The patient was found to have a positive antinuclear antibody titer of 1:320 (reference range, <1:80) with a speckled pattern. A computed tomography (CT) scan of the chest showed patchy bilateral ground-glass opacities that were concerning for ILD. The cutaneous erosions, absence of myalgias, considerable proximal weakness, radiographic evidence of ILD, and positive antinuclear antibody test were clinically suggestive of anti-MDA5 DM. Further workup confirmed this diagnosis with positive reactivity to MDA5 by line immunoassay. The patient was treated with intravenous corticosteroids and was discharged after a 17-day hospitalization; however, she presented 2 months later to outpatient dermatology for progression of the cutaneous ulcerations, at which time an ulcerative heliotrope rash (Figure 1) was identified. Despite compliance with oral corticosteroids (1 mg/kg/d), she was hospitalized 1 month later for progressive respiratory insufficiency. A chest CT showed ground-glass linear opacities centrally located in all lobes of both lungs, consistent with rapidly progressive ILD. Over the course of her 5-day hospitalization, she was treated with corticosteroids, intravenous immunoglobulin (IVIG), and mycophenolate mofetil. The patient responded well to these therapies, leading to resolution of the respiratory symptoms, and she was discharged with plans to continue this regimen as an outpatient.

Patient 2
A woman in her late 30s with a history of known anti-MDA5 DM confirmed by line immunoassay 1 year prior presented to the emergency department with shortness of breath due to progressive ILD and a worsening exanthem. Dermatology was consulted to provide treatment recommendations. The treatment team was concerned for infection or anti-MDA5 DM disease progression. Physical examination revealed an ulcerative heliotrope rash (Figure 2) in addition to cutaneous findings classic for anti-MDA5 DM. Despite interventions, including high-dose corticosteroids, rituximab, IVIG, and plasma exchange, the ILD continued to progress, and the patient and her family elected to de-escalate aggressive medical care and pursue comfort care. The patient later died in in patient hospice.

Comment

Clinical Presentation of Anti-MDA5 DM
Dermatomyositis classically presents with cutaneous manifestations including a heliotropic erythematous rash and Gottron papules as well as accompanying muscle weakness.² However, a subtype known as amyopathic DM, which includes anti-MDA5 DM, usually presents without muscle involvement.³ Clinical muscle weakness has been reported in cases of anti-MDA5 DM, though it is less likely in these patients.⁴ The characteristic cutaneous phenotype of anti-MDA5 DM was described by Fiorentino et al⁵ in 2011 through a seminal retrospective study. Kurtzman and Vleugels⁶ provided validation of the clinical features of anti-MDA5 DM in their 2018 review. The classic cutaneous phenotype of anti-MDA5 DM consists of tender palmar papules and/or skin ulcerations that commonly develop over Gottron papules on the knuckles and digits, lateral nail folds, and elbows.^7-10 A meta-analysis of 1500 patients with anti-MDA5 DM found a statistically significant association with alopecia, Gottron sign or papules, mechanic’s hands, and V rash (P<.05), as well as skin ulcers, panniculitis, arthritis/arthralgia, pneumomediastinum, and rapidly progressive ILD (RP-ILD)(P≤.01).⁴ Rapidly progressive ILD is highly associated with anti-MDA5 DM.^6,11

While a heliotrope rash is classic for DM, and ulcerations are a hallmark of the anti-MDA5 DM subtype, overlap of these cutaneous manifestations is not commonly reported. In both cases presented here, ulcerations of the lateral canthi were associated with progression of ILD.

Diagnosis of Anti-MDA5 DM
Anti-MDA5 DM is defined by the presence of the anti-MDA5 antibody in the serum, named for its reactivity against the RNA helicase encoded by MDA5, within the clinical context of cutaneous signs of DM as described above.¹²

As described by Rider et al,¹³ a thorough laboratory analysis, including complete blood cell count, serum electrolytes, calcium, magnesium, phosphorus, and thyroid-stimulating hormone, is necessary to rule out conditions with similar presentations. Additionally, serum analysis for elevated muscle enzymes (creatinine phosphokinase, aldolase, lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase) is necessary to assess for subclinical muscle involvement. Serologic evidence of myositis usually denotes an alternative diagnosis.¹³ Antinuclear antibodies and myositis-specific antibody positivity are much less frequent in the anti-MDA5 DM subtype than in other forms of DM.⁶

Anti-MDA5 antibody titer, ferritin, and IL-18 can be trended and may be useful in the evaluation of the response to treatment and ILD status in patients with anti-MDA5 DM.^14,15 Elevated alveolar-arterial gradient, serum ferritin, serum chitotriosidase, and serum chitinase-3-like protein 1 (YKL-40) have each been associated with poorer prognosis of anti-MDA5 DM. The aforementioned serologies therefore may be helpful in determination of risk stratification and treatment aggressiveness.^16-19

Because of its strong association with RP-ILD, screening for pulmonary disease is necessary in all patients with confirmed or strongly suspected anti-MDA5 DM. Screening can be performed with pulmonary function testing; however, high-resolution chest CT is the gold standard for diagnosis of ILD.²⁰

Finally, all patients with a new diagnosis of DM should be evaluated for underlying malignancy through cancer screenings, given the propensity for DM to present as a paraneoplastic process.²¹ However, reports have indicated that the anti-MDA5 DM subtype may have a reduced risk for or an inverse relationship with underlying malignancy.⁵

Treatment Options for Anti-MDA5 DM
Early and aggressive therapy should be considered in the treatment of anti-MDA5 DM because of its association with RP-ILD. No treatment protocol is well established; thus, an individualized therapeutic approach may be guided by symptom severity and the clinical, radiographic, or functional evidence of ILD.⁶ High-dose systemic corticosteroids are first line, either in combination with or as a bridge to corticosteroid-sparing agents for immunosuppression. Many steroid-sparing medications have been employed with varying success. Mycophenolate mofetil is a reasonable first-line corticosteroid-sparing immunosuppressant agent, given its added benefit of attenuating ILD progression.⁶ A combination of high-dose corticosteroids, cyclosporine, and cyclophosphamide is utilized by some initially in the treatment of anti-MDA5 with ILD.^22,23 While others have used combinations of these immunomodulatory agents with mycophenolate mofetil, IVIG, rituximab, azathioprine, tofacitinib, and polymyxin B, direct hemoperfusion has been added, leading to successful remission.^23-28

Conclusion

We present 2 patients with anti-MDA5 DM who demonstrated a rare cutaneous manifestation of an ulcerative heliotrope rash. In both cases, this cutaneous finding was associated with the development of RP-ILD. Because of the strong association with and rapid progression of ILD seen in anti-MDA5 DM, early identification and aggressive treatment of this subtype are imperative. The clinician should recognize nonacral locations of cutaneous ulcerations, including an ulcerated heliotrope rash, to optimize diagnosis and management.

Dermatomyositis (DM) is an autoimmune condition characterized by skin and muscle inflammation with an estimated incidence of 9 cases per 1 million people. The incidence of amyopathic DM, which includes antimelanoma differentiation–associated gene 5 (anti-MDA5) DM, is approximately 2 cases per 1 million people.¹ Classic cutaneous manifestations of DM include a heliotrope rash, Gottron papules, and the shawl sign. Features of anti-MDA5 DM include cutaneous ulcerations, most commonly overlying Gottron papules on the elbows and digits, as well as painful palmar macules and papules. We describe 2 patients with anti-MDA5 DM who presented with an ulcerative heliotrope rash. Although heliotrope rash is classic for DM and cutaneous ulcerations are a hallmark of the anti-MDA5 subtype of DM, overlap of these cutaneous manifestations is not commonly reported. Furthermore, ulcerations of the lateral canthi were associated with rapidly progressive interstitial lung disease (ILD).

Case Reports

Patient 1
A woman in her 30s presented with diffuse arthralgias, bilateral eyelid edema, fatigue, and a progressive diffuse exanthem of 3 months’ duration. A review of systems was notable for the absence of myalgias. Physical examination revealed periorbital poikilodermatous patches with erythematous-to-violaceous plaques along the eyelid margins, violaceous papules on the dorsal knuckles, and edematous eroded plaques on the palmar fingertips. The patient was found to have a positive antinuclear antibody titer of 1:320 (reference range, <1:80) with a speckled pattern. A computed tomography (CT) scan of the chest showed patchy bilateral ground-glass opacities that were concerning for ILD. The cutaneous erosions, absence of myalgias, considerable proximal weakness, radiographic evidence of ILD, and positive antinuclear antibody test were clinically suggestive of anti-MDA5 DM. Further workup confirmed this diagnosis with positive reactivity to MDA5 by line immunoassay. The patient was treated with intravenous corticosteroids and was discharged after a 17-day hospitalization; however, she presented 2 months later to outpatient dermatology for progression of the cutaneous ulcerations, at which time an ulcerative heliotrope rash (Figure 1) was identified. Despite compliance with oral corticosteroids (1 mg/kg/d), she was hospitalized 1 month later for progressive respiratory insufficiency. A chest CT showed ground-glass linear opacities centrally located in all lobes of both lungs, consistent with rapidly progressive ILD. Over the course of her 5-day hospitalization, she was treated with corticosteroids, intravenous immunoglobulin (IVIG), and mycophenolate mofetil. The patient responded well to these therapies, leading to resolution of the respiratory symptoms, and she was discharged with plans to continue this regimen as an outpatient.

Patient 2
A woman in her late 30s with a history of known anti-MDA5 DM confirmed by line immunoassay 1 year prior presented to the emergency department with shortness of breath due to progressive ILD and a worsening exanthem. Dermatology was consulted to provide treatment recommendations. The treatment team was concerned for infection or anti-MDA5 DM disease progression. Physical examination revealed an ulcerative heliotrope rash (Figure 2) in addition to cutaneous findings classic for anti-MDA5 DM. Despite interventions, including high-dose corticosteroids, rituximab, IVIG, and plasma exchange, the ILD continued to progress, and the patient and her family elected to de-escalate aggressive medical care and pursue comfort care. The patient later died in in patient hospice.

Comment

Clinical Presentation of Anti-MDA5 DM
Dermatomyositis classically presents with cutaneous manifestations including a heliotropic erythematous rash and Gottron papules as well as accompanying muscle weakness.² However, a subtype known as amyopathic DM, which includes anti-MDA5 DM, usually presents without muscle involvement.³ Clinical muscle weakness has been reported in cases of anti-MDA5 DM, though it is less likely in these patients.⁴ The characteristic cutaneous phenotype of anti-MDA5 DM was described by Fiorentino et al⁵ in 2011 through a seminal retrospective study. Kurtzman and Vleugels⁶ provided validation of the clinical features of anti-MDA5 DM in their 2018 review. The classic cutaneous phenotype of anti-MDA5 DM consists of tender palmar papules and/or skin ulcerations that commonly develop over Gottron papules on the knuckles and digits, lateral nail folds, and elbows.^7-10 A meta-analysis of 1500 patients with anti-MDA5 DM found a statistically significant association with alopecia, Gottron sign or papules, mechanic’s hands, and V rash (P<.05), as well as skin ulcers, panniculitis, arthritis/arthralgia, pneumomediastinum, and rapidly progressive ILD (RP-ILD)(P≤.01).⁴ Rapidly progressive ILD is highly associated with anti-MDA5 DM.^6,11

While a heliotrope rash is classic for DM, and ulcerations are a hallmark of the anti-MDA5 DM subtype, overlap of these cutaneous manifestations is not commonly reported. In both cases presented here, ulcerations of the lateral canthi were associated with progression of ILD.

