Expert recommendations: the use of the fixed combination calcipotriol and betamethasone dipropionate gel for the topical treatment of psoriasis

Transcription

1 DOI: /jdv JEADV REVIEW ARTICLE Expert recommendations: the use of the fixed combination calcipotriol and betamethasone dipropionate for the topical treatment of psoriasis E. Dauden, 1, * A. Bewley, 2 J. Lambert, 3 G. Girolomoni, 4 F. Cambazard 5 K. Reich 6 1 Department of Dermatology, Hospital Universitario de la Princesa, Madrid, Spain 2 Department of Dermatology, Barts Health NHS Trust, London, UK 3 Department of Dermatology, Ghent University Hospital, Ghent, Belgium 4 Department of Dermatology, University of Verona, Verona, Italy 5 Jean Monnet University, St Etienne, France 6 Dermatologikum Hamburg, Hamburg, Germany *Correspondence: E. Dauden. estebandauden@medynet.com Abstract Treatment non-adherence is a general challenge and a complex problem. It is a key factor that impacts the real-life effectiveness of topical treatments for chronic disorders, such as psoriasis. Here, we provide our expert opinion on the real-life effectiveness of topical psoriasis treatment, using the fixed combination (Daivobet â ; calcipotriol plus betamethasone dipropionate) as a case study. The fixed combination is a first-line topical treatment for mild-to-moderate psoriasis, developed to be the gold-standard therapy for psoriasis patients. This fixed combination is an effective and well-tolerated topical psoriasis treatment that the majority of our patients prefer to the ointment formulation. We assessed our real-life experience and considered any gaps between daily practice and clinical trials data. We recommend a multifaceted approach to improve real-life effectiveness and bridge the gap between investigational trials and treatment reality and propose the following recommendations: (1) educate primary healthcare providers on how to effectively manage topical psoriasis treatment and the patients who use the treatment; (2) educate the patient on why treatment needs to be maintained, even when symptoms improve; and (3) provide a supportive environment that will not allow the patient to feel abandoned. A patient-centric approach may improve adherence, which will lead to patients receiving more effective treatment for psoriasis. Received: 21 January 2014; Accepted: 6 February 2014 Literature search terms ((Xamiol OR Daivobet OR Taclonex) AND ( or topical suspension)) OR (calcipotri$3 AND betamethasone) Conflicts of interest Esteban Dauden has served as an advisory board member, consultant, or clinical trial investigator, or received grants, research support, or honoraria from the following companies: Abbott, Amgen, Astellas, Celgene, Centocor, Galderma, GlaxoSmithKline, Janssen, LEO Pharma, MSD, Novartis and Pfizer. Anthony Bewley has received ad hoc consultancy payments from AbbVie, Galderma, LEO Pharma and Novartis. Jo Lambert has served as an advisory board member, consultant, or clinical trial investigator, or received grants, research support, or speaker s fees from the following companies: Abbott, Amgen, Celgene, Centocor, Galderma, Janssen, LEO Pharma, MSD, Novartis and Pfizer. Giampiero Girolomoni has received advisory/speaker honoraria and/or research funding from Abbott, Almirall, Boehringer Inheim, Celgene, Dompe, Eli Lilly, Galderma, GlaxoSmithKline, Janssen, LEO Pharma, Otsuka, Merck-Serono, Maruho, MSD, Novartis and Pfizer. Frederic Cambazard has served as a consultant, investigator and speaker for AbbVie, Janssen, LEO Pharma, MSD and Pfizer. Kristian Reich has received honoraria as a consultant and/or advisory board member and/or acted as a paid speaker and/or participated in clinical trials sponsored by: AbbVie, Amgen, Biogen-Idec, Celgene, Centocor, Covagen, Eli Lilly, Forward Pharma, GlaxoSmithKline, Janssen, LEO Pharma, Medac, MSD, Novartis, Ocean Pharma, Pfizer, Takeda and Vertex. Funding source Medical writing support was provided by Zo e van Helmond, PhD, from Mudskipper Business Ltd, which was funded by LEO Pharma.

