Cutis

To the Editor:

Nail psoriasis is highly prevalent in patients with cutaneous psoriasis and also may present as an isolated finding. There is a strong association between nail psoriasis and development of psoriatic arthritis (PsA). However, publications on nail psoriasis are sparse compared with articles describing cutaneous psoriasis.¹ Our objectives were to analyze the nail psoriasis literature for content, citations, and media attention.

The Web of Science database was searched for the term nail psoriasis on April 27, 2020, and publications by year, subject, and article type were compiled. Total and average yearly citations were calculated to create a list of the top 100 most-cited articles (eTable). First and last authors, sex, and Altmetric Attention Scores were then recorded. The Wilcoxon rank sum test was calculated to compare the relationship of Altmetric scores between nail psoriasis–specific references and others on the list.

In our data set, the average total number of citations was 134.09 (range, 42–1617), with average yearly citations ranging from 2 to 108. Altmetric scores—measures of media attention of scholarly work—were available for 58 of 100 papers (58%), with an average score of 33.2 (range, 1–509).

Of the top 100 most-cited articles using the search term nail psoriasis, only 20% focused on nail psoriasis, with the remainder concentrating on psoriasis/PsA. Only 32% and 24% of first and last authors, respectively, were female. Fifty-two percent and 31% of the articles were published in dermatology and arthritis/rheumatology journals, respectively. There was no statistically significant difference in Altmetric scores between nail psoriasis–specific and other articles in our data set (P=.7551).

For the nail psoriasis–specific articles, all 20 highlighted a lack of nail clinical trials, a positive association with PsA, and a correlation of increased cutaneous psoriasis body surface area with increased onychodystrophy likelihood.² Three of 20 (15%) articles stated that nail psoriasis often is overlooked, despite the negative impact on quality of life,¹ and emphasized the importance of patient compliance owing to the chronic nature of the disease. Only 1 of 20 (5%) articles focused on nail psoriasis treatments.³ There was no overlap between the 100 most-cited psoriasis articles from 1970 to 2012 and our top 100 articles on nail psoriasis.⁴

Treatment recommendations for nail psoriasis by consensus were published by a nail expert group in 2019.⁵ For 3 or fewer nails involved, suggested first-line treatment is intralesional matrix injections with triamcinolone acetonide. For more than 3 affected nails, systemic treatment with oral or biologic therapy is recommended.⁵ Although this article is likely to change clinical practice, it did not qualify for our list because it did not garner sufficient citations in the brief period between its publication date and our search (July 2019–April 2020).

This study is subject to several limitations. Only the Web of Science database was utilized, and only the term nail psoriasis was searched, potentially excluding relevant articles. Using total citations biases toward older articles.

Our bibliometric analysis highlights a lack of publications on nail psoriasis, with most articles focusing on psoriasis and PsA. This deficiency in highly cited nail psoriasis references is likely to be a barrier to physicians in managing patients with nail disease. There is a need for controlled clinical trials and better mechanisms to disseminate information on management of nail psoriasis to practicing physicians.

The eTable is available in the PDF of this article

To the Editor:

Nail psoriasis is highly prevalent in patients with cutaneous psoriasis and also may present as an isolated finding. There is a strong association between nail psoriasis and development of psoriatic arthritis (PsA). However, publications on nail psoriasis are sparse compared with articles describing cutaneous psoriasis.¹ Our objectives were to analyze the nail psoriasis literature for content, citations, and media attention.

The Web of Science database was searched for the term nail psoriasis on April 27, 2020, and publications by year, subject, and article type were compiled. Total and average yearly citations were calculated to create a list of the top 100 most-cited articles (eTable). First and last authors, sex, and Altmetric Attention Scores were then recorded. The Wilcoxon rank sum test was calculated to compare the relationship of Altmetric scores between nail psoriasis–specific references and others on the list.

In our data set, the average total number of citations was 134.09 (range, 42–1617), with average yearly citations ranging from 2 to 108. Altmetric scores—measures of media attention of scholarly work—were available for 58 of 100 papers (58%), with an average score of 33.2 (range, 1–509).

Of the top 100 most-cited articles using the search term nail psoriasis, only 20% focused on nail psoriasis, with the remainder concentrating on psoriasis/PsA. Only 32% and 24% of first and last authors, respectively, were female. Fifty-two percent and 31% of the articles were published in dermatology and arthritis/rheumatology journals, respectively. There was no statistically significant difference in Altmetric scores between nail psoriasis–specific and other articles in our data set (P=.7551).

For the nail psoriasis–specific articles, all 20 highlighted a lack of nail clinical trials, a positive association with PsA, and a correlation of increased cutaneous psoriasis body surface area with increased onychodystrophy likelihood.² Three of 20 (15%) articles stated that nail psoriasis often is overlooked, despite the negative impact on quality of life,¹ and emphasized the importance of patient compliance owing to the chronic nature of the disease. Only 1 of 20 (5%) articles focused on nail psoriasis treatments.³ There was no overlap between the 100 most-cited psoriasis articles from 1970 to 2012 and our top 100 articles on nail psoriasis.⁴

Treatment recommendations for nail psoriasis by consensus were published by a nail expert group in 2019.⁵ For 3 or fewer nails involved, suggested first-line treatment is intralesional matrix injections with triamcinolone acetonide. For more than 3 affected nails, systemic treatment with oral or biologic therapy is recommended.⁵ Although this article is likely to change clinical practice, it did not qualify for our list because it did not garner sufficient citations in the brief period between its publication date and our search (July 2019–April 2020).

This study is subject to several limitations. Only the Web of Science database was utilized, and only the term nail psoriasis was searched, potentially excluding relevant articles. Using total citations biases toward older articles.

Our bibliometric analysis highlights a lack of publications on nail psoriasis, with most articles focusing on psoriasis and PsA. This deficiency in highly cited nail psoriasis references is likely to be a barrier to physicians in managing patients with nail disease. There is a need for controlled clinical trials and better mechanisms to disseminate information on management of nail psoriasis to practicing physicians.

The eTable is available in the PDF of this article

To the Editor:

Nail psoriasis is highly prevalent in patients with cutaneous psoriasis and also may present as an isolated finding. There is a strong association between nail psoriasis and development of psoriatic arthritis (PsA). However, publications on nail psoriasis are sparse compared with articles describing cutaneous psoriasis.¹ Our objectives were to analyze the nail psoriasis literature for content, citations, and media attention.

The Web of Science database was searched for the term nail psoriasis on April 27, 2020, and publications by year, subject, and article type were compiled. Total and average yearly citations were calculated to create a list of the top 100 most-cited articles (eTable). First and last authors, sex, and Altmetric Attention Scores were then recorded. The Wilcoxon rank sum test was calculated to compare the relationship of Altmetric scores between nail psoriasis–specific references and others on the list.

In our data set, the average total number of citations was 134.09 (range, 42–1617), with average yearly citations ranging from 2 to 108. Altmetric scores—measures of media attention of scholarly work—were available for 58 of 100 papers (58%), with an average score of 33.2 (range, 1–509).

Of the top 100 most-cited articles using the search term nail psoriasis, only 20% focused on nail psoriasis, with the remainder concentrating on psoriasis/PsA. Only 32% and 24% of first and last authors, respectively, were female. Fifty-two percent and 31% of the articles were published in dermatology and arthritis/rheumatology journals, respectively. There was no statistically significant difference in Altmetric scores between nail psoriasis–specific and other articles in our data set (P=.7551).

For the nail psoriasis–specific articles, all 20 highlighted a lack of nail clinical trials, a positive association with PsA, and a correlation of increased cutaneous psoriasis body surface area with increased onychodystrophy likelihood.² Three of 20 (15%) articles stated that nail psoriasis often is overlooked, despite the negative impact on quality of life,¹ and emphasized the importance of patient compliance owing to the chronic nature of the disease. Only 1 of 20 (5%) articles focused on nail psoriasis treatments.³ There was no overlap between the 100 most-cited psoriasis articles from 1970 to 2012 and our top 100 articles on nail psoriasis.⁴

Treatment recommendations for nail psoriasis by consensus were published by a nail expert group in 2019.⁵ For 3 or fewer nails involved, suggested first-line treatment is intralesional matrix injections with triamcinolone acetonide. For more than 3 affected nails, systemic treatment with oral or biologic therapy is recommended.⁵ Although this article is likely to change clinical practice, it did not qualify for our list because it did not garner sufficient citations in the brief period between its publication date and our search (July 2019–April 2020).

This study is subject to several limitations. Only the Web of Science database was utilized, and only the term nail psoriasis was searched, potentially excluding relevant articles. Using total citations biases toward older articles.

Our bibliometric analysis highlights a lack of publications on nail psoriasis, with most articles focusing on psoriasis and PsA. This deficiency in highly cited nail psoriasis references is likely to be a barrier to physicians in managing patients with nail disease. There is a need for controlled clinical trials and better mechanisms to disseminate information on management of nail psoriasis to practicing physicians.

The eTable is available in the PDF of this article

The Diagnosis: Erythema Ab Igne

Based on the clinical findings and history, a diagnosis of erythema ab igne (EAI), a skin reaction to chronic infrared radiation exposure, was made. The name of this condition translates from Latin as “redness from fire”; other names include toasted skin syndrome and fire stains. The most common presentation is reticulated hyperpigmentation, erythema, and cutaneous atrophy, as well as possible crusting, scaling, or telangiectasia. The rash also typically presents in areas of heat exposure—from heated blankets, heating pads, or the use of infrared heaters or lamps.^1,2 The patient usually will have pain and pruritus over the affected areas. The diagnosis of EAI largely is clinical and based on the patient’s history of exposure; it rarely requires biopsy and histologic analysis. However, some of the common histopathologic findings include hyperkeratosis, a hyperpigmented basal layer, hemosiderin deposits, prominent melanophages, basal cell degeneration, course collagen, and elastosis.^2,3 These changes are common with UV radiation exposure and thermal damage. The primary treatment in all cases is to remove or reduce the source of infrared radiation. However, EAI has been reported to be successfully treated with removal of the insult as well as topical agents such as imiquimod and 5-fluorouracil.⁴ Possible complications include increased risk for malignancies such as squamous cell carcinoma in the affected area.¹

The possible differential for EAI includes livedo reticularis, livedo racemosa, cutis marmorata, and cutis marmorata telangiectatica congenita. All of these conditions are related to dysfunction of the cutaneous vasculature that creates a reticular, mottled, reddish purple rash. When the livedo is reversible and idiopathic, it is referred to as livedo reticularis, but when it is generalized and permanent it is referred to as livedo racemosa. Livedo racemosa can be caused by a variety of conditions, including systemic lupus erythematosus and antiphospholipid syndrome.¹ Physiologic livedo reticularis that is more transient and can be reversed by warming is referred to as cutis marmorata. Finally, cutis marmorata telangiectatica congenita primarily is found in neonates, and although persistent, it usually improves with age. Erythema ab igne also is a type of livedo with a known heat exposure and localized distribution.

Our patient was educated on the etiology of the rash, specifically related to heating pad usage for multiple years, and the risk for cutaneous malignancy after longstanding EAI. It was recommended that she discontinue use of a heating pad on the affected areas to allow them to properly heal. If she found that heating pad usage was necessary, she was advised to limit use to 5 to 10 minutes with 2 to 3 hours in between applications. In addition, she was advised to apply petroleum jelly daily for assistance with wound healing as well as anti-itch sensitive lotion twice daily on the arms and back to alleviate some of the tingling pain. We explained that areas of hyperpigmentation may improve with time; however, areas of erythema/ atrophy may be long-lasting.

The Diagnosis: Erythema Ab Igne

Based on the clinical findings and history, a diagnosis of erythema ab igne (EAI), a skin reaction to chronic infrared radiation exposure, was made. The name of this condition translates from Latin as “redness from fire”; other names include toasted skin syndrome and fire stains. The most common presentation is reticulated hyperpigmentation, erythema, and cutaneous atrophy, as well as possible crusting, scaling, or telangiectasia. The rash also typically presents in areas of heat exposure—from heated blankets, heating pads, or the use of infrared heaters or lamps.^1,2 The patient usually will have pain and pruritus over the affected areas. The diagnosis of EAI largely is clinical and based on the patient’s history of exposure; it rarely requires biopsy and histologic analysis. However, some of the common histopathologic findings include hyperkeratosis, a hyperpigmented basal layer, hemosiderin deposits, prominent melanophages, basal cell degeneration, course collagen, and elastosis.^2,3 These changes are common with UV radiation exposure and thermal damage. The primary treatment in all cases is to remove or reduce the source of infrared radiation. However, EAI has been reported to be successfully treated with removal of the insult as well as topical agents such as imiquimod and 5-fluorouracil.⁴ Possible complications include increased risk for malignancies such as squamous cell carcinoma in the affected area.¹

The possible differential for EAI includes livedo reticularis, livedo racemosa, cutis marmorata, and cutis marmorata telangiectatica congenita. All of these conditions are related to dysfunction of the cutaneous vasculature that creates a reticular, mottled, reddish purple rash. When the livedo is reversible and idiopathic, it is referred to as livedo reticularis, but when it is generalized and permanent it is referred to as livedo racemosa. Livedo racemosa can be caused by a variety of conditions, including systemic lupus erythematosus and antiphospholipid syndrome.¹ Physiologic livedo reticularis that is more transient and can be reversed by warming is referred to as cutis marmorata. Finally, cutis marmorata telangiectatica congenita primarily is found in neonates, and although persistent, it usually improves with age. Erythema ab igne also is a type of livedo with a known heat exposure and localized distribution.

Our patient was educated on the etiology of the rash, specifically related to heating pad usage for multiple years, and the risk for cutaneous malignancy after longstanding EAI. It was recommended that she discontinue use of a heating pad on the affected areas to allow them to properly heal. If she found that heating pad usage was necessary, she was advised to limit use to 5 to 10 minutes with 2 to 3 hours in between applications. In addition, she was advised to apply petroleum jelly daily for assistance with wound healing as well as anti-itch sensitive lotion twice daily on the arms and back to alleviate some of the tingling pain. We explained that areas of hyperpigmentation may improve with time; however, areas of erythema/ atrophy may be long-lasting.

The Diagnosis: Erythema Ab Igne

Based on the clinical findings and history, a diagnosis of erythema ab igne (EAI), a skin reaction to chronic infrared radiation exposure, was made. The name of this condition translates from Latin as “redness from fire”; other names include toasted skin syndrome and fire stains. The most common presentation is reticulated hyperpigmentation, erythema, and cutaneous atrophy, as well as possible crusting, scaling, or telangiectasia. The rash also typically presents in areas of heat exposure—from heated blankets, heating pads, or the use of infrared heaters or lamps.^1,2 The patient usually will have pain and pruritus over the affected areas. The diagnosis of EAI largely is clinical and based on the patient’s history of exposure; it rarely requires biopsy and histologic analysis. However, some of the common histopathologic findings include hyperkeratosis, a hyperpigmented basal layer, hemosiderin deposits, prominent melanophages, basal cell degeneration, course collagen, and elastosis.^2,3 These changes are common with UV radiation exposure and thermal damage. The primary treatment in all cases is to remove or reduce the source of infrared radiation. However, EAI has been reported to be successfully treated with removal of the insult as well as topical agents such as imiquimod and 5-fluorouracil.⁴ Possible complications include increased risk for malignancies such as squamous cell carcinoma in the affected area.¹

The possible differential for EAI includes livedo reticularis, livedo racemosa, cutis marmorata, and cutis marmorata telangiectatica congenita. All of these conditions are related to dysfunction of the cutaneous vasculature that creates a reticular, mottled, reddish purple rash. When the livedo is reversible and idiopathic, it is referred to as livedo reticularis, but when it is generalized and permanent it is referred to as livedo racemosa. Livedo racemosa can be caused by a variety of conditions, including systemic lupus erythematosus and antiphospholipid syndrome.¹ Physiologic livedo reticularis that is more transient and can be reversed by warming is referred to as cutis marmorata. Finally, cutis marmorata telangiectatica congenita primarily is found in neonates, and although persistent, it usually improves with age. Erythema ab igne also is a type of livedo with a known heat exposure and localized distribution.

Our patient was educated on the etiology of the rash, specifically related to heating pad usage for multiple years, and the risk for cutaneous malignancy after longstanding EAI. It was recommended that she discontinue use of a heating pad on the affected areas to allow them to properly heal. If she found that heating pad usage was necessary, she was advised to limit use to 5 to 10 minutes with 2 to 3 hours in between applications. In addition, she was advised to apply petroleum jelly daily for assistance with wound healing as well as anti-itch sensitive lotion twice daily on the arms and back to alleviate some of the tingling pain. We explained that areas of hyperpigmentation may improve with time; however, areas of erythema/ atrophy may be long-lasting.

Complementary alternative medicine (CAM) has been described by the National Center for Complementary and Integrative Medicine as “health care approaches that are not typically part of conventional medical care or that may have origins outside of usual Western practice.”¹ Although this definition is broad, CAM encompasses therapies such as traditional Chinese medicine, herbal therapies, dietary supplements, and mind/body interventions. The use of CAM has grown, and according to a 2012 National Center for Complementary and Integrative Health survey, more than 30% of US adults and 12% of US children use health care approaches that are considered outside of conventional medical practice. In a survey study of US adults, at least 17.7% of respondents said they had taken a dietary supplement other than a vitamin or mineral in the last year.¹ Data from the 2007 National Health Interview Survey showed that the prevalence of adults with skin conditions using CAM was 84.5% compared to 38.3% in the general population.² In addition, 8.15 million US patients with dermatologic conditions reported using CAM over a 5-year period.³ Complementary alternative medicine has emerged as an alternative or adjunct to standard treatments, making it important for dermatologists to understand the existing literature on these therapies. Herein, we review the current evidence-based literature that exists on CAM for the treatment of atopic dermatitis (AD), psoriasis, and alopecia areata (AA).

Atopic Dermatitis

Atopic dermatitis is a chronic, pruritic, inflammatory skin condition with considerable morbidity.^4,5 The pathophysiology of AD is multifactorial and includes aspects of barrier dysfunction, IgE hypersensitivity, abnormal cell-mediated immune response, and environmental factors.⁶ Atopic dermatitis also is one of the most common inflammatory skin conditions in adults, affecting more than 7% of the US population and up to 20% of the total population in developed countries. Of those affected, 40% have moderate or severe symptoms that result in a substantial impact on quality of life.⁷ Despite advances in understanding disease pathology and treatment, a subset of patients opt to defer conventional treatments such as topical and systemic corticosteroids, antibiotics, nonsteroidal immunomodulators, and biologics. Patients may seek alternative therapies when typical treatments fail or when the perceived side effects outweigh the benefits.^5,8 The use of CAM has been well described in patients with AD; however, the existing evidence supporting its use along with its safety profile have not been thoroughly explored. Herein, we will discuss some of the most well-studied supplements for treatment of AD, including evening primrose oil (EPO), fish oil, and probiotics.⁵

Oral supplementation with polyunsaturated fatty acids commonly is reported in patients with AD.^5,8 The idea that a fatty acid deficiency could lead to atopic skin conditions has been around since 1937, when it was suggested that patients with AD had lower levels of blood unsaturated fatty acids.⁹ Conflicting evidence regarding oral fatty acid ingestion and AD disease severity has emerged.^10,11 One unsaturated fatty acid, γ-linolenic acid (GLA), has demonstrated anti-inflammatory properties and involvement in barrier repair.¹² It is converted to dihomo-GLA in the body, which acts on cyclooxygenase enzymes to produce the inflammatory mediator prostaglandin E₁. The production of GLA is mediated by the enzyme delta-6 desaturase in the metabolization of linoleic acid.¹² However, it has been reported that in a subset of patients with AD, a malfunction of delta-6 desaturase may play a role in disease progression and result in lower baseline levels of GLA.^10,12 Evening primrose oil and borage oil contain high amounts of GLA (8%–10% and 23%, respectively); thus, supplementation with these oils has been studied in AD.¹³

EPO for AD
Studies investigating EPO (Oenothera biennis) and its association with AD severity have shown mixed results. A Cochrane review reported that oral borage oil and EPO were not effective treatments for AD,¹⁴ while another larger randomized controlled trial (RCT) found no statistically significant improvement in AD symptoms.¹⁵ However, multiple smaller studies have found that clinical symptoms of AD, such as erythema, xerosis, pruritus, and total body surface area involved, did improve with oral EPO supplementation when compared to placebo, and the results were statistically significant (P=.04).^16,17 One study looked at different dosages of EPO and found that groups ingesting both 160 mg and 320 mg daily experienced reductions in eczema area and severity index score, with greater improvement noted with the higher dosage.¹⁷ Side effects associated with oral EPO include an anticoagulant effect and transient gastrointestinal tract upset.^8,14 There currently is not enough evidence or safety data to recommend this supplement to AD patients.

