JEADV
DOI: 10.1111/jdv.12443
REVIEW ARTICLE
Expert recommendations: the use of the fixed combination calcipotriol and betamethasone dipropionate gel for the topical treatment of psoriasis n,1,* A. Bewley,2 J. Lambert,3 G. Girolomoni,4 F. Cambazard5 K. Reich6 E. Daude 1
Department of Dermatology, Hospital Universitario de la Princesa, Madrid, Spain 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 n. E-mail: [email protected] *Correspondence: E. Daude 2
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 gel (Daivobetâ gel; calcipotriol plus betamethasone dipropionate) as a case study. The fixed combination gel is a first-line topical treatment for mild-to-moderate psoriasis, developed to be the gold-standard therapy for psoriasis patients. This fixed combination gel 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 (gel or topical suspension)) OR (calcipotri$3 AND betamethasone)
Conflicts of interest n has served as an advisory board member, consultant, or clinical trial investigator, or received grants, Esteban Daude 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 , Eli Lilly, advisory/speaker honoraria and/or research funding from Abbott, Almirall, Boehringer Ingelheim, Celgene, Dompe de ric Galderma, GlaxoSmithKline, Janssen, LEO Pharma, Otsuka, Merck-Serono, Maruho, MSD, Novartis and Pfizer. Fre 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 € van Helmond, PhD, from Mudskipper Business Ltd, which was funded by Medical writing support was provided by Zoe LEO Pharma.
JEADV 2014, 28 (Suppl. 2), 22–32
© 2014 European Academy of Dermatology and Venereology
Expert recommendations for topical psoriasis treatment
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.12–14 The fixed combination of calcipotriol and betamethasone dipropionate in a gel formulation (Daivobetâ gel [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 gel benefits from the synergistic action of the fixed combination of the vitamin D analogue calcipotriol and the potent corticosteroid betamethasone diproprionate16 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 gel resulted in significant improvements in patient quality of life versus twice-daily calcipotriol scalp solution.17
23
Evidence from clinical trials shows that this fixed combination gel has superior efficacy over the individual active components administered as monotherapies in the gel 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.12–14,19 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 gel, 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 gel 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 gel 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 gel 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 gel 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 gel (71.2% and 68.4% respectively), compared with the active
Table 1 Patient preference to three topical treatment vehicles (gel, 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?*
93
85
84
Which vehicle was the least visible on the skin?†
76
64
59
Which vehicle required the least effort to apply?†
72
71
56
Which vehicle required the least amount of time to apply?†
76
72
51
Which vehicle was the least greasy?†
69
78
53
Which vehicle was the fastest to be absorbed?†
69
75
56
*Proportion of patients who responded ‘yes’. †Proportion of patients who rated the vehicle first or second.
JEADV 2014, 28 (Suppl. 2), 22–32
© 2014 European Academy of Dermatology and Venereology
n et al. Daude
24
Figure 1 Overview of the studies evaluating calcipotriol plus betamethasone dipropionate gel in psoriasis vulgaris.
mono-components in the gel vehicle (betamethasone dipropionate gel, 64.0% and 61.0%; calcipotriol gel, 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 gel, with a faster onset compared with the active comparators.24 The superiority of the fixed combination gel 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 gel (4.7% and 6.2% respectively) versus betamethasone dipropionate gel (5.3% and 5.8%) and calcipotriol gel (13.2% and 12.8%).20,21 The long-term safety trial recruited patients with at least moderate severity 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 gel 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 gel, 29%; betamethasone
JEADV 2014, 28 (Suppl. 2), 22–32
