A systematic review of contact dermatitis treatment and prevention

CLINICAL

REVIEW

A systematic review of contact dermatitis treatment and prevention Joan Saary, MD, MSc, FRCPC,a,b Roohi Qureshi, MD, MEng, FRCPC,a,b Valerie Palda, MD, MSc, FRCPC,c Joel DeKoven, MD, MHSc, FRCPC,a,b Melanie Pratt, MD, FRCPC,d,e Sandy Skotnicki-Grant, MD, FRCPC,a,b and Linn Holness, MD, MHSc, FRCPCa,b Toronto and Ottawa, Ontario, Canada Background: Contact dermatitis (CD) is a common occupational disease. There have been no systematic reviews of CD treatment or prevention. Methods: Multiple databases were systematically searched. Using independent double review and published quality review criteria, articles were rated as good, fair, or poor. Treatment benefit data were tabulated and conclusions were based on the rated strength of published evidence. Results: In all, 49 studies met inclusion criteria. Barrier creams containing dimethicone or perfluoropolyethers, cotton liners, and softened fabrics prevent irritant CD. Lipid-rich moisturizers both prevent and treat irritant CD. Topical skin protectant and quaternium 18 bentonite (organoclay) prevent rhus dermatitis. Diethylenetriamine pentaacetic acid (chelator) cream prevents nickel, chrome, and copper dermatitis. Potent or moderately potent steroids effectively treat allergic CD. There were no macrolide immunomodulator trials that met inclusion criteria. This review did not include studies of children, animals, or non-English language publications. Conclusions: A limited number of interventions effectively prevent or treat irritant and allergic CD, but well-controlled, outcome-blinded studies, particularly in the area of allergic CD prevention are needed. ( J Am Acad Dermatol 2005;53:845-55.)

A

significant proportion of occupational disease is accounted for by occupational contact dermatitis (OCD)1,2 with incidence rates ranging from 24/100,000 to 170/100,000.3-6 The extent of morbidity is underestimated,7,8 and ameliorating the

From the Gage Occupational and Environmental Health Unit, Department of Occupational and Environmental Health, St Michael’s Hospital,a and Departments of Medicine and Public Health Sciences, University of Torontob; Departments of Medicine and Health Policy Management and Evaluation, University of Torontoc; and Department of Medicine, Ottawa Hospital,d and Department of Medicine, University of Ottawa.e Funding source: The Workplace Safety and Insurance Board of Ontario. Conflicts of interest: None identified. This work has been provided to the Workplace Safety and Insurance Board as a technical report and has been orally presented at the Annual Meeting of the American Contact Dermatitis Society in Washington, DC, on February 5, 2004. Reprint requests: Joan Saary, MD, MSc, FRCPC, Department of Occupational and Environmental Health, St Michael’s Hospital, 4th Floor Shuter Wing, 30 Bond St, Toronto, Ontario M5B 1W8, Canada. E-mail: [email protected]. 0190-9622/$30.00 ª 2005 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2005.04.075

Abbreviations used: ACD: CD: ICD: OCD: TEWL: WSIB:

allergic contact dermatitis contact dermatitis irritant contact dermatitis occupational contact dermatitis transepidermal water loss Workplace Safety and Insurance Board

effects of OCD is an ongoing challenge. The National Institute of Occupational Safety and Health has identified OCD as a priority research area,9 noting that ‘‘there has been relatively little occupational research to . . . assist workers who have developed skin diseases that commonly afflict them for the rest of their lives.’’10 Medical management has had little impact on clinical outcome in OCD for more than 4 decades with descriptive and nonexperimental studies (eg, retrospective cohorts) reporting persistent disease in 33% to 81% of the individuals.11-23 Work outcomes have also been poor with between 29% and 72% of OCD-affected individuals reporting skin-related job changes.1,14,16,18,20,24-26 845

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The Workplace Safety and Insurance Board (WSIB) of Ontario, Canada, has developed a program of care for OCD. This required that treatment decisions be evidence-based. Given the significance of OCD and the historic lack of ability to modify the clinical outcome, WSIB solicited an independent review of the literature to aid in the provision of evidence-based recommendations.

METHODS A literature search was conducted using the MEDLINE, EMBASE, and Cochrane databases from January 1966 to June 2003 to identify relevant English-language publications. Key search terms included: contact dermatitis (CD), contact allergy, eczema, controlled study, clinical trial, and treatment. Complete search strategies are listed in Appendix A. In addition, references of relevant articles and reviews were manually searched for additional sources. Bibliographies of retrieved publications were reviewed to identify sources not obtained in our search. Two authors (R. Q., J. S.) independently reviewed the abstracts to find those that met eligibility (inclusion and exclusion) criteria. Any disagreement was resolved by arbitration by a third author (V. P.). A study was included if it dealt with prevention or treatment of CD, either naturally occurring or experimentally induced, even if not explicitly stated (ie, includes those articles that show correlation between modifiable factor and CD), or if the study did not deal exclusively with treatment for CD, but data of patients with CD were presented separately, so that they could be abstracted independently of other data. A study was excluded if its subjects were not human or not adult, the language of publication was not English, it was not a controlled trial, or there were less than 10 subjects. Also excluded were studies dealing with only one contact allergen and its specific treatment, immediate hypersensitivity (type I) reactions, contact urticaria, or atopy. The rationale for the decision to exclude the latter was that atopy represents a distinct clinical entity from CD, despite the fact that they may occur together. The incidence of allergic CD (ACD) superimposed on atopy remains controversial, with some studies reporting no greater incidence of ACD among those with atopy than healthy participants. Conversely, the atopic response to irritants is increased compared with control subjects.27-29 Studies meeting eligibility criteria were then independently abstracted by two authors (R. Q. and J. S.) using predetermined quality criteria, and were rated as good, fair, or poor (Appendix B). In

addition, studies achieving good or fair ratings were abstracted independently by two authors (R. Q. and J. S.) for statistically significant differences in clinical, biophysical, and subjective outcomes (see Appendix C for description of bioengineering outcomes). A summary of the evidence and proposed recommendations were then generated.

RESULTS In 413 initial articles, we found studies examining 63 different treatments, and 37 different preventive measures for irritant CD (ICD) and ACD (Table I). Generally, treatments and preventive measures could be classified as corticosteroids, nonsteroidal medications such as macrolide immunomodulators, barrier creams, emollients, natural or herbal products, gloverelated interventions, modifications to work process or environment, and psychosocial or educational interventions. Although other treatments have been proposed (eg, psychiatric intervention, introduction of nurse practitioner) no controlled studies that would meet the inclusion and exclusion criteria were found. After the application of inclusion and exclusion criteria, only 49 articles that addressed the prevention and treatment of CD met eligibility criteria. In all, 12 met the criteria for good quality,33-44 16 were rated as fair,45-60 and 21 were rated as poor and were not further abstracted for results (Table II).61-81 Studies are randomized controlled trial unless otherwise stated. The details of quality evaluations and results for individual studies are outlined in online supplemental tables available at www.eblue.org. Prevention of ICD There is evidence from good-quality studies that certain barrier creams, moisturizing creams, and use of softened fabrics are effective in preventing the development of ICD. Fair-quality studies indicated that short-term use of certain moisturizers and barrier creams and use of cotton glove liners were effective. Educational interventions were less promising. Barrier creams. Two good-quality43,44 and two fair-quality47-52 studies found barrier creams to be effective in preventing ICD, and one good-quality study did not.40 Schliemann-Willers et al43 investigated the ability of pretreatment with different concentrations of perfluoropolyether phosphate (Fomblin HC/P2) in different gel bases to prevent experimentally induced ICD to 4 different irritants. Results indicated that 5% HC/P2 was significantly better than untreated control in preventing irritation (as measured by visual erythema scores, transepidermal water loss [TEWL], and chromametry) from

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Table I. Available treatment and prevention methods for contact dermatitis evaluated in controlled trials ACD

Treatment method or substance Steroids Bufexamac (Parfenac) 5% cream Desonide 0.05% cream Doxepin 5% cream Short-term parenteral betamethasone sodium phosphate 4.0 mg/mL Short-term parenteral dexamethasone sodium phosphate 4.0 mg/mL Clobetasone butyrate 0.05% (Eumovate) Clobetasol propionate 0.05% Hydorcortisone 1% Flumethasone pivalate Mometasone furoate 0.1% Betamethasone valerate 0.1% (od, bid) Cutivate with 0.05% micronized fluticasone propionate (alone of in combination with Dermalex barrier cream) Comparisons of different potencies of steroids Cyclosporin (oral and topical) Nonsteroidal medication Doxepin cream 5% Tacrolimus/FK506 Fomblin HC/P2 (perfluoropolyether phosphate) SDZ ASM 981 (selective cytokine inhibitor) Azathioprine Indomethacin 2.5% in skin-base cream Topical pentoxifylline Barrier creams Hollister moisture barrier Mentor shield skin Hydropel Uniderm Dermofilm Emollients/ Locobase lipids Lipid mixtures Lipid mix and steroid Oil-in-water emulsion with 4% evening primrose oil

Other

Subcutaneous hyposensitization and UVB combined UVB (total body and partial body) Oral hyposensitization Dietary restriction Organoclay Extract of jewelweed Dermapor semipermeable glove Cotton glove liners

