BJD British Journal of Dermatology. Summary SYSTEMATIC REVIEW

SYSTEMATIC REVIEW BJD British Journal of Dermatology Topical therapies for the treatment of plaque psoriasis: systematic review and network meta-analyses E.J. Samarasekera, 1 L. Sawyer, 2 D. Wonderling, 1 R. Tucker 3 and C.H. Smith 4 1 National Clinical Guideline Centre, Royal College of Physicians of London, 11 St Andrews Place, London NW1 4LE, U.K. 2 Symmetron Ltd, Kinetic Centre, Theobald St, Borehamwood WD6 4PJ, U.K. 3 Faculty of Health and Social Care, University of Hull, Hull HU6 7RX, U.K. 4 Division of Medicine and Molecular Genetics, St John s Institute of Dermatology, Guy s Hospital, London SE1 9RT, U.K. Summary Correspondence Catherine H. Smith. E-mail: catherine.smith@kcl.ac.uk Accepted for publication 10 February 2013 Funding sources National Institute for Health and Clinical Excellence, and National Institute for Health Research. Conflicts of interest All authors were members of the NICE Psoriasis Guideline Development Group (C.H.S chaired the group, E.S was the research fellow, L.S and O.W were the health economists, and R.T was the pharmacist). After completing the guideline analysis but before its publication, L.S joined Symmetron Limited. DOI 10.1111/bjd.12276 The majority of people with psoriasis have localized disease, where topical therapy forms the cornerstone of treatment. We set out to summarize evidence on the relative efficacy, safety and tolerability of different topical treatments used in plaque psoriasis. We undertook a systematic review and meta-analyses of randomized trial data of U.K.-licensed topical therapies. The primary outcome was clear or nearly clear status stratified for (i) trunk and limbs; and (ii) scalp. Network meta-analyses allowed ranking of treatment efficacy. In total, 48 studies were available for trunk and limb psoriasis, and 17 for scalp psoriasis (22 028 patients in total); the majority included people with at least moderate severity psoriasis. Strategies containing potent corticosteroids (alone or in combination with a vitamin D analogue) or very potent corticosteroids dominated the treatment hierarchy at both sites (trunk and limbs, scalp); coal tar and retinoids were no better than placebo. No significant differences in achievement of clear or nearly clear status were observed between twice- and once-daily application of the same intervention or between any of the following: combined vitamin D analogue and potent corticosteroid (applied separately or in a single product), very potent corticosteroids, or potent corticosteroids (applied twice daily). Investigator and patient assessment of response differed significantly for some interventions (response rates to very potent corticosteroids: 78% and 39%, respectively). No significant differences were noted for tolerability or steroid atrophy, but data were limited. In conclusion, corticosteroids are highly effective in psoriasis when used continuously for up to 8 weeks and intermittently for up to 52 weeks. Coal tar and retinoids are of limited benefit. There is a lack of long-term efficacy and safety data available on topical interventions used for psoriasis. Psoriasis is a common chronic inflammatory skin condition and, although generally not life threatening, it can have a profound impact on physical, psychological and social wellbeing. 1 While recent advances and investment in high-cost biological therapies have revolutionized outcomes for people with severe disease, comparatively little attention has been paid to topical therapy, which forms the cornerstone of management for the majority of people with psoriasis. 2 Furthermore, the degree of disability does not necessarily correlate with objective measures of disease extent or severity, 3 and people with minimal involvement (less than the equivalent of three palm areas) state that psoriasis has a major effect on their life, 4 underscoring the importance of effective treatment in this group. Corticosteroids, vitamin D 3 and its analogues, calcineurin inhibitors, retinoids, tar, dithranol and keratolytic agents such as salicylic acid and urea are all used, 5 and come in a vast array of formulations, combinations and potencies. Choice of treatment is tailored to the needs of the patient and includes consideration of the nature of the psoriasis (type, site, extent) and practical aspects such as cosmetic acceptability and time available for application. How these factors, as well as patients mood, beliefs and perceptions about psoriasis, might impact on treatment adherence is also relevant. 6 However, in 954

Topical therapies for plaque psoriasis, E.J. Samarasekera et al. 955 the context of these considerations, prescribers need reliable evidence on the relative efficacy, tolerability and safety of the available topical agents in order to devise a management strategy that delivers the best chance of achieving a satisfactory outcome. The aim of this analysis is therefore twofold: (i) to summarize the evidence on topical treatments in chronic plaque psoriasis (stratified for trunk and limbs, and scalp) to allow comparison of their efficacy, tolerability and safety; and (ii) to synthesize data on efficacy to inform original costeffectiveness modelling. 7 Data arising from this work were used to inform recommendations on the use of topical therapy for the National Institute for Health and Clinical Excellence guideline on Assessment and Management of Psoriasis. 8 Materials and methods Search strategy and selection criteria A systematic literature search was conducted according to a predefined protocol for randomized, placebo-controlled or head-to-head trials of U.K.-licensed topical therapies for plaque psoriasis. Outcomes for the scalp were considered separately from those of the trunk and limbs because the scalp is considered a high need, difficult-to-treat site due to difficulties with application of topical therapies, differences in formulations, and acceptable frequencies of application. Comprehensive searches of Medline, Embase, Cinahl and The Cochrane Library were conducted and last updated on 8 March 2012, restricted to articles published in English (see Table S1, Supporting Information, for full search strategy). Abstracts were screened, and articles that appeared to meet the inclusion criteria were assessed further. Studies were excluded if they were not published as full reports, due to high risk of bias. Reference lists of relevant articles were scrutinized to identify additional reports. Eligible studies were required to have at least 25 people in each study arm and to report induction or maintenance of remission. The unit of randomization could be the individual patient or one side of the body. Interventions included were: vitamin D and vitamin D analogues (henceforth referred to as vitamin D analogues), potent or very potent corticosteroids, combined application of vitamin D analogue and potent corticosteroid either as a two-compound formulation (TCF) product (Dovobet TM ; LEO Pharma, Princes Risborough, U.K.) or applied separately, one in the morning and one in the evening [two-compound application; TCA (am/pm)], tar, dithranol and retinoids. The included