dipropionate gel, 21.5%; calcipotriol gel, 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 gel treatment. Incidence of ADRs was low in this study: 5.0% of patients treated with fixed combination gel, 3.1% with betamethasone dipropionate gel, 5.3% with calcipotriol gel and 4.2% with gel vehicle. In moderate-to-severe psoriasis of the body, superior efficacy of the fixed combination gel versus tacalcitol ointment 4 lg/g as monohydrate (Curatodermâ, Hermal, Germany) has been demonstrated.22 Controlled disease was achieved by a significantly larger proportion of patients treated with the fixed combination gel (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 gel. The proportion of patients reporting one or more ADR was significantly lower with the fixed combination gel (8.8%) than for tacalcitol gel (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
© 2014 European Academy of Dermatology and Venereology
Study design
JEADV 2014, 28 (Suppl. 2), 22–32
Randomized, double-blind, active and vehicle controlled
Menter et al.15
Randomized, double-blind, active controlled
van de Kerkhof et al.21
Phase II – psoriasis of the body
Randomized, double-blind, active and vehicle controlled
Jemec et al.20
Phase III – scalp psoriasis
Randomized, investigatorblind, active and vehicle controlled
Langley et al.22
Phase III – psoriasis of the body
Short-term studies (≤12 weeks’ duration)
Reference
8
8
8
8
Mild-tomoderate
At least moderate severity
Disease severity
At least mild severity
At least mild severity
Study duration (weeks)
286
Calcipotriol gel
NC
NC
NC
NC
8.6 & 21.9
12.0 & 21.5
44.7 (P < 0.0001)
43.4 (P < 0.0001)
PASI, change at weeks 4 & 8
69.6 59.9 (P = 0.0006)
68.4
38.3 (P < 0.0001) 20.7 (P < 0.0001)
36.8 (P < 0.0001) 22.8 (P < 0.0001) 61.0 (P = 0.0079)
68.6 62.5 (P = 0.2)
64.0 (P < 0.011)
PaGA-treatment success,‡ patients
20.9 (P < 0.001)
43.6 (P < 0.001)
48.6 (P < 0.001)
17.9 (P < 0.001)
41.9 (P < 0.001)
29.7 & 40.4
PaGA-treatment success,‡% patients
71.2
IGA-responders║ at weeks 4 & 8, patients
568 563
Fixed combination gel
272 136
Calcipotriol gel Gel vehicle Betamethasone dipropionate gel
556
Betamethasone dipropionate gel
17.4 (P < 0.001) &
2.1 (P = 0.001) & 6.3 (P ≤ 0.008)
95
Gel vehicle
IGA-treatment success,§ patients
32.2 (P < 0.001) &
5.2 (P = 0.019) & 14.6 (P ≤ 0.008)
96
Calcipotriol gel
541
42.7 (P = 0.038) &
12.5 (P = 0.82) & 21.5 (P ≤ 0.008)
479
Betamethasone dipropionate gel
Fixed combination gel
46.4 &
55.8
13.3 (P < 0.001) &
1.1 (P < 0.001) & 5.5 (P < 0.001) 13.3 & 29
91
Gel vehicle
37.3 (P < 0.001) &
6.5 (P < 0.001) & 17.9 (P < 0.001)
482
184
Tacalcitol ointment
57.0
53.1 &
PASI,% change at weeks 4 & 8
18.6 & 39.9
IGA-controlled disease,† % patients at weeks 4 &8
Study outcomes (statistical comparisons versus fixed combination gel)
Fixed combination gel
183
n
Fixed combination gel
Treatment*
Table 2 Clinical trials evaluating efficacy and safety of calcipotriol plus betamethasone dipropionate gel in psoriasis vulgaris
Expert recommendations for topical psoriasis treatment 25
© 2014 European Academy of Dermatology and Venereology
JEADV 2014, 28 (Suppl. 2), 22–32
Open-label, single-arm
Silver et al.25
Randomized, investigatorblind, active and vehicle controlled
Randomized, double-blind, vehicle controlled
Randomized, non-controlled
Kragballe et al.27
Tyring et al.28
Saraceno et al.29
Long-term study (52 weeks’ duration)
Randomized, double-blind, active controlled
Buckley et al.26
Phase II – scalp psoriasis
Randomized, doubleblind, active and vehicle controlled
Fleming et al.18
Phase II – psoriasis of the body
Table 2 Continued
8
8
12
8
8
8
Mild-to-moderate
At least moderate severity
At least moderate severity
At least mild severity
441 444
Fixed combination gel, twice weekly Fixed combination gel, as required
135 42
Gel vehicle
Calcipotriol scalp solution, twice daily
Fixed combination gel
207 105
Fixed combination gel
108
0.03
0.4
Significantly greater with twice weekly treatment by week 12 (P < 0.01)
NC
62.2 35.7 (P = 0.004)
71.9
34.3 (P < 0.001)
82.1
82.6 (P = 0.027)
92.5
PaGA-treatment success,‡ patients
–0.42
Change in urinary calcium:creatinine ratio, mmol/g
40.5 (P < 0.001)
NC
NC
8.8 more patients achieved treatment success with the fixed combination gel vs comparator (P = 0.11)
IGA-treatment success,§ patients
7.0 & 0.0
110
43
Betamethasone dipropionate gel
Fixed combination gel
Change in 24-h urinary calcium excretion, mmol/24 h
16.9 (P < 0.001) & 11.9 (P < 0.001)
2.5 (P = 0.027) & 0.0 (P < 0.001)
40
Gel vehicle Change in serum calcium, mmol/L
32.7 (P < 0.001) & 41.2 (P < 0.001)
3.8 (P = 0.006) & 11.4 (P = 0.006)
79
Calcipotriol gel
Serum cortisol ≤18 lg/dL¶ (weeks 4 & 8), patients
40.9 (P = 0.04) & 49.8 (P = 0.13)
9.6 (P = 0.11) & 16.9 (P = 0.027)
83
Betamethasone dipropionate gel
55.3
48.1 &
16.0 & 27.2
162
PASI, change at weeks 4 & 8
Fixed combination gel
Fixed combination gel
Extensive psoriasis (15–30 BSA) of at least moderate severity
At least mild severity
IGA-responders║ at weeks 4 & 8, patients
26
n et al. Daude
© 2014 European Academy of Dermatology and Venereology
*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.