Although topical use of fatty acids with high concentrations of GLA, such as EPO and borage oil, have demonstrated improvement in subjective symptom severity, most studies have not reached statistical significance.^10,11 One study used a 10% EPO cream for 2 weeks compared to placebo and found statistically significant improvement in patient-reported AD symptoms (P=.045). However, this study only included 10 participants, and therefore larger studies are necessary to confirm this result.¹⁸ Some RCTs have shown that topical coconut oil, sunflower seed oil, and sandalwood album oil improve AD symptom severity, but again, large controlled trials are needed.⁵ Unfortunately, many essential oils, including EPO, can cause a secondary allergic contact dermatitis and potentially worsen AD.¹⁹

Fish Oil for AD
Fish oil is a commonly used supplement for AD due to its high content of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Omega-3 fatty acids exert anti-inflammatory effects by displacing arachidonic acid, a proinflammatory omega-6 fatty acid thought to increase IgE, as well as helper T cell (T_H2) cytokines and prostaglandin E₂.^8,20 A 2012 Cochrane review found that, while some studies revealed mild improvement in AD symptoms with oral fish oil supplementation, these RCTs were of poor methodological quality.²¹ Multiple smaller studies have shown a decrease in pruritus, severity, and physician-rated clinical scores with fish oil use.^5,8,20,22 One study with 145 participants reported that 6 g of fish oil once daily compared to isoenergetic corn oil for 16 weeks identified no statistically significant differences between the treatment groups.²⁰ No adverse events were identified in any of the reported trials. Further studies should be conducted to assess the utility and dosing of fish oil supplements in AD patients.

Probiotics for AD
Probiotics consist of live microorganisms that enhance the microflora of the gastrointestinal tract.^8,20 They have been shown to influence food digestion and also have demonstrated potential influence on the skin-gut axis.²³ The theory that intestinal dysbiosis plays a role in AD pathogenesis has been investigated in multiple studies.^23-25 The central premise is that low-fiber and high-fat Western diets lead to fundamental changes in the gut microbiome, resulting in fewer anti-inflammatory metabolites, such as short-chain fatty acids (SCFAs).^23-25 These SCFAs are produced by microbes during the fermentation of dietary fiber and are known for their effect on epithelial barrier integrity and anti-inflammatory properties mediated through G protein–coupled receptor 43.²⁵ Multiple studies have shown that the gut microbiome in patients with AD have higher proportions of Clostridium difficile, Escherichia coli, and Staphylococcus aureus and lower levels of Bifidobacterium, Bacteroidetes, and Bacteroides species compared to healthy controls.^26,27 Metagenomic analysis of fecal samples from patients with AD have shown a reduction of Faecalibacterium prausnitzii species when compared to controls, along with a decreased SCFA production, leading to the hypothesis that the gut microbiome may play a role in epithelial barrier disruption.^28,29 Systematic reviews and smaller studies have found that oral probiotic use does lead to AD symptom improvement.^8,30,31 A systematic review of 25 RCTs with 1599 participants found that supplementation with oral probiotics significantly decreased the SCORAD (SCORing Atopic Dermatitis) index in adults and children older than 1 year with AD but had no effect on infants younger than 1 year (P<.001). They also found that supplementation with diverse microbes or Lactobacillus species showed greater benefit than Bifidobacterium species alone.³⁰ Another study analyzed the effect of oral Lactobacillus fermentum (1×10⁹ CFU twice daily) in 53 children with AD vs placebo for 16 weeks. This study found a statically significant decrease in SCORAD index between oral probiotics and placebo, with 92% (n=24) of participants supplementing with probiotics having a lower SCORAD index than baseline compared to 63% (n=17) in the placebo group (P=.01).³¹ However, the use of probiotics for AD treatment has remained controversial. Two recent systematic reviews, including 39 RCTs of 2599 randomized patients, found that the use of currently available oral probiotics made little or no difference in patient-rated AD symptoms, investigator-rated AD symptoms, or quality of life.^32,33 No adverse effects were observed in the included studies. Unfortunately, the individual RCTs included were heterogeneous, and future studies with standardized probiotic supplementation should be undertaken before probiotics can be routinely recommended.

The use of topical probiotics in AD also has recently emerged. Multiple studies have shown that patients with AD have higher levels of colonization with S aureus, which is associated with T-cell dysfunction, more severe allergic skin reactions, and disruptions in barrier function.^34,35 Therefore, altering the skin microbiota through topical probiotics could theoretically reduce AD symptoms and flares. Multiple RCTs and smaller studies have shown that topical probiotics can alter the skin microbiota, improve erythema, and decrease scaling and pruritus in AD patients.^35-38 One study used a heat-treated Lactobacillus johnsonii 0.3% lotion twice daily for 3 weeks vs placebo in patients with AD with positive S aureus skin cultures. The S aureus load decreased in patients using the topical probiotic lotion, which correlated with lower SCORAD index that was statistically significant compared to placebo (P=.012).³⁶ More robust studies are needed to determine if topical probiotics should routinely be recommended in AD.

Psoriasis

Psoriasis vulgaris is a chronic inflammatory skin condition characterized by pruritic, hyperkeratotic, scaly plaques.^39,40 Keratinocyte hyperproliferation is central to psoriasis pathogenesis and is thought to be a T-cell–driven reaction to antigens or trauma in genetically predisposed individuals. Standard treatments for psoriasis currently include topical corticosteroids and anti-inflammatories, oral immunomodulatory therapy, biologic agents, and phototherapy.⁴⁰ The use of CAM is highly prevalent among patients with psoriasis, with one study reporting that 51% (n=162) of psoriatic patients interviewed had used CAM.⁴¹ The most common reasons for CAM use included dissatisfaction with current treatment, adverse side effects of standard therapy, and patient-reported attempts at “trying everything to heal disease.”⁴² Herein, we will discuss some of the most frequently used supplements for treatment of psoriatic disease.³⁹

Fish Oil for Psoriasis
One of the most common supplements used by patients with psoriasis is fish oil due to its purported anti-inflammatory qualities.^20,39 The consensus on fish oil supplementation for psoriasis is mixed.^43-45 Multiple RCTs have reported reductions in psoriasis area and severity index (PASI) scores or symptomatic improvement with variable doses of fish oil.^44,46 One RCT found that using EPA 1.8 g once daily and DHA 1.2 g once daily for 12 weeks resulted in significant improvement in pruritus, scaling, and erythema (P<.05).⁴⁴ Another study reported a significant decrease in erythema (P=.02) and total body surface area affected (P=.0001) with EPA 3.6 g once daily and DHA 2.4 g once daily supplementation compared to olive oil supplementation for 15 weeks.⁴⁶ Alternatively, multiple studies have failed to show statistically significant improvement in psoriatic symptoms with fish oil supplementation at variable doses and time frames (14–216 mg daily EPA, 9–80 mg daily DHA, from 2 weeks to 9 months).^40,47,48 Fish oil may impart anticoagulant properties and should not be started without the guidance of a physician. Currently, there are no data to make specific recommendations on the use of fish oil as an adjunct psoriatic treatment.

Curcumin for Psoriasis
Another supplement routinely utilized in patients with psoriasis is curcumin,^40,49,50 a yellow phytochemical that is a major component of the spice turmeric. Curcumin has been shown to inhibit certain proinflammatory cytokines including IL-17, IL-6, IFN-γ, and tumor necrosis factor α and has been regarded as having immune-modulating, anti-inflammatory, and antibacterial properties.^40,50 Curcumin also has been reported to suppress phosphorylase kinase, an enzyme that has increased activity in psoriatic plaques that correlates with markers of psoriatic hyperproliferation.^50,51 When applied topically, turmeric microgel 0.5% has been reported to decrease scaling, erythema, and psoriatic plaque thickness over the course of 9 weeks.⁵⁰ In a nonrandomized trial with 10 participants, researchers found that phosphorylase kinase activity levels in psoriatic skin biopsies of patients applying topical curcumin 1% were lower than placebo and topical calcipotriol applied in combination. The lower phosphorylase kinase levels correlated with level of disease severity, and topical curcumin 1% showed a superior outcome when compared to topical calcipotriol.^40,49 Although these preliminary results are interesting, there still are not enough data at this time to recommend topical curcumin as a treatment of psoriasis. No known adverse events have been reported with the use of topical curcumin to date.

Oral curcumin has poor oral bioavailability, and 40% to 90% of oral doses are excreted, making supplementation a challenge.⁴⁰ In one RCT, oral curcumin 2 g daily (using a lecithin-based delivery system to increase bioavailability) was administered in combination with topical methylprednisolone aceponate 0.1%, resulting in significant improvement in psoriatic symptoms and lower IL-22 compared to placebo and topical methylprednisolone aceponate (P<.05).⁵² Other studies also have reported decreased PASI scores with oral curcumin supplementation.^53,54 Adverse effects reported with oral curcumin included gastrointestinal tract upset and hot flashes.⁵³ Although there is early evidence that may support the use of oral curcumin supplementation for psoriasis, more data are needed before recommending this therapy.

Indigo Naturalis for Psoriasis
Topical indigo naturalis (IN) also has been reported to improve psoriasis symptoms.^39,53,55 The antipsoriatic effects are thought to occur through the active ingredient in IN (indirubin), which is responsible for inhibition of keratinocyte proliferation.⁴⁰ One study reported that topical IN 1.4% containing indirubin 0.16% with a petroleum ointment vehicle applied to psoriatic plaques over 12 weeks resulted in a significant decrease in PASI scores from 18.9 at baseline to 6.3 after IN treatment (P<.001).⁵⁶ Another study found that over 8 weeks, topical application of IN 2.83% containing indirubin 0.24% to psoriatic plaques vs petroleum jelly resulted in 56.3% (n=9) of the treatment group achieving PASI 75 compared to 0% in the placebo group (n=24).⁵⁵ One deterrent in topical IN treatment is the dark blue pigment it contains; however, no other adverse outcomes were found with topical IN treatment.⁵⁶ Larger clinical trials are necessary to further explore IN as a potential adjunct treatment in patients with mild psoriatic disease. When taken orally, IN has caused gastrointestinal tract disturbance and elevated liver enzyme levels.⁵⁷

Herbal Toxicities
It is important to consider that oral supplements including curcumin and IN are widely available over-the-counter and online without oversight by the US Food and Drug Administration.⁴⁰ Herbal supplements typically are compounded with other ingredients and have been associated with hepatotoxicity as well as drug-supplement interactions, including abnormal bleeding and clotting.⁵⁸ There exists a lack of general surveillance data, making the true burden of herbal toxicities more difficult to accurately discern. Although some supplements have been associated with anti-inflammatory qualities and disease improvement, other herbal supplements have been shown to possess immunostimulatory characteristics. Herbal supplements such as spirulina, chlorella, Aphanizomenon flos-aquae, and echinacea have been shown to upregulate inflammatory pathways in a variety of autoimmune skin conditions.⁵⁹

Probiotics for Psoriasis
Data on probiotic use in patients with psoriasis are limited.²³ A distinct pattern of dysbiosis has been identified in psoriatic patients, as there is thought to be depletion of beneficial bacteria such as Bifidobacterium, lactobacilli, and F prausnitzii and increased colonization with pathogenic organisms such as Salmonella, E coli, Heliobacter, Campylobacter, and Alcaligenes in psoriasis patients.^23,59,60 Early mouse studies have supported this hypothesis, as mice fed with Lactobacillus pentosus have developed milder forms of imiquimod-induced psoriasis compared to placebo,⁵⁵ and mice receiving probiotic supplementation have lower levels of psoriasis-related proinflammatory markers such as T_H17-associated cytokines.⁶¹ Another study in humans found that daily oral Bifidobacterium infantis supplementation for 8 weeks in psoriatic patients resulted in lower C-reactive protein and tumor necrosis factor α levels compared to placebo.⁶² Studies on the use of topical probiotics in psoriasis have been limited, and more research is needed to explore this relationship.³⁸ At this time, no specific recommendations can be made on the use of probiotics in psoriatic patients.

Alopecia Areata

Alopecia areata is nonscarring hair loss that can affect the scalp, face, or body.^63,64 The pathophysiology of AA involves the attack of the hair follicle matrix epithelium by inflammatory cells without hair follicle stem cell destruction. The precise events that precipitate these episodes are unknown, but triggers such as emotional or physical stress, vaccines, or viral infections have been reported.⁶⁵ There is no cure for AA, and current treatments such as topical minoxidil and corticosteroids (topical, intralesional, or oral) vary widely in efficacy.⁶⁴ Although Janus kinase inhibitors recently have shown promising results in the treatment of AA, the need for prolonged therapy may be frustrating to patients.⁶⁶ Severity of AA also can vary, with 30% of patients experiencing extensive hair loss.⁶⁷ The use of CAM has been widely reported in AA due to high levels of dissatisfaction with existing therapies.⁶⁸ Herein, we discuss the most studied alternative treatments used in AA

Garlic and Onion for Alopecia
One alternative treatment that has shown promising initial results is application of topical garlic and onion extracts to affected areas.^64,69,70 Both garlic and onion belong to the Allium genus and are high in sulfur and phenolic compounds.⁷⁰ They have been reported to possess bactericidal and vasodilatory activity,⁷¹ and it has been hypothesized that onion and garlic extracts may induce therapeutic effects through induction of a mild contact dermatitis.⁷⁰ One single-blinded, controlled trial using topical crude onion juice reported that 86.9% (n=20) of patients had full regrowth of hair compared to 13.3% (n=2) of patients treated with a tap water placebo at 8 weeks (P<.0001). This study also noted that patients using onion juice had a higher rate of erythema at application site; unfortunately, the study was small with only 38 patients.⁷⁰ Another double-blind RCT using garlic gel 5% with betamethasone valerate cream 0.1% compared to betamethasone valerate cream alone found that after 3 months, patients in the garlic gel group had increased terminal hairs and smaller patch sizes compared to the betamethasone valerate cream group.⁶⁹ More studies are needed to confirm these results.

Aromatherapy With Essential Oils for Alopecia
Another alternative treatment in AA that has demonstrated positive results is aromatherapy skin massage with essential oils to patches of alopecia.⁷² Although certain essential oils, such as tea tree oil, have been reported to have specific antibacterial or anti-inflammatory properties, essential oils have been reported to cause allergic contact dermatitis and should be used with caution.^73,74 For example, tea tree oil is a well-known cause of allergic contact dermatitis, and positive patch testing has ranged from 0.1% to 3.5% in studies assessing topical tea tree oil 5% application.⁷⁵ Overall, there have been nearly 80 essential oils implicated in contact dermatitis, with high-concentration products being one of the highest risk factors for an allergic contact reaction.⁷⁶ One RCT compared daily scalp massage with essential oils (rosemary, lavender, thyme, and cedarwood in a carrier oil) to daily scalp massage with a placebo carrier oil in AA patients. The results showed that at 7 months of treatment, 44% (n=19) of the aromatherapy group showed improvement compared to 15% (n=6) in the control group.⁷⁷ Another study used a similar group of essential oils (thyme, rosemary, atlas cedar, lavender, and EPO in a carrier oil) with daily scalp massage and reported similar improvement of AA symptoms compared to control; the investigators also reported irritation at application site in 1 patient.⁷⁸ There currently are not enough data to recommend aromatherapy skin massage for the treatment of AA, and this practice may cause harm to the patient by induction of allergic contact dermatitis.

There have been a few studies to suggest that the use of total glucosides of peony with compound glycyrrhizin and oral Korean red ginseng may have beneficial effects on AA treatment, but efficacy and safety data are lacking, and these therapies should not be recommended without more information.^64,79,80

Final Thoughts

Dermatologic patients frequently are opting for CAM,² and although some therapies may show promising initial results, alternative medicines also can drive adverse events.^19,30 The lack of oversight from the US Food and Drug Administration on the products leads to many unknowns for true health risks with over-the-counter CAM supplements.⁴⁰ As the use of CAM becomes increasingly common among dermatologic patients, it is important for dermatologists to understand the benefits and risks, especially for commonly treated conditions. More data is needed before CAM can be routinely recommended.

Complementary alternative medicine (CAM) has been described by the National Center for Complementary and Integrative Medicine as “health care approaches that are not typically part of conventional medical care or that may have origins outside of usual Western practice.”¹ Although this definition is broad, CAM encompasses therapies such as traditional Chinese medicine, herbal therapies, dietary supplements, and mind/body interventions. The use of CAM has grown, and according to a 2012 National Center for Complementary and Integrative Health survey, more than 30% of US adults and 12% of US children use health care approaches that are considered outside of conventional medical practice. In a survey study of US adults, at least 17.7% of respondents said they had taken a dietary supplement other than a vitamin or mineral in the last year.¹ Data from the 2007 National Health Interview Survey showed that the prevalence of adults with skin conditions using CAM was 84.5% compared to 38.3% in the general population.² In addition, 8.15 million US patients with dermatologic conditions reported using CAM over a 5-year period.³ Complementary alternative medicine has emerged as an alternative or adjunct to standard treatments, making it important for dermatologists to understand the existing literature on these therapies. Herein, we review the current evidence-based literature that exists on CAM for the treatment of atopic dermatitis (AD), psoriasis, and alopecia areata (AA).

Atopic Dermatitis

Atopic dermatitis is a chronic, pruritic, inflammatory skin condition with considerable morbidity.^4,5 The pathophysiology of AD is multifactorial and includes aspects of barrier dysfunction, IgE hypersensitivity, abnormal cell-mediated immune response, and environmental factors.⁶ Atopic dermatitis also is one of the most common inflammatory skin conditions in adults, affecting more than 7% of the US population and up to 20% of the total population in developed countries. Of those affected, 40% have moderate or severe symptoms that result in a substantial impact on quality of life.⁷ Despite advances in understanding disease pathology and treatment, a subset of patients opt to defer conventional treatments such as topical and systemic corticosteroids, antibiotics, nonsteroidal immunomodulators, and biologics. Patients may seek alternative therapies when typical treatments fail or when the perceived side effects outweigh the benefits.^5,8 The use of CAM has been well described in patients with AD; however, the existing evidence supporting its use along with its safety profile have not been thoroughly explored. Herein, we will discuss some of the most well-studied supplements for treatment of AD, including evening primrose oil (EPO), fish oil, and probiotics.⁵

Oral supplementation with polyunsaturated fatty acids commonly is reported in patients with AD.^5,8 The idea that a fatty acid deficiency could lead to atopic skin conditions has been around since 1937, when it was suggested that patients with AD had lower levels of blood unsaturated fatty acids.⁹ Conflicting evidence regarding oral fatty acid ingestion and AD disease severity has emerged.^10,11 One unsaturated fatty acid, γ-linolenic acid (GLA), has demonstrated anti-inflammatory properties and involvement in barrier repair.¹² It is converted to dihomo-GLA in the body, which acts on cyclooxygenase enzymes to produce the inflammatory mediator prostaglandin E₁. The production of GLA is mediated by the enzyme delta-6 desaturase in the metabolization of linoleic acid.¹² However, it has been reported that in a subset of patients with AD, a malfunction of delta-6 desaturase may play a role in disease progression and result in lower baseline levels of GLA.^10,12 Evening primrose oil and borage oil contain high amounts of GLA (8%–10% and 23%, respectively); thus, supplementation with these oils has been studied in AD.¹³

EPO for AD
Studies investigating EPO (Oenothera biennis) and its association with AD severity have shown mixed results. A Cochrane review reported that oral borage oil and EPO were not effective treatments for AD,¹⁴ while another larger randomized controlled trial (RCT) found no statistically significant improvement in AD symptoms.¹⁵ However, multiple smaller studies have found that clinical symptoms of AD, such as erythema, xerosis, pruritus, and total body surface area involved, did improve with oral EPO supplementation when compared to placebo, and the results were statistically significant (P=.04).^16,17 One study looked at different dosages of EPO and found that groups ingesting both 160 mg and 320 mg daily experienced reductions in eczema area and severity index score, with greater improvement noted with the higher dosage.¹⁷ Side effects associated with oral EPO include an anticoagulant effect and transient gastrointestinal tract upset.^8,14 There currently is not enough evidence or safety data to recommend this supplement to AD patients.

