Topical corticosteroids in plaque psoriasis: a systematic review of efficacy and treatment modalities

Transcription

1 DOI: /j x JEADV REVIEW ARTICLE Topical corticosteroids in plaque psoriasis: a systematic review of efficacy and treatment modalities E. Castela, E. Archier, S. Devaux, A. Gallini, S. Aractingi,** B. Cribier, D. Jullien, F. Aubin, H. Bachelez, P. Joly,*** M. Le Maître, L. Misery, M.-A. Richard, C. Paul, J.P. Ortonne Dermatology Department, Nice University, L Archet II Hospital, Nice Dermatology Department, Aix-Marseille University, UMR 911, INSERM CRO2, Timone Hospital, Marseille Dermatology Department UMR 1027 INSERM, Paul Sabatier University, Toulouse **Dermatology Department, Tenon Hospital, APHP and Paris 6 University, Paris Dermatology Department, University Hospital, Strasbourg Dermatology Department, Edouard Herriot Hospital, Lyon Dermatology Department, Franche Comté University, EA3181, IFR133, University Hospital, Besançon Dermatology Department, Saint-Louis Hospital, Paris ***Dermatology Department, Charles Nicolle Hospital, INSERM U 905 University of Rouen, Rouen Dermatologist, Caen Dermatology Department, University Hospital, Brest, France *Correspondence: E. Castela. emelinecastela@yahoo.fr Abstract Introduction Topical steroids are used for more than 50 years to treat mild-to-moderate plaque psoriasis. The purpose of this systematic review was to evaluate the efficacy but also the optimal modalities of administration of topical corticosteroids in psoriasis i.e. influence of steroid potency on clinical response, putative impact of topical formulation, occlusion procedure, rate of application to control the initial response and the potential interest of a maintenance treatment to prolong psoriasis clearance. Material and methods A systematic search was performed between 1980 and January 2011 in Medline, Embase and Cochrane databases (English and French language, adults), using the keywords psoriasis exp mj AND corticosteroid exp mj. To analyse response across studies, three levels of response were categorized depending on the data available in studies: percentage of patients who achieved more than 50%, 75% or 90% improvement of initial psoriasis severity. Results From an initial selection of 1269 references, 1166 references were excluded on reading the title or the abstract and 32 on reading the article and 71 were finally retained and analysed. Fifty randomized controlled trials (RCT) assessing topical steroids in the initial treatment of mild-to-severe psoriasis body plaque psoriasis were retained: 40 were parallel-group studies and 10 were within-patient studies. Treatment duration was mostly 4 weeks. Sample size varied from 30 to patients. Outcome measures to assess efficacy were highly variable. A total of 30 90% patients across parallel group studies experienced more than 50% of initial mild-to-severe psoriasis improvement while from 7% to 85% experienced more than 75% improvement and from 5% to 85% experienced at least 90% of improvement. The success rate in the within-patient studies varied from 10% to 70%. Eighteen RCT were performed in scalp psoriasis: 16 were parallel-group and two were within-patient studies, with a treatment follow-up time from 2 weeks to 6 months, enrolling patients. A total from 40% to 75% patients across studies experienced more than 75% of initial scalp psoriasis improvement and from 43% to 90% experienced more than 90% initial psoriasis improvement. Only three RCT studies evaluated topical steroids as a maintenance treatment for body psoriasis and one for scalp lesions. Despite heterogeneity in treatment schedule, topical steroid intermittent maintenance treatment was shown to prolong remission. The literature analysis did not provide with high evidence-based quality data on the role of formulation, topical steroid potency, number of applications per day to obtain the highest rate of success excepting occlusion dressing which provided with additional benefit.

2 Topical corticosteroids in plaque psoriasis 37 Conclusion The clinical development of topical steroids in psoriasis did not follow state of the art modern methodology. Treatment success appears to be highly variable across studies. Maintenance intermittent treatment appears to be useful to prolong remission. Recommendations concerning topical steroids treatment modalities in plaque psoriasis should be mostly based on expert opinion. Received: 10 February 2012; Accepted: 20 February 2012 Funding sources Abbott France provided financial support for publication but took no further part in the project. The authors have no financial interest in the subject matter or materials discussed in the manuscript. Conflicts of interest All the authors have been paid consultants of Abbott. In addition C. Paul has been investigator and consultant for Janssen-Cilag, Leo, Novartis and Wyeth. H. Bachelez has been paid for consulting activities for Centocor, Janssen- Cilag, Leo Pharma, Novartis, Pfizer, and Schering-Plough. B. Cribier has been paid for consulting activities for Pfizer, for redaction activities by Leo Pharma and Janssen Cilag and speaker for Pfizer, Leo Pharma and Schering Plough. D Jullien has been consultant for Merck, Janssen-Cilag, Novartis, Pfizer, and Schering-Plough MSD. JP Ortonne has been investigator, speaker and advisor for Schering-Plough MSD, Abbott, Merck Serono, Centocor, Pfizer, Janssen Cilag, Pierre Fabre, Galderma, Leo Pharma, Meda. L. Misery has been a paid consultant of Novartis, Janssen-Cilag, Leo Pharma, Pfizer and Pierre Fabre. MA Richard has been investigator and consultant for Janssen- Cilag, Novartis, Pfizer. Introduction Chronicplaquepsoriasisisthemostcommontypeofpsoriasis. First line management of adult mild-to-moderate adult plaque psoriasis is with topical treatment, including vitamin D analogues and topical corticosteroids. Topical corticosteroids are available in different potencies and formulations but despite more than 40 years of experience, their use remains mostly based on individual experience. Published guidelines often specify the place of topical steroids within psoriasis treatment strategies 1 3 but not the efficacy and practical modalities of use. Moreover, as psoriasis is a chronic disease, strategies to maintain remission are important to define. Maintenance regimens have therefore been developed to prevent relapses and to allow prolonged treatment with these agents while minimizing side-effects. The aim of this study was to perform a systematic literature review to prepare for evidence-based recommendations on the efficacy of topical steroids in plaque psoriasis including treatment modalities to induce remission and prevent recurrence. The reviewing process leading to these recommendations is described in detail in the same issue of this journal. 