Atopic Dermatitis

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.

Atopic Dermatitis (AD) is complex with heterogeneous symptoms (e.g. skin-pain, sleep disturbance), signs (e.g. lichenification, prurigo nodules, follicular accentuation), and longitudinal course (intermittent, persistent). These disparate signs and symptoms should be addressed in optimize disease control.

Multiple extracellular cytokines are upregulated in skin of AD patients, including interleukins 4, 5, 13, 22, 31 and thymic stromal lymphopoietin, all of which signal intracellularly through Janus Kinase (JAK)-Signal Transducer and Activator of Transcription (STAT) pathways. Differential cytokine expression is proposed to underlie clinical variability. It may be necessary to inhibit signaling of multiple cytokines to achieve adequate control of AD.

Dupilumab is currently the only biologic treatment approved in the United States for moderate-severe AD. Dupilumab revolutionized AD management. However, there remain unmet needs, including the need for faster and more potent efficacy, and oral treatment options. Recently, oral JAK-inhibitors were investigated as treatments for moderate-severe AD. Multiple JAK-inhibitors demonstrated strong and rapid efficacy across multiple clinician-reported and patient-reported outcomes.

• Miao et al. recently conducted a meta-analysis of 10 randomized controlled trials and found that patients receiving JAK inhibitors showed significantly higher efficacy for eczema area and severity index (EASI) and Numeric Rating Scale (NRS)-itch scores and similar rates of adverse-events.
• Kim et al. pooled data from 3 randomized controlled trials of abrocitinib and found significantly higher proportions of clinically meaningful responses for itch in patients receiving abrocitinib 200 mg and 100 mg vs placebo as early as week 2 which continued through week 12.
• Lio et al. performed a post-hoc analysis of a phase 3 study of conducted in North America and found significant improvements for itch severity and sleep disturbance in patients treated with baricitinib 1 mg and 2 mg vs placebo. In particular, patients who achieved improvement of itch or sleep disturbance compared to those who did not were more likely to report having no impact on quality of life impact and improved work productivity.

This new therapeutic class will be an important addition to our therapeutic armamentarium and has potential to transform the AD treatment landscape.

• Many patients prefer taking pills over injections.
• Rapid-onset of efficacy for JAK-inhibitors will certainly be appreciated by patients, especially when trying to control tough flares. It may even guide clinical decision-making. Patients who have a good clinical response to JAK-inhibitors tend to do so within 4-8 weeks. By 8 weeks, if patients have no clinical response, they are likely not going to respond and may benefit from switching to alternative therapies.
• JAK-inhibitors can have robust efficacy, with higher doses of upadacitinib and abrocritinib showing greater efficacy than dupilumab at 12-16 weeks. This makes them attractive options to consider in patients who previously failed dupilumab.
• On the other hand, JAK-inhibitors have laboratory monitoring requirements, including complete blood count, comprehensive metabolic panel, lipid panel, etc.
• JAK-inhibitors warrant adverse-event monitoring for headache, nausea, acne, herpesvirus infections, risk of venous thromboembolism, etc.

Future research is needed to identify patient subsets who will benefit most from JAK-inhibitor therapy and where to position these agents in treatment guidelines.

Atopic Dermatitis (AD) is complex with heterogeneous symptoms (e.g. skin-pain, sleep disturbance), signs (e.g. lichenification, prurigo nodules, follicular accentuation), and longitudinal course (intermittent, persistent). These disparate signs and symptoms should be addressed in optimize disease control.

Multiple extracellular cytokines are upregulated in skin of AD patients, including interleukins 4, 5, 13, 22, 31 and thymic stromal lymphopoietin, all of which signal intracellularly through Janus Kinase (JAK)-Signal Transducer and Activator of Transcription (STAT) pathways. Differential cytokine expression is proposed to underlie clinical variability. It may be necessary to inhibit signaling of multiple cytokines to achieve adequate control of AD.