2 Expert recommendations for topical psoriasis treatment 23 Introduction Non-adherence to medication is a universal challenge a drug that demonstrates high efficacy may still be a therapeutic failure if not accepted by the patient and occurs irrespective of the route of administration. 1 Patients who suffer from chronic disorders are less likely to adhere to their treatment regimen compared with those with acute conditions. 1 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. 2 Topical therapy remains the mainstay in the treatment of psoriasis, with more than 80% of patients managing their psoriasis with topicals alone; most patients on systemic treatments also benefit from concurrent topical treatment for greatest clearance of disease. 3 9 However, with topical products, non-adherence is further exacerbated by the necessity of application, which can be cumbersome and time-consuming, combined with patients poor acceptability of certain treatment vehicles, such as ointments, that are perceived to be messy (Table 1). 10,11 Non-adherence is a key factor that impacts the real-life effectiveness of topical treatments for chronic disorders, such as psoriasis The fixed combination of calcipotriol and betamethasone dipropionate in a formulation (Daivobet â [LEO Pharma, Ballerup, Denmark]) has been approved in Europe for the once-daily treatment of mild-to-moderate psoriasis vulgaris of the body and all severities of psoriasis vulgaris of the scalp in adults and is recommended as a first-line topical treatment for mild-to-moderate psoriasis. 15 This benefits from the synergistic action of the fixed combination of the vitamin D analogue calcipotriol and the potent corticosteroid betamethasone diproprionate 16 and was developed to be the gold-standard therapy for psoriasis patients, offering minimal impact on the patient s daily routine and thereby promoting patient adherence. Furthermore, in an 8-week randomized study, once-daily treatment of scalp psoriasis with the fixed combination resulted in significant improvements in patient quality of life versus twice-daily calcipotriol scalp solution. 17 Evidence from clinical trials shows that this fixed combination has superior efficacy over the individual active components administered as monotherapies in the vehicle and is well tolerated in patients with mild-to-moderate psoriasis. 15,18 However, evidence of effectiveness in the real-life setting is limited ,19 In the absence of any long-term, European-wide data, a roundtable discussion was convened to share evidence on the real-life effectiveness of the fixed combination, drawing from our own experiences in daily practice. Our objectives were to provide clear recommendations in response to the following questions: (1) Can we test the hypothesis that the fixed combination advances topical psoriasis treatment and is more readily acceptable by the patient (compared with the ointment formulation)? (2) Does patient acceptability of the fixed combination translate into real-life effectiveness? (3) If we are unable to issue clear recommendations in response to (1) and (2), where are the knowledge gaps? Evidence from clinical trials Twelve clinical trials have evaluated the efficacy and safety of the fixed combination for the treatment of psoriasis of the scalp (7 studies) and body (5 studies), with 3767 patients receiving this drug treatment (Fig. 1; Table 2). All studies demonstrated improved efficacy of the fixed combination versus active and vehicle comparators with a favourable safety and tolerability profile. Four international, Phase 3 trials (two each for scalp and body psoriasis) have assessed short-term (8-week) treatment, 15,20 22 and an additional Phase 3 study in scalp psoriasis has assessed the safety of long-term (52-week) treatment. 23 Across all clinical trials, an increase in the efficacy over time (i.e. treatment week 8 versus week 4) has been demonstrated with the fixed combination, for treatment of psoriasis of both body and scalp. In both of the 8-week, Phase 3 scalp psoriasis studies, a significantly greater proportion of patients achieved treatment success [defined as absent or very mild disease, according to the investigator s global assessment (IGA)] with the fixed combination (71.2% and 68.4% respectively), compared with the active Table 1 Patient preference to three topical treatment vehicles (, cream and ointment). Adapted from Bewley et al. 10 Question, % responders Formulation Gel (non-alcoholic) Cream Ointment Was the vehicle very easy or easy to apply?* Which vehicle was the least visible on the skin? Which vehicle required the least effort to apply? Which vehicle required the least amount of time to apply? Which vehicle was the least greasy? Which vehicle was the fastest to be absorbed? *Proportion of patients who responded yes. Proportion of patients who rated the vehicle first or second.

