Topical long-term therapy of psoriasis with vitamin D 3

Review Article Submitted: 9.5.2014 Accepted: 12.5.2014 DOI: 10.1111/ddg.12396 Topical long-term therapy of psoriasis with vitamin D 3 analogues, corticosteroids and their two compound formulations: position paper on evidence and use in daily practice Matthias Augustin 1, Ulrich Mrowietz 2, Bernd Bonnekoh 3, Thomas Rosenbach 4, Diamant Thaçi 5, Michael Reusch 6, Michael Ardabili 7, Kristian Reich 8 (1) CVderm Centre of Excellence for Health Services Research in Dermatology; Institute for Health Services Research in Dermatology and Nursing, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (2) Psoriasis Center, Department of Dermatology, Venereology and Allergy, University Medical Center Schleswig-Holstein, Campus Kiel, Germany (3) Clinic for Dermatology and Venereology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany (4) Private Practice, Osnabrück, Germany (5) Comprehensive Center for Inflammation Medicine, University Medical Center Schleswig-Holstein, Campus Lübeck, University of Lübeck, Lübeck, Germany (6) Private Practice, Hamburg, Germany (7) Private Practice, Bochum, Germany (8) Dermatologikum Hamburg, Germany Summary Background: Current data from daily practice show that vitamin D 3 analogues, corticosteroids and their fixed combination products are used heterogeneously for topical long-term treatment of psoriasis. Aim: To evaluate scientific evidence about topical long-term therapy with vitamin D 3 analogues, corticosteroids and their two-compound-products in psoriasis vulgaris and scalp psoriasis and to develop daily practice recommendations. Methods: Systematic literature review via PubMed and Embase and informal expert consensus. Results: The search strategy identified 21 relevant clinical trials. Best evidence regarding topical long term treatment was available for the two-compound-formulation containing calcipotriene and betamethasone. In a comparative trial in psoriasis vulgaris the two-compound-formulation showed superior tolerability and cost effectiveness compared to monotherapy. In scalp psoriasis the two-compound-gel was superior compared to calcipotriene monotherapy. Standardized and simplified treatment application modes resulted in a better clinical outcome comparing to on-demand therapies. Daily practice recommendations: Patients should be proactively involved in the choice of treatment, formulation and mode of application. Besides long-term treatment with the two-compound-formulation other treatment regimens including calcipotriene monotherapy can also be considered. Due to a favorable risk-benefit ratio in maintenance trials and due to better cost-effectiveness the application of two-compound-products once or twice a week after initial therapy is recommended. Background and Introduction Topical vitamin D 3 analogues alone or in combination with topical corticosteroids are recommended as standard for induction therapy of mild to moderate psoriasis by current S3 guidelines [1]. According to daily practice data from 681 German private practice dermatology centers, topical therapy with vitamin D 3 analogues is widely used, with a high variation in application methods [2]. There was great variability in the percentage of induction vs. follow-up treatment with steroids and vitamin D 3 analogues, in the distribution of vitamin D 3 analogue treatment alone versus combination with corticosteroids and in the percentage of fixed combinations vs. individual combination regimens. Both the duration of treatment and the sequence of corticosteroid and vitamin D 3 analogues application varied as well. Current S3 guidelines 667

Table 1 Number of hits derived from the search strategy for topical long-term treatment in psoriasis with vitamin D 3 analogues, their two compound formulations and corticosteroids. # Search term and combinations PubMed hits 1 Embase hits 2 1 psoriasis AND clinical trial (Publication type) 2 768 5 682 2 vitamin* d OR calcipotriol OR tacalcitol OR calcitriol OR steroid* OR 190 136 2 559 930 cortisol* OR betamethasone* OR flumethasone* OR prednisolone* OR prednicarbate* OR hydrocortisone* OR fluticasone* OR clobetasol* OR mometasone* OR halobetasol* 3 long-term OR maintenance treatment OR 24 weeks OR 25 weeks OR 1 078 587 3 149 928 26 weeks (.) OR 54 weeks OR 6 months OR 7 months OR 8 months (..) OR 24 months OR 1 year* OR 2 year* OR 3 year* 4 #1 AND #2 AND #3 62 217 1 Data base: MEDLINE 2 Data bases: BIOSIS Previews, Embase, International Pharmaceutical Abstracts, PASCAL, SciSearch do not provide detailed recommendations for long-term treatment of psoriasis with these substances. Aim of the Paper Based on a systematic review of the current literature, this position paper aims to evaluate the available evidence on topical long-term treatment of psoriasis vulgaris and scalp psoriasis with vitamin D 3 analogues, corticosteroids and their combinations. In addition areas in which further research is needed should be indicated. Based on these results, daily practice recommendations were developed, which should help to standardize topical long term management of psoriasis and to provide the basis for further clinical studies. Methods The position paper was developed in two phases: 1. Systematic review of the available literature in international medical online databases including adjusted analyses of efficacy and tolerability 2. Expert review of available data and development of consensus recommendations for daily practice during an expert meeting Definition of inclusion and exclusion criteria The position paper included only interventional studies which fulfilled the following criteria: prospective trials on adult subjects trials on patients with plaque psoriasis of the trunk and the extremities and/ or the scalp excluding psoriasis pustulosa and erythrodermic psoriasis trials, which only evaluated topical therapy with a vitamin D 3 analogue, a corticosteroid or a fixed or free combination of both trials, in which topical therapy is used as continuous maintenance therapy (daily use, use on demand, use 1 2x weekly) trials with a treatment duration of at least 24 weeks trials, in which a validated, reproducible score-based efficacy measure (PASI, TSS, PGA, TLA, BSA, DLQI) was used, if efficacy was the primary end point trial reports in German or English Literature research The literature review was performed according to the method used in the current S3 guidelines on psoriasis vulgaris [3] and conducted in the PubMed and Embase databases (Table 1), including studies from 1971 until August 2013. Each study was evaluated according to the inclusion criteria given above by using standardized literature evaluation forms, and listed in evidence tables [3]. To include studies not listed in Pub- Med / Embase, reference lists of all included studies were re-viewed as well. Evidence level evaluation Evidence level evaluation was conducted in accordance with current S3 guidelines on psoriasis vulgaris [3] (Table 2). Evaluation of efficacy and tolerability The expert consensus decided to use the Physician Global Assessment (PGA) as the primary measure of efficacy (Tables 3 5), as PGA was, in contrast to other common scores, available 668