4 Material and methods A systematic review of all studies investigating topical corticosteroids in adult plaque-type psoriasis published between 1980 and February 2011 was performed to assess topical steroids efficacy including treatment modalities to induce remission, frequency of application, use of occlusion dressing, importance of formulation, role of topical steroid potency and efficacy of maintenance treatment strategies to prolong psoriasis clearance. The Cochrane, Embase and Medline databases were systematically searched. We used a combination of Medical Subject Headings (Mesh) for our search: psoriasis [Majr] AND Corticosteroids [Majr]. We limited the literature search to articles on human subjects over 19 years of age, articles in English or French and articles reporting original data. Two reviewers (EC, JPO) independently performed parts of the systematic electronic search and data extraction. The selection of relevant studies was initially made by reviewing title and abstract, excluding manuscripts which did not address the previously mentioned topics, then for remaining studies by reading the complete article. Disagreements were resolved by discussion and reviewers were 100% unanimous in their final decisions. We selected only randomized controlled (RCT) trials in the analysis. Trials could be either placebo-controlled or active-controlled with a vitamin D preparation. Three types of study design were eligible for inclusion: parallel group (between-patient or inter-individual) studies, cross-over and within-patient designs (within-patient or intra-individual studies). For within-patient studies, we included only studies having adopted a left right comparative design. Studies with fewer than 30 patients were excluded. To assess efficacy of topical steroids in the treatment of psoriasis we also excluded studies where plaques in a same patient are treated with more than two products (plaque to plaque comparison). We also excluded studies evaluating the effect of treatment on a single

3 38 Castela et al. target lesion with the exception of the evaluation of occlusive dressings. Indeed occlusive steroid dressings were only assessed in blinded within-patient studies on target lesions. The following data were extracted for the articles: database, author, year, study design, inclusion period, number of psoriasis patients, severity of psoriasis at baseline, potency of topical steroids assessed in the trial, frequency of topical steroid applications, formulation, the use of occlusion dressing, duration of treatment, efficacy outcome measures and criteria for treatment success, number of patients achieving treatment success, strategy for maintenance regimen including frequency of application and treatment duration. Analyses were performed separately for studies investigating body and scalp psoriasis. We defined three levels of response treatment success according to the parameters used in the studies: percentage of patients achieving at least a 50%, 75% or 90% improvement of their initial psoriasis. The method for grouping of the different outcome parameters employed in articles is described in Table 1. If different success rate definitions were available for the same study, we retained only the most stringent definition. Corresponding binomial 95% confidence intervals (CI) of success rates were calculated using STATA software (StataCorp Stata Statistical Software: Release 11. College Station, TX, USA: StataCorp LP). Due to the large heterogeneity in studies regarding outcome parameters, topical steroid molecule, we only performed graphical representations according to the different levels of response on forest plots without any meta-analysis. As the primary indication of topical steroids is mild-to-moderate psoriasis, we performed a separate analysis of efficacy in this population defined by a body surface area (BSA) < 10%. Table 1 Efficacy outcome parameters in topical steroids clinical trials and corresponding response levels Level of response At least 50% At least 75% At least 90% Efficacy outcome parameters in trials Clear or marked, or moderate improvement Improvement at least moderate Clear, or marked improvement Healing or marked improvement PASI 75 Good or excellent investigator global assessment (IGA) PGA : clear or good or excellent GSS = 0 or 0.5 or 1 Clearance or considerable improvement Clear Completely clear Clear or almost clear PGSA = 0 or 1 PASI 90 PASI, Psoriasis Area Severity Index, PASI 75, improvement of at least 75% of the PASI, PASI 90, improvement of at least 90% of the PASI; PGA, Physician Global Assessment; GSS, Global Severity score. Results From an initial selection of 1269 references: 1166 were excluded on reading the title or the abstract, 32 on reading the article and finally 71 references were retained including 50 studies about topical steroids published in 48 articles with 40 parallel-group and 10 within-patient studies assessing topical steroids for body plaque psoriasis, 18 trials assessed the use of topical steroids for scalp psoriasis, four studies evaluated their use for maintenance treatment for body plaque or scalp psoriasis and one assessed the potential for occlusion to improve psoriasis clearance. Among the 32 excluded articles, 11 were individual plaque studies, three assessed the combination of a topical steroid without a topical steroid only arm, five evaluated a single target lesion and the 13 remaining studies were rejected mainly for various reasons. The detailed flowchart describing both selection process and reasons for exclusion is illustrated in Fig. 1. Efficacy of topical steroids in the treatment of body plaque psoriasis: (Fig. 2, 3 and 4) Fifty RCTs (published in 48 articles) evaluated the efficacy of topical steroids in the treatment of body plaque psoriasis The number of enrolled patients varied from patients according to the trial (mean 200 patients). Forty of these studies were between-patient studies 5 19,22 24,26 32,34 39,41,43,44,46,48 51,53 ;ofthose 11 were placebo-controlled studies 6,8,11,15,18,28,31,36,38,39,49, and 20 studies were comparative between two topical steroids. 