Dupilumab is currently the only biologic treatment approved in the United States for moderate-severe AD. Dupilumab revolutionized AD management. However, there remain unmet needs, including the need for faster and more potent efficacy, and oral treatment options. Recently, oral JAK-inhibitors were investigated as treatments for moderate-severe AD. Multiple JAK-inhibitors demonstrated strong and rapid efficacy across multiple clinician-reported and patient-reported outcomes.

• Miao et al. recently conducted a meta-analysis of 10 randomized controlled trials and found that patients receiving JAK inhibitors showed significantly higher efficacy for eczema area and severity index (EASI) and Numeric Rating Scale (NRS)-itch scores and similar rates of adverse-events.
• Kim et al. pooled data from 3 randomized controlled trials of abrocitinib and found significantly higher proportions of clinically meaningful responses for itch in patients receiving abrocitinib 200 mg and 100 mg vs placebo as early as week 2 which continued through week 12.
• Lio et al. performed a post-hoc analysis of a phase 3 study of conducted in North America and found significant improvements for itch severity and sleep disturbance in patients treated with baricitinib 1 mg and 2 mg vs placebo. In particular, patients who achieved improvement of itch or sleep disturbance compared to those who did not were more likely to report having no impact on quality of life impact and improved work productivity.

This new therapeutic class will be an important addition to our therapeutic armamentarium and has potential to transform the AD treatment landscape.

• Many patients prefer taking pills over injections.
• Rapid-onset of efficacy for JAK-inhibitors will certainly be appreciated by patients, especially when trying to control tough flares. It may even guide clinical decision-making. Patients who have a good clinical response to JAK-inhibitors tend to do so within 4-8 weeks. By 8 weeks, if patients have no clinical response, they are likely not going to respond and may benefit from switching to alternative therapies.
• JAK-inhibitors can have robust efficacy, with higher doses of upadacitinib and abrocritinib showing greater efficacy than dupilumab at 12-16 weeks. This makes them attractive options to consider in patients who previously failed dupilumab.
• On the other hand, JAK-inhibitors have laboratory monitoring requirements, including complete blood count, comprehensive metabolic panel, lipid panel, etc.
• JAK-inhibitors warrant adverse-event monitoring for headache, nausea, acne, herpesvirus infections, risk of venous thromboembolism, etc.

Future research is needed to identify patient subsets who will benefit most from JAK-inhibitor therapy and where to position these agents in treatment guidelines.

Atopic Dermatitis (AD) is complex with heterogeneous symptoms (e.g. skin-pain, sleep disturbance), signs (e.g. lichenification, prurigo nodules, follicular accentuation), and longitudinal course (intermittent, persistent). These disparate signs and symptoms should be addressed in optimize disease control.

Multiple extracellular cytokines are upregulated in skin of AD patients, including interleukins 4, 5, 13, 22, 31 and thymic stromal lymphopoietin, all of which signal intracellularly through Janus Kinase (JAK)-Signal Transducer and Activator of Transcription (STAT) pathways. Differential cytokine expression is proposed to underlie clinical variability. It may be necessary to inhibit signaling of multiple cytokines to achieve adequate control of AD.

Dupilumab is currently the only biologic treatment approved in the United States for moderate-severe AD. Dupilumab revolutionized AD management. However, there remain unmet needs, including the need for faster and more potent efficacy, and oral treatment options. Recently, oral JAK-inhibitors were investigated as treatments for moderate-severe AD. Multiple JAK-inhibitors demonstrated strong and rapid efficacy across multiple clinician-reported and patient-reported outcomes.