Diagnosis of Anti-MDA5 DM
Anti-MDA5 DM is defined by the presence of the anti-MDA5 antibody in the serum, named for its reactivity against the RNA helicase encoded by MDA5, within the clinical context of cutaneous signs of DM as described above.¹²

As described by Rider et al,¹³ a thorough laboratory analysis, including complete blood cell count, serum electrolytes, calcium, magnesium, phosphorus, and thyroid-stimulating hormone, is necessary to rule out conditions with similar presentations. Additionally, serum analysis for elevated muscle enzymes (creatinine phosphokinase, aldolase, lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase) is necessary to assess for subclinical muscle involvement. Serologic evidence of myositis usually denotes an alternative diagnosis.¹³ Antinuclear antibodies and myositis-specific antibody positivity are much less frequent in the anti-MDA5 DM subtype than in other forms of DM.⁶

Anti-MDA5 antibody titer, ferritin, and IL-18 can be trended and may be useful in the evaluation of the response to treatment and ILD status in patients with anti-MDA5 DM.^14,15 Elevated alveolar-arterial gradient, serum ferritin, serum chitotriosidase, and serum chitinase-3-like protein 1 (YKL-40) have each been associated with poorer prognosis of anti-MDA5 DM. The aforementioned serologies therefore may be helpful in determination of risk stratification and treatment aggressiveness.^16-19

Because of its strong association with RP-ILD, screening for pulmonary disease is necessary in all patients with confirmed or strongly suspected anti-MDA5 DM. Screening can be performed with pulmonary function testing; however, high-resolution chest CT is the gold standard for diagnosis of ILD.²⁰

Finally, all patients with a new diagnosis of DM should be evaluated for underlying malignancy through cancer screenings, given the propensity for DM to present as a paraneoplastic process.²¹ However, reports have indicated that the anti-MDA5 DM subtype may have a reduced risk for or an inverse relationship with underlying malignancy.⁵

Treatment Options for Anti-MDA5 DM
Early and aggressive therapy should be considered in the treatment of anti-MDA5 DM because of its association with RP-ILD. No treatment protocol is well established; thus, an individualized therapeutic approach may be guided by symptom severity and the clinical, radiographic, or functional evidence of ILD.⁶ High-dose systemic corticosteroids are first line, either in combination with or as a bridge to corticosteroid-sparing agents for immunosuppression. Many steroid-sparing medications have been employed with varying success. Mycophenolate mofetil is a reasonable first-line corticosteroid-sparing immunosuppressant agent, given its added benefit of attenuating ILD progression.⁶ A combination of high-dose corticosteroids, cyclosporine, and cyclophosphamide is utilized by some initially in the treatment of anti-MDA5 with ILD.^22,23 While others have used combinations of these immunomodulatory agents with mycophenolate mofetil, IVIG, rituximab, azathioprine, tofacitinib, and polymyxin B, direct hemoperfusion has been added, leading to successful remission.^23-28

Conclusion

We present 2 patients with anti-MDA5 DM who demonstrated a rare cutaneous manifestation of an ulcerative heliotrope rash. In both cases, this cutaneous finding was associated with the development of RP-ILD. Because of the strong association with and rapid progression of ILD seen in anti-MDA5 DM, early identification and aggressive treatment of this subtype are imperative. The clinician should recognize nonacral locations of cutaneous ulcerations, including an ulcerated heliotrope rash, to optimize diagnosis and management.

Tumor necrosis factor α (TNF-α) inhibitor–induced psoriasis is a known paradoxical adverse effect of this family of medications, which includes infliximab, adalimumab, etanercept, golimumab, and certolizumab. In the pediatric population, these therapies recently gained approval for nondermatologic conditions—meaning that this phenomenon is encountered more frequently.¹ In a systematic review of TNF-α inhibitor–induced psoriasis, severe scalp involvement was associated with alopecia in 7.5% of cases.² Onset of scalp psoriasis with alopecia in patients being treated with a TNF-α inhibitor should lead to consideration of this condition.

Psoriatic alopecia is an uncommon presentation of psoriasis. Although well described, alopecia as a clinical manifestation of scalp psoriasis is not a well-known concept among clinicians and has never been widely accepted. Adding to the diagnostic challenge is that psoriatic alopecia secondary to TNF-α inhibitor–induced psoriasis rarely has been reported in adults or children.^3-5 Including our case, our review of the literature yielded 7 pediatric cases (≤18 years) of TNF-α inhibitor–induced psoriatic alopecia.^6,7 A primary literature search of PubMed articles indexed for MEDLINE was conducted using the terms psoriatic alopecia, psoriasiform alopecia, TNF-α inhibitors, infliximab, adalimumab, etanercept, golimumab, and certolizumab.

We present the case of a pediatric patient with psoriatic alopecia secondary to treatment with adalimumab for Crohn disease (CD). We also provide a review of reported cases of psoriatic alopecia induced by a TNF-α inhibitor in the literature.

Case Report

A 12-year-old girl presented to our dermatology clinic with erythematous scaly plaques on the trunk, scalp, arms, and legs of 2 months’ duration. The lesions involved approximately 15% of the body surface area. The patient’s medical history was remarkable for CD diagnosed 4 years prior to presentation of the skin lesions. She had been treated for the past 2 years with adalimumab 40 mg once every 2 weeks and azathioprine 100 mg once daily. Because her CD was poorly controlled, the dosage of adalimumab was increased to 40 mg once weekly 6 months prior to the current presentation.

Our diagnosis was TNF-α inhibitor-induced psoriasis secondary to treatment with adalimumab.

The patient was treated with mometasone lotion 0.1% for the scalp lesions and triamcinolone cream 0.1% for the body lesions. Because of the extent of the psoriasis, we recommended changing adalimumab to ustekinumab, which is approved for CD in adults but is off label in children.

At 1-month follow-up, after receiving the induction dose of ustekinumab, the patient presented with partial improvement of the skin lesions but had developed a large, alopecic, erythematous plaque with thick yellowish scales on the scalp (Figure 1). She also had a positive hair pull test. The presumptive initial diagnosis of the alopecic scalp lesion was tinea capitis, for which multiple potassium hydroxide preparations of scales were performed, all yielding negative results. In addition, histopathologic examination with hematoxylin and eosin staining was performed (Figures 2A and 2B). Sterile tissue cultures for bacteria, fungi, and acid-fast bacilli were obtained and showed no growth. Periodic acid–Schiff staining was negative for fungal structures.

Comment

Psoriatic alopecia induced by a TNF-α inhibitor was first reported in 2007 in a 30-year-old woman with ankylosing spondylitis who was being treated with adalimumab.⁸ She had erythematous, scaly, alopecic plaques on the scalp and palmoplantar pustulosis. Findings on skin biopsy were compatible with psoriasis. The patient’s severe scalp psoriasis failed to respond to topical steroid treatment and adalimumab cessation. The extensive hair loss responded to cyclosporine 3 mg/kg daily.⁸

After conducting an extensive literature review, we found 26 cases of TNF-α–induced psoriatic alopecia, including the current case (Table).^6-16 The mean age at diagnosis was 27.8 years (SD, 13.6 years; range, 7–60 years). The female-to-male ratio was 3.3:1. The most common underlying condition for which TNF-α inhibitors were prescribed was CD (77% [20/26]). Psoriatic alopecia most commonly was reported secondary to treatment with infliximab (54% [14/26]), followed by adalimumab (42% [11/26]). Golimumab was the causative drug in 1 (4%) case. We did not find reports of etanercept or certolizumab having induced this manifestation. The onset of the scalp lesions occurred 2 to 46 months after starting treatment with the causative medication.

Previously reported cases have demonstrated various treatment options that yielded improvement or resolution of TNF-α inhibitor–induced psoriatic alopecia. These include either continuation or discontinuation of the TNF-α inhibitor combined with topical or intralesional steroids, methotrexate, or cyclosporine. Another option is to switch the TNF-α inhibitor to another biologic. Outcomes vary from patient to patient, making the physician’s clinical judgment crucial in deciding which treatment route to take. Our patient showed notable improvement when she was switched from adalimumab to ustekinumab as well as the combination of ustekinumab and clobetasol lotion 0.05%.

Conclusion

We recommend an individualized approach that provides patients with the safest and least invasive treatment option for TNF-α inhibitor–induced psoriatic alopecia. In most reported cases, the problem resolved with treatment, thereby classifying this form of alopecia as noncicatricial alopecia.

Tumor necrosis factor α (TNF-α) inhibitor–induced psoriasis is a known paradoxical adverse effect of this family of medications, which includes infliximab, adalimumab, etanercept, golimumab, and certolizumab. In the pediatric population, these therapies recently gained approval for nondermatologic conditions—meaning that this phenomenon is encountered more frequently.¹ In a systematic review of TNF-α inhibitor–induced psoriasis, severe scalp involvement was associated with alopecia in 7.5% of cases.² Onset of scalp psoriasis with alopecia in patients being treated with a TNF-α inhibitor should lead to consideration of this condition.

Psoriatic alopecia is an uncommon presentation of psoriasis. Although well described, alopecia as a clinical manifestation of scalp psoriasis is not a well-known concept among clinicians and has never been widely accepted. Adding to the diagnostic challenge is that psoriatic alopecia secondary to TNF-α inhibitor–induced psoriasis rarely has been reported in adults or children.^3-5 Including our case, our review of the literature yielded 7 pediatric cases (≤18 years) of TNF-α inhibitor–induced psoriatic alopecia.^6,7 A primary literature search of PubMed articles indexed for MEDLINE was conducted using the terms psoriatic alopecia, psoriasiform alopecia, TNF-α inhibitors, infliximab, adalimumab, etanercept, golimumab, and certolizumab.

We present the case of a pediatric patient with psoriatic alopecia secondary to treatment with adalimumab for Crohn disease (CD). We also provide a review of reported cases of psoriatic alopecia induced by a TNF-α inhibitor in the literature.