ICD

Cyclosporin (oral) Doxepin cream 5%

Hydrogel Dimethicone Excipial protect (active ingredient aluminum chlorohydrate 5%) Locobase Locobase repair Doublebase Ultrabase Diprobase Ceridal lipogel Petrolatum Decubal Essex Oil-in-water emulsion with 4% evening primrose oil Cream containing urea 5% and hydrogenated canola oil 5% Lipid mix and steroid Sea water (Pacific Ocean) NaCl solution KCl solution MgCl2 solution CaCl2 solution Dermapor semipermeable glove Cotton glove liners

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Table I. Cont’d ACD

Prevention method or substance Barrier cream Dermashield Hollister moisture barrier Mentor shield skin Hydropel Uniderm Dermofilm Emollient/lipid

Other

Low molecular-weight heparin Topical pentoxifylline Nonlatex gloves Ginkgo biloba pretreatment Quaternuim-18 bentonite Topical skin protectanteemulsion of Teflon polymer in perfluoroalkylpolyether

ICD

Arretil Aluminum chlorohydrate-containing cream Hand sense Stoko emulsion Combinations of barrier and emollient creams Keri lotion, coconut, soy, sunflower, rape seed, palm, palm kernel, palm and rapeseed combination, fish oil, borage oil, canola, shea butter, fractions of unsaponifiable lipids from canola oil and shea butter Fabrics treated with fabric softener Substituting simple washing for brush washing Substituting emulsion cleansing for washing with soap Pro-Q aerosol skin protectant Temperature of irritant or water Educational interventions Alpha hydroxyacids (glycolic, lactic, tartaric acids and gluconolactone)

ACD, Allergic contact dermatitis; bid, twice a day; CaCl2, calcium chloride; ICD, irritant contact dermatitis; KCL, potassium chloride; mg, milligram; MgCl2, magnesium chloride; mL, millilitre; NaCl, sodium chloride; od, once daily; UVB, ultraviolet B.

water-soluble irritants. The lack of efficacy of 2% HC/P2 against such irritants suggests a dose-response effect although no interproduct comparisons were made, only product versus untreated control. Zhai et al44 tested the ability of dimethicone skin protectant lotion to prevent experimentally induced ICD as measured by visual scoring, TEWL, chromametry, and laser Doppler flow. The dimethicone lotion was significantly better than either vehicletreated or untreated control on 2 of 4 (visual, TEWL) parameters measured. Both of these studies were conducted using healthy Caucasian volunteers, which may limit generalizability (ie, external validity). Conversely, Perrenoud et al40 demonstrated that a barrier cream containing aluminum chlorohydrate as the active ingredient was ineffective in preventing ICD, and in fact was worse than a vehicle control on capacitance measures. Moisturizers. Two good-quality studies examined the role of moisturizers in the prevention of ICD. Held and Agner35 examined the ability of both high- and low-lipid content moisturizers to prevent ICD and found that the high-lipid content moisturizer significantly prevented experimentally induced ICD as measured by TEWL, capacitance, chromametry, and clinical scores, compared with a lower-lipid content moisturizer that only showed a preventive effect with capacitance measures. In 1997, Loden37 investigated the application of moisturizing cream

containing 5% urea and 5% hydrogenated canola oil in preventing experimentally induced ICD and found this cream to be significantly better than the untreated control by both clinical and TEWL measures. Four fair-quality studies also generally found moisturizers to be beneficial.48,55,56,60 Fabric softener. The good-quality study of Pierard et al41 evaluated whether fabrics treated with fabric softener were less irritating than untreated fabrics to experimentally irritated and normal but sensitive skin. In this study, the intervention involved two repetitions of rubbing a wet towel (treated with fabric softener or untreated) on the forearm, then patting dry 3 times a day for 5 days. Results indicated better clinical ratings and improvement in stratum corneum structure and barrier function and hydration in skin exposed to fabrics treated with fabric softener (compared with untreated fabrics). Although the study method may simulate towel use, it may not be an adequate model of clothing wear. Educational strategies. No studies examining educational criteria met good-quality criteria. Two fair-quality cohort studies49,50 examined the effectiveness of educational interventions in preventing ICD. Among nursing home workers, participants in the intervention group scored higher on a quiz, and showed greater change than the control group on 3 of 6 targeted areas for behavioural change. Selfreported symptoms were no different between

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Table II. Characteristics of studies abstracted

Key question

Total treatment search

No. of titles and abstracts screened

No. of articles selected for further review

No. of articles meeting criteria

413

131

49

ICD prevention ICD treatment ACD prevention ACD treatment

Study design/ quality rating of articles

Data abstraction from G- or F-quality articles*

RCT: 39 G/F/P:10/13/16 Cohort: 10 G/F/P:2/3/5

RCT: 23 Cohort: 5

16 5 5 5

Total No. of patients studied in G- or F-quality articles

632 97 291 84

ACD, Allergic contact dermatitis; F, fair; G, good; ICD, irritant contact dermatitis; P, poor; RCT, randomized controlled trial. *Column sum does not add to total because of some studies addressing either both ACD and ICD or both treatment and prevention.

groups, but clinical examination was significantly different, although the examination was not blinded and was, thus, potentially biased particularly given the differing results between the assessors and a blinded dermatologist.50 In a different study also investigating an educational intervention in auxiliary nurses49 no significant difference between intervention and control groups were found on either clinical or bioengineering (TEWL) measures). Gloves. A fair-quality study by Ramsing and Agner54 found that occlusive glove use worsened bioengineering measures of ICD, and that use of a cotton liner led to better results than a glove alone. Treatment of ICD There is evidence from good-36-38 and fair-rated55 studies that lipid-rich moisturizers are effective in the short-term treatment of experimentally induced ICD. Loden37 investigated the impact of applying a moisturizing cream containing 5% urea and 5% hydrogenated canola oil to an experimentally induced ICD site twice daily for 14 days. Barrier function (TEWL), skin hydration, and clinical evaluations were all significantly improved compared with an untreated control site. The generalizability of these results is limited to acute situations given the end point at 14 days. Loden and Andersson38 evaluated 9 different lipids and concluded that canola oil, its sterolenriched fraction, and hydrocortisone were the only substances affecting the degree of irritation. Held et al36 also examined a variety of (6 different) moisturizers and found moisturizers generally effective for both clinical and bioengineering measures, with lipid-rich moisturizers such as petrolatum showing greater improvement than less lipid-rich moisturizers. One other fair-quality study60 tested a moisturizer applied to dry hands before gloving, and found less

dryness by visual examination but no difference from control in either TEWL or erythema. None of the studies used quality of life or return to work as indicators of outcome. Prevention of ACD There were no studies with a good-quality rating that examined the prevention of ACD. Among the fair-rated studies there was a wide variety of interventions tested.45,46,51,58,59 Two studies demonstrated that rhus dermatitis can be reduced in severity or prevented with quaternium-18-bentonite (organoclay) lotion,51 and topical skin protectant (an emulsion with perfluroalkylpolyether, similar to Teflon [DuPont, Wilmington, Del]).58 The chelator diethylenetriamine pentaacetic acid was effective in preventing and reducing the severity of patch tests to nickel, and preventing reactions to cobalt and copper, but was ineffective against palladium and potassium.59 Brehler et al45 found pretreatment with pentoxifylline clinically ineffective in preventing nickel allergy reactions. Treatment of ACD There were 4 good-quality studies that evaluated treatments for ACD.33,34,39,42 All studies evaluated the effectiveness of various steroids including: fluticasone propionate .05% with or without barrier cream, clobetasone butyrate .05%, and clobetasol propionate .05% (Dermoval). In studies by Hachem et al,33,34 fluticasone propionate .05% was found to improve clinical and nonclinical outcomes compared with control, and when combined with barrier cream, fluticasone improved nonclinical outcomes. Clinical outcome was improved by barrier cream alone. Parneix-Spake et al39 found nonclinical outcomes to be significantly better with clobetasone butyrate than either 1% hydrocortisone or untreated

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Table III. Recommendations Maneuver

ICD prevention and therapy

Effectiveness

Barrier creams 5% Perfluoropolyethers (Fomblin HC/P2) Dimethicone skin protectant lotion Hand sense barrier cream Excipal protect with aluminum chlorohydrate

High-lipid content moisturizers Locobase 5% urea 1 5% hydrogenated canola oil Petrolatum Eucerin Palm fats Rapeseed in 3/4 measures Canola Stoko emulsion prevent latex gloveinduced ICD in 3 of 5 measured (P \ .05)] Fabric softening Fabrics treated with fabric softener less irritating untreated fabrics Cotton liners Occlusive glove use leads to worse bioengineering measures of ICD, and liners under an occlusive glove mitigate ACD prevention and therapy

Level of evidence for prevention*

Level of evidence for treatment*

I-Good40,43,44

I-Fair47,52

I-Good35,37 I-Good36-38 I-Fair48,55,56,60 I-Fair55,60

I-Good41

I-Fair54

Quaternium18-bentonite prevents rhus dermatitis

I-Fair51

TSP prevents rhus dermatitis DTPA prevents nickel, copper, cobalt dermatitis

I-Fair58 I-Fair59

Recommendation*

There is good-quality evidence to recommend certain barrier creams for the prevention of ICD, recognizing some limitations of generalizability. There is good evidence to recommend against the use of aluminum chlorohydrate-containing barrier creams There is good-quality evidence to recommend the use of moisturizers with high lipid content for both prevention and treatment of ICD, recognizing some limitations of generalizability

There is good-quality evidence to recommend softened fabrics to prevent ICD, recognizing significant limitations of generalizability There is fair-quality evidence to recommend the use of cotton glove liners to prevent ICD, recognizing some limitations of generalizability There is good-quality evidence to recommend certain allergen-specific measures for the prevention of ACD, recognizing some limitations of generalizability

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Table III. Cont’d Maneuver

Effectiveness

Level of evidence for prevention*

Good33,34,39,42 I-Fair57

Moderate to potent steroids - Fluticasone propionate - Clobetasol butyrate - Clobetasol propionate

QOL and return to work

Level of evidence for treatment*

No studies found

Recommendation*

There is good-quality evidence to recommend the use of moderate- to high-potency steroids to treat ACD, recognizing some limitations of generalizability The authors conclude there is insufficient evidence to recommend any treatment to improve the outcomes of return to work and QOL

ACD, Allergic contact dermatitis; DTPA, diethylenetriamine pentaacetic acid; ICD, irritant contact dermatitis; QOL, quality of life; TSP, topical skin protectant. *See Appendix B for definitions of quality ratings.

control. Clobetasol propionate proved clinically better than 1% hydrocortisone, and 2.5% indomethacin and 5.0% bufexamac (Parfenac).42 However, these good-quality studies have limited generalizability because the majority of study participants were Caucasian female volunteers. Clobetasol propionate .05% was also evaluated in one fair-rated study by Vernon and Olsen57 who found it to be clinically effective in treating rhus dermatitis compared with white petrolatum. None of the studies used quality of life or return to work as indicators of outcome.