Table 2 Evaluation of evidence criteria according to S3 guidelines of Psoriasis. Evidence criteria Meta-analysis containing at least one trial of level A2 and of which the results of individual trials are consistent Randomized double-blind comparative clinical trials of good quality (e.g. sample size calculation, flow chart, ITT analysis, sufficient size) Randomized clinical trials of moderate (weak) quality or other comparative trials (non-randomized, cohort studies, patient-control studies) Non-comparative trials for the majority of the included studies. The PGA score given in the original study is shown first. Adjusted response rates makes it possible to compare efficacy within a given evidence level. To this end, the 50% of positive PGA scores (3 best scores, such as healed / very mild / mild if a 6-point scale had been used, 2 best scores such as excellent / good if a 4-point scale had been used) were selected. Response rates were basically calculated on the intention-to-treat population (ITT). Last-Observation-Carried-Forward (LOCF) analyses were, if available, preferred for determining adjusted efficacy. Adverse events (AE) are shown as AE rates (percentage of patients with AEs), including all AEs with or without a suspected causal relation. Local AEs are listed separately and if possible specified as irritation (Irr.), deterioration of psoriasis (Pso.) or corticosteroid-related skin reactions (Cort.). Systemic AEs (lab values) were rare and only described in the text. All percentages given in the tables are related to either ITT population or the safety data analysis set or, if none of the above was available, to the initially included patient number. Results Evidence level A total of 62 publications (PubMed ) and 217 publications (Embase ) were found, of which 17 and 15, respectively, fulfilled the inclusion criteria stated above (Figure 1). Two additional studies [4, 5] were identified by reference list analysis, rendering a total of 21 studies available for evaluation of topical long-term therapy. Of these, 18 studies focused on plaque psoriasis affecting the trunk and extremities [4 25], two studies on scalp psoriasis [26 28], one study included both [29]. Only three of these [7, 8, 26 28] were randomized double-blind comparative clinical trials of good quality A1 A2 B C (evidence level A2). Highest evidence (12 trials in total) for topical long-term therapy was found for calcipotriol and its combinations (n = 5), while the long-term use of both tacalcitol (n = 4) and calcitriol (n = 1) has only been studied in open, non-randomized observational studies of evidence level C. Among topically used corticosteroids, mostly betamethasone (n = 3 combination study with calcipotriol, n = 3 in monotherapy) and clobetasol (n = 1 combination study with calcipotriol, n = 3 in monotherapy) showed evidence for psoriasis maintenance therapy. Monotherapy trials for psoriasis vulgaris are listed in table 3 (topical vitamin D 3 analogues), 4 (vitamin D 3 analogues in combinations) and 5 (topical corticosteroids), table 6 lists trials for scalp psoriasis separately. Monotherapy with vitamin D3 analogues for longterm treatment of psoriasis vulgaris (Tables 3 and 4) The first open pilot study on topical long-term use of calcipotriol 50 μg/g was conducted in 1991 by Kragballe et al. in 15 patients with psoriasis vulgaris for six months [22]. At the end of the study 80% had shown an at least moderate response to the treatment with an overall good tolerability. A number of non-randomized open observational studies followed (evidence level C) for calcipotriol 50 μg/g [4, 11, 20, 21, 29], calcitriol 3 μg/g [17 19] and tacalcitol 4 20 μg/g [9, 13 16]. The most impressive therapeutic results of topical treatment with vitamin D 3 analogues usually became evident during the first 4 weeks after treatment was initiated [11, 20]. Later on improvement of the skin condition was only moderate. In blinded trials, a 4-week induction therapy with a fixed combination of calcipotriol 50 μg/g with betamethasone dipropionate (BMD) 0.5 mg/g followed by a maintenance monotherapy with calcipotriol 50 μg/g yielded an at least satisfactory therapeutic result in 56 % (adjusted efficacy) [7] to 58 % (adjusted efficacy) [12] of the patients after 52 weeks (Table 4). In open observational studies (Table 3), adjusted response rates were higher: 78 % [21] to 80 % [22] with calcipotriol, while a standard regimen of tacalcitol (4 μg/g) led to an adjusted response rate of 56 59 % [9, 14], increasing to 69 % at higher dosages (20 μg/g) [13]. For calcitriol 3 μg/g, the adjusted response rate was 40 % [17 19]. None of the studies identified severe AEs (saes) caused by treatment with vitamin D 3 analogues. Overall AE frequency for calcipotriol was 30 % to 40 % (Table 3). Local AEs occurred in 20 32 %. For tacalcitol, the frequency of local AEs was dosage-dependent: 38 % at 20 μg/g [13] and 18 % at 4 μg/g [14]. For calcitriol, skin-related AEs occurred in only 15%, while a few cases (2 %) of mild hypercalcemia were observed [17 19], which normalized during continued treatment. For high-dose tacalcitol (20 μg/g), significant reductions of parathyroid hormone and 1-alpha,25-(OH) 2 D 3 serum levels were detected, while calcium homeostasis was 669

Table 3 Summary of long-term trials in psoriasis vulgaris with topical vitamin D 3 analogues in monotherapy. Design Efficacy (PGA) Tolerability Author (year) n Severity at inclusion Duration of treatment in W Dosage Randomization Blinding ITT Responder selection Efficacy measure Primary end point Efficacy Trial A2 B C Adjusted Efficacy (according to Evidence Level) AE (%) AE (skin) (%) Drop-out Miyachi 2002 [13] 154 mean PASI 21.38 26 + 54 Tacalcitol 20 μg/g once daily PGA improvement (6 pt. scale) End point: % in remission or with good/moderate improvement 93 % (PP) 69 % (ITT) 45 % (ITT) n.a. in % Pat. 38 % 25 % 52 % Lambert 2002 [14] 157 mean PASI 9.36 24 Tacalcitol 4 μg/g once daily + PGA severity grade (4 pt. scale) End point: % with severity grade excellent, good or moderate, reduction of mean PASI 88 % (PP) PASI reduction by 67 % 56 % (PP) n.a. 18 % 48 % van de Kerkhof 2002 [15, 16] 197 mean PASI 4.6 72 Tacalcitol 4 μg/g once + daily. PGA response (4 pt. scale) End point: % with excellent, good or moderate response; PASI 90 % (PP) PASI 4.6 3.25 n.a. n.a. 21 %; 15 % Irr; 3 % Pso 42 % van de Kerkhof 1997 [9] 58 Sum Score 7.9 60 Tacalcitol 4 μg/g once + daily PGA response (4 pt. scale) End point: % very good/ good/moderate response, symptom score 95 % (PP) 59 % (ITT) 26 % 14 % 28 % Langner 1996 [18] van de Kerkhof 1996 [19] Gerritsen 2001 [18] 253 Mod. (41 %), severe (43 %), very severe (4 %) 78 (-) Calcitriol 3 μg/g twice daily + PGA improvement (6 pt. scale) End point: % with remission, visible or substantial improvement 40 % (ITT) 40 n. a. 15 % 64 % % ( ) (ITT) 670