5,7,10,14,17,19,23,24,26,27,30,32,35,36,44,46 48,50,54 Six studies compared a topical steroid and a vitamine D analogue 13,16,34,37,41,51, two studies compared a topical steroid alone with the combination of topical steroid and salicylic acid or salicylic acid alone 9,22 and one study compared topical steroid with aloe vera. 29 Ten studies were within-patient studies 20,21,25,27,31,33,40,42,45,52 including four placebo-controlled studies 31,33,42,45 and six studies comparing two topical steroids. 20,21,25,27,40,52 Treatment duration needed to control or to clear the disease was defined prospectively without clear justification. It ranged from 2 5,8,10,12,20,24,25,27,31,36,39,42,44,46,50 52 to 12 weeks 33,themajority of studies investigating 4 weeks treatment. 7,11,14,15,17,18,21,26,28,30,34,35,37,38,40 Efficacy outcome measures were highly variable across studies. Only five studies used the Psoriasis Area Severity Index (PASI). 16,29,34,37,41 Overall, the mean percentage change in PASI at 4 or 8 weeks ranged from )45% to 60% in the five studies (Table 2). Molin et al. 16, compared calcipotriol cream (210 patients) with betamethasone 17-valerate cream 1 mg g both applied twice daily, without occlusion, for 8 weeks or up to complete clearance in 211 patients. The mean reduction from baseline in PASI in patients treated with betamethasone was 2.8 (95% CI ) corresponding to a mean 45.4% reduction in PASI. Singh et al. 34 compared PASI in 25 patients with stable plaque psoriasis treated with betamethasone dipropionate (BMP) 0.05% cream once daily in the first and third week and calcipotriene 0.005%

4 Topical corticosteroids in plaque psoriasis 39 Potentially relevant articles published between 1975 and 2010 identified by electronic search: N = 1269 Pubmed : n = 629 ; Embase : n = 530 ; Cochrane : n = 110 Studies excluded (by reading of title or abstract) N = 1166 Did not address the question n = 1021 Assessed ratio benefits costs : n = 2 Less than 30 patients included: n = 15 Quality of life studies: n = 2 Safety studies: n = 3 Association vitamine D and topical steroids without any arm with topical steroids alone: n = 20 Duplicates: n = 103 Studies excluded (by reading of article) N = 32 Intraindividual studies plaque vs plaque : n = 11 No general assessment: n = 5 Concerned the same patients: n = 1 Children: n = 3 Duplicates: n = 2 Not randomized: n = 2 Cohort: n = 1 Complexity of study design: n = 1 Fewer than 30 patients: n = 2 Factor of confusion: n = 3 Only nail psoriasis: n = 1 71 articles included Figure 1 Flow-chart of study selection process. Study TS Study duration (weeks) N (arm) Huntley 85 AMC 2 16 Huntley 85 BMD 2 15 Ellis 89 BMD Ellis 89 FLUO Schupack 93 DIFLO 2 22 Schupack 93 BMD 2 22 Lebwohl 02 CP 2 61 Sears 97 HYD 3 94 Katz 98 MO Fabry 83 HALOM 4 94 Peharda 00 MO 4 30 Peharda 00 Bruce 94 BMD FLUO Response 50% Jegasothy 85 CP 2 57 Jegasothy 85 FLUO 2 57 Lebwohl 02 CP 2 61 Bernard 91 HB 3 36 Katz 87 BMD 3 20 Katz 87 CP 3 20 Leibsohn 82 DIF 3 48 Leibsohn 82 BMD 3 52 Sears 97 HYD 3 94 Koo 98 MO Aggerwal 82 ACLO 3 16 Aggerwal 82 CLOB 3 15 Mensing 91 HB 4 53 Mensing 91 BMD 4 52 Goldberg 91 HB 4 68 Goldberg 91 CP 4 66 O sen 96 FC 4 88 Olsen 96 FC Roberts 96 FC 4 37 Roberts 96 BMD 4 37 Fabry 83 HALOM 4 94 Lowe 05 CP Decroix 04 CP Blum 91 HB 4 42 Blum 91 BMV 4 42 Choonhakarn 10 TRIAM 8 40 Response 75% Molin 97 BMV Gootlieb 03 CP Mraz 08 CP 2 36 Mraz 08 CP 4 41 Kaufmann 02 BMD Jarratt 06 CP 4 60 Pierard 96 HYD 4 69 Pierard 96 BMV 4 67 Singh 00 BMD 4 27 Response 90% Fleming 10 BMD Patients with a response to topical steroids (%) Abbreviations: ACLO: aclomethasone, AMC: amcinonide, BMD: betamethasone dipropionate, BMV: betarnethasone valerate, FLUO: fluocinonide, CP: clobetasol propionate, DIF: diflorasone, DMT: desoximethasone, FC: fluticasone, FLUO: fluocinonide, HALOM: halomethasone, HB: halobetasol, HYD: hydrocortisone, MO: mometasone, N: number of patients in the topical steroid arm TRIAM: triamcinolone, TS: topical steroids assessed. Figure 2 Efficacy of topical steroids in mild-to-severe body plaque psoriasis: parallel-group studies.

5 40 Castela et al. Study TS Study duration N (arm) (weeks) Peharda 00 MO 4 30 Peharda 00 BMD 4 30 Bruce 94 FLUO 6 57 Bernard 91 HB 3 36 Sears 97 HYD 3 94 Mensing 91 HB 4 53 Mensing 91 BMD 4 52 Goldberg 91 HB 4 68 Goldberg 91 CP 4 66 Olsen 96 FC 4 88 Olsen 96 FC Blum 91 HB 4 42 Blum 91 BMV 4 42 Choonhakam 10 TRIAM 8 40 Molin 97 BMV Gootlieb 03 CP Mraz 08 CP 2 36 Mraz 08 CP 4 41 Kaufmann 02 BMD Jarratt 06 CP 4 60 Singh 00 BMD 4 27 Response 50% Response 75% Response 90% Patients with a response to topical steroids (%) Abbreviations: ACLO: aclomethasone, AMC: amcinonide, BMD: betamethasone dipropionate, BMV: betamethasone valerate, FLUO: fluocinonide, CP: clobetasol propionate, DIF: diflorasone, DMT: desoximethasone, FC: fluticasone, FLUO: fluocinonide, HALOM: halomethasone, HB: halobetasol, HYD: hydrocortisone, MO: mometasone, N: number of patients in the topical steroid arm, TRIAM: triamcinolone, TS: topical steroids assessed. Figure 3 Efficacy of topical steroids in mild-to-moderate body plaque psoriasis: parallel-group studies. Study TS Study duration N (arm) (weeks) Lebwohl 95 a Krueger 98 a Krueger 98 a Lebwohl 95 a Jacobson 86 a Jacobson 86 a Gip 94 b Stein 01 c FLUO FLUR 4 30 DIF 4 30 DIF CP BMD BMV 4 67 BMV Patients with a response to topical steroids * (%) * Response was defined by the investigators as following: a improvement > 75% b clear c improvement > 80% Abbreviations: BMD: betamethasone dipropionate, BM\/: betamethasone valerate, CP: clobetasol propionate, DIF: diflorasone, FLUO: fluocinonide, FLUR: flurandrenolide, N: number of patients in the topical steroid arm, TS: topical steroid assessed Figure 4 Efficacy of topical steroids in the treatment of mild-to-severe body psoriasis: within patient studies. ointment twice daily in the second and fourth week vs. a control group of 27 patients using continuous betamethasone once daily for 4 weeks. In the control group, 5 of 27 patients 18.5%, [95% CI ] had a 90% or greater reduction in baseline PASI at 4 weeks. Kaufmann et al. 37 randomized psoriasis patients to receive a combination of betamethasone and calcipotriol (n =490)vs.betamethasone(n = 476) or calcipotriol (n = 480) or vehicle (n =157)oncedailyforupto4weeks.Themeanpercentage reduction in the PASI at the end of treatment was )57.2 in the betamethasone arm. Choonhakarn et al. 29 assessing the respective efficacy of aloe vera (AV) and 0.1% triamcinolone acetonide (TA) demonstrated the mean PASI decreased from 10.9 to

6 Topical corticosteroids in plaque psoriasis 41 Table 2 Summary of the five topical steroid studies using PASI as efficacy outcome in mild-to-severe body plaque psoriasis Study Topical steroid assessed (TS) Study duration (weeks) N Mean PASI at baseline ± SD Mean % change in PASI Choonhakarn TRIAM ± 3.1 )60.5 Fleming BMP ± 4.4 )49.8 Molin BMV NA )45.4 Kaufmann BMP ± NA )57.2 Singh BMP ± 6.4 )45 approx* *approximated from a figure inserted in the article. TRIAM, Triamcinolon; BMP, betamethasone dipropionate; dibmv, betamethasone valerate; N, number of patients in the topical steroid arm; TS, topical steroid; NA, not available in the published article. 4.3 () 6.6) in the TA group after 8 weeks of treatment and that four patients (10.5%) and 20 patients (54.1%) respectively achieved PASI 75 and PASI 50 by week 8. Fleming et al. 41, compare the efficacy and safety of once daily treatment of the two-compound betamethasone-calcipotriol gel with the single components in the same gel vehicle and the gel vehicle alone, in 364 patients with mild-to-moderate psoriasis of the trunk and or limbs. The mean percentage change in PASI was )40.9% at week 4 in the BMP gel group (absolute reduction 7.85, [95% CI )15.5 to )0.5]) and ) 49.8% at week 8 (absolute reduction 6.16, [95% CI )14.2 to 1.9]) in patients with 28.9% of patients achieving PASI 75. In the remaining studies, commonly used outcomes included individual signs score for psoriasis (erythema, scaling, induration, pruritus) on a target lesion (30 studies, 5,7 10,12,13,15,18 25,27,28,30,32,33,40,42,45 50,52 ) ± total severity score (TSS) or total sign score (8 studies, 5 7,9,22,47,48,50 ), the investigator assessment of overall improvement (IAGI) (44 studies, 5 17,19 27,30 36,38 40,42 52 )± patient assessment of overall global improvement or PAGI, (16 studies 5,6,10,12,15 17,20,24,30,31,40,42,46,48,55 ). Two studies used the Global Severity Score (GSS). 18,28 Comparison of success rates between trials provided with a high degree of variability. Across the 40 parallel-group patient trials, the success rate ranged from 5% to 95% according to the level of response considered (Fig. 2). A total of 30 90% patients across studies experienced more than 50% of initial psoriasis improvement 5 13 while from 7% to 85% experienced more than 75% initial psoriasis improvement 6,8,11,14 18,22 24,26,28 32,53,56 and from 5% to 85% experienced at least 90% of improvement ,41,57 The success rate remained highly variable across studies with the same molecule or when considering identical treatment durations. Sixteen studies of topical steroids in mild-to-moderate bodyplaque psoriasis were retained in the final analysis 6 8,13,15 17,26,29 31,34,36 39 (Fig. 3). Again, success rate was highly variable with the same molecule even between studies (Fig. 3). A total of 5 95% of the patients achieved more than 50% of initial psoriasis improvement. Ten within-patients RCT trials 20,21,25,27,31,33,40,42,45,52 assessed the efficacy of topical steroids in the treatment of the body plaque psoriasis. Five were excluded 27,31,42,45,52 because of imprecise data or methodological issues. In the remaining five studies 20,21,25,33,40 the success rate defined by more than 75% of improvement, using the same outcome measures as previously defined, varied from 10% to 70% (Fig. 4). Efficacy of topical steroids in the treatment of scalp psoriasis: (Fig. 5) Eighteen trials focused on the use of topical steroids for scalp psoriasis ,58 71 Sixteen were between-patient 53 56,58 66,68 70 and two were within-patient studies. 67,71 Treatment duration ranged from 2 to 8 weeks with the majority of durations being less than 6 weeks 27,53 56,59 63,66 69,71 The number of enrolled patients varied from 42 to 1417 patients according to the trial (mean 395 patients). Criteria for success was at least 75% improvement in initial psoriasis severity in seven trials 53,54,56,59,60,63,69 and at least 90% (clear or almost clear) in seven trials. 55,58,61,64,66,70,71 In four studies 27,62,67,68, efficacy could not be assessed according to the definition of treatment success. A total of 40 75% patients across studies experienced more than 75% of initial scalp psoriasis improvement and from 43% to 90% experienced more than 90% initial psoriasis improvement as displayed in Fig. 5. Efficacy of topical corticosteroids and frequency of application Senter et al. 43 compared once-a-day application using fluocinonide vs. a four-times-a-day application schedule for 6 weeks in 55 psoriasis patients. A mean amount of 429 g of fluocinonide was used per patient in the four times daily application group compared with 132 g in the once daily application group. There was no significant difference between the two groups in terms of efficacy. Influence of occlusion dressing on psoriasis clearance Among studies assessing the influence of occlusion on psoriasis clearance, only one 72 could be included in the review. Other studies were designed as within-patient plaque comparisons using more than two treatments or were open studies or compared two hydrocolloid dressing without topical steroid as a control arm. 81 Pacifico et al. 72 published a plaque to plaque comparison study including 42 patients having widespread