• Miao et al. recently conducted a meta-analysis of 10 randomized controlled trials and found that patients receiving JAK inhibitors showed significantly higher efficacy for eczema area and severity index (EASI) and Numeric Rating Scale (NRS)-itch scores and similar rates of adverse-events.
• Kim et al. pooled data from 3 randomized controlled trials of abrocitinib and found significantly higher proportions of clinically meaningful responses for itch in patients receiving abrocitinib 200 mg and 100 mg vs placebo as early as week 2 which continued through week 12.
• Lio et al. performed a post-hoc analysis of a phase 3 study of conducted in North America and found significant improvements for itch severity and sleep disturbance in patients treated with baricitinib 1 mg and 2 mg vs placebo. In particular, patients who achieved improvement of itch or sleep disturbance compared to those who did not were more likely to report having no impact on quality of life impact and improved work productivity.

This new therapeutic class will be an important addition to our therapeutic armamentarium and has potential to transform the AD treatment landscape.

• Many patients prefer taking pills over injections.
• Rapid-onset of efficacy for JAK-inhibitors will certainly be appreciated by patients, especially when trying to control tough flares. It may even guide clinical decision-making. Patients who have a good clinical response to JAK-inhibitors tend to do so within 4-8 weeks. By 8 weeks, if patients have no clinical response, they are likely not going to respond and may benefit from switching to alternative therapies.
• JAK-inhibitors can have robust efficacy, with higher doses of upadacitinib and abrocritinib showing greater efficacy than dupilumab at 12-16 weeks. This makes them attractive options to consider in patients who previously failed dupilumab.
• On the other hand, JAK-inhibitors have laboratory monitoring requirements, including complete blood count, comprehensive metabolic panel, lipid panel, etc.
• JAK-inhibitors warrant adverse-event monitoring for headache, nausea, acne, herpesvirus infections, risk of venous thromboembolism, etc.

Future research is needed to identify patient subsets who will benefit most from JAK-inhibitor therapy and where to position these agents in treatment guidelines.

Key clinical point: Janus kinase (JAK) inhibitors were safe and effective in reducing the intensity of signs and symptoms of atopic dermatitis (AD) with significant improvements observed for Eczema Area and Severity Index (EASI) and pruritus numerical rating scale (NRS) scores.

Major finding: Patients receiving JAK inhibitors showed significant improvements in both total EASI score (mean difference [MD], −0.31; 95% confidence interval [CI], −0.46 to −0.17) and pruritus NRS score (MD, −1.15; 95% CI, −1.48 to −0.83). The risk of total adverse events was not significantly different between JAK inhibitor and control groups (risk ratio, 1.02; P = .745).

Study details: Findings are from a meta-analysis of 10 randomized controlled trials including 2583 patients with AD, of which 1,761 were in JAK inhibitor and 822 in control groups.

Disclosures: The study did not report any source of funding. No conflicts of interest were reported.

Source: Miao M et al. J Dermatolog Treat. 2021 Jun 16. doi: 10.1080/09546634.2021.1942422.

Key clinical point: Janus kinase (JAK) inhibitors were safe and effective in reducing the intensity of signs and symptoms of atopic dermatitis (AD) with significant improvements observed for Eczema Area and Severity Index (EASI) and pruritus numerical rating scale (NRS) scores.

Major finding: Patients receiving JAK inhibitors showed significant improvements in both total EASI score (mean difference [MD], −0.31; 95% confidence interval [CI], −0.46 to −0.17) and pruritus NRS score (MD, −1.15; 95% CI, −1.48 to −0.83). The risk of total adverse events was not significantly different between JAK inhibitor and control groups (risk ratio, 1.02; P = .745).

Study details: Findings are from a meta-analysis of 10 randomized controlled trials including 2583 patients with AD, of which 1,761 were in JAK inhibitor and 822 in control groups.

Disclosures: The study did not report any source of funding. No conflicts of interest were reported.

Source: Miao M et al. J Dermatolog Treat. 2021 Jun 16. doi: 10.1080/09546634.2021.1942422.