Table 3 Continued. Design Efficacy (PGA) Tolerability Author (year) n Severity at inclusion Duration of treatment in W Dosage Randomization Blinding ITT Responder selection Efficacy measure Primary end point Efficacy Trial A2 B C Adjusted Efficacy (according to Evidence Level) AE (%) AE (skin) (%) Drop-out Ramsay 1994 [20] 167 mean PASI 3.90 52 Calcipotriol 50 μg/g twice + daily (+) PGA response (3 pt. scale) End point: % good/satisfactory response; PASI 94 % (PP) PASI 8.1 2.71 n.a. 32 % 32 %; 25 % Irr. 24 % Poyner 1993 203 [21] Mild (8 %), mod. 48 (63 %), severe (29 %) Calcipotriol 50 μg/g twice + daily PGA severity scale (4 pt. scale) End point: % absent or mild Pso. 78 % (vs. 8 % at 78 % 41 % enrolment) 20 % Irr.; 10 % 29 % Pso. Kragballe 1991 [22] 15 14 % KO 26 Calcipotriol 50 μg/g twice daily (++) + + PGA improvement (6 pt. scale) Symptom Score (4 pt. scale) End point: % with at least moderate improvement 80 % (ITT) 80 % (ITT) 20 % 20 %; 0 % 13 % Irr. Abbr.: BMD, Betamethasone dipropionate; db, double-blind; ITT, Intention To Treat; Irr., irritative skin reaction; LOCF, Last Observation Carried Forward; Pso., deterioration of psoriasis; n.a., not available; n.s., not significant; PGA, Physician s Global Assessment; Pt., point; PP, Per Protocol; AE, adverse event; W, week; WE, weekend. + continuous therapy until week 26, stopped (remission); Induction with tacalcitol for 12 weeks; only patients with > 30 % reduction of symptoms were enrolled in maintenance therapy (77 %); study subjects from db, placebo-controlled induction study with tacalcitol enrolled. Following a 4-week intermission, enrolment in open follow-up study (46 %); no available PGA data per scale, Top 2 out of 3 values would result in too positive value for adjusted efficacy; no available PGA data per scale; Top 3 out of 4 values would result in too positive value for adjusted efficacy; # Induction with calcipotriol for 8 weeks, only satisfactory responders included in maintenance therapy. ## Induction for 8 weeks with dithranol at max. tolerable dosage; only dithranol non-responders enrolled, no available PGA data per scale, Top 2 out of 3 values would result in a too positive value for adjusted efficacy (+) only responders without severe AEs from induction study were enrolled. (++) Patients had responded to calcipotriol, with consecutive relapse; (-) No data on total no. of patients in remission; # only 75 Pat. treated for at least 12 M; ( ) 46 cleared patients, discontinued treatment, not included in ITT but listed as drop-outs. 672

Table 4 Summary of long-term trials in psoriasis vulgaris with topical vitamin D3 analogues in fixed or separated two compound formulations. Design Effectivity (1) Tolerability (2) Author (year) n Severity grade Duration of treatment Dosage Randomization Blinding ITT Responder selection Efficacy measure Primary end point Efficacy Physician Global Assessment in Trial A2 B C AE (%) AE (skin) (%) Drop-out Adjusted efficacy Physician Global Assessment (according to Evidence Level) Fleming 2010 [6] 19 16 % 52 KO Calcipotriol 50 μg/g +BMD 0.5 mg/g (fixed) once daily.* Calcipotriol 50 μg/g + BMD 0.5 mg/g (fixed) alternating every 4 + db + weeks with calcipotriol 50 μg/g once daily.* Calcipotriol 50 μg/g once daily.*. ** End point: cortisol suppression during n.a. n.a. long-term treatment 0 % 16 % (1/6) cortisol n.a. n.a. suppression 16 % (1/6) cortisol suppression Kragballe 2006 634 [7, 8] Mod. (70 %); 52 severe (30 %) Calcipotriol 50 μg/g +BMD 0.5 mg/g (fixed) once daily.* Calcipotriol 50 μg/g + BMD 0.5 mg/g (fixed) + db + alternating every 4 weeks with calcipotriol 50 μg/g once daily.* PGA severity (6 pt. scale); End point: % with absent, very mild or mild Pso. (along all visits per pat.) 84 % (p = 0.025 vs. C.) 63 % (W52, LOCF) 22 % (p < 0.001 vs. C.) 5 % Pso.; 5 % Cort.; 30 % n.s. 4 % Pso.; 75 % 62 % 30 % 26 % 3 % Cort. Calcipotriol 50 μg/g 70 % 56 % 38 % once daily.*, ** 7 % Pso.; 34 % 3 % Cort. 673

Table 4 Continued. Design Effectivity (1) Tolerability (2) Author (year) n Severity grade Duration of treatment Dosage Randomization Blinding ITT Responder selection Efficacy measure Primary end point Efficacy Physician Global Assessment in Trial A2 B C AE (%) AE (skin) (%) Drop-out Adjusted efficacy Physician Global Assessment (according to Evidence Level) Koo (part II) 38 2006 # [12] PGA 3,16 24 mod. Calcipotriol ointment 50 μg/g twice daily on weekdays + Clobetasol propionate foam 0.05 % dur. WE + db + + Calcipotriol ointment 50 μg/g twice daily on weekdays + placebo dur. WE (foam 0.00 %) PGA severity scale (6 pt. scale) End point: Stabilization or improvement of remission 85 % (PP) (n.s.) 62 % (PP) 68 % (ITT, LOCF) n.a. n.a. 32 % 58 % Lebwohl 1998 ## 40 n.a. 24 [10] Halobetasol twice daily dur. WE, calcipotriol twice daily on weekdays + db + Halobetasol twice daily dur. WE, placebo twice daily on weekdays PGA severity scale (6 pt. scale) End point: Maintenance or improvement of remission (def. as 75 % improvement or value 2 in PGA) 76 % (PP) (p = 0,045) 40 % 65 % (ITT, 20 % 20 % LOCF) 10 % (PP) 20 % 5 % 5 % Abbr.: BMD; betamethasone dipropionate; C, calcipotriol; db, double-blind; fix, fixed combination; ITT, Intention to treat; LOCF, Last Observation Carried Forward; Pso., deterioration of psoriasis; n.a., not available n.s., not significant; PGA, Physician s Global Assessment; Pt., point; PP, Per Protocol; AE, adverse event; W, week. *on demand; **Following a 4-week induction phase with calcipotriol 50 μg/g + BMD 0.5 mg/g (fixed); # 2-part study: In db induction phase (2 weeks) combination reached significantly higher efficacy. Only pats. with 50 % improvement enrolled in maintenance study. ## 2-part trial: 2-week induction with calcipotriol (morning)/ halobetasol (evening); Only pats. with 50 % improvement enrolled in maintenance study (90 % of patients). 674