Case Report

A 12-year-old girl presented to our dermatology clinic with erythematous scaly plaques on the trunk, scalp, arms, and legs of 2 months’ duration. The lesions involved approximately 15% of the body surface area. The patient’s medical history was remarkable for CD diagnosed 4 years prior to presentation of the skin lesions. She had been treated for the past 2 years with adalimumab 40 mg once every 2 weeks and azathioprine 100 mg once daily. Because her CD was poorly controlled, the dosage of adalimumab was increased to 40 mg once weekly 6 months prior to the current presentation.

Our diagnosis was TNF-α inhibitor-induced psoriasis secondary to treatment with adalimumab.

The patient was treated with mometasone lotion 0.1% for the scalp lesions and triamcinolone cream 0.1% for the body lesions. Because of the extent of the psoriasis, we recommended changing adalimumab to ustekinumab, which is approved for CD in adults but is off label in children.

At 1-month follow-up, after receiving the induction dose of ustekinumab, the patient presented with partial improvement of the skin lesions but had developed a large, alopecic, erythematous plaque with thick yellowish scales on the scalp (Figure 1). She also had a positive hair pull test. The presumptive initial diagnosis of the alopecic scalp lesion was tinea capitis, for which multiple potassium hydroxide preparations of scales were performed, all yielding negative results. In addition, histopathologic examination with hematoxylin and eosin staining was performed (Figures 2A and 2B). Sterile tissue cultures for bacteria, fungi, and acid-fast bacilli were obtained and showed no growth. Periodic acid–Schiff staining was negative for fungal structures.

Comment

Psoriatic alopecia induced by a TNF-α inhibitor was first reported in 2007 in a 30-year-old woman with ankylosing spondylitis who was being treated with adalimumab.⁸ She had erythematous, scaly, alopecic plaques on the scalp and palmoplantar pustulosis. Findings on skin biopsy were compatible with psoriasis. The patient’s severe scalp psoriasis failed to respond to topical steroid treatment and adalimumab cessation. The extensive hair loss responded to cyclosporine 3 mg/kg daily.⁸

After conducting an extensive literature review, we found 26 cases of TNF-α–induced psoriatic alopecia, including the current case (Table).^6-16 The mean age at diagnosis was 27.8 years (SD, 13.6 years; range, 7–60 years). The female-to-male ratio was 3.3:1. The most common underlying condition for which TNF-α inhibitors were prescribed was CD (77% [20/26]). Psoriatic alopecia most commonly was reported secondary to treatment with infliximab (54% [14/26]), followed by adalimumab (42% [11/26]). Golimumab was the causative drug in 1 (4%) case. We did not find reports of etanercept or certolizumab having induced this manifestation. The onset of the scalp lesions occurred 2 to 46 months after starting treatment with the causative medication.

Previously reported cases have demonstrated various treatment options that yielded improvement or resolution of TNF-α inhibitor–induced psoriatic alopecia. These include either continuation or discontinuation of the TNF-α inhibitor combined with topical or intralesional steroids, methotrexate, or cyclosporine. Another option is to switch the TNF-α inhibitor to another biologic. Outcomes vary from patient to patient, making the physician’s clinical judgment crucial in deciding which treatment route to take. Our patient showed notable improvement when she was switched from adalimumab to ustekinumab as well as the combination of ustekinumab and clobetasol lotion 0.05%.

Conclusion

We recommend an individualized approach that provides patients with the safest and least invasive treatment option for TNF-α inhibitor–induced psoriatic alopecia. In most reported cases, the problem resolved with treatment, thereby classifying this form of alopecia as noncicatricial alopecia.

Tumor necrosis factor α (TNF-α) inhibitor–induced psoriasis is a known paradoxical adverse effect of this family of medications, which includes infliximab, adalimumab, etanercept, golimumab, and certolizumab. In the pediatric population, these therapies recently gained approval for nondermatologic conditions—meaning that this phenomenon is encountered more frequently.¹ In a systematic review of TNF-α inhibitor–induced psoriasis, severe scalp involvement was associated with alopecia in 7.5% of cases.² Onset of scalp psoriasis with alopecia in patients being treated with a TNF-α inhibitor should lead to consideration of this condition.

Psoriatic alopecia is an uncommon presentation of psoriasis. Although well described, alopecia as a clinical manifestation of scalp psoriasis is not a well-known concept among clinicians and has never been widely accepted. Adding to the diagnostic challenge is that psoriatic alopecia secondary to TNF-α inhibitor–induced psoriasis rarely has been reported in adults or children.^3-5 Including our case, our review of the literature yielded 7 pediatric cases (≤18 years) of TNF-α inhibitor–induced psoriatic alopecia.^6,7 A primary literature search of PubMed articles indexed for MEDLINE was conducted using the terms psoriatic alopecia, psoriasiform alopecia, TNF-α inhibitors, infliximab, adalimumab, etanercept, golimumab, and certolizumab.

We present the case of a pediatric patient with psoriatic alopecia secondary to treatment with adalimumab for Crohn disease (CD). We also provide a review of reported cases of psoriatic alopecia induced by a TNF-α inhibitor in the literature.

Case Report

A 12-year-old girl presented to our dermatology clinic with erythematous scaly plaques on the trunk, scalp, arms, and legs of 2 months’ duration. The lesions involved approximately 15% of the body surface area. The patient’s medical history was remarkable for CD diagnosed 4 years prior to presentation of the skin lesions. She had been treated for the past 2 years with adalimumab 40 mg once every 2 weeks and azathioprine 100 mg once daily. Because her CD was poorly controlled, the dosage of adalimumab was increased to 40 mg once weekly 6 months prior to the current presentation.

Our diagnosis was TNF-α inhibitor-induced psoriasis secondary to treatment with adalimumab.

The patient was treated with mometasone lotion 0.1% for the scalp lesions and triamcinolone cream 0.1% for the body lesions. Because of the extent of the psoriasis, we recommended changing adalimumab to ustekinumab, which is approved for CD in adults but is off label in children.

At 1-month follow-up, after receiving the induction dose of ustekinumab, the patient presented with partial improvement of the skin lesions but had developed a large, alopecic, erythematous plaque with thick yellowish scales on the scalp (Figure 1). She also had a positive hair pull test. The presumptive initial diagnosis of the alopecic scalp lesion was tinea capitis, for which multiple potassium hydroxide preparations of scales were performed, all yielding negative results. In addition, histopathologic examination with hematoxylin and eosin staining was performed (Figures 2A and 2B). Sterile tissue cultures for bacteria, fungi, and acid-fast bacilli were obtained and showed no growth. Periodic acid–Schiff staining was negative for fungal structures.

Comment

Psoriatic alopecia induced by a TNF-α inhibitor was first reported in 2007 in a 30-year-old woman with ankylosing spondylitis who was being treated with adalimumab.⁸ She had erythematous, scaly, alopecic plaques on the scalp and palmoplantar pustulosis. Findings on skin biopsy were compatible with psoriasis. The patient’s severe scalp psoriasis failed to respond to topical steroid treatment and adalimumab cessation. The extensive hair loss responded to cyclosporine 3 mg/kg daily.⁸

After conducting an extensive literature review, we found 26 cases of TNF-α–induced psoriatic alopecia, including the current case (Table).^6-16 The mean age at diagnosis was 27.8 years (SD, 13.6 years; range, 7–60 years). The female-to-male ratio was 3.3:1. The most common underlying condition for which TNF-α inhibitors were prescribed was CD (77% [20/26]). Psoriatic alopecia most commonly was reported secondary to treatment with infliximab (54% [14/26]), followed by adalimumab (42% [11/26]). Golimumab was the causative drug in 1 (4%) case. We did not find reports of etanercept or certolizumab having induced this manifestation. The onset of the scalp lesions occurred 2 to 46 months after starting treatment with the causative medication.

Previously reported cases have demonstrated various treatment options that yielded improvement or resolution of TNF-α inhibitor–induced psoriatic alopecia. These include either continuation or discontinuation of the TNF-α inhibitor combined with topical or intralesional steroids, methotrexate, or cyclosporine. Another option is to switch the TNF-α inhibitor to another biologic. Outcomes vary from patient to patient, making the physician’s clinical judgment crucial in deciding which treatment route to take. Our patient showed notable improvement when she was switched from adalimumab to ustekinumab as well as the combination of ustekinumab and clobetasol lotion 0.05%.

Conclusion

We recommend an individualized approach that provides patients with the safest and least invasive treatment option for TNF-α inhibitor–induced psoriatic alopecia. In most reported cases, the problem resolved with treatment, thereby classifying this form of alopecia as noncicatricial alopecia.

A panel of federal advisers on May 6 lent support to the ChemoCentryx bid for approval of avacopan for a rare and serious autoimmune condition. But they also flagged concerns about both the evidence supporting claims of a benefit for this experimental drug and its safety.

At a meeting of the Food and Drug Administration’s Arthritis Advisory Committee, panelists voted 10-8 on a question of whether the risk-benefit profile of avacopan is adequate to support approval.

ChemoCentryx is seeking approval of avacopan for antineutrophil cytoplasmic autoantibody (ANCA)–associated vasculitis in the subtypes of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).

Regardless of their vote on this approval question, the panelists shared an interest in avacopan’s potential to reduce glucocorticoid use among some patients with ANCA-associated vasculitis, also called AAV. Mara L. Becker, MD, MSCE, the chair of the FDA’s panel, was among the panelists who said they reluctantly voted no.

“It pains me because I really want more steroid-sparing” medicines, said Dr. Becker of Duke University, Durham, N.C., who cited a need to gather more data on avacopan.

Margrit Wiesendanger, MD, PhD, of the Icahn School of Medicine at Mount Sinai, New York, who was among the panelists voting yes, spoke of a need for caution if the FDA approves avacopan.

“Judicious use of this new medication will be warranted and perhaps additional guidance could be given to rheumatologists to help them decide for whom this medication is best,” she said.

Panelists had spoken earlier of avacopan as a possible alternative medicine for people with AAV who have conditions that make glucocorticoids riskier for them, such as those who have diabetes.
 

Close votes on safety profile, efficacy

The panel also voted 10-8 on a question about whether the safety profile of avacopan is adequate to support approval of avacopan for the treatment of adult patients with AAV.

In addition, the panel voted 9-9 on a question about whether efficacy data support approval of avacopan for the treatment of adult patients with AAV.

The FDA considers the recommendations of its advisory panels, but is not bound by them.

The FDA staff clearly expressed the view that ChemoCentryx fell short with the evidence presented for avacopan approval. Shares of San Carlos, Calif.–based ChemoCentryx dropped sharply from a May 3 closing price of $48.82 to a May 4 closing price of $26.63 after the FDA released the staff’s review of avacopan.

In a briefing prepared for the meeting, FDA staff detailed concerns about the evidence ChemoCentryx is using to seek approval. While acknowledging a need for new treatments for AAV as a rare condition, FDA staff honed in on what they described flaws in the testing of this experimental medicine, which is a small-molecule antagonist of the receptor of C5a, an end product of the complement cascade that acts as a potent neutrophil chemoattractant and agonist.