7 42 Castela et al. Study TS Study N (arm) duration (weeks) Katz 95 a CP 2 99 Olsen 91 b CP Katz 95 a BMD 2 98 Willis 86 b DMT 2 62 Willis 86 b FLUO 2 61 V.d.Ploeg 89 a MO V.d.Ploeg 89 a BMV Ellis 88 a AMC 3 77 Klaber 94 a BMV Duweb 00 a BMV 4 18 Andreassi 03 c BMV Franz 99 c BMV 4 57 Franz 99 c BMV 4 58 Reygane 05 c CP 4 76 Jarratt 04 d CP 4 95 Jemec 08 d BMD Buckley 08 d BMD V.d.Kerkhof 09 d BMD Response 75% Response 90% Patients with a response to topical steroids * (%) * The response was defined by the investigators as following: a clear or marked improvement b at least 75% improvement c clear or almost clear d absence of disease or very mild disease Abbreviations: CP: clobetasol, BMD: betamethasone dipropionate, DMT: desoximethasone, FLUO: fluocinonide, MO: mometasone, N: number of patients in the topical steroid arm, BMV: betamethasone valerate, AMC: amcinonide; TS: topical steroid assessed Each line of the graph represents one arm of each study treated by topical steroids (14 studies, 18 arms) Figure 5 Efficacy of topical steroids in the treatment of scalp psoriasis. symmetrical psoriasis. Paired target lesions, in similar anatomic locations and with equal baseline severity scores were treated once daily for 30 days with either BMV 0.1% tape (30 lg cm 2 ) or BMV 0.12% cream (standard dose of 100 mg 4cm 2 ). Lesions treated with BMV 0.1% tape showed higher reductions from baseline in PASI and in the self-administered Psoriasis Area Severity Index (SAPASI) (mean reduction 61.7% and 59.3%, respectively), compared with lesions treated with BMV 0.12% cream alone (mean reduction 39.5% and 34.0%, respectively). Moreover, skin hydration was significantly increased with BMV tape but not with BMV cream when evaluated with a corneometer. Influence of formulation on psoriasis clearance Greenspan et al. 49 compared a lotion formulation of 0.05% desonide with its vehicle and with 0.05% desonide cream in a double-blind, randomized, parallel study in 80 patients with mild-to-moderate psoriasis. All treatments were applied three times daily for up to 3 weeks with weekly examinations. The authors concluded that the lotion formulation of desonide was similar in both efficacy and safety to a 0.05% cream formulation when assessing a global evaluation of the change in psoriasis severity using a 5-point scale (1 = clear, 2 = 76 99% improvement, 3 = 50 75% improvement, 4 = < 50% improvement, 5 = exacerbation). Two studies compared the efficacy of clobetasol lotion with clobetasol propionate (CP) emollient in body plaque psoriasis. 18,28 Decroix et al. 28 assessed the respective efficacy of CP lotion and CP cream in psoriasis using global severity and BSA scores. After 4 weeks of treatment, among the 222 treated patients, CP lotion was found to be of similar efficacy to CP cream: 81% of the patients in the CP cream group were cleared or almost cleared compared with 79% of the patients in the CP lotion group. Lowe et al. 18 compared CP lotion vs. CP emollient cream and a lotion vehicle all applied twice daily for 4 weeks in 192 subjects with moderate-to-severe plaque-type psoriasis. At week 4, the efficacy was similar for the lotion and the cream. Influence of steroid potency on response rate The literature analysis did not find any study specifically designed to assess the respective benefit of potent and very potent topical corticosteroids for the treatment of psoriasis. Efficacy of topical steroids as a maintenance treatment for body plaque psoriasis Three studies assessed the maintenance treatment of body plaque psoriasis with only two providing with maintenance efficacy data Katz et al. 83 conducted an open label screening phase with augmented bethametasone dipropionate (ABD) twice daily for 3 or 4 weeks. In responders, 46 patients received subsequently three consecutive applications of ABD 12 h a part, once a week, for 5 months and 44 patients received vehicle with the same schedule. At 6 months, 65% of patients treated with ABD remained in remission vs. 20% of vehicle patients.

8 Topical corticosteroids in plaque psoriasis 43 Lebwhol et al. 84 treated 44 patients with a 2-week run in period with daily calcipotriene ointment in the morning and halobetasol ointment. Patients who were at least moderately (50% or greater) improved were randomized to receive halobetasol ointment twice daily on week-end and calcipotriene ointment twice daily on weekdays (20 patients), or to receive halobetasol ointment twice daily on week-end and placebo ointment twice daily on weekdays (20 patients). Forty percent (n = 8) of patients applying halobetasol ointment on week-end only with the vehicle on weekdays were able to maintain remission for 6 months compared with 76% (n = 13) of patients applying halobetasol ointment on week-end and calcipotriene ointment on weekdays suggesting that the addition of calcipotriene ointment applied on weekdays to a week-end pulse therapy regimen of superpotent corticosteroid can increase the duration of psoriasis remission. Topical steroids as a maintenance treatment for scalp psoriasis The only study assessing the benefit of a maintenance treatment for scalp psoriasis was published by Poulin et al. 85 Inthetrial,212 participants with moderate-to-severe scalp psoriasis were initially treated with CP shampoo once a day for up to 4 weeks. Responders were subsequently randomized to receive the CP shampoo or vehicle twice weekly on a maintenance regimen for up to 6 months. When a relapse occurred defined as GSS > 2, participants resumed daily CP shampoo treatment. When the symptoms diminished (GSS < or = 2), they returned to the twice-weekly maintenance regimen. After 6 months 31.1% (33 106) of participants in the CP shampoo group were still relapse free, vs. 8.1% (9 111) of participants in the vehicle group (P < 0.01). Discussion Topical steroids are used for more than 50 years in the treatment for mild-to-moderate plaque psoriasis. Their action is anti-inflammatory, antiproliferative and immunosuppressive. The clinical development of topical steroids in psoriasis did not follow state of the art modern methodology. Treatment success appears to be highly variable