SUMMARY AND RECOMMENDATIONS ICD Prevention. As shown in Table III, there is goodand fair-quality evidence that barrier creams containing dimethicone or a high concentration of active ingredients such as perfluoropolyethers, short-term use of high-lipid content moisturizers, use of cotton liners if occlusive gloves are worn, and use of softened fabrics can prevent the development of ICD. There is good-quality evidence that barrier cream containing aluminum chlorohydrate is not effective in preventing ICD. More research is required to evaluate educational interventions as preventive strategies. Treatment of induced ICD. There is good- and fair-quality evidence that lipid-rich moisturizers can effectively treat ICD. ACD Prevention. There is fair-quality evidence that the topical skin protectant and quaternium-18-

bentonite can prevent rhus dermatitis and diethylenetriamine pentaacetic acid can prevent nickel, chrome, and copper dermatitis. There is fair evidence that pentoxifylline is not effective in preventing nickel allergy. Treatment of induced ACD. There is goodand fair-quality evidence that potent or moderately potent steroids can treat ACD. Return to Work and Quality of Life No published studies were found examining these outcomes, and as such there is insufficient evidence to recommend that any treatment improves the outcomes of return to work and quality of life in CD.

FUTURE RESEARCH Based on the results of this study, and the process undertaken to complete it, we recommend the following as research priorities in the area of CD generally and OCD specifically: (1) studies that assess the effectiveness of preventive measures for ACD, particularly generally applicable methods, rather than allergen-specific ways to prevent ACD; (2) studies evaluating treatments for chronic ACD and ICD; (3) studies designed to evaluate treatments and preventive strategies in the real-world setting; (4) studies with a focus on return to work as an outcome measure; (5) the use of nonsteroid medications to treat ACD needs closer examination; and (6) studies of educational interventions. REFERENCES 1. Holness DL, Nethercott JR. Work outcome in workers with occupational skin disease. Am J Ind Med 1995;27:807-15.

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26. Wall LM, Gebauer KA. A follow-up study of occupational skin disease in Western Australia. Contact Dermatitis 1991;24:241-3. 27. Rees J, Friedmann PS, Matthews JN. Contact sensitivity to dinitrochlorobenzene is impaired in atopic subjects. Arch Dermatol 1990;126:1173. 28. de Groot AC. The frequency of contact allergy in atopic patients with dermatitis. Contact Dermatitis 1990;22:273. 29. Rietschel RL, Fowler JF Jr, editors. Fisher’s contact dermatitis. 4th ed. Baltimore: Williams and Wilkins; 1995. 30. Harris RP, Helfand M, Woolf SH, Lohr KN, Mulrow CD, Teutsch SM, et al, for the Methods Work Group, Third US Preventive Services Task Force. Current methods of the US Preventive Services Task Force. Am J Prev Med 2001;20:21-35. 31. De Paepe K, Janssens K, Hachem JP, Roseeuw D, Rogiers V. Squamometry as a screening method for the evaluation of hydrating products. Skin Res Technol 2001;7:184-92. 32. Lee CM, Maibach HI. Bioengineering analysis of water hydration: an overview. Exogenous Dermatol 2002;1:269-75. 33. Hachem JP, De Paepe K, Vanpee E, Bogaerts M, Kaufman L, Rogiers V, Roseeuw D. Efficacy of topical corticosteroids in nickel-induced contact allergy. Clin Exp Dermatol 2002; 27:47-50. 34. Hachem JP, De Paepe K, Vanpee E, Kaufman L, Rogiers V, Roseeuw D. Combination therapy improves the recovery of the skin barrier function: an experimental model using a contact allergy patch test combined with TEWL measurements. Dermatology 2001;202:314-9. 35. Held E, Agner T. Effect of moisturizers on skin susceptibility to irritants. Acta Derm Venereol 2001;81:104-7. 36. Held E, Lund H, Agner T. Effect of different moisturizers on SLS-irritated human skin. Contact Dermatitis 2001;44:229-34. 37. Loden M. Barrier recovery and influence of irritant stimuli in skin treated with a moisturizing cream. Contact Dermatitis 1997;36:256-60. 38. Loden M, Andersson AC. Effect of topically applied lipids on surfactant-irritated skin. Br J Dermatol 1996;134:215-20. 39. Parneix-Spake A, Goustas P, Green R. Eumovate (clobetasone butyrate) 0.05% cream with its moisturizing emollient base has better healing properties than hydrocortisone 1% cream: a study in nickel-induced contact dermatitis. J Dermatol Treat 2001;12:191-7. 40. Perrenoud D, Gallezot D, van Melle G. The efficacy of a protective cream in a real-world apprentice hairdresser environment. Contact Dermatitis 2001;45:134-8. 41. Pierard GE, Arrese JE, Rodriguez C, Daskaleros PA. Effects of softened and unsoftened fabrics on sensitive skin. Contact Dermatitis 1994;30:286-91. 42. Quielle-Roussel C, Duteil L, Padilla JM, Poncet M, Czernielewski J. Objective assessment of topical anti-inflammatory drug activity on experimentally induced nickel contact dermatitis: comparison between visual scoring, colorimetry, laser Doppler velocimetry and transepidermal water loss. Skin Pharmacol 1990;3:248-55. 43. Schliemann-Willers S, Wigger-Alberti W, Elsner P. Efficacy of a new class of perfluoropolyethers in the prevention of irritant contact dermatitis. Acta Derm Venereol 2001;81:392-4. 44. Zhai H, Brachman F, Pelosi A, Anigbogu A, Ramos MB, Torralba MC, Maibach HI. A bioengineering study on the efficacy of a skin protectant lotion in prevention SLS-induced dermatitis. Skin Res Technol 2000;6:77-80. 45. Brehler R, Maurer O, Grabbe S, Schwarz T. Topically applied pentoxifylline has no effect on allergic patch responses. J Am Acad Dermatol 1998;39:1017-21. 46. Di Nardo A, Giusti G, Mantovani L, Bianchi B, Seidenari S. Inhibition of elicitation of contact dermatitis in humans by

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65.

66.

mometasone furoate: evaluation by means of 20-MHz B scanning associated with image analysis. Dermatology 1997; 195:137-41. Elsner P, Wigger-Alberti, Pantini G. Perfluoropolyethers in the prevention of irritant contact dermatitis. Dermatology 1998;197:141-5. Held E, Sveinsdottir S, Agner T. Effect of long-term use of moisturizer on skin hydration, barrier function and susceptibility to irritants. Acta Derm Venereol 1999;79:49-51. Held E, Wolff C, Gyntelberg F, Agner T. Prevention of workrelated skin problems in student auxilliary nurses: an intervention study. Contact Dermatitis 2001;44:297-303. Held E, Mygind K, Wolff C, Gyntelberg F, Agner T. Prevention of work related skin problems: an intervention study in wet work employees. Occup Environ Med 2002;59:556-61. Marks JG, Fowler JF, Sherertz E, Rietschel R. Prevention of poison ivy and poison oak allergic contact dermatitis by quaternium-18 bentonite. J Am Acad Dermatol 1995;33:212-6. McCormick R, Buchman TL, Maki DG. Double-blind, randomized trial of schedules use of a novel barrier cream and an oilcontaining lotion for protecting the hands of health care workers. Am J Infect Control 2000;28:302-10. Ohlenschlaeger J, Friberg J, Ramsing D, Agner T. Temperature dependency of skin susceptibility to water and detergents. Acta Derm Venereol 1996;76:274-6. Ramsing D, Agner T. Effect of glove occlusion on human skin (II). Contact Dermatitis 1996;34:258-62. Ramsing D, Anger T. Preventive and therapeutic effects of a moisturizer. Acta Derm Venereol 1997;77:335-7. Schleimann-Willers S, Grieshaber R, Elsner P. Natural vegetable fats in the prevention of irritant contact dermatitis. Contact Dermatitis 2002;46:6-12. Vernon HJ, Olsen EA. A controlled trial of clobetasol propionate ointment 0.05% in the treatment of experimentally induced rhus dermatitis. J Am Acad Dermatol 1990;23:829-32. Vidmar DA, Iwane MK. Assessment of the ability of the topical skin protectant (TSP) to protect against contact dermatitis to urushiol (Rhus) antigen. Am J Contact Dermatitis 1999;10:190-7. Wohrl S, Kriechbaumer N, Hemmer W, Focke M, Brannath W, Gotz M, Jarisch R. A cream containing the chelator DTPA (diethylenetriaminepenta-acetic acid) can prevent contact allergic reactions to metals. Contact Dermatitis 2001;44:224-8. Zhai H, Schmidt R, Levin C, et al. Prevention and therapeutic effects of a model emulsion on glove-induced irritation and dry skin in man. Occup Environ Med 2002;50:134-8. Barsky S. Clinical comparison of desonide cream with fluocinonide cream in steroid-responsive dermatologic disorders. Cutis 1976;18:826-30. Bauer A, Kelterer D, Bartsch R, Schlegel A, Pearson J, Stadeler M, et al. Prevention of hand dermatitis in bakers’ apprentices: different efficacy of skin protection measures and UVB hardening. Int Arch Occup Environ Health 2002;75:491-9. Berardesca E, Distante F, Vignoli GP, Oresajo C, Green B. Alpha hydroxyacids modulates stratum corneum barrier function. Br J Dermatol 1997;137:934-8. Berardesca E, Barbareschi M, Veraldi S, Pimpinelli N. Evaluation of efficacy of a skin lipid mixture in patients with irritant contact dermatitis, allergic contact dermatitis or atopic dermatitis: a multicenter study. Contact Dermatitis 2001;45:280-5. Berndt U, Wigger-Alberti W, Gabard B, Elsner P. Efficacy of a barrier cream and its vehicle as protective measures against occupational irritant contact dermatitis. Contact Dermatitis 2000;42:77-80. Dickey R. Parenteral short-term corticosteroid therapy in moderate to severe dermatoses. Cutis 1976;17:179-83.