3 24 Dauden et al. Figure 1 Overview of the studies evaluating calcipotriol plus betamethasone dipropionate in psoriasis vulgaris. mono-components in the vehicle (betamethasone dipropionate, 64.0% and 61.0%; calcipotriol, 36.8% and 43.4% respectively). 20,21 Retrospective analysis of pooled data from these two Phase 3 studies demonstrated that a clinical response was already observed after the first week of treatment with the fixed combination, with a faster onset compared with the active comparators. 24 The superiority of the fixed combination was also reflected in assessment of total sign score (TSS) and patient-reported assessment of efficacy. 20,21 In both studies, the incidence of adverse events (AEs) was low, with lesional/perilesional AEs reported in a smaller proportion of patients treated with the fixed combination (4.7% and 6.2% respectively) versus betamethasone dipropionate (5.3% and 5.8%) and calcipotriol (13.2% and 12.8%). 20,21 The long-term safety trial recruited patients with at least moderate scalp psoriasis and reported no increase in the incidence of frequently reported adverse drug reactions (ADRs) over the course of the study, indicating no increased risk with prolonged use. 23 Findings from the Phase 3 studies in psoriasis of the body generally agree with those in scalp psoriasis. Treatment of mild-to-moderate psoriasis of the body with the fixed combination resulted in a significantly larger proportion of patients achieving controlled disease (defined as clear or almost clear disease, according to IGA, with a minimum two-point change from baseline) versus the active monocomponents (fixed combination, 29%; betamethasone dipropionate, 21.5%; calcipotriol, 6.3%). 15 Significantly greater improvements in Psoriasis Area Severity Index (PASI) scores and the proportion of patients achieving PASI 50 and PASI 75 at week 8 were also demonstrated with fixed combination treatment. Incidence of ADRs was low in this study: 5.0% of patients treated with fixed combination, 3.1% with betamethasone dipropionate, 5.3% with calcipotriol and 4.2% with vehicle. In moderate-to-severe psoriasis of the body, superior efficacy of the fixed combination versus tacalcitol ointment 4 lg/g as monohydrate (Curatoderm â, Hermal, Germany) has been demonstrated. 22 Controlled disease was achieved by a significantly larger proportion of patients treated with the fixed combination (39.9% versus 17.9%) and, again, was further supported by greater improvements in PASI scores, the proportion of patients achieving PASI 75 and patient-assessed treatment success (40.4% versus 21.5%) following treatment with the fixed combination. The proportion of patients reporting one or more ADR was significantly lower with the fixed combination (8.8%) than for tacalcitol (15.8%; P = 0.042), with pruritus and skin irritation being most frequently reported. Evidence from non-interventional studies In this section, we review published data collated from observational real-life studies, where treatment is performed outside the compliant-friendly environment of the clinical trial and

4 Expert recommendations for topical psoriasis treatment 25 Table 2 Clinical trials evaluating efficacy and safety of calcipotriol plus betamethasone dipropionate in psoriasis vulgaris Reference Study design Study duration (weeks) Disease Treatment* n Study outcomes (statistical comparisons versus fixed combination ) Short-term studies ( 12 weeks duration) Phase III psoriasis of the body Langley Randomized, investigatorblind, et al. 22 active and vehicle controlled Menter Randomized, double-blind, et al. 15 active and vehicle controlled Phase III scalp psoriasis Jemec et al. 20 Randomized, double-blind, active and vehicle controlled van de Kerkhof et al. 21 Randomized, double-blind, active controlled 8 At least moderate 8 Mild-tomoderate Fixed combination Tacalcitol ointment IGA-controlled disease, % patients at weeks 4 &8 PASI,% change at weeks 4 & 8 PaGA-treatment success, % patients & & & (P < 0.001) & 17.9 (P < 0.001) Gel vehicle (P < 0.001) & 5.5 (P < 0.001) Fixed combination Betamethasone dipropionate 37.3 (P < 0.001) & 41.9 (P < 0.001) 12.0 & (P < 0.001) & 17.9 (P < 0.001) 8.6 & & & 55.8 NC (P = 0.82) & 21.5 (P 0.008) Calcipotriol (P = 0.019) & 14.6 (P 0.008) Gel vehicle (P = 0.001) & 6.3 (P 0.008) 42.7 (P = 0.038) & 48.6 (P < 0.001) NC 32.2 (P < 0.001) & 43.6 (P < 0.001) NC 17.4 (P < 0.001) & 20.9 (P < 0.001) NC IGA-treatment success, patients PaGA-treatment success, patients 8 At least mild Fixed combination Betamethasone dipropionate (P < 0.011) 62.5 (P = 0.2) Calcipotriol (P < ) 38.3 (P < ) Gel vehicle (P < ) 20.7 (P < ) 8 At least mild Fixed combination Betamethasone dipropionate (P = ) 59.9 (P = ) Calcipotriol (P < ) 44.7 (P < ) Phase II psoriasis of the body IGA-responders at weeks 4 & 8, patients PASI, change at weeks 4 & 8

