Complementary and Alternative Medicine for Atopic Dermatitis

An Evidence-Based Review

Brittany L. Vieira; Neil R. Lim; Mary E. Lohman; Peter A. Lio;

Am J Clin Dermatol. 2016;17(6):557-581.

Methods

A review of the medical literature was completed following the recommendations of the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement criteria.^[6] In conjunction with a research librarian, a search of PubMed, EMBASE, the Cochrane Central Register of Controlled Trials and Cochrane Database of Systemic Reviews, and the Global Resource for EczemA Trials (GREAT) databases was conducted through March 2015 to identify all studies reporting complementary or alternative therapies of AD. Medical subject headings (MeSH) used in the literature search included atopic dermatitis or atopic eczema and complementary therapies, alternative medicine, therapies, integrative medicine, natural, diet therapy, diet modification, nutrition therapy, dietary supplement, pyridoxine, vitamins, zinc, herb therapy, herbal medicine, homeopathy, massage, acupuncture, balneotherapy, phytotherapy, traditional Chinese medicine, aromatherapy, naturopathy, hypnosis, acupressure, oil, vitamin D, cryotherapy, hydrotherapy, and biofeedback, as well as permutations of these words found in the title or abstract.

The inclusion and exclusion criteria were prospectively limited to publications in the English language and randomized controlled trials (RCTs) of ten or more human subjects, and included adults, adolescents, children, or infants with AD. We excluded trials that did not assess the alternative or complementary therapy as the primary intervention to which the experimental group was exposed. Trials assessing probiotics were also excluded; while controversies remain, they have their own robust and more conventional literature. The primary outcomes of interest included clinical signs and symptoms, long-term control of flares, and quality of life.

The authors conducted a manual review of the titles and abstracts identified from the search. Details were independently obtained about the patient population, study design, intervention, and outcome measure. A study met inclusion criteria for this review if it was determined to be an RCT with a sample size of ≥10, if it evaluated an alternative therapy, and if it assessed clinical improvement of AD severity as the primary outcome; discrepancies were resolved by consensus. The authors obtained the full text of the studies for independent assessment and determined eligibility again after full-text review. Disagreements were resolved by discussion among all authors. The authors were not blinded to the names of authors, journals, or institutions.

Authors' conclusions are based on available evidence.

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Next Section

Abstract and Introduction
Methods
Results and Implications for Future Research
Discussion
Conclusions
References
Sidebar

Table 1. Acupuncture and acupressure
References	Treatment	Study design	Number of patients enrolled	Duration (weeks)	Baseline AD assessment	Assessment of AD improvement	Age range (years)	Results	Adverse effects
Lee et al. [11]	Acupressure	Ran, contr, sc, nb	15	4	AD, VAS, IGA, EASI	VAS, IGA, EASI	19–79	Acupressure significantly improved pruritus and lichenification scores compared with control group	None
Pfab et al. [9]	VA	Ran, sc, db, contr, triple crossover	30	Not listed	AD, SCORAD >18	EIQ, wheel and flare response size via laser Doppler	18–50	VA significantly reduced type I hypersensitivity itch compared with placebo and no treatment	Not listed
Pfab et al. [10]	VA vs. oral antihistamine (cetirizine)	Ran, sc, db, contr, crossover	20	Not listed	AD, physician diagnosed, SCORAD >20	VAS, EIQ	18–50	Both VA and cetirizine significantly reduced type I hypersensitivity itch compared with placebo and no treatment. Abortive VA was more effective than preventive VA or cetirizine	Not listed

AD atopic dermatitis, contr controlled, db double blinded, EASI Eczema Area and Severity Index, EIQ Eppendorf Itch Questionnaire, IGA Investigator Global Assessment, nb nonblinded, Ran randomized, sc single center, SCORAD SCORing Atopic Dermatitis, VA verum acupuncture, VAS visual analog scale