The FDA usually requires two phase 3 studies for approval of a new medicine but will do so with a single trial in cases of exceptional need, the agency staff said. But in these cases, the bar rises for the evidence provided from that single trial.
 

Difficulties in interpretation of complex study design

In the case of avacopan, though, the data from the key avacopan trial, Study CL010_168, known as ADVOCATE, there were substantial uncertainties around the phase 3 study design and results, raising questions about the adequacy of this single trial to inform the benefit-risk assessment.

In the briefing document, the FDA staff noted that it had “communicated many of the concerns” about ChemoCentryx’s research earlier to the company.

“Complexities of the study design, as detailed in the briefing document, raise questions about the interpretability of the data to define a clinically meaningful benefit of avacopan and its role in the management of AAV,” the FDA staff wrote.

“We acknowledge that AAV is a rare and serious disease associated with high morbidity and increased mortality. It is also a disease with high unmet need for new therapies. However, FDA wants to ensure that new products have a defined context of use, i.e., how a product would be used, and a favorable benefit-risk assessment for patients,” the staff added.

In addition, there were differences in the assessments performed by investigators and the adjudication committee, most frequently related to the attribution of persistent vasculitis, the FDA staff noted.

Statistical analyses of the primary endpoint using investigators’ estimates “resulted in more conservative estimates of treatment effect, e.g., statistical significance for superiority would no longer be demonstrated,” the FDA staff noted. “While the prespecified analysis used the Adjudicator assessments, the assessment based on the Investigators, experienced in management of vasculitis, may better reflect real-world use.”
 

Imbalances in use of glucocorticoids and maintenance therapy

Also among the complications in assessing the ADVOCATE trial data were the glucocorticoids taken by patients in the study, the FDA staff said.

In the avacopan arm of the trial, 86% of patients received non–study-supplied glucocorticoids. In addition, more avacopan‐treated patients experienced adverse events and serious adverse events within the hepatobiliary system leading to discontinuation.

Subgroups given different treatments represented another challenge in interpreting ADVOCATE results for the FDA staff.

At week 26, the proportion of patients in disease remission in the avacopan group (72.3%) was noninferior to the prednisone group (70.1%), the FDA staff said in the briefing document.

But at week 52, a disparity was observed between subgroups that had received rituximab and cyclophosphamide (intravenous and oral) induction treatment. The estimated risk difference for disease remission at week 52 was 15.0% (95% CI, 2.2%-27.7%) in the subgroup receiving induction with rituximab and 3.3% (95% CI, –14.8% to 21.4%) in the cyclophosphamide plus maintenance azathioprine subgroup, the agency’s staff said.

“Based on the data, there is no evidence of clinically meaningful treatment effect in the cyclophosphamide induction subgroup,” the FDA staff wrote. “Further, the treatment comparison in the complementary rituximab induction subgroup may not be considered meaningful because these patients did not receive maintenance therapy, i.e., due to undertreating of patients, the effect observed in the rituximab subgroup may not represent a clinically meaningful treatment effect, compared to standard of care.”

Bruce Jancin/MDedge News

Rachel L. Glaser, MD, clinical team leader in FDA’s division of rheumatology and transplant medicine, reiterated these concerns to the advisory committee at the May 6 meeting.

“Throughout the development program, FDA advised the applicant that a noninferiority comparison would not be sufficient to show that avacopan can replaced glucocorticoids as it would be difficult to establish whether avacopan is effective or whether an effect was due to the rituximab or cyclophosphamide administered to both treatment arms,” she said.

In its briefing for the meeting, ChemoCentryx noted the limits of treatments now available for AAV. It also emphasized the toll of the condition, ranging from skin manifestations to glomerulonephritis to life-threatening pulmonary hemorrhage. If untreated, 80% of patients with GPA or MPA die within 2 years of disease onset, ChemoCentryx said in its briefing materials for the meeting.

The side effects of glucocorticoids were well known to the FDA panelists and the ChemoCentryx presenters. Witnesses at an open public hearing told their own stories of depression, anxiety, and irritability caused by these medicines.

Bruce Jancin/MDedge News

During the ChemoCentryx presentation, a presenter for the company, Peter Merkel, MD, MPH, of the University of Pennsylvania, Philadelphia, said avacopan would provide patients with AAV with an alternative allowing them “to go on a much lower glucocorticoids regimen.”

A similar view was presented in a February 2021 editorial in the New England Journal of Medicine, titled “Avacopan – Time to Replace Glucocorticoids?” Written by Kenneth J. Warrington, MD, of the Mayo Clinic, Rochester, Minn., the opinion article called the ADVOCATE trial “a milestone in the treatment of ANCA-associated vasculitis; complement inhibition with avacopan has glucocorticoid-sparing effects and results in superior disease control.”

Dr. Warrington reported no conflicts in connection with his editorial nor payments from ChemoCentryx. He did report grants from other firms such as Eli Lilly.

Julia Lewis, MD, of Vanderbilt University, Nashville, Tenn., was among the more skeptical members of the FDA panel. She was among the “nays” in all three voting questions put to the panel. Still, she said there were signs of “clinically meaningful benefit” in the data presented, but noted that the nonstudy use of glucocorticoids made it difficult to interpret the ADVOCATE results.

Dr. Lewis noted that the FDA usually requires two studies for a drug approval, particularly with a compound not yet cleared for any use. While ANCA-associated vasculitis is rare, it would be possible to recruit patients for another trial of avacopan, adding to the results reported already for avacopan from ADVOCATE, she said.

“Were there to be another study, this would certainly be a supportive study and maybe qualify as two studies,” she said.

A panel of federal advisers on May 6 lent support to the ChemoCentryx bid for approval of avacopan for a rare and serious autoimmune condition. But they also flagged concerns about both the evidence supporting claims of a benefit for this experimental drug and its safety.

At a meeting of the Food and Drug Administration’s Arthritis Advisory Committee, panelists voted 10-8 on a question of whether the risk-benefit profile of avacopan is adequate to support approval.

ChemoCentryx is seeking approval of avacopan for antineutrophil cytoplasmic autoantibody (ANCA)–associated vasculitis in the subtypes of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).

Regardless of their vote on this approval question, the panelists shared an interest in avacopan’s potential to reduce glucocorticoid use among some patients with ANCA-associated vasculitis, also called AAV. Mara L. Becker, MD, MSCE, the chair of the FDA’s panel, was among the panelists who said they reluctantly voted no.

“It pains me because I really want more steroid-sparing” medicines, said Dr. Becker of Duke University, Durham, N.C., who cited a need to gather more data on avacopan.

Margrit Wiesendanger, MD, PhD, of the Icahn School of Medicine at Mount Sinai, New York, who was among the panelists voting yes, spoke of a need for caution if the FDA approves avacopan.

“Judicious use of this new medication will be warranted and perhaps additional guidance could be given to rheumatologists to help them decide for whom this medication is best,” she said.

Panelists had spoken earlier of avacopan as a possible alternative medicine for people with AAV who have conditions that make glucocorticoids riskier for them, such as those who have diabetes.
 

Close votes on safety profile, efficacy

The panel also voted 10-8 on a question about whether the safety profile of avacopan is adequate to support approval of avacopan for the treatment of adult patients with AAV.

In addition, the panel voted 9-9 on a question about whether efficacy data support approval of avacopan for the treatment of adult patients with AAV.

The FDA considers the recommendations of its advisory panels, but is not bound by them.

The FDA staff clearly expressed the view that ChemoCentryx fell short with the evidence presented for avacopan approval. Shares of San Carlos, Calif.–based ChemoCentryx dropped sharply from a May 3 closing price of $48.82 to a May 4 closing price of $26.63 after the FDA released the staff’s review of avacopan.

In a briefing prepared for the meeting, FDA staff detailed concerns about the evidence ChemoCentryx is using to seek approval. While acknowledging a need for new treatments for AAV as a rare condition, FDA staff honed in on what they described flaws in the testing of this experimental medicine, which is a small-molecule antagonist of the receptor of C5a, an end product of the complement cascade that acts as a potent neutrophil chemoattractant and agonist.

The FDA usually requires two phase 3 studies for approval of a new medicine but will do so with a single trial in cases of exceptional need, the agency staff said. But in these cases, the bar rises for the evidence provided from that single trial.
 

Difficulties in interpretation of complex study design

In the case of avacopan, though, the data from the key avacopan trial, Study CL010_168, known as ADVOCATE, there were substantial uncertainties around the phase 3 study design and results, raising questions about the adequacy of this single trial to inform the benefit-risk assessment.

In the briefing document, the FDA staff noted that it had “communicated many of the concerns” about ChemoCentryx’s research earlier to the company.

“Complexities of the study design, as detailed in the briefing document, raise questions about the interpretability of the data to define a clinically meaningful benefit of avacopan and its role in the management of AAV,” the FDA staff wrote.

“We acknowledge that AAV is a rare and serious disease associated with high morbidity and increased mortality. It is also a disease with high unmet need for new therapies. However, FDA wants to ensure that new products have a defined context of use, i.e., how a product would be used, and a favorable benefit-risk assessment for patients,” the staff added.

In addition, there were differences in the assessments performed by investigators and the adjudication committee, most frequently related to the attribution of persistent vasculitis, the FDA staff noted.

Statistical analyses of the primary endpoint using investigators’ estimates “resulted in more conservative estimates of treatment effect, e.g., statistical significance for superiority would no longer be demonstrated,” the FDA staff noted. “While the prespecified analysis used the Adjudicator assessments, the assessment based on the Investigators, experienced in management of vasculitis, may better reflect real-world use.”
 

Imbalances in use of glucocorticoids and maintenance therapy

Also among the complications in assessing the ADVOCATE trial data were the glucocorticoids taken by patients in the study, the FDA staff said.

In the avacopan arm of the trial, 86% of patients received non–study-supplied glucocorticoids. In addition, more avacopan‐treated patients experienced adverse events and serious adverse events within the hepatobiliary system leading to discontinuation.

Subgroups given different treatments represented another challenge in interpreting ADVOCATE results for the FDA staff.

At week 26, the proportion of patients in disease remission in the avacopan group (72.3%) was noninferior to the prednisone group (70.1%), the FDA staff said in the briefing document.

But at week 52, a disparity was observed between subgroups that had received rituximab and cyclophosphamide (intravenous and oral) induction treatment. The estimated risk difference for disease remission at week 52 was 15.0% (95% CI, 2.2%-27.7%) in the subgroup receiving induction with rituximab and 3.3% (95% CI, –14.8% to 21.4%) in the cyclophosphamide plus maintenance azathioprine subgroup, the agency’s staff said.

“Based on the data, there is no evidence of clinically meaningful treatment effect in the cyclophosphamide induction subgroup,” the FDA staff wrote. “Further, the treatment comparison in the complementary rituximab induction subgroup may not be considered meaningful because these patients did not receive maintenance therapy, i.e., due to undertreating of patients, the effect observed in the rituximab subgroup may not represent a clinically meaningful treatment effect, compared to standard of care.”