Although topical use of fatty acids with high concentrations of GLA, such as EPO and borage oil, have demonstrated improvement in subjective symptom severity, most studies have not reached statistical significance.^10,11 One study used a 10% EPO cream for 2 weeks compared to placebo and found statistically significant improvement in patient-reported AD symptoms (P=.045). However, this study only included 10 participants, and therefore larger studies are necessary to confirm this result.¹⁸ Some RCTs have shown that topical coconut oil, sunflower seed oil, and sandalwood album oil improve AD symptom severity, but again, large controlled trials are needed.⁵ Unfortunately, many essential oils, including EPO, can cause a secondary allergic contact dermatitis and potentially worsen AD.¹⁹

Fish Oil for AD
Fish oil is a commonly used supplement for AD due to its high content of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Omega-3 fatty acids exert anti-inflammatory effects by displacing arachidonic acid, a proinflammatory omega-6 fatty acid thought to increase IgE, as well as helper T cell (T_H2) cytokines and prostaglandin E₂.^8,20 A 2012 Cochrane review found that, while some studies revealed mild improvement in AD symptoms with oral fish oil supplementation, these RCTs were of poor methodological quality.²¹ Multiple smaller studies have shown a decrease in pruritus, severity, and physician-rated clinical scores with fish oil use.^5,8,20,22 One study with 145 participants reported that 6 g of fish oil once daily compared to isoenergetic corn oil for 16 weeks identified no statistically significant differences between the treatment groups.²⁰ No adverse events were identified in any of the reported trials. Further studies should be conducted to assess the utility and dosing of fish oil supplements in AD patients.

Probiotics for AD
Probiotics consist of live microorganisms that enhance the microflora of the gastrointestinal tract.^8,20 They have been shown to influence food digestion and also have demonstrated potential influence on the skin-gut axis.²³ The theory that intestinal dysbiosis plays a role in AD pathogenesis has been investigated in multiple studies.^23-25 The central premise is that low-fiber and high-fat Western diets lead to fundamental changes in the gut microbiome, resulting in fewer anti-inflammatory metabolites, such as short-chain fatty acids (SCFAs).^23-25 These SCFAs are produced by microbes during the fermentation of dietary fiber and are known for their effect on epithelial barrier integrity and anti-inflammatory properties mediated through G protein–coupled receptor 43.²⁵ Multiple studies have shown that the gut microbiome in patients with AD have higher proportions of Clostridium difficile, Escherichia coli, and Staphylococcus aureus and lower levels of Bifidobacterium, Bacteroidetes, and Bacteroides species compared to healthy controls.^26,27 Metagenomic analysis of fecal samples from patients with AD have shown a reduction of Faecalibacterium prausnitzii species when compared to controls, along with a decreased SCFA production, leading to the hypothesis that the gut microbiome may play a role in epithelial barrier disruption.^28,29 Systematic reviews and smaller studies have found that oral probiotic use does lead to AD symptom improvement.^8,30,31 A systematic review of 25 RCTs with 1599 participants found that supplementation with oral probiotics significantly decreased the SCORAD (SCORing Atopic Dermatitis) index in adults and children older than 1 year with AD but had no effect on infants younger than 1 year (P<.001). They also found that supplementation with diverse microbes or Lactobacillus species showed greater benefit than Bifidobacterium species alone.³⁰ Another study analyzed the effect of oral Lactobacillus fermentum (1×10⁹ CFU twice daily) in 53 children with AD vs placebo for 16 weeks. This study found a statically significant decrease in SCORAD index between oral probiotics and placebo, with 92% (n=24) of participants supplementing with probiotics having a lower SCORAD index than baseline compared to 63% (n=17) in the placebo group (P=.01).³¹ However, the use of probiotics for AD treatment has remained controversial. Two recent systematic reviews, including 39 RCTs of 2599 randomized patients, found that the use of currently available oral probiotics made little or no difference in patient-rated AD symptoms, investigator-rated AD symptoms, or quality of life.^32,33 No adverse effects were observed in the included studies. Unfortunately, the individual RCTs included were heterogeneous, and future studies with standardized probiotic supplementation should be undertaken before probiotics can be routinely recommended.

The use of topical probiotics in AD also has recently emerged. Multiple studies have shown that patients with AD have higher levels of colonization with S aureus, which is associated with T-cell dysfunction, more severe allergic skin reactions, and disruptions in barrier function.^34,35 Therefore, altering the skin microbiota through topical probiotics could theoretically reduce AD symptoms and flares. Multiple RCTs and smaller studies have shown that topical probiotics can alter the skin microbiota, improve erythema, and decrease scaling and pruritus in AD patients.^35-38 One study used a heat-treated Lactobacillus johnsonii 0.3% lotion twice daily for 3 weeks vs placebo in patients with AD with positive S aureus skin cultures. The S aureus load decreased in patients using the topical probiotic lotion, which correlated with lower SCORAD index that was statistically significant compared to placebo (P=.012).³⁶ More robust studies are needed to determine if topical probiotics should routinely be recommended in AD.

Psoriasis

Psoriasis vulgaris is a chronic inflammatory skin condition characterized by pruritic, hyperkeratotic, scaly plaques.^39,40 Keratinocyte hyperproliferation is central to psoriasis pathogenesis and is thought to be a T-cell–driven reaction to antigens or trauma in genetically predisposed individuals. Standard treatments for psoriasis currently include topical corticosteroids and anti-inflammatories, oral immunomodulatory therapy, biologic agents, and phototherapy.⁴⁰ The use of CAM is highly prevalent among patients with psoriasis, with one study reporting that 51% (n=162) of psoriatic patients interviewed had used CAM.⁴¹ The most common reasons for CAM use included dissatisfaction with current treatment, adverse side effects of standard therapy, and patient-reported attempts at “trying everything to heal disease.”⁴² Herein, we will discuss some of the most frequently used supplements for treatment of psoriatic disease.³⁹

Fish Oil for Psoriasis
One of the most common supplements used by patients with psoriasis is fish oil due to its purported anti-inflammatory qualities.^20,39 The consensus on fish oil supplementation for psoriasis is mixed.^43-45 Multiple RCTs have reported reductions in psoriasis area and severity index (PASI) scores or symptomatic improvement with variable doses of fish oil.^44,46 One RCT found that using EPA 1.8 g once daily and DHA 1.2 g once daily for 12 weeks resulted in significant improvement in pruritus, scaling, and erythema (P<.05).⁴⁴ Another study reported a significant decrease in erythema (P=.02) and total body surface area affected (P=.0001) with EPA 3.6 g once daily and DHA 2.4 g once daily supplementation compared to olive oil supplementation for 15 weeks.⁴⁶ Alternatively, multiple studies have failed to show statistically significant improvement in psoriatic symptoms with fish oil supplementation at variable doses and time frames (14–216 mg daily EPA, 9–80 mg daily DHA, from 2 weeks to 9 months).^40,47,48 Fish oil may impart anticoagulant properties and should not be started without the guidance of a physician. Currently, there are no data to make specific recommendations on the use of fish oil as an adjunct psoriatic treatment.

Curcumin for Psoriasis
Another supplement routinely utilized in patients with psoriasis is curcumin,^40,49,50 a yellow phytochemical that is a major component of the spice turmeric. Curcumin has been shown to inhibit certain proinflammatory cytokines including IL-17, IL-6, IFN-γ, and tumor necrosis factor α and has been regarded as having immune-modulating, anti-inflammatory, and antibacterial properties.^40,50 Curcumin also has been reported to suppress phosphorylase kinase, an enzyme that has increased activity in psoriatic plaques that correlates with markers of psoriatic hyperproliferation.^50,51 When applied topically, turmeric microgel 0.5% has been reported to decrease scaling, erythema, and psoriatic plaque thickness over the course of 9 weeks.⁵⁰ In a nonrandomized trial with 10 participants, researchers found that phosphorylase kinase activity levels in psoriatic skin biopsies of patients applying topical curcumin 1% were lower than placebo and topical calcipotriol applied in combination. The lower phosphorylase kinase levels correlated with level of disease severity, and topical curcumin 1% showed a superior outcome when compared to topical calcipotriol.^40,49 Although these preliminary results are interesting, there still are not enough data at this time to recommend topical curcumin as a treatment of psoriasis. No known adverse events have been reported with the use of topical curcumin to date.

Oral curcumin has poor oral bioavailability, and 40% to 90% of oral doses are excreted, making supplementation a challenge.⁴⁰ In one RCT, oral curcumin 2 g daily (using a lecithin-based delivery system to increase bioavailability) was administered in combination with topical methylprednisolone aceponate 0.1%, resulting in significant improvement in psoriatic symptoms and lower IL-22 compared to placebo and topical methylprednisolone aceponate (P<.05).⁵² Other studies also have reported decreased PASI scores with oral curcumin supplementation.^53,54 Adverse effects reported with oral curcumin included gastrointestinal tract upset and hot flashes.⁵³ Although there is early evidence that may support the use of oral curcumin supplementation for psoriasis, more data are needed before recommending this therapy.

Indigo Naturalis for Psoriasis
Topical indigo naturalis (IN) also has been reported to improve psoriasis symptoms.^39,53,55 The antipsoriatic effects are thought to occur through the active ingredient in IN (indirubin), which is responsible for inhibition of keratinocyte proliferation.⁴⁰ One study reported that topical IN 1.4% containing indirubin 0.16% with a petroleum ointment vehicle applied to psoriatic plaques over 12 weeks resulted in a significant decrease in PASI scores from 18.9 at baseline to 6.3 after IN treatment (P<.001).⁵⁶ Another study found that over 8 weeks, topical application of IN 2.83% containing indirubin 0.24% to psoriatic plaques vs petroleum jelly resulted in 56.3% (n=9) of the treatment group achieving PASI 75 compared to 0% in the placebo group (n=24).⁵⁵ One deterrent in topical IN treatment is the dark blue pigment it contains; however, no other adverse outcomes were found with topical IN treatment.⁵⁶ Larger clinical trials are necessary to further explore IN as a potential adjunct treatment in patients with mild psoriatic disease. When taken orally, IN has caused gastrointestinal tract disturbance and elevated liver enzyme levels.⁵⁷

Herbal Toxicities
It is important to consider that oral supplements including curcumin and IN are widely available over-the-counter and online without oversight by the US Food and Drug Administration.⁴⁰ Herbal supplements typically are compounded with other ingredients and have been associated with hepatotoxicity as well as drug-supplement interactions, including abnormal bleeding and clotting.⁵⁸ There exists a lack of general surveillance data, making the true burden of herbal toxicities more difficult to accurately discern. Although some supplements have been associated with anti-inflammatory qualities and disease improvement, other herbal supplements have been shown to possess immunostimulatory characteristics. Herbal supplements such as spirulina, chlorella, Aphanizomenon flos-aquae, and echinacea have been shown to upregulate inflammatory pathways in a variety of autoimmune skin conditions.⁵⁹

Probiotics for Psoriasis
Data on probiotic use in patients with psoriasis are limited.²³ A distinct pattern of dysbiosis has been identified in psoriatic patients, as there is thought to be depletion of beneficial bacteria such as Bifidobacterium, lactobacilli, and F prausnitzii and increased colonization with pathogenic organisms such as Salmonella, E coli, Heliobacter, Campylobacter, and Alcaligenes in psoriasis patients.^23,59,60 Early mouse studies have supported this hypothesis, as mice fed with Lactobacillus pentosus have developed milder forms of imiquimod-induced psoriasis compared to placebo,⁵⁵ and mice receiving probiotic supplementation have lower levels of psoriasis-related proinflammatory markers such as T_H17-associated cytokines.⁶¹ Another study in humans found that daily oral Bifidobacterium infantis supplementation for 8 weeks in psoriatic patients resulted in lower C-reactive protein and tumor necrosis factor α levels compared to placebo.⁶² Studies on the use of topical probiotics in psoriasis have been limited, and more research is needed to explore this relationship.³⁸ At this time, no specific recommendations can be made on the use of probiotics in psoriatic patients.

Alopecia Areata

Alopecia areata is nonscarring hair loss that can affect the scalp, face, or body.^63,64 The pathophysiology of AA involves the attack of the hair follicle matrix epithelium by inflammatory cells without hair follicle stem cell destruction. The precise events that precipitate these episodes are unknown, but triggers such as emotional or physical stress, vaccines, or viral infections have been reported.⁶⁵ There is no cure for AA, and current treatments such as topical minoxidil and corticosteroids (topical, intralesional, or oral) vary widely in efficacy.⁶⁴ Although Janus kinase inhibitors recently have shown promising results in the treatment of AA, the need for prolonged therapy may be frustrating to patients.⁶⁶ Severity of AA also can vary, with 30% of patients experiencing extensive hair loss.⁶⁷ The use of CAM has been widely reported in AA due to high levels of dissatisfaction with existing therapies.⁶⁸ Herein, we discuss the most studied alternative treatments used in AA

Garlic and Onion for Alopecia
One alternative treatment that has shown promising initial results is application of topical garlic and onion extracts to affected areas.^64,69,70 Both garlic and onion belong to the Allium genus and are high in sulfur and phenolic compounds.⁷⁰ They have been reported to possess bactericidal and vasodilatory activity,⁷¹ and it has been hypothesized that onion and garlic extracts may induce therapeutic effects through induction of a mild contact dermatitis.⁷⁰ One single-blinded, controlled trial using topical crude onion juice reported that 86.9% (n=20) of patients had full regrowth of hair compared to 13.3% (n=2) of patients treated with a tap water placebo at 8 weeks (P<.0001). This study also noted that patients using onion juice had a higher rate of erythema at application site; unfortunately, the study was small with only 38 patients.⁷⁰ Another double-blind RCT using garlic gel 5% with betamethasone valerate cream 0.1% compared to betamethasone valerate cream alone found that after 3 months, patients in the garlic gel group had increased terminal hairs and smaller patch sizes compared to the betamethasone valerate cream group.⁶⁹ More studies are needed to confirm these results.

Aromatherapy With Essential Oils for Alopecia
Another alternative treatment in AA that has demonstrated positive results is aromatherapy skin massage with essential oils to patches of alopecia.⁷² Although certain essential oils, such as tea tree oil, have been reported to have specific antibacterial or anti-inflammatory properties, essential oils have been reported to cause allergic contact dermatitis and should be used with caution.^73,74 For example, tea tree oil is a well-known cause of allergic contact dermatitis, and positive patch testing has ranged from 0.1% to 3.5% in studies assessing topical tea tree oil 5% application.⁷⁵ Overall, there have been nearly 80 essential oils implicated in contact dermatitis, with high-concentration products being one of the highest risk factors for an allergic contact reaction.⁷⁶ One RCT compared daily scalp massage with essential oils (rosemary, lavender, thyme, and cedarwood in a carrier oil) to daily scalp massage with a placebo carrier oil in AA patients. The results showed that at 7 months of treatment, 44% (n=19) of the aromatherapy group showed improvement compared to 15% (n=6) in the control group.⁷⁷ Another study used a similar group of essential oils (thyme, rosemary, atlas cedar, lavender, and EPO in a carrier oil) with daily scalp massage and reported similar improvement of AA symptoms compared to control; the investigators also reported irritation at application site in 1 patient.⁷⁸ There currently are not enough data to recommend aromatherapy skin massage for the treatment of AA, and this practice may cause harm to the patient by induction of allergic contact dermatitis.

There have been a few studies to suggest that the use of total glucosides of peony with compound glycyrrhizin and oral Korean red ginseng may have beneficial effects on AA treatment, but efficacy and safety data are lacking, and these therapies should not be recommended without more information.^64,79,80

Final Thoughts

Dermatologic patients frequently are opting for CAM,² and although some therapies may show promising initial results, alternative medicines also can drive adverse events.^19,30 The lack of oversight from the US Food and Drug Administration on the products leads to many unknowns for true health risks with over-the-counter CAM supplements.⁴⁰ As the use of CAM becomes increasingly common among dermatologic patients, it is important for dermatologists to understand the benefits and risks, especially for commonly treated conditions. More data is needed before CAM can be routinely recommended.

Complementary alternative medicine (CAM) has been described by the National Center for Complementary and Integrative Medicine as “health care approaches that are not typically part of conventional medical care or that may have origins outside of usual Western practice.”¹ Although this definition is broad, CAM encompasses therapies such as traditional Chinese medicine, herbal therapies, dietary supplements, and mind/body interventions. The use of CAM has grown, and according to a 2012 National Center for Complementary and Integrative Health survey, more than 30% of US adults and 12% of US children use health care approaches that are considered outside of conventional medical practice. In a survey study of US adults, at least 17.7% of respondents said they had taken a dietary supplement other than a vitamin or mineral in the last year.¹ Data from the 2007 National Health Interview Survey showed that the prevalence of adults with skin conditions using CAM was 84.5% compared to 38.3% in the general population.² In addition, 8.15 million US patients with dermatologic conditions reported using CAM over a 5-year period.³ Complementary alternative medicine has emerged as an alternative or adjunct to standard treatments, making it important for dermatologists to understand the existing literature on these therapies. Herein, we review the current evidence-based literature that exists on CAM for the treatment of atopic dermatitis (AD), psoriasis, and alopecia areata (AA).

Atopic Dermatitis

Atopic dermatitis is a chronic, pruritic, inflammatory skin condition with considerable morbidity.^4,5 The pathophysiology of AD is multifactorial and includes aspects of barrier dysfunction, IgE hypersensitivity, abnormal cell-mediated immune response, and environmental factors.⁶ Atopic dermatitis also is one of the most common inflammatory skin conditions in adults, affecting more than 7% of the US population and up to 20% of the total population in developed countries. Of those affected, 40% have moderate or severe symptoms that result in a substantial impact on quality of life.⁷ Despite advances in understanding disease pathology and treatment, a subset of patients opt to defer conventional treatments such as topical and systemic corticosteroids, antibiotics, nonsteroidal immunomodulators, and biologics. Patients may seek alternative therapies when typical treatments fail or when the perceived side effects outweigh the benefits.^5,8 The use of CAM has been well described in patients with AD; however, the existing evidence supporting its use along with its safety profile have not been thoroughly explored. Herein, we will discuss some of the most well-studied supplements for treatment of AD, including evening primrose oil (EPO), fish oil, and probiotics.⁵

Oral supplementation with polyunsaturated fatty acids commonly is reported in patients with AD.^5,8 The idea that a fatty acid deficiency could lead to atopic skin conditions has been around since 1937, when it was suggested that patients with AD had lower levels of blood unsaturated fatty acids.⁹ Conflicting evidence regarding oral fatty acid ingestion and AD disease severity has emerged.^10,11 One unsaturated fatty acid, γ-linolenic acid (GLA), has demonstrated anti-inflammatory properties and involvement in barrier repair.¹² It is converted to dihomo-GLA in the body, which acts on cyclooxygenase enzymes to produce the inflammatory mediator prostaglandin E₁. The production of GLA is mediated by the enzyme delta-6 desaturase in the metabolization of linoleic acid.¹² However, it has been reported that in a subset of patients with AD, a malfunction of delta-6 desaturase may play a role in disease progression and result in lower baseline levels of GLA.^10,12 Evening primrose oil and borage oil contain high amounts of GLA (8%–10% and 23%, respectively); thus, supplementation with these oils has been studied in AD.¹³

EPO for AD
Studies investigating EPO (Oenothera biennis) and its association with AD severity have shown mixed results. A Cochrane review reported that oral borage oil and EPO were not effective treatments for AD,¹⁴ while another larger randomized controlled trial (RCT) found no statistically significant improvement in AD symptoms.¹⁵ However, multiple smaller studies have found that clinical symptoms of AD, such as erythema, xerosis, pruritus, and total body surface area involved, did improve with oral EPO supplementation when compared to placebo, and the results were statistically significant (P=.04).^16,17 One study looked at different dosages of EPO and found that groups ingesting both 160 mg and 320 mg daily experienced reductions in eczema area and severity index score, with greater improvement noted with the higher dosage.¹⁷ Side effects associated with oral EPO include an anticoagulant effect and transient gastrointestinal tract upset.^8,14 There currently is not enough evidence or safety data to recommend this supplement to AD patients.

Although topical use of fatty acids with high concentrations of GLA, such as EPO and borage oil, have demonstrated improvement in subjective symptom severity, most studies have not reached statistical significance.^10,11 One study used a 10% EPO cream for 2 weeks compared to placebo and found statistically significant improvement in patient-reported AD symptoms (P=.045). However, this study only included 10 participants, and therefore larger studies are necessary to confirm this result.¹⁸ Some RCTs have shown that topical coconut oil, sunflower seed oil, and sandalwood album oil improve AD symptom severity, but again, large controlled trials are needed.⁵ Unfortunately, many essential oils, including EPO, can cause a secondary allergic contact dermatitis and potentially worsen AD.¹⁹

Fish Oil for AD
Fish oil is a commonly used supplement for AD due to its high content of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Omega-3 fatty acids exert anti-inflammatory effects by displacing arachidonic acid, a proinflammatory omega-6 fatty acid thought to increase IgE, as well as helper T cell (T_H2) cytokines and prostaglandin E₂.^8,20 A 2012 Cochrane review found that, while some studies revealed mild improvement in AD symptoms with oral fish oil supplementation, these RCTs were of poor methodological quality.²¹ Multiple smaller studies have shown a decrease in pruritus, severity, and physician-rated clinical scores with fish oil use.^5,8,20,22 One study with 145 participants reported that 6 g of fish oil once daily compared to isoenergetic corn oil for 16 weeks identified no statistically significant differences between the treatment groups.²⁰ No adverse events were identified in any of the reported trials. Further studies should be conducted to assess the utility and dosing of fish oil supplements in AD patients.