Table 2. Hypnotherapy, relaxation, and massage
References	Treatment	Study design	Number of patients enrolled	Duration (weeks)	Baseline AD assessment	Assessment of AD improvement	Age range (years)	Results	Adverse effects
Anderson et al. [19]	Massage therapy with or without aromatherapeutic essential oils	Ran, db, contr	16	8	Refractory AD, NS	Day-time irritation scores, night-time disturbance score, assessed by mother; general improvement scores by therapist, mother and GP	3–7	General improvement scores showed no significant difference between essential oil group and massage only control group	Worsening of night-time disturbance in essential oil group after subsequent sessions beyond 8 weeks
Bae et al. [18]	Standard of care with or without progressive muscle relaxation therapy	Ran, sc, contr, nb	25	4	At least moderate extrinsic AD, HRC	EASI, VAS, LOS	12–40	Progressive muscle relaxation significantly reduced pruritus and LOS from baseline. No significant difference in improved EASI scores between groups	Not listed
Ehlers et al. [16]	Educational program (DE) vs. autogenic training (AT) vs. cognitive-behavioral treatment (BT) vs. combined DE and BT (DE/BT)	Ran, contr, sc, ib, parallel	113	52	AD, HRC	Standardized disease severity score, amount of corticosteroids used, patient self-reported itching, Marburg Atopic Dermatitis Questionnaire, patient global disability rating	17–55	AT, BT, and DE/BT significantly reduced disease severity and amount of topical steroids used far greater than DE alone or standard medical care control	Not listed
Miller and Coger [14]	Training for increasing vs. decreasing skin conductance	Ran, parallel, ib, sc	33	4	Diagnosis of dyshidrotic eczema	Investigator assessment using 6-point standard clinical scale, skin conductance, anxiety levels via STAI	Male: mean 28.7; female: mean 32.5	Patients who were trained to decrease skin conductance showed significant improvement in disease severity, while patients trained to increase skin conductance showed worsened severity	Eczema exacerbations
Schachner et al. [17]	Standard topical care with or without massage therapy	Ran, contr, sc, ib, parallel	20	4	AD, HRC	Behavior Observation Assessments, global/focal dermatologist assessments	2–8	Massage significantly improved redness, scaling, lichenification, excoriation, and pruritus compared with control	Not listed
Schut [15]	Cognitive behavioral stress management therapy	Ran, sc, ib, contr	28	14	AD, HRC	SCORAD, salivary cortisol, Multidimensional Mood Questionnaire	Not listed	Cognitive behavioral stress management therapy showed no significant improvement in disease severity over non-treatment group	None
Sokel et al. [13]	Hypnotherapy vs. biofeedback	Ran, ib, sc, parallel, contr	44	20	Refractory AD, NS	Scoring sheets for erythema, surface damage, and lichenification assessed by dermatologist	5–15	Both hypnotherapy and biofeedback groups had significant reduction in surface damage and lichenification compared with control group. Neither treatment group was better than the other	Not listed

AD atopic dermatitis, contr controlled, db double blinded, EASI Eczema Area and Severity Index, GP general practitioner, HRC Hanifin and Rajka's criteria, ib investigator blinded, LOS loss of sleep, nb nonblinded, NS not specified, Ran randomized, sc single center, SCORAD SCORing Atopic Dermatitis, STAI State-Trait Anxiety Inventory, VAS visual analog scale

Table 3. Balneotherapy
References	Treatment	Study design	Number of patients enrolled	Duration (weeks)	Baseline AD assessment	Assessment of AD improvement	Age range	Results	Adverse effects
Farina et al. [26]	Balneotherapy vs. TCS	Ran, nb, sc, parallel	104	2	Mild to moderate AD, SCORAD, IGA, PSGA, CDLQI, FDIQ	SCORAD, IGA, PSGA, CDLQI, FDIQ	1–14 years	Both treatments significantly improved disease severity. TCS showed significant improvements in SCORAD; however, no significant difference between groups in IGA, PSGA and CDLQI and FDIQ. Balneotherapy patients had fewer relapses post-treatment at 4 months	Mild erythema and burning sensation
Heinlin et al. [25]	Synchronous balneophototherapy vs. narrow-band UVB monotherapy	Ran, mc, nb, contr	180	24	AD, dermatologistdiagnosed, SCORAD >35	SCORAD, Sickness Impact Profile, 6-step Likert scale, FLQA	≥18 years, mean 41	Synchronous balneophototherapy significantly reduced AD severity compared with narrow-band UVB monotherapy	Erythema, light dermatoses, gastrointestinal diseases, infections and parasitic diseases, sunburn. Tolerability comparable among both groups
Thomas et al. [23]	Normal eczema care with or without ion-exchange water softeners	Ran, mc, contr, crossover, ib	336	16	AD, physician diagnosed, SASSAD ≥10	SASSAD score, POEM, Dermatitis FDIQ, EQ-5D, filaggrin saliva sample	6 months–16 years	Ion-exchange water softeners provide no additional benefit to normal eczema care	Not listed
Togawa [24]	Ultra-pure soft water	Ran, db, pc, crossover	12	14	Mild to moderate AD, EASI score ≤20	EASI, VAS, TEWL, serum biomarkers, out-in skin transparency	3–6 years	Ultra-pure soft water significantly improved pruritus and out-in skin transparency compared with placebo, but not eczema severity	Not listed