across studies. Analysing data taken fromtheliterature,wecanonlyconcludethatthelevelofefficacy of topical steroids i.e. the ability of a topical steroid to induce a significant clearance of treated lesions, according to the studies, is varying from 5% to 90% for the treatment of body plaque psoriasis and from 40% to 90% for the treatment of scalp psoriasis. Despite the fact that outcome measures of the studies differed and that strict comparison of results is not possible, studies using PASI score as primary outcome suggest than the level of efficacy of topical steroids after 4 8 weeks of treatment is about 45 50% mean improvement in PASI. Considering that the compliance to topical treatment in psoriasis is suboptimal in clinical practice, the efficacy results might be lower in real life. 86 It not possible to determine a specific success rate for a particular molecule, in other words, none of the molecules seems to be superior to another to induce psoriasis remission. Our literature analysis also did not allow us to assess the respective benefit of potent (e.g. BMP) and very potent (e.g. CP) topical corticosteroids or draw conclusions about on the optimal use of topical steroids for the treatment of plaque psoriasis, e.g. optimal treatment duration, or number of application. Our systematic literature search was only able to demonstrate the additive effect of occlusion on topical steroid efficacy in plaque psoriasis with thick plaques covering small surface of the body. Recently, a systematic review was published by the Cochrane Library on the topical treatment of psoriasis, especially randomized trials comparing treatments against placebo or against vitamin D analogues in people with chronic plaque psoriasis 86 In this review, with one exception, all corticosteroids performed better than placebo, with potent corticosteroids [SMD: )0.95 (95% CI: )1.11 to )0.80; I 2 : 61.1%; 17 studies; 2386 participants)] having smaller benefits than very potent corticosteroids [SMD: )1.29 (95% CI: )1.45 to )1.13; I 2 : 53.2%; 11 studies; 1571 participants)]. Two recent trials using state of the art methodology, one with BMP for body psoriasis (week-end therapy) 83 and one with CP shampoo for scalp psoriasis, suggest that maintenance intermittent treatment is useful to prolong remission. 87 There are several findings that could explain the discrepancy in the efficacy of topical steroids for the treatment of psoriasis: (i) considering the importance of their use, corticosteroids have been studied in relatively few large-scale, randomized, placebo-controlled trials; (ii) the study design (within vs. between patient studies); (iii) variation in trial duration and disease severity as many studies also included patients with severe psoriasis who should primarily be treated with systemic agents; (iv) heterogeneity of outcome measures selected to assess the efficacy of the topical steroids, which does not allow for a direct comparison between studies; and (v) imprecision in number of application, steroid potency, amount of topical steroids applied, effect of formulation. Of note, the PASI score which is actually one of the most commonly used score to assess clinical psoriasis severity was only used in five studies. 16,29,34,37,41 In the light of this systematic review, it appears that guidelines concerning the modalities of treatment should mostly be based on expert opinion. However, there are huge differences between recommendations from different countries: German guidelines 1 recommend a combination of topical steroids with salicylic acid, whereas US guidelines 3 recommend the use of topical steroids as monotherapy in mild-to-moderate psoriasis or in combination with other topical and systemic agents in moderate-to-severe disease. Recently, European guidelines have restricted the use of topical steroid to 1 month of treatment then if there is no change (and the patient is adhering to treatment) initiating phototherapy. 2 Generally speaking, all these guidelines have taken into consideration the position of topical steroids in combination with a wide range of systemic treatments. In the last 10 years, systemic

9 44 Castela et al. and biological agents have considerably changed the treatment of moderate-to-severe psoriasis, extending treatment possibilities and improving patients quality of life. In this context, the primary indication of topical treatment in general should be mildto-moderate psoriasis. References 1 Nast A, Kopp I, Augustin M et al. German evidence-based guidelines for the treatment of Psoriasis vulgaris (short version). Arch Dermatol Res 2007; 299: Murphy G, Reich K. In touch with psoriasis: topical treatments and current guidelines. J Eur Acad Dermatol Venereol 2011; 25: Menter A, Korman NJ, Elmets CA et al. Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 3. Guidelines of care for the management and treatment of psoriasis with topical therapies. J Am Acad Dermatol 2009; 60: Paul C, Gallini A, Archier E. et al. Evidence-based recommendations on topical treatment and phototherapy of psoriasis: systematic review and expert opinion of a panel of dermatologists. JEADV 2012; 26 (Suppl. 3): Shupack JL, Jondreau L, Kenny C et al. Diflorasone diacetate ointment 0.05% versus betamethasone dipropionate ointment 0.05% in moderate-severe plaque-type psoriasis. Dermatology 1993; 186: Sears H.W. A double-blind, randomized, placebo-controlled evaluation of the efficacy and safety of hydrocortisone buteprate 0.1% cream in the treatment of psoriasis. Adv Ther 1997; 14: Peharda V, Gruber F, Prpic L, Kastelan M, Brajac I. Comparison of mometasone furoate 0.1% ointment and betamethasone dipropionate 0.05% ointment in the treatment of psoriasis vulgaris. Acta Dermatovenerol Croat. 