Probiotics for AD
Probiotics consist of live microorganisms that enhance the microflora of the gastrointestinal tract.^8,20 They have been shown to influence food digestion and also have demonstrated potential influence on the skin-gut axis.²³ The theory that intestinal dysbiosis plays a role in AD pathogenesis has been investigated in multiple studies.^23-25 The central premise is that low-fiber and high-fat Western diets lead to fundamental changes in the gut microbiome, resulting in fewer anti-inflammatory metabolites, such as short-chain fatty acids (SCFAs).^23-25 These SCFAs are produced by microbes during the fermentation of dietary fiber and are known for their effect on epithelial barrier integrity and anti-inflammatory properties mediated through G protein–coupled receptor 43.²⁵ Multiple studies have shown that the gut microbiome in patients with AD have higher proportions of Clostridium difficile, Escherichia coli, and Staphylococcus aureus and lower levels of Bifidobacterium, Bacteroidetes, and Bacteroides species compared to healthy controls.^26,27 Metagenomic analysis of fecal samples from patients with AD have shown a reduction of Faecalibacterium prausnitzii species when compared to controls, along with a decreased SCFA production, leading to the hypothesis that the gut microbiome may play a role in epithelial barrier disruption.^28,29 Systematic reviews and smaller studies have found that oral probiotic use does lead to AD symptom improvement.^8,30,31 A systematic review of 25 RCTs with 1599 participants found that supplementation with oral probiotics significantly decreased the SCORAD (SCORing Atopic Dermatitis) index in adults and children older than 1 year with AD but had no effect on infants younger than 1 year (P<.001). They also found that supplementation with diverse microbes or Lactobacillus species showed greater benefit than Bifidobacterium species alone.³⁰ Another study analyzed the effect of oral Lactobacillus fermentum (1×10⁹ CFU twice daily) in 53 children with AD vs placebo for 16 weeks. This study found a statically significant decrease in SCORAD index between oral probiotics and placebo, with 92% (n=24) of participants supplementing with probiotics having a lower SCORAD index than baseline compared to 63% (n=17) in the placebo group (P=.01).³¹ However, the use of probiotics for AD treatment has remained controversial. Two recent systematic reviews, including 39 RCTs of 2599 randomized patients, found that the use of currently available oral probiotics made little or no difference in patient-rated AD symptoms, investigator-rated AD symptoms, or quality of life.^32,33 No adverse effects were observed in the included studies. Unfortunately, the individual RCTs included were heterogeneous, and future studies with standardized probiotic supplementation should be undertaken before probiotics can be routinely recommended.

The use of topical probiotics in AD also has recently emerged. Multiple studies have shown that patients with AD have higher levels of colonization with S aureus, which is associated with T-cell dysfunction, more severe allergic skin reactions, and disruptions in barrier function.^34,35 Therefore, altering the skin microbiota through topical probiotics could theoretically reduce AD symptoms and flares. Multiple RCTs and smaller studies have shown that topical probiotics can alter the skin microbiota, improve erythema, and decrease scaling and pruritus in AD patients.^35-38 One study used a heat-treated Lactobacillus johnsonii 0.3% lotion twice daily for 3 weeks vs placebo in patients with AD with positive S aureus skin cultures. The S aureus load decreased in patients using the topical probiotic lotion, which correlated with lower SCORAD index that was statistically significant compared to placebo (P=.012).³⁶ More robust studies are needed to determine if topical probiotics should routinely be recommended in AD.

Psoriasis

Psoriasis vulgaris is a chronic inflammatory skin condition characterized by pruritic, hyperkeratotic, scaly plaques.^39,40 Keratinocyte hyperproliferation is central to psoriasis pathogenesis and is thought to be a T-cell–driven reaction to antigens or trauma in genetically predisposed individuals. Standard treatments for psoriasis currently include topical corticosteroids and anti-inflammatories, oral immunomodulatory therapy, biologic agents, and phototherapy.⁴⁰ The use of CAM is highly prevalent among patients with psoriasis, with one study reporting that 51% (n=162) of psoriatic patients interviewed had used CAM.⁴¹ The most common reasons for CAM use included dissatisfaction with current treatment, adverse side effects of standard therapy, and patient-reported attempts at “trying everything to heal disease.”⁴² Herein, we will discuss some of the most frequently used supplements for treatment of psoriatic disease.³⁹

Fish Oil for Psoriasis
One of the most common supplements used by patients with psoriasis is fish oil due to its purported anti-inflammatory qualities.^20,39 The consensus on fish oil supplementation for psoriasis is mixed.^43-45 Multiple RCTs have reported reductions in psoriasis area and severity index (PASI) scores or symptomatic improvement with variable doses of fish oil.^44,46 One RCT found that using EPA 1.8 g once daily and DHA 1.2 g once daily for 12 weeks resulted in significant improvement in pruritus, scaling, and erythema (P<.05).⁴⁴ Another study reported a significant decrease in erythema (P=.02) and total body surface area affected (P=.0001) with EPA 3.6 g once daily and DHA 2.4 g once daily supplementation compared to olive oil supplementation for 15 weeks.⁴⁶ Alternatively, multiple studies have failed to show statistically significant improvement in psoriatic symptoms with fish oil supplementation at variable doses and time frames (14–216 mg daily EPA, 9–80 mg daily DHA, from 2 weeks to 9 months).^40,47,48 Fish oil may impart anticoagulant properties and should not be started without the guidance of a physician. Currently, there are no data to make specific recommendations on the use of fish oil as an adjunct psoriatic treatment.

Curcumin for Psoriasis
Another supplement routinely utilized in patients with psoriasis is curcumin,^40,49,50 a yellow phytochemical that is a major component of the spice turmeric. Curcumin has been shown to inhibit certain proinflammatory cytokines including IL-17, IL-6, IFN-γ, and tumor necrosis factor α and has been regarded as having immune-modulating, anti-inflammatory, and antibacterial properties.^40,50 Curcumin also has been reported to suppress phosphorylase kinase, an enzyme that has increased activity in psoriatic plaques that correlates with markers of psoriatic hyperproliferation.^50,51 When applied topically, turmeric microgel 0.5% has been reported to decrease scaling, erythema, and psoriatic plaque thickness over the course of 9 weeks.⁵⁰ In a nonrandomized trial with 10 participants, researchers found that phosphorylase kinase activity levels in psoriatic skin biopsies of patients applying topical curcumin 1% were lower than placebo and topical calcipotriol applied in combination. The lower phosphorylase kinase levels correlated with level of disease severity, and topical curcumin 1% showed a superior outcome when compared to topical calcipotriol.^40,49 Although these preliminary results are interesting, there still are not enough data at this time to recommend topical curcumin as a treatment of psoriasis. No known adverse events have been reported with the use of topical curcumin to date.

Oral curcumin has poor oral bioavailability, and 40% to 90% of oral doses are excreted, making supplementation a challenge.⁴⁰ In one RCT, oral curcumin 2 g daily (using a lecithin-based delivery system to increase bioavailability) was administered in combination with topical methylprednisolone aceponate 0.1%, resulting in significant improvement in psoriatic symptoms and lower IL-22 compared to placebo and topical methylprednisolone aceponate (P<.05).⁵² Other studies also have reported decreased PASI scores with oral curcumin supplementation.^53,54 Adverse effects reported with oral curcumin included gastrointestinal tract upset and hot flashes.⁵³ Although there is early evidence that may support the use of oral curcumin supplementation for psoriasis, more data are needed before recommending this therapy.

Indigo Naturalis for Psoriasis
Topical indigo naturalis (IN) also has been reported to improve psoriasis symptoms.^39,53,55 The antipsoriatic effects are thought to occur through the active ingredient in IN (indirubin), which is responsible for inhibition of keratinocyte proliferation.⁴⁰ One study reported that topical IN 1.4% containing indirubin 0.16% with a petroleum ointment vehicle applied to psoriatic plaques over 12 weeks resulted in a significant decrease in PASI scores from 18.9 at baseline to 6.3 after IN treatment (P<.001).⁵⁶ Another study found that over 8 weeks, topical application of IN 2.83% containing indirubin 0.24% to psoriatic plaques vs petroleum jelly resulted in 56.3% (n=9) of the treatment group achieving PASI 75 compared to 0% in the placebo group (n=24).⁵⁵ One deterrent in topical IN treatment is the dark blue pigment it contains; however, no other adverse outcomes were found with topical IN treatment.⁵⁶ Larger clinical trials are necessary to further explore IN as a potential adjunct treatment in patients with mild psoriatic disease. When taken orally, IN has caused gastrointestinal tract disturbance and elevated liver enzyme levels.⁵⁷

Herbal Toxicities
It is important to consider that oral supplements including curcumin and IN are widely available over-the-counter and online without oversight by the US Food and Drug Administration.⁴⁰ Herbal supplements typically are compounded with other ingredients and have been associated with hepatotoxicity as well as drug-supplement interactions, including abnormal bleeding and clotting.⁵⁸ There exists a lack of general surveillance data, making the true burden of herbal toxicities more difficult to accurately discern. Although some supplements have been associated with anti-inflammatory qualities and disease improvement, other herbal supplements have been shown to possess immunostimulatory characteristics. Herbal supplements such as spirulina, chlorella, Aphanizomenon flos-aquae, and echinacea have been shown to upregulate inflammatory pathways in a variety of autoimmune skin conditions.⁵⁹

Probiotics for Psoriasis
Data on probiotic use in patients with psoriasis are limited.²³ A distinct pattern of dysbiosis has been identified in psoriatic patients, as there is thought to be depletion of beneficial bacteria such as Bifidobacterium, lactobacilli, and F prausnitzii and increased colonization with pathogenic organisms such as Salmonella, E coli, Heliobacter, Campylobacter, and Alcaligenes in psoriasis patients.^23,59,60 Early mouse studies have supported this hypothesis, as mice fed with Lactobacillus pentosus have developed milder forms of imiquimod-induced psoriasis compared to placebo,⁵⁵ and mice receiving probiotic supplementation have lower levels of psoriasis-related proinflammatory markers such as T_H17-associated cytokines.⁶¹ Another study in humans found that daily oral Bifidobacterium infantis supplementation for 8 weeks in psoriatic patients resulted in lower C-reactive protein and tumor necrosis factor α levels compared to placebo.⁶² Studies on the use of topical probiotics in psoriasis have been limited, and more research is needed to explore this relationship.³⁸ At this time, no specific recommendations can be made on the use of probiotics in psoriatic patients.

Alopecia Areata

Alopecia areata is nonscarring hair loss that can affect the scalp, face, or body.^63,64 The pathophysiology of AA involves the attack of the hair follicle matrix epithelium by inflammatory cells without hair follicle stem cell destruction. The precise events that precipitate these episodes are unknown, but triggers such as emotional or physical stress, vaccines, or viral infections have been reported.⁶⁵ There is no cure for AA, and current treatments such as topical minoxidil and corticosteroids (topical, intralesional, or oral) vary widely in efficacy.⁶⁴ Although Janus kinase inhibitors recently have shown promising results in the treatment of AA, the need for prolonged therapy may be frustrating to patients.⁶⁶ Severity of AA also can vary, with 30% of patients experiencing extensive hair loss.⁶⁷ The use of CAM has been widely reported in AA due to high levels of dissatisfaction with existing therapies.⁶⁸ Herein, we discuss the most studied alternative treatments used in AA

Garlic and Onion for Alopecia
One alternative treatment that has shown promising initial results is application of topical garlic and onion extracts to affected areas.^64,69,70 Both garlic and onion belong to the Allium genus and are high in sulfur and phenolic compounds.⁷⁰ They have been reported to possess bactericidal and vasodilatory activity,⁷¹ and it has been hypothesized that onion and garlic extracts may induce therapeutic effects through induction of a mild contact dermatitis.⁷⁰ One single-blinded, controlled trial using topical crude onion juice reported that 86.9% (n=20) of patients had full regrowth of hair compared to 13.3% (n=2) of patients treated with a tap water placebo at 8 weeks (P<.0001). This study also noted that patients using onion juice had a higher rate of erythema at application site; unfortunately, the study was small with only 38 patients.⁷⁰ Another double-blind RCT using garlic gel 5% with betamethasone valerate cream 0.1% compared to betamethasone valerate cream alone found that after 3 months, patients in the garlic gel group had increased terminal hairs and smaller patch sizes compared to the betamethasone valerate cream group.⁶⁹ More studies are needed to confirm these results.

Aromatherapy With Essential Oils for Alopecia
Another alternative treatment in AA that has demonstrated positive results is aromatherapy skin massage with essential oils to patches of alopecia.⁷² Although certain essential oils, such as tea tree oil, have been reported to have specific antibacterial or anti-inflammatory properties, essential oils have been reported to cause allergic contact dermatitis and should be used with caution.^73,74 For example, tea tree oil is a well-known cause of allergic contact dermatitis, and positive patch testing has ranged from 0.1% to 3.5% in studies assessing topical tea tree oil 5% application.⁷⁵ Overall, there have been nearly 80 essential oils implicated in contact dermatitis, with high-concentration products being one of the highest risk factors for an allergic contact reaction.⁷⁶ One RCT compared daily scalp massage with essential oils (rosemary, lavender, thyme, and cedarwood in a carrier oil) to daily scalp massage with a placebo carrier oil in AA patients. The results showed that at 7 months of treatment, 44% (n=19) of the aromatherapy group showed improvement compared to 15% (n=6) in the control group.⁷⁷ Another study used a similar group of essential oils (thyme, rosemary, atlas cedar, lavender, and EPO in a carrier oil) with daily scalp massage and reported similar improvement of AA symptoms compared to control; the investigators also reported irritation at application site in 1 patient.⁷⁸ There currently are not enough data to recommend aromatherapy skin massage for the treatment of AA, and this practice may cause harm to the patient by induction of allergic contact dermatitis.

There have been a few studies to suggest that the use of total glucosides of peony with compound glycyrrhizin and oral Korean red ginseng may have beneficial effects on AA treatment, but efficacy and safety data are lacking, and these therapies should not be recommended without more information.^64,79,80

Final Thoughts

Dermatologic patients frequently are opting for CAM,² and although some therapies may show promising initial results, alternative medicines also can drive adverse events.^19,30 The lack of oversight from the US Food and Drug Administration on the products leads to many unknowns for true health risks with over-the-counter CAM supplements.⁴⁰ As the use of CAM becomes increasingly common among dermatologic patients, it is important for dermatologists to understand the benefits and risks, especially for commonly treated conditions. More data is needed before CAM can be routinely recommended.

Rashes that develop during pregnancy often result in considerable anxiety or concern for patients and their families. Recognizing these pregnancy-specific dermatoses is important in identifying fetal risks as well as providing appropriate management and expert guidance for patients regarding future pregnancies. Managing cutaneous manifestations of pregnancy-related disorders is challenging and requires knowledge of potential side effects of therapy for both the mother and fetus. It also is important to appreciate the physiologic cutaneous changes of pregnancy along with their clinical significance and management.

In 2006, Ambrose-Rudolph et al¹ proposed reclassification of pregnancy-specific dermatoses, which has since been widely accepted by the academic dermatology community. The 4 most prominent disorders include intrahepatic cholestasis of pregnancy (ICP); pemphigoid gestationis (PG); polymorphic eruption of pregnancy (PEP), also known as pruritic urticarial papules and plaques of pregnancy; and atopic eruption of pregnancy.² It is important to recognize these pregnancy-specific disorders and to understand their clinical significance. The morphology of the eruption as well as the location and timing of the onset of the rash are important clues in making an accurate diagnosis.³

Clinical Presentation

Intrahepatic cholestasis of pregnancy presents with severe generalized pruritus, usually with involvement of the palms and soles, in the late second or third trimester. Pemphigoid gestationis presents with urticarial papules and/or bullae, often in the second or third trimester or postpartum. An important diagnostic clue for PG is involvement near the umbilicus. Polymorphic eruption of pregnancy presents with urticarial papules and plaques; onset occurs in the third trimester or postpartum and initially involves the striae while sparing the umbilicus, unlike in PG. Atopic eruption of pregnancy has an earlier onset than the other pregnancy-specific dermatoses, often in the first or second trimester, and presents with widespread eczematous lesions.³

Diagnosis

The pregnancy dermatoses with the greatest potential for fetal risks are ICP and PG; therefore, it is critical for health care providers to diagnose these dermatoses in a timely manner and initiate appropriate management. Intrahepatic cholestasis of pregnancy is confirmed by elevated serum bile acids (ie, >10 µmol/L), often during the third trimester. The risk of fetal morbidity is high in ICP with increased bile acids crossing the placenta causing placental anoxia and impaired cardiomyocyte function.⁴ Fetal risks, including preterm delivery, meconium-stained amniotic fluid, and stillbirth, correlate with the level of bile acids in the serum.⁵ Maternal prognosis is favorable, but there is an increased association with hepatitis C and hepatobiliary disease.⁶

Diagnosis of PG is confirmed by classic biopsy results and direct immunofluorescence revealing C3 with or without IgG in a linear band along the basement membrane zone. Additionally, complement indirect immunofluorescence reveals circulating IgG anti–basement membrane zone antibodies. Pemphigoid gestationis is associated with increased fetal risks of preterm labor and intrauterine growth retardation.⁷ Clinical findings of PG may present in the fetus upon delivery due to transmission of autoantibodies across the placenta. The symptoms usually are mild.⁸ An increased risk of Graves disease has been reported in mothers with PG.

In most cases, diagnosis of PEP is based on history and morphology, but if the presentation is not classic, skin biopsy must be used to differentiate it from PG as well as more common dermatologic conditions such as contact dermatitis, drug and viral eruptions, and urticaria.

Atopic eruption of pregnancy manifests as widespread eczematous excoriated papules and plaques. Lesions of prurigo nodularis are common.

Comorbidities

It is important to be aware of specific clinical associations related to pregnancy-specific dermatoses. Pemphigoid gestationis has been associated with gestational trophoblastic tumors including hydatiform mole and choriocarcinoma.⁴ An increased risk for Graves disease has been reported in patients with PG.⁹ Patients who develop ICP have a higher incidence of hepatitis C, postpartum cholecystitis, gallstones, and nonalcoholic cirrhosis.⁸ Polymorphic eruption of pregnancy is associated with a notably higher incidence in multiple gestation pregnancies.²

Treatment and Management

Management of ICP requires an accurate and timely diagnosis, and advanced neonatal-obstetric management is critical.³ Ursodeoxycholic acid is the treatment of choice and reduces pruritus, prolongs pregnancy, and reduces fetal risk.⁴ Most stillbirths cluster at the 38th week of pregnancy, and patients with ICP and highly elevated serum bile acids (>40 µmol/L) should be considered for delivery at 37 weeks or earlier.⁵

Management of the other cutaneous disorders of pregnancy can be challenging for health care providers based on safety concerns for the fetus. Although it is important to minimize risks to the fetus, it also is important to adequately treat the mother’s cutaneous disease, which requires a solid knowledge of drug safety during pregnancy. The former US Food and Drug Administration classification system using A, B, C, D, and X pregnancy categories was replaced by the Pregnancy Lactation Label Final Rule, which provides counseling on medication safety during pregnancy.¹⁰ In 2014, Murase et al¹¹ published a review of dermatologic medication safety during pregnancy, which serves as an excellent guide.

Before instituting treatment, the therapeutic plan should be discussed with the physician managing the patient’s pregnancy. In general, topical steroids are considered safe during pregnancy, and low-potency to moderate-potency topical steroids are preferred. If possible, use of topical steroids should be limited to less than 300 g for the duration of the pregnancy. Fluticasone propionate should be avoided during pregnancy because it is not metabolized by the placenta. When systemic steroids are considered appropriate for management during pregnancy, nonhalogenated corticosteroids such as prednisone and prednisolone are preferred because they are enzymatically inactivated by the placenta, which results in a favorable maternal-fetal gradient.¹² There has been concern expressed in the medical literature that systemic steroids during the first trimester may increase the risk of cleft lip and cleft palate.^3,12 When managing pregnancy dermatoses, consideration should be given to keep prednisone exposure below 20 mg/d, and try to limit prolonged use to 7.5 mg/d. However, this may not be possible in PG.³ Vitamin D and calcium supplementation may be appropriate when patients are on prolonged systemic steroids to control disease.