AD atopic dermatitis, contr controlled, db double blinded, CDLQI Children's Dermatology Life Quality Index, EASI Eczema Area and Severity Index, EQ-5D European Quality of Life-5 Dimensions, FDIQ Family Dermatitis Impact Questionnaire, FLQA Freiburg Life Quality Assessment, ib investigator blinded, IGA Investigator Global Assessment, mc multicenter, nb nonblinded, pc placebo controlled, POEM Patient-Oriented Eczema Measure, PSGA Patient's Self Global Assessment, Ran randomized, SASSAD Six Area, Six Sign Atopic Dermatitis Severity Score, sc single center, SCORAD SCORing Atopic Dermatitis, TCS topical corticosteroids, TEWL transepidermal water loss, VAS visual analog scale

Table 4. Herbal therapy
References	Treatment	Study design	Number of patients enrolled	Duration (weeks)	Baseline AD assessment	Assessment of AD improvement	Age range (years)	Results	Adverse effects
Cheng et al. [30]	Chinese herbal product (oral Xiao-Feng-San)	Ran, db, pc, sc	71	8	Refractory AD, HRC	Standardized disease scoring system, patient self-reporting of itch and sleep loss	Mean 13.1	Xiao-Feng-San significantly lessened disease severity, itch, and sleep loss compared with placebo	None other than unpalatability
Choi et al. [31]	Oral herbal formula TJ-15 with and without herbal formula TJ-17	Ran, db, parallel, sc	24	4	Dampness-heat pattern AD, physician-diagnosed, HRC	SCORAD, EASI	5–32	Both SCORAD and EASI results showed more improvement in treatment group vs. control, but difference not of statistical significance. Symptom severity decreased in both groups, changes were similar and not significant	None
Fung et al. [35]	Traditional Chinese oral herbal medicine (Zemaphyte)	Ran, pc, crossover, db, double-center	40	20	Moderate to severe, refractory AD, HRC	Unspecified standardized disease scoring system	7–50	Zemaphyte did not result in a significant treatment effect over placebo	Minor transient dizziness, gastrointestinal upset
Henderson et al. [36]	Chinese herbal infusion vs. freeze-dried preparation of Chinese herbal infusion (oral)	Ran, nb, sc, parallel, no control	32	8	Moderate to severe refractory AD, NS	Standardized disease scoring system, CD4/CD8 circulating lymphocytes	17–60	Both herbal preparations were similarly effective in reducing eczema symptoms, but study was performed without control	Bad taste, nausea, dizziness, mild abdominal discomfort, loose bowels, flatulence
Hon et al. [38]	Traditional Chinese oral herbal medicine (5 herb extracts)	Ran, db, pc, sc	85	12	Moderate to severe AD, SCORAD >15	SCORAD, Allergic Rhinitis Score, serum biomarkers, CDLQI, corticosteroid use	5–21	Traditional Chinese herbal medicine did not significantly decrease disease symptoms or severity, but did improve the CLDQI and decrease corticosteroid use compared with placebo	None
Klovekorn et al. [45]	Topical herbal ointment with Mahonia aquifolium, Viola tricolor, and Centella asiatica	Ran, db, vehicle-controlled, sc	88	4	Mild to moderate AD, HRC with RLC	Standard severity scale, VAS, IGA	18–65	Herbal ointment did not significantly reduce symptoms compared with vehicle control	None
Kobayashi et al. [37]	Hochu-ekki-to oral herbal medicine	Ran, db, pc, mc	91	24	Patients with Kikyo and moderate-severe AD, physician-diagnosed with JDA	JDA scoring system, amount of topical agents used per day (TEA)	20–40	Hochu-ekki-to significantly reduced dose of topical steroids and/or tacrolimus without aggravating AD	Nausea, diarrhea, stomach discomfort in both groups, without statistical difference
Patzelt-Wenczler and Ponce-Poschl [43]	Topical Kamillosan cream vs. 0.5 % hydrocortisone	Ran, partially db, vehicle-controlled, sc, phase III	72	2	Moderate to severe AD, NS	Standardized disease severity score, IGA	Mean 45.5	Kamillosan produced mild symptom improvement compared with 0.5 % hydrocortisone, but only marginal difference compared with placebo	Not listed
Ramirez-Bosca et al. [41]	Oral Polypodium leucotomos (PL) extract	Ran, db, pc, mc, phase IV	105	24	AD, HRC, SCORAD between 20 and 40 inclusive	Amount of additional corticosteroid use, IGA, SCORAD, frequency of and time to first flare-up	2–17	Oral PL extract significantly reduced oral antihistamine use, but did not significantly reduce use of corticosteroids compared with placebo	Mild and moderate adverse effects were more common in placebo group than PL extract group
Saeedi et al. [44]	Topical 2 % licorice extract vs. 1 % licorice extract vs. placebo	Ran, db, pc, sc	108	2	Mild to moderate AD, NS	IGA	16–53	Both 1 and 2 % licorice extract significantly reduced erythema, edema, and itching compared with placebo. 2 % extract was more effective than 1 % extract	None
Shapira et al. [39]	Tri-herbal combination of oral Eleutherococcus senticosus, Achillea millefolium, and Lamium album	Ran, db, pc, sc	49	2	Moderate AD	SCORAD, body surface area, intensity score, subjective score	>1	Herbal combination group demonstrated no significant difference in disease compared with placebo	None listed
Schempp et al. [42]	Topical St. John's wort cream	Ran, db, half-side comparison, vehicle-controlled, sc	21	4	Mild to moderate AD, SCORAD <80	SCORAD, bacterial colonization of skin lesions, skin tolerance	12–59	St. John's wort cream significantly reduced disease intensity compared with vehicle control. Staphylococcus aureus skin colonization reduction was greater in treatment group, but did not reach statistical significance	Acute episode of AD, contact eczema
Sheehan and Atherton [33]	Traditional Chinese oral herbal therapy (Zemaphyte)	Ran, db, pc, crossover, sc	47	20	Moderate-severe refractory AD, NS	Unspecified disease scoring system	1.5–18.1	Zemaphyte resulted in significant improvement in erythema, surface area of involvement and subjective itching and loss of sleep when compared with placebo	Unpalatable but no hematological, renal or hepatic toxicity
Sheehan et al. [34]	Traditional Chinese oral herbal therapy (Zemaphyte)	Ran, db, pc, crossover, sc	40	20	Refractory AD, HRC	Standardized disease scoring system, serum biomarkers, patient self-reports	16–65	Zemaphyte resulted in significant improvement in erythema and surface damage, as well as subjective improvement in itch and loss of sleep compared with placebo	Unpalatable, mild abdominal distension, headaches
X et al. [32]	Chinese oral herbal medicine with and without flying needle acupuncture	Ran, sc	60	12	Mild to severe AD, NS	SCORAD	12–65	Both treatments resulted in significant improvement in disease severity. No significant difference in improvement between groups	Nausea, dizziness, vomiting, fatigue, headaches