67. Drake LA, Millikan LE. The antipruritic effect of 5% doxepin cream in patients with eczematous dermatitis. Arch Dermatol 1995;131:1403-8. 68. Epstein WL, Byers VS, Frankart W. Induction of antigen specific hyposensitization to poison oak in sensitized adults. Arch Dermatol 1982;118:630-3. 69. Goh CL, Gan SL. Efficacies of a barrier cream and an afterwork emollient cream against cutting fluid dermatitis in metalworkers: a prospective study. Contact Dermatitis 1994;31:176-80. 70. Granlund H, Erkko P, Eriksson E, Reitamo S. Comparison of cyclosporine and topical betamethasone-17, 21 dipropionate in the treatment of severe chronic hand eczema. Acta Derm Venereol 1996;76:371-6. 71. Grevelink SA, Murrell MA, Olsen EA. Effectiveness of various barrier preparations in preventing and/or ameliorating experimentally produced Toxicodendron dermatitis. J Am Acad Dermatol 1992;27:182-8. 72. Halkier-Sorensen L, Thestrup-Pedersen K. The efficacy of a moisturizer (Locobase) among cleaners and kitchen assistants during everyday exposure to water and detergents. Contact Dermatitis 1993;29:266-71. 73. Ingber A, Trattner A, Cohen I, Mekori Y. Low doses of low molecular weight heparin in vivo inhibits the elicitation of contact hypersensitivity. Acta Derm Venereol 1994;74:454-6. 74. Kikuchi-Numagami K, Saishu T, Fukaya M, Kanazawa E, Tagami H. Irritancy of scrubbing up for surgery with or without a brush. Acta Derm Venereol 1999;79:230-2. 75. Lauharanta J, Ojajarvi J, Sarna S, Makela P. Prevention of dryness and eczema of the hands of hospital staff by emulsion cleansing instead of washing with soap. J Hosp Infect 1991;17:207-15. 76. Medansky RS, Handler RM. Analysis of a new corticosteroid aerosol in treatment of contact dermatitis. Cutis 1978;21:108-10. 77. Patterson SE, Williams JV, Marks JG. Prevention of sodium lauryl sulfate irritant contact dermatitis by Pro-Q aerosol foam skin protectant. J Am Acad Dermatol 1999;40:783-5. 78. Pigatto PD, Bigardi S, Legori A, Altomare GF, Finzi AF. Are barrier creams of any use in contact dermatitis? Contact Dermatitis 1992;26:197. 79. Troost RJJ, Kozel MMA, van Helden-Meeuwsen CG, van Joost T, Mulder PG, Benner R, Prens EP. Hyposensitization in nickel allergic contact dermatitis: clinical and immunologic monitoring. J Am Acad Dermatol 1995;32:576-83. 80. Veien NK, Hattel T, Justesen O, Norholm N. Oral challenge with balsam of Peru. Contact Dermatitis 1985;12:104-7. 81. Wolf-Jurgensen P. Efficacy of bufexamac cream versus betamethasone valerate cream in contact dermatitis: a doubleblind trial. Curr Med Res Opin 1979;5:779-84.

Appendix A. Search terms Search 1: EMBASE \1980 to 2003[ 1. Contact dermatitis/dt 2. Controlled study/ 3. Clinical trial/ 4. Contact allergy/dt 5. 1 or 4 6. 2 or 3 7. 5 and 6 8. Limit 7 to (human and English language) Search 2: EMBASE \1980 to 2003[ 1. exp Eczema/ 2. Lichen simplex dermatitis.mp.

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J AM ACAD DERMATOL NOVEMBER 2005

3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28.

Shoe dermatitis.mp. Latex contact dermatitis.mp. Animal dermatitis.mp. Insect dermatitis.mp. Chemical dermatitis.mp. Metal dermatitis.mp. Water dermatitis.mp. Plant dermatitis.mp. 3 or 4 or 5 or 7 or 8 or 10 1 or 11 Treatment.mp. or therapeutics/ Environmental scan.mp. exp Questionnaires/ 13 or 14 or 15 Prevention.mp. or exp primary prevention/ exp Education/ exp Engineering/ exp Environment, controlled/ or environmental control.mp. exp Protective clothing/ or exp protective devices/ 16 or 17 or 18 or 19 or 20 or 21 12 and 22 Limit 23 to (human and English language and article and adult \18-64 years[) exp Controlled study/ or exp randomized controlled trial/ 24 and 25 exp Randomized controlled trial/ 24 and 27

Search 3: MEDLINE \1966 to 2003[ 1. exp Contact dermatitis/ 2. Limit 1 to (human and English language and adult \19-44 years> and randomized controlled trial) Search 4: MEDLINE \1966 to 2003[ 1. exp Eczema/ 2. Lichen simplex dermatitis.mp. 3. Shoe dermatitis.mp. 4. Latex contact dermatitis.mp. 5. Animal dermatitis.mp. 6. Insect dermatitis.mp. 7. Chemical dermatitis.mp. 8. Metal dermatitis.mp. 9. Water dermatitis.mp. 10. Plant dermatitis.mp. 11. 3 or 4 or 5 or 7 or 8 or 10 12. 1 or 11 13. Treatment.mp. or therapeutics/ 14. Environmental scan.mp. 15. exp Questionnaires/ 16. 13 or 14 or 15 17. Prevention.mp. or exp primary prevention/ 18. exp Education/

19. exp Engineering/ 20. exp Environment, controlled/ or environmental control.mp. 21. exp Protective clothing/ or exp protective devices/ 22. 16 or 17 or 18 or 19 or 20 or 21 23. 12 and 22 24. Limit 23 to (human and English language and all adult \19 plus years[ and [controlled clinical trial or randomized controlled trial]) Search 5: EBM Reviews—Cochrane Central Register of Controlled Trials 2003 1. exp Dermatitis, allergic contact/ or exp dermatitis, contact/ 2. Limit 1 to randomized controlled trial

Appendix B. Criteria for rating individual studies* GOOD—All the following are met: Comparable groups assembled initially and maintained throughout study OR body split-site design Interventions are clearly described Important clinical and nonclinical outcomes are considered Outcome measurement is well described Outcome assessment is blinded Randomized control trial: intention-to-treat analysis Cohort: confounders/contaminants noted and corrected for FAIR—One or more of the following occur, but none of the flaws listed in ‘‘poor’’ occur: Generally comparable groups Only clinical or only nonclinical outcomes are considered Measurement instrument acceptable, but not ideal (ie, scale not described); and generally applied equally Randomized controlled trial: no intention-to-treat analysis Cohort: some important confounders considered and adjusted for in analysis (see above) Lack of blinding to outcome assessment or can not tell POOR—One or more of the following fatal flaws exist: Groups assembled are not comparable either initially or throughout the study, or can not tell Unreliable or invalid measurement methods, or measures not applied equally, or can not tell Key confounders not addressed Inadequate power to detect equivalency *As described by the US Preventive Services Task Force.30

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Appendix C. Bioengineering outcomes description Electrical capacitance/corneometry

Chromametry/colorimetry/spectrophotometry Echographic evaluation Laser Doppler flow Patch test Squamometry

TEWL

Water sorption-desorption test

Capacitance (measured on skin surface) is directly proportional to water content of the horny layer of the skin. A plate capacitor, which builds up an electrical field at its edges, is used to measure capacitance. Measurement of skin redness/color, which indicates erythema Skin thickness is measured or the difference in extent of area of inflammation compared with a control This measures blood flow rate, which is an indicator of dermal vascularity Prevention of positivity or reduction in severity of allergic reaction Corneocytes are sampled using adhesive coated disks. The cells are stained and then color measurements are made using image analysis or chromametry (measuring reflected light).31 TEWL is a good indicator of skin barrier function. An evaporimeter, consisting of a sensor placed 3 or 6 mm above the surface of the skin, measures the amount of water loss by evaporation. Damage to the skin will result in increased water loss. This method involves hydrating the skin with water and then observing the subsequent dehydration activity by means of serial recording with electrical instruments. It is a useful tool to measure the dynamic hydration of the skin and the stratum corneum water-holding properties. Damage to the stratum corneum reduces its ability to hold water.32