Antihistamines can be used to control pruritus complicating pregnancy-associated dermatoses. First-generation antihistamines such as chlorpheniramine and diphenhydramine are preferred due to long-term safety data.^3,11,12 Loratadine is the first choice and cetirizine is the second choice if a second-generation antihistamine is preferred.³ Loratadine is preferred during breastfeeding due to less sedation.¹² High-dose antihistamines prior to delivery may cause concerns for potential side effects in the newborn, including tremulousness, irritability, and poor feeding.

Recurrence

Women with pregnancy dermatoses often are concerned about recurrence with future pregnancies. Pemphigoid gestationis may flare with subsequent pregnancies, subsequent menses, or with oral contraceptive use.³ Recurrence of PEP in subsequent pregnancies is rare and usually is less severe than the primary eruption.⁸ Often, the rare recurrent eruption of PEP is associated with multigestational pregnancies.² Mothers can anticipate a recurrence of ICP in up to 60% to 70% of future pregnancies. Patients with AEP have an underlying atopic diathesis, and recurrence in future pregnancies is not uncommon.⁸

Final Thoughts

In summary, it is important for health care providers to recognize the specific cutaneous disorders of pregnancy and their potential fetal complications. The anatomical location of onset of the dermatosis and timing of onset during pregnancy can give important clues. Appropriate management, especially with ICP, can minimize fetal complications. A fundamental knowledge of medication safety and management during pregnancy is essential. Rashes during pregnancy can cause anxiety in the mother and family and require support, comfort, and guidance.

Rashes that develop during pregnancy often result in considerable anxiety or concern for patients and their families. Recognizing these pregnancy-specific dermatoses is important in identifying fetal risks as well as providing appropriate management and expert guidance for patients regarding future pregnancies. Managing cutaneous manifestations of pregnancy-related disorders is challenging and requires knowledge of potential side effects of therapy for both the mother and fetus. It also is important to appreciate the physiologic cutaneous changes of pregnancy along with their clinical significance and management.

In 2006, Ambrose-Rudolph et al¹ proposed reclassification of pregnancy-specific dermatoses, which has since been widely accepted by the academic dermatology community. The 4 most prominent disorders include intrahepatic cholestasis of pregnancy (ICP); pemphigoid gestationis (PG); polymorphic eruption of pregnancy (PEP), also known as pruritic urticarial papules and plaques of pregnancy; and atopic eruption of pregnancy.² It is important to recognize these pregnancy-specific disorders and to understand their clinical significance. The morphology of the eruption as well as the location and timing of the onset of the rash are important clues in making an accurate diagnosis.³

Clinical Presentation

Intrahepatic cholestasis of pregnancy presents with severe generalized pruritus, usually with involvement of the palms and soles, in the late second or third trimester. Pemphigoid gestationis presents with urticarial papules and/or bullae, often in the second or third trimester or postpartum. An important diagnostic clue for PG is involvement near the umbilicus. Polymorphic eruption of pregnancy presents with urticarial papules and plaques; onset occurs in the third trimester or postpartum and initially involves the striae while sparing the umbilicus, unlike in PG. Atopic eruption of pregnancy has an earlier onset than the other pregnancy-specific dermatoses, often in the first or second trimester, and presents with widespread eczematous lesions.³

Diagnosis

The pregnancy dermatoses with the greatest potential for fetal risks are ICP and PG; therefore, it is critical for health care providers to diagnose these dermatoses in a timely manner and initiate appropriate management. Intrahepatic cholestasis of pregnancy is confirmed by elevated serum bile acids (ie, >10 µmol/L), often during the third trimester. The risk of fetal morbidity is high in ICP with increased bile acids crossing the placenta causing placental anoxia and impaired cardiomyocyte function.⁴ Fetal risks, including preterm delivery, meconium-stained amniotic fluid, and stillbirth, correlate with the level of bile acids in the serum.⁵ Maternal prognosis is favorable, but there is an increased association with hepatitis C and hepatobiliary disease.⁶

Diagnosis of PG is confirmed by classic biopsy results and direct immunofluorescence revealing C3 with or without IgG in a linear band along the basement membrane zone. Additionally, complement indirect immunofluorescence reveals circulating IgG anti–basement membrane zone antibodies. Pemphigoid gestationis is associated with increased fetal risks of preterm labor and intrauterine growth retardation.⁷ Clinical findings of PG may present in the fetus upon delivery due to transmission of autoantibodies across the placenta. The symptoms usually are mild.⁸ An increased risk of Graves disease has been reported in mothers with PG.

In most cases, diagnosis of PEP is based on history and morphology, but if the presentation is not classic, skin biopsy must be used to differentiate it from PG as well as more common dermatologic conditions such as contact dermatitis, drug and viral eruptions, and urticaria.

Atopic eruption of pregnancy manifests as widespread eczematous excoriated papules and plaques. Lesions of prurigo nodularis are common.

Comorbidities

It is important to be aware of specific clinical associations related to pregnancy-specific dermatoses. Pemphigoid gestationis has been associated with gestational trophoblastic tumors including hydatiform mole and choriocarcinoma.⁴ An increased risk for Graves disease has been reported in patients with PG.⁹ Patients who develop ICP have a higher incidence of hepatitis C, postpartum cholecystitis, gallstones, and nonalcoholic cirrhosis.⁸ Polymorphic eruption of pregnancy is associated with a notably higher incidence in multiple gestation pregnancies.²

Treatment and Management

Management of ICP requires an accurate and timely diagnosis, and advanced neonatal-obstetric management is critical.³ Ursodeoxycholic acid is the treatment of choice and reduces pruritus, prolongs pregnancy, and reduces fetal risk.⁴ Most stillbirths cluster at the 38th week of pregnancy, and patients with ICP and highly elevated serum bile acids (>40 µmol/L) should be considered for delivery at 37 weeks or earlier.⁵

Management of the other cutaneous disorders of pregnancy can be challenging for health care providers based on safety concerns for the fetus. Although it is important to minimize risks to the fetus, it also is important to adequately treat the mother’s cutaneous disease, which requires a solid knowledge of drug safety during pregnancy. The former US Food and Drug Administration classification system using A, B, C, D, and X pregnancy categories was replaced by the Pregnancy Lactation Label Final Rule, which provides counseling on medication safety during pregnancy.¹⁰ In 2014, Murase et al¹¹ published a review of dermatologic medication safety during pregnancy, which serves as an excellent guide.

Before instituting treatment, the therapeutic plan should be discussed with the physician managing the patient’s pregnancy. In general, topical steroids are considered safe during pregnancy, and low-potency to moderate-potency topical steroids are preferred. If possible, use of topical steroids should be limited to less than 300 g for the duration of the pregnancy. Fluticasone propionate should be avoided during pregnancy because it is not metabolized by the placenta. When systemic steroids are considered appropriate for management during pregnancy, nonhalogenated corticosteroids such as prednisone and prednisolone are preferred because they are enzymatically inactivated by the placenta, which results in a favorable maternal-fetal gradient.¹² There has been concern expressed in the medical literature that systemic steroids during the first trimester may increase the risk of cleft lip and cleft palate.^3,12 When managing pregnancy dermatoses, consideration should be given to keep prednisone exposure below 20 mg/d, and try to limit prolonged use to 7.5 mg/d. However, this may not be possible in PG.³ Vitamin D and calcium supplementation may be appropriate when patients are on prolonged systemic steroids to control disease.

Antihistamines can be used to control pruritus complicating pregnancy-associated dermatoses. First-generation antihistamines such as chlorpheniramine and diphenhydramine are preferred due to long-term safety data.^3,11,12 Loratadine is the first choice and cetirizine is the second choice if a second-generation antihistamine is preferred.³ Loratadine is preferred during breastfeeding due to less sedation.¹² High-dose antihistamines prior to delivery may cause concerns for potential side effects in the newborn, including tremulousness, irritability, and poor feeding.

Recurrence

Women with pregnancy dermatoses often are concerned about recurrence with future pregnancies. Pemphigoid gestationis may flare with subsequent pregnancies, subsequent menses, or with oral contraceptive use.³ Recurrence of PEP in subsequent pregnancies is rare and usually is less severe than the primary eruption.⁸ Often, the rare recurrent eruption of PEP is associated with multigestational pregnancies.² Mothers can anticipate a recurrence of ICP in up to 60% to 70% of future pregnancies. Patients with AEP have an underlying atopic diathesis, and recurrence in future pregnancies is not uncommon.⁸

Final Thoughts

In summary, it is important for health care providers to recognize the specific cutaneous disorders of pregnancy and their potential fetal complications. The anatomical location of onset of the dermatosis and timing of onset during pregnancy can give important clues. Appropriate management, especially with ICP, can minimize fetal complications. A fundamental knowledge of medication safety and management during pregnancy is essential. Rashes during pregnancy can cause anxiety in the mother and family and require support, comfort, and guidance.

Rashes that develop during pregnancy often result in considerable anxiety or concern for patients and their families. Recognizing these pregnancy-specific dermatoses is important in identifying fetal risks as well as providing appropriate management and expert guidance for patients regarding future pregnancies. Managing cutaneous manifestations of pregnancy-related disorders is challenging and requires knowledge of potential side effects of therapy for both the mother and fetus. It also is important to appreciate the physiologic cutaneous changes of pregnancy along with their clinical significance and management.

In 2006, Ambrose-Rudolph et al¹ proposed reclassification of pregnancy-specific dermatoses, which has since been widely accepted by the academic dermatology community. The 4 most prominent disorders include intrahepatic cholestasis of pregnancy (ICP); pemphigoid gestationis (PG); polymorphic eruption of pregnancy (PEP), also known as pruritic urticarial papules and plaques of pregnancy; and atopic eruption of pregnancy.² It is important to recognize these pregnancy-specific disorders and to understand their clinical significance. The morphology of the eruption as well as the location and timing of the onset of the rash are important clues in making an accurate diagnosis.³

Clinical Presentation

Intrahepatic cholestasis of pregnancy presents with severe generalized pruritus, usually with involvement of the palms and soles, in the late second or third trimester. Pemphigoid gestationis presents with urticarial papules and/or bullae, often in the second or third trimester or postpartum. An important diagnostic clue for PG is involvement near the umbilicus. Polymorphic eruption of pregnancy presents with urticarial papules and plaques; onset occurs in the third trimester or postpartum and initially involves the striae while sparing the umbilicus, unlike in PG. Atopic eruption of pregnancy has an earlier onset than the other pregnancy-specific dermatoses, often in the first or second trimester, and presents with widespread eczematous lesions.³

Diagnosis

The pregnancy dermatoses with the greatest potential for fetal risks are ICP and PG; therefore, it is critical for health care providers to diagnose these dermatoses in a timely manner and initiate appropriate management. Intrahepatic cholestasis of pregnancy is confirmed by elevated serum bile acids (ie, >10 µmol/L), often during the third trimester. The risk of fetal morbidity is high in ICP with increased bile acids crossing the placenta causing placental anoxia and impaired cardiomyocyte function.⁴ Fetal risks, including preterm delivery, meconium-stained amniotic fluid, and stillbirth, correlate with the level of bile acids in the serum.⁵ Maternal prognosis is favorable, but there is an increased association with hepatitis C and hepatobiliary disease.⁶

Diagnosis of PG is confirmed by classic biopsy results and direct immunofluorescence revealing C3 with or without IgG in a linear band along the basement membrane zone. Additionally, complement indirect immunofluorescence reveals circulating IgG anti–basement membrane zone antibodies. Pemphigoid gestationis is associated with increased fetal risks of preterm labor and intrauterine growth retardation.⁷ Clinical findings of PG may present in the fetus upon delivery due to transmission of autoantibodies across the placenta. The symptoms usually are mild.⁸ An increased risk of Graves disease has been reported in mothers with PG.

In most cases, diagnosis of PEP is based on history and morphology, but if the presentation is not classic, skin biopsy must be used to differentiate it from PG as well as more common dermatologic conditions such as contact dermatitis, drug and viral eruptions, and urticaria.

Atopic eruption of pregnancy manifests as widespread eczematous excoriated papules and plaques. Lesions of prurigo nodularis are common.

Comorbidities

It is important to be aware of specific clinical associations related to pregnancy-specific dermatoses. Pemphigoid gestationis has been associated with gestational trophoblastic tumors including hydatiform mole and choriocarcinoma.⁴ An increased risk for Graves disease has been reported in patients with PG.⁹ Patients who develop ICP have a higher incidence of hepatitis C, postpartum cholecystitis, gallstones, and nonalcoholic cirrhosis.⁸ Polymorphic eruption of pregnancy is associated with a notably higher incidence in multiple gestation pregnancies.²

Treatment and Management

Management of ICP requires an accurate and timely diagnosis, and advanced neonatal-obstetric management is critical.³ Ursodeoxycholic acid is the treatment of choice and reduces pruritus, prolongs pregnancy, and reduces fetal risk.⁴ Most stillbirths cluster at the 38th week of pregnancy, and patients with ICP and highly elevated serum bile acids (>40 µmol/L) should be considered for delivery at 37 weeks or earlier.⁵

Management of the other cutaneous disorders of pregnancy can be challenging for health care providers based on safety concerns for the fetus. Although it is important to minimize risks to the fetus, it also is important to adequately treat the mother’s cutaneous disease, which requires a solid knowledge of drug safety during pregnancy. The former US Food and Drug Administration classification system using A, B, C, D, and X pregnancy categories was replaced by the Pregnancy Lactation Label Final Rule, which provides counseling on medication safety during pregnancy.¹⁰ In 2014, Murase et al¹¹ published a review of dermatologic medication safety during pregnancy, which serves as an excellent guide.

Before instituting treatment, the therapeutic plan should be discussed with the physician managing the patient’s pregnancy. In general, topical steroids are considered safe during pregnancy, and low-potency to moderate-potency topical steroids are preferred. If possible, use of topical steroids should be limited to less than 300 g for the duration of the pregnancy. Fluticasone propionate should be avoided during pregnancy because it is not metabolized by the placenta. When systemic steroids are considered appropriate for management during pregnancy, nonhalogenated corticosteroids such as prednisone and prednisolone are preferred because they are enzymatically inactivated by the placenta, which results in a favorable maternal-fetal gradient.¹² There has been concern expressed in the medical literature that systemic steroids during the first trimester may increase the risk of cleft lip and cleft palate.^3,12 When managing pregnancy dermatoses, consideration should be given to keep prednisone exposure below 20 mg/d, and try to limit prolonged use to 7.5 mg/d. However, this may not be possible in PG.³ Vitamin D and calcium supplementation may be appropriate when patients are on prolonged systemic steroids to control disease.

Antihistamines can be used to control pruritus complicating pregnancy-associated dermatoses. First-generation antihistamines such as chlorpheniramine and diphenhydramine are preferred due to long-term safety data.^3,11,12 Loratadine is the first choice and cetirizine is the second choice if a second-generation antihistamine is preferred.³ Loratadine is preferred during breastfeeding due to less sedation.¹² High-dose antihistamines prior to delivery may cause concerns for potential side effects in the newborn, including tremulousness, irritability, and poor feeding.

Recurrence

Women with pregnancy dermatoses often are concerned about recurrence with future pregnancies. Pemphigoid gestationis may flare with subsequent pregnancies, subsequent menses, or with oral contraceptive use.³ Recurrence of PEP in subsequent pregnancies is rare and usually is less severe than the primary eruption.⁸ Often, the rare recurrent eruption of PEP is associated with multigestational pregnancies.² Mothers can anticipate a recurrence of ICP in up to 60% to 70% of future pregnancies. Patients with AEP have an underlying atopic diathesis, and recurrence in future pregnancies is not uncommon.⁸

Final Thoughts

In summary, it is important for health care providers to recognize the specific cutaneous disorders of pregnancy and their potential fetal complications. The anatomical location of onset of the dermatosis and timing of onset during pregnancy can give important clues. Appropriate management, especially with ICP, can minimize fetal complications. A fundamental knowledge of medication safety and management during pregnancy is essential. Rashes during pregnancy can cause anxiety in the mother and family and require support, comfort, and guidance.

Dupilumab is a fully humanized monoclonal antibody to the α subunit of the IL-4 receptor that inhibits the action of helper T cell (T_H2)–type cytokines IL-4 and IL-13. Dupilumab was approved by the US Food and Drug Administration (FDA) in 2017 for the treatment of moderate to severe atopic dermatitis (AD). We report 2 patients with AD who were treated with dupilumab and subsequently developed facial flushing after consuming alcohol.

Case Report

Patient 1
A 24-year-old woman presented to the dermatology clinic with a lifelong history of moderate to severe AD. She had a medical history of asthma and seasonal allergies, which were treated with fexofenadine and an inhaler, as needed. The patient had an affected body surface area of approximately 70% and had achieved only partial relief with topical corticosteroids and topical calcineurin inhibitors.

Because her disease was severe, the patient was started on dupilumab at FDA-approved dosing for AD: a 600-mg subcutaneous (SC) loading dose, followed by 300 mg SC every 2 weeks. She reported rapid skin clearance within 2 weeks of the start of treatment. Her course was complicated by mild head and neck dermatitis.

Seven months after starting treatment, the patient began to acutely experience erythema and warmth over the entire face that was triggered by drinking alcohol (Figure). Before starting dupilumab, she had consumed alcohol on multiple occasions without a flushing effect. This new finding was distinguishable from her facial dermatitis. Onset was within a few minutes after drinking alcohol; flushing self-resolved in 15 to 30 minutes. Although diffuse, erythema and warmth were concentrated around the jawline, eyebrows, and ears and occurred every time the patient drank alcohol. Moreover, she reported that consumption of hard (ie, distilled) liquor, specifically tequila, caused a more severe presentation. She denied other symptoms associated with dupilumab.

Comment

Two other single-patient case reports have discussed similar findings of alcohol-induced flushing associated with dupilumab.^1,2 Both of those patients—a 19-year-old woman and a 26-year-old woman—had not experienced flushing before beginning treatment with dupilumab for AD. Both experienced onset of facial flushing months after beginning dupilumab even though both had consumed alcohol before starting dupilumab, similar to the cases presented here. One patient had a history of asthma; the other had a history of seasonal and environmental allergies.

Possible Mechanism of Action
Acute alcohol ingestion causes dermal vasodilation of the skin (ie, flushing).³ A proposed mechanism is that flushing results from direct action on central vascular-control mechanisms. This theory results from observations that individuals with quadriplegia lack notable ethanol-induced vasodilation, suggesting that ethanol has a central neural site of action.Although some research has indicated that ethanol might induce these effects by altering the action of certain hormones (eg, angiotensin, vasopressin, and catecholamines), the precise mechanism by which ethanol alters vascular function in humans remains unexplained.³

Deficiencies in alcohol dehydrogenase (ADH), aldehyde dehydrogenase 2, and certain cytochrome P450 enzymes also might contribute to facial flushing. People of Asian, especially East Asian, descent often respond to an acute dose of ethanol with symptoms of facial flushing—predominantly the result of an elevated blood level of acetaldehyde caused by an inherited deficiency of aldehyde dehydrogenase 2,⁴ which is downstream from ADH in the metabolic pathway of alcohol. The major enzyme system responsible for metabolism of ethanol is ADH; however, the cytochrome P450–dependent ethanol-oxidizing system—including major CYP450 isoforms CYP3A, CYP2C19, CYP2C9, CYP1A2, and CYP2D6, as well as minor CYP450 isoforms, such as CYP2E1— also are involved, to a lesser extent.⁵

A Role for Dupilumab?
A recent pharmacokinetic study found that dupilumab appears to have little effect on the activity of the major CYP450 isoforms. However, the drug’s effect on ADH and minor CYP450 minor isoforms is unknown. Prior drug-drug interaction studies have shown that certain cytokines and cytokine modulators can markedly influence the expression, stability, and activity of specific CYP450 enzymes.⁶ For example, IL-6 causes a reduction in messenger RNA for CYP3A4 and, to a lesser extent, for other isoforms.⁷ Whether dupilumab influences enzymes involved in processing alcohol requires further study.

Conclusion

We describe 2 cases of dupilumab-induced facial flushing after alcohol consumption. The mechanism of this dupilumab-associated flushing is unknown and requires further research.

Dupilumab is a fully humanized monoclonal antibody to the α subunit of the IL-4 receptor that inhibits the action of helper T cell (T_H2)–type cytokines IL-4 and IL-13. Dupilumab was approved by the US Food and Drug Administration (FDA) in 2017 for the treatment of moderate to severe atopic dermatitis (AD). We report 2 patients with AD who were treated with dupilumab and subsequently developed facial flushing after consuming alcohol.