11.9
21.6 (P < 0.001) 440 Calcipotriol gel
Lesional/perilesional events, patients ADRs, patients
29.5 (P < 0.001)
429
Randomized, double-blind, active controlled Luger et al.23
Phase III – scalp psoriasis
Table 2 Continued
52
At least moderate severity
Fixed combination gel
17.2
Expert recommendations for topical psoriasis treatment
JEADV 2014, 28 (Suppl. 2), 22–32
27
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 gel 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 severity 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 gel as ‘better’ and ‘much better’, respectively, than their previous treatments. The second study assessed real-life effectiveness of the fixed combination gel 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 severity 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 gel, 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 gel. The mean time for application was significantly reduced by 3 min with the fixed combination gel, from 10 min with prior treatments (30% reduction; P < 0.0001), as was the lag time before patients could dress following application, reduced by 2.5 min with the fixed combination gel, from 11.5 min with prior treatments (22% reduction; P < 0.0001). Most patients (66.1%) therefore reported to be ‘very satisfied’ with the convenience of the fixed combination gel, compared with 11.6% of patients with their previous therapies, and handling of the fixed combination gel 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 gel data from national healthcare registries.
© 2014 European Academy of Dermatology and Venereology
n et al. Daude
28
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 gel was projected to increase patient qualityadjusted life-years (incremental gain of approximately 0.0025 per year) with cost savings of £20–30 per patient per year.19 A cost-minimization analysis has also been performed to assess the cost-effectiveness of the fixed combination gel 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 gel 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 gel 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 gel 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 gel 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 MarketScanâ (MarketScan is a registered trademark of Thomson Reuters Healthcare, Inc) US claims data, patients who only used the fixed combination gel (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 gel: 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 gel that are supported by clinical evidence and which we observe in our daily practices: 1. The fixed combination gel is an effective topical psoriasis treatment. The fixed combination gel 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 gel, 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 gel 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 gel has
Table 3 Non-interventional studies evaluating the effectiveness of calcipotriol plus betamethasone dipropionate gel in psoriasis vulgaris Reference
Mrowietz et al.13
Sticherling et al.14
Study duration (weeks)
4
4
Indication
Scalp psoriasis of all severities
Mild-to-moderate psoriasis of the body
JEADV 2014, 28 (Suppl. 2), 22–32
n
721
588
Study outcomes
Change in% patients with ≥ moderate scalp psoriasis (by IGA)
Change in% patients with ‘no’ or ‘almost no’ lesions (by IGA)
Early discontinuation due to total clearance of disease, % patients
Effectiveness of fixed combination gel as ‘better’ and ‘much better’ than previous treatment,% patients
From 87.8 (baseline) to 15.6% (week 4)
From 1.7 (baseline) to 53.7% (week 4)
8.7
43.0 & 44.9
Change in% patients with ≥ moderate scalp psoriasis (by IGA)
‘Satisfied’ or ‘very satisfied’ with the efficacy of the fixed combination gel vs prior treatment,% patients
From 82.9 (baseline) to 21.2 (week 4)
85.7 vs 27.6
© 2014 European Academy of Dermatology and Venereology
Expert recommendations for topical psoriasis treatment
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 gel. The fixed combination gel 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 gel is well tolerated. The fixed combination gel 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 gel 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 gel that could potentially be attributed to the calcipotriol component. 4. Patients prefer the fixed combination gel over the ointment. For the majority of our patients, using the fixed combination gel to treat their psoriasis is more convenient and user-friendly than using the ointment. The gel 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 gel versus the ointment formulation (PRO-long).32 However, a small number of patients do prefer the fixed combination ointment over the gel 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 gel 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,
JEADV 2014, 28 (Suppl. 2), 22–32
29
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 gel 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 gel demonstrated within the clinical trials have not fully translated into real-life effectiveness. Despite the fixed combination gel being positively received by our patients, we still observe nonadherence in those using this product. Some patients will use the fixed combination gel 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 gel is marketed in bottles that contain a maximum of 30 or 60 g of the gel. In one recent, non-interventional study, 60 g of the fixed combination gel 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
© 2014 European Academy of Dermatology and Venereology
n et al. Daude
30
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 gel, 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 gel 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 gel, 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 gel for the treatment of scalp psoriasis. In our experience, some patients, particularly women, do not like to use the gel 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 gel 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
JEADV 2014, 28 (Suppl. 2), 22–32
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; NCT01587755). 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 gel.