AD atopic dermatitis, db double blinded, CDLQI Children's Dermatology Life Quality Index, EASI Eczema Area and Severity Index, HRC Hanifin and Rajka's criteria, IGA Investigator Global Assessment, JDA Japanese Dermatological Association, mc multicenter, nb nonblinded, NS not specified, pc placebo controlled, Ran randomized, RLC Rajka and Langeland criteria, sc single center, SCORAD SCORing Atopic Dermatitis, TEA total equivalent amount, TJ-15 Hwang-Yeon-Hae-Dok-San, TJ-17 Ou-Ryung-San, VAS visual analog scale

Table 5. Topical oils
References	Treatment	Study design	Number of patients enrolled	Duration (weeks)	Baseline AD assessment	Assessment of AD improvement	Age range	Results	Adverse effects
Anstey et al. [55]	Topical evening primrose oil	Ran, db, pc, half-side comparison, sc	12	2	Mild to moderate AD, NS	Patient self-assessment, IGA	4–46 years	Evening primrose oil significantly improved subjective patient symptom scores. Improvement of physician-assessed symptoms did not reach significance	None
Danby et al. [48]	Olive oil vs. sunflower seed oil	Ran, half-side comparison, ib, sc, parallel	19	5	AD, NS	Skin-surface pH, stratum corneum hydration, erythema, TEWL	Cohort 1: mean 46 years; cohort 2: mean 34 years	Olive oil significantly reduced stratum corneum integrity and induced erythema. Sunflower seed oil preserved stratum corneum integrity and improved skin hydration	Olive oil: erythema
De Belilovsky et al. [47]	2 % sunflower oleodistillate cream vs. hydrocortisone butyropropionate 1 mg/g	Ran, nb, sc, ib, parallel	80	3	Mild to moderate AD, SCORAD between 15 and 60	SCORAD, IGA, QoL questionnaire, Infant's DLQI, FDIQ	3 months–4 years	2 % sunflower oleodistillate cream exhibits improvement in disease severity and QoL comparable to topical steroid	None
Evangelista et al. [53]	Topical virgin coconut oil vs. mineral oil	Ran, db, sc, parallel	117	8	Mild to moderate AD, HRC	SCORAD, TEWL, skin capacitance	1–13 years	Both treatment groups significantly improved SCORAD, TEWL, and skin capacitance scores compared with baseline. Virgin coconut oil was significantly superior on all accounts compared with mineral oil after 8 weeks	Mineral oil: erythema, pruritus; virgin coconut oil: no events; however, no statistically significant difference in events between groups
Ferreira et al. [56]	Nioleol vs. Uriage vs. Atoderm: 3 emollients containing gammalinolenic acid	Ran, contr, parallel, nb, sc	23	12	AD in clinical remission (no eczema), NS	Standard disease severity score, TEWL, cutaneous hydration	3–15 years	All 3 emollients with gamma-linolenic acid and control emollient improved symptom severity and TEWL, but no treatment group reached statistical significance vs. control. All 3 treatment groups did significantly improve cutaneous hydration vs. control	None listed
Kanehara et al. [57]	Undershirts coated with borage oil	Ran, db, pc, sc	32	2	Mild to moderate AD, HRC, standardized disease severity score	Standardized disease severity score, TEWL	1–10 years	Undershirts coated with borage oil significantly improved symptoms of erythema, itch, and TEWL compared with baseline, while placebo group not significantly different from baseline	None
Korting et al. [58]	Pale sulfonated shale oil cream, 4 %	Ran, mc, vehicle-controlled, nb	99	4	Mild to moderate AD, standardized disease severity score <21	Standardized disease severity score	0–12 years	Pale sulfonated shale oil cream significantly improved disease symptoms compared with vehicle control	Bacterial superinfection, itch, erythema. Comparable effects in both treatment and vehicle
Verallo-Rowell et al. [52]	Virgin coconut oil vs. virgin olive oil	Ran, db, double center, parallel	52	4	AD, modified HRC, SCORAD (O-SSI)	SCORAD (OSSI), Staphylococcus aureus cultures, photography	18–40 years	Both coconut oil and olive oil reduced Staphylococcus aureus colonies and improved disease severity, but coconut oil was significantly superior to olive oil	Olive oil: contact dermatitis; coconut oil: none

AD atopic dermatitis, contr controlled, db double blinded, DLQI Dermatology Life Quality Index, FDIQ Family Dermatitis Impact Questionnaire, HRC Hanifin and Rajka's criteria, ib investigator blinded, IGA Investigator Global Assessment, mc multicenter, nb nonblinded, NS not specified, O-SSI Objective-SCORAD Severity Index, pc placebo controlled, QoL quality of life, Ran randomized, sc single center, SCORAD SCORing Atopic Dermatitis, TEWL transepidermal water loss