Case Report

Patient 1
A 24-year-old woman presented to the dermatology clinic with a lifelong history of moderate to severe AD. She had a medical history of asthma and seasonal allergies, which were treated with fexofenadine and an inhaler, as needed. The patient had an affected body surface area of approximately 70% and had achieved only partial relief with topical corticosteroids and topical calcineurin inhibitors.

Because her disease was severe, the patient was started on dupilumab at FDA-approved dosing for AD: a 600-mg subcutaneous (SC) loading dose, followed by 300 mg SC every 2 weeks. She reported rapid skin clearance within 2 weeks of the start of treatment. Her course was complicated by mild head and neck dermatitis.

Seven months after starting treatment, the patient began to acutely experience erythema and warmth over the entire face that was triggered by drinking alcohol (Figure). Before starting dupilumab, she had consumed alcohol on multiple occasions without a flushing effect. This new finding was distinguishable from her facial dermatitis. Onset was within a few minutes after drinking alcohol; flushing self-resolved in 15 to 30 minutes. Although diffuse, erythema and warmth were concentrated around the jawline, eyebrows, and ears and occurred every time the patient drank alcohol. Moreover, she reported that consumption of hard (ie, distilled) liquor, specifically tequila, caused a more severe presentation. She denied other symptoms associated with dupilumab.

Comment

Two other single-patient case reports have discussed similar findings of alcohol-induced flushing associated with dupilumab.^1,2 Both of those patients—a 19-year-old woman and a 26-year-old woman—had not experienced flushing before beginning treatment with dupilumab for AD. Both experienced onset of facial flushing months after beginning dupilumab even though both had consumed alcohol before starting dupilumab, similar to the cases presented here. One patient had a history of asthma; the other had a history of seasonal and environmental allergies.

Possible Mechanism of Action
Acute alcohol ingestion causes dermal vasodilation of the skin (ie, flushing).³ A proposed mechanism is that flushing results from direct action on central vascular-control mechanisms. This theory results from observations that individuals with quadriplegia lack notable ethanol-induced vasodilation, suggesting that ethanol has a central neural site of action.Although some research has indicated that ethanol might induce these effects by altering the action of certain hormones (eg, angiotensin, vasopressin, and catecholamines), the precise mechanism by which ethanol alters vascular function in humans remains unexplained.³

Deficiencies in alcohol dehydrogenase (ADH), aldehyde dehydrogenase 2, and certain cytochrome P450 enzymes also might contribute to facial flushing. People of Asian, especially East Asian, descent often respond to an acute dose of ethanol with symptoms of facial flushing—predominantly the result of an elevated blood level of acetaldehyde caused by an inherited deficiency of aldehyde dehydrogenase 2,⁴ which is downstream from ADH in the metabolic pathway of alcohol. The major enzyme system responsible for metabolism of ethanol is ADH; however, the cytochrome P450–dependent ethanol-oxidizing system—including major CYP450 isoforms CYP3A, CYP2C19, CYP2C9, CYP1A2, and CYP2D6, as well as minor CYP450 isoforms, such as CYP2E1— also are involved, to a lesser extent.⁵

A Role for Dupilumab?
A recent pharmacokinetic study found that dupilumab appears to have little effect on the activity of the major CYP450 isoforms. However, the drug’s effect on ADH and minor CYP450 minor isoforms is unknown. Prior drug-drug interaction studies have shown that certain cytokines and cytokine modulators can markedly influence the expression, stability, and activity of specific CYP450 enzymes.⁶ For example, IL-6 causes a reduction in messenger RNA for CYP3A4 and, to a lesser extent, for other isoforms.⁷ Whether dupilumab influences enzymes involved in processing alcohol requires further study.

Conclusion

We describe 2 cases of dupilumab-induced facial flushing after alcohol consumption. The mechanism of this dupilumab-associated flushing is unknown and requires further research.

Dupilumab is a fully humanized monoclonal antibody to the α subunit of the IL-4 receptor that inhibits the action of helper T cell (T_H2)–type cytokines IL-4 and IL-13. Dupilumab was approved by the US Food and Drug Administration (FDA) in 2017 for the treatment of moderate to severe atopic dermatitis (AD). We report 2 patients with AD who were treated with dupilumab and subsequently developed facial flushing after consuming alcohol.

Case Report

Patient 1
A 24-year-old woman presented to the dermatology clinic with a lifelong history of moderate to severe AD. She had a medical history of asthma and seasonal allergies, which were treated with fexofenadine and an inhaler, as needed. The patient had an affected body surface area of approximately 70% and had achieved only partial relief with topical corticosteroids and topical calcineurin inhibitors.

Because her disease was severe, the patient was started on dupilumab at FDA-approved dosing for AD: a 600-mg subcutaneous (SC) loading dose, followed by 300 mg SC every 2 weeks. She reported rapid skin clearance within 2 weeks of the start of treatment. Her course was complicated by mild head and neck dermatitis.

Seven months after starting treatment, the patient began to acutely experience erythema and warmth over the entire face that was triggered by drinking alcohol (Figure). Before starting dupilumab, she had consumed alcohol on multiple occasions without a flushing effect. This new finding was distinguishable from her facial dermatitis. Onset was within a few minutes after drinking alcohol; flushing self-resolved in 15 to 30 minutes. Although diffuse, erythema and warmth were concentrated around the jawline, eyebrows, and ears and occurred every time the patient drank alcohol. Moreover, she reported that consumption of hard (ie, distilled) liquor, specifically tequila, caused a more severe presentation. She denied other symptoms associated with dupilumab.

Comment

Two other single-patient case reports have discussed similar findings of alcohol-induced flushing associated with dupilumab.^1,2 Both of those patients—a 19-year-old woman and a 26-year-old woman—had not experienced flushing before beginning treatment with dupilumab for AD. Both experienced onset of facial flushing months after beginning dupilumab even though both had consumed alcohol before starting dupilumab, similar to the cases presented here. One patient had a history of asthma; the other had a history of seasonal and environmental allergies.

Possible Mechanism of Action
Acute alcohol ingestion causes dermal vasodilation of the skin (ie, flushing).³ A proposed mechanism is that flushing results from direct action on central vascular-control mechanisms. This theory results from observations that individuals with quadriplegia lack notable ethanol-induced vasodilation, suggesting that ethanol has a central neural site of action.Although some research has indicated that ethanol might induce these effects by altering the action of certain hormones (eg, angiotensin, vasopressin, and catecholamines), the precise mechanism by which ethanol alters vascular function in humans remains unexplained.³

Deficiencies in alcohol dehydrogenase (ADH), aldehyde dehydrogenase 2, and certain cytochrome P450 enzymes also might contribute to facial flushing. People of Asian, especially East Asian, descent often respond to an acute dose of ethanol with symptoms of facial flushing—predominantly the result of an elevated blood level of acetaldehyde caused by an inherited deficiency of aldehyde dehydrogenase 2,⁴ which is downstream from ADH in the metabolic pathway of alcohol. The major enzyme system responsible for metabolism of ethanol is ADH; however, the cytochrome P450–dependent ethanol-oxidizing system—including major CYP450 isoforms CYP3A, CYP2C19, CYP2C9, CYP1A2, and CYP2D6, as well as minor CYP450 isoforms, such as CYP2E1— also are involved, to a lesser extent.⁵

A Role for Dupilumab?
A recent pharmacokinetic study found that dupilumab appears to have little effect on the activity of the major CYP450 isoforms. However, the drug’s effect on ADH and minor CYP450 minor isoforms is unknown. Prior drug-drug interaction studies have shown that certain cytokines and cytokine modulators can markedly influence the expression, stability, and activity of specific CYP450 enzymes.⁶ For example, IL-6 causes a reduction in messenger RNA for CYP3A4 and, to a lesser extent, for other isoforms.⁷ Whether dupilumab influences enzymes involved in processing alcohol requires further study.

Conclusion

We describe 2 cases of dupilumab-induced facial flushing after alcohol consumption. The mechanism of this dupilumab-associated flushing is unknown and requires further research.

Practice Gap

It is well established that surgical complications and a poor scar outcome can have a remarkable impact on patient satisfaction.¹ A common complication following dermatologic surgery is suture spitting, in which a buried suture is extruded through the skin surface. When repairing a cutaneous defect following dermatologic surgery, absorbable or nonabsorbable sutures are placed under the skin surface to approximate wound edges, eliminate dead space, and reduce tension on the edges of the wound, improving the cosmetic outcomes.

Absorbable sutures constitute most buried sutures in cutaneous surgery and can be made of natural or synthetic fibers.² Absorbable sutures made from synthetic fibers are degraded by hydrolysis, in which water breaks down polymer chains of the suture filament. Natural absorbable sutures are composed of mammalian collagen; they are broken down by the enzymatic process of proteolysis.

Tensile strength is lost long before a suture is fully absorbed. Although synthetic fibers have, in general, higher tensile strength and generate less tissue inflammation, they take much longer to absorb.² During absorption, in some cases, a buried suture is pushed to the surface and extrudes along the wound edge or scar, which is known as spitting³ (Figure 1).

The Technique

Choice of suture material for buried sutures can influence the risk of spitting.

Factors Impacting Increased Spitting
The 3 most common absorbable sutures in dermatologic surgery include poliglecaprone 25, polyglactin 910, and polydioxanone; of them, polyglactin 910 has been found to have a higher rate of spitting than poliglecaprone 25 and polydioxanone.² However, because complete absorption of polydioxanone can take as long as 8 months, this suture might “spit” much later than polyglactin 910 or poliglecaprone 25, which typically are fully hydrolyzed by 3 and 4 months, respectively.² Placing sutures superficially in the dermis has been found to increase the rate of spitting.⁵ Throwing more knots per closure also has been found to increase the rate of spitting.⁵

How to Decrease Spitting
Careful choice of suture material and proper depth of suture placement might decrease the risk for spitting in dermatologic surgery. Furthermore, if polyglactin 910 or a long-lasting suture is to be used, sutures should be placed deeply.

What to Do If Sutures Spit
When a suture has begun to spit, the extruding foreign material needs to be removed and the surgical site assessed for infection or abscess. Exposed suture material typically can be removed with forceps without local anesthesia. In some cases, fine-tipped Bishop-Harmon tissue forceps or jewelers forceps might be required.

If the suture cannot be removed completely, it should be trimmed as short as possible. This can be accomplished by pulling on the exposed end of the suture, tenting the skin, and trimming it as close as possible to the surface. Once the foreign material is removed, assessment for signs of infection is paramount.

How to Manage Infection—Postoperative infection associated with a spitting suture can take the form of a periwound cellulitis or stitch abscess.³ A stitch abscess can reflect a sterile inflammatory response to the buried suture or a true infection⁴; the former is more common.³ In the event of an infected stitch abscess, provide warm compresses, obtain specimens for culture, and prescribe antibiotics after the spitting suture has been removed. Incision and drainage also might be required if notable fluctuance is present.

It is crucial for dermatologic surgeons to identify and manage these complications. Figure 2 illustrates an algorithmic approach to managing spitting sutures.

Practical Implications

Spitting sutures are a common occurrence following dermatologic surgery that can lead to remarkable patient distress. Fortunately, in the absence of superimposed infection, spitting sutures have not been shown to worsen outcomes of healing and scarring.⁵ Nevertheless, it is important to identify and appropriately treat this common complication. The simple algorithm we provide (Figure 2) aids in cutaneous surgery by providing a straightforward approach to managing spitting sutures and their complications.

Practice Gap

It is well established that surgical complications and a poor scar outcome can have a remarkable impact on patient satisfaction.¹ A common complication following dermatologic surgery is suture spitting, in which a buried suture is extruded through the skin surface. When repairing a cutaneous defect following dermatologic surgery, absorbable or nonabsorbable sutures are placed under the skin surface to approximate wound edges, eliminate dead space, and reduce tension on the edges of the wound, improving the cosmetic outcomes.

Absorbable sutures constitute most buried sutures in cutaneous surgery and can be made of natural or synthetic fibers.² Absorbable sutures made from synthetic fibers are degraded by hydrolysis, in which water breaks down polymer chains of the suture filament. Natural absorbable sutures are composed of mammalian collagen; they are broken down by the enzymatic process of proteolysis.

Tensile strength is lost long before a suture is fully absorbed. Although synthetic fibers have, in general, higher tensile strength and generate less tissue inflammation, they take much longer to absorb.² During absorption, in some cases, a buried suture is pushed to the surface and extrudes along the wound edge or scar, which is known as spitting³ (Figure 1).

The Technique

Choice of suture material for buried sutures can influence the risk of spitting.

Factors Impacting Increased Spitting
The 3 most common absorbable sutures in dermatologic surgery include poliglecaprone 25, polyglactin 910, and polydioxanone; of them, polyglactin 910 has been found to have a higher rate of spitting than poliglecaprone 25 and polydioxanone.² However, because complete absorption of polydioxanone can take as long as 8 months, this suture might “spit” much later than polyglactin 910 or poliglecaprone 25, which typically are fully hydrolyzed by 3 and 4 months, respectively.² Placing sutures superficially in the dermis has been found to increase the rate of spitting.⁵ Throwing more knots per closure also has been found to increase the rate of spitting.⁵

How to Decrease Spitting
Careful choice of suture material and proper depth of suture placement might decrease the risk for spitting in dermatologic surgery. Furthermore, if polyglactin 910 or a long-lasting suture is to be used, sutures should be placed deeply.

What to Do If Sutures Spit
When a suture has begun to spit, the extruding foreign material needs to be removed and the surgical site assessed for infection or abscess. Exposed suture material typically can be removed with forceps without local anesthesia. In some cases, fine-tipped Bishop-Harmon tissue forceps or jewelers forceps might be required.

If the suture cannot be removed completely, it should be trimmed as short as possible. This can be accomplished by pulling on the exposed end of the suture, tenting the skin, and trimming it as close as possible to the surface. Once the foreign material is removed, assessment for signs of infection is paramount.

How to Manage Infection—Postoperative infection associated with a spitting suture can take the form of a periwound cellulitis or stitch abscess.³ A stitch abscess can reflect a sterile inflammatory response to the buried suture or a true infection⁴; the former is more common.³ In the event of an infected stitch abscess, provide warm compresses, obtain specimens for culture, and prescribe antibiotics after the spitting suture has been removed. Incision and drainage also might be required if notable fluctuance is present.

It is crucial for dermatologic surgeons to identify and manage these complications. Figure 2 illustrates an algorithmic approach to managing spitting sutures.

Practical Implications

Spitting sutures are a common occurrence following dermatologic surgery that can lead to remarkable patient distress. Fortunately, in the absence of superimposed infection, spitting sutures have not been shown to worsen outcomes of healing and scarring.⁵ Nevertheless, it is important to identify and appropriately treat this common complication. The simple algorithm we provide (Figure 2) aids in cutaneous surgery by providing a straightforward approach to managing spitting sutures and their complications.

Practice Gap

It is well established that surgical complications and a poor scar outcome can have a remarkable impact on patient satisfaction.¹ A common complication following dermatologic surgery is suture spitting, in which a buried suture is extruded through the skin surface. When repairing a cutaneous defect following dermatologic surgery, absorbable or nonabsorbable sutures are placed under the skin surface to approximate wound edges, eliminate dead space, and reduce tension on the edges of the wound, improving the cosmetic outcomes.

Absorbable sutures constitute most buried sutures in cutaneous surgery and can be made of natural or synthetic fibers.² Absorbable sutures made from synthetic fibers are degraded by hydrolysis, in which water breaks down polymer chains of the suture filament. Natural absorbable sutures are composed of mammalian collagen; they are broken down by the enzymatic process of proteolysis.

Tensile strength is lost long before a suture is fully absorbed. Although synthetic fibers have, in general, higher tensile strength and generate less tissue inflammation, they take much longer to absorb.² During absorption, in some cases, a buried suture is pushed to the surface and extrudes along the wound edge or scar, which is known as spitting³ (Figure 1).

The Technique

Choice of suture material for buried sutures can influence the risk of spitting.

Factors Impacting Increased Spitting
The 3 most common absorbable sutures in dermatologic surgery include poliglecaprone 25, polyglactin 910, and polydioxanone; of them, polyglactin 910 has been found to have a higher rate of spitting than poliglecaprone 25 and polydioxanone.² However, because complete absorption of polydioxanone can take as long as 8 months, this suture might “spit” much later than polyglactin 910 or poliglecaprone 25, which typically are fully hydrolyzed by 3 and 4 months, respectively.² Placing sutures superficially in the dermis has been found to increase the rate of spitting.⁵ Throwing more knots per closure also has been found to increase the rate of spitting.⁵

How to Decrease Spitting
Careful choice of suture material and proper depth of suture placement might decrease the risk for spitting in dermatologic surgery. Furthermore, if polyglactin 910 or a long-lasting suture is to be used, sutures should be placed deeply.

What to Do If Sutures Spit
When a suture has begun to spit, the extruding foreign material needs to be removed and the surgical site assessed for infection or abscess. Exposed suture material typically can be removed with forceps without local anesthesia. In some cases, fine-tipped Bishop-Harmon tissue forceps or jewelers forceps might be required.

If the suture cannot be removed completely, it should be trimmed as short as possible. This can be accomplished by pulling on the exposed end of the suture, tenting the skin, and trimming it as close as possible to the surface. Once the foreign material is removed, assessment for signs of infection is paramount.

How to Manage Infection—Postoperative infection associated with a spitting suture can take the form of a periwound cellulitis or stitch abscess.³ A stitch abscess can reflect a sterile inflammatory response to the buried suture or a true infection⁴; the former is more common.³ In the event of an infected stitch abscess, provide warm compresses, obtain specimens for culture, and prescribe antibiotics after the spitting suture has been removed. Incision and drainage also might be required if notable fluctuance is present.

It is crucial for dermatologic surgeons to identify and manage these complications. Figure 2 illustrates an algorithmic approach to managing spitting sutures.

Practical Implications

Spitting sutures are a common occurrence following dermatologic surgery that can lead to remarkable patient distress. Fortunately, in the absence of superimposed infection, spitting sutures have not been shown to worsen outcomes of healing and scarring.⁵ Nevertheless, it is important to identify and appropriately treat this common complication. The simple algorithm we provide (Figure 2) aids in cutaneous surgery by providing a straightforward approach to managing spitting sutures and their complications.

Irritable bowel syndrome (IBS) is one of the most common disorders managed by primary care physicians and gastroenterologists.¹ Characterized by abdominal pain coinciding with altered stool form and/or frequency as defined by the Rome IV diagnostic criteria,² symptoms range from mild to debilitating and may remarkably impair quality of life and work productivity.¹

The cause of IBS is poorly understood. Proposed pathophysiologic factors include impaired mucosal function, microbial imbalance, visceral hypersensitivity, psychologic dysfunction, genetic factors, neurotransmitter imbalance, postinfectious gastroenteritis, inflammation, and food intolerance, any or all of which may lead to the development and maintenance of IBS symptoms.³ More recent observations of inflammation in the intestinal lining^4,5 and proinflammatory peripherally circulating cytokines⁶ challenge its traditional classification as a functional disorder.

The cause of this inflammation is of intense interest, with speculation that the bacterial microbiota, bile acids, association with postinfectious gastroenteritis and inflammatory bowel disease cases, and/or foods may contribute. Although approximately 50% of individuals with IBS report that foods aggravate their symptoms,⁷ studies investigating type I antibody–mediated immediate hypersensitivity have largely failed to demonstrate a substantial link, prompting many authorities to regard these associations as food “intolerances” rather than true allergies. Based on this body of literature, a large 2010 consensus report on all aspects of food allergies advises against food allergy testing for IBS.⁸

In contrast, by utilizing type IV food allergen skin patch testing, 2 proof-of-concept studies^9,10 investigated a different allergic mechanism in IBS, namely cell-mediated delayed-type hypersensitivity. Because many foods and food additives are known to cause allergic contact dermatitis,¹¹ it was hypothesized that these foods may elicit a similar delayed-type hypersensitivity response in the intestinal lining in previously sensitized individuals. By following a patch test–guided food avoidance diet, a large subpopulation of patients with IBS experienced partial or complete IBS symptom relief.^9,10 Our study further investigates a role for food-related delayed-type hypersensitivities in the pathogenesis of IBS.

Methods

Patient Selection
This study was conducted in a secondary care community-based setting. All patients were self-referred over an 18-month period ending in October 2019, had physician-diagnosed IBS, and/or met the Rome IV criteria for IBS and presented expressly for the food patch testing on a fee-for-service basis. Subtype of IBS was determined on presentation by the self-reported historically predominant symptom. Duration of IBS symptoms was self-reported and was rounded to the nearest year for purposes of data collection.

Exclusion criteria included pregnancy, known allergy to adhesive tape or any of the food allergens used in the study, severe skin rash, symptoms that had a known cause other than IBS, or active treatment with systemic immunosuppressive medications.