comparisons for the pairwise analyses for trunk and limb psoriasis were (i) any of the topical monotherapies compared with vitamin D analogues or with placebo or vehicle; and (ii) combined vitamin D analogue and potent corticosteroid [TCF or TCA (am/pm)] compared with the constituent monotherapies. For scalp psoriasis all comparisons were included in the pairwise analysis. The primary outcome was the proportion of patients achieving clear or nearly clear status on either the Investigator s Assessment of Overall Global Improvement (IAGI) or dynamic Physician s Global Assessment (PGA), or the static PGA. The secondary outcome was clear or nearly clear status as assessed by either the Patient s Assessment of Overall Global Improvement (PAGI) or the static patient s global assessment. Consistent data extraction for the outcome of clear or nearly clear across the different scales was achieved by aligning the descriptors as follows: clear, nearly clear, 75% improvement, excellent improvement, marked improvement or minimal for dynamic scales; and minimal or very mild for static scales. Other outcomes were duration of remission or time to relapse, skin atrophy and withdrawal due to adverse events (as a marker of tolerability). Data extraction and quality assessment Data were extracted according to a standard template. Assessment of methodological quality and methods of analysis are reported elsewhere. 8 Statistical analysis Data were stratified according to the site of psoriasis: (i) trunk and limbs; and (ii) scalp. Given the number of different interventions, data on all agents within a drug class were pooled into one analysis; however, once- and twice-daily applications were kept as separate comparators for the network meta-analysis (NMA). Additionally, although it was not possible to adjust data from within-patient comparison trials for the correlation coefficient relating to the comparison of paired data, within- and between-patient data were pooled. This provided a conservative estimate, accepting that it may result in underweighting of the within-patient studies. A series of pairwise meta-analyses for the primary and secondary outcomes for induction of remission produced 12 direct comparisons for trunk and limb psoriasis and 10 for scalp psoriasis. To synthesize all data (both direct and indirect comparisons) into a single, coherent set of effect sizes, a hierarchical Bayesian NMA was performed. 9 This produced odds ratios (and 95% confidence intervals) for each treatment compared with all the others. We then derived relative risks and absolute risks for each treatment from these odds ratios using the absolute risk from data on twice-daily vehicle or placebo. The analysis was performed in WinBUGS 19 (Medical Research Council, Cambridge, U.K.) using a multi-arm, random-effects logistic regression model, with parameters estimated by Markov chain Monte Carlo Simulation (Appendices S1 and S2; see Supporting Information). The model used the assumption that the between-trial heterogeneity was equal across all comparisons. For each analysis, 20 000 burn-in simulations were run for convergence followed by a further 40 000 simulations to produce the outputs. Full details of the analysis methods have been published elsewhere. 8 Inconsistency in the direct evidence was assessed using Bucher s method, 10 comparing the odds ratios from the pairwise meta-analysis wherever a loop of direct evidence was available. We also compared estimates of effect from the pairwise meta-analyses and NMAs. No significant inconsistency was identified.

956 Topical therapies for plaque psoriasis, E.J. Samarasekera et al. Results Search results and study characteristics Of 2619 abstracts retrieved, 48 studies 11 59 were included for trunk and limb psoriasis and 17 60 76 for scalp psoriasis (see Fig. 1 for full selection process). Details of the included studies for trunk and limb psoriasis and scalp psoriasis are summarized in Tables S2 and S3, respectively (see Supporting Information). There was variation in methodology and reporting between the studies, for example in treatment duration (range: 2 12 weeks for trunk and limbs; 2 8 weeks for scalp; maintenance studies up to 52 weeks). Evidence quality varied between outcomes and comparisons (range: very low to high); common limitations were unclear allocation concealment and blinding, and imprecise estimates for safety or tolerability measures. There were also differences in the baseline disease severity. For trunk and limb psoriasis approximately half of the studies included populations with moderate-tosevere psoriasis assessed by PASI, PGA or body surface area (BSA), while others included either mild-to-moderate psoriasis, any disease severity or did not specify severity as an inclusion criterion. Therefore, there would have been a range from limited to more widespread disease among the studies included. For scalp psoriasis, the majority of studies 60,62,63,65,68,70 73 included those with moderateto-severe scalp involvement, with three 64,67,69 stipulating mild-to-moderate scalp disease and three 61,66,74 allowing any severity to be included. Achievement of clear or nearly clear Pairwise results (investigator and patient assessments) Tables 1 and 2 summarize the individual study results; the outputs of the direct pairwise meta-analysis that were used as inputs for the NMA are available in Figures S1 and S2 (see Supporting Information) for psoriasis of the trunk and limbs, and scalp, respectively. Time to remission varied among the interventions (Table S4; see Supporting Information), and variations in study length and frequency of application made direct comparisons difficult. Overall, the most rapid improvement in response occurred during the first 2 4 weeks for corticosteroids, and the first 4 weeks for vitamin D analoguecontaining interventions, dithranol and coal tar. Data from long-term or maintenance studies were not included in the NMA (see Tables 3 and 4), and a separate NMA for long-term data was not possible as only two studies were available for each of trunk and limb 57 59 and scalp 75,76 psoriasis, and one of these 76 did not report the primary outcome. (a) TRUNK & LIMBS 2619 Records identified (b) SCALP 2470 Records excluded 2586 Records excluded 101 Full-text articles excluded 30 Insufficient sample size 19 Incorrect outcomes 22 Incorrect comparison 22 Incorrect study/article type 4 Inadequate reporting 4 Not English language 149 Full-text articles assessed for eligibility 33 Full-text articles assessed for eligibility 16 Full-text articles excluded 10 Incorrect outcomes 2 Incorrect comparison 2 Incorrect population 2 Incorrect study/article type 48 Studies included in quantitative synthesis 17 Studies included in quantitative synthesis 9 Excluded from NMA Did not report primary or secondary outcomes, or longterm maintenance studies 4 Excluded from NMA Did not report primary outcome, or long-term maintenance studies 39 Studies included in NMA 13 Studies included in NMA Fig 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow chart for selection of studies; (a) for trunk and limb psoriasis and (b) for scalp psoriasis. NMA, network meta-analysis.