2000;8: Lebwohl M, Sherer D, Washenik K et al. A randomized, double-blind, placebo-controlled study of clobetasol propionate 0.05% foam in the treatment of nonscalp psoriasis. Int J Dermatol 2002; 41: Katz HAA. A comparison of the efficacy and safety of the combination mometasone furoate 0,1% salicylic acid 5% ointment with each of its components in psoriasis. J Dermatol Treat 1998; 3: Huntley AC, Isseroff R. Amcinonide vs. betamethasone dipropionate ointments in the treatment of psoriasis. Cutis 1985; 35: Fabry H, Yawalkar SJ. A comparative multicentre trial of halometasone ointment and fluocortolone plus fluocortolone caproate ointment in the treatment of psoriasis. J Int Med Res 1983; 11: Ellis CN, Katz HI, Rex IHJ et al. A controlled clinical trial of a new formulation of betamethasone dipropionate cream in once-daily treatment of psoriasis. Clin Ther 1989; 11: Bruce S, Epinette WW, Funicella T et al. Comparative study of calcipotriene (MC 903) ointment and fluocinonide ointment in the treatment of psoriasis. J Am Acad Dermatol 1994; 31: Roberts DT. Comparison of fluticasone propionate ointment, 0.005%, and betamethasone-17,21-dipropionate ointment, 0.05%, in the treatment of psoriasis. Cutis 1996; 57: Olsen EA. Efficacy and safety of fluticasone propionate 0.005% ointment in the treatment of psoriasis. Cutis 1996; 57: Molin L, Cutler TP, Helander I et al. Comparative efficacy of calcipotriol (MC903) cream and betamethasone 17-valerate cream in the treatment of chronic plaque psoriasis. A randomized, double-blind, parallel group multicentre study. Calcipotriol Study Group. Br J Dermatol 1997; 136: Mensing H, Korsukewitz G, Yawalkar S. A double-blind, multicenter comparison between 0.05% halobetasol propionate ointment and 0.05% betamethasone dipropionate ointment in chronic plaque psoriasis. JAm Acad Dermatol 1991; 25: Lowe N, Feldman SR, Sherer D et al. Clobetasol propionate lotion, an efficient and safe alternative to clobetasol propionate emollient cream in subjects with moderate to severe plaque-type psoriasis. J Dermatolog Treat 2005; 16: Leibsohn E. Comparison of diflorasone diacetate and betamethasone dipropionate ointment in the treatment of psoriasis. J Int Med Res 1982; 10: Lebwohl MG, Medansky RS, Savin RC, Alton AV. Diflorasone diacetate cream in an optimized vehicle versus fluocinonide cream for the treatment of psoriasis. J Dermatol Treat 1995; 6: Krueger GG, O Reilly MA, Weidner M et al. Comparative efficacy of once-daily flurandrenolide tape versus twice-daily diflorasone diacetate ointment in the treatment of psoriasis. J Am Acad Dermatol 1998; 38: Koo J, Cuffie CA, Tanner DJ et al. Mometasone furoate 0.1%-salicylic acid 5% ointment versus mometasone furoate 0.1% ointment in the treatment of moderate-to-severe psoriasis: a multicenter study. Clin Ther 1998; 20: Katz HI, Hien NT, Prawer SE et al. Superpotent topical steroid treatment of psoriasis vulgaris clinical efficacy and adrenal function. JAm Acad Dermatol 1987; 16: Jegasothy B, Jacobson C, Levine N et al. Clobetasol propionate versus fluocinonide creams in psoriasis and eczema. Int J Dermatol 1985; 24: Jacobson C, Cornell RC, Savin RC. A comparison of clobetasol propionate 0.05 percent ointment and an optimized betamethasone dipropionate 0.05 percent ointment in the treatment of psoriasis. Cutis 1986; 216: Goldberg B, Hartdegen R, Presbury D et al. A double-blind, multicenter comparison of 0.05% halobetasol propionate ointment and 0.05% clobetasol propionate ointment in patients with chronic, localized plaque psoriasis. J Am Acad Dermatol 1991; 25: Fredriksson T, Salde L. A double-blind trial of budesonide and betamethasone- 17,21-dipropionate in psoriasis. Curr Med Res Opin 1982; 8: Decroix J, Pres H, Tsankov N et al. Clobetasol propionate lotion in the treatment of moderate to severe plaque-type psoriasis. Cutis 2004; 74: Choonhakarn C, Busaracome P, Sripanidkulchai B et al. A prospective, randomized clinical trial comparing topical aloe vera with 0.1% triamcinolone acetonide in mild to moderate plaque psoriasis. J Eur Acad Dermatol Venereol 2010; 24: Blum G, Yawalkar S. A comparative, multicenter, double blind trial of 0.05% halobetasol propionate ointment and 0.1% betamethasone valerate ointment in the treatment of patients with chronic, localized plaque psoriasis. J Am Acad Dermatol 1991; 25: Bernhard J, Whitmore C, Guzzo C et al. Evaluation of halobetasol propionate ointment in the treatment of plaque psoriasis: report on two double-blind, vehicle-controlled studies. J Am Acad Dermatol 1991; 25: Aggerwal A, Maddin S. Alclometasone dipropionate in psoriasis: a clinical study. J Int Med Res 1982; 10: Stein LF, Sherr A, Solodkina G et al. Betamethasone valerate foam for treatment of nonscalp psoriasis. J Cutan Med Surg 2001; 5: Singh S, Reddy DC, Pandey SS. Topical therapy for psoriasis with the use of augmented betamethasone and calcipotriene on alternate weeks. J Am Acad Dermatol 2000; 43: Pierard GE, Lachapelle JM, Frentz G, Schopf E, Stolz E. Hydrocortisone 17-butyrate topical emulsion (Locoid Crelo(registered trademark)) in psoriasis. J Eur Acad Dermatol Venereol 1996: Mraz S, Leonardi C, Colón LE et al. Different treatment outcomes with different formulations of clobetasol propionate 0.05% for the treatment of plaque psoriasis. J Dermatolog Treat 2008; 19: Kaufmann R, Bibby AJ, Bissonnette R et al. A new calcipotriol betamethasone dipropionate formulation (Daivobet) is an effective once-daily treatment for psoriasis vulgaris. Dermatology 2002; 205:

10 Topical corticosteroids in plaque psoriasis Jarratt MT, Clark SD, Savin RC et al. Evaluation of the efficacy and safety of clobetasol propionate spray in the treatment of plaque-type psoriasis. Cutis 2006; 78: Gottlieb AB, Ford RO, Spellman MC. The efficacy and tolerability of clobetasol propionate foam 0.05% in the treatment of mild to moderate plaque-type psoriasis of nonscalp regions. J Cutan Med Surg 2003; 7: Gip L, Søndergaard J, Thestrup-Pedersen K. A double blind comparison of betamethoasone 17-valerate 0.1% Lipocream and betamethasone 17-valerate 0.1% ointment in the treatment of patients with psoriasis vulgaris. Eur J Clin Res 1994; 5: Fleming C, Ganslandt C, Guenther L et al. Calcipotriol plus betamethasone dipropionate gel compared with its active components in the same vehicle and the vehicle alone in the treatment of psoriasis vulgaris: a randomised, parallel group, double-blind, exploratory study. Eur J Dermatol 2010; 20: Katz HI, Gross E, Buxman M et al. A double-blind, vehicle-controlled paired comparison of halobetasol propionate cream on patients with plaque psoriasis. J