Patch Testing
Skin patch testing was initiated using an extensive panel of 117 type IV food allergens (eTable)¹¹ identified in the literature,¹² most of which utilized standard compounded formulations¹³ or were available from reputable patch test manufacturers (Brial Allergen GmbH; Chemotechnique Diagnostics). This panel was not approved by the US Food and Drug Administration. The freeze-dried vegetable formulations were taken from the 2018 report.⁹ Standard skin patch test procedure protocols¹² were used, affixing the patches to the upper aspect of the back.

Following patch test application on day 1, two follow-up visits occurred on day 3 and either day 4 or day 5. On day 3, patches were removed, and the initial results were read by a board-certified dermatologist according to a standard grading system.¹⁴ Interpretation of patch tests included no reaction, questionable reaction consisting of macular erythema, weak reaction consisting of erythema and slight edema, or strong reaction consisting of erythema and marked edema. On day 4 or day 5, the final patch test reading was performed, and patients were informed of their results. Patients were advised to avoid ingestion of all foods that elicited a questionable or positive patch test response for at least 3 months, and information about the foods and their avoidance also was distributed and reviewed.

Food Avoidance Questionnaire
Patients with questionable or positive patch tests at 72 or 96 hours were advised of their eligibility to participate in an institutional review board–approved food avoidance questionnaire study investigating the utility of patch test–guided food avoidance on IBS symptoms. The questionnaire assessed the following: (1) baseline average abdominal pain prior to patch test–guided avoidance diet (0=no symptoms; 10=very severe); (2) average abdominal pain since initiation of patch test–guided avoidance diet (0=no symptoms; 10=very severe); (3) degree of improvement in overall IBS symptoms by the end of the food avoidance period (0=no improvement; 10=great improvement); (4) compliance with the avoidance diet for the duration of the avoidance period (completely, partially, not at all, or not sure).

Questionnaires and informed consent were mailed to patients via the US Postal Service 3 months after completing the patch testing. The questionnaire and consent were to be completed and returned after dietary avoidance of the identified allergens for at least 3 months. Patients were not compensated for participation in the study.

Statistical Analysis
Statistical analysis of data collected from study questionnaires was performed with Microsoft Excel. Mean abdominal pain and mean global improvement scores were reported along with 1 SD of the mean. For comparison of mean abdominal pain and improvement in global IBS symptoms from baseline to after 3 months of identified allergen avoidance, a Mann-Whitney U test was performed, with P<.05 being considered statistically significant.

Results

Thirty-seven consecutive patients underwent the testing and were eligible for the study. Nineteen patients were included in the study by virtue of completing and returning their posttest food avoidance questionnaire and informed consent. Eighteen patients were White and 1 was Asian. Subcategories of IBS were diarrhea predominant (9 [47.4%]), constipation predominant (3 [15.8%]), mixed type (5 [26.3%]), and undetermined type (2 [10.5%]). Questionnaire answers were reported after a mean (SD) duration of patch test–directed food avoidance of 4.5 (3.0) months (Table 1).

Overall Improvement
Fifteen (78.9%) patients reported at least slight to great improvement in their global IBS symptoms, and 4 (21.1%) reported no improvement (Table 2), with a mean (SD) improvement score of 5.1 (3.3)(P<.00001).

Comment

Despite intense research interest and a growing number of new medications for IBS approved by the US Food and Drug Administration, there remains a large void in the search for cost-effective and efficacious approaches for IBS evaluation and treatment. In addition to major disturbances in quality of life,^14,15 the cost to society in direct medical expenses and indirect costs associated with loss of productivity and work absenteeism is considerable; estimates range from $21 billion or more annually.¹⁶

Food Hypersensitivities Triggering IBS
This study further evaluated a role for skin patch testing to identify delayed-type (type IV) food hypersensitivities that trigger IBS symptoms and differed from the prior investigations^9,10 in that the symptoms used to define IBS were updated from the Rome III¹⁷ to the newer Rome IV² criteria. The data presented here show moderate to great improvement in global IBS symptoms in 58% (11/19) of patients, which is in line with a 2018 report of 40 study participants for whom follow-up at 3 or more months was available,⁹ providing additional support for a role for type IV food allergies in causing the same gastrointestinal tract symptoms that define IBS. The distinction between food-related studies, including this one, that implicate food allergies^9,10 and prior studies that did not support a role for food allergies in IBS pathogenesis⁸ can be accounted for by the type of allergy investigated. Conclusions that IBS flares after food ingestion were attributable to intolerance rather than true allergy were based on results investigating only the humoral arm and failed to consider the cell-mediated arm of the immune system. As such, foods that appear to trigger IBS symptoms on an allergic basis in our study are recognized in the literature¹² as type IV allergens that elicit cell-mediated immunologic responses rather than more widely recognized type I allergens, such as peanuts and shellfish, that elicit immediate-type hypersensitivity responses. Although any type IV food allergen(s) could be responsible, a pattern emerged in this study and the study published in 2018.⁹ Namely, some foods stood out as more frequently inducing patch test reactions, with the 3 most common being carmine, cinnamon bark oil, and sodium bisulfite (eTable). The sample size is relatively small, but the results raise the question of whether these foods are the most likely to trigger IBS symptoms in the general population. If so, is it the result of a higher innate sensitizing potential and/or a higher frequency of exposure in commonly eaten foods? Larger randomized clinical trials are needed.

Immune Response and IBS
There is mounting evidence that the immune system may play a role in the pathophysiology of IBS.¹⁸ Both lymphocyte infiltration of the myenteric plexus and an increase in intestinal mucosal T lymphocytes have been observed, and it is generally accepted that the mucosal immune system seems to be activated, at least in a subset of patients with IBS.¹⁹ Irritable bowel syndrome associations with quiescent inflammatory bowel disease or postinfectious gastroenteritis provide 2 potential causes for the inflammation, but most IBS patients have had neither.²⁰ The mucosal lining of the intestine and immune system have vast exposure to intraluminal allergens in transit, and it is hypothesized that the same delayed-type hypersensitivity response elicited in the skin by patch testing is elicited in the intestine, resulting in the inflammation that triggers IBS symptoms.¹⁰ The results here add to the growing body of evidence that ingestion of type IV food allergens by previously sensitized individuals could, in fact, be the primary source of the inflammation observed in a large subpopulation of individuals who carry a diagnosis of IBS.

Food Allergens in Patch Testing
Many of the food allergens used in this study are commonly found in various nonfood products that may contact the skin. For example, many flavorings are used as fragrances, and many preservatives, binders, thickeners, emulsifiers, and stabilizers serve the same role in moisturizers, cosmetics, and topical medications. Likewise, nickel sulfate hexahydrate, ubiquitous in foods that arise from the earth, often is found in metal in jewelry, clothing components, and cell phones. All are potential sensitizers. Thus, the question may arise whether the causal relationship between the food allergens identified by patch testing and IBS symptoms might be more of a systemic effect akin to systemic contact dermatitis as sometimes follows ingestion of an allergen to which an individual has been topically sensitized, rather than the proposed localized immunologic response in the intestinal lining. We were unaware of patient history of allergic contact dermatitis to any of the patch test allergens in this study, but the dermatologist author here (M.S.) has unpublished experience with 2 other patients with IBS who have benefited from low-nickel diets after having had positive patch tests to nickel sulfate hexahydrate and who, in retrospect, did report a history of earring dermatitis. Future investigations using pre– and post–food challenge histologic assessments of the intestinal mucosa in patients who benefit from patch test–guided food avoidance diets should help to better define the mechanism.

Because IBS has not been traditionally associated with structural or biochemical abnormalities detectable with current routine diagnostic tools, it has long been viewed as a functional disorder. The findings published more recently,^9,10 in addition to this study’s results, would negate this functional classification in the subset of patients with IBS symptoms who experience sustained relief of their symptoms by patch test–directed food avoidance. The underlying delayed-type hypersensitivity pathogenesis of the IBS-like symptoms in these individuals would mandate an organic classification, aptly named allergic contact enteritis.¹⁰

Follow-up Data
The mean (SD) follow-up duration for this study and the 2018 report⁹ was 4.5 (3.0) months and 7.6 (3.9) months, respectively. The placebo effect is a concern for disorders such as IBS in which primarily subjective outcome measures are available,²¹ and in a retrospective analysis of 25 randomized, placebo-controlled IBS clinical trials, Spiller²² concluded the optimum length of such trials to be more than 3 months, which these studies exceed. Although not blinded or placebo controlled, the length of follow-up in the 2018 report⁹ and here enhances the validity of the results.

Limitation
The retrospective manner in which the self-assessments were reported in this study introduces the potential for recall bias, a variable that could affect results. The presence and direction of bias by any given individual cannot be known, making it difficult to determine any effect it may have had. Further investigation should include daily assessments and refine the primary study end points to include both abdominal pain and the defecation considerations that define IBS.

Conclusion

Food patch testing has the potential to offer a safe, cost-effective approach to the evaluation and management of IBS symptoms. Randomized clinical trials are needed to further investigate the validity of the proof-of-concept results to date. For patients who benefit from a patch test–guided avoidance diet, invasive and costly endoscopic, radiologic, and laboratory testing and pharmacologic management could be averted. Symptomatic relief could be attained simply by avoiding the implicated foods, essentially doing more by doing less. 


Irritable bowel syndrome (IBS) is one of the most common disorders managed by primary care physicians and gastroenterologists.¹ Characterized by abdominal pain coinciding with altered stool form and/or frequency as defined by the Rome IV diagnostic criteria,² symptoms range from mild to debilitating and may remarkably impair quality of life and work productivity.¹

The cause of IBS is poorly understood. Proposed pathophysiologic factors include impaired mucosal function, microbial imbalance, visceral hypersensitivity, psychologic dysfunction, genetic factors, neurotransmitter imbalance, postinfectious gastroenteritis, inflammation, and food intolerance, any or all of which may lead to the development and maintenance of IBS symptoms.³ More recent observations of inflammation in the intestinal lining^4,5 and proinflammatory peripherally circulating cytokines⁶ challenge its traditional classification as a functional disorder.

The cause of this inflammation is of intense interest, with speculation that the bacterial microbiota, bile acids, association with postinfectious gastroenteritis and inflammatory bowel disease cases, and/or foods may contribute. Although approximately 50% of individuals with IBS report that foods aggravate their symptoms,⁷ studies investigating type I antibody–mediated immediate hypersensitivity have largely failed to demonstrate a substantial link, prompting many authorities to regard these associations as food “intolerances” rather than true allergies. Based on this body of literature, a large 2010 consensus report on all aspects of food allergies advises against food allergy testing for IBS.⁸

In contrast, by utilizing type IV food allergen skin patch testing, 2 proof-of-concept studies^9,10 investigated a different allergic mechanism in IBS, namely cell-mediated delayed-type hypersensitivity. Because many foods and food additives are known to cause allergic contact dermatitis,¹¹ it was hypothesized that these foods may elicit a similar delayed-type hypersensitivity response in the intestinal lining in previously sensitized individuals. By following a patch test–guided food avoidance diet, a large subpopulation of patients with IBS experienced partial or complete IBS symptom relief.^9,10 Our study further investigates a role for food-related delayed-type hypersensitivities in the pathogenesis of IBS.

Methods

Patient Selection
This study was conducted in a secondary care community-based setting. All patients were self-referred over an 18-month period ending in October 2019, had physician-diagnosed IBS, and/or met the Rome IV criteria for IBS and presented expressly for the food patch testing on a fee-for-service basis. Subtype of IBS was determined on presentation by the self-reported historically predominant symptom. Duration of IBS symptoms was self-reported and was rounded to the nearest year for purposes of data collection.

Exclusion criteria included pregnancy, known allergy to adhesive tape or any of the food allergens used in the study, severe skin rash, symptoms that had a known cause other than IBS, or active treatment with systemic immunosuppressive medications.

Patch Testing
Skin patch testing was initiated using an extensive panel of 117 type IV food allergens (eTable)¹¹ identified in the literature,¹² most of which utilized standard compounded formulations¹³ or were available from reputable patch test manufacturers (Brial Allergen GmbH; Chemotechnique Diagnostics). This panel was not approved by the US Food and Drug Administration. The freeze-dried vegetable formulations were taken from the 2018 report.⁹ Standard skin patch test procedure protocols¹² were used, affixing the patches to the upper aspect of the back.

Following patch test application on day 1, two follow-up visits occurred on day 3 and either day 4 or day 5. On day 3, patches were removed, and the initial results were read by a board-certified dermatologist according to a standard grading system.¹⁴ Interpretation of patch tests included no reaction, questionable reaction consisting of macular erythema, weak reaction consisting of erythema and slight edema, or strong reaction consisting of erythema and marked edema. On day 4 or day 5, the final patch test reading was performed, and patients were informed of their results. Patients were advised to avoid ingestion of all foods that elicited a questionable or positive patch test response for at least 3 months, and information about the foods and their avoidance also was distributed and reviewed.

Food Avoidance Questionnaire
Patients with questionable or positive patch tests at 72 or 96 hours were advised of their eligibility to participate in an institutional review board–approved food avoidance questionnaire study investigating the utility of patch test–guided food avoidance on IBS symptoms. The questionnaire assessed the following: (1) baseline average abdominal pain prior to patch test–guided avoidance diet (0=no symptoms; 10=very severe); (2) average abdominal pain since initiation of patch test–guided avoidance diet (0=no symptoms; 10=very severe); (3) degree of improvement in overall IBS symptoms by the end of the food avoidance period (0=no improvement; 10=great improvement); (4) compliance with the avoidance diet for the duration of the avoidance period (completely, partially, not at all, or not sure).

Questionnaires and informed consent were mailed to patients via the US Postal Service 3 months after completing the patch testing. The questionnaire and consent were to be completed and returned after dietary avoidance of the identified allergens for at least 3 months. Patients were not compensated for participation in the study.

Statistical Analysis
Statistical analysis of data collected from study questionnaires was performed with Microsoft Excel. Mean abdominal pain and mean global improvement scores were reported along with 1 SD of the mean. For comparison of mean abdominal pain and improvement in global IBS symptoms from baseline to after 3 months of identified allergen avoidance, a Mann-Whitney U test was performed, with P<.05 being considered statistically significant.

Results

Thirty-seven consecutive patients underwent the testing and were eligible for the study. Nineteen patients were included in the study by virtue of completing and returning their posttest food avoidance questionnaire and informed consent. Eighteen patients were White and 1 was Asian. Subcategories of IBS were diarrhea predominant (9 [47.4%]), constipation predominant (3 [15.8%]), mixed type (5 [26.3%]), and undetermined type (2 [10.5%]). Questionnaire answers were reported after a mean (SD) duration of patch test–directed food avoidance of 4.5 (3.0) months (Table 1).

Overall Improvement
Fifteen (78.9%) patients reported at least slight to great improvement in their global IBS symptoms, and 4 (21.1%) reported no improvement (Table 2), with a mean (SD) improvement score of 5.1 (3.3)(P<.00001).

Comment

Despite intense research interest and a growing number of new medications for IBS approved by the US Food and Drug Administration, there remains a large void in the search for cost-effective and efficacious approaches for IBS evaluation and treatment. In addition to major disturbances in quality of life,^14,15 the cost to society in direct medical expenses and indirect costs associated with loss of productivity and work absenteeism is considerable; estimates range from $21 billion or more annually.¹⁶

Food Hypersensitivities Triggering IBS
This study further evaluated a role for skin patch testing to identify delayed-type (type IV) food hypersensitivities that trigger IBS symptoms and differed from the prior investigations^9,10 in that the symptoms used to define IBS were updated from the Rome III¹⁷ to the newer Rome IV² criteria. The data presented here show moderate to great improvement in global IBS symptoms in 58% (11/19) of patients, which is in line with a 2018 report of 40 study participants for whom follow-up at 3 or more months was available,⁹ providing additional support for a role for type IV food allergies in causing the same gastrointestinal tract symptoms that define IBS. The distinction between food-related studies, including this one, that implicate food allergies^9,10 and prior studies that did not support a role for food allergies in IBS pathogenesis⁸ can be accounted for by the type of allergy investigated. Conclusions that IBS flares after food ingestion were attributable to intolerance rather than true allergy were based on results investigating only the humoral arm and failed to consider the cell-mediated arm of the immune system. As such, foods that appear to trigger IBS symptoms on an allergic basis in our study are recognized in the literature¹² as type IV allergens that elicit cell-mediated immunologic responses rather than more widely recognized type I allergens, such as peanuts and shellfish, that elicit immediate-type hypersensitivity responses. Although any type IV food allergen(s) could be responsible, a pattern emerged in this study and the study published in 2018.⁹ Namely, some foods stood out as more frequently inducing patch test reactions, with the 3 most common being carmine, cinnamon bark oil, and sodium bisulfite (eTable). The sample size is relatively small, but the results raise the question of whether these foods are the most likely to trigger IBS symptoms in the general population. If so, is it the result of a higher innate sensitizing potential and/or a higher frequency of exposure in commonly eaten foods? Larger randomized clinical trials are needed.

Immune Response and IBS
There is mounting evidence that the immune system may play a role in the pathophysiology of IBS.¹⁸ Both lymphocyte infiltration of the myenteric plexus and an increase in intestinal mucosal T lymphocytes have been observed, and it is generally accepted that the mucosal immune system seems to be activated, at least in a subset of patients with IBS.¹⁹ Irritable bowel syndrome associations with quiescent inflammatory bowel disease or postinfectious gastroenteritis provide 2 potential causes for the inflammation, but most IBS patients have had neither.²⁰ The mucosal lining of the intestine and immune system have vast exposure to intraluminal allergens in transit, and it is hypothesized that the same delayed-type hypersensitivity response elicited in the skin by patch testing is elicited in the intestine, resulting in the inflammation that triggers IBS symptoms.¹⁰ The results here add to the growing body of evidence that ingestion of type IV food allergens by previously sensitized individuals could, in fact, be the primary source of the inflammation observed in a large subpopulation of individuals who carry a diagnosis of IBS.

Food Allergens in Patch Testing
Many of the food allergens used in this study are commonly found in various nonfood products that may contact the skin. For example, many flavorings are used as fragrances, and many preservatives, binders, thickeners, emulsifiers, and stabilizers serve the same role in moisturizers, cosmetics, and topical medications. Likewise, nickel sulfate hexahydrate, ubiquitous in foods that arise from the earth, often is found in metal in jewelry, clothing components, and cell phones. All are potential sensitizers. Thus, the question may arise whether the causal relationship between the food allergens identified by patch testing and IBS symptoms might be more of a systemic effect akin to systemic contact dermatitis as sometimes follows ingestion of an allergen to which an individual has been topically sensitized, rather than the proposed localized immunologic response in the intestinal lining. We were unaware of patient history of allergic contact dermatitis to any of the patch test allergens in this study, but the dermatologist author here (M.S.) has unpublished experience with 2 other patients with IBS who have benefited from low-nickel diets after having had positive patch tests to nickel sulfate hexahydrate and who, in retrospect, did report a history of earring dermatitis. Future investigations using pre– and post–food challenge histologic assessments of the intestinal mucosa in patients who benefit from patch test–guided food avoidance diets should help to better define the mechanism.

Because IBS has not been traditionally associated with structural or biochemical abnormalities detectable with current routine diagnostic tools, it has long been viewed as a functional disorder. The findings published more recently,^9,10 in addition to this study’s results, would negate this functional classification in the subset of patients with IBS symptoms who experience sustained relief of their symptoms by patch test–directed food avoidance. The underlying delayed-type hypersensitivity pathogenesis of the IBS-like symptoms in these individuals would mandate an organic classification, aptly named allergic contact enteritis.¹⁰

Follow-up Data
The mean (SD) follow-up duration for this study and the 2018 report⁹ was 4.5 (3.0) months and 7.6 (3.9) months, respectively. The placebo effect is a concern for disorders such as IBS in which primarily subjective outcome measures are available,²¹ and in a retrospective analysis of 25 randomized, placebo-controlled IBS clinical trials, Spiller²² concluded the optimum length of such trials to be more than 3 months, which these studies exceed. Although not blinded or placebo controlled, the length of follow-up in the 2018 report⁹ and here enhances the validity of the results.

Limitation
The retrospective manner in which the self-assessments were reported in this study introduces the potential for recall bias, a variable that could affect results. The presence and direction of bias by any given individual cannot be known, making it difficult to determine any effect it may have had. Further investigation should include daily assessments and refine the primary study end points to include both abdominal pain and the defecation considerations that define IBS.