Bruce Jancin/MDedge News

Rachel L. Glaser, MD, clinical team leader in FDA’s division of rheumatology and transplant medicine, reiterated these concerns to the advisory committee at the May 6 meeting.

“Throughout the development program, FDA advised the applicant that a noninferiority comparison would not be sufficient to show that avacopan can replaced glucocorticoids as it would be difficult to establish whether avacopan is effective or whether an effect was due to the rituximab or cyclophosphamide administered to both treatment arms,” she said.

In its briefing for the meeting, ChemoCentryx noted the limits of treatments now available for AAV. It also emphasized the toll of the condition, ranging from skin manifestations to glomerulonephritis to life-threatening pulmonary hemorrhage. If untreated, 80% of patients with GPA or MPA die within 2 years of disease onset, ChemoCentryx said in its briefing materials for the meeting.

The side effects of glucocorticoids were well known to the FDA panelists and the ChemoCentryx presenters. Witnesses at an open public hearing told their own stories of depression, anxiety, and irritability caused by these medicines.

Bruce Jancin/MDedge News

During the ChemoCentryx presentation, a presenter for the company, Peter Merkel, MD, MPH, of the University of Pennsylvania, Philadelphia, said avacopan would provide patients with AAV with an alternative allowing them “to go on a much lower glucocorticoids regimen.”

A similar view was presented in a February 2021 editorial in the New England Journal of Medicine, titled “Avacopan – Time to Replace Glucocorticoids?” Written by Kenneth J. Warrington, MD, of the Mayo Clinic, Rochester, Minn., the opinion article called the ADVOCATE trial “a milestone in the treatment of ANCA-associated vasculitis; complement inhibition with avacopan has glucocorticoid-sparing effects and results in superior disease control.”

Dr. Warrington reported no conflicts in connection with his editorial nor payments from ChemoCentryx. He did report grants from other firms such as Eli Lilly.

Julia Lewis, MD, of Vanderbilt University, Nashville, Tenn., was among the more skeptical members of the FDA panel. She was among the “nays” in all three voting questions put to the panel. Still, she said there were signs of “clinically meaningful benefit” in the data presented, but noted that the nonstudy use of glucocorticoids made it difficult to interpret the ADVOCATE results.

Dr. Lewis noted that the FDA usually requires two studies for a drug approval, particularly with a compound not yet cleared for any use. While ANCA-associated vasculitis is rare, it would be possible to recruit patients for another trial of avacopan, adding to the results reported already for avacopan from ADVOCATE, she said.

“Were there to be another study, this would certainly be a supportive study and maybe qualify as two studies,” she said.

A panel of federal advisers on May 6 lent support to the ChemoCentryx bid for approval of avacopan for a rare and serious autoimmune condition. But they also flagged concerns about both the evidence supporting claims of a benefit for this experimental drug and its safety.

At a meeting of the Food and Drug Administration’s Arthritis Advisory Committee, panelists voted 10-8 on a question of whether the risk-benefit profile of avacopan is adequate to support approval.

ChemoCentryx is seeking approval of avacopan for antineutrophil cytoplasmic autoantibody (ANCA)–associated vasculitis in the subtypes of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).

Regardless of their vote on this approval question, the panelists shared an interest in avacopan’s potential to reduce glucocorticoid use among some patients with ANCA-associated vasculitis, also called AAV. Mara L. Becker, MD, MSCE, the chair of the FDA’s panel, was among the panelists who said they reluctantly voted no.

“It pains me because I really want more steroid-sparing” medicines, said Dr. Becker of Duke University, Durham, N.C., who cited a need to gather more data on avacopan.

Margrit Wiesendanger, MD, PhD, of the Icahn School of Medicine at Mount Sinai, New York, who was among the panelists voting yes, spoke of a need for caution if the FDA approves avacopan.

“Judicious use of this new medication will be warranted and perhaps additional guidance could be given to rheumatologists to help them decide for whom this medication is best,” she said.

Panelists had spoken earlier of avacopan as a possible alternative medicine for people with AAV who have conditions that make glucocorticoids riskier for them, such as those who have diabetes.
 

Close votes on safety profile, efficacy

The panel also voted 10-8 on a question about whether the safety profile of avacopan is adequate to support approval of avacopan for the treatment of adult patients with AAV.

In addition, the panel voted 9-9 on a question about whether efficacy data support approval of avacopan for the treatment of adult patients with AAV.

The FDA considers the recommendations of its advisory panels, but is not bound by them.

The FDA staff clearly expressed the view that ChemoCentryx fell short with the evidence presented for avacopan approval. Shares of San Carlos, Calif.–based ChemoCentryx dropped sharply from a May 3 closing price of $48.82 to a May 4 closing price of $26.63 after the FDA released the staff’s review of avacopan.

In a briefing prepared for the meeting, FDA staff detailed concerns about the evidence ChemoCentryx is using to seek approval. While acknowledging a need for new treatments for AAV as a rare condition, FDA staff honed in on what they described flaws in the testing of this experimental medicine, which is a small-molecule antagonist of the receptor of C5a, an end product of the complement cascade that acts as a potent neutrophil chemoattractant and agonist.

The FDA usually requires two phase 3 studies for approval of a new medicine but will do so with a single trial in cases of exceptional need, the agency staff said. But in these cases, the bar rises for the evidence provided from that single trial.
 

Difficulties in interpretation of complex study design

In the case of avacopan, though, the data from the key avacopan trial, Study CL010_168, known as ADVOCATE, there were substantial uncertainties around the phase 3 study design and results, raising questions about the adequacy of this single trial to inform the benefit-risk assessment.

In the briefing document, the FDA staff noted that it had “communicated many of the concerns” about ChemoCentryx’s research earlier to the company.

“Complexities of the study design, as detailed in the briefing document, raise questions about the interpretability of the data to define a clinically meaningful benefit of avacopan and its role in the management of AAV,” the FDA staff wrote.

“We acknowledge that AAV is a rare and serious disease associated with high morbidity and increased mortality. It is also a disease with high unmet need for new therapies. However, FDA wants to ensure that new products have a defined context of use, i.e., how a product would be used, and a favorable benefit-risk assessment for patients,” the staff added.

In addition, there were differences in the assessments performed by investigators and the adjudication committee, most frequently related to the attribution of persistent vasculitis, the FDA staff noted.

Statistical analyses of the primary endpoint using investigators’ estimates “resulted in more conservative estimates of treatment effect, e.g., statistical significance for superiority would no longer be demonstrated,” the FDA staff noted. “While the prespecified analysis used the Adjudicator assessments, the assessment based on the Investigators, experienced in management of vasculitis, may better reflect real-world use.”
 

Imbalances in use of glucocorticoids and maintenance therapy

Also among the complications in assessing the ADVOCATE trial data were the glucocorticoids taken by patients in the study, the FDA staff said.

In the avacopan arm of the trial, 86% of patients received non–study-supplied glucocorticoids. In addition, more avacopan‐treated patients experienced adverse events and serious adverse events within the hepatobiliary system leading to discontinuation.

Subgroups given different treatments represented another challenge in interpreting ADVOCATE results for the FDA staff.

At week 26, the proportion of patients in disease remission in the avacopan group (72.3%) was noninferior to the prednisone group (70.1%), the FDA staff said in the briefing document.

But at week 52, a disparity was observed between subgroups that had received rituximab and cyclophosphamide (intravenous and oral) induction treatment. The estimated risk difference for disease remission at week 52 was 15.0% (95% CI, 2.2%-27.7%) in the subgroup receiving induction with rituximab and 3.3% (95% CI, –14.8% to 21.4%) in the cyclophosphamide plus maintenance azathioprine subgroup, the agency’s staff said.

“Based on the data, there is no evidence of clinically meaningful treatment effect in the cyclophosphamide induction subgroup,” the FDA staff wrote. “Further, the treatment comparison in the complementary rituximab induction subgroup may not be considered meaningful because these patients did not receive maintenance therapy, i.e., due to undertreating of patients, the effect observed in the rituximab subgroup may not represent a clinically meaningful treatment effect, compared to standard of care.”

Bruce Jancin/MDedge News

Rachel L. Glaser, MD, clinical team leader in FDA’s division of rheumatology and transplant medicine, reiterated these concerns to the advisory committee at the May 6 meeting.

“Throughout the development program, FDA advised the applicant that a noninferiority comparison would not be sufficient to show that avacopan can replaced glucocorticoids as it would be difficult to establish whether avacopan is effective or whether an effect was due to the rituximab or cyclophosphamide administered to both treatment arms,” she said.

In its briefing for the meeting, ChemoCentryx noted the limits of treatments now available for AAV. It also emphasized the toll of the condition, ranging from skin manifestations to glomerulonephritis to life-threatening pulmonary hemorrhage. If untreated, 80% of patients with GPA or MPA die within 2 years of disease onset, ChemoCentryx said in its briefing materials for the meeting.

The side effects of glucocorticoids were well known to the FDA panelists and the ChemoCentryx presenters. Witnesses at an open public hearing told their own stories of depression, anxiety, and irritability caused by these medicines.

Bruce Jancin/MDedge News

During the ChemoCentryx presentation, a presenter for the company, Peter Merkel, MD, MPH, of the University of Pennsylvania, Philadelphia, said avacopan would provide patients with AAV with an alternative allowing them “to go on a much lower glucocorticoids regimen.”

A similar view was presented in a February 2021 editorial in the New England Journal of Medicine, titled “Avacopan – Time to Replace Glucocorticoids?” Written by Kenneth J. Warrington, MD, of the Mayo Clinic, Rochester, Minn., the opinion article called the ADVOCATE trial “a milestone in the treatment of ANCA-associated vasculitis; complement inhibition with avacopan has glucocorticoid-sparing effects and results in superior disease control.”

Dr. Warrington reported no conflicts in connection with his editorial nor payments from ChemoCentryx. He did report grants from other firms such as Eli Lilly.

Julia Lewis, MD, of Vanderbilt University, Nashville, Tenn., was among the more skeptical members of the FDA panel. She was among the “nays” in all three voting questions put to the panel. Still, she said there were signs of “clinically meaningful benefit” in the data presented, but noted that the nonstudy use of glucocorticoids made it difficult to interpret the ADVOCATE results.

Dr. Lewis noted that the FDA usually requires two studies for a drug approval, particularly with a compound not yet cleared for any use. While ANCA-associated vasculitis is rare, it would be possible to recruit patients for another trial of avacopan, adding to the results reported already for avacopan from ADVOCATE, she said.

“Were there to be another study, this would certainly be a supportive study and maybe qualify as two studies,” she said.