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Supplemental Table I. Quality assessment of randomized controlled trials in contact dermatitis

Study author(s), year published Hachem et al, 200233 Held and Agner, 200135 Held, Lund, and Agner, 200136 Perrenoud et al, 200140 Schleimann-Willers, Wigger-Alberti, and Elsner, 200143 Zhai et al, 200044 Loden, 199737 Loden and Andersson, 199638 Pierard et al, 199441 Queille-Roussel et al, 199042 Zhai et al, 200260 Schliemann-Willers et al, 200256 Wohrl et al, 200159 McCormick et al, 200052 Held et al,199948 Brehler et al, 1998445 Elsner et al, 199847 Di Nardo et al, 199746 Ramsing and Agner, 199755 Ohlenschlaeger et al, 199653 Ramsing and Agner, 199654 Marks et al, 199551 Vernon and Olsen, 199057 Berardesca et al, 200164 Berndt et al, 200065 Kikuchi-Numagami et al, 199974 Patterson et al, 199977 Berardesca et al, 199763 Granlund et al, 199670 Drake and Millikan, 199567 Troost et al 199579 Halkier-Sorensen and Thestrup-Pedersen, 199372 Grevelink et al, 199271 Lauharanta et al, 199175 Veien et al, 198580 Wolf-Jurgensen, 197981 Medansky and Handler 197876 Barsky, 197661 Dickey, 197666

Quality rating Good Good Good Good Good Good Good Good Good Good Fair Fair Fair Fair Fair Fair Fair Fair Fair Fair Fair Fair Fair Poor Poor Poor Poor Poor Poor Poor Poor Poor Poor Poor Poor Poor Poor Poor Poor

ACD, Allergic contact dermatitis; ICD, irritant contact dermatitis; N, no; SS, split site; Y, yes.

Outcome assessment blinded? Y Y Y Y Y Y Y Y Y Y N N Y Y N N N N Y N N Y Y N Y N N Y Y N N N Y Y Y Y Y Y Y

Comparable groups assembled initially and maintained throughout study or body split-site design Initial Maintenance SS SS SS Y Y SS SS SS SS SS SS SS SS SS Y Y SS SS SS SS SS SS SS SS SS Y Y N N N N SS SS N N N N N N N N SS Y N Y Y N N N N N N Y Y

Outcome measurement is well described Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y N Y Y Y Y Y Y Y Y N N Y N

Interventions are clearly described Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y N N N Y Y Y Y Y Y Y Y Y Y N Y N

Important clinical and nonclinical outcomes are considered Y Y Y Y Y Y Y Y Y Y Y Y N N N N Y N N Y N N N N Y N Y N Y Y Y N N N N N N N

ACD or ICD ACD ICD ICD ICD ICD ICD ICD ICD ICD ICD ICD ICD ACD ICD ICD ACD ICD ACD ICD ICD ICD ACD ACD ACD, ICD ICD ICD ICD ICD ACD ICD ACD ICD ACD ICD ACD ACD, ICD ACD, ICD ACD ACD

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Supplemental Table II. Quality assessment of cohort studies in contact dermatitis

Study authors, year published Hachem et al, 200134 Parneix-Spake et al, 200139 Held et al, 200250 Held et al, 200149 Vidmar and Iwane, 199958 Bauer et al, 200262 Goh and Gan, 199469 Ingber et al, 199473 Pigatto et al, 199278 Epstein et al, 198268

Quality rating Good Good Fair Fair Fair Poor Poor Poor Poor Poor

Confounders/Contaminants considered? Y Y Y Y Y Y N N Y N

ACD, Allergic contact dermatitis; ICD, irritant contact dermatitis; N, no; SS, split site; Y, yes.

Outcome assessment: Blinded? Y Y N N N N N N N Y

Comparable groups assembled initially and maintained throughout study or body split-site design Initial Maintenance SS SS Y Y Y Y SS N N N N N N SS N N

Outcome measurement well described Y Y N Y Y Y Y Y N Y

Interventions clearly described Y Y Y Y Y Y Y Y Y Y

Important clinical and nonclinical outcomes considered? Y Y N Y N Y Y N N N

ACD or ICD ACD ACD ICD ICD ACD ICD ICD ACD ACD ACD

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Supplemental Table III. Summary of results: Effect of preventive interventions on irritant contact dermatitis Study author(s), year published Perrenoud et al, 200140

Schleimann-Willers, Wigger-Alberti, and Elsner, 200143

Quality rating Good

Good

No. of subjects 21 (5)†

20

Population Apprentice hairdressers, starting their 2nd year of studies; age 16-30 y (20 female, 1 male)

Intervention Barrier cream (Excipal Protect) applied to hands Tues-Sat × 4 wk, while subjects exposed to irritants at work (eg, repeated shampooing, exposure to hair care products)

Healthy Caucasian volunteers; age 18-33 y (13 women, 7 men)

Control: Vehicle Application of 0.05 mL of various PFPE phosphate gels to skin once daily (Mon-Fri week 1, Mon-Thurs week 2)

Outcomes: All outcomes considered Clinical score (dryness, redness, skin breaks): 0-9 Subjective TEWL Capacitance Chromametry

Results*

Higher in control vs treatment

P value NS NS NS <.01 NS

Comments: Strengths, weaknesses, EV Incl: At least 5 shampoos per day done without gloves Excl: Broken/oozing skin, open wounds, known allergies, use of potent corticosteroids or any other tx that would interfere with the study

C: Lower vs control (LA)

d.05

Excl: Skin disease

E: Lower vs control (NaOH, week 1)

d.05

Allowed to shower but prohibited from application of detergents, moisturizers, or emollients, exposure to sun beds/solar radiation during 12 d of investigation

F: Lower vs control (NaOH, week 1)

d.05

D: Lower vs control (SLS at day 5, 12)

d.05

D: Gel base 1 + 5% HC/P2 1000

E: Lower vs control (SLS, day 5)

d.05

E: Gel base 2 (Carbomer) + 5% HC/P2 1000

E: Lower vs control (NaOH week 1)

d.05

E: Lower vs control (LA, week 1)

d.05

F: Lower vs control (SLS at day 5)

d.05

F: Lower vs control (NaOH, week 1)

d.05

Chromametry (a*)

C: Lower vs control (LA) E: Lower vs control (SLS at day 5) E: Lower vs control (NaOH, week 1) F: Lower vs control (NaOH, week 1)

d.05 d.05 d.05 d.05

Clinical: Visual

Less in treated vs untreated control

<.01

Excl: None stated

Less in treated vs. vehicle control

<.05

ICD: Induced by SLS exposure

Less in treated vs untreated controls at day 5 Less in treated vs vehicle control at day 5

d.014

Clinical exam: Visual (erythema)

Gels: B: Gel base 1 (xanthan gum) as placebo C: Gel base 1 + 2% HC/P2 1000

TEWL (g/m2/h)

ICD: Induced by exposure to all of the following (at different sites): SLS 5% NaOH 0.5% LA 20% TOL 100% EV: Limited

F: Gel base 1 + 5% HC/P2 2000 Control: Untreated Gel base

Zhai et al, 200044

Good

12

Healthy Caucasian volunteers age 43.3 r 7.7 y (7 women; 5 men)

Application of dimethicone skin protectant lotion to test area before irritant exposure Controls: Untreated (ie, irritant only) Vehicle

TEWL (g/m2/h)

Good

19 (1)‡

Healthy Caucasian volunteers; age 24-58 y (15 women, 4 men)

High lipid content moisturizer (Locobase, A) vs moderate/low lipid content moisturizer (Decubal, B) applied tid × 5 d before exposure to irritant

Laser Doppler flow (BFV) TEWL

Laser Doppler

EV: Limited

NS

Chromametry (a*)

Held and Agner, 200135

<.05

Magnitude of test effect not stated

NS A higher vs control (day 8, 12)

<.05

B vs control

NS

A vs control

NS

B vs control

NS

Excl: Hx/clinical signs of AD or CD Prohibited: Use of other moisturizers on arms 7 d before or during study ICD: Induced by SLS exposure

Control: Untreated

EV: Limited Colorimetry (a*)

A higher vs control (day 8, 12) B vs control

<.05 NS

Note: Results indicate that Locobase increases susceptibility to irritants.