Key clinical point: Janus kinase (JAK) inhibitors were safe and effective in reducing the intensity of signs and symptoms of atopic dermatitis (AD) with significant improvements observed for Eczema Area and Severity Index (EASI) and pruritus numerical rating scale (NRS) scores.

Major finding: Patients receiving JAK inhibitors showed significant improvements in both total EASI score (mean difference [MD], −0.31; 95% confidence interval [CI], −0.46 to −0.17) and pruritus NRS score (MD, −1.15; 95% CI, −1.48 to −0.83). The risk of total adverse events was not significantly different between JAK inhibitor and control groups (risk ratio, 1.02; P = .745).

Study details: Findings are from a meta-analysis of 10 randomized controlled trials including 2583 patients with AD, of which 1,761 were in JAK inhibitor and 822 in control groups.

Disclosures: The study did not report any source of funding. No conflicts of interest were reported.

Source: Miao M et al. J Dermatolog Treat. 2021 Jun 16. doi: 10.1080/09546634.2021.1942422.

Key clinical point: Analysis of serum biomarker profiles in pediatric patients with atopic dermatitis (AD) indicates the existence of unique endotypes that could predict patients at risk of persistent disease and guide personalized, endotype-driven therapeutic approaches.

Major finding: Distinct biomarker profiles identified Th2/retinol dominant (mean Eczema Area Severity Index [EASI] score: 9.2), skin-homing dominant (mean EASI score: 27.8), Th1/Th2/Th17/IL-1 dominant (mean EASI score: 10.5), and Th1/IL-1/eosinophil inferior (mean EASI score: 12.3) as the 4 distinct pediatric clusters. The clusters were influenced by disease severity and not age, with the skin-homing dominant cluster having more severe AD than other clusters (P less than .001).

Study details: Findings are from an analysis of biomarker profiles of 240 pediatric patients with AD aged 0-17 years compared with previously found profiles in adult patients with AD.

Disclosures: This study was funded by Regeneron and Sanofi-Genzyme pharmaceuticals, Inc. Dr. M de Graaf, Dr. MS de Bruin-Weller, Dr. DS Bakker, Dr. E Knol, and Dr. JL Thijs declared being speaker, principal investigator, consultant, and/or advisory board member for various sources including Sanofi-Genzyme and Regeneron.

Source: Bakker DS et al. J Allergy Clin Immun. 2021 Jul 6. doi: 10.1016/j.jaci.2021.06.029.

Key clinical point: Analysis of serum biomarker profiles in pediatric patients with atopic dermatitis (AD) indicates the existence of unique endotypes that could predict patients at risk of persistent disease and guide personalized, endotype-driven therapeutic approaches.

Major finding: Distinct biomarker profiles identified Th2/retinol dominant (mean Eczema Area Severity Index [EASI] score: 9.2), skin-homing dominant (mean EASI score: 27.8), Th1/Th2/Th17/IL-1 dominant (mean EASI score: 10.5), and Th1/IL-1/eosinophil inferior (mean EASI score: 12.3) as the 4 distinct pediatric clusters. The clusters were influenced by disease severity and not age, with the skin-homing dominant cluster having more severe AD than other clusters (P less than .001).

Study details: Findings are from an analysis of biomarker profiles of 240 pediatric patients with AD aged 0-17 years compared with previously found profiles in adult patients with AD.

Disclosures: This study was funded by Regeneron and Sanofi-Genzyme pharmaceuticals, Inc. Dr. M de Graaf, Dr. MS de Bruin-Weller, Dr. DS Bakker, Dr. E Knol, and Dr. JL Thijs declared being speaker, principal investigator, consultant, and/or advisory board member for various sources including Sanofi-Genzyme and Regeneron.

Source: Bakker DS et al. J Allergy Clin Immun. 2021 Jul 6. doi: 10.1016/j.jaci.2021.06.029.

Key clinical point: Analysis of serum biomarker profiles in pediatric patients with atopic dermatitis (AD) indicates the existence of unique endotypes that could predict patients at risk of persistent disease and guide personalized, endotype-driven therapeutic approaches.