Table 5 Summary of long-term trials in psoriasis vulgaris with topical corticosteroids in monotherapy. Design Efficacy (PGA) Tolerability Author (year) n Severity at inclusion Duration of treatment in W Dosage Randomization Blinding ITT Responder selection Efficacy measure Primary end point Efficacy Trial A2 B C Adjusted Efficacy (according to Evidence Level) AE (%) AE (skin) (%) Drop-out Katz 90 1991 [5] cleared- 24 mild Intermitt. aug. BMD 0.05 % ointment on 3 consecutive days /W* + db + + Intermitt. placebo on 3 consecutive days /W* PGA severity (4 pt. scale); mod. PASI; End point: time to relapse (mod. PASI > 2.5 or PGA mod./severe) 65 % (PP) (p = 0.001) 20 % (PP) 62 % 0 % 0 % 4 % (ITT) 20 % 0 % 0 % 4 % (ITT) Cornell 1981 [23] 22 23 > 30 % KO 24 Desoximetasone 0.25 % cream 2 x daily + db Betamethasone 17-valerate 0.1 % cream 2 x daily Symptom Score (5 pt. scale) End point: % with at least 50 % improvement 72 % n.a.** 41 % 34 % 0 % cortisol suppression n.a. 7 % Corbett 1976 [25] 12 max. 15 % KO 24 Clobetasol propionate 0.05 % ointment 2 x daily (unilat.) Betamethasone-17- valerate 0.1 % ointment 2 x daily (unilat.) SC db % with complete or partial remission; preferred substance 42% with cleared or less elevated lesions after 24 W; 100 % clobetasol preferred n.a. 0 % n.a. 14 % Floden 29 n.a. 24 1975 [24] Clobetasol propionate 0.05 % ointment 2 x daily (unilat.) SC db Fluocinolone acetonide 0.025 % ointment 2 x daily (unilat.) End point: preferred substance 94 % clobetasol n.a. 0 % n.a. n.a. preferred Abbr.: AE, adverse event; aug., augmented; BMD, betamethasone dipropionate; db, double-blind; ITT, Intention to treat; n. a., not available; PGA, Physician s Global Assessment; Pt., point; PP, per Protocol; SC, side-wise comparison; W, week. *2-part study: Open screening phase with aug. BMD 2 x daily for 3 4 W. Only cleared or mild Pso. pats. enrolled in long-term observation **PGA not assessed, only improvement in symptom score compared to baseline. 675

Figure 1 Literature hits of the online-search about topical long-term therapy of psoriasis with vitamin D 3 analogues, corticosteroids and their two compound formulations (Abbr.: Ps, psoriasis). unaffected [13]. No significant differences between studies with or without positive responder selection could be found. (Fixed) two compound formulations of calcipotriol plus corticosteroid for the long-term treatment of psoriasis vulgaris (Table 4) Already small double-blind comparative trials of Lebwohl et al. (1998) (n = 44) and Koo et al. (2006) (n = 38) had shown potential advantages of a combination of calcipotriol with a corticosteroid (halobetasol [10] or clobetasol propionate [12]) over monotherapy regimens. Following a weekend monotherapy with halobetasol, 40% of the patients remained in remission for 24 weeks, while a combination therapy of calcipotriol on weekdays and halobetasol during the weekend maintained 76 % of patients (adjusted efficacy 65 %) in remission [10]. On the other side calcipotriol monotherapy maintained or improved the clinical status in 62 % (adjusted efficacy 58 %) of the patients, while a combination with clobetasol propionate foam maintained remission in 85 % of cases (adjusted efficacy 68 %) [12]. The fixed two-compound-formulation of calcipotriol and betamethasone for psoriasis vulgaris was investigated in a prospective double-blind randomized trial by Kragballe et al. (n = 634) [7, 8]. The authors compared the fixed two- compoundformulation of calcipotriol 50 μg/g plus betamethasone dipropionate 0.5 mg/g (fixed combination group) with a therapeutic regimen alternating every four weeks between the fixed combination and calcipotriol monotherapy (alternating group) and a third group in which a four-week induction therapy with the fixed two-compound-formulation was followed by calcipotriol 50 μg/g monotherapy (monotherapy group). Primarily the study was targeted to assess long-term safety [8], however, efficacy data were assessed every four weeks [7]. In the fixed combination group, satisfactory response was observed in 84% of patients (adjusted efficacy 63 %) as compared to 676

Table 6 Summary of long-term trials in scalp psoriasis with topical vitamin D 3 analogues, their two compound formulations and corticosteroids. Design Efficacy (PGA) Tolerability Author (year) n Severity at inclusion Duration of treatment in W Dosage Randomization Blinding ITT Responder selection Efficacy measure Primary end point Efficacy Trial A2 B C Adjusted Efficacy (according to Evidence Level) AE (%) AE (skin) (%) Drop-out Luger 869 2008 [28] Barnes 2000 202 [29] Poulin 2010 136 [26, 27] Mod. 56 %; severe 38%; 52 very severe 7 % Mild 31 %; mod. 58 %; 52 severe 11 % Clear, very mild, mild 24 84% Calcipotriol 50 μg/g + BMD 0.5 mg/g (fixed; gel) 1 x daily + db + Calcipotriol 50 μg/g 1 x daily Calcipotriol 50 μg/g solution (scalp) 2 x daily Calcipotriol 50 μg/g cream (body) 2 x daily Clobetasol 0.0 5 % shampoo 1 x daily, if improved, 2x daily + db + +* Placebo vehicle shampoo 1x daily, if improved, 2x daily PGA severity scale (6 pt. scale) End point: % with absent, very mild or mild psoriasis (along all visits, per patient) Scalp: PGA severity scale (4 pt. scale) Zeilenumbruch End point: % pats. that did not need treatment (= 0) or mild severity (= 1) after 52 W PGA severity (6 pt. scale) End point: % pats. with PGA 0 2 ( = no relapse) at end-ofstudy 92.3 % (p < 0.001) 69 % (W52; ITT) 17.2 % (p < 0.001) 12 % Irr. 2.6 % 21 % Cort. 22 % Irr 80.0 % 45 % 29.5 % 3.0 % 40 % Cort. 75.2 % (scalp) (PP) 40.3 % (p < 0.001) 58 % (scalp) (ITT) 40.3 % (W26) n.a. in % Pat. 42 % n.a. in % 32 % Pat. 4.5 % 13 % Cort. 1.4 % 11.6 % 11.6 % 60 % 25 % Cort. Abbr.: BMD, betamethasone dipropionate; Cort., corticosteroid-associated cutaneous AEs; db, double-blind; fixed, fixed combination; ITT, Intention to treat; Irr., irritative skin lesions (lesion or perilesional); LOCF, Last Observation Carried Forward; Pso., deterioration of Psoriasis as AE; n. a., not available; n.s., not significant; PGA, Physician s Global Assessment; Pt., point; PP, per Protocol; AE, adverse event; W, week; WE, weekend. *2-part study: open induction with clobetasol shampoo for 4 weeks, only pats. with a severity score 0 2 after induction were enrolled in maintenance therapy 677