Table 6. Oral oils and fatty acid supplementation
References	Treatment	Study design	Number of patients enrolled	Duration (weeks unless otherwise stated)	Baseline AD assessment	Assessment of AD improvement	Age range	Results	Adverse effects
Evening primrose oil
Bamford et al. [68]	Evening primrose oil	Ran, db, crossover, pc, sc	154	12	''Active'' AD (specific criteria listed)	Standardized disease severity score, amount of topical steroid used, patient self-assessment of appetite and stress	2–66 years	Evening primrose oil did not significantly improve disease severity compared with placebo	Nausea, bloating, hyperactivity, eczema exacerbation
Berth-Jones and Graham-Brown [70]	Evening primrose oil with or without fish oil	Ran, pc, parallel, db, sc	123	16	AD, HRC, Leicester score (described)	Leicester score, Costa score, amount of topical steroid usage, patient self-assessment, VAS	7 months–60 years	Evening primrose oil with and without fish oil did not significantly improve disease symptoms compared with placebo	Eczema exacerbation, nausea, diarrhea
Biagi et al. [71]	High vs. low dose evening primrose oil	Ran, pc, db, sc	51	8	AD, HRC	Simple standardized disease severity score, erythrocyte microviscosity	2.2–8.5 years	High dose evening primrose oil significantly reduced disease severity compared with placebo and low dose primrose oil	None
Bordoni et al. [64]	Evening primrose oil	Ran, pc, db, sc	24	4	AD, NS. Assessed by simple physician scoring system	Simple physician scoring system	2–4 years	Evening primrose oil significantly improved eczema symptoms compared with placebo	None
Chung [72]	High vs. low dose evening primrose oil	Ran, parallel, sc, nb	40	8	AD, HRC, EASI score between 3 and 9	EASI	2–15 years	High dose evening primrose oil significantly improved disease symptoms. Low dose evening primrose oil improved symptoms, but failed to reach statistical significance	None
Humphreys et al. [66]	Evening primrose oil	Ran, db, parallel, pc, sc	58	16	Moderate-severe AD, HRC	Standardized disease scoring system, BSA, amount of topical corticosteroid used, serum biomarkers, patient self-assessment, VAS	16–64 years	Evening primrose oil significantly improved erythema and surface damage compared with placebo, but not lichenification	Diarrhea, worsening eczema, urticarial rash
Schalin-Karrila et al. [65]	Evening primrose oil	Ran, db, pc, sc	25	12	Moderate to severe AD, physician diagnosis (NS)	Standardized disease severity score, serum biomarkers	19–31 years	Both primrose oil and placebo significantly improved disease severity, inflammation, dryness, and itch. Response to treatment was significantly greater in every clinical parameter in the primrose oil group	None
Senapati et al. [67]	Evening primrose oil	Ran, sc, pc	25	20	AD, HRC, BSA, standardized disease severity scoring system	Intensity Item Score Aggregate score (described)	4 months–46 years	Evening primrose oil significantly improved all measured disease symptoms. Placebo also significantly improved some disease symptoms, to a lesser degree. The difference in outcome between groups was statistically significant	None
Wright and Burton [73]	High vs. low dose evening primrose oil	Ran, db, pc, crossover, sc	99: 39 children (20 low dose, 19 high dose; 60 adults (20 high dose, 20 moderate dose, 20 low dose)	24	Moderate to severe AD, HRC	VAS, IGA, patient self-assessment	0.7–14 years; 16–60 years	High dose evening primrose oil improved patients' subjective evaluation of itch, scaling, and overall severity, and physician assessment of overall severity. Low dose evening primrose oil significantly improved only itch	None attributed to treatment