Major finding: Distinct biomarker profiles identified Th2/retinol dominant (mean Eczema Area Severity Index [EASI] score: 9.2), skin-homing dominant (mean EASI score: 27.8), Th1/Th2/Th17/IL-1 dominant (mean EASI score: 10.5), and Th1/IL-1/eosinophil inferior (mean EASI score: 12.3) as the 4 distinct pediatric clusters. The clusters were influenced by disease severity and not age, with the skin-homing dominant cluster having more severe AD than other clusters (P less than .001).

Study details: Findings are from an analysis of biomarker profiles of 240 pediatric patients with AD aged 0-17 years compared with previously found profiles in adult patients with AD.

Disclosures: This study was funded by Regeneron and Sanofi-Genzyme pharmaceuticals, Inc. Dr. M de Graaf, Dr. MS de Bruin-Weller, Dr. DS Bakker, Dr. E Knol, and Dr. JL Thijs declared being speaker, principal investigator, consultant, and/or advisory board member for various sources including Sanofi-Genzyme and Regeneron.

Source: Bakker DS et al. J Allergy Clin Immun. 2021 Jul 6. doi: 10.1016/j.jaci.2021.06.029.

Key clinical point: Higher maternal serum 25-hydroxyvitamin D (25[OH]D) levels during pregnancy may be associated with increased risk for early-onset infant atopic dermatitis (AD).

Major finding: Overall, 26.5% of infants developed AD before 1 year of age. Higher maternal serum 25(OH)D levels during pregnancy were associated with increased risks for AD in infants before 1 year of age with borderline statistical significance, particularly in the first trimester (per ln unit increase, adjusted odds ratio [aOR], 1.93; 95% confidence interval [CI], 0.96-3.88) and the second trimester (per ln unit increase, aOR, 1.72; 95% CI, 0.93-3.19).

Study details: Findings are from the analysis of pregnant women from the MKFOAD birth cohort and their infants (n=456) who received routine child care visits at birth, day 42, and 6 and 12 months after birth.

Disclosures: This study was funded by Shanghai Public Health Three-Year Action Plan, National Key Research and Development Program, Canada-China Clinical Research Program, Collaboration Grant of Children’s Hospital of Fudan University, and Pigeon Maternal and Infant Skin Care Research Institute. The authors declared no conflicts of interest.

Source: Tian Y et al. Pediatr Allergy Immunol. 2021 Jun 23. doi: 10.1111/pai.13582. 

Key clinical point: Higher maternal serum 25-hydroxyvitamin D (25[OH]D) levels during pregnancy may be associated with increased risk for early-onset infant atopic dermatitis (AD).

Major finding: Overall, 26.5% of infants developed AD before 1 year of age. Higher maternal serum 25(OH)D levels during pregnancy were associated with increased risks for AD in infants before 1 year of age with borderline statistical significance, particularly in the first trimester (per ln unit increase, adjusted odds ratio [aOR], 1.93; 95% confidence interval [CI], 0.96-3.88) and the second trimester (per ln unit increase, aOR, 1.72; 95% CI, 0.93-3.19).

Study details: Findings are from the analysis of pregnant women from the MKFOAD birth cohort and their infants (n=456) who received routine child care visits at birth, day 42, and 6 and 12 months after birth.

Disclosures: This study was funded by Shanghai Public Health Three-Year Action Plan, National Key Research and Development Program, Canada-China Clinical Research Program, Collaboration Grant of Children’s Hospital of Fudan University, and Pigeon Maternal and Infant Skin Care Research Institute. The authors declared no conflicts of interest.

Source: Tian Y et al. Pediatr Allergy Immunol. 2021 Jun 23. doi: 10.1111/pai.13582. 