75 % (adjusted efficacy 62 %) in the alternating group and 70 % (adjusted efficacy 56 %) in the monotherapy group. With regard to efficacy, the authors concluded a trend in favor of a long-term use of the fixed combination. For a conclusive efficacy analysis, however a sample size of 304 490 (as compared to the actual 204 213) patients per group would have been necessary [7]. For an objective assessment of corticosteroid related AEs during long-term treatment, all dermatological findings in this trial were reviewed by an independent expert committee. The fixed combination group showed a significant lower overall number of AEs (especially burning, itching or erythema of the skin) as compared to the monotherapy group (21.7 % vs. 37.9 %, p < 0.001) [8]. AEs related to corticosteroid application (mainly atrophic skin or folliculitis) occurred more often in the fixed combination group (4.8 %) as compared to the alternating (2.8 %) or monotherapy (2.9 %) groups. Overall frequency was low and most of the symptoms observed were reversible, except for the skin atrophy in one patient who had undergone >10 years of corticosteroid treatment prior to enrolment [8]. The sample size in this study was sufficient to assess tolerability of the tested treatment regimens. Thus the results suggest that a long-term treatment with a fixed two-compound-formulation for psoriasis, either as a long-term or alternating (every four weeks) regimen, is both safe and well tolerated [8]. An additional smaller safety study [6] of the same design, which enrolled 19 patients with, in part, extensive psoriasis, showed that a suppression of the hypothalamic pituitary axis (HPA) is not to be expected after 52 weeks. Long-term use of topical corticosteroids for psoriasis vulgaris (Tables 4 and 5) Long-term monotherapy with topical corticosteroids has only been assessed in studies with small sample size (n = 12 90) [5, 10, 23 25]. In principle safety and efficacy depend on the respective substance, applicated amount on affected body surface, localization and application frequency (daily or intermittent), leading to very heterogeneous results. All studies were limited to a maximum duration of 6 months, with remission rates (adjusted efficacy) between 40 % [10] and 62 % [5]. Continuous and extensive application of desoximetasone 0.25 % cream b.i.d. led to a 50 % improvement of the psoriatic symptoms in 72 % of patients, while, however, a suppression of the hypothalamic pituitary axis was seen in 41 %, which did not occur with topical betamethasone 17-valerate in the same study [23]. In other longterm studies assessing topical corticosteroid monotherapy for psoriasis vulgaris [5, 23 25] neither betamethasone nor clobetasol caused skin atrophy [5] or HPA suppression after 24 weeks [5, 23 25]. Topical long-term therapy of scalp psoriasis In an open label trial over 52 weeks, Barnes et al. (2002) assessed the efficacy of calcipotriol 50 μg/g solution for scalp psoriasis [29]. Substantial improvement was seen during the first 10 weeks. After 52 weeks, 75.2 % of patients reported either none or very few symptoms (adjusted efficacy 58 %). An irritation of the facial skin was the most often reported AE, occurring mainly during the first two weeks of treatment. Luger et al. (2008) studied 869 patients with moderate to severe psoriasis of the scalp treated either with the fixed two-compound-formulation of calcipotriol 50 μg/g plus betamethasone dipropionate 0.05 mg/g once daily or calcipotriol 50 μg/g as a monotherapy for 52 weeks [28]. In the fixed combination group, symptoms were adequately controlled in 92.3% along all visits during the study vs. 80% in the monotherapy group (adjusted efficacy at week 52 was 70 % vs. 46 %), a difference which was significant (p < 0.001). AE rates (itching, skin irritations, burning and erythema) were significantly lower in the two-compound-group compared to monotherapy. There was no significant difference (p = 0.73) between both groups with regard to typical corticosteroid AEs (2.6 % in the combination group vs. 3 % in the calcipotriol group). Skin atrophy did not occur. The authors concluded an advantage of the fixed two-compound-gel for the long-term treatment of scalp psoriasis over calcipotriol monotherapy regarding both efficacy and tolerability [28] (Table 6). Poulin et al. assessed the efficacy of clobetasol 0.05 % shampoo vs. placebo over 24 weeks for moderate scalp psoriasis [26]. Only patients who had responded well to an open 4-week induction therapy with clobetasol were enrolled, however, only in 40.3% remission could be maintained after 6 months (p < 0.001 vs. placebo). Corticosteroid- typical AEs (skin atrophy, telangiectasia or HPA suppression) did not occur more frequently. Discussion This is the first systematic review of the literature and analysis of clinical evidence regarding topical long-term treatment with vitamin D 3 analogues, topical corticosteroids and their combinations. The current Cochrane review on longterm therapy by Mason et al. (2013) [30] included mainly studies with an evidence level of A2. Recommendations for daily practice can hardly be drawn from these. In addition, the current S3 guideline does not provide recommendations for topical long-term therapy of psoriasis [1]. Thus, an expert board initiated this literature review, compared the results with current daily practice use in Germany and elaborated the following recommendations for daily practice during an expert meeting. In the brackets after the recommendationsthe 678