Black patients diagnosed by dermatologists with cutaneous sarcoidosis were significantly more likely to have unrecognized systemic organ involvement than were non-Black patients, according to a retrospective chart review of patients seen at Massachusetts General Hospital and Brigham and Women’s Hospital, both in Boston.

Black patients were also significantly more likely to have two or more organs involved and have higher rates of cardiac involvement, the latter of which is associated with worse prognosis. “Our data suggest there may be substantial variations in organ involvement between racial groups of patients presenting with cutaneous sarcoidosis,” said medical student Kylee Kus, a medical student at Oakland University, Auburn Hills, Mich., who presented the findings with Bina Kassamali, a medical student at Harvard University, Boston, at the annual Skin of Color Society scientific symposium.

Sotonye Imadojemu, MD, MBE; Avery LeChance, MD, MPH; and Ruth Anne Vleugels, MD, MPH, MBA; of Brigham and Women’s Hospital, are cosenior authors of the abstract.

The researchers identified 111 patients who were diagnosed with cutaneous sarcoidosis over a 20-year period (January 2000–December 2019), 50 of whom presented without established extracutaneous disease. They examined the charts of these 50 patients for whether subsequent work-up revealed systemic disease.

Of the 50 patients, 9 were Black. Seven of these nine patients (77.8%), were found to have systemic involvement, compared with 14 of 41 (46.3%) non-Black patients – a 31.5% higher probability (P < .05). One-third of the nine Black patients were found to have disease in one organ, and 44.4% in two or more organs. In non-Black patients, these rates were 12.2% and 34.1%, respectively.

Cardiovascular involvement was not found in any of the non-Black patients who had extracutaneous disease, but was found in 29% of the Black patients with extracutaneous disease, a statistically significant difference.

Black patients are known to be at higher risk for sarcoidosis than non-Black patients, and because “there is an association between cardiac sarcoid involvement and poor prognosis largely due to manifestations such as heart block, arrhythmias, and heart failure ... the study helps demonstrate how this organ involvement can disproportionately affect the Black population,” Ms. Kassamali said in an interview after the meeting.

A separate, recently published analysis of data from the same patient population examined the work-ups that patients received after a dermatologist’s diagnosis of sarcoidosis and found that patients with no previous systemic work-up were subsequently assessed for cardiac involvement in only 58.3% of cases. Assessment for pulmonary and ocular disease was completed more than 90% of the time.

“Crucial testing for cardiac involvement fell short,” Dr. Imadojemu, of the department of dermatology, Brigham and Women’s Hospital, and coinvestigators wrote in the research letter.

“Because the cutaneous manifestations of sarcoidosis often present at disease onset, dermatologists may be the first physicians to diagnose a patient with sarcoidosis,” they wrote. “As such, dermatologists are often responsible for initiating the appropriate evaluation of patients with sarcoidosis.”

Pulmonary involvement occurs in nearly all cases of sarcoidosis, while ocular and cardiac disease develop in approximately 25% and 10% of patients, respectively. Cardiac sarcoidosis is usually asymptomatic and accounts for 13%-25% of sarcoidosis-related deaths in the United States, they wrote.

An electrocardiogram is the appropriate initial screening tool and “is warranted in all patients with sarcoidosis,” they advised.

Black patients diagnosed by dermatologists with cutaneous sarcoidosis were significantly more likely to have unrecognized systemic organ involvement than were non-Black patients, according to a retrospective chart review of patients seen at Massachusetts General Hospital and Brigham and Women’s Hospital, both in Boston.

Black patients were also significantly more likely to have two or more organs involved and have higher rates of cardiac involvement, the latter of which is associated with worse prognosis. “Our data suggest there may be substantial variations in organ involvement between racial groups of patients presenting with cutaneous sarcoidosis,” said medical student Kylee Kus, a medical student at Oakland University, Auburn Hills, Mich., who presented the findings with Bina Kassamali, a medical student at Harvard University, Boston, at the annual Skin of Color Society scientific symposium.

Sotonye Imadojemu, MD, MBE; Avery LeChance, MD, MPH; and Ruth Anne Vleugels, MD, MPH, MBA; of Brigham and Women’s Hospital, are cosenior authors of the abstract.

The researchers identified 111 patients who were diagnosed with cutaneous sarcoidosis over a 20-year period (January 2000–December 2019), 50 of whom presented without established extracutaneous disease. They examined the charts of these 50 patients for whether subsequent work-up revealed systemic disease.

Of the 50 patients, 9 were Black. Seven of these nine patients (77.8%), were found to have systemic involvement, compared with 14 of 41 (46.3%) non-Black patients – a 31.5% higher probability (P < .05). One-third of the nine Black patients were found to have disease in one organ, and 44.4% in two or more organs. In non-Black patients, these rates were 12.2% and 34.1%, respectively.

Cardiovascular involvement was not found in any of the non-Black patients who had extracutaneous disease, but was found in 29% of the Black patients with extracutaneous disease, a statistically significant difference.

Black patients are known to be at higher risk for sarcoidosis than non-Black patients, and because “there is an association between cardiac sarcoid involvement and poor prognosis largely due to manifestations such as heart block, arrhythmias, and heart failure ... the study helps demonstrate how this organ involvement can disproportionately affect the Black population,” Ms. Kassamali said in an interview after the meeting.

A separate, recently published analysis of data from the same patient population examined the work-ups that patients received after a dermatologist’s diagnosis of sarcoidosis and found that patients with no previous systemic work-up were subsequently assessed for cardiac involvement in only 58.3% of cases. Assessment for pulmonary and ocular disease was completed more than 90% of the time.

“Crucial testing for cardiac involvement fell short,” Dr. Imadojemu, of the department of dermatology, Brigham and Women’s Hospital, and coinvestigators wrote in the research letter.

“Because the cutaneous manifestations of sarcoidosis often present at disease onset, dermatologists may be the first physicians to diagnose a patient with sarcoidosis,” they wrote. “As such, dermatologists are often responsible for initiating the appropriate evaluation of patients with sarcoidosis.”

Pulmonary involvement occurs in nearly all cases of sarcoidosis, while ocular and cardiac disease develop in approximately 25% and 10% of patients, respectively. Cardiac sarcoidosis is usually asymptomatic and accounts for 13%-25% of sarcoidosis-related deaths in the United States, they wrote.

An electrocardiogram is the appropriate initial screening tool and “is warranted in all patients with sarcoidosis,” they advised.

Black patients diagnosed by dermatologists with cutaneous sarcoidosis were significantly more likely to have unrecognized systemic organ involvement than were non-Black patients, according to a retrospective chart review of patients seen at Massachusetts General Hospital and Brigham and Women’s Hospital, both in Boston.

Black patients were also significantly more likely to have two or more organs involved and have higher rates of cardiac involvement, the latter of which is associated with worse prognosis. “Our data suggest there may be substantial variations in organ involvement between racial groups of patients presenting with cutaneous sarcoidosis,” said medical student Kylee Kus, a medical student at Oakland University, Auburn Hills, Mich., who presented the findings with Bina Kassamali, a medical student at Harvard University, Boston, at the annual Skin of Color Society scientific symposium.

Sotonye Imadojemu, MD, MBE; Avery LeChance, MD, MPH; and Ruth Anne Vleugels, MD, MPH, MBA; of Brigham and Women’s Hospital, are cosenior authors of the abstract.

The researchers identified 111 patients who were diagnosed with cutaneous sarcoidosis over a 20-year period (January 2000–December 2019), 50 of whom presented without established extracutaneous disease. They examined the charts of these 50 patients for whether subsequent work-up revealed systemic disease.

Of the 50 patients, 9 were Black. Seven of these nine patients (77.8%), were found to have systemic involvement, compared with 14 of 41 (46.3%) non-Black patients – a 31.5% higher probability (P < .05). One-third of the nine Black patients were found to have disease in one organ, and 44.4% in two or more organs. In non-Black patients, these rates were 12.2% and 34.1%, respectively.

Cardiovascular involvement was not found in any of the non-Black patients who had extracutaneous disease, but was found in 29% of the Black patients with extracutaneous disease, a statistically significant difference.

Black patients are known to be at higher risk for sarcoidosis than non-Black patients, and because “there is an association between cardiac sarcoid involvement and poor prognosis largely due to manifestations such as heart block, arrhythmias, and heart failure ... the study helps demonstrate how this organ involvement can disproportionately affect the Black population,” Ms. Kassamali said in an interview after the meeting.

A separate, recently published analysis of data from the same patient population examined the work-ups that patients received after a dermatologist’s diagnosis of sarcoidosis and found that patients with no previous systemic work-up were subsequently assessed for cardiac involvement in only 58.3% of cases. Assessment for pulmonary and ocular disease was completed more than 90% of the time.

“Crucial testing for cardiac involvement fell short,” Dr. Imadojemu, of the department of dermatology, Brigham and Women’s Hospital, and coinvestigators wrote in the research letter.

“Because the cutaneous manifestations of sarcoidosis often present at disease onset, dermatologists may be the first physicians to diagnose a patient with sarcoidosis,” they wrote. “As such, dermatologists are often responsible for initiating the appropriate evaluation of patients with sarcoidosis.”

Pulmonary involvement occurs in nearly all cases of sarcoidosis, while ocular and cardiac disease develop in approximately 25% and 10% of patients, respectively. Cardiac sarcoidosis is usually asymptomatic and accounts for 13%-25% of sarcoidosis-related deaths in the United States, they wrote.

An electrocardiogram is the appropriate initial screening tool and “is warranted in all patients with sarcoidosis,” they advised.

To the Editor:

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition with high morbidity rates. Symptoms typically develop between puberty and the third decade of life, affecting twice as many females as males, with an overall disease prevalence of 1% to 4%.¹ The pathogenesis is theorized to be related to an immune response to follicular occlusion and rupture in genetically susceptible individuals.

Among the complications associated with HS, the development of cutaneous squamous cell carcinoma (SCC) is 4.6-times more likely within HS lesions than in normal skin and typically is seen in the setting of long-standing disease, particularly in men with HS lesions located on the buttocks and genital region for more than 20 years.² In 2015, the tumor necrosis factor (TNF) inhibitor adalimumab was approved by the US Food and Drug Administration for the treatment of HS. Tumor necrosis factor α inhibitors have been associated with an increased risk for skin cancer in other clinical settings.^3,4 We present a case of locally advanced SCC that developed in a patient with HS who was treated with adalimumab and infliximab (both TNF-α inhibitors), ultimately leading to the patient’s death.

A 59-year-old man who smoked with a 40-year history of severe HS, who previously was lost to follow-up, presented to our dermatology clinic with lesions on the buttocks. Physical examination demonstrated confluent, indurated, boggy plaques; scattered sinus tracts with purulent drainage; scattered cystlike nodules; and tenderness to palpation consistent with Hurley stage III disease (Figure 1A). No involvement of the axillae or groin was noted. He was started on doxycycline and a prednisone taper with minimal improvement and subsequently was switched to adalimumab 3 months later. Adalimumab provided little relief and was discontinued; therapy was transitioned to infliximab 3 months later.