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Quality rating

No. of subjects

Good

13

Population

Intervention

Outcomes: All outcomes considered Clinical erythema (0-3)

P value <.001

Results* A (1.3) vs control (0.8) B vs control

Loden, 199737

Healthy subjects; age 24-58 y (10 women, 3 men)

Application of moisturizing cream (5% urea and 5% hydrogenated canola oil) to normal skin bid × 14 d; then induction of irritation with 14% SLS for 7 h Control: Untreated

Pierard et al, 199441

Good

15

Healthy volunteers; age 24-46 y

Arm washed with wet softened towel for few seconds and then patted dry with dry, softened towel (repeated 3 ×/d, 2 ×/arm, for 10 d)

Comments: Strengths, weaknesses, EV

NS

TEWL (g/m2/h)

Lower at cream-treated skin (12.4) vs control (19.7)

<.01

Visual scoring: Sum of 0-3 score for erythema, induration, and vesiculation expressed as % of maximum Clinical

Lower in cream-treated skin (11.1) than in untreated skin (26.4)

<.05

Smoothness greater at ICD sites treated with softened towel (day 8) Redness less at ICD sites treated with softened towel (day 5) Dryness less at ICD sites treated with softened towel (day 5-8)

<.05

Incl: Sensitive skin (confirmed by exam and hx)

<.05

Excl: Acute skin disease (on exam), ACD to fabrics/materials used in study

Excl: Visible signs of skin disease; allowed to wash normally but prohibited from using any other skin care products on arms EV: Limited

<.05 ICD: Induced by SLS exposure

Control: Unsoftened towel Dryness less at normal sites treated with softened towel (day 8)

Weakness: Poor model for simulation of wearing clothes <.05 EV: Limited

TEWL (g/m2/h) Capacitance (AU) Colorimetry (a*) Squamametry (c*) Schliemann-Willers et al, 200256

Fair

20

Healthy Caucasians; age 20-38 y (13 women, 7 men)

Topical application of natural fat bid (× 4 d)

Visual score (0-6)

Control: Untreated

'TEWL (g/m2/h)

Lower at ICD sites treated with softened towel (day 5, 8) Higher at ICD sites treated with softened towel (day 5, 8) Lower at ICD sites treated with softened towel (day 3-5) Lower at ICD sites treated with softened towel (day 3, 5, 8, 12) Soy B 2.55 Rapeseed B 1.15 Palm/rapeseed 1.10 Palm A 1.30 Palm B 1.75 Palm D 1.90 Eucerin 0.05 Petrolatum 0.10 vs Control 3.80 Soy A 31.8

<.05 <.05 <.05 <.05 d.05 <.01 d.01 d.01 d.01 d.01 d.01 d.01 d.01

Soy B

27.6

d.01

Rapeseed B

16.3

d.01

Palm/rapeseed

15.2

d.01

Palm A

14.9

d.01

Palm B

21.0

d.01

Palm C

30.0

d.05

Palm D

24.0

d.01

Eucerin

2.7

d.01

Petrolatum

2.8

d.01

vs Control 40.8 'Chromametry (a*)

Rapeseed B

2.60

d.01

Poorly defined incl/excl criteria: Acute induced ICD (to SLS) Subjects permitted to shower but not bathe Use of detergents, moisturizers, emollients on back not permitted Exposure to sun beds, solar radiation discouraged EV: Limited

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Study author(s), year published

Quality rating

No. of subjects

Population

Intervention

Outcomes: All outcomes considered Palm/rapeseed

2.34

P value d.01

Palm A

2.41

d.01

Palm B

3.09

d.01

Palm D

3.48

d.01

Eucerin

0.07

d.01

Petrolatum

0.07

d.01

Palm A

–3

d.05

Eucerin

3

d.01

Petrolatum

2

d.01

Results*

Comments: Strengths, weaknesses, EV

vs Control 6.77 'Corneometry (AU)

vs Control -11 Held et al, 200250

Fair

375||

Employees in elder care homes; age 19-62 y (342 women, 33 men)

Formalized educational program delivered to “participatory team” of 10-20 workers in each workplace. They were then free to pass information to other workers as they wished.

NS

Skin symptoms

Excl: None stated Power analysis calculated to detect 20% improvement (clinical evaluation) in intervention group Workplaces randomized to treatment or control

Control: Workers at workplaces where no educational intervention was given

Clinical exam (no, very mild, mild, moderate, severe symptoms)

Zhai et al, 200260

Fair

15

Healthy Caucasian volunteers; age |32-64 y (10 men, 5 women)

Application of test emulsion to dorsum of hand before gloving, once daily, × 5 d Control: Untreated

Held et al, 200149

Fair

107-13 dropouts = 94

Student auxiliary nurses; age19-55 y (96 women, 11 men)

2 × 2-h educational interventions using video and booklets, covering topics of skin physiology, evidence-based skin care program, plus

Greater reduction in symptoms in treated group vs control (after 5 mo)

<.0002

Dryness (visual) (0-4)

NS

Poorly defined incl/excl criteria

Erythema (visual) (0-4) Water sorptiondesorption test TEWL (g/m2/h) Capacitance (AU)

NS

EV: Limited

Clinical exam: Extent of erythema or irritation (0-74)

Increased water holding capacity in treated subjects Lower TEWL in treated subjects Increased in treated subjects

<.05 <.05 <.05 NS

Excl: None stated Good control for confounders Logistic regression

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Quality rating

No. of subjects

Population

Intervention provision of free moisturizer

Outcomes: All outcomes considered TEWL

Results*

P value NS

Comments: Strengths, weaknesses, EV Power analysis calculated on basis of TEWL values

Control: Student auxiliary nurses who did not receive educational intervention

McCormick, Buchman, and Maki, 200052

Fair

54-2|| eliminated = 52

Hospital employees with long-standing, severe hand irritation

Liberal application of barrier cream (Hand Sense) to both hands bid (4 wk)

Questionnaire: No. of subjects reporting skin problems Hand condition (scaling, cracking, pain)

NS

–2.1 points (6.5 o2.7) (treated) vs –3.8 points (6.8 o 4.7) (control)

Control : Oil containing lotion (Lubriderm) NS

Hand flora

Held et al, 199948

Fair

20

Healthy volunteers; age 21-57 y (17 women, 3 men)

.006

Locobase moisturizer to forearms tid × 27 d

Handwashing frequency TEWL (g/m2/h)

Control group washing frequency 50% > treatment group at end of study Higher in treated vs control (day 30)

.04 <.05

Excl: Hypersensitivity dermatitis, eczema, chronic skin diseases, work <20 h/wk (*) Confounders: Gloves, number of handwashings, antiseptic vs regular handwash all noted. Lotion provided to all subjects for use, ad libitum; however, amount used was noted. Also, by end of study, control group washing hands more frequently—any bias from this source should have favored barrier cream. EV: Result generalizable to chronic dermatitis Excl: Hx/signs of dermatological disease, dry/scaly skin Permitted to bathe/wash as usual

Control: Untreated ICD: Induced by exposure to SLS Elsner et al, 199847

Fair

10

Healthy volunteers; mean age 25.5 y (7 male, 3 female)

Application of PFPE before exposure to irritant, once daily (Mon-Fri week 1, Mon-Thurs week 2) PFPEs tested: PFPE 0.5% PFPE 1.0% PFPE 2.0% PFPE 4.0%

Clinical examination: Erythema (0-5)

TEWL (g/m2/h)

Controls: Untreated Vehicle Chromametry (a*)

Lower for all PFPEs vs untreated control (SLS, week 1) Lower for all PFPEs vs untreated control (NaOH, week 1 and 2)

<.05

Lower for all PFPEs vs untreated control (SLS, week 1 and 2) Lower for all PFPEs vs untreated control (NaOH, week 1 and 2)

<.05

Lower for PFPEs 4% vs untreated control (LA, day 12)

<.05

Lower for PFPEs 4% vs untreated control (TOL, day 5)

<.05

Fair

12

Healthy volunteers; age 25-56 y (11 women, 1 man)

Application of moisturizer 15 min before exposure to irritant bid × 2d Control: Some had immersion regimen in sterile water at 20°C

Ohlenschlaeger et al, 199653

Fair

10

Healthy female volunteers; age 21-49 y

Forearm immersion in sterile water at 40°C for 10 min bid × 2 d

<.05

EV: Limited

Lower for all PFPEs vs untreated control (SLS, week 1 and 2) Lower for all PFPEs vs untreated control (NaOH, week 1 and 2)

Ramsing and Agner, 199755

<.05

EV: Limited Irritants tested: SLS NaOH LA TOL

<.01

TEWL (g/m2/h)

Higher in control vs treated (day 3)

.001

Excl: Skin disease

Laser Doppler flowmetry (BFV) EC (AU)

Higher in control vs treated (day 3)

.008

Subjects: Permitted to wash hands normally, ensuring that both hands were equally exposed

Lower in control vs treated (day 3)

.002 No other moisturizer permitted 12 h before and during study period

TEWL (g/m2/h)

NS

Amount of moisturizer used (g) noted No significant results as no signs of irritation developed

EC (AU)

NS

EV: Limited

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Study author(s), year published

Ramsing and Agner, 199654

Quality rating

No. of subjects

Fair

19 (1)||

18

Population

A: Healthy women; age 24-55 y

B: Healthy women; age 20-48 y

Intervention

Outcomes: All outcomes considered Spectrometry: Erythema (a*)

Occlusive glove 6 h/d × 14 d

Clinical exam: Erythema, scaling TEWL (g/m2/h)

Control: Bare hand

EC (AU)

Cotton glove worn under occlusive glove 6 h/d × 14 d

Inflammation/ erythema index (spectrometry) TEWL (g/m2/h) EC

Control: Gloved hand (no cotton glove)

Inflammation/erythe ma index (spectrometry)

Results*

P value NS

Comments: Strengths, weaknesses, EV Note: Another part of this study found a significantly higher TEWL with immersion in SLS solution at 40°C compared with 20°C. This study did not meet our inclusion criteria (minimum 10 subjects).