underlying level of evidence or, if unavailable, the expert consensus, is indicated. Long-term topical treatment with vitamin D 3 analogues in combination with corticosteroids is, according to all available data, safe and effective. (A2, B) Topical treatment with vitamin D 3 analogues and their combinations may be continued as a maintenance therapy. (A2, B) Best clinical evidence for long-term treatment of psoriasis is available for the two-compound-formation of calcipotriol and betamethasone. (A2) In direct comparative trials, the tolerability of (fixed) two- compound-formulations was better than the tolerability of vitamin D 3 analogues alone. (A2, B) A comparative trial on maintenance therapy for psoriasis of the body, i.e. excluding the scalp, showed a trend towards a better clinical efficacy of the two-compoundformulation compared to the monotherapy with calcipotriol alone. (A2) A comparative trial on maintenance therapy for psoriasis of the scalp showed a superior clinical efficacy of the two-compound-gel compared to the monotherapy with calcipotriol alone. (A2) Topical corticosteroids for long-term use For the long-term use of topical corticosteroid-monotherapy in psoriasis vulgaris only small trials with an evidence level B are available. Solely the extensive continuous use of desoximetasone 0.25% led to an HPA axis suppression [23], while neither systemic nor local AEs occurred with betamethasone 17-valerate 0.1 % cream, betamethasone dipropionate 0.05 % ointment, or clobetasol propionate 0.05 % ointment. However, clinical experience shows that skin atrophy, especially in the perilesional regions, may occur in long-term use of topical corticosteroids. Based on its side effect profile, the continuous extensive use of desoximetasone 0.25 % cream is not recommended. (B) Class-IV-corticosteroids are not recommended to be used longer than 2 4 weeks as a continuous monotherapy for psoriasis vulgaris, according to their SPC and current knowledge (expert consensus). The long-term use of corticosteroids in fixed combinations for psoriasis according to current data and in contrast to atopic dermatitis, seems not to increase the risk of skin atrophy. Experimental data suggest an ameliorating effect on skin atrophy when vitamin D 3 analogues are combined with topical corticosteroids [31]. However, long-term studies with validated, objective parameters (e.g. ultrasound) or measurement of biomarkers for skin atrophy are not yet available. On the other side long-term treatment with corticosteroids alone is approved and daily practice for psoriasis of the scalp. Comparative trials with vitamin D 3 analogues in fixed or free combinations vs. corticosteroids alone are not available. Our analyses of adjusted efficacy in scalp psoriasis show a trend which favors the use of the topical use of the twocompound-gel over either calcipotriol or clobetasol 0.05 % shampoo alone (Table 6). According to the currently available literature, the calcipotriol two-compound-gel shows a good efficacy in the long-term treatment of scalp psoriasis, and is superior to calcipotriol-monotherapy (A2). Economic factors In addition to clinical aspects, economic factors determine topical long-term therapy. Cost and efficiency data are specific for national health systems. Two pharmacoeconomic analyses have been published on the long-term use of vitamin D 3 analogues in Germany [32, 33]. Using the Markov decision model, cost effectiveness of the daily use of the twocompound-formulation of calcipotriol with betamethasone was analysed and compared to a daily treatment with both substances in monotherapy. For the simulated duration of 48 weeks, the two-compound-formulation was significantly more cost effective than the free combination of both drugs (total cost 571.33 vs. 705.23; costs per additional symptom-free day 21.38 vs. 47.07) [33]. Another analysis showed an economic advantage of the calcipotriol / betamethasone two-compound-product over both the free combination of the monosubstances and the treatment with tacalcitol b.i.d. herein, total costs for a therapy over 48 weeks were 431.36, 488.04 and 652.27, costs per symptom-free day 16.14 as compared to 32.58 and 35.80. The pharmacoeconomic advantage remains valid when current pricings from 2013 are considered [32]. The two compound product, used once daily, is more economic than the free combination of both substances used once daily each. (C) Adherence factors According to the WHO, adherence is among the critical factors for the efficacy of a treatment in chronic diseases such as psoriasis [34]. An estimated 50 60 % of patients with psoriasis are assumed to be adherent to topical therapy [35]. Adherence is compromised by low or late-onset efficacy, unfavorable cosmetic or galenic characteristics or smelling, time-consuming application (twice versus once daily), low user-friendliness and AEs. One study showed that adherence was reduced by 10 % for each point (on a 9 point scale) by which psoriatic symptoms were ameliorated [36]. In the study by Sticherling et al. (2012) on the a two-compound-gel with calcipotriol 50 μg/g and 679

betamethasone 50 μg/g, a retrospective comparison showed that 85.7 % of the patients were either very satisfied or satisfied after 4 weeks, while prior topical therapy with other formulations (73.6 % ointments, 42.5 % creams, 8.7 % foams, 2.8 % lotions) received these ratings in 27.6 % of the patients [37]. Regarding both the time needed for application (reduction by 30%) and the handling (66.1 % vs. 11.6 % very satisfied), the gel-formulation was significantly better rated than prior treatments with other applications. For psoriasis of the scalp, application of the topical gel for 4 weeks was evaluated in 89.5 % of the patients as more effective as compared to prior topical treatments. 90.4% of the patients rated the application as easy or very easy [38]. Specific studies on adherence in topical long-term therapy are not available. Due to the continuing burden of the treatment the chronic character of the disease and the relatively rapid onset of treatment effects following induction therapy, a low adherence to long-term therapy has to be expected, underlining the importance of choosing an effective, well-tolerated and user-friendly long-term product, which is accepted and used by the patient. Ideally, the patient should be involved in the choice of the product, the formulation and the mode of application in the sense of patient empowerment. It has been shown that shared decision making improves long-term adherence [39]. Adherence is crucial for efficacy of chronic treatments. Patients must be actively involved in the choice of the product, formulation and mode of application. (C) Evaluation of treatment regimens Besides the handling, clear instructions and a simple regimen determine adherence [40]. In the trials reported by Kragballe et al. and Luger et al., application was once daily on demand [7, 8, 28]. In another 12-week study, the on-demand regimen was restricted to be used 2 3 times per week and proved successful for daily practice [41]. Another 12-week study on scalp psoriasis compared the classical on demand regimen of the two compound gel with a regimen to be used twice a week. A significantly higher percentage of remissions was achieved with the twiceweekly regimen (p < 0.05) compared to the on demand regimen [42]. Standardized, simple treatment regimens seem to achieve better therapeutic results than on-demand regimens. (B) Neither data are available to compare different treatment modalities (re-induction therapy, on demand regimens) regarding their efficacy, safety and adherence for therapeutic intervals >12 weeks, nor to determine the optimum time point to switch from a daily treatment to a once-to twice weekly maintenance therapy. Conclusion Combining evidence and clinical experience, the following expert recommendations for the topical long-term treatment of psoriasis with vitamin D 3 analogues and their combinations can be given: Besides long-term treatment (1 2x weekly) with two-compound-formulations, also alternative regimens including calcipotriol monotherapy have shown to be effective in daily practice. (expert consensus) Due to its favorable risk-benefit profile in maintenance studies of high evidence (A2) and due to its economic benefits (C), the 1 2x weekly application of a twocompound-formulation after initial therapy is recommended. (expert consensus) Due to high patient satisfaction values the gel-formulation of the two-compound-products is recommended for maintenance therapy. (expert consensus) Acknowledgement Research of the literature, data compilation and manuscript preparation were supported by Dr. med. Michaela Dippel (MD Medscript & -consult, Bad Dürkheim, Germany). Costs were covered by Leo Pharma, Neu Isenburg, Germany. Conflict of Interest M. Augustin has functioned as a consultant and/or referent and/or participant in clinical studies for the following companies: Abbott/AbbVie, Almirall-Hermal, Amgen, Biogen Idec, Celgene, Centocor, Janssen-Cilag, Leo Pharma, medac, MSD (formerly Essex, Schering-Plough), Novartis, Pfizer (formerly Wyeth). U. Mrowietz has functioned as a consultant for and/or referent for and/or recipient of research funding from the following companies: Abbott/AbbVie, Almirall-Hermal, Amgen, BASF, Biogen Idec, Celgene, Centocor, Eli Lilly, Forward Pharma, Galderma, Janssen, Leo Pharma, Medac, MSD, Miltenyi Biotech, Novartis, Pfizer, Teva, VBL, Xenoport. B. Bonnekoh has functioned as a consultant for and/ or referent for and/or recipient of research funding and/or participant in clinical studies from the following companies: Abbott/AbbVie, Biogen Idec, Janssen, Leo Pharma, MSD, Novartis, Pfizer. T. Rosenbach has functioned as a consultant for and/ or referent for and/or recipient of research funding and/or participant in clinical studies from the following companies: Abbvie, Biogen-Idec, Janssen-Cilag, Leo, Lilly, Medac, MSD, Novartis, Pfizer. D. Thaci has functioned as a consultant for and/or referent for and/or recipient of research funding and/or 680