Am Acad Dermatol 1991; 25: Senter TP, Stimson DH, Charles G et al. Comparison of two therapeutic regimens using the same topical corticoid for stable psoriasis. West J Med 1983; 139: Larry E, Millikan LE, Mroczkowski TF. A comparative study of amcinonide and halcinonide 0.1% ointments in the treatment of psoriasis. Int J Dermatol 1986; 25: Sefton J, Loder JS, Kyriakopoulos AA. Clinical evaluation of hydrocortisone valerate 0.2% ointment. Clin Ther 1984; 6: Cornell RC. Comparison of amcinonide ointment 0.1 percent twice daily and fluocinonide ointment 0.05 percent three times daily in the treatment of psoriasis. Cutis 1983; 31: Frost P, Horwitz SN. Clinical comparison of alclometasone dipropionate and desonide ointments (0.05%) in the management of psoriasis. J Int Med Res 1982; 10: De Villez RL. Efficacy and safety of mometasone furoate 0.1% once daily versus fluticasone propionate 0.005% twice daily in the management of psoriasis. Adv Ther 1998; 15: Greenspan A, Herndon JH Jr, Baker MD, Cheney T. Controlled evaluation of 0.05% desonide lotion and desonide cream in psoriasis. Curr Therapeu Res Clin Exp 1993; 53: Chuang T-Y S. Clinical efficacy and safety of augmented betamethasone dipropionate ointment and diflorasone diacetate ointment for psoriasis a multicentre, randomized, double-blinded study. J Dermatol Treat 1991; 2: Koo J, Blum RR, Lebwohl M. A randomized, multicenter study of calcipotriene ointment and clobetasol propionate foam in the sequential treatment of localized plaque-type psoriasis: short- and long-term outcomes. J Am Acad Dermatol 2006; 55: Katz HI, Prawer SE, Watson MJ. Comparison of therapeutic efficacy of two different preparations of fluocinonide cream in the treatment of Psoriasis vulgaris. Drug Invest 1991; 3: Olsen EA, Cram DL, Ellis CN et al. A double-blind, vehicle-controlled study of clobetasol propionate 0.05% (Temovate) scalp application in the treatment of moderate to severe scalp psoriasis. J Am Acad Dermatol 1991; 24: Ellis CN, Horwitz SN, Menter A. Amcinonide lotion 0.1% in the treatment of patients with psoriasis of the scalp. Curr Therapeu Res Clin Exp 1988; 44: Franz TJ, Parsell DA, Halualani RM et al. Betamethasone valerate foam 0.12%: a novel vehicle with enhanced delivery and efficacy. Int J Dermatol 1999; 38: Katz HI, Lindholm JS, Weiss JS et al. Efficacy and safety of twice-daily augmented betamethasone dipropionate lotion versus clobetasol propionate solution in patients with moderate-to-severe scalp psoriasis. Clin Ther 1995; 17: Leer JAJ. Efficacy of a betamethasone dipropionate topical glycol preparation in the management of severe psoriasis. Clin Ther 1980; 3: Van de Kerkhof PCM, Hoffmann V, Anstey A et al. A new scalp formulation of calcipotriol plus betamethasone dipropionate compared with each of its active ingredients in the same vehicle for the treatment of scalp psoriasis: a randomized, double-blind, controlled trial. Br J Dermatol 2009; 160: Willis I, Cornell RC, Penneys NS et al. Multicenter study comparing 0.05% gel formulations of desoximetasone and fluocinonide in patients with scalp psoriasis. Clin Ther 1986; 8: VanderPloeg DE, Cornell RC, Binder R et al. Clinical trial in scalp psoriasis mometasone furoate lotion 0.1% apllied once daily vs betamethasone valerate lotion 0.1% applied twice daily. Acta Therapeutica 1989; 15: Reygagne P, Mrowietz U, Decroix J et al. Clobetasol propionate shampoo 0.05% and calcipotriol solution 0.005%: a randomized comparison of efficacy and safety in subjects with scalp psoriasis. J Dermatolog Treat 2005; 16: Pauporte M, Maibach H, Lowe N et al. Fluocinolone acetonide topical oil for scalp psoriasis. J Dermatolog Treat 2004; 15: Klaber MR, Hutchinson PE, Pedvis-Leftick A et al. Comparative effects of calcipotriol solution (50 micrograms ml) and betamethasone 17-valerate solution (1 mg ml) in the treatment of scalp psoriasis. Br J Dermatol 1994; 131: Jemec GBE, Ganslandt C, Ortonne J et al. A new scalp formulation of calcipotriene plus betamethasone compared with its active ingredients and the vehicle in the treatment of scalp psoriasis: a randomized, double-blind, controlled trial. J Am Acad Dermatol 2008; 59: Jemec GBE, van de Kerkhof PCM, Enevold A et al. Significant one week efficacy of a calcipotriol plus betamethasone dipropionate scalp formulation. J Eur Acad Dermatol Venereol 2011; 25: Jarratt M, Breneman D, Gottlieb AB et al. Clobetasol propionate shampoo 0.05%: a new option to treat patients with moderate to severe scalp psoriasis. J Drugs Dermatol 2004; 3: Jarratt M, Davis JG, Giltner MP, Jones ML, Peets EA. Comparative studies of augmented betamethasone dipropionate lotion 0.05% and clobetasol propionate solution 0.05%: correlation of the vasoconstriction assay and clinical activity in scalp psoriasis. Adv Ther 1991; 8: Feldman SR, Ravis SM, Fleischer ABJ et al. Betamethasone valerate in foam vehicle is effective with both daily and twice a day dosing: a single-blind, open-label study in the treatment of scalp psoriasis. J Cutan Med Surg 2001; 5: Duweb GA, Abuzariba O, Rahim M et al. Scalp psoriasis: topical calcipotriol 50 micrograms g ml solution vs. betamethasone valerate 1% lotion. Int J Clin Pharmacol Res 2000; 20: Buckley C, Hoffmann V, Shapiro J et al. Calcipotriol plus betamethasone dipropionate scalp formulation is effective and well tolerated in the treatment of scalp psoriasis: a phase II study. Dermatology 2008; 217: Andreassi L, Giannetti A, Milani M. Efficacy of betamethasone valerate mousse in comparison with standard therapies on scalp psoriasis: an open, multicentre, randomized, controlled, cross-over study on 241 patients. Br J Dermatol 2003; 148: Pacifico A, Daidone R, Peris K. A new formulation of an occlusive dressing containing betamethasone valerate 0.1% in the treatment of mild to moderate psoriasis. J Eur Acad Dermatol Venereol 2006; 20: Griffiths CE, Tranfaglia MG, Kang S. Prolonged occlusion in the treatment of psoriasis: a clinical and immunohistologic study. J Am Acad Dermatol 1995; 32: Fiskerstrand EJ VG. Weekly treatment of psoriasis vulgaris with corticosteroids and a hydrocolloid dressing is superior to the steroid alone or to UVB. J Dermatol Treat 1992; 3: