A Systematic Review Of Topical Corticosteroid Withdrawal .

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REVIEWA systematic review of topical corticosteroidwithdrawal (‘‘steroid addiction’’) in patientswith atopic dermatitis and other dermatosesTamar Hajar, MD,a Yael A. Leshem, MD,a Jon M. Hanifin, MD,a Susan T. Nedorost, MD,b Peter A. Lio, MD,cAmy S. Paller, MD,c Julie Block, BA,d and Eric L. Simpson, MD, MCR,a (the National Eczema Association Task Force)Portland, Oregon; Cleveland, Ohio; Chicago, Illinois; and San Rafael, CaliforniaBackground: The National Eczema Association has received increasing numbers of patient inquiriesregarding ‘‘steroid addiction syndrome,’’ coinciding with the growing presence of social media dedicated tothis topic. Although many of the side effects of topical corticosteroids (TCS) are addressed in guidelines,TCS addiction is not.Objective: We sought to assess the current evidence regarding addiction/withdrawal.Methods: We performed a systematic review of the current literature.Results: Our initial search yielded 294 results with 34 studies meeting inclusion criteria. TCS withdrawalwas reported mostly on the face and genital area (99.3%) of women (81.0%) primarily in the setting oflong-term inappropriate use of potent TCS. Burning and stinging were the most frequently reportedsymptoms (65.5%) with erythema being the most common sign (92.3%). TCS withdrawal syndrome can bedivided into papulopustular and erythematoedematous subtypes, with the latter presenting with moreburning and edema.Limitations: Low quality of evidence, variability in the extent of data, and the lack of studies with rigoroussteroid addiction methodology are limitations.Conclusions: TCS withdrawal is likely a distinct clinical adverse effect of TCS misuse. Patientsand providers should be aware of its clinical presentation and risk factors. ( J Am Acad Dermatol http://dx.doi.org/10.1016/j.jaad.2014.11.024.)Key words: atopic dermatitis; pruritus; red face; side effects; steroid addiction; topical corticosteroidwithdrawal; topical corticosteroids.opical corticosteroids (TCS) are the first-linetherapy for the treatment of atopicdermatitis according to various independently published international guidelines from bothdermatology and allergy groups worldwide1-6 andhave been shown to have a positive impact on thequality of life of patients.7,8 TCS have been shown tobe a safe treatment option both in short-term dailyuse and long-term intermittent application.9TThere has been a growing presence of socialmedia addressing side effects from chronic TCS use,especially when TCS are withdrawn. This concernfor possible ‘‘steroid addiction’’ may contribute toreduced adherence and therapeutic failure.10,11Several Internet sites and patient blogs recommendthat TCS not be used in the management ofatopic dermatitis to avoid steroid addiction. Suchrecommendations and commentaries are in starkFrom the Oregon Health and Science Universitya; UniversityHospital Case Medical Center, Clevelandb; Northwestern University, Chicagoc; and National Eczema Association, San Rafael.dFunding sources: None.Conflicts of interest: None declared.Accepted for publication November 20, 2014.Reprint requests: Eric L. Simpson, MD, MCR, Department ofDermatology (Mail Code CH16D), Oregon Health and ScienceUniversity, 3303 SW Bond Ave, Portland, OR 97239-4501. E-mail:[email protected] online January 12, 2015.0190-9622/ 36.00Ó 2014 by the American Academy of Dermatology, Inc.http://dx.doi.org/10.1016/j.jaad.2014.11.0241