Topical therapies for plaque psoriasis, E.J. Samarasekera et al. 957 Table 1 Trunk and limb psoriasis Investigator s Assessment of Overall Global Improvement (IAGI), Physician s Global Assessment (PGA) and Patient s Assessment of Overall Global Improvement (PAGI) efficacy data for induction of remission IAGI or PGA clear/ nearly clear PAGI clear/nearly clear Study Topical Dose r n % r n % Barker 1999 11 Placebo OD 1 26 3.8 Vitamin D OD 13 28 46.4 Perez 1996 12 Placebo OD 0 84 0.0 Vitamin D OD 37 84 44.0 Fleming 2010 13 Placebo OD 0 40 0.0 Vitamin D OD 9 79 11.4 Potent corticosteroid OD 14 83 16.9 Combined vitamin D and potent corticosteroid OD 44 162 272 Kaufmann 2002 14 Placebo OD 16 157 102 15 157 96 Vitamin D OD 107 480 223 137 480 285 Potent corticosteroid OD 176 476 370 216 476 454 Combined vitamin D and potent corticosteroid OD 276 490 563 316 490 645 Langley 2011 15 Placebo OD 5 91 5.5 14 64 21.9 Vitamin D OD 33 184 179 35 163 215 Combined vitamin D and potent corticosteroid OD 73 183 399 69 171 404 Medansky 1987 16 Placebo OD 7 45 15.6 Potent corticosteroid OD 18 50 36.0 Decroix 2004 17 Placebo OD 5 33 15.2 Very potent corticosteroid OD 144 189 762 Weinstein study A 2003 18 Placebo OD 7 229 31 Retinoid OD 24 439 55 Weinstein study B 2003 18 Placebo OD 2 214 09 Retinoid OD 26 421 62 Langner 1992 19 Placebo BD 9 29 31.0 Vitamin D BD 21 29 72.4 Langner 1993 20 Placebo BD 13 32 40.6 Vitamin D BD 24 32 75.0 Highton 1995 21 Placebo BD 23 123 187 Vitamin D BD 87 124 702 Dubertret 1992 22 Placebo BD 11 62 17.7 Vitamin D BD 46 62 74.2 Harrington 1996 23 Placebo BD 13 71 18.3 Vitamin D BD 148 291 509 Oranje 1997 47,a Placebo BD 15 43 34.9 16 34 47.1 Vitamin D BD 26 43 60.5 21 43 48.8 Papp 2003 24,b Placebo BD 8 107 75 13 107 121 Vitamin D BD 103 308 334 99 308 321 Potent corticosteroid BD 174 312 558 195 312 625 Combined vitamin D and potent corticosteroid BD c 229 301 761 223 301 741 Guenther 2002 25 Placebo BD 19 206 92 26 206 126 Vitamin D BD 115 227 507 117 227 515 Combined vitamin D and potent corticosteroid OD 95 150 633 98 150 653 Combined vitamin D and potent corticosteroid BD c 172 234 735 164 234 701 Wortzel 1975 26 Placebo BD 4 37 10.8 Potent corticosteroid BD 15 39 38.5 Sears 1997 27 Placebo BD 1 83 1.2 2 83 2.4 Potent corticosteroid BD 12 78 15.4 12 78 15.4 Lowe 2005 28 Placebo BD 0 29 0.0 Very potent corticosteroid BD 84 162 519 Gottlieb 2003 29 Placebo BD 27 125 216 36 140 257 Very potent corticosteroid BD 85 120 708 79 139 568 Lebwohl 2002 30 Placebo BD 1 20 5.0 1 20 5.0 Very potent corticosteroid BD 10 61 16.4 8 61 13.1 Jarratt 2006 31 Placebo BD 2 60 3.3 Very potent corticosteroid BD 47 60 78.3

958 Topical therapies for plaque psoriasis, E.J. Samarasekera et al. Table 1 (Continued) IAGI or PGA clear/ nearly clear PAGI clear/nearly clear Study Topical Dose r n % r n % Kragballe 1998 32 Vitamin D OD 49 172 285 46 172 267 Vitamin D BD 69 172 401 69 172 401 Concurrent vitamin D and potent corticosteroid 73 172 424 89 174 511 Ortonne 2004 33 Vitamin D OD 43 252 171 44 252 175 Combined vitamin D and potent corticosteroid OD 143 249 574 135 249 542 Camarasa 2003 34 Vitamin D BD 67 128 523 Potent corticosteroid BD 81 130 623 Molin 1997 35 Vitamin D BD 119 205 580 Potent corticosteroid BD 116 207 560 Kragballe 1991 36 Vitamin D BD 281 342 822 Potent corticosteroid BD 237 342 693 Cunliffe 1992 37 Vitamin D BD 123 201 612 Potent corticosteroid BD 101 200 505 Douglas 2002 38 Vitamin D BD 142 365 389 140 365 384 Potent corticosteroid BD 169 363 466 183 363 504 Combined vitamin D and potent corticosteroid BD c 251 369 680 248 369 672 Ruzicka 1998 39 Vitamin D BD 22 49 44.9 Concurrent vitamin D and potent corticosteroid 27 39 69.2 Tham 1994 40 Vitamin D BD 13 27 48.1 Coal tar OD 3 27 11.1 Alora-Palli 2010 41 Vitamin D BD 6 28 21.4 Coal tar BD 14 27 51.9 Pinheiro 1997 42 Vitamin D BD 47 65 72.3 Coal tar BD 28 57 49.1 Hutchinson 2000 43 Vitamin D BD 23 60 38.3 Dithranol OD 24 54 44.4 Wall 1998 44 Vitamin D BD 92 153 601 93 153 608 Dithranol OD 67 131 511 65 131 496 Berth-Jones 1992 45 Vitamin D BD 180 231 779 180 231 779 Dithranol OD 116 227 511 123 227 542 Christensen 1999 46 Vitamin D BD 6 89 6.7 Dithranol OD 4 77 5.2 Thawornchaisit 2007 49,d Potent corticosteroid BD 23 30 76.7 Coal tar BD 7 28 25.0 Menter 2009 48,e Very potent corticosteroid BD 32 44 72.7 Combined vitamin D and potent corticosteroid OD 32 49 65.3 OD, once daily; BD, twice daily. Bold text denotes data included only in the sensitivity analysis of the network meta-analysis. a Oranje 1997 evaluated treatments in a paediatric population. b Data from Papp 2003 for IAGI/PGA were included in the base case, but only PAGI data were included in the sensitivity analysis because they were excluded from the clinical review of direct evidence, given that in the paper they were reported graphically. c Twice-daily combined vitamin D and potent corticosteroid was included only as a comparator in the sensitivity analysis given that it is currently unlicensed in the U.K. at this dose. d The protocol for the clinical review of direct evidence included only comparisons of single topical therapies with either placebo/vehicle or vitamin D; therefore, the comparison of potent corticosteroid and coal