5 26 Dauden et al. Table 2 Continued Phase II psoriasis of the body Fleming Randomized, doubleblind, et al. 18 active and vehicle controlled 8 At least mild Fixed combination Silver Open-label, single-arm 8 Extensive psoriasis (15 30 et al. 25 BSA) of at least moderate Betamethasone dipropionate IGA-responders at weeks 4 & 8, patients PASI, change at weeks 4 & & & (P = 0.11) & 16.9 (P = 0.027) 40.9 (P = 0.04) & 49.8 (P = 0.13) Calcipotriol (P = 0.006) & 11.4 (P = 0.006) 32.7 (P < 0.001) & 41.2 (P < 0.001) Gel vehicle (P = 0.027) & 0.0 (P < 0.001) 16.9 (P < 0.001) & 11.9 (P < 0.001) Fixed combination Serum cortisol 18 lg/dl (weeks 4 & 8), patients Change in serum calcium, mmol/l Change in 24-h urinary calcium excretion, mmol/24 h & Change in urinary calcium:creatinine ratio, mmol/g Phase II scalp psoriasis Buckley et al. 26 Randomized, double-blind, active controlled Kragballe et al. 27 Randomized, investigatorblind, active and vehicle controlled Tyring et al. 28 Randomized, double-blind, vehicle controlled Saraceno et al. 29 Randomized, non-controlled Long-term study (52 weeks duration) 8 At least mild 8 At least moderate 8 At least moderate IGA-treatment success, patients PaGA-treatment success, patients Fixed combination more patients achieved treatment success with 92.5 Betamethasone 110 the fixed combination vs comparator (P = 0.11) 82.6 (P = 0.027) dipropionate Fixed combination 207 NC 82.1 Calcipotriol scalp solution, twice daily 12 Mild-to-moderate Fixed combination, twice weekly 105 NC 34.3 (P < 0.001) Fixed combination Gel vehicle (P < 0.001) 35.7 (P = 0.004) Fixed combination, as required 441 Significantly greater with twice weekly treatment by week 12 (P < 0.01) 444 NC

6 Expert recommendations for topical psoriasis treatment 27 Table 2 Continued Phase III scalp psoriasis ADRs, patients Lesional/perilesional events, patients Fixed combination Calcipotriol (P < 0.001) 21.6 (P < 0.001) 52 At least moderate Luger et al. 23 Randomized, double-blind, active controlled *Treatment was once daily unless stated otherwise. Controlled disease, defined as clear or almost clear according to the IGA scale, requiring a minimum two-point change from baseline. PaGA-treatment success, defined as marked improvement, almost clear or clear disease, according to the patient global assessment. IGA-treatment success, defined as clear or almost clear according to the IGA scale. For patients with at least moderate disease at baseline, a responder was defined as a patient whose psoriasis was scored as either clear or almost clear ; for patients with mild disease, a responder had a score of clear. 30 min after adrenocorticotropic hormone stimulation. ADR, adverse drug reaction; BSA, body surface area; IGA, investigator s global assessment; PaGA, patient s global assessment. where patient acceptability of the treatment regimen may have a greater influence on the effectiveness of a topical psoriasis product. Two prospective, short-term (4-week), non-interventional studies assessing the effectiveness of the fixed combination in daily practice (both in Germany) have been published to date (Table 3). The first is an assessment of patients with all severities of scalp psoriasis registered at 259 German dermatological practices. 13 By the end of treatment, the proportions of patients presenting with at least moderate scalp psoriasis (as assessed by IGA) had decreased from 87.8% to 15.6% and, with no or almost no lesions, increased from 1.7% at baseline to 53.7%. Early discontinuation of treatment because of total clearance of disease was reported for 63 patients (8.7%). Of the 388 patients with a history of previous psoriasis therapies, 167 (43.0%) and 174 (44.9%) judged the effectiveness of the fixed combination as better and much better, respectively, than their previous treatments. The second study assessed real-life effectiveness of the fixed combination in 588 patients (206 participating centres) with mild-to-moderate psoriasis of the body, and included assessment of the burden of treatment. 