2 Hajar et alJ AM ACAD DERMATOLof the eruption at some point after TCS cessationcontrast to the published evidence-based atopicwas considered contributory to the diagnosis.dermatitis treatment guidelines,1-4,6,12 which statethat proper use of TCS is integral to the treatment of3. Study design: Because of the anticipated lowmost patients with atopic dermatitis.number of studies and lack of uniformityA clearer understanding of this adverse effect willregarding disease definition, we elected toallow for fully informed choices by providers, parents,include all relevant published studies regardlessand patients during the management of atopic dermaof study design.titis and other dermatoses.Exclusion criteria.The objective of thissystematic review was to1. Lack of a clear temporalCAPSULE SUMMARYbetter define the steroidrelationship among TCSaddiction/withdrawal synLittle is known about steroid withdrawaluse, TCS withdrawal, anddrome, outline its signssyndrome and there is a growingthe eruption.and symptoms, identifypresence of social media around this2. Reviews or expert opinpotential risk factors, andtopic.ions that do not includereview existing therapiesspecific case d on the scientific3.Lack of precise data e.exact number of patientsPatients and providers should be awarewith the syndrome in theof the clinical features and risk factors toMETHODSreport).identify and prevent this complication.This systematic review wasregistered with PROSPEROData extractionInternational prospective regTwo independent reister of systematic reviews (CRD42013005370). Weviewers extracted the data of included studies ontosearched Ovid MEDLINE, PubMed, the Cochranean Excel (Microsoft, Redmond, WA) extraction dataLibrary, and grey literature from January 1946 toform, which includes the fields shown in Tables II toApril 2014, using search terms relating to TCSVI.withdrawal, addiction, abuse, tolerance, rebound,dependence, rosacea, red skin, red face, red scrotum,Quality assessmenttachyphylaxis and status cosmeticus, perioral dermaAt the individual study level, quality wastitis, acneiform, and rosacea-like eruptions. Theevaluated according to the GRADE guidelines.13search strategy is outlined in Table I (available atWe defined the level of evidence (levels 1-4)http://www.jaad.org). References of key articles weresupporting each article.14hand searched to find additional articles.dddAll captured titles and abstracts were screened by 2reviewers (T. H. and Y. A. L.). The remaining articleswere studied by the same reviewers for relevanceusing inclusion exclusion criteria. Only studies thatreported symptoms after withdrawal of TCS wereincluded. Studies of adverse effects that occur duringthe use of TCS were not included.Study selection criteriaInclusion criteria.1. Language: English.2. Relevance: Articles must have described at least 1case of steroid withdrawal as defined by thefollowing criteria: (A) Cutaneous eruption thatfollowed TCS use, which either appeared:(i) after discontinuation of TCS or (ii) whenelevated doses and applications of TCS wereneeded to prevent it from appearing. (B) Theeruption was localized to the site(s) ofapplication (at least primarily). (C) ResolutionData synthesisData were combined at the aggregate level andevaluated using descriptive methods. The followingoutcomes were defined:Primary outcome.1. Clinical features of TCS withdrawalA. Patient factors: Age, gender, indication forTCSB. TCS factors: potency, duration of useC. Signs including morphology and locationD. SymptomsSecondary outcomes.1. Histologic features of TCS withdrawal2. TreatmentA. Treatment modalitiesB. Response to treatmentC. Duration of treatments

Hajar et al 3J AM ACAD DERMATOLTable II. Studies included in the systematic reviewAuthorsYearArticle type (No. of patients*)Level of 0620072008200820092010201120112011201120112013Case series (8)Case report (1)Case series (6)Case series (2)Case series (10)Case report (1)Case series (3)Case series (25)Cross-sectional (259)Case report (1)Case series (23)Case series (2)Case series (135)Case report (1)Case series (100)Case series (5)Case report (1)Case report (1)Case report (3)Case report (1)Case series (10)Case report (1)Case series (5)Case seriesz (40)Case series (9)Case seriesz (50)Case report (1)Case series (312)Case report (1)Case series (110)Cross-sectional (65)Case report (1)Case report (1)Case series ddon163Weber174Burry185Leyden et al196Stegman207Kligman218Urabe and Koda229Wilkinson et al2310Franco and Weston2411Sheu and Chang2512Wells and Brodell2613Uehara et al2714Velangi et al2815Rapaport and Rapaport2916Rapaport and Rapaport3017Brodell and O’Brien3118Fukaya3219Goldman3320Pabby et al3421Rapaport and Lebwohl3522Zalaudek et al3623Rathi3724Chu et al3825Abbas et al3926Liu and Du4027Chen and Zirwas4128Lu et al4229Del Rosso4330Rathi and Kumrah4431Saraswat et al4532Zhang and Zhu4633Monroe et al4734Narang et al481206 total patientsGRADE wlowlowlowlowlowlowlowlowlowlowlowlowlowlowlow*No. of patients with topical corticosteroid withdrawal syndrome (not to the total No. of reported patients in publication).yQuality of evidence in regard to topical corticosteroid withdrawal, not overall quality of evidence.zBefore-after study.3. Evaluation for exclusion of alternate diagnoses(eg, patch testing, phototesting)4. Nomenclaturestudies and identified as being a lower level ofevidence (level 4). All studies were ranked as verylow quality according to the GRADE guidelines.13RESULTSPrimary outcomeeclinical featuresPatient factors. The majority of patients withmanifestations of TCS withdrawal were women(81%) who had used TCS on their face (97%). Theprimary indication for the initial use of TCS wasatopic dermatitis in 33.3% followed by cosmetic useand pigmentary disorders in 14.3% and a variety ofother conditions (Table III).TCS factors. The majority of the describedpatients were using either mid- or high-potencyTCS (98.6%). Data regarding frequency of use wereThe search yielded a total of 294 articles. After 2independent reviewers screened titles and abstracts,123 articles remained. Review of the references ofkey articles for relevant articles added 69 additionalcitations. A total of 192 full-text articles were thenevaluated applying the inclusion/exclusion criteria.The review included 34 studies for analysis (Fig 1 andTable II), with the oldest article published in 1969and the most recent in 2013. The level of evidenceand study quality were consistent throughout the