tar was included only in the sensitivity analysis. e The protocol for the clinical review of direct evidence included only comparisons of combination therapies with either vitamin D or potent corticosteroid; therefore, the comparison of combined vitamin D and potent corticosteroid and very potent corticosteroid was included only in the sensitivity analysis. Network meta-analysis results for trunk and limb psoriasis Investigator s assessment of response Thirty four stidues 11 35,38 46 were available for the base-case network for the primary outcome of investigator s assessment of achieving clear or nearly clear status, including 11 604 patients randomized to 14 interventions. Seventeen of these studies included people with at least moderate disease severity, most commonly measured by having over 10% BSA coverage. There was a notable absence of trials comparing the TCF product with TCA (am/ pm) (see Fig. S3, Supporting Information, showing direct comparisons forming the network). All active interventions were significantly more effective than placebo twice daily, except coal tar used once daily and retinoids (Fig. 2). Very potent steroids were the most effective treatment option (calculated response rate of 782% when applied twice daily). For other active interventions, response rates ranged from 122% for once-daily coal tar to 709% for once-daily TCF product

Topical therapies for plaque psoriasis, E.J. Samarasekera et al. 959 Table 2 Scalp psoriasis Investigator s Assessment of Overall Global Improvement (IAGI), Physician s Global Assessment (PGA) and Patient s Assessment of Overall Global Improvement (PAGI) efficacy data for induction of remission IAGI or PGA clear/ nearly clear PAGI clear/nearly clear Study Topical Dose r n % r n % Buckley 2008 61 Potent corticosteroid OD 91 110 827 Combined vitamin D and potent corticosteroid OD 100 108 926 Franz 1999 62 Placebo BD 12 57 21.1 10 57 17.5 Potent corticosteroid BD 68 115 591 71 115 617 Franz 2000 63 Placebo BD 5 63 7.9 4 63 6.3 Very potent corticosteroid BD 86 125 688 77 125 616 Green 1994 64 Placebo OD 4 24 16.7 Vitamin D OD 15 25 60.0 Jarratt 2004 65 Placebo OD 1 47 2.1 Very potent corticosteroid OD 40 95 42.1 Jemec 2008 66 Placebo OD 31 136 228 28 136 206 Vitamin D OD 100 272 368 104 272 382 Potent corticosteroid OD 356 556 640 348 556 626 Combined vitamin D and potent corticosteroid OD 385 541 712 371 541 686 Klaber 1994 67 Vitamin D BD 138 236 585 136 236 576 Potent corticosteroid BD 175 232 754 171 232 737 Kragballe 2009 68 Vitamin D BD 33 105 314 Combined vitamin D and potent corticosteroid OD 142 207 686 McKinnon 2000 69 Vitamin D BD 120 210 571 Coal tar polytherapy OD 79 213 371 Olsen 1991 70 Placebo BD 16 189 85 Very potent corticosteroid BD 129 188 686 Reygagne 2005 71 Vitamin D BD 21 75 28.0 23 75 30.7 Very potent corticosteroid OD 38 76 50.0 36 76 47.4 Sofen 2011 72 Placebo BD 5 40 12.5 Very potent corticosteroid BD 35 41 85.4 Tyring 2010 73 Placebo OD 17 42 40.5 15 42 35.7 Combined vitamin D and potent corticosteroid OD 97 135 719 84 135 622 van de Kerkhof 2009 74 Vitamin D OD 124 286 434 128 286 448 Potent corticosteroid OD 343 562 610 227 562 404 Combined vitamin D and potent corticosteroid OD 388 567 684 395 567 697 OD, once daily; BD, twice daily. Bold text denotes data not included in the network meta-analysis. (Fig. 3 and Table S5; see Supporting Information). The probability distributions for the rank order of each intervention within the treatment hierarchy are shown in Figure S4 (see Supporting Information). When comparing the odds of response between different active interventions, for the majority of comparisons there were no significant differences, including between TCF product and TCA (am/pm) (Fig. S1; see Supporting Information). However, the TCF product was significantly more effective than once-daily application of vitamin D analogues, potent corticosteroids, retinoids or coal tar. There was a trend to suggest that twice-daily application of any given intervention was more effective than once-daily application (especially for coal tar), but any differences were not statistically significant when comparing odds of response. A sensitivity analysis investigating the impact of including three studies excluded from the base case (one paediatric study 47 and two studies 48,49 with comparisons that did not match the protocol) did not alter the overall findings, with twice-daily application of a very potent steroid still being the most effective treatment compared with vehicle twice daily [relative risk (RR) 610 in base case vs. 573 in sensitivity analysis]. The only notable difference was that the estimated efficacy of twice-daily coal tar was reduced markedly by the inclusion of a study with shorter duration (6 weeks vs. 8 12 weeks in base-case studies); see also Reference 8 for full details of this analysis. Patient s assessment of response For the secondary outcome of patient assessment of response, 14 studies were available (n = 7644), 14,15,23,25,27,29,30,32,33,36 38,44 46 substantially fewer than for investigator assessment (Fig. S5; see Supporting Information). Regarding the hierarchy of efficacy, notable differences from the outcomes based on the investigators assessment included very potent corticosteroid twice daily being ranked much lower by the patient assessment (sixth vs.