Key clinical point: Higher maternal serum 25-hydroxyvitamin D (25[OH]D) levels during pregnancy may be associated with increased risk for early-onset infant atopic dermatitis (AD).

Major finding: Overall, 26.5% of infants developed AD before 1 year of age. Higher maternal serum 25(OH)D levels during pregnancy were associated with increased risks for AD in infants before 1 year of age with borderline statistical significance, particularly in the first trimester (per ln unit increase, adjusted odds ratio [aOR], 1.93; 95% confidence interval [CI], 0.96-3.88) and the second trimester (per ln unit increase, aOR, 1.72; 95% CI, 0.93-3.19).

Study details: Findings are from the analysis of pregnant women from the MKFOAD birth cohort and their infants (n=456) who received routine child care visits at birth, day 42, and 6 and 12 months after birth.

Disclosures: This study was funded by Shanghai Public Health Three-Year Action Plan, National Key Research and Development Program, Canada-China Clinical Research Program, Collaboration Grant of Children’s Hospital of Fudan University, and Pigeon Maternal and Infant Skin Care Research Institute. The authors declared no conflicts of interest.

Source: Tian Y et al. Pediatr Allergy Immunol. 2021 Jun 23. doi: 10.1111/pai.13582. 

Key clinical point: Dupilumab with or without topical corticosteroids (TCS) was beneficial in adults with moderate-to-severe atopic dermatitis (AD) regardless of any prior use of systemic nonsteroidal immunosuppressants (NSISS).

Major finding: Compared with placebo with/without TCS, dupilumab with/without TCS showed significant improvement in Eczema Area and Severity Index, SCORing AD, Peak Pruritus Numerical Rating Scale, and quality of life in patients with/without prior use of NSISS (P less than .001) by week 16 which continued through week 52 of treatment.

Study details: Findings are from a post hoc analysis of 4 phase 3 clinical trials including 1553 patients with moderate-to-severe AD randomly assigned to placebo or dupilumab as monotherapy for 16 weeks or with concomitant TCS for 16/52 weeks.

Disclosures: This study was funded by Sanofi and Regeneron Pharmaceuticals, Inc. Some of the authors declared receiving grants, honoraria and serving as consultant or speaker or on advisory board for various sources. Some of the authors declared being employees and/or holding stocks/stock options at Sanofi, Regeneron Pharmaceuticals, Inc or Sanofi Genzyme.

Source: Griffiths C et al. Dermatol Ther (Heidelb). 2021 Jun 18. doi: 10.1007/s13555-021-00558-0.

Key clinical point: Dupilumab with or without topical corticosteroids (TCS) was beneficial in adults with moderate-to-severe atopic dermatitis (AD) regardless of any prior use of systemic nonsteroidal immunosuppressants (NSISS).

Major finding: Compared with placebo with/without TCS, dupilumab with/without TCS showed significant improvement in Eczema Area and Severity Index, SCORing AD, Peak Pruritus Numerical Rating Scale, and quality of life in patients with/without prior use of NSISS (P less than .001) by week 16 which continued through week 52 of treatment.

Study details: Findings are from a post hoc analysis of 4 phase 3 clinical trials including 1553 patients with moderate-to-severe AD randomly assigned to placebo or dupilumab as monotherapy for 16 weeks or with concomitant TCS for 16/52 weeks.

Disclosures: This study was funded by Sanofi and Regeneron Pharmaceuticals, Inc. Some of the authors declared receiving grants, honoraria and serving as consultant or speaker or on advisory board for various sources. Some of the authors declared being employees and/or holding stocks/stock options at Sanofi, Regeneron Pharmaceuticals, Inc or Sanofi Genzyme.

Source: Griffiths C et al. Dermatol Ther (Heidelb). 2021 Jun 18. doi: 10.1007/s13555-021-00558-0.

Key clinical point: Dupilumab with or without topical corticosteroids (TCS) was beneficial in adults with moderate-to-severe atopic dermatitis (AD) regardless of any prior use of systemic nonsteroidal immunosuppressants (NSISS).