NS Increased in gloved hand

.0007

Higher on gloved hand (day 3 and 8) but no significant difference day 11-14

<.0083 NS

Excl: Previous hand eczema, anamnesis of AD, sensitized to ubiquitous allergens Groups comparable with regard to age and gender. No mention was made of moisturizer use during study EV: Limited

Increased in gloved hand (no cotton) from day 3 to 14 Increased in cotton-gloved hand, but significant only on day 11

d.0077 .0066 NS

a*, balance between red (+ values) and green (– values); AD, Atopic dermatitis; AU, arbitrary unit; b*, the balance between yellow (+ values) and blue (– values); BFV, blood flow volume; bid, twice a day; c*, [(a*)2 + (b*)2]1/2; CD, contact dermatitis; EC, electrical capacitance; EV, external validity, Excl, exclusions from study being discussed; HC/P2, fomblin HC/P2 (perfluoropolyether phosphate); Hx/hx, history; L*, luminance; LA, lactic acid; NaOH, sodium hydroxide; NS, no statistical significance; PFPE, perfluoropolyether; SLS, sodium lauryl sulphate; TEWL, transepidermal water loss; tid, 3 times a day; TOL, toluene. *For example, reduction in relative risk/absolute risk, number of events (treatment vs control). †Five subjects dropped out for reasons not associated with the study. ‡One subject excluded for noncompliance. §There were 88 dropouts from the study. ||One subject excluded because of development of dermatitis, day 3.

845.e8

J AM ACAD DERMATOL NOVEMBER 2005

Supplemental Table IV. Summary of results: Effect of treatments on irritant contact dermatitis Study author(s), year published Held, Lund, and Agner, 200136

Quality rating Good

No. of subjects 36

Population Healthy volunteers; age 18-58 y (29 women; 7 men)

Intervention Application of moisturizer tid × 5 d; moisturizers tested: Ceridal Lipogel, petrolatum, Locobase Repair, Locobase, Decubal, Essex

Outcomes: All outcomes considered TEWL (g/m2/h) EC (AU) Laser Doppler flowmetry (BFV) Erythema index (spectrometry) (AU) Clinical: Erythema Clinical: Scaling

Loden, 199737

Good

13

Healthy subjects; age 24-58 y (10 women, 3 men)

A: Application of moisturizing cream (5% urea and 5% hydrogenated canola oil) to ICD site bid × 14 d

TEWL (g/m2/h)

Results Lower for all moisturizers vs control; rank order (lowest TEWL to highest): petrolatum, Ceridal Lipogel, Locobase, Locobase Repair, Essex, Decubal Higher for Ceridal Lipogel, petrolatum, Locobase Repair, and Decubal vs control Lower for Ceridal Lipogel, petrolatum, Locobase Repair, Locobase, and Decubal, vs control Lower for petrolatum, and Locobase Repair Lower for Ceridal Lipogel, petrolatum, and Locobase Repair vs control Lower for Ceridal Lipogel, petrolatum, Locobase Repair, Decubal, and Essex vs control Lower in treated vs control from graph

P value <.05

ICD: Induced by exposure to SLS <.05 EV: Limited <.05 <.05 <.05 <.05 <.05

Control: Untreated

B: Application of moisturizing cream (5% urea and 5% hydrogenated canola oil) to normal skin bid × 14 d

Comments: Induction agent/technique, strengths, weaknesses, EV Excl: Hand eczema, atopic dermatitis

<.05

Skin hydration (corneometry) (AU)

Higher in treated vs control (day 4-14)

Clinical: Visual evaluation (0-3)

Treated (0) vs control (0)

TEWL (g/m2/h)

Treated (5.5 r 0.8) vs control (6.37 r 1.4) (day 14 only)

<.01

Skin hydration (corneometry) (AU)

Higher in treated vs control (day 1-14)

<.05

Clinical: Visual evaluation (0-3)

Not described

N/A

Visible signs of irritation

Hydrocortisone vs control Petrolatum vs control Fish oil vs control Borage oil vs control Sunflower seed oil vs control Canola oil vs control Canola USF lower vs control Shea butter vs control Shea USF vs control Hydrocortisone lower vs control Petrolatum vs control Fish oil vs control Borage oil vs control Sunflower seed oil vs control Canola oil vs control Canola USF lower vs control Shea butter vs control Shea USF vs control Hydrocortisone lower vs control Petrolatum vs control

Excl: Visible signs of skin disease Allowed to wash normally but prohibited from using any other skin care products on arms ICD: Induced by exposure to SLS solution

NS

EV: Limited Done in conjunction with a prevention study

Control: Untreated

Loden and Andersson, 199638

Good

21

Healthy subjects; age 22-57 y (14 women, 7 men)

Irritant-exposed skin treated with various topically applied lipids × 17 h Control: Water Lipids: Hydrocortisone; petrolatum; fish oil; borage oil; sunflower seed oil; canola oil; shea butter; fractions of unsaponified lipids from canola oil and shea butter

Laser Doppler (skin blood flow)

TEWL

NS NS NS NS NS NS <.05 NS NS .0031 NS NS NS NS NS .0004 NS NS .0003 NS

Excl: Visible signs of skin disease ICD: Induced by exposure to SLS EV: Limited

845.e9

J AM ACAD DERMATOL VOLUME 53, NUMBER 5

Study author(s), year published

Zhai et al, 200260

Ramsing and Agner, 199755

Quality rating

Fair

Fair

No. of subjects

15

12

Population

Healthy Caucasian volunteers; age 32-64 y with moderately dry skin of hands

Healthy volunteers; age 21-55 y (11 women, 1 man)

Intervention

Application of test emulsion to dorsum of hand before gloving, once daily × 5 d

Application of moisturizer to ICD-affected skin tid × 5 d

Outcomes: All outcomes considered

Dryness (visual) (0-4) Erythema (visual) (0-4) Water sorptiondesorption test (AU) TEWL (g/m2/h) Capacitance (AU) TEWL (g/m2/h) Laser Doppler flowmetry (BFV) EC (AU)

Results Fish oil vs control Borage oil vs control Sunflower seed oil vs control Canola oil lower vs control Canola USF lower vs control Shea butter vs control Shea USF vs control Less in treated subjects

P value NS NS NS .0054 .0003 NS NS <.05 NS

Comments: Induction agent/technique, strengths, weaknesses, EV

Poorly defined incl/excl criteria EV: Limited

<.05 NS Not noted Higher in control vs treated (day 5 of treatment)

Lower in control vs treated (day 5 of treatment)

.012

Excl: Skin disease

NS

ICD: Induced by exposure to SLS

.001

Subjects permitted to wash hands normally, ensuring that both hands were equally exposed No other moisturizer permitted 12 h before and during study period Amount of moisturizer used (g) noted

AU, arbitrary unit; BFV, blood flow volume; bid, twice a day; EC, electrical capacitance; EV, external validity, Excl, exclusions from study being discussed; ICD, irritant contact dermatitis; incl, inclusion; LA, lactic acid; N/A, not applicable; NS, no statistical significance; SLS, sodium lauryl sulfate; tid, 3 times a day; TEWL, transepidermal water loss; USF, unsaturated fat.

845.e10

J AM ACAD DERMATOL NOVEMBER 2005

Supplemental Table V. Summary of results: Effect of preventive interventions on allergic contact dermatitis Study authors, year published Wohrl et al, 200159

Quality rating Fair

No. of subjects 45

Population 45 adults with posi patch tests to Ni, Co, Cu, Pd, r Cr (41 women, 4 men)

Intervention Application of DTPA before exposure to allergens (metal) Controls Vehicle at patch test site (pos control) Vehicle r DTPA

Outcomes: All outcomes considered Prevention of pos patch test as determined by ICDRG criteria

Reduction in severity of patch test reactions (absolute No. of 3+ reactions)

Results* 2.5% NiSO4: 1/28 pos vs 24/28 control 5% NiSO4:17/32 pos vs. 30/32 control 1% CoCl2: 6/20 pos vs 19/20 control 5% CuSO4: 5/14 pos vs 13/14 control 1% PdCl2: 16/23 pos vs 17/23 control KCr: 7/13 pos vs 9/13 control 2.5% NiSO4 vs pos control

<.001

5.0% NiSO4 vs pos control

<.001

Fair

48

Healthy service members with self-admitted hx of poison ivy/oak ACD, 92% Caucasian; age 18-44 y (34 men, 14 women)

Application of TSP before patch testing with urushiol (Rhus antigen) Controls Pos control (untreated) Neg control (vehicle)

Handwashing frequency Clinical: Patch test reaction severity (9 point scale from 0-4, using 0.5 increments)

Comments: Strengths, weaknesses, EV Well controlled; however, it was not explicitly stated that all subjects had Ni allergy. Excl: None stated EV: Difficult to assess Patch test readings at 72 h Clinically relevant end point

NS

Hand flora

Vidmar and Iwane,199958

P value <.0001 .0005 .001 .02 NS NS

Control group washing frequency 50% > treatment group at end of study 0.37 (treated) vs 2.39 (control) (ie, mean difference between treated and control sites = –2.02, 95% CI: 2.18, –1.87)

.04 <.001

Excl: Pregnant, HIV+, atopic, significant dermatologic condition (determined by investigator), allergic to glycols/skin care products, systemic corticosteroids or antihistamines within 1 mo, topical steroids on arms/forearms within 2 wk, exposed forearms to sunlight to point of erythema within 7 d, sunburn anywhere within 1 mo, NSAID use within 14 d Thorough screening process included hx, physical exam, HIV and pregnancy testing Patch test evaluation at up to 96 h (powered to detect t0.2 point difference in score)

Brehler et al, 199845

Fair

35-2†

Volunteers with history of Ni contact hypersensitivity; age 20-45 y

Pentoxifylline cream applied to normal skin bid × 8 d (occluded on day 8) before exposure to Ni patch

NS

Clinical score (Rietschel)

EV: Limited EV: Limited

Control: Cream base

Di Nardo et al, 199746

Fair

22

Ni-sensitized women; age 18-45 y

MF applied to patch test site 16 h and 40 h after Ni patch test application (occluded)

Echographic evaluation (skin thickness in mm)

Control: Untreated Ni patch

CB vs control CP vs control

1.38 ± 0.35 vs 1.68 1.23 ± 0.26 vs 1.68

HC acetate vs control MF vs control Image analysis (echo): ' in extent of area of inflammation compared with control echo amplitude on an arbitrary numerical scale (0-255)

Not stated

Patch test evaluation at 64.5 h

Not stated

Both outcomes revealed MF to be significantly different from all products tested, except CP; however, no P values are reported. These data should be interpreted with caution.