960 Topical therapies for plaque psoriasis, E.J. Samarasekera et al. Table 3 Long-term maintenance of remission IAGI or PGA clear/ nearly clear Study Topical Dose Duration of follow-up r n %* Trunk and limbs Kragballe 2006 58,a Combined vitamin D and potent corticosteroid OD 52 weeks 80 104 769 Combined vitamin D and potent corticosteroid OD 52 weeks 62 89 69.7 (4 weeks) then vitamin D (48 weeks) Alternating 4-week periods of combined vitamin OD 52 weeks 78 104 75 D and potent corticosteroid, and vitamin D Katz 1991 57,b Potent corticosteroid 6 months 27 46 58.7 Placebo 6 months 7 44 15.9 IAGI, Investigator s Assessment of Overall Global Improvement; PGA, Physician s Global Assessment; OD, once daily. a This maintenance study enrolled patients with plaque psoriasis of at least moderate severity and allowed treatment once daily according to the randomized intervention schedule for up to 52 weeks for application when required. b This maintenance study included participants who achieved remission after 3 4 weeks treatment with betamethasone dipropionate. The maintenance regimen was intermittent betamethasone dipropionate applied to the site of the healed lesion (three consecutive applications 12 h apart, once a week for a maximum treatment period of 6 months). first) and once-daily application of potent corticosteroid or placebo appearing to be more effective than twice-daily application of the same agent (Fig. 4). There was also a trend across the majority of interventions showing that the patient assessment of response produced a lower estimate of the proportion responding than the investigator s assessment (Table S5; see Supporting Information). This difference was most pronounced for twice-daily application of potent corticosteroid and once-daily dithranol. Sensitivity analysis showed that including two studies initially excluded from the protocol for direct comparisons, one in a paediatric population 47 and one because the results were presented only graphically, 24 did not alter the overall findings, with the TCF product still being the most effective compared with vehicle twice daily (RR 463 in the base case vs. 428 in sensitivity analysis). See also Reference 8 for full details of this analysis. Network meta-analysis results for scalp psoriasis Investigator s assessment of response Thirteen studies 62 74 were available in the base-case network for the primary outcome of investigator s assessment of achieving clear or nearly clear status, including 5640 patients randomized to 10 different interventions (Fig. S6, see Supporting Information, showing direct comparisons forming the network). Ten of the studies reported on scalp psoriasis of at least moderate severity. All active interventions were more efficacious than placebo applied twice daily, although there was uncertainty about this for coal-tar shampoo and vitamin D analogues used once daily (see Fig. 5 for relative risks and Fig. 6 for absolute risks of each intervention compared with the baseline risk of response). As with psoriasis of the trunk and limbs, very potent steroids were the most effective treatment option (response rates 7835% for twice-daily and 6926% for oncedaily applications). Twice-daily coal-tar shampoo was no better than placebo (1892% and 1809%, respectively). The probability distribution of being ranked in a certain position in the treatment hierarchy for each intervention is shown in Figure S7 (see Supporting Information). Considering comparisons between different active interventions, very few demonstrated a statistically significant difference (Fig. S2). Exceptions were that once-daily application of potent corticosteroid or the TCF product was significantly more effective than vitamin D analogues once daily, and very potent corticosteroids were significantly better than vitamin D analogues regardless of frequency of application. Additionally, very potent corticosteroids and the TCF product were significantly more effective than coal-tar shampoo once daily. Unlike the results for trunk and limb psoriasis, across all interventions there was no consistent trend that increasing treatment frequency was linked to improved efficacy. It was not possible to analyse the patient-assessed outcomes as no single connected network could be formed based on published comparisons. Duration of remission Clear evidence regarding the duration of remission was lacking, with only seven studies, three for trunk and limbs 57,67,68 and four for scalp, 15,34,46,75 reporting this outcome (Table 4). One study for scalp 68 and one for trunk and limb 34 psoriasis suggested that the relapse rate was greater for interventions containing steroids compared with vitamin D analogues. The proportion relapsing following treatment withdrawal across all interventions ranged from 20% to 80% in the short term, up to 88% after 6 months, with no consistent evidence for superiority of any one intervention. Tolerability and adverse effects Withdrawals from trials due to toxicity (as a proxy marker of tolerability) and reported cases of skin atrophy (as the principal local