Major finding: Compared with placebo with/without TCS, dupilumab with/without TCS showed significant improvement in Eczema Area and Severity Index, SCORing AD, Peak Pruritus Numerical Rating Scale, and quality of life in patients with/without prior use of NSISS (P less than .001) by week 16 which continued through week 52 of treatment.

Study details: Findings are from a post hoc analysis of 4 phase 3 clinical trials including 1553 patients with moderate-to-severe AD randomly assigned to placebo or dupilumab as monotherapy for 16 weeks or with concomitant TCS for 16/52 weeks.

Disclosures: This study was funded by Sanofi and Regeneron Pharmaceuticals, Inc. Some of the authors declared receiving grants, honoraria and serving as consultant or speaker or on advisory board for various sources. Some of the authors declared being employees and/or holding stocks/stock options at Sanofi, Regeneron Pharmaceuticals, Inc or Sanofi Genzyme.

Source: Griffiths C et al. Dermatol Ther (Heidelb). 2021 Jun 18. doi: 10.1007/s13555-021-00558-0.

Key clinical point: In real world clinical practice, combination of tacrolimus ointment and dupilumab was an effective and safe treatment option for facial atopic dermatitis (AD).

Major finding: On 16 weeks of treatment, a significant decrease was observed in average scores including Investigator’s Global Assessment, overall Eczema Area and Severity Index (EASI), and head/neck EASI (P less than .0001). Moreover, the rate of improvement in head/neck EASI scores significantly correlated with the rate of improvement in the overall EASI scores (Pearson’s r, 0.61; P less than .01). None of the patients developed herpes simplex, whereas 2 patients developed conjunctivitis.

Study details: Findings are from a retrospective chart review of 109 patients with moderate-to-severe AD who initiated dupilumab, of which 60 patients also used tacrolimus ointment. Of these, 20 patients used tacrolimus ointment without any topical steroids.

Disclosures: This work was supported by grants from Japan Society for the Promotion of Science. The authors did not declare any conflicts of interest.

Source: Matsutani M et al. J Dermatol. 2021 Jun 22. doi: 10.1111/1346-8138.16039.

Key clinical point: In real world clinical practice, combination of tacrolimus ointment and dupilumab was an effective and safe treatment option for facial atopic dermatitis (AD).

Major finding: On 16 weeks of treatment, a significant decrease was observed in average scores including Investigator’s Global Assessment, overall Eczema Area and Severity Index (EASI), and head/neck EASI (P less than .0001). Moreover, the rate of improvement in head/neck EASI scores significantly correlated with the rate of improvement in the overall EASI scores (Pearson’s r, 0.61; P less than .01). None of the patients developed herpes simplex, whereas 2 patients developed conjunctivitis.

Study details: Findings are from a retrospective chart review of 109 patients with moderate-to-severe AD who initiated dupilumab, of which 60 patients also used tacrolimus ointment. Of these, 20 patients used tacrolimus ointment without any topical steroids.

Disclosures: This work was supported by grants from Japan Society for the Promotion of Science. The authors did not declare any conflicts of interest.

Source: Matsutani M et al. J Dermatol. 2021 Jun 22. doi: 10.1111/1346-8138.16039.

Key clinical point: In real world clinical practice, combination of tacrolimus ointment and dupilumab was an effective and safe treatment option for facial atopic dermatitis (AD).

Major finding: On 16 weeks of treatment, a significant decrease was observed in average scores including Investigator’s Global Assessment, overall Eczema Area and Severity Index (EASI), and head/neck EASI (P less than .0001). Moreover, the rate of improvement in head/neck EASI scores significantly correlated with the rate of improvement in the overall EASI scores (Pearson’s r, 0.61; P less than .01). None of the patients developed herpes simplex, whereas 2 patients developed conjunctivitis.