Borage oil
Henz et al. [61]	Borage oil	Ran, db, mc, pc	160	24	Stable, moderate AD, HRC, Costa score 20–36 points	Costa score, amount of corticosteroid usage until response, serum biomarkers	14–65 years	Overall response to borage oil did not reach statistical significance	Headache, nausea, diarrhea, vomiting, increased serum cholesterol and triglycerides
Takwale et al. [62]	Borage oil	Ran, db, pc, sc	151	12	AD, HRC, SASSAD score	SASSAD score, VAS, patient self-assessment, amount of corticosteroids used	>2 years	Borage oil did not provide any significant benefit over placebo in any outcome measure	Upper RTI, diarrhea, nausea, vomiting, abdominal pain, asthma, allergic rhinitis, urticarial, rash, musculoskeletal pains, skin sepsis, fever, headache
Valsecchi et al. [63]	Borage oil	Ran, pc, nb, sc	31	14	AD, HRC	Standardized disease severity score, BSA, IgE levels	2–38 years	Both borage oil and placebo significantly improved disease symptoms compared with baseline. However, there was no statistically significant difference between treatment and placebo outcomes	None listed
Fish oil
Bjorneboe et al. [75]	Eicosapentaenoic acid dietary supplementation	Ran, db, pc, sc	31	12	Moderate to severe AD, HRC	Standardized disease severity scale, patient self-assessment, amount of topical steroid used, serum biomarkers	16–56 years	Eicosapentaenoic acid supplementation significantly improved subjective manifestations of disease severity compared with placebo. Objective evaluation showed symptom improvement, but failed to reach statistical significance	Not listed
Mayser et al. [74]	n-3 (eicosapentaenoic acid) vs. n-6 fatty acid-based lipid IV infusion	Ran, db, pc, sc	22	10 days	Moderate to severe AD, HRC, BSA	Standardized disease severity scoring system, patient self-assessment	18–34 years	Both treatments showed improvement from baseline; however, change was significantly more pronounced in the n-3 group when compared with the n-6 group. Of note, patients who received n-3 treatment experienced greater relapse post-treatment when compared with the n-6 group, which showed nearly constant long-term improvement in post-treatment phase	Vertigo, whistling in ears, pallor, hypertriglyceridemia, oily taste
Soyland et al. [76]	Fish oil supplement	Ran, db, mc, pc, parallel	145	16	Moderate to severe AD, HRC	Standardized disease severity score, patient self-assessment, IgE levels	18–64 years	Fish oil and placebo both significantly improved disease symptoms. There was no statistically significant difference between treatment and placebo	Not listed
Other oils
Callaway et al. [77]	Dietary hempseed oil	Ran, ib, crossover, sc, contr	20	20	AD, HRC	Patient self-assessment of itch and loss of sleep, TEWL, amount of dermal medication used	25–60 years	Dietary hempseed oil significantly improved subjective evaluations of skin dryness and itching, and reduced dermal medication usage	Bad taste
Gimenez-Arnau et al. [79]	Linolenic acid vs. eicosapentaenoic acid with DHA	Ran, parallel, db, pc, sc	48	12	Chronic and severe AD, RLC ≥7	RLC, BSA, punch biopsy	Mean 24.2 years	Only linolenic acid significantly reduced symptom severity compared with placebo	Nausea, vomiting, bad taste, severe itch, eczema worsening
Koch et al. [78]	DHA supplementation	Ran, db, pc, sc	53	8	AD, HRC, SCORAD	SCORAD, IgE production	18–40 years	DHA supplementation resulted in significant clinical improvement. Placebo also improved symptoms compared with baseline, but did not reach significance	Slight gastrointestinal discomfort