participant in clinical studies from the following companies: Abbott/AbbVie, Almirall-Hermal, Amgen, Biogen Idec, Celgene, Centocor, Eli Lilly, Forward Pharma, Galderma, Janssen, Leo Pharma, Maruho, Meda, Medac, Mitsubishi Pharma, MSD, Novartis, Pfizer, VBL. M. Reusch has functioned as a consultant for and/or referent for and/or participant in clinical studies from the following companies: AbbVie, Janssen-Cilag, Leo, Novartis. M. Ardabili has functioned as a consultant for and/or referent for and/or recipient of research funding and/or participant in clinical studies from the following companies: Amgen, Biogen-Idec, Janssen-Cilag, Leo, Novartis, Pfizer. K. Reich has functioned as a consultant for and/or referent for and/or recipient of research funding and/or participant in clinical studies from the following companies: Abbvie, Amgen, Biogen-Idec, Celgene, Centocor, Covagen, Forward Pharma, GSK, Janssen-Cilag, Leo, Lilly, Medac, MSD, Novartis, Pfizer, Vertex, Takeda. Correspondence to Prof. Dr. med. Matthias Augustin CVderm Centre of Excellence for Health Services Research in Dermatology Institute for Health Services Research in Dermatology and Nursing University Medical Center Hamburg-Eppendorf Martinistraße 52 20246 Hamburg, Germany E-mail: m.augustin@derma.de References 1 Nast A, Boehncke WH, Mrowietz U et al. S 3 -Leitlinie zur Therapie der Psoriasis vulgaris Update. J Dtsch Dermatol Ges 2012; 10 Suppl 2: S1 S95. 2 Krensel M, Reich K, Bonnekoh B et al. Characterization of topical treatment for mild psoriasis by dermatologist in Germany [accepted at Acta Dermatol Venereol on 24 January, 2014]. 3 Nast A, Rosumeck S, Sammain A et al. Special Issue: S 3 -Leitlinie zur Therapie der Psoriasis vulgaris Methodenreport. J Dtsch Dermatol Ges 2011; 9 (Suppl. 2): e64 e84. 4 Ellis JP, Griffiths WAD, Klaber MR. Longterm treatment of chronic plaque psoriasis with calcipotriol ointment in patients unresponsive to short contact dithranol. Eur J Clin Res 1995; 7: 247 57. 5 Katz HI, Prawer SE, Medansky RS et al. Intermittent corticosteroid maintenance treatment of psoriasis: a double-blind multicenter trial of augmented betamethasone dipropionate ointment in a pulse dose treatment regimen. Dermatologica 1991; 183(4): 269 74. 6 Fleming C, Ganslandt C, Leese GP. Short- and long-term safety assessment of a two-compound ointment containing calcipotriene/ betamethasone dipropionate (Taclonex/Daivobet/Dovobet ointment): hypothalamic-pituitary-adrenal axis function in patients with psoriasis vulgaris. J Drugs Dermatol 2010; 9(8): 969 74. 7 Kragballe K, Austad J, Barnes L et al. Efficacy results of a 52- week, randomised, double-blind, safety study of a calcipotriol/betamethasone dipropionate two-compound product (Daivobet/Dovobet/Taclonex) in the treatment of psoriasis vulgaris. Dermatology 2006; 213(4): 319 26. 8 Kragballe K, Austad J, Barnes L et al. A 52-week randomized safety study of a calcipotriol/betamethasone dipropionate two-compound product (Dovobet/Daivobet/Taclonex) in the treatment of psoriasis vulgaris. Br J Dermatol 2006; 154(6): 1155 60. 9 Van de Kerkhof P, Van der Vleuten C, Gerritsen M et al. Longterm efficacy and safety of once daily treatment of chronic plaque psoriasis with tacalcitol ointment. Eur J Dermatol 1997; 7(6): 421 5. 10 Lebwohl M, Yoles A, Lombardi K, Lou W: Calcipotriene ointment and halobetasol ointment in the long-term treatment of psoriasis: Effects on the duration of improvement. J Am Acad Dermatol 1998; 39: 447 50. 11 Cullen SI: Long-term effectiveness and safety of topical calcipotriene for psoriasis. South Med J 1996; 89 (11): 1053 6. 12 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 (4): 637 41. 13 Miyachi Y, Ohkawara A, Ohkido M et al. Long-term safety and efficacy of high-concentration (20 μg/g) tacalcitol ointment in psoriasis vulgaris. Eur J Dermatol 2002; 12 (5): 463 8. 14 Lambert J, Trompke C. Tacalcitol ointment for long-term control of chronic plaque psoriasis in dermatological practice. Dermatology 2002; 204 (4): 321 4. 15 van dekerkhof PC, Berth-Jones J, Griffiths CE et al. Long-term efficacy and safety of tacalcitol ointment in patients with chronic plaque psoriasis. Br J Dermatol 2002; 146 (3): 414 22. 16 van dekerkhof PC, Berth-Jones J, Griffiths CE et al. Long-term efficacy and safety of tacalcitol ointment in patients with chronic plaque psoriasis. H+G Zeitschrift für Hautkrankheiten 2002; 77 (9): 424 32. 17 Gerritsen MJ, vande Kerkhof PC, Langner A. Long-term safety of topical calcitriol 3 microg g(-1) ointment. Br J Dermatol 2001; 144 (Suppl 58): 17 9. 18 Langner A, Ashton P, van De Kerkhof PC, Verjans H. A longterm multicentre assessment of the safety and tolerability of calcitriol ointment in the treatment of chronic plaque psoriasis. Br J Dermatol 1996; 135 (3): 385 9. 19 van de Kerkhof PC, van Harten J, Verjans H. A long term assessment of the safety and tolerability of calcitriol ointment in the treatment of chronic plaque psoriasis. J Dermatol Treat 1996; 7 (Suppl 1): 11 4. 20 Ramsay CA, Berth-Jones J, Brundin G et al. Long-term use of topical calcipotriol in chronic plaque psoriasis. Dermatology 1994; 189 (3): 260 4. 21 Poyner T, Hughes JW, Dass BK, Adnitt PI. Long term treatment of chronic plaque psoriasis with calcipotriol. J Dermatol Treat 1993; 4: 173 7. 681