4 Hajar et alJ AM ACAD DERMATOLTable III. Patient and steroid characteristics of topical corticosteroid withdrawalAllErythematoedematousFeature (No. of patients)*GenderFemaleAge, y\18[18Indication for TCS useAtopic dermatitisCosmetic use and pigmentary disordersFacial rash, red scrotumSeborrheic dermatitis, pityriasis simplexAcneOtheryRosaceaPerioral dermatitisLocation of TCS usezFaceGenitalOtherxTCS potency//LowMidHighFrequency of useContinuous daily useDuration of use, mo\11-3[3-6[6-12[12PapulopustularNo. of patients (%)(n 1085)879 (81)(n 963)69 (7.1)894 (92.8)(n 752)251 (33.3)121 (16.0)105 (13.9)72 (9.5)69 (9.1)65 (8.6)44 (5.8)21 (2.7)(n 1147)1113 (97)27 (2.3)7 (0.6)(n 364)5 (1.3)134 (36.8)225 (61.8)(n 40)40 (100)(n 210)7 (3.3)7 (3.3)2 (0.9)12 (5.7)179 (85.2)(n 263)158 (60)(n 128)0128 (100)(n 263)210 (79.8)4 (1.5)17 (6.4)26 (9.8)4 (1.5)2 (0.7)00(n 194)184 (94.8)6 (3)4 (2)(n 67)4 (5.9)26 (38.8)37 (55.2)(n 10)10 (100)(n 187)7 (3.7)7 (3.7)010 (5.3)163 (87.1)(n 446)394 (88.3)(n 456)41 (8.9)415 (91)(n 273)7 (2.5)111 (40.6)93 (34)20 (7.3)22 (8)5 (1.8)12 (4.3)3 (1)(n 472)469 (99.3)1 (0.2)2 (0.4)(n 297)1 (0.3)107 (36)189 (63.6)(n 14)14 (100)(n 29)01 (3.4)2 (6.8)7 (24.1)19 (65.5)TCS, Topical corticosteroid.*No. of patients with reported data for the specified feature. If partial or imprecise data were reported, we estimated the data to the best ofour understanding.ySeasonal, eyelid, contact, hand eczema, lichen simplex chronicus, winter itch, solar dermatitis, pityriasis alba, scaling, tinea, intertrigo, postsunburn, vitiligo, herpes simplex virus infection, folliculitis, urticarial.zIn 31 patients the eruptions expanded beyond the application site (initial sites: 29 facial, 1 genital, 1 forearm).xn 1 for each: perianal; arms; back of hands; right forearm; legs; erythroderma.//TCS potency was defined as follows: low class 6-7; medium class 4-5; high class 1-3. Potency descriptions (eg, medium strength)without specified formulations were included. The last applied formulation is the one depicted in the table.limited. Only 1 study clearly specified the frequencyof use in the patients with steroid withdrawal. Thisstudy of 40 patients reported that all patients withTCS withdrawal had been using TCS daily.38 Dataregarding duration of use were reported in 14 studies(210 total patients) and 85.2% reported their use formore than 12 months.Signs. Data on signs were able to be extractedfrom 1141 patients in this category; not all articlesincluded each of the clinical features (Table IV). Themost common sign was erythema (92.3%). Onearticle (n 100 patients) described a sharp cutoffbetween red and normal-appearing skin that oftenran down the mid to outer cheeks whereas the noseand the ears remained clear, referred to as the‘‘headlight’’ sign.29 Papules 6 nodules and pustuleswere reported in half of the patients.Symptoms. The most frequently reportedsymptoms were burning/stinging, exacerbationwith heat or sun, pruritus, pain, and facial hotflashes.Subtypes. Clinical features and patient factorsare described in Tables III and IV. Three articles wereexcluded from this subanalysis because the datacould not be extracted by subtype,40,42 and 1because it did not describe clinical features.45 In apost hoc analysis of the data, 2 morphologicallydistinct subtypes emerged: (1) a papulopustular

Hajar et al 5J AM ACAD DERMATOLTable IV. Clinical features of topical corticosteroid withdrawalAllFeature (No. of patients)*Onset of symptoms upon withdrawaly24-48 hr48-96 hr4-14 d14-21 dSymptomsBurning/stingingExacerbation with heat or sunP