14 The proportion of patients with at least moderate psoriasis decreased from 82.9% to 21.2%. Overall, 85.7% of patients were reported to have been satisfied or very satisfied with the efficacy of the fixed combination, compared with only 27.6% of patients when referring to their prior treatments. The proportion of patients who had to change clothing more frequently because of their topical psoriasis treatment also declined from 59.5% at baseline to 19.4% while using the fixed combination. The mean time for application was significantly reduced by 3 min with the fixed combination, from 10 min with prior treatments (30% reduction; P < ), as was the lag time before patients could dress following application, reduced by 2.5 min with the fixed combination, from 11.5 min with prior treatments (22% reduction; P < ). Most patients (66.1%) therefore reported to be very satisfied with the convenience of the fixed combination, compared with 11.6% of patients with their previous therapies, and handling of the fixed combination was judged as more pleasant or much more pleasant versus their previous treatment by 81.2% of the study patients. Evidence from pharmacoeconomic evaluations Lack of patient adherence can have highly detrimental effects on effective management of psoriasis: non-adherence results in poorer prognosis, more hospitalizations and significantly higher healthcare costs. 30 This exacerbates the already considerable financial burden associated with psoriasis, due to the chronic nature of the disease and its associated comorbidities. Here, we provide an overview of pharmacoeconomic analyses that have been performed on fixed combination data from national healthcare registries.

7 28 Dauden et al. A cost-utility analysis of topical treatment pathways (first-, second- and third-line) for scalp psoriasis was performed on patients registered within Scottish primary care. 19 The use of the fixed combination was projected to increase patient qualityadjusted life-years (incremental gain of approximately per year) with cost savings of per patient per year. 19 A cost-minimization analysis has also been performed to assess the cost-effectiveness of the fixed combination formulation versus the fixed combination ointment formulation in the treatment of mild-to-moderate psoriasis, using data from the Italian National Healthcare Service. 12 Analysis showed that the benefits of the formulation over the ointment were two-fold: benefiting the patient by improving treatment adherence and therefore the effectiveness of treatment, and a benefit to the Italian National Healthcare Service by delaying the time to use of particularly expensive systemic therapies, such as biologics. Treatment with the fixed combination reduced the number of patients potentially requiring treatment with more costly therapies (phototherapy, conventional systemics, biologics) by 5% compared with the ointment formulation, despite an increase in resource consumption for topical therapies. The total annual cost for the use of the fixed combination per patient was calculated as 18.6% less than for the use of the ointment. However, as with any modelled analyses, there are limitations to these studies, primarily due to the lack of quality comparator data that can be used to inform the models. 12,19 For example, within the Scottish healthcare system, the use of potent steroid combinations with salicylic acid is quite common; however, there are no published clinical data for this treatment regimen, and therefore assumptions, rather than evidence, were included in the costutility model. 19 The fixed combination has also been shown to be more cost-effective because of its dual indication rather than using two separate products for treatment of psoriasis of the scalp and body. In a retrospective study analysing Thomson Reuters MarketScan â (MarketScan is a registered trademark of Thomson Reuters Healthcare, Inc) US claims data, patients who only used the fixed combination (n = 367/1923) to treat both their body and scalp psoriasis had significantly lower overall healthcare costs, needed fewer outpatient visits and used less systemic agents compared with patients who used multiple scalp and body psoriasis medications (n = 1556/1923), during a 6-month observation period. 31 Expert opinion The benefits of the fixed combination : from clinical evidence to daily practice From our review of the published clinical evidence, consensus was reached for four key benefits of the fixed combination that are supported by clinical evidence and which we observe in our daily practices: 1. The fixed combination is an effective topical psoriasis treatment. The fixed combination is a useful advancement in topical psoriasis treatment and is an effective first-line therapy for the treatment, both short-term and long-term, of mild-tomoderate psoriasis. Rapid responses to treatment are observed with the fixed combination, in agreement with the retrospective analysis of data from the two Phase 3 scalp psoriasis studies. 