NS Not stated

CB vs control

1.35 ± 0.39 vs 1.68 1245 ± 2985

CP vs control

4090 ± 3143

?

HC acetate vs control

5275 ± 3052

?

?

EV: Limited

845.e11

J AM ACAD DERMATOL VOLUME 53, NUMBER 5

Study authors, year published

Quality rating

No. of subjects

Population

Intervention

Outcomes: All outcomes considered

P value ?

Comments: Strengths, weaknesses, EV

Lower scores in treated vs control

<.0001

Lower max scores in treated 98 (68%) treated vs 1 (0.69%) control

<.0001 <.0001

Excl: Immunosuppressive disease/meds, topical steroid/other med application to test sites, pregnant, nursing, significant cutaneous disorder, absent or questionable reaction at control site

Longer time to appearance of reaction in treated vs control

<.0001

Results* MF vs control

Marks et al, 199551

Fair

144

Healthy volunteers with hx of naturally occurring ACD to poison oak/ivy with one episode in past 5 y

Application of 5% quaternium-18 bentonite lotion before patch testing with urushiol (Rhus antigen)

Clinical: Mean score on 0-7 scale Clinical: max scores Clinical: No. with no reaction Clinical: Time to appearance of reaction

3617 ± 3154

EV: Limited

Control: Untreated ', Change; CB, clobetasol butyrate; CI, confidence interval; CP, clobetasol propionate; DTPA, diethylenetriamine pentaacetic acid; EV, external validity; Excl, exclusions from study being discussed; HC, hydrocortisone; hx, history; ICDRG, International Contact Dermatitis Research Group; max, maximum; MF, mometasone furoate; neg, negative; NS, no statistical significance; NSAID, nonsteroidal anti-inflammatory drugs; pos, positive; TSP, topical skin protectant. *For example, reduction in relative risk/absolute risk, number of events (treatment vs control). †Two subjects excluded for missing appointments.

845.e12

J AM ACAD DERMATOL NOVEMBER 2005

Supplemental Table VI. Summary of results: Effect of treatments on ACD Study authors, year published Hachem et al, 200233

Hachem et al, 200134

Quality rating Good

Good

No of subjects 20

14

Population White, female volunteers with Ni contact allergy (confirmed before study); age 22-42 y

Healthy, white, female volunteers with patchconfirmed Ni contact allergy; age 24-36 y

Intervention 0.05% Micronized fluticasone propionate bid × 4 d (started 48 h after Ni patch application) Controls: Saline patch on normal skin (neg control); vehicle applied to Ni patch site (pos control); untreated Ni patch site (pos control) Combination therapy A + B: A = 0.05% fluticasone propionate, B = Dermalex (barrier cream) applied bid (day 4-7) Controls: Untreated Only steroid (A) Only barrier cream (B)

Outcomes: All outcomes considered TEWL (g/m2/h) SC hydration (capacitance [AU]) Clinical score (sum of erythema [0-3], papulation [0-3], itch [0-3]) TEWL (g/m2/h)

SC capacitance (AU)

Clinical score (sum of erythema [0-3], papulation [0-3], itch [0-3])

Parmeix-Spake, Goustas, and Green, 200139

Good

18

Healthy female volunteers with hx of Ni ACD (confirmed by patch testing); age 18-45 y

Immediately after patch test (48 h after application) 10 PL of Eumovate (CB) 0.05% cream applied to test site, then bid for 7d Controls: Untreated Emollient base HC 1% cream

Clinical

TEWL (' from CB) (g/m2/h)

Colorimetry (' from CB) (AU)

Comments: Induction agent/technique, strengths, weaknesses, EV Excl: Active dermatitis, irritant dermatitis, atopic dermatitis

Results Less in treated (day 4, ie, 6 h after treatment application) compared with untreated control Improved in vehicle control compared with untreated (day 8), but no significant effect of treatment compared with either vehicle or untreated control Lower in treated (day 7, 8) compared with untreated control

P value <.001

Decreased in A + B vs untreated (day 5, 6, 8)

<.009

Decreased in A + B vs A (day 8)

.002

Decreased in A + B vs B (day 5)

.022

Excl: Active dermatitis, irritant dermatitis, atopic dermatitis

Decreased in A vs B (day 8)

.022

EV: Limited

Increased in A + B vs untreated (day 6, 8) Increased in A + B vs A (day 7, 8) Increased in B vs untreated (day 5-8) Increased in B vs A (day 6-8) A + B (2.00) vs B (1.43) (day 7)

d.035 .035 d.026 d.019 .041

B (1.43) vs A (1.86) (day 7)

.038

B (1.43, 0.86) vs untreated (2.00, 1.07) (day 7, 8)

d.031

Visual: No significant difference in rate of healing Patient rated pruritus

NS

HC 1% cream (–7.1; 95% CI: 11, –3.4)

<.001

Untreated (–8.5, 95% CI: 12, –4.9)

<.001

CB base (–2.8, 95% CI: 6.5, –0.8)

NS

.007 ACD: Induced using Ni patch EV: Limited <.014

NS

A: Induced using Ni patch

Excl: Skin that would not allow accurate evaluation (too dark, too much hair, too many nevi, clinically significant dermatosis), hx of hypersensitivity/allergy to any drug incl study meds or their constituents, treatment with topical or systemic corticosteroids within previous 4 wk, hx of alcoholism/drug abuse

HC 1% cream

NS

Untreated (-1.5, 95% CI: 2.3, –0.7)

<.001

Prohibited: Use of concomitant medication (systemic/topical) during study that may have affected outcome Phototherapy/UV exposure

CB cream base

NS

A: Induced using Ni patch Questionable validity of Physician Global Assessment as outcome measure, incompatible with blinded assessment

Queille-Roussel et al, 199042

Good

12

Healthy volunteers with Ni contact allergy (based on hx of pos patch test); age 21-38 y (11 women, 1 man)

Application of antiinflammatory agents (CP 0.05%, HC 1%, indomethacin 2.5%, or bufexamac 5.0%) bid × 4.5 d

Clinical: Visual (0-9) ('day7-day3)

Dermoval showed improvement

Control: vehicle

Colorimetry (a*) ('day7-day3)

Dermoval showed improvement –6.41 r 0.93

<.05

EV: limited Excl: Local/systemic treatment A: Induced using Ni patch

<.05

Note: Regression model demonstrated that the following were predictive of 'VS: 'a* 'L* 'b*

845.e13

J AM ACAD DERMATOL VOLUME 53, NUMBER 5

Study authors, year published

Quality rating

No of subjects

Population

Intervention

Outcomes: All outcomes considered Colorimetry (L*) ('day7-day3) TEWL (g/m2/h) ('day7-day3) Laser Doppler velocimetry (SBF) ('day7-day3)

Vernon and Ohlsen, 199057

Fair

20

Subjects with Rhus contact allergy; age 20-40 y

CP ointment to patch-tested area (Rhus antigen) bid started at 12 (CP 12), 24 (CP 24), or 48 h (CP 48) after application of patch; continued bid for 14 d Control: White petrolatum

Erythema

Induration/edema

P value <.05

Comments: Induction agent/technique, strengths, weaknesses, EV Log (SBF) (day 7) Log (TEWL) (day 7)

NS

Poor/incomplete reporting of results

Dermoval showed improvement –1.17 r 0.20

<.05

EV: Limited

Less at CP 12 (day 4) v. control

<.03

Less at all sites (day 7-10) vs control

<.01

Less at CP12 and CP 24 (day 14) vs control

Not stated <.01

Excl: Pregnant, nursing, dermatitis in study area, topical steroids within 2 wk, immunosuppressed/systemic corticosteroids within 1 mo, atopic dermatitis, asthma, allergic rhinitis, immune disorder, diabetes mellitus

Results Dermoval showed improvement 3.16 r 0.75

Less at all sites at day 7 vs control Less at CP 12 and CP 24 (day 14)

Pruritus

Less at CP 12 vs/ control (day 2)

Not stated .05

Vesiculation

Less at CP12 (from day 2-14) vs control

<.05

Less at CP 24 (from day 4-14) v. control

<.05

Less at CP 48 (from day 7-14) vs control

<.05

EV: Limited

', Change; 'VS, change in visual score; AU, allergenic unit; bid, twice a day; CB, clobetasol butyrate; CI, confidence interval; CP, clobetasol propionate; EV, external validity, Excl, exclusions from study being discussed; HC, hydrocortisone; hx, history; neg, negative; NS, no statistical significance; pos, positive; SBF, skin blood flow; SC, stratum corneum TEWL, transepidermal water loss.