Topical therapies for plaque psoriasis, E.J. Samarasekera et al. 961 Table 4 Duration of remission and relapse rates Study Definitions Intervention Relapse rate Time to relapse Trunk and limbs Langley 2011 15 Camarasa 2003 34 Christensen 1999 46 Katz 1991 57,a Scalp Klaber 1994 67 Kragballe 2009 68 Poulin 2010 75,b Remission: clear/nearly clear on IAGA. Relapse: reduction in PASI improvement from baseline Remission: clear/nearly clear. Relapse: requiring retreatment (not maintaining clear/nearly clear) Remission: at least 50% improvement. Relapse: requiring retreatment (loss of response) Remission: clear or slight on a 4-point scale (clear, slight, moderate, severe). Relapse: moderate or severe disease or TSS 25 at two consecutive visits Remission: not applicable no relapse among responders only. Relapse: increase in the total sign score to at least 50% of the score at the start of double-blind treatment Remission: clear or minimal disease according to PGA. Relapse: recurrence of at least moderate disease according to PGA Remission: at least mild on PGA. Relapse: PGA > 2 (moderate, severe or very severe scalp psoriasis) Dovobet c OD Tacalcitol OD Placebo Calcitriol BD Betamethasone dipropionate BD Calcipotriol BD Dithranol OD Intermittent betamethasone dipropionate Placebo Calcipotriol BD Betamethasone valerate BD Xamiol c OD Calcipotriol BD Clobetasol propionate twice weekly Placebo 28/67 responders (42%) 7/31 responders (23%) 3/5 responders (60%) 30/58 responders (52%) 55/73 responders (75%) 50/62 responders (81%) 8 weeks post treatment: 19/33 responders (58%) During 24-week maintenance: 16/46 (35%) During 24-week maintenance: 35/44 (80%) 4 weeks post-treatment: 75/99 (76%) 4 weeks post-treatment: 102/129 (791%) 73/135 responders (541%) 10/29 responders (34%) Number still in remission after 6 months of maintenance: 27/67 (40%) Number still in remission after 6 months of maintenance: 8/69 (12%) Median: 63 days Median: 61 days Median: 61 days Mean: 234 days Mean: 253 days Median: 29 days Median: 56 days Hazard ratio 037 (95% CI 021 067) Median: 35 days Median: 58 days Median: 141 days Median: 305 days IAGA, Investigator s Assessment of Overall Global Improvement; PASI, Psoriasis Area and Severity Index; OD, once daily; BD, twice daily; TSS, total severity score; CI, confidence interval; PGA, Physician s Global Assessment. a This was a maintenance study that included participants who achieved remission after 3 4 weeks treatment with betamethasone dipropionate. The maintenance regimen was intermittent betamethasone dipropionate applied to the site of the healed lesion (three consecutive applications 12 h apart, once a week for a maximum treatment period of 6 months). b This was a maintenance study with treatment for up to 6 months among those who had achieved clear, very mild or mild disease during a 4-week induction phase with once-daily clobetasol propionate. During the maintenance phase clobetasol propionate was used twice weekly (3 days apart), but once-daily dosing was permitted for up to 4 weeks if relapse occurred. c Leo Pharma, Princes Risborough, U.K. adverse effect associated with corticosteroids) across all comparisons and both populations showed low event rates, even in the long term and in maintenance studies up to 52 weeks. The relative estimates were very imprecise, but in absolute terms demonstrated precise evidence of no clinically relevant differences between the interventions because the numbers involved were so low. There was no statistically significant increased risk of steroid atrophy with corticosteroid use compared with other interventions, although the majority of cases of steroid atrophy reported did occur in people who received corticosteroids, and greater numbers of withdrawals due to adverse effects were seen with twice-daily potent corticosteroid compared with once-daily use. See also Reference 8 for full details of these outcomes. Discussion Overall, the NMA hierarchy of effectiveness for topical therapy for trunk and limb psoriasis indicated that, discounting very

962 Topical therapies for plaque psoriasis, E.J. Samarasekera et al. Very potent corticosteroid BD: 6 10 (4 48 7 14) TCF OD: 5 55 (3 49 6 88) Very potent corticosteroid OD: 5 31 (1 44 7 38) TCA (am/pm): 5 12 (2 87 6 78) Potent corticosteroid BD: 4 90 (3 40 6 14) Coal tar BD: 4 23 (1 90 6 49) Vitamin D BD: 4 26 (3 06 5 42) Potent corticosteroid OD: 3 78 (1 46 6 14) Vitamin D OD: 3 44 (1 56 5 63) Dithranol OD: 3 38 (1 71 5 34) Retinoid OD: 2 17 (0 43 5 57) Coal tar OD: 0 98 (0 12 4 18) Placebo OD: 0 78 (0 21 2 29) 0 1 1 1 2 1 3 1 4 1 5 1 6 1 7 1 8 1 Risk Ratio Fig 2. Summary of relative risk of response for all interventions compared with twice-daily placebo for trunk and limb psoriasis based on investigator s assessment of response. BD, twice daily; TCF, two-compound formulation product containing potent corticosteroid and vitamin D analogue; OD, once daily; TCA (am/pm), two-compound application of potent corticosteroid and vitamin D analogue, one in the morning and one in the evening. 