To the Editor:

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition with high morbidity rates. Symptoms typically develop between puberty and the third decade of life, affecting twice as many females as males, with an overall disease prevalence of 1% to 4%.¹ The pathogenesis is theorized to be related to an immune response to follicular occlusion and rupture in genetically susceptible individuals.

Among the complications associated with HS, the development of cutaneous squamous cell carcinoma (SCC) is 4.6-times more likely within HS lesions than in normal skin and typically is seen in the setting of long-standing disease, particularly in men with HS lesions located on the buttocks and genital region for more than 20 years.² In 2015, the tumor necrosis factor (TNF) inhibitor adalimumab was approved by the US Food and Drug Administration for the treatment of HS. Tumor necrosis factor α inhibitors have been associated with an increased risk for skin cancer in other clinical settings.^3,4 We present a case of locally advanced SCC that developed in a patient with HS who was treated with adalimumab and infliximab (both TNF-α inhibitors), ultimately leading to the patient’s death.

A 59-year-old man who smoked with a 40-year history of severe HS, who previously was lost to follow-up, presented to our dermatology clinic with lesions on the buttocks. Physical examination demonstrated confluent, indurated, boggy plaques; scattered sinus tracts with purulent drainage; scattered cystlike nodules; and tenderness to palpation consistent with Hurley stage III disease (Figure 1A). No involvement of the axillae or groin was noted. He was started on doxycycline and a prednisone taper with minimal improvement and subsequently was switched to adalimumab 3 months later. Adalimumab provided little relief and was discontinued; therapy was transitioned to infliximab 3 months later.

To the Editor:

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition with high morbidity rates. Symptoms typically develop between puberty and the third decade of life, affecting twice as many females as males, with an overall disease prevalence of 1% to 4%.¹ The pathogenesis is theorized to be related to an immune response to follicular occlusion and rupture in genetically susceptible individuals.

Among the complications associated with HS, the development of cutaneous squamous cell carcinoma (SCC) is 4.6-times more likely within HS lesions than in normal skin and typically is seen in the setting of long-standing disease, particularly in men with HS lesions located on the buttocks and genital region for more than 20 years.² In 2015, the tumor necrosis factor (TNF) inhibitor adalimumab was approved by the US Food and Drug Administration for the treatment of HS. Tumor necrosis factor α inhibitors have been associated with an increased risk for skin cancer in other clinical settings.^3,4 We present a case of locally advanced SCC that developed in a patient with HS who was treated with adalimumab and infliximab (both TNF-α inhibitors), ultimately leading to the patient’s death.

A 59-year-old man who smoked with a 40-year history of severe HS, who previously was lost to follow-up, presented to our dermatology clinic with lesions on the buttocks. Physical examination demonstrated confluent, indurated, boggy plaques; scattered sinus tracts with purulent drainage; scattered cystlike nodules; and tenderness to palpation consistent with Hurley stage III disease (Figure 1A). No involvement of the axillae or groin was noted. He was started on doxycycline and a prednisone taper with minimal improvement and subsequently was switched to adalimumab 3 months later. Adalimumab provided little relief and was discontinued; therapy was transitioned to infliximab 3 months later.

Severe COVID-19 infection was more likely in hospitalized patients with systemic lupus erythematosus (SLE) who had comorbidities and risk factors associated with severe infection in the general population, notably older age, male gender, and hypertension, based on data from a nationwide epidemiologic study of inpatients in France.

“Recently, anti-interferon antibodies have been implicated in severe SARS-CoV-2 infection while it has been known for decades that patients with SLE may produce such autoantibodies,” but large-scale data on the risk of severe COVID-19 infection in SLE patients are limited, Arthur Mageau, MD, of Bichat–Claude Bernard Hospital in Paris, and colleagues wrote.

In a research letter published in Annals of the Rheumatic Diseases, the researchers used the French health care database Programme de Médicalisation des Systèmes d’Information to identify 11,055 adult SLE patients who had at least one hospital stay between March 1, 2020, and Oct.31, 2020. Of these, 1,411 (12.8%) also were diagnosed with COVID-19, and these patients had a total of 1,721 hospital stays.

Overall, in-hospital mortality was approximately four times higher among SLE patients with COVID-19 infection, compared with SLE patients without COVID-19 infection (9.5% vs. 2.4%, P < .001), and 293 (17%) of the COVID-19 hospital stays involved an intensive care unit. In the ICU, 78 (26.7%) of the COVID-19 patients required invasive ventilation, and 71 (24.7%) required noninvasive mechanical ventilation.

The SLE patients with COVID-19 who died were significantly more likely than the SLE patients with COVID-19 who recovered to be older and male, and to have conditions including chronic kidney disease, high blood pressure, chronic pulmonary disease, and a history of cardiovascular events or lupus nephritis. The study findings were limited by the focus on hospitalized patients only, so the results cannot be generalized to all lupus patients, the researchers said.

“Interestingly, while the overall mortality rate was lower in SLE/COVID-19–positive inpatients as compared with the total population admitted for SARS-CoV-2 infection in France during the same period (9.5% vs 15.7%, P < .0001), the mortality rate at a younger age tended to be higher in patients with SLE,” the researchers wrote, but the difference for these younger patients was not statistically significant. This disparity may be caused by the reduced need for immunosuppressive drugs in SLE patients as they age, and the observed increased mortality in younger SLE patients, compared with the general population, suggests that SLE may promote poor outcomes from COVID-19 infection.

Dr. Mageau received PhD fellowship support from the Agence Nationale pour la recherche. He and the other researchers had no financial conflicts to disclose. The study received no outside funding.

Severe COVID-19 infection was more likely in hospitalized patients with systemic lupus erythematosus (SLE) who had comorbidities and risk factors associated with severe infection in the general population, notably older age, male gender, and hypertension, based on data from a nationwide epidemiologic study of inpatients in France.

“Recently, anti-interferon antibodies have been implicated in severe SARS-CoV-2 infection while it has been known for decades that patients with SLE may produce such autoantibodies,” but large-scale data on the risk of severe COVID-19 infection in SLE patients are limited, Arthur Mageau, MD, of Bichat–Claude Bernard Hospital in Paris, and colleagues wrote.

In a research letter published in Annals of the Rheumatic Diseases, the researchers used the French health care database Programme de Médicalisation des Systèmes d’Information to identify 11,055 adult SLE patients who had at least one hospital stay between March 1, 2020, and Oct.31, 2020. Of these, 1,411 (12.8%) also were diagnosed with COVID-19, and these patients had a total of 1,721 hospital stays.

Overall, in-hospital mortality was approximately four times higher among SLE patients with COVID-19 infection, compared with SLE patients without COVID-19 infection (9.5% vs. 2.4%, P < .001), and 293 (17%) of the COVID-19 hospital stays involved an intensive care unit. In the ICU, 78 (26.7%) of the COVID-19 patients required invasive ventilation, and 71 (24.7%) required noninvasive mechanical ventilation.

The SLE patients with COVID-19 who died were significantly more likely than the SLE patients with COVID-19 who recovered to be older and male, and to have conditions including chronic kidney disease, high blood pressure, chronic pulmonary disease, and a history of cardiovascular events or lupus nephritis. The study findings were limited by the focus on hospitalized patients only, so the results cannot be generalized to all lupus patients, the researchers said.

“Interestingly, while the overall mortality rate was lower in SLE/COVID-19–positive inpatients as compared with the total population admitted for SARS-CoV-2 infection in France during the same period (9.5% vs 15.7%, P < .0001), the mortality rate at a younger age tended to be higher in patients with SLE,” the researchers wrote, but the difference for these younger patients was not statistically significant. This disparity may be caused by the reduced need for immunosuppressive drugs in SLE patients as they age, and the observed increased mortality in younger SLE patients, compared with the general population, suggests that SLE may promote poor outcomes from COVID-19 infection.

Dr. Mageau received PhD fellowship support from the Agence Nationale pour la recherche. He and the other researchers had no financial conflicts to disclose. The study received no outside funding.

Severe COVID-19 infection was more likely in hospitalized patients with systemic lupus erythematosus (SLE) who had comorbidities and risk factors associated with severe infection in the general population, notably older age, male gender, and hypertension, based on data from a nationwide epidemiologic study of inpatients in France.

“Recently, anti-interferon antibodies have been implicated in severe SARS-CoV-2 infection while it has been known for decades that patients with SLE may produce such autoantibodies,” but large-scale data on the risk of severe COVID-19 infection in SLE patients are limited, Arthur Mageau, MD, of Bichat–Claude Bernard Hospital in Paris, and colleagues wrote.

In a research letter published in Annals of the Rheumatic Diseases, the researchers used the French health care database Programme de Médicalisation des Systèmes d’Information to identify 11,055 adult SLE patients who had at least one hospital stay between March 1, 2020, and Oct.31, 2020. Of these, 1,411 (12.8%) also were diagnosed with COVID-19, and these patients had a total of 1,721 hospital stays.

Overall, in-hospital mortality was approximately four times higher among SLE patients with COVID-19 infection, compared with SLE patients without COVID-19 infection (9.5% vs. 2.4%, P < .001), and 293 (17%) of the COVID-19 hospital stays involved an intensive care unit. In the ICU, 78 (26.7%) of the COVID-19 patients required invasive ventilation, and 71 (24.7%) required noninvasive mechanical ventilation.

The SLE patients with COVID-19 who died were significantly more likely than the SLE patients with COVID-19 who recovered to be older and male, and to have conditions including chronic kidney disease, high blood pressure, chronic pulmonary disease, and a history of cardiovascular events or lupus nephritis. The study findings were limited by the focus on hospitalized patients only, so the results cannot be generalized to all lupus patients, the researchers said.

“Interestingly, while the overall mortality rate was lower in SLE/COVID-19–positive inpatients as compared with the total population admitted for SARS-CoV-2 infection in France during the same period (9.5% vs 15.7%, P < .0001), the mortality rate at a younger age tended to be higher in patients with SLE,” the researchers wrote, but the difference for these younger patients was not statistically significant. This disparity may be caused by the reduced need for immunosuppressive drugs in SLE patients as they age, and the observed increased mortality in younger SLE patients, compared with the general population, suggests that SLE may promote poor outcomes from COVID-19 infection.

Dr. Mageau received PhD fellowship support from the Agence Nationale pour la recherche. He and the other researchers had no financial conflicts to disclose. The study received no outside funding.