Conclusion

Food patch testing has the potential to offer a safe, cost-effective approach to the evaluation and management of IBS symptoms. Randomized clinical trials are needed to further investigate the validity of the proof-of-concept results to date. For patients who benefit from a patch test–guided avoidance diet, invasive and costly endoscopic, radiologic, and laboratory testing and pharmacologic management could be averted. Symptomatic relief could be attained simply by avoiding the implicated foods, essentially doing more by doing less. 


Irritable bowel syndrome (IBS) is one of the most common disorders managed by primary care physicians and gastroenterologists.¹ Characterized by abdominal pain coinciding with altered stool form and/or frequency as defined by the Rome IV diagnostic criteria,² symptoms range from mild to debilitating and may remarkably impair quality of life and work productivity.¹

The cause of IBS is poorly understood. Proposed pathophysiologic factors include impaired mucosal function, microbial imbalance, visceral hypersensitivity, psychologic dysfunction, genetic factors, neurotransmitter imbalance, postinfectious gastroenteritis, inflammation, and food intolerance, any or all of which may lead to the development and maintenance of IBS symptoms.³ More recent observations of inflammation in the intestinal lining^4,5 and proinflammatory peripherally circulating cytokines⁶ challenge its traditional classification as a functional disorder.

The cause of this inflammation is of intense interest, with speculation that the bacterial microbiota, bile acids, association with postinfectious gastroenteritis and inflammatory bowel disease cases, and/or foods may contribute. Although approximately 50% of individuals with IBS report that foods aggravate their symptoms,⁷ studies investigating type I antibody–mediated immediate hypersensitivity have largely failed to demonstrate a substantial link, prompting many authorities to regard these associations as food “intolerances” rather than true allergies. Based on this body of literature, a large 2010 consensus report on all aspects of food allergies advises against food allergy testing for IBS.⁸

In contrast, by utilizing type IV food allergen skin patch testing, 2 proof-of-concept studies^9,10 investigated a different allergic mechanism in IBS, namely cell-mediated delayed-type hypersensitivity. Because many foods and food additives are known to cause allergic contact dermatitis,¹¹ it was hypothesized that these foods may elicit a similar delayed-type hypersensitivity response in the intestinal lining in previously sensitized individuals. By following a patch test–guided food avoidance diet, a large subpopulation of patients with IBS experienced partial or complete IBS symptom relief.^9,10 Our study further investigates a role for food-related delayed-type hypersensitivities in the pathogenesis of IBS.

Methods

Patient Selection
This study was conducted in a secondary care community-based setting. All patients were self-referred over an 18-month period ending in October 2019, had physician-diagnosed IBS, and/or met the Rome IV criteria for IBS and presented expressly for the food patch testing on a fee-for-service basis. Subtype of IBS was determined on presentation by the self-reported historically predominant symptom. Duration of IBS symptoms was self-reported and was rounded to the nearest year for purposes of data collection.

Exclusion criteria included pregnancy, known allergy to adhesive tape or any of the food allergens used in the study, severe skin rash, symptoms that had a known cause other than IBS, or active treatment with systemic immunosuppressive medications.

Patch Testing
Skin patch testing was initiated using an extensive panel of 117 type IV food allergens (eTable)¹¹ identified in the literature,¹² most of which utilized standard compounded formulations¹³ or were available from reputable patch test manufacturers (Brial Allergen GmbH; Chemotechnique Diagnostics). This panel was not approved by the US Food and Drug Administration. The freeze-dried vegetable formulations were taken from the 2018 report.⁹ Standard skin patch test procedure protocols¹² were used, affixing the patches to the upper aspect of the back.

Following patch test application on day 1, two follow-up visits occurred on day 3 and either day 4 or day 5. On day 3, patches were removed, and the initial results were read by a board-certified dermatologist according to a standard grading system.¹⁴ Interpretation of patch tests included no reaction, questionable reaction consisting of macular erythema, weak reaction consisting of erythema and slight edema, or strong reaction consisting of erythema and marked edema. On day 4 or day 5, the final patch test reading was performed, and patients were informed of their results. Patients were advised to avoid ingestion of all foods that elicited a questionable or positive patch test response for at least 3 months, and information about the foods and their avoidance also was distributed and reviewed.

Food Avoidance Questionnaire
Patients with questionable or positive patch tests at 72 or 96 hours were advised of their eligibility to participate in an institutional review board–approved food avoidance questionnaire study investigating the utility of patch test–guided food avoidance on IBS symptoms. The questionnaire assessed the following: (1) baseline average abdominal pain prior to patch test–guided avoidance diet (0=no symptoms; 10=very severe); (2) average abdominal pain since initiation of patch test–guided avoidance diet (0=no symptoms; 10=very severe); (3) degree of improvement in overall IBS symptoms by the end of the food avoidance period (0=no improvement; 10=great improvement); (4) compliance with the avoidance diet for the duration of the avoidance period (completely, partially, not at all, or not sure).

Questionnaires and informed consent were mailed to patients via the US Postal Service 3 months after completing the patch testing. The questionnaire and consent were to be completed and returned after dietary avoidance of the identified allergens for at least 3 months. Patients were not compensated for participation in the study.

Statistical Analysis
Statistical analysis of data collected from study questionnaires was performed with Microsoft Excel. Mean abdominal pain and mean global improvement scores were reported along with 1 SD of the mean. For comparison of mean abdominal pain and improvement in global IBS symptoms from baseline to after 3 months of identified allergen avoidance, a Mann-Whitney U test was performed, with P<.05 being considered statistically significant.

Results

Thirty-seven consecutive patients underwent the testing and were eligible for the study. Nineteen patients were included in the study by virtue of completing and returning their posttest food avoidance questionnaire and informed consent. Eighteen patients were White and 1 was Asian. Subcategories of IBS were diarrhea predominant (9 [47.4%]), constipation predominant (3 [15.8%]), mixed type (5 [26.3%]), and undetermined type (2 [10.5%]). Questionnaire answers were reported after a mean (SD) duration of patch test–directed food avoidance of 4.5 (3.0) months (Table 1).

Overall Improvement
Fifteen (78.9%) patients reported at least slight to great improvement in their global IBS symptoms, and 4 (21.1%) reported no improvement (Table 2), with a mean (SD) improvement score of 5.1 (3.3)(P<.00001).

Comment

Despite intense research interest and a growing number of new medications for IBS approved by the US Food and Drug Administration, there remains a large void in the search for cost-effective and efficacious approaches for IBS evaluation and treatment. In addition to major disturbances in quality of life,^14,15 the cost to society in direct medical expenses and indirect costs associated with loss of productivity and work absenteeism is considerable; estimates range from $21 billion or more annually.¹⁶

Food Hypersensitivities Triggering IBS
This study further evaluated a role for skin patch testing to identify delayed-type (type IV) food hypersensitivities that trigger IBS symptoms and differed from the prior investigations^9,10 in that the symptoms used to define IBS were updated from the Rome III¹⁷ to the newer Rome IV² criteria. The data presented here show moderate to great improvement in global IBS symptoms in 58% (11/19) of patients, which is in line with a 2018 report of 40 study participants for whom follow-up at 3 or more months was available,⁹ providing additional support for a role for type IV food allergies in causing the same gastrointestinal tract symptoms that define IBS. The distinction between food-related studies, including this one, that implicate food allergies^9,10 and prior studies that did not support a role for food allergies in IBS pathogenesis⁸ can be accounted for by the type of allergy investigated. Conclusions that IBS flares after food ingestion were attributable to intolerance rather than true allergy were based on results investigating only the humoral arm and failed to consider the cell-mediated arm of the immune system. As such, foods that appear to trigger IBS symptoms on an allergic basis in our study are recognized in the literature¹² as type IV allergens that elicit cell-mediated immunologic responses rather than more widely recognized type I allergens, such as peanuts and shellfish, that elicit immediate-type hypersensitivity responses. Although any type IV food allergen(s) could be responsible, a pattern emerged in this study and the study published in 2018.⁹ Namely, some foods stood out as more frequently inducing patch test reactions, with the 3 most common being carmine, cinnamon bark oil, and sodium bisulfite (eTable). The sample size is relatively small, but the results raise the question of whether these foods are the most likely to trigger IBS symptoms in the general population. If so, is it the result of a higher innate sensitizing potential and/or a higher frequency of exposure in commonly eaten foods? Larger randomized clinical trials are needed.

Immune Response and IBS
There is mounting evidence that the immune system may play a role in the pathophysiology of IBS.¹⁸ Both lymphocyte infiltration of the myenteric plexus and an increase in intestinal mucosal T lymphocytes have been observed, and it is generally accepted that the mucosal immune system seems to be activated, at least in a subset of patients with IBS.¹⁹ Irritable bowel syndrome associations with quiescent inflammatory bowel disease or postinfectious gastroenteritis provide 2 potential causes for the inflammation, but most IBS patients have had neither.²⁰ The mucosal lining of the intestine and immune system have vast exposure to intraluminal allergens in transit, and it is hypothesized that the same delayed-type hypersensitivity response elicited in the skin by patch testing is elicited in the intestine, resulting in the inflammation that triggers IBS symptoms.¹⁰ The results here add to the growing body of evidence that ingestion of type IV food allergens by previously sensitized individuals could, in fact, be the primary source of the inflammation observed in a large subpopulation of individuals who carry a diagnosis of IBS.

Food Allergens in Patch Testing
Many of the food allergens used in this study are commonly found in various nonfood products that may contact the skin. For example, many flavorings are used as fragrances, and many preservatives, binders, thickeners, emulsifiers, and stabilizers serve the same role in moisturizers, cosmetics, and topical medications. Likewise, nickel sulfate hexahydrate, ubiquitous in foods that arise from the earth, often is found in metal in jewelry, clothing components, and cell phones. All are potential sensitizers. Thus, the question may arise whether the causal relationship between the food allergens identified by patch testing and IBS symptoms might be more of a systemic effect akin to systemic contact dermatitis as sometimes follows ingestion of an allergen to which an individual has been topically sensitized, rather than the proposed localized immunologic response in the intestinal lining. We were unaware of patient history of allergic contact dermatitis to any of the patch test allergens in this study, but the dermatologist author here (M.S.) has unpublished experience with 2 other patients with IBS who have benefited from low-nickel diets after having had positive patch tests to nickel sulfate hexahydrate and who, in retrospect, did report a history of earring dermatitis. Future investigations using pre– and post–food challenge histologic assessments of the intestinal mucosa in patients who benefit from patch test–guided food avoidance diets should help to better define the mechanism.

Because IBS has not been traditionally associated with structural or biochemical abnormalities detectable with current routine diagnostic tools, it has long been viewed as a functional disorder. The findings published more recently,^9,10 in addition to this study’s results, would negate this functional classification in the subset of patients with IBS symptoms who experience sustained relief of their symptoms by patch test–directed food avoidance. The underlying delayed-type hypersensitivity pathogenesis of the IBS-like symptoms in these individuals would mandate an organic classification, aptly named allergic contact enteritis.¹⁰

Follow-up Data
The mean (SD) follow-up duration for this study and the 2018 report⁹ was 4.5 (3.0) months and 7.6 (3.9) months, respectively. The placebo effect is a concern for disorders such as IBS in which primarily subjective outcome measures are available,²¹ and in a retrospective analysis of 25 randomized, placebo-controlled IBS clinical trials, Spiller²² concluded the optimum length of such trials to be more than 3 months, which these studies exceed. Although not blinded or placebo controlled, the length of follow-up in the 2018 report⁹ and here enhances the validity of the results.

Limitation
The retrospective manner in which the self-assessments were reported in this study introduces the potential for recall bias, a variable that could affect results. The presence and direction of bias by any given individual cannot be known, making it difficult to determine any effect it may have had. Further investigation should include daily assessments and refine the primary study end points to include both abdominal pain and the defecation considerations that define IBS.

Conclusion

Food patch testing has the potential to offer a safe, cost-effective approach to the evaluation and management of IBS symptoms. Randomized clinical trials are needed to further investigate the validity of the proof-of-concept results to date. For patients who benefit from a patch test–guided avoidance diet, invasive and costly endoscopic, radiologic, and laboratory testing and pharmacologic management could be averted. Symptomatic relief could be attained simply by avoiding the implicated foods, essentially doing more by doing less. 


To the Editor:

Granular parakeratosis is a rare condition with an unclear etiology that results from a myriad of factors, including exposure to irritants, friction, moisture, and heat. The diagnosis is made based on a distinct histologic reaction pattern that may be protective against the triggers. We present a case of isolated scrotal granular parakeratosis in a patient with compensatory hyperhidrosis after endoscopic thoracic sympathectomy.

A 52-year-old man presented with a 5-year history of a recurrent rash affecting the scrotum. He experienced monthly flares that were exacerbated by inguinal hyperhidrosis. His symptoms included a burning sensation and pruritus followed by superficial desquamation, with gradual yet temporary improvement. His medical history was remarkable for primary axillary and palmoplantar hyperhidrosis, with compensatory inguinal hyperhidrosis after endoscopic thoracic sympathectomy 8 years prior to presentation.

Physical examination revealed a well-demarcated, scaly, erythematous plaque affecting the scrotal skin with sparing of the median raphe, penis, and inguinal folds (Figure 1). There were no other lesions noted in the axillary region or other skin folds.

Murine models have postulated that granular parakeratosis may result from a deficiency in caspase 14, a protease vital to the formation of a well-functioning skin barrier.⁹ A cornified envelope often is noted in granular parakeratotic cells with no defects in desmosomes and cell membranes, suggesting that the pathogenesis lies within processing of profilaggrin to filaggrin, resulting in a failure to degrade keratohyalin granules and aggregation of keratin filaments.¹⁰ Granular parakeratosis is not known to be associated with other medical conditions, but it has been observed in patients receiving chemotherapy for breast¹¹ and ovarian¹² carcinomas. In infants with atopic dermatitis, granular parakeratosis was reported in 5 out of 7 cases.⁶ In our patient with secondary inguinal hyperhidrosis after thoracic sympathectomy, granular parakeratosis may be reactive to excess sweating and friction in the scrotal area.

Granular parakeratosis follows a waxing and waning pattern that may spontaneously resolve without any treatment; it also can follow a protracted course, as in a case with associated facial papules that persisted for 20 years.¹³ Topical corticosteroids alone or in combination with topical antifungal agents have been used for the treatment of granular parakeratosis with the goal of accelerating resolution.^2,14 However, the efficacy of these therapeutic interventions is limited, and no controlled trials are underway. Topical vitamin D analogues^15,16 and topical retinoids¹⁷ also have been reported with successful outcomes. Spontaneous resolution also has been observed in 2 different cases after previously being unresponsive to topical treatment.^18,19 Treatment with Clostridium botulinum toxin A resulted in complete remission of the disease observed at 6-month follow-up. The pharmacologic action of the neurotoxin disrupts the stimulation of eccrine sweat glands, resulting in decreased sweating, a known exacerbating factor of granular parakeratosis.²⁰

In summary, our case represents a unique clinical presentation of granular parakeratosis with classic histopathologic features. A high index of suspicion and a biopsy are vital to arriving at the correct diagnosis.

To the Editor:

Granular parakeratosis is a rare condition with an unclear etiology that results from a myriad of factors, including exposure to irritants, friction, moisture, and heat. The diagnosis is made based on a distinct histologic reaction pattern that may be protective against the triggers. We present a case of isolated scrotal granular parakeratosis in a patient with compensatory hyperhidrosis after endoscopic thoracic sympathectomy.

A 52-year-old man presented with a 5-year history of a recurrent rash affecting the scrotum. He experienced monthly flares that were exacerbated by inguinal hyperhidrosis. His symptoms included a burning sensation and pruritus followed by superficial desquamation, with gradual yet temporary improvement. His medical history was remarkable for primary axillary and palmoplantar hyperhidrosis, with compensatory inguinal hyperhidrosis after endoscopic thoracic sympathectomy 8 years prior to presentation.

Physical examination revealed a well-demarcated, scaly, erythematous plaque affecting the scrotal skin with sparing of the median raphe, penis, and inguinal folds (Figure 1). There were no other lesions noted in the axillary region or other skin folds.

Murine models have postulated that granular parakeratosis may result from a deficiency in caspase 14, a protease vital to the formation of a well-functioning skin barrier.⁹ A cornified envelope often is noted in granular parakeratotic cells with no defects in desmosomes and cell membranes, suggesting that the pathogenesis lies within processing of profilaggrin to filaggrin, resulting in a failure to degrade keratohyalin granules and aggregation of keratin filaments.¹⁰ Granular parakeratosis is not known to be associated with other medical conditions, but it has been observed in patients receiving chemotherapy for breast¹¹ and ovarian¹² carcinomas. In infants with atopic dermatitis, granular parakeratosis was reported in 5 out of 7 cases.⁶ In our patient with secondary inguinal hyperhidrosis after thoracic sympathectomy, granular parakeratosis may be reactive to excess sweating and friction in the scrotal area.

Granular parakeratosis follows a waxing and waning pattern that may spontaneously resolve without any treatment; it also can follow a protracted course, as in a case with associated facial papules that persisted for 20 years.¹³ Topical corticosteroids alone or in combination with topical antifungal agents have been used for the treatment of granular parakeratosis with the goal of accelerating resolution.^2,14 However, the efficacy of these therapeutic interventions is limited, and no controlled trials are underway. Topical vitamin D analogues^15,16 and topical retinoids¹⁷ also have been reported with successful outcomes. Spontaneous resolution also has been observed in 2 different cases after previously being unresponsive to topical treatment.^18,19 Treatment with Clostridium botulinum toxin A resulted in complete remission of the disease observed at 6-month follow-up. The pharmacologic action of the neurotoxin disrupts the stimulation of eccrine sweat glands, resulting in decreased sweating, a known exacerbating factor of granular parakeratosis.²⁰

In summary, our case represents a unique clinical presentation of granular parakeratosis with classic histopathologic features. A high index of suspicion and a biopsy are vital to arriving at the correct diagnosis.

To the Editor:

Granular parakeratosis is a rare condition with an unclear etiology that results from a myriad of factors, including exposure to irritants, friction, moisture, and heat. The diagnosis is made based on a distinct histologic reaction pattern that may be protective against the triggers. We present a case of isolated scrotal granular parakeratosis in a patient with compensatory hyperhidrosis after endoscopic thoracic sympathectomy.

A 52-year-old man presented with a 5-year history of a recurrent rash affecting the scrotum. He experienced monthly flares that were exacerbated by inguinal hyperhidrosis. His symptoms included a burning sensation and pruritus followed by superficial desquamation, with gradual yet temporary improvement. His medical history was remarkable for primary axillary and palmoplantar hyperhidrosis, with compensatory inguinal hyperhidrosis after endoscopic thoracic sympathectomy 8 years prior to presentation.

Physical examination revealed a well-demarcated, scaly, erythematous plaque affecting the scrotal skin with sparing of the median raphe, penis, and inguinal folds (Figure 1). There were no other lesions noted in the axillary region or other skin folds.

Murine models have postulated that granular parakeratosis may result from a deficiency in caspase 14, a protease vital to the formation of a well-functioning skin barrier.⁹ A cornified envelope often is noted in granular parakeratotic cells with no defects in desmosomes and cell membranes, suggesting that the pathogenesis lies within processing of profilaggrin to filaggrin, resulting in a failure to degrade keratohyalin granules and aggregation of keratin filaments.¹⁰ Granular parakeratosis is not known to be associated with other medical conditions, but it has been observed in patients receiving chemotherapy for breast¹¹ and ovarian¹² carcinomas. In infants with atopic dermatitis, granular parakeratosis was reported in 5 out of 7 cases.⁶ In our patient with secondary inguinal hyperhidrosis after thoracic sympathectomy, granular parakeratosis may be reactive to excess sweating and friction in the scrotal area.

Granular parakeratosis follows a waxing and waning pattern that may spontaneously resolve without any treatment; it also can follow a protracted course, as in a case with associated facial papules that persisted for 20 years.¹³ Topical corticosteroids alone or in combination with topical antifungal agents have been used for the treatment of granular parakeratosis with the goal of accelerating resolution.^2,14 However, the efficacy of these therapeutic interventions is limited, and no controlled trials are underway. Topical vitamin D analogues^15,16 and topical retinoids¹⁷ also have been reported with successful outcomes. Spontaneous resolution also has been observed in 2 different cases after previously being unresponsive to topical treatment.^18,19 Treatment with Clostridium botulinum toxin A resulted in complete remission of the disease observed at 6-month follow-up. The pharmacologic action of the neurotoxin disrupts the stimulation of eccrine sweat glands, resulting in decreased sweating, a known exacerbating factor of granular parakeratosis.²⁰

In summary, our case represents a unique clinical presentation of granular parakeratosis with classic histopathologic features. A high index of suspicion and a biopsy are vital to arriving at the correct diagnosis.