22 Kragballe K, Fogh K, Søgaard H. Long-term efficacy and tolerability of topical calcipotriol in psoriasis. Results of an open study. Acta Derm-Venereol 1991; 71 (6): 475 8. 23 Cornell RC, Stoughton RB. Six-month controlled study of effect of desoximetasone and betamethasone 17-valerate on the pituitary-adrenal axis. Br J Dermatol 1981; 105 (1): 91 5. 24 Floden CH, Woodbridge P, Samman P, Kurwa AR. Comparison of the response of psoriasis over a 6-month period, to clobetasol propionate and fluocinolone acetonide ointments. Curr Med Res Opin 1975; 3 (6): 375 81. 25 Corbett MF. The response of psoriasis to betamethasone valerate and clobetasol propionate. A 6-month controlled study. Br J Dermatol 1976; 94 (Suppl 12): 89 93. 26 Poulin Y, Papp K, Bissonnette R et al. Clobetasol propionate shampoo 0.05 % is efficacious and safe for long-term control of scalp psoriasis. Cutis 2010; 85 (1): 43 50. 27 Poulin Y, Papp K, Bissonnette R et al. Clobetasol propionate shampoo 0.05 % is efficacious and safe for long-term control of moderate scalp psoriasis. J Dermatolog Treat 2010; 21 (3): 185 92. 28 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 (4): 321 8. 29 Barnes L, Altmeyer P, Fôrstrôm L, Stenström MH. Long-term treatment of psoriasis with calcipotriol scalp solution and cream. Eur J Dermatol 2000; 10 (3): 199 204. 30 Mason AR, Mason J, Cork M et al. Topical treatments for chronic plaque psoriasis. Cochrane Database Syst Rev 2013; 28 (3): CD005028. 31 Norsgaard H, Gonzalez T, Duenstl G et al. Beneficial effects of the fixed combination of calcipotriol and betamethasone dipropionate on skin atrophy biomarkers. Poster presented at 21st EADV, 2012: No. PRA12 0845. 32 Augustin M, Peeters P, Radtke M et al. Cost-effectiveness model of topical treatment of mild to moderate psoriasis vulgaris in Germany. A comparison of calcipotriol/betamethasone (Daivobet/Dovobet/Taclonex) once daily and a morning/evening non-fix combination of calcipotriol and betamethasone. Dermatology 2007; 215 (3): 219 28. 33 Augustin M, Radtke M, van Engen A et al. Pharmakoökonomisches Modell zur Kosten-Effektivität topischer Behandlungsformen bei leichter bis mittelschwerer Psoriasis vulgaris in Deutschland. J Dtsch Dermatol Ges 2009; 7 (4): 329 38. 34 World Health Organization: Adherence to long term therapy: evidence for action. 2003 http://www.who.int/chp/knowledge/ publications/adherence_full_report.pdf (accessed Oct 2011). 35 Augustin M, Holland B, Dartsch D et al. Adherence in the treatment of psoriasis: a systematic review. Dermatology 2011; 222 (4): 363 74. 36 Carroll CL, Feldman SR, Camacho FT et al. Better medication adherence results in greater improvement in severity of psoriasis. Br J Dermatol 2004; 151: 895 97. 37 Sticherling M, Eicke C, Anger T. Praktikabilität der kombinierten Anwendung von Calcipotriol/ Betamethason in Gel-Form und Verbesserung der Lebensqualität bei Patienten mit Psoriasis. J Dtsch Dermatol Ges 2013; 11 (5): 420 7. 38 Mrowietz U, Macheleidt O, Eicke C. Effective treatment and improvement of quality of life in patients with scalp psoriasis by topical use of calcipotriol/betamethasone (Xamiol -Gel): results form a study in 721 patients. J Dtsch Dermatol Ges 2011; 9 (10): 825 31. 39 Umar N, Schaarschmidt M, Schmieder A et al. Matching physicians treatment recommendations to patients treatment preferences is associated with improvement in treatment satisfaction. J Eur Acad Dermatol Venereol 2013; 27 (6): 763 70. 40 Brown KK, Rehmus WE, Kimball AB. Determining the relative importance of patient motivations for non-adherence to topical corticosteroid therapy in psoriasis. J Am Acad Dermatol 2006; 55: 607 13. 41 White S, Vender R, Thaçi D et al. Use of calcipotriene cream (Dovonex cream) following acute treatment of psoriasis vulgaris with the calcipotriene/betamethasone dipropionate two-compound product (Taclonex): a randomized, parallelgroup clinical trial. Am J Clin Dermatol 2006: 7 (8): 177 184. 42 Saraceno R, Camplone G, D Agostino M et al. Efficacy and maintenance strategies of two-compound formulation calcipotriol and betamethasone dipropionate gel (Xamiol gel) in the treatment of scalp psoriasis: results from a study in 885 patients. J Dermatolog Treat 2014; 25(1): 30 3. 682