90% Probability of response 80% 70% 60% 50% 40% 30% 20% 10% Once daily Twice daily 27 30% 12 50% 9 70% 42 80% 12 20% 54 90% 54 20% 43 50% 47 90% 62 40% 65 40% 70 90% 67 90% 78 20% 0% Vehicle Tazarotene Dithranol Coal tar Vitamin D Potent TCA (am/pm) TCF product Very potent corticosteroid corticosteroid Fig 3. Absolute response rates for trunk and limb psoriasis based on investigator s assessment of response. TCF, two-compound formulation product containing potent corticosteroid and vitamin D analogue; TCA (am/pm), two-compound application of potent corticosteroid and vitamin D analogue, one in the morning and one in the evening. potent steroids (which many dermatologists would not consider a suitable option for most patients based on clinical experience of local adverse effects), the combination of potent corticosteroid and vitamin D analogue, either applied once daily in a single TCF product or applied separately, was the most effective intervention, with no significant difference

Topical therapies for plaque psoriasis, E.J. Samarasekera et al. 963 TCF OD: 4 63 (2 86 5 86) TCA (am/pm): 4 22 (1 85 5 92) Potent corticosteroid OD: 3 85 (1 50 5 82) Vitamin D BD: 3 56 (2 16 4 92) Potent corticosteroid BD: 3 29 (1 73 4 97) Very potent corticosteroid BD: 2 65 (1 09 4 65) Vitamin D OD: 2 45 (0 99 4 43) Dithranol OD: 2 29 (0 83 4 43) Placebo OD: 1 54 (0 45 3 80) 0 1 2 1 Risk Ratio 4 1 6 1 Fig 4. Summary of relative risk of response for all interventions compared with twice-daily placebo for trunk and limb psoriasis based on patient s assessment of response. TCF, two-compound formulation product containing potent corticosteroid and vitamin D analogue; OD, once daily; TCA (am/pm), two-compound application of potent corticosteroid and vitamin D analogue, one in the morning and one in the evening; BD, twice daily. Very potent corticosteroid BD: 6 96 (5 62 7 96) Very potent corticosteroid OD: 6 15 (2 99 8 31) TCF OD: 5 71 (2 35 7 95) Potent corticosteroid OD: 5 04 (1 61 7 79) Potent corticosteroid BD: 4 38 (2 22 6 68) Vitamin D BD: 3 10 (1 31 5 94) Vitamin D OD 3 07 (0 71 6 59) Placebo OD: 1 74 (0 37 4 89) Coal tar polytherapy OD: 1 68 (0 42 5 29) 0 1 1 1 2 1 3 1 4 1 5 1 6 1 7 1 8 1 9 1 Risk Ratio Fig 5. Summary of relative risk of response for all interventions compared with twice-daily placebo for scalp psoriasis based on investigator s assessment of response. BD, twice daily; OD, once daily; TCF, two-compound formulation product containing potent corticosteroid and vitamin D analogue. between these application methods. No important differences in terms of tolerability or toxicity were evident between these treatment options. The rank order of efficacy (confined to investigator s assessment) was similar for the scalp; however, perhaps not surprisingly given difficulties with application, there was a lack of any consistent trend linking frequency of

964 Topical therapies for plaque psoriasis, E.J. Samarasekera et al. 90% 80% 70% Once daily Twice daily 64 24% 69 26% 78 35% Probability of response 60% 50% 40% 30% 20% 18 09% 18 92% 34 59% 34 89% 56 75% 49 31% 10% 11 26% 0% Vehicle Coal tar polytherapy Vitamin D Potent corticosteroid TCF product Very potent corticosteroid Fig 6. Absolute response rates for scalp psoriasis based on investigator s assessment of response. TCF, two-compound formulation product containing potent corticosteroid and vitamin D analogue. application to improved efficacy. Very potent steroids were the most effective treatment and vitamin D analogues and coal-tar shampoo were the least effective overall, with coal-tar shampoo showing similar response rates to placebo. This effect estimate was based on just one study for coal tar 69 and may be unreliable, but the absence of evidence for efficacy is important to note given that coal-tar shampoo is commonly prescribed in primary care. 77,78 For trunk and limb psoriasis, some discordance was evident between results for physician- and patient-assessed outcomes, which may be caused by the relative paucity of evidence to inform the effect estimates for the patient-assessed outcome. However, for most interventions, patients were less positive in their evaluation of response than investigators, particularly for twice-daily application of potent corticosteroid and once-daily dithranol. This may indicate differences between patients and physicians perception of clear or nearly clear and highlights the importance of including both outcomes when evaluating topical interventions. Similarly, the nonsignificant trend towards twice-daily applications being more effective than once-daily application was not seen in the patient-assessed data, which might reflect the preference of patients for oncedaily applications to reduce the burden of treatment. Strengths of this study include the additional power afforded by synthesizing all of the available data in one coherent network. Additionally, the assumption that between-trial heterogeneity is equal across all comparisons may allow heterogeneity to be more accurately estimated for comparisons with few studies. For example, for the comparison of TCF vs. vitamin D twice daily the confidence interval from the direct evidence (based on only two trials) was narrower than that based on the NMA. In this case the NMA estimate is more conservative than the direct evidence, but if more trials were conducted we might find that the existing direct evidence is underestimating