AD atopic dermatitis, BSA body surface area, contr controlled, db double blinded, DHA docosahexaenoic acid, EASI Eczema Area and Severity Index, HRC Hanifin and Rajka's criteria, ib investigator blinded, IGA Investigator Global Assessment, mc multicenter, nb nonblinded, NS not specified, pc placebo controlled, Ran randomized, RLC Rajka and Langeland criteria, SASSAD Six Area, Six Sign Atopic Dermatitis Severity Score, sc single center, SCORAD SCORing Atopic Dermatitis, TEWL transepidermal water loss, VAS visual analog scale

Table 7. Vitamins and minerals
References	Treatment	Study design	Number of patients enrolled	Duration (weeks)	Baseline AD assessment	Assessment of AD improvement	Age range	Results	Adverse effects
Vitamin B
Januchowski [91]	Topical vitamin B₁₂	Ran, db, pc, half-sided comparison, sc	22	4	AD, modified SCORAD	Modified SCORAD	6 months–18 years	Topical vitamin B₁₂ significantly improved disease symptoms compared with placebo	Localized skin reaction in 1 patient on both treatment and placebo arms
Stucker et al. [92]	Topical vitamin B₁₂	Ran, pc, phase III, mc, half-sided comparison, db	49	8	Chronic AD, HRC, modified SASSAD score	SASSAD score, investigator assessment, patient self-assessment	18–70 years	Both topical vitamin B₁₂ and placebo significantly reduced the extent and severity of disease, but topical vitamin B₁₂ showed significant superiority over placebo	Burning, itching, redness, hyperthermia, formication, swelling
Mabin et al. [81]	Pyridoxine hydrochloride	Ran, db, pc, sc	48	4	Moderate to severe AD, HRC	BSA, standardized disease severity score, parental overall assessment, parental assessment of sleep quality	2.2–15.2 years	Pyridoxine hydrochloride did not significantly improve disease symptoms compared with placebo	Erythematous rash
Vitamin D
Amestejani et al. [85]	Vitamin D (1600 IU/day) supplementation	Ran, db, pc, sc	60	8.67	Mild to severe AD, HRC, SCORAD	SCORAD, Three Item Severity Score	Mean 23.3 years	Vitamin D group showed significant improvement in disease symptoms compared with baseline, while placebo group showed no significant improvement. Groups not statistically compared	None listed
Camargo et al. [86]	Vitamin D (1000 IU/day) supplementation	Ran, db, pc, mc	107	4	Winter-related AD, EASI 10 to 72	EASI, IGA, parental assessment	2–17 years	Vitamin D significantly improved disease symptoms compared with placebo. Patients studied were Mongolian children, a population likely to be vitamin- D deficient in wintertime	None
Hata et al. [87]	Vitamin D (4000 IU/day) supplementation	Ran, mc, pc, db	Subset of 30 with AD	3	Moderate to severe AD, RLC from 4 to 9	EASI, punch biopsy, serum biomarkers	Mean 31.2 years	Vitamin D did not significantly improve disease symptoms	None related to treatment
Javanbakht et al. [89]	Vitamin D (1600 IU/day) with and without vitamin E (600 IU/day)	Ran, db, pc, mc	45	8.5	AD, HRC, SCORAD 10–70	SCORAD, amount of topical steroid usage	13–45 years	Vitamin D alone, vitamin E alone, and vitamin D and E together all significantly improved disease symptoms compared with placebo. Combination vitamin D and vitamin E demonstrated greatest improvement	One event of eczema exacerbation with vitamin E alone
Sidbury et al. [88]	Vitamin D (1000 IU/day) supplementation	Ran, pc, sc, db	11	4	Mild AD to moderate AD, EASI from 10 to 18.6	IGA	2–13 years	Vitamin D did not significantly improve disease symptoms compared with placebo	None
Minerals
Ewing et al. [83]	Oral zinc sulphate	Ran, db, pc, sc	50	8	AD, HRC	BSA, standardized disease severity score, amount of topical steroids and emollients used, patient self-assessment	1–16 years	Zinc sulphate did not significantly improve disease symptoms compared with placebo	Eczema exacerbation, itchy maculopapular rash
Faghihi et al. [90]	0.05 % clobetasol with and without 2.5 % zinc sulphate	Ran, db, parallel, double center	47	2	Patients with both-sided chronic hand eczema of similar severity for longer than 4 weeks	Standardized disease severity scale, VAS	17–74 years	Both treatments significantly improved disease symptoms. Clobetasol with zinc sulphate was significantly more effective on all assessments. Recurrence rate was significantly lower in patients treated with combination treatment	None
Fairris et al. [82]	Selenium with or without vitamin E supplementation	Ran, db, pc, parallel, sc	60	12	Moderate to severe AD, NS. Standardized disease scoring system	Standardized disease scoring system, skin biopsy	≥18 years	Neither selenium with vitamin E nor selenium alone significantly improved disease symptoms compared with placebo	None listed