Study details: Findings are from a retrospective chart review of 109 patients with moderate-to-severe AD who initiated dupilumab, of which 60 patients also used tacrolimus ointment. Of these, 20 patients used tacrolimus ointment without any topical steroids.

Disclosures: This work was supported by grants from Japan Society for the Promotion of Science. The authors did not declare any conflicts of interest.

Source: Matsutani M et al. J Dermatol. 2021 Jun 22. doi: 10.1111/1346-8138.16039.

Key clinical point: Baricitinib therapy resulted in clinically meaningful improvement in itch severity leading to significantly better quality of life (QoL) in patients with moderate-to-severe atopic dermatitis (AD).

Major finding: By week 16, higher proportion of patients receiving baricitinib 2 mg (25.2%; P less than .0001) and 1 mg (15.9%; P = .0114) vs placebo (5.7%) experienced improvements in itch severity. Higher proportion of patients with vs without itch improvement showed no impact of AD on QoL (P less than .0001).

Study details: Findings are from a post hoc analysis of phase 3 trial, BREEZE-AD5 involving 440 adults with moderate-to-severe AD who received baricitinib 1 mg, 2 mg, or placebo once daily.

Disclosures: This work was funded by Eli Lilly and Company. Some of the authors declared receiving grants, funding, consulting fees, and/or honoraria from and/or serving as board member, speaker, advisor, and/or investigator for various sources including Eli Lilly. Five of the authors declared being employees and shareholders of Eli Lilly.

Source: Lio PA et al. J Dermatolog Treat. 2021 Jun 28. doi: 10.1080/09546634.2021.1914308.

Key clinical point: Baricitinib therapy resulted in clinically meaningful improvement in itch severity leading to significantly better quality of life (QoL) in patients with moderate-to-severe atopic dermatitis (AD).

Major finding: By week 16, higher proportion of patients receiving baricitinib 2 mg (25.2%; P less than .0001) and 1 mg (15.9%; P = .0114) vs placebo (5.7%) experienced improvements in itch severity. Higher proportion of patients with vs without itch improvement showed no impact of AD on QoL (P less than .0001).

Study details: Findings are from a post hoc analysis of phase 3 trial, BREEZE-AD5 involving 440 adults with moderate-to-severe AD who received baricitinib 1 mg, 2 mg, or placebo once daily.

Disclosures: This work was funded by Eli Lilly and Company. Some of the authors declared receiving grants, funding, consulting fees, and/or honoraria from and/or serving as board member, speaker, advisor, and/or investigator for various sources including Eli Lilly. Five of the authors declared being employees and shareholders of Eli Lilly.

Source: Lio PA et al. J Dermatolog Treat. 2021 Jun 28. doi: 10.1080/09546634.2021.1914308.

Key clinical point: Baricitinib therapy resulted in clinically meaningful improvement in itch severity leading to significantly better quality of life (QoL) in patients with moderate-to-severe atopic dermatitis (AD).

Major finding: By week 16, higher proportion of patients receiving baricitinib 2 mg (25.2%; P less than .0001) and 1 mg (15.9%; P = .0114) vs placebo (5.7%) experienced improvements in itch severity. Higher proportion of patients with vs without itch improvement showed no impact of AD on QoL (P less than .0001).

Study details: Findings are from a post hoc analysis of phase 3 trial, BREEZE-AD5 involving 440 adults with moderate-to-severe AD who received baricitinib 1 mg, 2 mg, or placebo once daily.

Disclosures: This work was funded by Eli Lilly and Company. Some of the authors declared receiving grants, funding, consulting fees, and/or honoraria from and/or serving as board member, speaker, advisor, and/or investigator for various sources including Eli Lilly. Five of the authors declared being employees and shareholders of Eli Lilly.

Source: Lio PA et al. J Dermatolog Treat. 2021 Jun 28. doi: 10.1080/09546634.2021.1914308.