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 gel 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 gel 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
© 2014 European Academy of Dermatology and Venereology
Expert recommendations for topical psoriasis treatment
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: 487–497. 2 Bhosle MJ, Kulkarni A, Feldman SR et al. Quality of life in patients with psoriasis. Health Qual Life Outcomes 2006; 4: 35. 3 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: 878–882. 4 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. Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 3. Guidelines of care for the management and treatment of psoriasis with topical therapies. J Am Acad Dermatol 2009; 60: 643–659. 6 Nast A, Boehncke WH, Mrowietz U et al. German S3-guidelines on the treatment of psoriasis vulgaris (short version). Arch Dermatol Res 2012; 304: 87–113. 7 Samarasekera E, Sawyer L, Parnham J et al. Assessment and management of psoriasis: summary of NICE guidance. BMJ 2012; 345: e6712. 8 Thaci D, Ortonne J-P, Chimenti S et al. A phase IIIb, multicentre, randomized, double-blind, vehicle-controlled study of the efficacy and safety of adalimumab with and without calcipotriol/betamethasone topical treatment in patients with moderate to severe psoriasis: the BELIEVE study. Br J Dermatol 2010; 163: 402–411. 9 Vena GA, Galluccio A, Pezza M et al. Combined treatment with low-dose cyclosporine and calcipotriol/betamethasone dipropionate ointment for moderate-to-severe plaque psoriasis: a randomized controlled open-label study. J Dermatolog Treat 2012; 23: 255–260. 10 Bewley A, Page B. Maximizing patient adherence for optimal outcomes in psoriasis. J Eur Acad Dermatol Venereol 2011; 25(Suppl 4): 9–14. 11 Devaux S, Castela A, Archier E et al. Adherence to topical treatment in psoriasis: a systematic literature review. J Eur Acad Dermatol Venereol 2012; 26 (Suppl 3): 61–67. 12 Colombo GL, Di Matteo S, Bruno G et al. Calcipotriol and betamethasone dipropionate in the treatment of mild-to-moderate psoriasis: a costeffectiveness analysis of the ointment versus gel formulation. Clinicoecon Outcomes Res 2012; 4: 261–268. 13 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 (Xamiolâ-gel): results. J Dtsch Dermatol Ges 2011; 9: 825–831. 14 Sticherling M, Eicke C, Anger T. Practicability of combined treatment with calcipotriol/betamethasone gel (Daivobetâ Gel) and improvement of quality of life in patients with psoriasis. J Dtsch Dermatol Ges 2013; 11: 420–427. 15 Menter A, Gold LS, Bukhalo M et al. Calcipotriene plus betamethasone dipropionate topical suspension for the treatment of mild to moderate psoriasis vulgaris on the body: a randomized, double-blind, vehicle-controlled trial. J Drugs Dermatol 2013; 12: 92–98. 16 Segaert S, Røpke M. The biological rationale for use of vitamin D analogs in combination with corticosteroids for the topical treatment of plaque psoriasis. J Drugs Dermatol 2013; 12: e129–e137. 17 Ortonne JP, Ganslandt C, Tan J et al. Quality of life in patients with scalp psoriasis treated with calcipotriol/betamethasone dipropionate scalp formulation: a randomized controlled trial. J Eur Acad Dermatol Venereol 2009; 23: 919–926.
JEADV 2014, 28 (Suppl. 2), 22–32
31
18 Fleming C, Ganslandt C, Guenther L et al. Calcipotriol plus betamethasone dipropionate gel compared with its active components in the same vehicle and the vehicle alone in the treatment of psoriasis vulgaris: a randomised, parallel group, double-blind, exploratory study. Eur J Dermatol 2010; 20: 465–471. 19 Affleck AG, Bottomley JM, Auland M et al. Cost effectiveness of the twocompound formulation calcipotriol and betamethasone dipropionate gel in the treatment of scalp psoriasis in Scotland. Curr Med Res Opin 2011; 27: 269–284. 20 Jemec GB, Ganslandt C, Ortonne J-P et al. A new scalp formulation of calcipotriene plus betamethasone compared with its active ingredients and the vehicle in the treatment of scalp psoriasis: a randomized, doubleblind, controlled trial. J Am Acad Dermatol 2008; 59: 455–463. 21 van de Kerkhof PC, Hoffmann V, Anstey A et al. A new scalp formulation of calcipotriol plus betamethasone dipropionate compared with each of its active ingredients in the same vehicle for the treatment of scalp psoriasis: a randomized, double-blind, controlled trial. Br J Dermatol 2009; 160: 170–176. 22 Langley RG, Gupta A, Papp K et al. Calcipotriol plus betamethasone dipropionate gel compared with tacalcitol ointment and the gel vehicle alone in patients with psoriasis vulgaris: a randomized, controlled clinical trial. Dermatology 2011; 222: 148–156. 23 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: 321–328. 24 Jemec GB, van de Kerkhof PC, Enevold A et al. Significant one week efficacy of a calcipotriol plus betamethasone dipropionate scalp formulation. J Eur Acad Dermatol Venereol 2011; 25: 27–32. 25 Silver S, Tuppal R, Gupta AK et al. Effect of calcipotriene plus betamethasone dipropionate topical suspension on the hypothalamic-pituitaryadrenal axis and calcium homeostasis in subjects with extensive psoriasis vulgaris: an open, non-controlled, 8-week trial. J Drugs Dermatol 2013; 12: 882–887. 26 Buckley C, Hoffmann V, Shapiro J, Saari S, Cambazard F, Milsgaard M. Calcipotriol plus betamethasone dipropionate scalp formulation is effective and well tolerated in the treatment of scalp psoriasis: a phase II study. Dermatology 2008; 217: 107–113. 27 Kragballe K, Hoffmann V, Ortonne JP, Tan J, Nordin P, Segaert S. Efficacy and safety of calcipotriol plus betamethasone dipropionate scalp formulation compared with calcipotriol scalp solution in the treatment of scalp psoriasis: a randomized controlled trial. Br J Dermatol 2009; 161: 159–166. 28 Tyring S, Mendoza N, Appell M et al. A calcipotriene/betamethasone dipropionate two-compound scalp formulation in the treatment of scalp psoriasis in Hispanic/Latino and Black/African American patients: results of the randomized, 8-week, double-blind phase of a clinical trial. Int J Dermatol 2010; 49: 1328–1333. 29 Saraceno R, Camplone G, D’Agostino M et al. Efficacy and maintenance strategies of two-compound formulation calcipotriol and betamethasone dipropionate gel (Xamiolâ gel) in the treatment of scalp psoriasis: results from a study in 885 patients. J Dermatolog Treat 2014; 25: 30–33. 30 McDonald HP, Garg AX, Haynes RB. Interventions to enhance patient adherence to medication prescriptions: scientific review. JAMA 2002; 288: 2868–2879. 31 Feldman SR, Levi E, Pathak P et al. Using a single product (calcipotriene/ betamethasone topical suspension) vs. multiple products to manage body and scalp psoriasis: comparisons in resource utilization and costs. J Med Econ 2013; 16: 1405–1413. 32 Lambert J, Griekspoor M, Vink J. Patient-reported effectiveness for calcipotriol and betamethasone dipropionate gel and ointment formulations in psoriasis vulgaris: 4- and 12-week interim results from PRO-long. 22nd Congress of the European Academy of Dermatology and Venereology (EADV). Istanbul, Turkey, 2–6 October 2013.
© 2014 European Academy of Dermatology and Venereology
32
33 Queille-Roussel C, Hoffmann V, Ganslandt C et al. Comparison of the antipsoriatic effect and tolerability of calcipotriol-containing products in the treatment of psoriasis vulgaris using a modified psoriasis plaque test. Clin Drug Investig 2012; 32: 613–619. 34 Simonsen L, Hoy G, Didriksen E et al. Development of a new formulation combining calcipotriol and betamethasone dipropionate in an ointment vehicle. Drug Dev Ind Pharm 2004; 30: 1095–1102. 35 Storm A, Andersen SE, Benfeldt E et al. One in 3 prescriptions are never redeemed: primary nonadherence in an outpatient clinic. J Am Acad Dermatol 2008; 59: 27–33.
JEADV 2014, 28 (Suppl. 2), 22–32
n et al. Daude
36 Linder D, Dall’olio E, Gisondi P et al. Perception of disease and doctorpatient relationship experienced by patients with psoriasis: a questionnaire-based study. Am J Clin Dermatol 2009; 10: 325–330. 37 Thorneloe RJ, Bundy C, Griffiths CE et al. Adherence to medication in patients with psoriasis: a systematic literature review. Br J Dermatol 2013; 168: 20–31. 38 Lora V, Gisondi P, Calza A et al. Efficacy of a single educative intervention in patients with chronic plaque psoriasis. Dermatology 2009; 219: 316–321.
© 2014 European Academy of Dermatology and Venereology
DOI: 10.1111/jdv.12443
REVIEW ARTICLE
Expert recommendations: the use of the fixed combination calcipotriol and betamethasone dipropionate gel for the topical treatment of psoriasis n,1,* A. Bewley,2 J. Lambert,3 G. Girolomoni,4 F. Cambazard5 K. Reich6 E. Daude 1
Department of Dermatology, Hospital Universitario de la Princesa, Madrid, Spain 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 n. E-mail: [email protected] *Correspondence: E. Daude 2
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 gel (Daivobetâ gel; calcipotriol plus betamethasone dipropionate) as a case study. The fixed combination gel is a first-line topical treatment for mild-to-moderate psoriasis, developed to be the gold-standard therapy for psoriasis patients. This fixed combination gel 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 (gel or topical suspension)) OR (calcipotri$3 AND betamethasone)
Conflicts of interest n has served as an advisory board member, consultant, or clinical trial investigator, or received grants, Esteban Daude 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 , Eli Lilly, advisory/speaker honoraria and/or research funding from Abbott, Almirall, Boehringer Ingelheim, Celgene, Dompe de ric Galderma, GlaxoSmithKline, Janssen, LEO Pharma, Otsuka, Merck-Serono, Maruho, MSD, Novartis and Pfizer. Fre 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 € van Helmond, PhD, from Mudskipper Business Ltd, which was funded by Medical writing support was provided by Zoe LEO Pharma.
JEADV 2014, 28 (Suppl. 2), 22–32
© 2014 European Academy of Dermatology and Venereology
Expert recommendations for topical psoriasis treatment
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.12–14 The fixed combination of calcipotriol and betamethasone dipropionate in a gel formulation (Daivobetâ gel [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 gel benefits from the synergistic action of the fixed combination of the vitamin D analogue calcipotriol and the potent corticosteroid betamethasone diproprionate16 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 gel resulted in significant improvements in patient quality of life versus twice-daily calcipotriol scalp solution.17
23
Evidence from clinical trials shows that this fixed combination gel has superior efficacy over the individual active components administered as monotherapies in the gel 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.12–14,19 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 gel, 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 gel 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 gel 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 gel 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 gel 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 gel (71.2% and 68.4% respectively), compared with the active
Table 1 Patient preference to three topical treatment vehicles (gel, 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?*
93
85
84
Which vehicle was the least visible on the skin?†
76
64
59
Which vehicle required the least effort to apply?†
72
71
56
Which vehicle required the least amount of time to apply?†
76
72
51
Which vehicle was the least greasy?†
69
78
53
Which vehicle was the fastest to be absorbed?†
69
75
56
*Proportion of patients who responded ‘yes’. †Proportion of patients who rated the vehicle first or second.
JEADV 2014, 28 (Suppl. 2), 22–32
© 2014 European Academy of Dermatology and Venereology
n et al. Daude
24
Figure 1 Overview of the studies evaluating calcipotriol plus betamethasone dipropionate gel in psoriasis vulgaris.
mono-components in the gel vehicle (betamethasone dipropionate gel, 64.0% and 61.0%; calcipotriol gel, 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 gel, with a faster onset compared with the active comparators.24 The superiority of the fixed combination gel 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 gel (4.7% and 6.2% respectively) versus betamethasone dipropionate gel (5.3% and 5.8%) and calcipotriol gel (13.2% and 12.8%).20,21 The long-term safety trial recruited patients with at least moderate severity 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 gel 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 gel, 29%; betamethasone
JEADV 2014, 28 (Suppl. 2), 22–32
dipropionate gel, 21.5%; calcipotriol gel, 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 gel treatment. Incidence of ADRs was low in this study: 5.0% of patients treated with fixed combination gel, 3.1% with betamethasone dipropionate gel, 5.3% with calcipotriol gel and 4.2% with gel vehicle. In moderate-to-severe psoriasis of the body, superior efficacy of the fixed combination gel versus tacalcitol ointment 4 lg/g as monohydrate (Curatodermâ, Hermal, Germany) has been demonstrated.22 Controlled disease was achieved by a significantly larger proportion of patients treated with the fixed combination gel (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 gel. The proportion of patients reporting one or more ADR was significantly lower with the fixed combination gel (8.8%) than for tacalcitol gel (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
© 2014 European Academy of Dermatology and Venereology
Study design
JEADV 2014, 28 (Suppl. 2), 22–32
Randomized, double-blind, active and vehicle controlled
Menter et al.15
Randomized, double-blind, active controlled
van de Kerkhof et al.21
Phase II – psoriasis of the body
Randomized, double-blind, active and vehicle controlled
Jemec et al.20
Phase III – scalp psoriasis
Randomized, investigatorblind, active and vehicle controlled
Langley et al.22
Phase III – psoriasis of the body
Short-term studies (≤12 weeks’ duration)
Reference
8
8
8
8
Mild-tomoderate
At least moderate severity
Disease severity
At least mild severity
At least mild severity
Study duration (weeks)
286
Calcipotriol gel
NC
NC
NC
NC
8.6 & 21.9
12.0 & 21.5
44.7 (P < 0.0001)
43.4 (P < 0.0001)
PASI, change at weeks 4 & 8
69.6 59.9 (P = 0.0006)
68.4
38.3 (P < 0.0001) 20.7 (P < 0.0001)
36.8 (P < 0.0001) 22.8 (P < 0.0001) 61.0 (P = 0.0079)
68.6 62.5 (P = 0.2)
64.0 (P < 0.011)
PaGA-treatment success,‡ patients
20.9 (P < 0.001)
43.6 (P < 0.001)
48.6 (P < 0.001)
17.9 (P < 0.001)
41.9 (P < 0.001)
29.7 & 40.4
PaGA-treatment success,‡% patients
71.2
IGA-responders║ at weeks 4 & 8, patients
568 563
Fixed combination gel
272 136
Calcipotriol gel Gel vehicle Betamethasone dipropionate gel
556
Betamethasone dipropionate gel
17.4 (P < 0.001) &
2.1 (P = 0.001) & 6.3 (P ≤ 0.008)
95
Gel vehicle
IGA-treatment success,§ patients
32.2 (P < 0.001) &
5.2 (P = 0.019) & 14.6 (P ≤ 0.008)
96
Calcipotriol gel
541
42.7 (P = 0.038) &
12.5 (P = 0.82) & 21.5 (P ≤ 0.008)
479
Betamethasone dipropionate gel
Fixed combination gel
46.4 &
55.8
13.3 (P < 0.001) &
1.1 (P < 0.001) & 5.5 (P < 0.001) 13.3 & 29
91
Gel vehicle
37.3 (P < 0.001) &
6.5 (P < 0.001) & 17.9 (P < 0.001)
482
184
Tacalcitol ointment
57.0
53.1 &
PASI,% change at weeks 4 & 8
18.6 & 39.9
IGA-controlled disease,† % patients at weeks 4 &8
Study outcomes (statistical comparisons versus fixed combination gel)
Fixed combination gel
183
n
Fixed combination gel
Treatment*
Table 2 Clinical trials evaluating efficacy and safety of calcipotriol plus betamethasone dipropionate gel in psoriasis vulgaris
Expert recommendations for topical psoriasis treatment 25
© 2014 European Academy of Dermatology and Venereology
JEADV 2014, 28 (Suppl. 2), 22–32
Open-label, single-arm
Silver et al.25
Randomized, investigatorblind, active and vehicle controlled
Randomized, double-blind, vehicle controlled
Randomized, non-controlled
Kragballe et al.27
Tyring et al.28
Saraceno et al.29
Long-term study (52 weeks’ duration)
Randomized, double-blind, active controlled
Buckley et al.26
Phase II – scalp psoriasis
Randomized, doubleblind, active and vehicle controlled
Fleming et al.18
Phase II – psoriasis of the body
Table 2 Continued
8
8
12
8
8
8
Mild-to-moderate
At least moderate severity
At least moderate severity
At least mild severity
441 444
Fixed combination gel, twice weekly Fixed combination gel, as required
135 42
Gel vehicle
Calcipotriol scalp solution, twice daily
Fixed combination gel
207 105
Fixed combination gel
108
0.03
0.4
Significantly greater with twice weekly treatment by week 12 (P < 0.01)
NC
62.2 35.7 (P = 0.004)
71.9
34.3 (P < 0.001)
82.1
82.6 (P = 0.027)
92.5
PaGA-treatment success,‡ patients
–0.42
Change in urinary calcium:creatinine ratio, mmol/g
40.5 (P < 0.001)
NC
NC
8.8 more patients achieved treatment success with the fixed combination gel vs comparator (P = 0.11)
IGA-treatment success,§ patients
7.0 & 0.0
110
43
Betamethasone dipropionate gel
Fixed combination gel
Change in 24-h urinary calcium excretion, mmol/24 h
16.9 (P < 0.001) & 11.9 (P < 0.001)
2.5 (P = 0.027) & 0.0 (P < 0.001)
40
Gel vehicle Change in serum calcium, mmol/L
32.7 (P < 0.001) & 41.2 (P < 0.001)
3.8 (P = 0.006) & 11.4 (P = 0.006)
79
Calcipotriol gel
Serum cortisol ≤18 lg/dL¶ (weeks 4 & 8), patients
40.9 (P = 0.04) & 49.8 (P = 0.13)
9.6 (P = 0.11) & 16.9 (P = 0.027)
83
Betamethasone dipropionate gel
55.3
48.1 &
16.0 & 27.2
162
PASI, change at weeks 4 & 8
Fixed combination gel
Fixed combination gel
Extensive psoriasis (15–30 BSA) of at least moderate severity
At least mild severity
IGA-responders║ at weeks 4 & 8, patients
26
n et al. Daude
© 2014 European Academy of Dermatology and Venereology
*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.
11.9
21.6 (P < 0.001) 440 Calcipotriol gel
Lesional/perilesional events, patients ADRs, patients
29.5 (P < 0.001)
429
Randomized, double-blind, active controlled Luger et al.23
Phase III – scalp psoriasis
Table 2 Continued
52
At least moderate severity
Fixed combination gel
17.2
Expert recommendations for topical psoriasis treatment
JEADV 2014, 28 (Suppl. 2), 22–32
27
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 gel 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 severity 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 gel as ‘better’ and ‘much better’, respectively, than their previous treatments. The second study assessed real-life effectiveness of the fixed combination gel 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 severity 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 gel, 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 gel. The mean time for application was significantly reduced by 3 min with the fixed combination gel, from 10 min with prior treatments (30% reduction; P < 0.0001), as was the lag time before patients could dress following application, reduced by 2.5 min with the fixed combination gel, from 11.5 min with prior treatments (22% reduction; P < 0.0001). Most patients (66.1%) therefore reported to be ‘very satisfied’ with the convenience of the fixed combination gel, compared with 11.6% of patients with their previous therapies, and handling of the fixed combination gel 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 gel data from national healthcare registries.
© 2014 European Academy of Dermatology and Venereology
n et al. Daude
28
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 gel was projected to increase patient qualityadjusted life-years (incremental gain of approximately 0.0025 per year) with cost savings of £20–30 per patient per year.19 A cost-minimization analysis has also been performed to assess the cost-effectiveness of the fixed combination gel 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 gel 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 gel 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 gel 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 gel 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 MarketScanâ (MarketScan is a registered trademark of Thomson Reuters Healthcare, Inc) US claims data, patients who only used the fixed combination gel (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 gel: 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 gel that are supported by clinical evidence and which we observe in our daily practices: 1. The fixed combination gel is an effective topical psoriasis treatment. The fixed combination gel 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 gel, 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 gel 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 gel has
Table 3 Non-interventional studies evaluating the effectiveness of calcipotriol plus betamethasone dipropionate gel in psoriasis vulgaris Reference
Mrowietz et al.13
Sticherling et al.14
Study duration (weeks)
4
4
Indication
Scalp psoriasis of all severities
Mild-to-moderate psoriasis of the body
JEADV 2014, 28 (Suppl. 2), 22–32
n
721
588
Study outcomes
Change in% patients with ≥ moderate scalp psoriasis (by IGA)
Change in% patients with ‘no’ or ‘almost no’ lesions (by IGA)
Early discontinuation due to total clearance of disease, % patients
Effectiveness of fixed combination gel as ‘better’ and ‘much better’ than previous treatment,% patients
From 87.8 (baseline) to 15.6% (week 4)
From 1.7 (baseline) to 53.7% (week 4)
8.7
43.0 & 44.9
Change in% patients with ≥ moderate scalp psoriasis (by IGA)
‘Satisfied’ or ‘very satisfied’ with the efficacy of the fixed combination gel vs prior treatment,% patients
From 82.9 (baseline) to 21.2 (week 4)
85.7 vs 27.6
© 2014 European Academy of Dermatology and Venereology
Expert recommendations for topical psoriasis treatment
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 gel. The fixed combination gel 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 gel is well tolerated. The fixed combination gel 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 gel 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 gel that could potentially be attributed to the calcipotriol component. 4. Patients prefer the fixed combination gel over the ointment. For the majority of our patients, using the fixed combination gel to treat their psoriasis is more convenient and user-friendly than using the ointment. The gel 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 gel versus the ointment formulation (PRO-long).32 However, a small number of patients do prefer the fixed combination ointment over the gel 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 gel 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,