AD atopic dermatitis, BSA body surface area, db double blinded, EASI Eczema Area and Severity Index, HRC Hanifin and Rajka's criteria, IGA Investigator Global Assessment, mc multicenter, NS not specified, pc placebo controlled, Ran randomized, RLC Rajka and Langeland criteria, SASSAD Six Area, Six Sign Atopic Dermatitis Severity Score, sc single center, SCORAD SCORing Atopic Dermatitis, VAS visual analog scale

Table 8. Miscellaneous
References	Treatment	Study design	Number of patients enrolled	Duration (weeks)	Baseline AD assessment	Assessment of AD improvement	Age range	Results	Adverse effects
Kwon [96]	Cyclosporin with or without glucosamine	Ran, crossover without washout, sc, ib	12	24	Patients with refractory AD who required systemic cyclosporine. NS	SCORAD, serum biomarkers	13–41 years	Cyclosporin combined with glucosamine improved symptoms better than cyclosporine alone, but not to a statistically significant degree	None
Schoni et al. [94]	Bioresonance therapy	Ran, sc, pc, db	32	4	AD, HRC, Costa score	Costa score, parental and investigator assessment of pruritus intensity and sleep quality, serum biomarkers, general questionnaire	1.5–16.8 years	Bioresonance therapy showed no statistically significant improvement of disease severity compared with sham therapy	None
Tripodi et al. [95]	Topical furfuryl palmitate	Ran, db, vehicle-controlled, mc	117	2	AD, UK Working Party Diagnostic Criteria, SCORAD	SCORAD, parent questionnaire, physician questionnaire	3 months–14 years	Furfuryl palmitate and vehicle control both significantly improved symptoms. Vehicle control was more efficacious overall	Itching, burning
Vita et al. [97]	Ass's milk vs. goat's milk	Ran, crossover, single-blind, contr, sc	28	36	Mild to severe AD, SCORAD >20	SCORAD, VAS	6 months–3 years	Ass's milk significantly improved disease symptoms when compared with both placebo and goat's milk, whereas goat's milk (control) had no measurable clinical effect	Urticaria, angioedema, eczema exacerbation, wheezing, rhinitis, vomiting, abdominal pain, diarrhea

AD atopic dermatitis, contr controlled, db double blinded, HRC Hanifin and Rajka's criteria, ib investigator blinded, mc multicenter, NS not specified, pc placebo controlled, Ran randomized, sc single center, SCORAD SCORing Atopic Dermatitis, VAS visual analog scale

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