heterogeneity. A recognized limitation of this analysis is that for the majority of trunk and limb studies included, the severity of psoriasis was recorded as moderate to severe. Consequently, our results may not be wholly generalizable to patients with mild-to-moderate disease for which topical therapy is the mainstay of treatment. Nevertheless, our analysis did include 12 studies with mild-to-moderate disease, which represents the majority of patients for whom topical therapy is appropriate. Additionally, generalizability may be further limited by the common risk of recruitment bias, meaning that the clinical trial participants may not be representative of those in clinical practice, owing to the restrictions on those included, although in the majority of studies the exclusion criteria were not excessively stringent. This review highlights important gaps in the evidence. There were no direct comparisons between TCA (am/pm) and TCF products. More importantly, the majority of the trials focused on achievement of remission, with very limited data on key outcomes of relevance to psoriasis such as relapse rates, the optimal point at which to reinstate treatment on relapse and strategies to maintain remission. The data do not suggest any major risk associated with corticosteroid use, even in the context of moderate or severe disease. While this is reassuring, these data should be interpreted with caution: most of the studies were short term and may be inadequately powered to accurately determine true risk. Furthermore, presence or absence of steroid atrophy was a key outcome in only a minority of studies, and no study used validated objective measures for assessment (e.g. skin ultrasound). Patients and clinicians should therefore remain vigilant for potential local (and systemic) sequelae associated with corticosteroids in psoriasis. However, nonsteroid-based treatments such as retinoids, coal tar and vitamin D are less effective, and so a strategy for the safe and effective long-term use of treatments for the maintenance of disease control in psoriasis is urgently needed.

Topical therapies for plaque psoriasis, E.J. Samarasekera et al. 965 Future studies should ensure that patients evaluations of treatment are included as outcomes. What s already known about this topic? Topical treatments are widely available and prescribed for plaque-type psoriasis. What does this study add? Explicit rank order of efficacy, showing that treatment strategies containing potent or very potent corticosteroids are the most effective. Investigator and patient evaluation of efficacy may differ. Twice-daily application of the same intervention offers no important benefit over once-daily application for most treatments. Acknowledgments This work was undertaken by the National Clinical Guideline Centre, which received funding from the National Institute for Health and Clinical Excellence. The views expressed in this publication are those of the authors and not necessarily those of the Institute. 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J Dermatolog Treat 2010; 21:185 92. 76 Luger TA, Cambazard F, Larsen FG et al. A study of the safety and efficacy of calcipotriol and betamethasone dipropionate scalp formulation in the long-term management of scalp psoriasis. Dermatology 2008; 217:321 8. 77 Smith DR, Bottomley JM, Auland M et al. Heterogeneity in the treatment of moderately severe scalp psoriasis in Scotland results of a survey of Scottish health professionals. Curr Med Res Opin 2011; 27:239 49. 78 British Association of Dermatologists, Primary Care Dermatology Society. Recommendations for the Initial Management of Psoriasis. London: British Association of Dermatologists, 2010. Supporting Information Additional Supporting Information may be found in the online version of this article at the publisher s website: Fig S1. Trunk and limb psoriasis odds ratios for clear/ nearly clear as measured by IAGI or PGA, results of conventional and network meta-analyses. Fig S2. Scalp psoriasis odds ratios for clear/nearly clear as measured by IAGI or PGA, results of conventional and network meta-analyses. Fig S3. Network of evidence for investigator s assessment of clear or nearly clear status for trunk and limb psoriasis (base case). Fig S4. Rank density plots for investigator assessed response trunk and limb psoriasis. Fig S5. Network of evidence for patient s assessment of clear or nearly clear status for trunk and limb psoriasis (base case). Fig S6. Network of evidence for investigator s assessment of clear or nearly clear status for scalp psoriasis (base case). Fig S7. Rank density plots for investigator assessed response scalp psoriasis. Table S1. Full search strategy (using Embase (OVID) as an example). Table S2. Included study characteristics trunk and limb psoriasis. Table S3. Included study characteristics scalp psoriasis. Table S4. Proportion achieving clear or nearly clear at different time-points during the trials. Table S5. Absolute response rates for all interventions for psoriasis of the trunk and limbs. Appendix S1. WinBUGS code for investigator assessment of trunk and limb psoriasis. Appendix S2. WinBUGS code for investigator assessment of scalp psoriasis.