Reexamining the Role of Diet in Dermatology

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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 results63,64; 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 suppurativa88,89; 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.

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  77. Wagner N, Dirk D, Peveling-Oberhag A, et al. A popular myth - low-histamine diet improves chronic spontaneous urticaria - fact or fiction? J Eur Acad Dermatol Venereol. 2017;31:650-655. 
  78. Esposito K, Marfella R, Ciotola M, et al. Effect of a Mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. JAMA. 2004;292:1440-1446. 
  79. Steffen LM, Van Horn L, Daviglus ML, et al. A modified Mediterranean diet score is associated with a lower risk of incident metabolic syndrome over 25 years among young adults: the CARDIA (coronary artery risk development in young adults) study. Br J Nutr. 2014;112:1654-1661. 
  80. Bower A, Marquez S, de Mejia EG. The health benefits of selected culinary herbs and spices found in the traditional Mediterranean diet. Crit Rev Food Sci Nutr. 2016;56:2728-2746. 
  81. Bosch R, Philips N, Suárez-Pérez JA, et al. Mechanisms of photoaging and cutaneous photocarcinogenesis, and photoprotective strategies with phytochemicals. Antioxidants (Basel). 2015;4:248-268. 
  82. Katsimbri P, Korakas E, Kountouri A, et al. The effect of antioxidant and anti-inflammatory capacity of diet on psoriasis and psoriatic arthritis phenotype: nutrition as therapeutic tool? Antioxidants. 2021;10:157. 
  83. Molina-Leyva A, Cuenca-Barrales C, Vega-Castillo JJ, et al. Adherence to Mediterranean diet in Spanish patients with psoriasis: cardiovascular benefits? Dermatol Ther. 2019;32:E12810. 
  84. Barrea L, Balato N, Di Somma C, et al. Nutrition and psoriasis: is there any association between the severity of the disease and adherence to the Mediterranean diet? J Transl Med. 2015;13:1-10. 
  85. Phan C, Touvier M, Kesse-Guyot E, et al. Association between Mediterranean anti-inflammatory dietary profile and severity of psoriasis: results from the NutriNet-Santé cohort. JAMA Dermatol. 2018;154:1017-1024. 
  86. Korovesi A, Dalamaga M, Kotopouli M, et al. Adherence to the Mediterranean diet is independently associated with psoriasis risk, severity, and quality of life: a cross-sectional observational study. Int J Dermatol. 2019;58:E164-E165. 
  87. Ford AR, Siegel M, Bagel J, et al. Dietary recommendations for adults with psoriasis or psoriatic arthritis from the medical board of the National Psoriasis Foundation: a systematic review. JAMA Dermatol. 2018;154:934-950. 
  88. Skroza N, Tolino E, Semyonov L, et al. Mediterranean diet and familial dysmetabolism as factors influencing the development of acne. Scand J Public Health. 2012;40:466-474. 
  89. Barrea L, Fabbrocini G, Annunziata G, et al. Role of nutrition and adherence to the Mediterranean diet in the multidisciplinary approach of hidradenitis suppurativa: evaluation of nutritional status and its association with severity of disease. Nutrients. 2018;11:57. 
  90. Nichols JA, Katiyar SK. Skin photoprotection by natural polyphenols: anti-inflammatory, antioxidant and DNA repair mechanisms. Arch Dermatol Res. 2010;302:71-83. 
  91. Huang T-H, Wang P-W, Yang S-C, et al. Cosmetic and therapeutic applications of fish oil's fatty acids on the skin. Mar Drugs. 2018;16:256. 
  92. Rizwan M, Rodriguez-Blanco I, Harbottle A, et al. Tomato paste rich in lycopene protects against cutaneous photodamage in humans in vivo: a randomized controlled trial. Br J Dermatol. 2011;164:154-162. 
  93. Leone A, Martínez-González M, Martin-Gorgojo A, et al. Mediterranean diet, dietary approaches to stop hypertension, and pro-vegetarian dietary pattern in relation to the risk of basal cell carcinoma: a nested case-control study within the Seguimiento Universidad de Navarra (SUN) cohort. Am J Clin Nutr. 2020;112:364-372. 
  94. Solway J, McBride M, Haq F, et al. Diet and dermatology: the role of a whole-food, plant-based diet in preventing and reversing skin aging--a review. J Clin Aesthet Dermatol. 2020;13:38-43. 
  95. Greger M. A whole food plant-based diet is effective for weight loss: the evidence. Am J Lifestyle Med. 2020;14:500-510. 
  96. Wright N, Wilson L, Smith M, et al. The BROAD study: a randomised controlled trial using a whole food plant-based diet in the community for obesity, ischaemic heart disease or diabetes. Nutr Diabetes. 2017;7:E256. 
  97. Ornish D, Lin J, Chan JM, et al. Effect of comprehensive lifestyle changes on telomerase activity and telomere length in men with biopsy-proven low-risk prostate cancer: 5-year follow-up of a descriptive pilot study. Lancet Oncol. 2013;14:1112-1120. 
  98. Ornish D, Lin J, Daubenmier J, et al. Increased telomerase activity and comprehensive lifestyle changes: a pilot study. Lancet Oncol. 2008;9:1048-1057. 
  99. Zouboulis CC, Makrantonaki E. Clinical aspects and molecular diagnostics of skin aging. Clin Dermatol. 2011;29:3-14. 
  100. Gupta L, Khandelwal D, Lal PR, et al. Palaeolithic diet in diabesity and endocrinopathies--a vegan's perspective. Eur Endocrinol. 2019;15:77-82. 
  101. Chassaing B, Van de Wiele T, De Bodt J, et al. Dietary emulsifiers directly alter human microbiota composition and gene expression ex vivo potentiating intestinal inflammation. Gut. 2017;66:1414-1427. 
  102. Thorburn Alison N, Macia L, Mackay Charles R. Diet, metabolites, and "Western lifestyle" inflammatory diseases. Immunity. 2014;40:833-842. 
  103. Katta R, Schlichte M. Diet and dermatitis: food triggers. J Clin Aesthet Dermatol. 2014;7:30-36. 
  104. Dhar S, Srinivas SM. Food allergy in atopic dermatitis. Indian J Dermatol. 2016;61:645-648. 
  105. Birmingham N, Thanesvorakul S, Gangur V. Relative immunogenicity of commonly allergenic foods versus rarely allergenic and nonallergenic foods in mice. J Food Prot. 2002;65:1988-1991. 
  106. Yu W, Freeland DMH, Nadeau KC. Food allergy: immune mechanisms, diagnosis and immunotherapy. Nat Rev Immunol. 2016;16:751-765. 
  107. Kowalski LM, Bujko J. Evaluation of biological and clinical potential of paleolithic diet [in Polish]. Rocz Panstw Zakl Hig. 2012;63:9-15. 
  108. Lee JE, Titcomb TJ, Bisht B, et al. A modified MCT-based ketogenic diet increases plasma β-hydroxybutyrate but has less effect on fatigue and quality of life in people with multiple sclerosis compared to a modified paleolithic diet: a waitlist-controlled, randomized pilot study. J Am Coll Nutr. 2021;40:13-25. 
  109. Abbott RD, Sadowski A, Alt AG. Efficacy of the autoimmune protocol diet as part of a multi-disciplinary, supported lifestyle intervention for Hashimoto's thyroiditis. Cureus. 2019;11:E4556. 
  110. Lindeberg S, Jönsson T, Granfeldt Y, et al. A palaeolithic diet improves glucose tolerance more than a Mediterranean-like diet in individuals with ischaemic heart disease. Diabetologia. 2007;50:1795-1807. 
  111. Jönsson T, Granfeldt Y, Ahrén B, et al. Beneficial effects of a paleolithic diet on cardiovascular risk factors in type 2 diabetes: a randomized cross-over pilot study. Cardiovasc Diabetol. 2009;8:35. 
  112. Boers I, Muskiet FAJ, Berkelaar E, et al. Favourable effects of consuming a palaeolithic-type diet on characteristics of the metabolic syndrome: a randomized controlled pilot-study. Lipids Health Dis. 2014;13:160. 
  113. Ghaedi E, Mohammadi M, Mohammadi H, et al. Effects of a paleolithic diet on cardiovascular disease risk factors: a systematic review and meta-analysis of randomized controlled trials. Adv Nutr. 2019;10:634-646. 
  114. Mellberg C, Sandberg S, Ryberg M, et al. Long-term effects of a palaeolithic-type diet in obese postmenopausal women: a 2-year randomized trial. Eur J Clin Nutr. 2014;68:350-357. 
  115. Pastore RL, Brooks JT, Carbone JW. Paleolithic nutrition improves plasma lipid concentrations of hypercholesterolemic adults to a greater extent than traditional heart-healthy dietary recommendations. Nutr Res. 2015;35:474-479. 
  116. Otten J, Stomby A, Waling M, et al. Benefits of a paleolithic diet with and without supervised exercise on fat mass, insulin sensitivity, and glycemic control: a randomized controlled trial in individuals with type 2 diabetes. Diabetes Metab Res Rev. 2017;33:E2828. 
  117. Stefanadi EC, Dimitrakakis G, Antoniou C-K, et al. Metabolic syndrome and the skin: a more than superficial association. reviewing the association between skin diseases and metabolic syndrome and a clinical decision algorithm for high risk patients. Diabetol Metab Syndr. 2018;10:9. 
  118. Mann N. Meat in the human diet: an anthropological perspective. Nutr Dietetics. 2007;64(suppl 4):S102-S107. 
  119. Bramble DM, Lieberman DE. Endurance running and the evolution of Homo. Nature. 2004;432:345-352. 
  120. Kuhn JE. Throwing, the shoulder, and human evolution. Am J Orthop (Belle Mead NJ). 2016;45:110-114. 
  121. Kobayashi H, Kohshima S. Unique morphology of the human eye and its adaptive meaning: comparative studies on external morphology of the primate eye. J Hum Evol. 2001;40:419-435. 
  122. Cordain L, Eaton SB, Miller JB, et al. The paradoxical nature of hunter-gatherer diets: meat-based, yet non-atherogenic. Eur J Clin Nutr. 2002;56(suppl 1):S42-S52. 
  123. McClellan WS, Du Bois EF. Clinical calorimetry: XLV. prolonged meat diets with a study of kidney function and ketosis. J Biol Chem. 1930;87:651-668. 
  124. O'Hearn A. Can a carnivore diet provide all essential nutrients? Curr Opin Endocrinol Diabetes Obes. 2020;27:312-316. 
  125. O'Hearn LA. A survey of improvements experienced on a carnivore diet compared to only carbohydrate restriction. Open Science Forum website. Published February 12, 2019. Accessed May 17, 2021. doi:10.17605/OSF.IO/5FU4D 
  126. Williams P. Nutritional composition of red meat. Nutrition & Dietetics. 2007;64(suppl 4):S113-S119. 
  127. Biel W, Czerniawska-Piątkowska E, Kowalczyk A. Offal chemical composition from veal, beef, and lamb maintained in organic production systems. Animals (Basel). 2019;9:489. 
  128. Elmadfa I, Meyer AL. The role of the status of selected micronutrients in shaping the immune function. Endocr Metab Immune Disord Drug Targets. 2019;19:1100-1115. 
  129. Babizhayev M. Treatment of skin aging and photoaging with innovative oral dosage forms of nonhydrolized carnosine and carcinine. Int J Clin Derm Res. 2017;5:116-143. 
  130. Danby FW. Nutrition and aging skin: sugar and glycation. Clin Dermatol. 2010;28:409-411. 
  131. Siefken W, Carstensen S, Springmann G, et al. Role of taurine accumulation in keratinocyte hydration. J Invest Dermatol. 2003;121:354-361. 
  132. Vollmer DL, West VA, Lephart ED. Enhancing skin health: by oral administration of natural compounds and minerals with implications to the dermal microbiome. Int J Mol Sci. 2018;19:3059. 
  133. Fischer F, Achterberg V, März A, et al. Folic acid and creatineimprove the firmness of human skin in vivo. J Cosmet Dermatol. 2011;10:15-23. 
  134. Blatt T, Lenz H, Weber T. Topical application of creatine is multibeneficial for human skin. J Am Acad Dermatol. 2005;52:P32.
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Mr. Svoboda is from the Virginia Tech Carilion School of Medicine, Roanoke. Dr. Christopher is from Ironwood Dermatology and Aesthetic Services, Tucson, Arizona. Dr. Shields is from the Department of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison.

The authors report no conflicts of interest.

Correspondence: Bridget E. Shields, MD, 1 S Park St, University of Wisconsin School of Medicine and Public Health, Department of Dermatology, Madison, WI 53711 ([email protected]).

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The authors report no conflicts of interest.

Correspondence: Bridget E. Shields, MD, 1 S Park St, University of Wisconsin School of Medicine and Public Health, Department of Dermatology, Madison, WI 53711 ([email protected]).

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Mr. Svoboda is from the Virginia Tech Carilion School of Medicine, Roanoke. Dr. Christopher is from Ironwood Dermatology and Aesthetic Services, Tucson, Arizona. Dr. Shields is from the Department of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison.

The authors report no conflicts of interest.

Correspondence: Bridget E. Shields, MD, 1 S Park St, University of Wisconsin School of Medicine and Public Health, Department of Dermatology, Madison, WI 53711 ([email protected]).

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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 results63,64; 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 suppurativa88,89; 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 results63,64; 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 suppurativa88,89; 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.

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  90. Nichols JA, Katiyar SK. Skin photoprotection by natural polyphenols: anti-inflammatory, antioxidant and DNA repair mechanisms. Arch Dermatol Res. 2010;302:71-83. 
  91. Huang T-H, Wang P-W, Yang S-C, et al. Cosmetic and therapeutic applications of fish oil's fatty acids on the skin. Mar Drugs. 2018;16:256. 
  92. Rizwan M, Rodriguez-Blanco I, Harbottle A, et al. Tomato paste rich in lycopene protects against cutaneous photodamage in humans in vivo: a randomized controlled trial. Br J Dermatol. 2011;164:154-162. 
  93. Leone A, Martínez-González M, Martin-Gorgojo A, et al. Mediterranean diet, dietary approaches to stop hypertension, and pro-vegetarian dietary pattern in relation to the risk of basal cell carcinoma: a nested case-control study within the Seguimiento Universidad de Navarra (SUN) cohort. Am J Clin Nutr. 2020;112:364-372. 
  94. Solway J, McBride M, Haq F, et al. Diet and dermatology: the role of a whole-food, plant-based diet in preventing and reversing skin aging--a review. J Clin Aesthet Dermatol. 2020;13:38-43. 
  95. Greger M. A whole food plant-based diet is effective for weight loss: the evidence. Am J Lifestyle Med. 2020;14:500-510. 
  96. Wright N, Wilson L, Smith M, et al. The BROAD study: a randomised controlled trial using a whole food plant-based diet in the community for obesity, ischaemic heart disease or diabetes. Nutr Diabetes. 2017;7:E256. 
  97. Ornish D, Lin J, Chan JM, et al. Effect of comprehensive lifestyle changes on telomerase activity and telomere length in men with biopsy-proven low-risk prostate cancer: 5-year follow-up of a descriptive pilot study. Lancet Oncol. 2013;14:1112-1120. 
  98. Ornish D, Lin J, Daubenmier J, et al. Increased telomerase activity and comprehensive lifestyle changes: a pilot study. Lancet Oncol. 2008;9:1048-1057. 
  99. Zouboulis CC, Makrantonaki E. Clinical aspects and molecular diagnostics of skin aging. Clin Dermatol. 2011;29:3-14. 
  100. Gupta L, Khandelwal D, Lal PR, et al. Palaeolithic diet in diabesity and endocrinopathies--a vegan's perspective. Eur Endocrinol. 2019;15:77-82. 
  101. Chassaing B, Van de Wiele T, De Bodt J, et al. Dietary emulsifiers directly alter human microbiota composition and gene expression ex vivo potentiating intestinal inflammation. Gut. 2017;66:1414-1427. 
  102. Thorburn Alison N, Macia L, Mackay Charles R. Diet, metabolites, and "Western lifestyle" inflammatory diseases. Immunity. 2014;40:833-842. 
  103. Katta R, Schlichte M. Diet and dermatitis: food triggers. J Clin Aesthet Dermatol. 2014;7:30-36. 
  104. Dhar S, Srinivas SM. Food allergy in atopic dermatitis. Indian J Dermatol. 2016;61:645-648. 
  105. Birmingham N, Thanesvorakul S, Gangur V. Relative immunogenicity of commonly allergenic foods versus rarely allergenic and nonallergenic foods in mice. J Food Prot. 2002;65:1988-1991. 
  106. Yu W, Freeland DMH, Nadeau KC. Food allergy: immune mechanisms, diagnosis and immunotherapy. Nat Rev Immunol. 2016;16:751-765. 
  107. Kowalski LM, Bujko J. Evaluation of biological and clinical potential of paleolithic diet [in Polish]. Rocz Panstw Zakl Hig. 2012;63:9-15. 
  108. Lee JE, Titcomb TJ, Bisht B, et al. A modified MCT-based ketogenic diet increases plasma β-hydroxybutyrate but has less effect on fatigue and quality of life in people with multiple sclerosis compared to a modified paleolithic diet: a waitlist-controlled, randomized pilot study. J Am Coll Nutr. 2021;40:13-25. 
  109. Abbott RD, Sadowski A, Alt AG. Efficacy of the autoimmune protocol diet as part of a multi-disciplinary, supported lifestyle intervention for Hashimoto's thyroiditis. Cureus. 2019;11:E4556. 
  110. Lindeberg S, Jönsson T, Granfeldt Y, et al. A palaeolithic diet improves glucose tolerance more than a Mediterranean-like diet in individuals with ischaemic heart disease. Diabetologia. 2007;50:1795-1807. 
  111. Jönsson T, Granfeldt Y, Ahrén B, et al. Beneficial effects of a paleolithic diet on cardiovascular risk factors in type 2 diabetes: a randomized cross-over pilot study. Cardiovasc Diabetol. 2009;8:35. 
  112. Boers I, Muskiet FAJ, Berkelaar E, et al. Favourable effects of consuming a palaeolithic-type diet on characteristics of the metabolic syndrome: a randomized controlled pilot-study. Lipids Health Dis. 2014;13:160. 
  113. Ghaedi E, Mohammadi M, Mohammadi H, et al. Effects of a paleolithic diet on cardiovascular disease risk factors: a systematic review and meta-analysis of randomized controlled trials. Adv Nutr. 2019;10:634-646. 
  114. Mellberg C, Sandberg S, Ryberg M, et al. Long-term effects of a palaeolithic-type diet in obese postmenopausal women: a 2-year randomized trial. Eur J Clin Nutr. 2014;68:350-357. 
  115. Pastore RL, Brooks JT, Carbone JW. Paleolithic nutrition improves plasma lipid concentrations of hypercholesterolemic adults to a greater extent than traditional heart-healthy dietary recommendations. Nutr Res. 2015;35:474-479. 
  116. Otten J, Stomby A, Waling M, et al. Benefits of a paleolithic diet with and without supervised exercise on fat mass, insulin sensitivity, and glycemic control: a randomized controlled trial in individuals with type 2 diabetes. Diabetes Metab Res Rev. 2017;33:E2828. 
  117. Stefanadi EC, Dimitrakakis G, Antoniou C-K, et al. Metabolic syndrome and the skin: a more than superficial association. reviewing the association between skin diseases and metabolic syndrome and a clinical decision algorithm for high risk patients. Diabetol Metab Syndr. 2018;10:9. 
  118. Mann N. Meat in the human diet: an anthropological perspective. Nutr Dietetics. 2007;64(suppl 4):S102-S107. 
  119. Bramble DM, Lieberman DE. Endurance running and the evolution of Homo. Nature. 2004;432:345-352. 
  120. Kuhn JE. Throwing, the shoulder, and human evolution. Am J Orthop (Belle Mead NJ). 2016;45:110-114. 
  121. Kobayashi H, Kohshima S. Unique morphology of the human eye and its adaptive meaning: comparative studies on external morphology of the primate eye. J Hum Evol. 2001;40:419-435. 
  122. Cordain L, Eaton SB, Miller JB, et al. The paradoxical nature of hunter-gatherer diets: meat-based, yet non-atherogenic. Eur J Clin Nutr. 2002;56(suppl 1):S42-S52. 
  123. McClellan WS, Du Bois EF. Clinical calorimetry: XLV. prolonged meat diets with a study of kidney function and ketosis. J Biol Chem. 1930;87:651-668. 
  124. O'Hearn A. Can a carnivore diet provide all essential nutrients? Curr Opin Endocrinol Diabetes Obes. 2020;27:312-316. 
  125. O'Hearn LA. A survey of improvements experienced on a carnivore diet compared to only carbohydrate restriction. Open Science Forum website. Published February 12, 2019. Accessed May 17, 2021. doi:10.17605/OSF.IO/5FU4D 
  126. Williams P. Nutritional composition of red meat. Nutrition & Dietetics. 2007;64(suppl 4):S113-S119. 
  127. Biel W, Czerniawska-Piątkowska E, Kowalczyk A. Offal chemical composition from veal, beef, and lamb maintained in organic production systems. Animals (Basel). 2019;9:489. 
  128. Elmadfa I, Meyer AL. The role of the status of selected micronutrients in shaping the immune function. Endocr Metab Immune Disord Drug Targets. 2019;19:1100-1115. 
  129. Babizhayev M. Treatment of skin aging and photoaging with innovative oral dosage forms of nonhydrolized carnosine and carcinine. Int J Clin Derm Res. 2017;5:116-143. 
  130. Danby FW. Nutrition and aging skin: sugar and glycation. Clin Dermatol. 2010;28:409-411. 
  131. Siefken W, Carstensen S, Springmann G, et al. Role of taurine accumulation in keratinocyte hydration. J Invest Dermatol. 2003;121:354-361. 
  132. Vollmer DL, West VA, Lephart ED. Enhancing skin health: by oral administration of natural compounds and minerals with implications to the dermal microbiome. Int J Mol Sci. 2018;19:3059. 
  133. Fischer F, Achterberg V, März A, et al. Folic acid and creatineimprove the firmness of human skin in vivo. J Cosmet Dermatol. 2011;10:15-23. 
  134. Blatt T, Lenz H, Weber T. Topical application of creatine is multibeneficial for human skin. J Am Acad Dermatol. 2005;52:P32.
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  • Patients are increasingly interested in dietary modifications that may influence skin appearance and aid in the treatment of cutaneous disease.
  • 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.
  • There remains a lack of randomized controlled trials assessing the efficacy of various dietary interventions in the dermatologic setting.
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E/M Coding in 2021: The Times (and More) Are A-Changin’

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Effective on January 1, 2021, the outpatient evaluation and management (E/M) codes underwent substantial changes, which were the culmination of multiple years of revision and surveying via the American Medical Association (AMA) Relative Value Scale Update Committee and Current Procedural Terminology (RUC-CPT) process to streamline definitions and promote consistency as well as to decrease the administrative burden for all specialties within the house of medicine.1 These updates represent a notable change from the previous documentation requirements for this oft used family of codes. Herein, we break down some of the highlights of the changes and how they may be applied for some commonly used dermatologic diagnoses.

Time Is Time Is Time

Prior to the 2021 revisions, a physician generally could only code for an E/M level by time for a face-to-face encounter dominated by counseling and/or care coordination. With the new updates, any encounter can be coded by total time spent by the physician with the patient1; however, clinical staff time is not included. There also are now clear guidelines of the time ranges corresponding to the level of E/M,1 as noted in Table 1.

Importantly, time now includes not just face-to-face time with the patient but also any time on the date of the encounter that the physician is involved in the care of the patient when not reported with a separate code. This can include reviewing notes or data before or after the examination, care coordination, ordering laboratory tests, and providing any documentation related to the encounter. Importantly, this applies only when these activities are done on the date of the encounter.



If you work with a nurse practitioner or physician assistant (PA) who assists you and you are the one reporting the service, you cannot double-dip. For example, if your PA spends 10 minutes alone with a patient, you are in the room together for 5 minutes, the PA spends another 10 minutes alone with the patient afterward, and you do chart work for 10 minutes at the end of the day, the total time spent is 35 minutes, not 40 minutes, as you cannot count the time you and the PA spent together twice.

Decisions, Decisions

Evaluation and management coding also can be determined via the level of medical decision-making (MDM). Per the 2021 guidelines, MDM is comprised of 3 categories: (1) number and complexity of problems addressed at the encounter, (2) amount and/or complexity of data to be reviewed or analyzed, and (3) risk of complications and/or morbidity or mortality of patient management.1 To reach a certain overall E/M level, 2 of 3 categories must be met or exceeded. Let’s dive into each of these in a little more detail.

Number and Complexity of Problems Addressed at the Encounter
First, it is important to understand the definition of a problem addressed. Per AMA guidelines, this includes a disease, condition, illness, injury, symptom, sign, finding, complaint, or other matter addressed at the encounter that is evaluated or treated at the encounter by the physician. If the problem is referred to another provider without evaluation or consideration of treatment, it is not considered to be a problem addressed and cannot count toward this first category. An example could be a patient with a lump on the abdomen that you refer to plastic or general surgery for evaluation and treatment.

Once you have determined that you are addressing a problem, you will need to determine the level of complexity of the problem, as outlined in Table 2. Keep in mind that some entities and disease states in dermatology may fit the requirements of more than 1 level of complexity depending on the clinical situation, while there are many entities in dermatology that may not be perfectly captured by any of the levels described. In these situations, clinical judgement is required to determine where the problem would best fit. Importantly, whatever you decide, your documentation should support that decision.



Amount and/or Complexity of Data to Be Reviewed and Analyzed
This category encompasses any external notes reviewed, unique laboratory tests or imaging ordered or reviewed, the need for an independent historian or discussion with external health care providers or appropriate sources, or independent interpretation of tests. Some high-yield definitions in this category are outlined in Table 3.



Risk of Complications and/or Morbidity or Mortality of Patient Management
In this category, risk relates to both the patient’s diagnosis and treatment(s). Importantly, for treatment and diagnostic options, these include both the options selected and those considered but not selected. Risk is defined as the probability and/or consequences of an event and is based on the usual behavior and thought processes of a physician in the same specialty. In other words, think of the risk as compared to risk in the setting of other dermatologists diagnosing and/or treating the same condition.

Social determinants of health also play a part in this category and are defined as economic and social conditions that influence the health of individuals and communities. Social determinants of health can be indicated by the specific corresponding International Statistical Classification of Diseases, Tenth Revision code and may need to be included in your billing according to specific institutional or carrier guidelines if they are a factor in your level of MDM.

For the purposes of MDM, risk is stratified into minimal, low, moderate, and high. Some examples for each level are outlined in Table 4.

Putting It All Together

Once you have determined each of the above 3 categories, you can put them together into the MDM chart to ascertain the overall level of MDM. (The official AMA medical decision-making grid is available online [https://www.ama-assn.org/system/files/2019-06/cpt-revised-mdm-grid.pdf]). Keep in mind that 2 of 3 columns in the table must be obtained in that level to reach an overall E/M level; for example, a visit that addresses 2 self-limited or minor problems (level 3) in which no data is reviewed (level 2) and involves prescribing a new medication (level 4), would be an overall level 3 visit.

Final Thoughts

The outpatient E/M guidelines have undergone substantial revisions; therefore, it is crucial to understand the updated definitions to ensure proper billing and documentation. History and physical examination documentation must be medically appropriate but are no longer used to determine overall E/M level; time and MDM are the sole options that can be used. Importantly, try to code as accurately as possible, documenting which problems were both noted and addressed. If you are unsure of a definition within the updated changes and MDM table, referencing the appropriate sources for guidance is recommended.

Although representing a considerable shift, the revaluation of this family of codes and the intended decrease in documentation burden has the ability to be a positive gain for dermatologists. Expect other code families to mirror these changes in the next few years.

References
  1. American Medical Association. CPT® Evaluation and management (E/M) office or other outpatient (99202-99215) and prolonged services (99354, 99355, 99356, 99417) code and guideline changes. Accessed May 14, 2021. https://www.ama-assn.org/system/files/2019-06/cpt-office-prolonged-svs-code-changes.pdf
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Dr. Flamm is from the Department of Dermatology, Penn State Hershey Medical Center. Dr. Bridges is from Richfield Laboratory of Dermatopathology, Dermpath Diagnostics, Cincinnati, Ohio. Dr. Siegel is from the Department of Dermatology, SUNY Downstate Medical Center, Brooklyn.

The authors report no conflict of interest.

Correspondence: Alexandra Flamm, MD, Penn State Hershey Medical Center, Department of Dermatology, 500 University Dr, Hershey, PA 17033 ([email protected]).

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Dr. Flamm is from the Department of Dermatology, Penn State Hershey Medical Center. Dr. Bridges is from Richfield Laboratory of Dermatopathology, Dermpath Diagnostics, Cincinnati, Ohio. Dr. Siegel is from the Department of Dermatology, SUNY Downstate Medical Center, Brooklyn.

The authors report no conflict of interest.

Correspondence: Alexandra Flamm, MD, Penn State Hershey Medical Center, Department of Dermatology, 500 University Dr, Hershey, PA 17033 ([email protected]).

Author and Disclosure Information

Dr. Flamm is from the Department of Dermatology, Penn State Hershey Medical Center. Dr. Bridges is from Richfield Laboratory of Dermatopathology, Dermpath Diagnostics, Cincinnati, Ohio. Dr. Siegel is from the Department of Dermatology, SUNY Downstate Medical Center, Brooklyn.

The authors report no conflict of interest.

Correspondence: Alexandra Flamm, MD, Penn State Hershey Medical Center, Department of Dermatology, 500 University Dr, Hershey, PA 17033 ([email protected]).

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Article PDF

Effective on January 1, 2021, the outpatient evaluation and management (E/M) codes underwent substantial changes, which were the culmination of multiple years of revision and surveying via the American Medical Association (AMA) Relative Value Scale Update Committee and Current Procedural Terminology (RUC-CPT) process to streamline definitions and promote consistency as well as to decrease the administrative burden for all specialties within the house of medicine.1 These updates represent a notable change from the previous documentation requirements for this oft used family of codes. Herein, we break down some of the highlights of the changes and how they may be applied for some commonly used dermatologic diagnoses.

Time Is Time Is Time

Prior to the 2021 revisions, a physician generally could only code for an E/M level by time for a face-to-face encounter dominated by counseling and/or care coordination. With the new updates, any encounter can be coded by total time spent by the physician with the patient1; however, clinical staff time is not included. There also are now clear guidelines of the time ranges corresponding to the level of E/M,1 as noted in Table 1.

Importantly, time now includes not just face-to-face time with the patient but also any time on the date of the encounter that the physician is involved in the care of the patient when not reported with a separate code. This can include reviewing notes or data before or after the examination, care coordination, ordering laboratory tests, and providing any documentation related to the encounter. Importantly, this applies only when these activities are done on the date of the encounter.



If you work with a nurse practitioner or physician assistant (PA) who assists you and you are the one reporting the service, you cannot double-dip. For example, if your PA spends 10 minutes alone with a patient, you are in the room together for 5 minutes, the PA spends another 10 minutes alone with the patient afterward, and you do chart work for 10 minutes at the end of the day, the total time spent is 35 minutes, not 40 minutes, as you cannot count the time you and the PA spent together twice.

Decisions, Decisions

Evaluation and management coding also can be determined via the level of medical decision-making (MDM). Per the 2021 guidelines, MDM is comprised of 3 categories: (1) number and complexity of problems addressed at the encounter, (2) amount and/or complexity of data to be reviewed or analyzed, and (3) risk of complications and/or morbidity or mortality of patient management.1 To reach a certain overall E/M level, 2 of 3 categories must be met or exceeded. Let’s dive into each of these in a little more detail.

Number and Complexity of Problems Addressed at the Encounter
First, it is important to understand the definition of a problem addressed. Per AMA guidelines, this includes a disease, condition, illness, injury, symptom, sign, finding, complaint, or other matter addressed at the encounter that is evaluated or treated at the encounter by the physician. If the problem is referred to another provider without evaluation or consideration of treatment, it is not considered to be a problem addressed and cannot count toward this first category. An example could be a patient with a lump on the abdomen that you refer to plastic or general surgery for evaluation and treatment.

Once you have determined that you are addressing a problem, you will need to determine the level of complexity of the problem, as outlined in Table 2. Keep in mind that some entities and disease states in dermatology may fit the requirements of more than 1 level of complexity depending on the clinical situation, while there are many entities in dermatology that may not be perfectly captured by any of the levels described. In these situations, clinical judgement is required to determine where the problem would best fit. Importantly, whatever you decide, your documentation should support that decision.



Amount and/or Complexity of Data to Be Reviewed and Analyzed
This category encompasses any external notes reviewed, unique laboratory tests or imaging ordered or reviewed, the need for an independent historian or discussion with external health care providers or appropriate sources, or independent interpretation of tests. Some high-yield definitions in this category are outlined in Table 3.



Risk of Complications and/or Morbidity or Mortality of Patient Management
In this category, risk relates to both the patient’s diagnosis and treatment(s). Importantly, for treatment and diagnostic options, these include both the options selected and those considered but not selected. Risk is defined as the probability and/or consequences of an event and is based on the usual behavior and thought processes of a physician in the same specialty. In other words, think of the risk as compared to risk in the setting of other dermatologists diagnosing and/or treating the same condition.

Social determinants of health also play a part in this category and are defined as economic and social conditions that influence the health of individuals and communities. Social determinants of health can be indicated by the specific corresponding International Statistical Classification of Diseases, Tenth Revision code and may need to be included in your billing according to specific institutional or carrier guidelines if they are a factor in your level of MDM.

For the purposes of MDM, risk is stratified into minimal, low, moderate, and high. Some examples for each level are outlined in Table 4.

Putting It All Together

Once you have determined each of the above 3 categories, you can put them together into the MDM chart to ascertain the overall level of MDM. (The official AMA medical decision-making grid is available online [https://www.ama-assn.org/system/files/2019-06/cpt-revised-mdm-grid.pdf]). Keep in mind that 2 of 3 columns in the table must be obtained in that level to reach an overall E/M level; for example, a visit that addresses 2 self-limited or minor problems (level 3) in which no data is reviewed (level 2) and involves prescribing a new medication (level 4), would be an overall level 3 visit.

Final Thoughts

The outpatient E/M guidelines have undergone substantial revisions; therefore, it is crucial to understand the updated definitions to ensure proper billing and documentation. History and physical examination documentation must be medically appropriate but are no longer used to determine overall E/M level; time and MDM are the sole options that can be used. Importantly, try to code as accurately as possible, documenting which problems were both noted and addressed. If you are unsure of a definition within the updated changes and MDM table, referencing the appropriate sources for guidance is recommended.

Although representing a considerable shift, the revaluation of this family of codes and the intended decrease in documentation burden has the ability to be a positive gain for dermatologists. Expect other code families to mirror these changes in the next few years.

Effective on January 1, 2021, the outpatient evaluation and management (E/M) codes underwent substantial changes, which were the culmination of multiple years of revision and surveying via the American Medical Association (AMA) Relative Value Scale Update Committee and Current Procedural Terminology (RUC-CPT) process to streamline definitions and promote consistency as well as to decrease the administrative burden for all specialties within the house of medicine.1 These updates represent a notable change from the previous documentation requirements for this oft used family of codes. Herein, we break down some of the highlights of the changes and how they may be applied for some commonly used dermatologic diagnoses.

Time Is Time Is Time

Prior to the 2021 revisions, a physician generally could only code for an E/M level by time for a face-to-face encounter dominated by counseling and/or care coordination. With the new updates, any encounter can be coded by total time spent by the physician with the patient1; however, clinical staff time is not included. There also are now clear guidelines of the time ranges corresponding to the level of E/M,1 as noted in Table 1.

Importantly, time now includes not just face-to-face time with the patient but also any time on the date of the encounter that the physician is involved in the care of the patient when not reported with a separate code. This can include reviewing notes or data before or after the examination, care coordination, ordering laboratory tests, and providing any documentation related to the encounter. Importantly, this applies only when these activities are done on the date of the encounter.



If you work with a nurse practitioner or physician assistant (PA) who assists you and you are the one reporting the service, you cannot double-dip. For example, if your PA spends 10 minutes alone with a patient, you are in the room together for 5 minutes, the PA spends another 10 minutes alone with the patient afterward, and you do chart work for 10 minutes at the end of the day, the total time spent is 35 minutes, not 40 minutes, as you cannot count the time you and the PA spent together twice.

Decisions, Decisions

Evaluation and management coding also can be determined via the level of medical decision-making (MDM). Per the 2021 guidelines, MDM is comprised of 3 categories: (1) number and complexity of problems addressed at the encounter, (2) amount and/or complexity of data to be reviewed or analyzed, and (3) risk of complications and/or morbidity or mortality of patient management.1 To reach a certain overall E/M level, 2 of 3 categories must be met or exceeded. Let’s dive into each of these in a little more detail.

Number and Complexity of Problems Addressed at the Encounter
First, it is important to understand the definition of a problem addressed. Per AMA guidelines, this includes a disease, condition, illness, injury, symptom, sign, finding, complaint, or other matter addressed at the encounter that is evaluated or treated at the encounter by the physician. If the problem is referred to another provider without evaluation or consideration of treatment, it is not considered to be a problem addressed and cannot count toward this first category. An example could be a patient with a lump on the abdomen that you refer to plastic or general surgery for evaluation and treatment.

Once you have determined that you are addressing a problem, you will need to determine the level of complexity of the problem, as outlined in Table 2. Keep in mind that some entities and disease states in dermatology may fit the requirements of more than 1 level of complexity depending on the clinical situation, while there are many entities in dermatology that may not be perfectly captured by any of the levels described. In these situations, clinical judgement is required to determine where the problem would best fit. Importantly, whatever you decide, your documentation should support that decision.



Amount and/or Complexity of Data to Be Reviewed and Analyzed
This category encompasses any external notes reviewed, unique laboratory tests or imaging ordered or reviewed, the need for an independent historian or discussion with external health care providers or appropriate sources, or independent interpretation of tests. Some high-yield definitions in this category are outlined in Table 3.



Risk of Complications and/or Morbidity or Mortality of Patient Management
In this category, risk relates to both the patient’s diagnosis and treatment(s). Importantly, for treatment and diagnostic options, these include both the options selected and those considered but not selected. Risk is defined as the probability and/or consequences of an event and is based on the usual behavior and thought processes of a physician in the same specialty. In other words, think of the risk as compared to risk in the setting of other dermatologists diagnosing and/or treating the same condition.

Social determinants of health also play a part in this category and are defined as economic and social conditions that influence the health of individuals and communities. Social determinants of health can be indicated by the specific corresponding International Statistical Classification of Diseases, Tenth Revision code and may need to be included in your billing according to specific institutional or carrier guidelines if they are a factor in your level of MDM.

For the purposes of MDM, risk is stratified into minimal, low, moderate, and high. Some examples for each level are outlined in Table 4.

Putting It All Together

Once you have determined each of the above 3 categories, you can put them together into the MDM chart to ascertain the overall level of MDM. (The official AMA medical decision-making grid is available online [https://www.ama-assn.org/system/files/2019-06/cpt-revised-mdm-grid.pdf]). Keep in mind that 2 of 3 columns in the table must be obtained in that level to reach an overall E/M level; for example, a visit that addresses 2 self-limited or minor problems (level 3) in which no data is reviewed (level 2) and involves prescribing a new medication (level 4), would be an overall level 3 visit.

Final Thoughts

The outpatient E/M guidelines have undergone substantial revisions; therefore, it is crucial to understand the updated definitions to ensure proper billing and documentation. History and physical examination documentation must be medically appropriate but are no longer used to determine overall E/M level; time and MDM are the sole options that can be used. Importantly, try to code as accurately as possible, documenting which problems were both noted and addressed. If you are unsure of a definition within the updated changes and MDM table, referencing the appropriate sources for guidance is recommended.

Although representing a considerable shift, the revaluation of this family of codes and the intended decrease in documentation burden has the ability to be a positive gain for dermatologists. Expect other code families to mirror these changes in the next few years.

References
  1. American Medical Association. CPT® Evaluation and management (E/M) office or other outpatient (99202-99215) and prolonged services (99354, 99355, 99356, 99417) code and guideline changes. Accessed May 14, 2021. https://www.ama-assn.org/system/files/2019-06/cpt-office-prolonged-svs-code-changes.pdf
References
  1. American Medical Association. CPT® Evaluation and management (E/M) office or other outpatient (99202-99215) and prolonged services (99354, 99355, 99356, 99417) code and guideline changes. Accessed May 14, 2021. https://www.ama-assn.org/system/files/2019-06/cpt-office-prolonged-svs-code-changes.pdf
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Practice Points

  • The outpatient evaluation and management (E/M) codes have undergone substantial changes that took effect January 1, 2021.
  • Outpatient E/M visits are now coded based on time or level of medical decision-making (MDM).
  • Time now includes all preservice, intraservice, and postservice time the physician spends with the patient on the date of the encounter.
  • Many of the key definitions used in order to determine level of MDM have been streamlined and updated.
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MDS: Elevated mature monocytes in bone marrow can supplement IPSS-R as a prognostic indicator

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Key clinical point: Increased percentage of mature monocyte in bone marrow (PMMBM) may assist the Revised International Prognostic Scoring System (IPSS-R) to predict poor prognosis in patients with myelodysplastic syndromes (MDS).

Major finding: Elevated (>6%) vs. normal PMMBM was associated with shorter overall survival (24 months vs. 37 months; P = .026) along with higher risk distribution in terms of IPSS-R (P = .025) and higher frequency of IDH2 mutation (P = .007).

Study details: The data come from a retrospective analysis of 216 MDS patients, categorized into elevated and normal PMMBM groups.

Disclosures: The study was supported by the Zhejiang Provincial Natural Science Foundation of China, Medical and Health Science and Technology Projects of Zhejiang Province, National Science Foundation of Ningbo, and Chinese Medicine Science and Technology Plan Project of Zhejiang Province. The authors declared no conflicts of interest.

Source: Wu A et al. BMC Cancer. 2021 May 13. doi: 10.1186/s12885-021-08303-8.

 

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Key clinical point: Increased percentage of mature monocyte in bone marrow (PMMBM) may assist the Revised International Prognostic Scoring System (IPSS-R) to predict poor prognosis in patients with myelodysplastic syndromes (MDS).

Major finding: Elevated (>6%) vs. normal PMMBM was associated with shorter overall survival (24 months vs. 37 months; P = .026) along with higher risk distribution in terms of IPSS-R (P = .025) and higher frequency of IDH2 mutation (P = .007).

Study details: The data come from a retrospective analysis of 216 MDS patients, categorized into elevated and normal PMMBM groups.

Disclosures: The study was supported by the Zhejiang Provincial Natural Science Foundation of China, Medical and Health Science and Technology Projects of Zhejiang Province, National Science Foundation of Ningbo, and Chinese Medicine Science and Technology Plan Project of Zhejiang Province. The authors declared no conflicts of interest.

Source: Wu A et al. BMC Cancer. 2021 May 13. doi: 10.1186/s12885-021-08303-8.

 

Key clinical point: Increased percentage of mature monocyte in bone marrow (PMMBM) may assist the Revised International Prognostic Scoring System (IPSS-R) to predict poor prognosis in patients with myelodysplastic syndromes (MDS).

Major finding: Elevated (>6%) vs. normal PMMBM was associated with shorter overall survival (24 months vs. 37 months; P = .026) along with higher risk distribution in terms of IPSS-R (P = .025) and higher frequency of IDH2 mutation (P = .007).

Study details: The data come from a retrospective analysis of 216 MDS patients, categorized into elevated and normal PMMBM groups.

Disclosures: The study was supported by the Zhejiang Provincial Natural Science Foundation of China, Medical and Health Science and Technology Projects of Zhejiang Province, National Science Foundation of Ningbo, and Chinese Medicine Science and Technology Plan Project of Zhejiang Province. The authors declared no conflicts of interest.

Source: Wu A et al. BMC Cancer. 2021 May 13. doi: 10.1186/s12885-021-08303-8.

 

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MDS: Antibiotics can be stopped after 3 days in patients with febrile neutropenia after chemotherapy

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Key clinical point: During remission induction chemotherapy in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), antibiotics can be safely stopped after 3 days of febrile neutropenia in the absence of infection.

Major finding: Serious medical complication (SMC) was seen in 12.5% of patients receiving the 3-day empirical broad-spectrum antibiotic therapy (EBAT) vs. 8.9% of patients receiving the prolonged regimen (P = .17). After adjustment for confounders, there was no significant difference between both strategies in the number of SMCs (hazard ratio, 1.357; P = .297).

Study details: AML or MDS patients who received chemotherapy were treated with either 3-day EBAT or a prolonged antibiotic regimen (until neutrophil recovery).

Disclosures: The study did not receive any specific funding. A Schauwvlieghe, J Maertens, and T Mercier reported relationships with various pharmaceutical companies. The remaining authors declared no conflicts of interest.

Source: Schauwvlieghe A et al. EClinicalMedicine. 2021 Apr 25. doi: 10.1016/j.eclinm.2021.100855.

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Key clinical point: During remission induction chemotherapy in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), antibiotics can be safely stopped after 3 days of febrile neutropenia in the absence of infection.

Major finding: Serious medical complication (SMC) was seen in 12.5% of patients receiving the 3-day empirical broad-spectrum antibiotic therapy (EBAT) vs. 8.9% of patients receiving the prolonged regimen (P = .17). After adjustment for confounders, there was no significant difference between both strategies in the number of SMCs (hazard ratio, 1.357; P = .297).

Study details: AML or MDS patients who received chemotherapy were treated with either 3-day EBAT or a prolonged antibiotic regimen (until neutrophil recovery).

Disclosures: The study did not receive any specific funding. A Schauwvlieghe, J Maertens, and T Mercier reported relationships with various pharmaceutical companies. The remaining authors declared no conflicts of interest.

Source: Schauwvlieghe A et al. EClinicalMedicine. 2021 Apr 25. doi: 10.1016/j.eclinm.2021.100855.

Key clinical point: During remission induction chemotherapy in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), antibiotics can be safely stopped after 3 days of febrile neutropenia in the absence of infection.

Major finding: Serious medical complication (SMC) was seen in 12.5% of patients receiving the 3-day empirical broad-spectrum antibiotic therapy (EBAT) vs. 8.9% of patients receiving the prolonged regimen (P = .17). After adjustment for confounders, there was no significant difference between both strategies in the number of SMCs (hazard ratio, 1.357; P = .297).

Study details: AML or MDS patients who received chemotherapy were treated with either 3-day EBAT or a prolonged antibiotic regimen (until neutrophil recovery).

Disclosures: The study did not receive any specific funding. A Schauwvlieghe, J Maertens, and T Mercier reported relationships with various pharmaceutical companies. The remaining authors declared no conflicts of interest.

Source: Schauwvlieghe A et al. EClinicalMedicine. 2021 Apr 25. doi: 10.1016/j.eclinm.2021.100855.

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De novo MDS: Pretransplant RBC and platelet transfusion burden tied to poor survival outcomes

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Key clinical point: Higher pretransplant red blood cell (RBC) and platelet transfusion burden has an independent association with higher overall and relapse-related mortality following allogeneic hematopoietic stem cell transplantation (allo-HSCT) for de novo myelodysplastic syndrome (MDS).

Major finding: A higher pretransplant RBC transfusion burden was significantly associated with lower overall survival (OS; P less than .001) and higher relapse-related mortality (P less than .001). Similarly, a higher pretransplant platelet transfusion burden was associated with lower OS (P less than .001) and higher relapse-related mortality (P = .001).

Study details: A retrospective study examined the effects of pretransplant RBC and platelet transfusion burden on outcomes after allo-HSCT in 1,007 adults with de novo MDS.

Disclosures: This study was supported in part by the Practical Research Project for Allergic Diseases and Immunology (Research Technology of Medical Transplantation) from the Japan Agency for Medical Research and Development. The authors declared no conflicts of interest.

Source: Konuma T et al. Transplant Cell Ther. 2021 May 12. doi: 10.1016/j.jtct.2021.05.003.

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Key clinical point: Higher pretransplant red blood cell (RBC) and platelet transfusion burden has an independent association with higher overall and relapse-related mortality following allogeneic hematopoietic stem cell transplantation (allo-HSCT) for de novo myelodysplastic syndrome (MDS).

Major finding: A higher pretransplant RBC transfusion burden was significantly associated with lower overall survival (OS; P less than .001) and higher relapse-related mortality (P less than .001). Similarly, a higher pretransplant platelet transfusion burden was associated with lower OS (P less than .001) and higher relapse-related mortality (P = .001).

Study details: A retrospective study examined the effects of pretransplant RBC and platelet transfusion burden on outcomes after allo-HSCT in 1,007 adults with de novo MDS.

Disclosures: This study was supported in part by the Practical Research Project for Allergic Diseases and Immunology (Research Technology of Medical Transplantation) from the Japan Agency for Medical Research and Development. The authors declared no conflicts of interest.

Source: Konuma T et al. Transplant Cell Ther. 2021 May 12. doi: 10.1016/j.jtct.2021.05.003.

Key clinical point: Higher pretransplant red blood cell (RBC) and platelet transfusion burden has an independent association with higher overall and relapse-related mortality following allogeneic hematopoietic stem cell transplantation (allo-HSCT) for de novo myelodysplastic syndrome (MDS).

Major finding: A higher pretransplant RBC transfusion burden was significantly associated with lower overall survival (OS; P less than .001) and higher relapse-related mortality (P less than .001). Similarly, a higher pretransplant platelet transfusion burden was associated with lower OS (P less than .001) and higher relapse-related mortality (P = .001).

Study details: A retrospective study examined the effects of pretransplant RBC and platelet transfusion burden on outcomes after allo-HSCT in 1,007 adults with de novo MDS.

Disclosures: This study was supported in part by the Practical Research Project for Allergic Diseases and Immunology (Research Technology of Medical Transplantation) from the Japan Agency for Medical Research and Development. The authors declared no conflicts of interest.

Source: Konuma T et al. Transplant Cell Ther. 2021 May 12. doi: 10.1016/j.jtct.2021.05.003.

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Less restrictive enrollment criteria warranted for MDS clinical trials

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Key clinical point: Less restrictive inclusion and exclusion criteria are warranted to improve the participation of patients with myelodysplastic syndrome (MDS) in clinical trials.

Major finding: Each trial was suitable for ~18% of patients in the cohort, whereas 34% of the patients were eligible for at least 1 of the 9 trials. Pharma-initiated trials excluded more than twice the fraction of patients vs. investigator-initiated trials (inclusion, 10% vs. 21%). Key reasons for exclusion included karyotype (average exclusion rate, 58%), comorbidities (40%), and previous therapies (55%)

Study details: A simulation exercise was performed to estimate the average proportion of MDS patients eligible for participation in a clinical trial. A total of 1,809 patients were included in the cohort.

Disclosures: This study did not receive any funding. K Nachtkamp, T Schroeder, E Schuler, J Kaivers, A Giagounidis, C Rautenberg, N Gattermann, and U Germing reported relationships with various pharmaceutical companies. The remaining authors declared no conflicts of interest.

Source: Nachtkamp K et al. Leuk Res. 2021 May 11. doi: 10.1016/j.leukres.2021.106611.

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Key clinical point: Less restrictive inclusion and exclusion criteria are warranted to improve the participation of patients with myelodysplastic syndrome (MDS) in clinical trials.

Major finding: Each trial was suitable for ~18% of patients in the cohort, whereas 34% of the patients were eligible for at least 1 of the 9 trials. Pharma-initiated trials excluded more than twice the fraction of patients vs. investigator-initiated trials (inclusion, 10% vs. 21%). Key reasons for exclusion included karyotype (average exclusion rate, 58%), comorbidities (40%), and previous therapies (55%)

Study details: A simulation exercise was performed to estimate the average proportion of MDS patients eligible for participation in a clinical trial. A total of 1,809 patients were included in the cohort.

Disclosures: This study did not receive any funding. K Nachtkamp, T Schroeder, E Schuler, J Kaivers, A Giagounidis, C Rautenberg, N Gattermann, and U Germing reported relationships with various pharmaceutical companies. The remaining authors declared no conflicts of interest.

Source: Nachtkamp K et al. Leuk Res. 2021 May 11. doi: 10.1016/j.leukres.2021.106611.


Key clinical point: Less restrictive inclusion and exclusion criteria are warranted to improve the participation of patients with myelodysplastic syndrome (MDS) in clinical trials.

Major finding: Each trial was suitable for ~18% of patients in the cohort, whereas 34% of the patients were eligible for at least 1 of the 9 trials. Pharma-initiated trials excluded more than twice the fraction of patients vs. investigator-initiated trials (inclusion, 10% vs. 21%). Key reasons for exclusion included karyotype (average exclusion rate, 58%), comorbidities (40%), and previous therapies (55%)

Study details: A simulation exercise was performed to estimate the average proportion of MDS patients eligible for participation in a clinical trial. A total of 1,809 patients were included in the cohort.

Disclosures: This study did not receive any funding. K Nachtkamp, T Schroeder, E Schuler, J Kaivers, A Giagounidis, C Rautenberg, N Gattermann, and U Germing reported relationships with various pharmaceutical companies. The remaining authors declared no conflicts of interest.

Source: Nachtkamp K et al. Leuk Res. 2021 May 11. doi: 10.1016/j.leukres.2021.106611.

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T-cell inhibition by PD-L1-expressing stem cells may play a role in MDS development

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Key clinical point: Inhibition of T cells by programmed death-ligand 1 (PD-L1)-expressing hematopoietic stem cells could be an underlying mechanism in the development of myelodysplastic syndrome (MDS). The findings support the potential use of immune checkpoint inhibitors in the treatment of suitable MDS patients.

Major finding: Significantly increased proportions of PD-L1+CD34+ stem cells were seen in MDS patients compared with hematopoietic stem cell transplantation (HSCT) recipients in remission for both the CD38 subset (P = .0127) and CD38+ subset (P = .0336).

Study details: The study included 7 MDS and 9 acute myeloid leukemia samples. Six HSCT recipients who remained in remission for more than 6 months were considered controls.

Disclosures: The study was supported by the Düsseldorf School of Oncology (funded by the Comprehensive Cancer Center Düsseldorf/Deutsche Krebshilfe and the Medical Faculty HHU Düsseldorf). The authors declared no conflicts of interest.

Source: Moskorz W et al. Br J Haematol. 2021 May 6. doi: 10.1111/bjh.17461.

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Key clinical point: Inhibition of T cells by programmed death-ligand 1 (PD-L1)-expressing hematopoietic stem cells could be an underlying mechanism in the development of myelodysplastic syndrome (MDS). The findings support the potential use of immune checkpoint inhibitors in the treatment of suitable MDS patients.

Major finding: Significantly increased proportions of PD-L1+CD34+ stem cells were seen in MDS patients compared with hematopoietic stem cell transplantation (HSCT) recipients in remission for both the CD38 subset (P = .0127) and CD38+ subset (P = .0336).

Study details: The study included 7 MDS and 9 acute myeloid leukemia samples. Six HSCT recipients who remained in remission for more than 6 months were considered controls.

Disclosures: The study was supported by the Düsseldorf School of Oncology (funded by the Comprehensive Cancer Center Düsseldorf/Deutsche Krebshilfe and the Medical Faculty HHU Düsseldorf). The authors declared no conflicts of interest.

Source: Moskorz W et al. Br J Haematol. 2021 May 6. doi: 10.1111/bjh.17461.

Key clinical point: Inhibition of T cells by programmed death-ligand 1 (PD-L1)-expressing hematopoietic stem cells could be an underlying mechanism in the development of myelodysplastic syndrome (MDS). The findings support the potential use of immune checkpoint inhibitors in the treatment of suitable MDS patients.

Major finding: Significantly increased proportions of PD-L1+CD34+ stem cells were seen in MDS patients compared with hematopoietic stem cell transplantation (HSCT) recipients in remission for both the CD38 subset (P = .0127) and CD38+ subset (P = .0336).

Study details: The study included 7 MDS and 9 acute myeloid leukemia samples. Six HSCT recipients who remained in remission for more than 6 months were considered controls.

Disclosures: The study was supported by the Düsseldorf School of Oncology (funded by the Comprehensive Cancer Center Düsseldorf/Deutsche Krebshilfe and the Medical Faculty HHU Düsseldorf). The authors declared no conflicts of interest.

Source: Moskorz W et al. Br J Haematol. 2021 May 6. doi: 10.1111/bjh.17461.

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Increased cumulative exposure to melphalan in multiple myeloma patients increases MDS risk

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Key clinical point: Increased cumulative exposure to the alkylating agent melphalan increases the subsequent risk for developing acute myeloid leukemia/myelodysplastic syndromes (AML/MDS) in patients with multiple myeloma (MM).

Major finding: Cumulative exposure to melphalan was significantly higher (odds ratio, 2.8; P less than .001) among patients with MM and AML/MDS (median, 988 mg) than control participants (median, 578 mg). The median time to development of AML/MDS was 3.8 years.

Study details: The study included 26,627 patients diagnosed with MM between 1985 and 2011, of which 124 (0.5%) patients developed subsequent AML/MDS. Each patient with MM and AML/MDS diagnosis was matched with a control MM patient without AML/MDS.

Disclosures: The study was supported by grants from the Asrun Einarsdottir Foundation in Iceland, University of Iceland Research Fund, Icelandic Centre for Research, Landspitali University Hospital Research Fund, Thorman’s foundation, and Sylvester Comprehensive Cancer Center NCI Core Grant. O Landgren and M Björkholm reported ties with various pharmaceutical companies. The remaining authors declared no conflicts of interest.

Source: Jonsdottir G et al. Eur J Haematol. 2021 May 9. doi: 10.1111/ejh.13650.

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Key clinical point: Increased cumulative exposure to the alkylating agent melphalan increases the subsequent risk for developing acute myeloid leukemia/myelodysplastic syndromes (AML/MDS) in patients with multiple myeloma (MM).

Major finding: Cumulative exposure to melphalan was significantly higher (odds ratio, 2.8; P less than .001) among patients with MM and AML/MDS (median, 988 mg) than control participants (median, 578 mg). The median time to development of AML/MDS was 3.8 years.

Study details: The study included 26,627 patients diagnosed with MM between 1985 and 2011, of which 124 (0.5%) patients developed subsequent AML/MDS. Each patient with MM and AML/MDS diagnosis was matched with a control MM patient without AML/MDS.

Disclosures: The study was supported by grants from the Asrun Einarsdottir Foundation in Iceland, University of Iceland Research Fund, Icelandic Centre for Research, Landspitali University Hospital Research Fund, Thorman’s foundation, and Sylvester Comprehensive Cancer Center NCI Core Grant. O Landgren and M Björkholm reported ties with various pharmaceutical companies. The remaining authors declared no conflicts of interest.

Source: Jonsdottir G et al. Eur J Haematol. 2021 May 9. doi: 10.1111/ejh.13650.

Key clinical point: Increased cumulative exposure to the alkylating agent melphalan increases the subsequent risk for developing acute myeloid leukemia/myelodysplastic syndromes (AML/MDS) in patients with multiple myeloma (MM).

Major finding: Cumulative exposure to melphalan was significantly higher (odds ratio, 2.8; P less than .001) among patients with MM and AML/MDS (median, 988 mg) than control participants (median, 578 mg). The median time to development of AML/MDS was 3.8 years.

Study details: The study included 26,627 patients diagnosed with MM between 1985 and 2011, of which 124 (0.5%) patients developed subsequent AML/MDS. Each patient with MM and AML/MDS diagnosis was matched with a control MM patient without AML/MDS.

Disclosures: The study was supported by grants from the Asrun Einarsdottir Foundation in Iceland, University of Iceland Research Fund, Icelandic Centre for Research, Landspitali University Hospital Research Fund, Thorman’s foundation, and Sylvester Comprehensive Cancer Center NCI Core Grant. O Landgren and M Björkholm reported ties with various pharmaceutical companies. The remaining authors declared no conflicts of interest.

Source: Jonsdottir G et al. Eur J Haematol. 2021 May 9. doi: 10.1111/ejh.13650.

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COVID-19 Vaccine Reactions in Dermatology: “Filling” in the Gaps

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As we marked the 1-year anniversary of the COVID-19 pandemic, nearly 100 million Americans had received their first dose of the COVID-19 vaccine, heralding some sense of relief and enabling us to envision a return to something resembling life before lockdown.1 Amid these breakthroughs and vaccination campaigns forging ahead worldwide, we saw new questions and problems arise. Vaccine hesitancy was already an issue in many segments of society where misinformation and mistrust of the medical establishment have served as barriers to the progress of public health. Once reports of adverse reactions following COVID-19 vaccination—such as those linked to use of facial fillers—made news headlines, many in the dermatology community began facing inquiries from patients questioning if they should wait to receive the vaccine or skip it entirely. As dermatologists, we must be informed and prepared to address these situations, to manage adverse reactions when they arise, and to encourage and promote vaccination during this critical time for public health in our society.

Cutaneous Vaccine Reactions and Facial Fillers

As public COVID-19 vaccinations move forward, dermatologic side effects, which were first noted during clinical trials, have received amplified attention, despite the fact that these cutaneous reactions—including localized injection-site redness and swelling, generalized urticarial and morbilliform eruptions, and even facial filler reactions—have been reported as relatively minor and self-limited.2 The excipient polyethylene glycol has been suspected as a possible etiology of vaccine-related allergic and hypersensitivity reactions, suggesting care be taken in those who are patch-test positive or have a history of allergy to polyethylene glycol–containing products (eg, penicillin, laxatives, makeup, certain dermal fillers).2,3 Although rare, facial and lip swelling reactions in those with a prior history of facial fillers in COVID-19 vaccine trials have drawn particular public concern and potential vaccine hesitancy given that more than 2.7 million Americans seek treatment with dermal fillers annually. There has been continued demand for these treatments during the pandemic, particularly due to aesthetic sensitivity surrounding video conferencing.4

Release of trial data from the Moderna COVID-19 vaccine prompted a discourse around safety and recommended protocols for filler procedures in the community of aesthetic medicine, as 3 participants in the experimental arm—all of whom had a history of treatment with facial filler injections—were reported to have facial or lip swelling shortly following vaccination. Two of these cases were considered to be serious adverse events due to extensive facial swelling, with the participants having received filler injections 6 months and 2 weeks prior to vaccination, respectively.5 A third participant experienced lip swelling only, which according to the US Food and Drug Administration briefing document was considered “medically significant” but not a serious adverse event, with unknown timing of the most recent filler injection. In all cases, symptom onset began 1 or 2 days following vaccination, and all resolved with either no or minimal intervention.6 The US Food and Drug Administration briefing document does not detail which type of fillers each participant had received, but subsequent reports indicated hyaluronic acid (HA) fillers. Of note, one patient in the placebo arm of the trial also developed progressive periorbital and facial edema in the setting of known filler injections performed 5 weeks prior, requiring treatment with corticosteroids and barring her from receiving a second injection in the trial.7

After public vaccination started, additional reports have emerged of facial edema occurring following administration of both the Pfizer and Moderna COVID-19 vaccines.2,8,9 In one series, 4 cases of facial swelling were reported in patients who had HA filler placed more than 1 year prior to vaccination.9 The first patient, who had a history of HA fillers in the temples and cheeks, developed moderate periorbital swelling 2 days following her second dose of the Pfizer vaccine. Another patient who had received a series of filler injections over the last 3 years experienced facial swelling 24 hours after her second dose of the Moderna vaccine and also reported a similar reaction in the past following an upper respiratory tract infection. The third patient developed perioral and infraorbital edema 18 hours after her first dose of the Moderna vaccine. The fourth patient developed inflammation in filler-treated areas 10 days after the first dose of the Pfizer vaccine and notably had a history of filler reaction to an unknown trigger in 2019 that was treated with hyaluronidase, intralesional steroids, and 5-fluorouracil. All cases of facial edema reportedly resolved.9

The observed adverse events have been proposed as delayed-type hypersensitivity reactions (DTRs) to facial fillers and are suspected to be triggered by the COVID-19 spike protein and subsequent immunogenic response. This reaction is not unique to the COVID-19 vaccines; in fact, many inflammatory stimuli such as sinus infections, flulike illnesses, facial injury, dental procedures, and exposure to certain medications and chemotherapeutics have triggered DTRs in filler patients, especially in those with genetic or immunologic risk factors including certain human leukocyte antigen subtypes or autoimmune disorders.3

Counseling Patients and Reducing Risks

As reports of DTRs to facial fillers after COVID-19 vaccination continue to emerge, it is not surprising that patients may become confused by potential side effects and postpone vaccination as a result. This evolving situation has called upon aesthetic physicians to adapt our practice and prepare our patients. Most importantly, we must continue to follow the data and integrate evidence-based COVID-19 vaccine–related counseling into our office visits. It is paramount to encourage vaccination and inform patients that these rare adverse events are both temporary and treatable. Given the currently available data, patients with a history of treatment with dermal fillers should not be discouraged from receiving the vaccine; however, we may provide suggestions to lessen the likelihood of adverse reactions and ease patient concerns. For example, it may be helpful to consider a time frame between vaccination and filler procedures that is longer than 2 weeks, just as would be advised for those having dental procedures or with recent infections, and potentially longer windows for those with risk factors such as prior sensitivity to dermal fillers, autoimmune disorders, or those on immunomodulatory medications. Dilution of fillers with saline or lidocaine or use of non-HA fillers also may be suggested around the time of vaccination to mitigate the risk of DTRs.3

Managing Vaccine Reactions

If facial swelling does occur despite these precautions and lasts longer than 48 hours, treatment with antihistamines, steroids, and/or hyaluronidase has been successful in vaccine trial and posttrial patients, both alone or in combination, and are likely to resolve edema promptly without altering the effectiveness of the vaccine.3,5,9 Angiotensin-converting enzyme inhibitors such as lisinopril more recently have been recommended for treatment of facial edema following COVID-19 vaccination,9 but questions remain regarding the true efficacy in this scenario given that the majority of swelling reactions resolve without this treatment. Additionally, there were no controls to indicate treatment with the angiotensin-converting enzyme inhibitor demonstrated an actual impact. Dermatologists generally are wary of adding medications of questionable utility that are associated with potential side effects and drug reactions, given that we often are tasked with managing the consequences of such mistakes. Thus, to avoid additional harm in the setting of insufficient evidence, as was seen following widespread use of hydroxychloroquine at the outset of the COVID-19 pandemic, well-structured studies are required before such interventions can be recommended.

If symptoms arise following the first vaccine injection, they can be managed if needed while patients are reassured and advised to obtain their second dose, with pretreatment considerations including antihistamines and instruction to present to the emergency department if a more severe reaction is suspected.2 In a larger sense, we also can contribute to the collective knowledge, growth, and preparedness of the medical community by reporting cases of adverse events to vaccine reporting systems and registries, such as the US Department of Health and Human Services’ Vaccine Adverse Event Reporting System, the Centers for Disease Control and Prevention’s V-Safe After Vaccination Health Checker, and the American Academy of Dermatology’s COVID-19 Dermatology Registry.

Final Thoughts

As dermatologists, we now find ourselves in the familiar role of balancing the aesthetic goals of our patients with our primary mission of public health and safety at a time when their health and well-being is particularly vulnerable. Adverse reactions will continue to occur as larger segments of the world’s population become vaccinated. Meanwhile, we must continue to manage symptoms, dispel myths, emphasize that any dermatologic risk posed by the COVID-19 vaccines is far outweighed by the benefits of immunization, and promote health and education, looking ahead to life beyond the pandemic.

References
  1. Ritchie H, Ortiz-Ospina E, Beltekian D, et al. Coronavirus (COVID-19) vaccinations. Our World in Data website. Accessed May 10, 2021. https://ourworldindata.org/covid-vaccinations
  2. McMahon DE, Amerson E, Rosenbach M, et al. Cutaneous reactions reported after Moderna and Pfizer COVID-19 vaccination: a registry-based study of 414 cases [published online April 7, 2021]. J Am Acad Dermatol. doi:10.1016/j.jaad.2021.03.092
  3. Rice SM, Ferree SD, Mesinkovska NA, et al. The art of prevention: COVID-19 vaccine preparedness for the dermatologist. Int J Womens Dermatol. 2021;7:209-212. doi:10.1016/j.ijwd.2021.01.007
  4. Rice SM, Siegel JA, Libby T, et al. Zooming into cosmetic procedures during the COVID-19 pandemic: the provider’s perspective. Int J Womens Dermatol. 2021;7:213-216.
  5. FDA Briefing Document: Moderna COVID-19 Vaccine. US Department of Health and Human Services; 2020. Accessed May 11, 2021. https://www.fda.gov/media/144434/download
  6. Moderna’s COVID-19 vaccine may cause swelling, inflammation in those with facial fillers. American Society of Plastic Surgeons website. Published December 27, 2020. Accessed May 11, 2021. http://www.plasticsurgery.org/for-medical-professionals/publications/psn-extra/news/modernas-covid19-vaccine-may-cause-swelling-inflammation-in-those-with-facial-fillers
  7. Munavalli GG, Guthridge R, Knutsen-Larson S, et al. COVID-19/SARS-CoV-2 virus spike protein-related delayed inflammatory reaction to hyaluronic acid dermal fillers: a challenging clinical conundrum in diagnosis and treatment [published online February 9, 2021]. Arch Dermatol Res. doi:10.1007/s00403-021-02190-6
  8. Schlessinger J. Update on COVID-19 vaccines and dermal fillers. Practical Dermatol. February 2021:46-47. Accessed May 10, 2021. https://practicaldermatology.com/articles/2021-feb/update-on-covid-19-vaccines-and-dermal-fillers/pdf
  9. Munavalli GG, Knutsen-Larson S, Lupo MP, et al. Oral angiotensin-converting enzyme inhibitors for treatment of delayed inflammatory reaction to dermal hyaluronic acid fillers following COVID-19 vaccination—a model for inhibition of angiotensin II-induced cutaneous inflammation. JAAD Case Rep. 2021;10:63-68. doi:10.1016/j.jdcr.2021.02.018
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Ms. Rice and Dr. Kourosh are from the Department of Dermatology, Massachusetts General Hospital, Boston. Dr. Kourosh also is from the Department of Dermatology, Harvard Medical School, Boston. Dr. Ferree is from the Department of Medicine, Cambridge Health Alliance, Massachusetts.

The authors report no conflict of interest.

Correspondence: Arianne S. Kourosh, MD, MPH ([email protected]).

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Ms. Rice and Dr. Kourosh are from the Department of Dermatology, Massachusetts General Hospital, Boston. Dr. Kourosh also is from the Department of Dermatology, Harvard Medical School, Boston. Dr. Ferree is from the Department of Medicine, Cambridge Health Alliance, Massachusetts.

The authors report no conflict of interest.

Correspondence: Arianne S. Kourosh, MD, MPH ([email protected]).

Author and Disclosure Information

Ms. Rice and Dr. Kourosh are from the Department of Dermatology, Massachusetts General Hospital, Boston. Dr. Kourosh also is from the Department of Dermatology, Harvard Medical School, Boston. Dr. Ferree is from the Department of Medicine, Cambridge Health Alliance, Massachusetts.

The authors report no conflict of interest.

Correspondence: Arianne S. Kourosh, MD, MPH ([email protected]).

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Article PDF

As we marked the 1-year anniversary of the COVID-19 pandemic, nearly 100 million Americans had received their first dose of the COVID-19 vaccine, heralding some sense of relief and enabling us to envision a return to something resembling life before lockdown.1 Amid these breakthroughs and vaccination campaigns forging ahead worldwide, we saw new questions and problems arise. Vaccine hesitancy was already an issue in many segments of society where misinformation and mistrust of the medical establishment have served as barriers to the progress of public health. Once reports of adverse reactions following COVID-19 vaccination—such as those linked to use of facial fillers—made news headlines, many in the dermatology community began facing inquiries from patients questioning if they should wait to receive the vaccine or skip it entirely. As dermatologists, we must be informed and prepared to address these situations, to manage adverse reactions when they arise, and to encourage and promote vaccination during this critical time for public health in our society.

Cutaneous Vaccine Reactions and Facial Fillers

As public COVID-19 vaccinations move forward, dermatologic side effects, which were first noted during clinical trials, have received amplified attention, despite the fact that these cutaneous reactions—including localized injection-site redness and swelling, generalized urticarial and morbilliform eruptions, and even facial filler reactions—have been reported as relatively minor and self-limited.2 The excipient polyethylene glycol has been suspected as a possible etiology of vaccine-related allergic and hypersensitivity reactions, suggesting care be taken in those who are patch-test positive or have a history of allergy to polyethylene glycol–containing products (eg, penicillin, laxatives, makeup, certain dermal fillers).2,3 Although rare, facial and lip swelling reactions in those with a prior history of facial fillers in COVID-19 vaccine trials have drawn particular public concern and potential vaccine hesitancy given that more than 2.7 million Americans seek treatment with dermal fillers annually. There has been continued demand for these treatments during the pandemic, particularly due to aesthetic sensitivity surrounding video conferencing.4

Release of trial data from the Moderna COVID-19 vaccine prompted a discourse around safety and recommended protocols for filler procedures in the community of aesthetic medicine, as 3 participants in the experimental arm—all of whom had a history of treatment with facial filler injections—were reported to have facial or lip swelling shortly following vaccination. Two of these cases were considered to be serious adverse events due to extensive facial swelling, with the participants having received filler injections 6 months and 2 weeks prior to vaccination, respectively.5 A third participant experienced lip swelling only, which according to the US Food and Drug Administration briefing document was considered “medically significant” but not a serious adverse event, with unknown timing of the most recent filler injection. In all cases, symptom onset began 1 or 2 days following vaccination, and all resolved with either no or minimal intervention.6 The US Food and Drug Administration briefing document does not detail which type of fillers each participant had received, but subsequent reports indicated hyaluronic acid (HA) fillers. Of note, one patient in the placebo arm of the trial also developed progressive periorbital and facial edema in the setting of known filler injections performed 5 weeks prior, requiring treatment with corticosteroids and barring her from receiving a second injection in the trial.7

After public vaccination started, additional reports have emerged of facial edema occurring following administration of both the Pfizer and Moderna COVID-19 vaccines.2,8,9 In one series, 4 cases of facial swelling were reported in patients who had HA filler placed more than 1 year prior to vaccination.9 The first patient, who had a history of HA fillers in the temples and cheeks, developed moderate periorbital swelling 2 days following her second dose of the Pfizer vaccine. Another patient who had received a series of filler injections over the last 3 years experienced facial swelling 24 hours after her second dose of the Moderna vaccine and also reported a similar reaction in the past following an upper respiratory tract infection. The third patient developed perioral and infraorbital edema 18 hours after her first dose of the Moderna vaccine. The fourth patient developed inflammation in filler-treated areas 10 days after the first dose of the Pfizer vaccine and notably had a history of filler reaction to an unknown trigger in 2019 that was treated with hyaluronidase, intralesional steroids, and 5-fluorouracil. All cases of facial edema reportedly resolved.9

The observed adverse events have been proposed as delayed-type hypersensitivity reactions (DTRs) to facial fillers and are suspected to be triggered by the COVID-19 spike protein and subsequent immunogenic response. This reaction is not unique to the COVID-19 vaccines; in fact, many inflammatory stimuli such as sinus infections, flulike illnesses, facial injury, dental procedures, and exposure to certain medications and chemotherapeutics have triggered DTRs in filler patients, especially in those with genetic or immunologic risk factors including certain human leukocyte antigen subtypes or autoimmune disorders.3

Counseling Patients and Reducing Risks

As reports of DTRs to facial fillers after COVID-19 vaccination continue to emerge, it is not surprising that patients may become confused by potential side effects and postpone vaccination as a result. This evolving situation has called upon aesthetic physicians to adapt our practice and prepare our patients. Most importantly, we must continue to follow the data and integrate evidence-based COVID-19 vaccine–related counseling into our office visits. It is paramount to encourage vaccination and inform patients that these rare adverse events are both temporary and treatable. Given the currently available data, patients with a history of treatment with dermal fillers should not be discouraged from receiving the vaccine; however, we may provide suggestions to lessen the likelihood of adverse reactions and ease patient concerns. For example, it may be helpful to consider a time frame between vaccination and filler procedures that is longer than 2 weeks, just as would be advised for those having dental procedures or with recent infections, and potentially longer windows for those with risk factors such as prior sensitivity to dermal fillers, autoimmune disorders, or those on immunomodulatory medications. Dilution of fillers with saline or lidocaine or use of non-HA fillers also may be suggested around the time of vaccination to mitigate the risk of DTRs.3

Managing Vaccine Reactions

If facial swelling does occur despite these precautions and lasts longer than 48 hours, treatment with antihistamines, steroids, and/or hyaluronidase has been successful in vaccine trial and posttrial patients, both alone or in combination, and are likely to resolve edema promptly without altering the effectiveness of the vaccine.3,5,9 Angiotensin-converting enzyme inhibitors such as lisinopril more recently have been recommended for treatment of facial edema following COVID-19 vaccination,9 but questions remain regarding the true efficacy in this scenario given that the majority of swelling reactions resolve without this treatment. Additionally, there were no controls to indicate treatment with the angiotensin-converting enzyme inhibitor demonstrated an actual impact. Dermatologists generally are wary of adding medications of questionable utility that are associated with potential side effects and drug reactions, given that we often are tasked with managing the consequences of such mistakes. Thus, to avoid additional harm in the setting of insufficient evidence, as was seen following widespread use of hydroxychloroquine at the outset of the COVID-19 pandemic, well-structured studies are required before such interventions can be recommended.

If symptoms arise following the first vaccine injection, they can be managed if needed while patients are reassured and advised to obtain their second dose, with pretreatment considerations including antihistamines and instruction to present to the emergency department if a more severe reaction is suspected.2 In a larger sense, we also can contribute to the collective knowledge, growth, and preparedness of the medical community by reporting cases of adverse events to vaccine reporting systems and registries, such as the US Department of Health and Human Services’ Vaccine Adverse Event Reporting System, the Centers for Disease Control and Prevention’s V-Safe After Vaccination Health Checker, and the American Academy of Dermatology’s COVID-19 Dermatology Registry.

Final Thoughts

As dermatologists, we now find ourselves in the familiar role of balancing the aesthetic goals of our patients with our primary mission of public health and safety at a time when their health and well-being is particularly vulnerable. Adverse reactions will continue to occur as larger segments of the world’s population become vaccinated. Meanwhile, we must continue to manage symptoms, dispel myths, emphasize that any dermatologic risk posed by the COVID-19 vaccines is far outweighed by the benefits of immunization, and promote health and education, looking ahead to life beyond the pandemic.

As we marked the 1-year anniversary of the COVID-19 pandemic, nearly 100 million Americans had received their first dose of the COVID-19 vaccine, heralding some sense of relief and enabling us to envision a return to something resembling life before lockdown.1 Amid these breakthroughs and vaccination campaigns forging ahead worldwide, we saw new questions and problems arise. Vaccine hesitancy was already an issue in many segments of society where misinformation and mistrust of the medical establishment have served as barriers to the progress of public health. Once reports of adverse reactions following COVID-19 vaccination—such as those linked to use of facial fillers—made news headlines, many in the dermatology community began facing inquiries from patients questioning if they should wait to receive the vaccine or skip it entirely. As dermatologists, we must be informed and prepared to address these situations, to manage adverse reactions when they arise, and to encourage and promote vaccination during this critical time for public health in our society.

Cutaneous Vaccine Reactions and Facial Fillers

As public COVID-19 vaccinations move forward, dermatologic side effects, which were first noted during clinical trials, have received amplified attention, despite the fact that these cutaneous reactions—including localized injection-site redness and swelling, generalized urticarial and morbilliform eruptions, and even facial filler reactions—have been reported as relatively minor and self-limited.2 The excipient polyethylene glycol has been suspected as a possible etiology of vaccine-related allergic and hypersensitivity reactions, suggesting care be taken in those who are patch-test positive or have a history of allergy to polyethylene glycol–containing products (eg, penicillin, laxatives, makeup, certain dermal fillers).2,3 Although rare, facial and lip swelling reactions in those with a prior history of facial fillers in COVID-19 vaccine trials have drawn particular public concern and potential vaccine hesitancy given that more than 2.7 million Americans seek treatment with dermal fillers annually. There has been continued demand for these treatments during the pandemic, particularly due to aesthetic sensitivity surrounding video conferencing.4

Release of trial data from the Moderna COVID-19 vaccine prompted a discourse around safety and recommended protocols for filler procedures in the community of aesthetic medicine, as 3 participants in the experimental arm—all of whom had a history of treatment with facial filler injections—were reported to have facial or lip swelling shortly following vaccination. Two of these cases were considered to be serious adverse events due to extensive facial swelling, with the participants having received filler injections 6 months and 2 weeks prior to vaccination, respectively.5 A third participant experienced lip swelling only, which according to the US Food and Drug Administration briefing document was considered “medically significant” but not a serious adverse event, with unknown timing of the most recent filler injection. In all cases, symptom onset began 1 or 2 days following vaccination, and all resolved with either no or minimal intervention.6 The US Food and Drug Administration briefing document does not detail which type of fillers each participant had received, but subsequent reports indicated hyaluronic acid (HA) fillers. Of note, one patient in the placebo arm of the trial also developed progressive periorbital and facial edema in the setting of known filler injections performed 5 weeks prior, requiring treatment with corticosteroids and barring her from receiving a second injection in the trial.7

After public vaccination started, additional reports have emerged of facial edema occurring following administration of both the Pfizer and Moderna COVID-19 vaccines.2,8,9 In one series, 4 cases of facial swelling were reported in patients who had HA filler placed more than 1 year prior to vaccination.9 The first patient, who had a history of HA fillers in the temples and cheeks, developed moderate periorbital swelling 2 days following her second dose of the Pfizer vaccine. Another patient who had received a series of filler injections over the last 3 years experienced facial swelling 24 hours after her second dose of the Moderna vaccine and also reported a similar reaction in the past following an upper respiratory tract infection. The third patient developed perioral and infraorbital edema 18 hours after her first dose of the Moderna vaccine. The fourth patient developed inflammation in filler-treated areas 10 days after the first dose of the Pfizer vaccine and notably had a history of filler reaction to an unknown trigger in 2019 that was treated with hyaluronidase, intralesional steroids, and 5-fluorouracil. All cases of facial edema reportedly resolved.9

The observed adverse events have been proposed as delayed-type hypersensitivity reactions (DTRs) to facial fillers and are suspected to be triggered by the COVID-19 spike protein and subsequent immunogenic response. This reaction is not unique to the COVID-19 vaccines; in fact, many inflammatory stimuli such as sinus infections, flulike illnesses, facial injury, dental procedures, and exposure to certain medications and chemotherapeutics have triggered DTRs in filler patients, especially in those with genetic or immunologic risk factors including certain human leukocyte antigen subtypes or autoimmune disorders.3

Counseling Patients and Reducing Risks

As reports of DTRs to facial fillers after COVID-19 vaccination continue to emerge, it is not surprising that patients may become confused by potential side effects and postpone vaccination as a result. This evolving situation has called upon aesthetic physicians to adapt our practice and prepare our patients. Most importantly, we must continue to follow the data and integrate evidence-based COVID-19 vaccine–related counseling into our office visits. It is paramount to encourage vaccination and inform patients that these rare adverse events are both temporary and treatable. Given the currently available data, patients with a history of treatment with dermal fillers should not be discouraged from receiving the vaccine; however, we may provide suggestions to lessen the likelihood of adverse reactions and ease patient concerns. For example, it may be helpful to consider a time frame between vaccination and filler procedures that is longer than 2 weeks, just as would be advised for those having dental procedures or with recent infections, and potentially longer windows for those with risk factors such as prior sensitivity to dermal fillers, autoimmune disorders, or those on immunomodulatory medications. Dilution of fillers with saline or lidocaine or use of non-HA fillers also may be suggested around the time of vaccination to mitigate the risk of DTRs.3

Managing Vaccine Reactions

If facial swelling does occur despite these precautions and lasts longer than 48 hours, treatment with antihistamines, steroids, and/or hyaluronidase has been successful in vaccine trial and posttrial patients, both alone or in combination, and are likely to resolve edema promptly without altering the effectiveness of the vaccine.3,5,9 Angiotensin-converting enzyme inhibitors such as lisinopril more recently have been recommended for treatment of facial edema following COVID-19 vaccination,9 but questions remain regarding the true efficacy in this scenario given that the majority of swelling reactions resolve without this treatment. Additionally, there were no controls to indicate treatment with the angiotensin-converting enzyme inhibitor demonstrated an actual impact. Dermatologists generally are wary of adding medications of questionable utility that are associated with potential side effects and drug reactions, given that we often are tasked with managing the consequences of such mistakes. Thus, to avoid additional harm in the setting of insufficient evidence, as was seen following widespread use of hydroxychloroquine at the outset of the COVID-19 pandemic, well-structured studies are required before such interventions can be recommended.

If symptoms arise following the first vaccine injection, they can be managed if needed while patients are reassured and advised to obtain their second dose, with pretreatment considerations including antihistamines and instruction to present to the emergency department if a more severe reaction is suspected.2 In a larger sense, we also can contribute to the collective knowledge, growth, and preparedness of the medical community by reporting cases of adverse events to vaccine reporting systems and registries, such as the US Department of Health and Human Services’ Vaccine Adverse Event Reporting System, the Centers for Disease Control and Prevention’s V-Safe After Vaccination Health Checker, and the American Academy of Dermatology’s COVID-19 Dermatology Registry.

Final Thoughts

As dermatologists, we now find ourselves in the familiar role of balancing the aesthetic goals of our patients with our primary mission of public health and safety at a time when their health and well-being is particularly vulnerable. Adverse reactions will continue to occur as larger segments of the world’s population become vaccinated. Meanwhile, we must continue to manage symptoms, dispel myths, emphasize that any dermatologic risk posed by the COVID-19 vaccines is far outweighed by the benefits of immunization, and promote health and education, looking ahead to life beyond the pandemic.

References
  1. Ritchie H, Ortiz-Ospina E, Beltekian D, et al. Coronavirus (COVID-19) vaccinations. Our World in Data website. Accessed May 10, 2021. https://ourworldindata.org/covid-vaccinations
  2. McMahon DE, Amerson E, Rosenbach M, et al. Cutaneous reactions reported after Moderna and Pfizer COVID-19 vaccination: a registry-based study of 414 cases [published online April 7, 2021]. J Am Acad Dermatol. doi:10.1016/j.jaad.2021.03.092
  3. Rice SM, Ferree SD, Mesinkovska NA, et al. The art of prevention: COVID-19 vaccine preparedness for the dermatologist. Int J Womens Dermatol. 2021;7:209-212. doi:10.1016/j.ijwd.2021.01.007
  4. Rice SM, Siegel JA, Libby T, et al. Zooming into cosmetic procedures during the COVID-19 pandemic: the provider’s perspective. Int J Womens Dermatol. 2021;7:213-216.
  5. FDA Briefing Document: Moderna COVID-19 Vaccine. US Department of Health and Human Services; 2020. Accessed May 11, 2021. https://www.fda.gov/media/144434/download
  6. Moderna’s COVID-19 vaccine may cause swelling, inflammation in those with facial fillers. American Society of Plastic Surgeons website. Published December 27, 2020. Accessed May 11, 2021. http://www.plasticsurgery.org/for-medical-professionals/publications/psn-extra/news/modernas-covid19-vaccine-may-cause-swelling-inflammation-in-those-with-facial-fillers
  7. Munavalli GG, Guthridge R, Knutsen-Larson S, et al. COVID-19/SARS-CoV-2 virus spike protein-related delayed inflammatory reaction to hyaluronic acid dermal fillers: a challenging clinical conundrum in diagnosis and treatment [published online February 9, 2021]. Arch Dermatol Res. doi:10.1007/s00403-021-02190-6
  8. Schlessinger J. Update on COVID-19 vaccines and dermal fillers. Practical Dermatol. February 2021:46-47. Accessed May 10, 2021. https://practicaldermatology.com/articles/2021-feb/update-on-covid-19-vaccines-and-dermal-fillers/pdf
  9. Munavalli GG, Knutsen-Larson S, Lupo MP, et al. Oral angiotensin-converting enzyme inhibitors for treatment of delayed inflammatory reaction to dermal hyaluronic acid fillers following COVID-19 vaccination—a model for inhibition of angiotensin II-induced cutaneous inflammation. JAAD Case Rep. 2021;10:63-68. doi:10.1016/j.jdcr.2021.02.018
References
  1. Ritchie H, Ortiz-Ospina E, Beltekian D, et al. Coronavirus (COVID-19) vaccinations. Our World in Data website. Accessed May 10, 2021. https://ourworldindata.org/covid-vaccinations
  2. McMahon DE, Amerson E, Rosenbach M, et al. Cutaneous reactions reported after Moderna and Pfizer COVID-19 vaccination: a registry-based study of 414 cases [published online April 7, 2021]. J Am Acad Dermatol. doi:10.1016/j.jaad.2021.03.092
  3. Rice SM, Ferree SD, Mesinkovska NA, et al. The art of prevention: COVID-19 vaccine preparedness for the dermatologist. Int J Womens Dermatol. 2021;7:209-212. doi:10.1016/j.ijwd.2021.01.007
  4. Rice SM, Siegel JA, Libby T, et al. Zooming into cosmetic procedures during the COVID-19 pandemic: the provider’s perspective. Int J Womens Dermatol. 2021;7:213-216.
  5. FDA Briefing Document: Moderna COVID-19 Vaccine. US Department of Health and Human Services; 2020. Accessed May 11, 2021. https://www.fda.gov/media/144434/download
  6. Moderna’s COVID-19 vaccine may cause swelling, inflammation in those with facial fillers. American Society of Plastic Surgeons website. Published December 27, 2020. Accessed May 11, 2021. http://www.plasticsurgery.org/for-medical-professionals/publications/psn-extra/news/modernas-covid19-vaccine-may-cause-swelling-inflammation-in-those-with-facial-fillers
  7. Munavalli GG, Guthridge R, Knutsen-Larson S, et al. COVID-19/SARS-CoV-2 virus spike protein-related delayed inflammatory reaction to hyaluronic acid dermal fillers: a challenging clinical conundrum in diagnosis and treatment [published online February 9, 2021]. Arch Dermatol Res. doi:10.1007/s00403-021-02190-6
  8. Schlessinger J. Update on COVID-19 vaccines and dermal fillers. Practical Dermatol. February 2021:46-47. Accessed May 10, 2021. https://practicaldermatology.com/articles/2021-feb/update-on-covid-19-vaccines-and-dermal-fillers/pdf
  9. Munavalli GG, Knutsen-Larson S, Lupo MP, et al. Oral angiotensin-converting enzyme inhibitors for treatment of delayed inflammatory reaction to dermal hyaluronic acid fillers following COVID-19 vaccination—a model for inhibition of angiotensin II-induced cutaneous inflammation. JAAD Case Rep. 2021;10:63-68. doi:10.1016/j.jdcr.2021.02.018
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Physician convicted in buprenorphine scheme faces up to 20 years in prison

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A West Virginia physician faces up to 20 years in prison in the wake of his conviction by a federal jury for illegally distributing buprenorphine.

The jury convicted Sriramloo Kesari, MD, 78, of Charleston, for distributing buprenorphine outside the scope of medical practice, according to a U.S. Department of Justice statement

Investigators from the Drug Enforcement Administration presented evidence at the trial that Dr. Kesari, a general practitioner, operated a cash-only business selling buprenorphine prescriptions.

Federal prosecutors said that the physician signed prescriptions, which were then distributed by an employee in exchange for cash. Dr. Kesari was often absent, at times physically located in California, according to the federal government.

Prosecutors indicted the West Virginia physician in September 2019 as part of an “opioid strikeforce takedown” in Ohio, Virginia, and West Virginia that resulted in charges against 13 individuals, including 11 physicians.

Dr. Kesari’s attorneys filed motions during the course of the lengthy case showing that psychiatric and neurological exams indicated that the physician was cognitively impaired. 

Based on that evidence and the federal indictment, the West Virginia Board of Medicine suspended Dr. Kesari’s license in February 2020, stating that he is not “mentally and/or physically fit to practice medicine and surgery with reasonable skill and safety.”

Dr. Kesari was first licensed in West Virginia in 1979. In 1987, the Board of Medicine placed Dr. Kesari on a 3-year probation because of his failure to keep records for patients for whom he was prescribing controlled substances. 

However, within a few months, the Board changed the probation order to allow Dr. Kesari to write prescriptions for schedule II and III substances in the Boone Hospital emergency room where he continued to work.

The physician had no other disciplinary actions until his license suspension, but the Board lists settlement of four malpractice cases and the dismissal of a fifth between 1986 and 2001.

Dr. Kesari is scheduled to be sentenced on August 25.

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

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A West Virginia physician faces up to 20 years in prison in the wake of his conviction by a federal jury for illegally distributing buprenorphine.

The jury convicted Sriramloo Kesari, MD, 78, of Charleston, for distributing buprenorphine outside the scope of medical practice, according to a U.S. Department of Justice statement

Investigators from the Drug Enforcement Administration presented evidence at the trial that Dr. Kesari, a general practitioner, operated a cash-only business selling buprenorphine prescriptions.

Federal prosecutors said that the physician signed prescriptions, which were then distributed by an employee in exchange for cash. Dr. Kesari was often absent, at times physically located in California, according to the federal government.

Prosecutors indicted the West Virginia physician in September 2019 as part of an “opioid strikeforce takedown” in Ohio, Virginia, and West Virginia that resulted in charges against 13 individuals, including 11 physicians.

Dr. Kesari’s attorneys filed motions during the course of the lengthy case showing that psychiatric and neurological exams indicated that the physician was cognitively impaired. 

Based on that evidence and the federal indictment, the West Virginia Board of Medicine suspended Dr. Kesari’s license in February 2020, stating that he is not “mentally and/or physically fit to practice medicine and surgery with reasonable skill and safety.”

Dr. Kesari was first licensed in West Virginia in 1979. In 1987, the Board of Medicine placed Dr. Kesari on a 3-year probation because of his failure to keep records for patients for whom he was prescribing controlled substances. 

However, within a few months, the Board changed the probation order to allow Dr. Kesari to write prescriptions for schedule II and III substances in the Boone Hospital emergency room where he continued to work.

The physician had no other disciplinary actions until his license suspension, but the Board lists settlement of four malpractice cases and the dismissal of a fifth between 1986 and 2001.

Dr. Kesari is scheduled to be sentenced on August 25.

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

 

A West Virginia physician faces up to 20 years in prison in the wake of his conviction by a federal jury for illegally distributing buprenorphine.

The jury convicted Sriramloo Kesari, MD, 78, of Charleston, for distributing buprenorphine outside the scope of medical practice, according to a U.S. Department of Justice statement

Investigators from the Drug Enforcement Administration presented evidence at the trial that Dr. Kesari, a general practitioner, operated a cash-only business selling buprenorphine prescriptions.

Federal prosecutors said that the physician signed prescriptions, which were then distributed by an employee in exchange for cash. Dr. Kesari was often absent, at times physically located in California, according to the federal government.

Prosecutors indicted the West Virginia physician in September 2019 as part of an “opioid strikeforce takedown” in Ohio, Virginia, and West Virginia that resulted in charges against 13 individuals, including 11 physicians.

Dr. Kesari’s attorneys filed motions during the course of the lengthy case showing that psychiatric and neurological exams indicated that the physician was cognitively impaired. 

Based on that evidence and the federal indictment, the West Virginia Board of Medicine suspended Dr. Kesari’s license in February 2020, stating that he is not “mentally and/or physically fit to practice medicine and surgery with reasonable skill and safety.”

Dr. Kesari was first licensed in West Virginia in 1979. In 1987, the Board of Medicine placed Dr. Kesari on a 3-year probation because of his failure to keep records for patients for whom he was prescribing controlled substances. 

However, within a few months, the Board changed the probation order to allow Dr. Kesari to write prescriptions for schedule II and III substances in the Boone Hospital emergency room where he continued to work.

The physician had no other disciplinary actions until his license suspension, but the Board lists settlement of four malpractice cases and the dismissal of a fifth between 1986 and 2001.

Dr. Kesari is scheduled to be sentenced on August 25.

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

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