To the Editor:

Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterized by the development of painful abscesses, fistulous tracts, and scars. It most commonly affects the apocrine gland–bearing areas of the body such as the axillary, inguinal, and anogenital regions. With a prevalence of approximately 1%, HS can lead to notable morbidity.¹ The pathogenesis is thought to be due to occlusion of terminal hair follicles that subsequently stimulates release of proinflammatory cytokines from nearby keratinocytes. The mechanism of initial occlusion is not well understood but may be due to friction or trauma. An inflammatory mechanism of disease also has been hypothesized; however, the exact cytokine profile is not known. Treatment of HS consists of several different modalities, including oral retinoids, antibiotics, antiandrogenic therapy, and surgery.^1,2 Adalimumab is a well-known biologic that has been approved by the US Food and Drug Administration for the treatment of HS.

Adalimumab is a human monoclonal antibody against tumor necrosis factor (TNF) α and is thought to improve HS by several mechanisms. Inhibition of TNF-α and other proinflammatory cytokines found in inflammatory lesions and apocrine glands directly decreases the severity of lesion size and the frequency of recurrence.³ Adalimumab also is thought to downregulate expression of keratin 6 and prevent the hyperkeratinization seen in HS.⁴ Additionally, TNF-α inhibition decreases production of IL-1, which has been shown to cause hypercornification of follicles and perpetuate HS pathogenesis.⁵

Adalimumab is considered a safe medication with a low toxicity profile and rarely is associated with serious adverse effects. The most common adverse effects are injection-site reaction, headache, and rash. However, as with any immunosuppressant, there is an elevated incidence of opportunistic infections. Anti-TNF medications have been associated with an increased incidence of viral, bacterial, and fungal infections. We present a patient who developed Candida esophagitis 6 weeks after starting treatment with adalimumab for the treatment of HS. This case highlights the development of esophageal candidiasis as a notable adverse event.

A 41-year-old woman with a history of endometriosis, adenomyosis, polycystic ovary syndrome, interstitial cystitis, asthma, fibromyalgia, depression, and Hashimoto thyroiditis presented to our dermatology clinic with active draining lesions and sinus tracts in the perivaginal area that were consistent with HS, which initially was treated with doxycycline 100 mg twice daily. She experienced minimal improvement of the HS lesions at 2-month follow-up.

Due to disease severity, adalimumab was started. The patient received a loading dose of 4 injections totaling 160 mg and 80 mg on day 15, followed by a maintenance dose of 40 mg/0.4 mL weekly. The patient reported substantial improvement of pain, and complete resolution of active lesions was noted on physical examination after 4 weeks of treatment with adalimumab.

Six weeks after adalimumab was started, the patient developed severe dysphagia. She was evaluated by a gastroenterologist and underwent endoscopy (Figure), which led to a diagnosis of esophageal candidiasis. Adalimumab was discontinued immediately thereafter. The patient started treatment with nystatin oral rinse 4 times daily and oral fluconazole 200 mg daily. The candidiasis resolved within 2 weeks; however, she experienced recurrence of HS with draining lesions in the perivaginal area approximately 8 weeks after discontinuation of adalimumab. The patient requested to restart adalimumab treatment despite the recent history of esophagitis. Adalimumab 40 mg/0.4 mL weekly was restarted along with oral fluconazole 200 mg twice weekly and nystatin oral rinse 4 times daily. This regimen resulted in complete resolution of HS symptoms within 6 weeks with no recurrence of esophageal candidiasis during 6 months of follow-up.

Patients receiving adalimumab for dermatologic or other conditions should be closely monitored for opportunistic infections. Although immunomodulatory medications offer promising therapeutic benefits in patients with HS, larger studies regarding treatment with anti-TNF agents in HS are warranted to prevent complications from treatment and promote long-term efficacy and safety.

To the Editor:

Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterized by the development of painful abscesses, fistulous tracts, and scars. It most commonly affects the apocrine gland–bearing areas of the body such as the axillary, inguinal, and anogenital regions. With a prevalence of approximately 1%, HS can lead to notable morbidity.¹ The pathogenesis is thought to be due to occlusion of terminal hair follicles that subsequently stimulates release of proinflammatory cytokines from nearby keratinocytes. The mechanism of initial occlusion is not well understood but may be due to friction or trauma. An inflammatory mechanism of disease also has been hypothesized; however, the exact cytokine profile is not known. Treatment of HS consists of several different modalities, including oral retinoids, antibiotics, antiandrogenic therapy, and surgery.^1,2 Adalimumab is a well-known biologic that has been approved by the US Food and Drug Administration for the treatment of HS.

Adalimumab is a human monoclonal antibody against tumor necrosis factor (TNF) α and is thought to improve HS by several mechanisms. Inhibition of TNF-α and other proinflammatory cytokines found in inflammatory lesions and apocrine glands directly decreases the severity of lesion size and the frequency of recurrence.³ Adalimumab also is thought to downregulate expression of keratin 6 and prevent the hyperkeratinization seen in HS.⁴ Additionally, TNF-α inhibition decreases production of IL-1, which has been shown to cause hypercornification of follicles and perpetuate HS pathogenesis.⁵

Adalimumab is considered a safe medication with a low toxicity profile and rarely is associated with serious adverse effects. The most common adverse effects are injection-site reaction, headache, and rash. However, as with any immunosuppressant, there is an elevated incidence of opportunistic infections. Anti-TNF medications have been associated with an increased incidence of viral, bacterial, and fungal infections. We present a patient who developed Candida esophagitis 6 weeks after starting treatment with adalimumab for the treatment of HS. This case highlights the development of esophageal candidiasis as a notable adverse event.

A 41-year-old woman with a history of endometriosis, adenomyosis, polycystic ovary syndrome, interstitial cystitis, asthma, fibromyalgia, depression, and Hashimoto thyroiditis presented to our dermatology clinic with active draining lesions and sinus tracts in the perivaginal area that were consistent with HS, which initially was treated with doxycycline 100 mg twice daily. She experienced minimal improvement of the HS lesions at 2-month follow-up.

Due to disease severity, adalimumab was started. The patient received a loading dose of 4 injections totaling 160 mg and 80 mg on day 15, followed by a maintenance dose of 40 mg/0.4 mL weekly. The patient reported substantial improvement of pain, and complete resolution of active lesions was noted on physical examination after 4 weeks of treatment with adalimumab.

Six weeks after adalimumab was started, the patient developed severe dysphagia. She was evaluated by a gastroenterologist and underwent endoscopy (Figure), which led to a diagnosis of esophageal candidiasis. Adalimumab was discontinued immediately thereafter. The patient started treatment with nystatin oral rinse 4 times daily and oral fluconazole 200 mg daily. The candidiasis resolved within 2 weeks; however, she experienced recurrence of HS with draining lesions in the perivaginal area approximately 8 weeks after discontinuation of adalimumab. The patient requested to restart adalimumab treatment despite the recent history of esophagitis. Adalimumab 40 mg/0.4 mL weekly was restarted along with oral fluconazole 200 mg twice weekly and nystatin oral rinse 4 times daily. This regimen resulted in complete resolution of HS symptoms within 6 weeks with no recurrence of esophageal candidiasis during 6 months of follow-up.

Patients receiving adalimumab for dermatologic or other conditions should be closely monitored for opportunistic infections. Although immunomodulatory medications offer promising therapeutic benefits in patients with HS, larger studies regarding treatment with anti-TNF agents in HS are warranted to prevent complications from treatment and promote long-term efficacy and safety.

To the Editor:

Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterized by the development of painful abscesses, fistulous tracts, and scars. It most commonly affects the apocrine gland–bearing areas of the body such as the axillary, inguinal, and anogenital regions. With a prevalence of approximately 1%, HS can lead to notable morbidity.¹ The pathogenesis is thought to be due to occlusion of terminal hair follicles that subsequently stimulates release of proinflammatory cytokines from nearby keratinocytes. The mechanism of initial occlusion is not well understood but may be due to friction or trauma. An inflammatory mechanism of disease also has been hypothesized; however, the exact cytokine profile is not known. Treatment of HS consists of several different modalities, including oral retinoids, antibiotics, antiandrogenic therapy, and surgery.^1,2 Adalimumab is a well-known biologic that has been approved by the US Food and Drug Administration for the treatment of HS.

Adalimumab is a human monoclonal antibody against tumor necrosis factor (TNF) α and is thought to improve HS by several mechanisms. Inhibition of TNF-α and other proinflammatory cytokines found in inflammatory lesions and apocrine glands directly decreases the severity of lesion size and the frequency of recurrence.³ Adalimumab also is thought to downregulate expression of keratin 6 and prevent the hyperkeratinization seen in HS.⁴ Additionally, TNF-α inhibition decreases production of IL-1, which has been shown to cause hypercornification of follicles and perpetuate HS pathogenesis.⁵

Adalimumab is considered a safe medication with a low toxicity profile and rarely is associated with serious adverse effects. The most common adverse effects are injection-site reaction, headache, and rash. However, as with any immunosuppressant, there is an elevated incidence of opportunistic infections. Anti-TNF medications have been associated with an increased incidence of viral, bacterial, and fungal infections. We present a patient who developed Candida esophagitis 6 weeks after starting treatment with adalimumab for the treatment of HS. This case highlights the development of esophageal candidiasis as a notable adverse event.

A 41-year-old woman with a history of endometriosis, adenomyosis, polycystic ovary syndrome, interstitial cystitis, asthma, fibromyalgia, depression, and Hashimoto thyroiditis presented to our dermatology clinic with active draining lesions and sinus tracts in the perivaginal area that were consistent with HS, which initially was treated with doxycycline 100 mg twice daily. She experienced minimal improvement of the HS lesions at 2-month follow-up.

Due to disease severity, adalimumab was started. The patient received a loading dose of 4 injections totaling 160 mg and 80 mg on day 15, followed by a maintenance dose of 40 mg/0.4 mL weekly. The patient reported substantial improvement of pain, and complete resolution of active lesions was noted on physical examination after 4 weeks of treatment with adalimumab.

Six weeks after adalimumab was started, the patient developed severe dysphagia. She was evaluated by a gastroenterologist and underwent endoscopy (Figure), which led to a diagnosis of esophageal candidiasis. Adalimumab was discontinued immediately thereafter. The patient started treatment with nystatin oral rinse 4 times daily and oral fluconazole 200 mg daily. The candidiasis resolved within 2 weeks; however, she experienced recurrence of HS with draining lesions in the perivaginal area approximately 8 weeks after discontinuation of adalimumab. The patient requested to restart adalimumab treatment despite the recent history of esophagitis. Adalimumab 40 mg/0.4 mL weekly was restarted along with oral fluconazole 200 mg twice weekly and nystatin oral rinse 4 times daily. This regimen resulted in complete resolution of HS symptoms within 6 weeks with no recurrence of esophageal candidiasis during 6 months of follow-up.

Patients receiving adalimumab for dermatologic or other conditions should be closely monitored for opportunistic infections. Although immunomodulatory medications offer promising therapeutic benefits in patients with HS, larger studies regarding treatment with anti-TNF agents in HS are warranted to prevent complications from treatment and promote long-term efficacy and safety.