20,21,24 We have also found that the fixed combination may also be effectively used under occlusion. We have not found tachyphylaxis with long-term treatment, although complete clearance of the skin may not always be achieved, with residual redness remaining on the skin, and recurrence of the disease can occur quite quickly once treatment is discontinued. From our experience, treatment with the fixed combination has Table 3 Non-interventional studies evaluating the effectiveness of calcipotriol plus betamethasone dipropionate in psoriasis vulgaris Reference Study duration (weeks) Indication n Study outcomes Mrowietz 4 Scalp psoriasis of et al. 13 all severities Sticherling 4 Mild-to-moderate et al. 14 psoriasis of the body Change in% patients with moderate scalp psoriasis (by IGA) 721 From 87.8 (baseline) to 15.6% (week 4) Change in% patients with no or almost no lesions (by IGA) From 1.7 (baseline) to 53.7% (week 4) Change in% patients with moderate scalp psoriasis (by IGA) 588 From 82.9 (baseline) to 21.2 (week 4) Early discontinuation due to total clearance of disease, % patients & 44.9 Effectiveness of fixed combination as better and much better than previous treatment,% patients Satisfied or very satisfied with the efficacy of the fixed combination vs prior treatment,% patients 85.7 vs 27.6

8 Expert recommendations for topical psoriasis treatment 29 prevented the need for escalation to more expensive systemic therapies in some patients, as previously reported in the Italian national cost-minimization analysis. 12 It is also a very useful treatment option when used in combination with systemic therapy; the dose level of the systemic can be reduced, while at the same time achieving improved effectiveness, and with a more rapid response, than when using the systemic alone. 2. The dual indication is a real advantage of the fixed combination. The fixed combination is indicated for once-daily treatment of both body and scalp psoriasis. Having a single product for all over treatment that requires only a single application per day is extremely beneficial for the patient, and improvement in treatment adherence, because of the convenience of application, is evident with this product. 3. The fixed combination is well tolerated. The fixed combination has been on the market for over 5 years and, throughout this time, we have observed very few side effects. Steroid-associated side effects and skin irritation are rare; and, although laboratory assessments are not generally requested, clinical presentation of metabolic alterations are not observed. The incidence of side effects in real-life appears to be lower than what has been reported in clinical trials. 23,25 When side effects occur, it is usually when the is not used as instructed or when the patient has not been given clear guidance on how to use it. When patients discontinue treatment, we have not observed a rebound effect with the fixed combination that could potentially be attributed to the calcipotriol component. 4. Patients prefer the fixed combination over the ointment. For the majority of our patients, using the fixed combination to treat their psoriasis is more convenient and user-friendly than using the ointment. The formulation is less greasy, it does not stick to clothes as much and takes less time to apply, leading to a much better overall experience. Our observations reflect findings from recently reported interim analyses of a long-term observational study assessing patient-reported effectiveness for the fixed combination versus the ointment formulation (PRO-long). 32 However, a small number of patients do prefer the fixed combination ointment over the formulation. The reasons for this remain unclear and are worth investigating; some patients are unwilling to switch to a new topical product when they are already satisfied with their current topical treatment; some do not experience a difference in the greasiness of the two formulations and therefore do not perceive one being more convenient over the other. Furthermore, some patients report that their psoriasis responds better to the fixed combination ointment, although clinical evidence has demonstrated that the two fixed combination formulations have comparable antipsoriatic effects. 33 A compromise between the ointment and formulations could be a cream. However, creams are waterbased, which is an incompatible environment for the fixed combination. 34 To maintain stability within a water-based formulation, calcipotriol requires an alkaline background, whereas, in contrast, betamethasone dipropionate requires an acidic bakground. 34 Of note, a previously reported patient preference study indicated comparable favour for aqueous cream and lipophilic formulations compared with ointment (Table 1). 10 Non-adherence remains an obstacle to achieving real-life effectiveness From our experience, the benefits of the fixed combination demonstrated within the clinical trials have not fully translated into real-life effectiveness. Despite the fixed combination being positively received by our patients, we still observe nonadherence in those using this product. Some patients will use the fixed combination for a few days, see an initial result, and then taper off or discontinue with their treatment regimen. This problem is increased in patients with more extensive psoriasis where the amount of product that is prescribed can become limiting. The fixed combination is marketed in bottles that contain a maximum of 30 or 60 g of the. In one recent, non-interventional study, 60 g of the fixed combination was adequate for 5 weeks of treatment. 14 In patients who need to treat a large body surface area, the smaller bottle may not last a complete treatment cycle; rather than picking up a second prescription, these patients are then more likely to stop using anything due to the significant inconvenience to keep returning to their healthcare provider for repeat prescriptions. 35 Expert recommendations to improve real-life effectiveness To provide recommendations to address the gap between clinical data and real-life experience, we first wished to define the reallife patient, and identify the challenges that these individuals may encounter when seeking medical treatment for mild-tomoderate psoriasis. This patient is generally not seen by a dermatologist, but rather by a primary care physician. The initial consultation will last only a few minutes whereby the patient will be prescribed a basic topical formulation (e.g. coal tar or corticosteroid lotion) but with very little discussion on how this should be used and what the patient should expect from using this treatment. The physician will usually not plan for a followup visit. And therein lies part of the problem; the sense of abandonment by the patient can lead to a feeling of hopelessness if their treatment does not work. 36 Treatment adherence is a complex issue, and more so for chronic diseases. 37 It depends on more subjective aspects than the efficacy and safety parameters measured as standard within clinical trials and is not simply related to the patient acceptability of the drug. A multifaceted approach is required to promote adherence choosing the right product for the patient, discussing the treatment goals and aligning treatment expectations, explaining how to use the product and providing patient support to encourage adherence to their treatment regimen. Here, we provide our recommendations to improve real-life

9 30 Dauden et al. effectiveness of topical psoriasis therapy. With these recommendations, it should be emphasized that each patient is unique and effort should be made to tailor treatment to meet the individual s requirements. 1. Healthcare provider education: how to effectively manage topical psoriasis treatment. In our experience, it is very important to have an individualized approach when prescribing topical psoriasis treatments; one that reflects the patient s preference for treatment vehicle and therefore favours treatment adherence. We also find that patients are generally directed to use first-line therapies, such as the fixed combination, daily until their psoriasis is under control, and then as needed. However, allowing the patient to use the treatment like this, without clear dosing instructions, appears not to be working and leads to treatment non-adherence. There is a need to establish a management strategy for long-term topical control of psoriasis with first-line therapies. Give the patient explicit instructions on how to use their topical treatment: Use it like this, and this is what you are going to expect. If you see this, you may want to do this. We recommend that the is applied at night, allowing the patients to clean the area the following morning and not be inconvenienced with the treatment during the day. In this way, the treatment regimen is tailored to be user-friendly, thereby encouraging treatment adherence. With respect to the fixed combination, instruction on shaking the bottle is key for attaining optimal effect. One example of using explicit instruction to facilitate adherence is with the use of the fixed combination for the treatment of scalp psoriasis. In our experience, some patients, particularly women, do not like to use the on their scalp because of the lipophilic formulation. However, with clear instruction (only use a little amount; use your fingertips to apply it to the scalp and not the hair; and then thoroughly wash out residual product, best achieved by initially applying shampoo directly to the treated area, before adding water), patients then do tend to adhere to this treatment. It is also very important to the patient that they observe amelioration of their psoriasis plaques; if their plaques are not improving, it is essential to tell the patient to increase the amount of product that they are using and not allow them to feel despondent about their treatment. The fixed combination has a favourable safety profile, so there are minimal risks of side effects using this treatment over long periods. Finally, prescribe the number of bottles of treatment that you want the patient to use until your next appointment; this will avoid the need for the patient to obtain repeat prescriptions. At your next appointment, ask the patient how many bottles were used, and closely monitor product consumption. 2. Patient education. Psoriasis is a chronic disease. Unlike other chronic diseases, such as diabetes, it is not immediately life-threatening and therefore patients do not perceive the same urgency to adhere to treatment. With psoriasis, educating the patient is crucial to convince them to use their treatment correctly, thereby facilitating adherence. 38 Explain to the patient that because psoriasis is a chronic disease, long-term management will be required, even when their lesions are minimal. Patients can become despondent with any long-term treatment, and frank discussion with the patient early in the initiation of their treatment may help to manage their expectations. 3. A supportive environment. Do not allow the patient to feel abandoned. Listen to your patient and explore their expectations regarding the treatment of their psoriasis and how the medical field can address these expectations. Once an appropriate treatment has been prescribed, have regular follow-up visits with the patient; for example, 6 weeks after the first consultation, then every 3 months thereafter until you are sure that the patient is adhering to the treatment regimen and effectively managing the disease. Support must be maintained to ensure that the patient is comfortable with the treatment regimen, thereby minimizing the risk of non-adherence. Patient support programmes may further enforce treatment adherence and optimize patient outcomes; one study aiming to evaluate the usefulness of such a programme to overcome challenges associated with non-adherence is expected to report on interim analyses shortly (PSO-TOP; NCT ). Validating our recommendations in real life The recommendations that we have made here are based on our experiences within daily practice. What is missing are data to demonstrate whether these recommendations do indeed improve real-life effectiveness and which would help to explain the complex problem of treatment non-adherence. We propose the establishment of a European-wide topical registry that documents observational data from dermatologist-treated psoriasis patients. In this way, the level of education and support dedicated to each psoriasis patient would be consistent, providing robust real-life data on the preference and real-life effectiveness of topical treatments, including the fixed combination. Conclusions In response to our original objectives, we have performed a review of the clinical trial evidence and the real-life data and, along with our own experiences in daily practice, we accept our original hypothesis that the fixed combination of calcipotriol and betamethasone dipropionate advances topical psoriasis treatment. It is a highly effective first-line topical treatment for mild-to-moderate psoriasis that is preferred over the fixed combination ointment by the majority of our patients. Despite this, translating patient acceptability of the fixed combination into real-life effectiveness remains a challenge. To bridge this gap, we have identified three aspects of the management of topical psoriasis treatment that could improve real-life effectiveness: HCP education, patient education and the provision of support. The medical community needs to look beyond randomized

10 Expert recommendations for topical psoriasis treatment 31 controlled trials to address the problems patients face with their day-to-day treatment; how can we turn treatment into a better patient outlook? Making treatment more patient-centric and providing educational and support programmes may allow patients the opportunity to treat their psoriasis effectively. References 1 Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 2005; 353: Bhosle MJ, Kulkarni A, Feldman SR et al. Quality of life in patients with psoriasis. Health Qual Life Outcomes 2006; 4: Kircik LH. Topical calcipotriene 0.005% and betamethasone dipropionate 0.064% maintains efficacy of etanercept after step-down dose in patients with moderate-to-severe plaque psoriasis: results of an open label trial. J Drugs Dermatol 2011; 10: Lebwohl M, Ting PT, Koo JY. Psoriasis treatment: traditional therapy. Ann Rheum Dis 2005;64 (Suppl 2): ii83 ii86. 5 Menter A, Korman NJ, Elmets CA et al. 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