JEADV 2014, 28 (Suppl. 2), 22–32
29
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 gel 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 gel demonstrated within the clinical trials have not fully translated into real-life effectiveness. Despite the fixed combination gel being positively received by our patients, we still observe nonadherence in those using this product. Some patients will use the fixed combination gel 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 gel is marketed in bottles that contain a maximum of 30 or 60 g of the gel. In one recent, non-interventional study, 60 g of the fixed combination gel 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
© 2014 European Academy of Dermatology and Venereology
n et al. Daude
30
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 gel, 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 gel 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 gel, 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 gel for the treatment of scalp psoriasis. In our experience, some patients, particularly women, do not like to use the gel 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 gel 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
JEADV 2014, 28 (Suppl. 2), 22–32
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; NCT01587755). 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 gel.
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 gel 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 gel 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
© 2014 European Academy of Dermatology and Venereology
Expert recommendations for topical psoriasis treatment
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: 487–497. 2 Bhosle MJ, Kulkarni A, Feldman SR et al. Quality of life in patients with psoriasis. Health Qual Life Outcomes 2006; 4: 35. 3 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: 878–882. 4 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. Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 3. Guidelines of care for the management and treatment of psoriasis with topical therapies. J Am Acad Dermatol 2009; 60: 643–659. 6 Nast A, Boehncke WH, Mrowietz U et al. German S3-guidelines on the treatment of psoriasis vulgaris (short version). Arch Dermatol Res 2012; 304: 87–113. 7 Samarasekera E, Sawyer L, Parnham J et al. Assessment and management of psoriasis: summary of NICE guidance. BMJ 2012; 345: e6712. 8 Thaci D, Ortonne J-P, Chimenti S et al. A phase IIIb, multicentre, randomized, double-blind, vehicle-controlled study of the efficacy and safety of adalimumab with and without calcipotriol/betamethasone topical treatment in patients with moderate to severe psoriasis: the BELIEVE study. Br J Dermatol 2010; 163: 402–411. 9 Vena GA, Galluccio A, Pezza M et al. Combined treatment with low-dose cyclosporine and calcipotriol/betamethasone dipropionate ointment for moderate-to-severe plaque psoriasis: a randomized controlled open-label study. J Dermatolog Treat 2012; 23: 255–260. 10 Bewley A, Page B. Maximizing patient adherence for optimal outcomes in psoriasis. J Eur Acad Dermatol Venereol 2011; 25(Suppl 4): 9–14. 11 Devaux S, Castela A, Archier E et al. Adherence to topical treatment in psoriasis: a systematic literature review. J Eur Acad Dermatol Venereol 2012; 26 (Suppl 3): 61–67. 12 Colombo GL, Di Matteo S, Bruno G et al. Calcipotriol and betamethasone dipropionate in the treatment of mild-to-moderate psoriasis: a costeffectiveness analysis of the ointment versus gel formulation. Clinicoecon Outcomes Res 2012; 4: 261–268. 13 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 (Xamiolâ-gel): results. J Dtsch Dermatol Ges 2011; 9: 825–831. 14 Sticherling M, Eicke C, Anger T. Practicability of combined treatment with calcipotriol/betamethasone gel (Daivobetâ Gel) and improvement of quality of life in patients with psoriasis. J Dtsch Dermatol Ges 2013; 11: 420–427. 15 Menter A, Gold LS, Bukhalo M et al. Calcipotriene plus betamethasone dipropionate topical suspension for the treatment of mild to moderate psoriasis vulgaris on the body: a randomized, double-blind, vehicle-controlled trial. J Drugs Dermatol 2013; 12: 92–98. 16 Segaert S, Røpke M. The biological rationale for use of vitamin D analogs in combination with corticosteroids for the topical treatment of plaque psoriasis. J Drugs Dermatol 2013; 12: e129–e137. 17 Ortonne JP, Ganslandt C, Tan J et al. Quality of life in patients with scalp psoriasis treated with calcipotriol/betamethasone dipropionate scalp formulation: a randomized controlled trial. J Eur Acad Dermatol Venereol 2009; 23: 919–926.
JEADV 2014, 28 (Suppl. 2), 22–32
31
18 Fleming C, Ganslandt C, Guenther L et al. Calcipotriol plus betamethasone dipropionate gel compared with its active components in the same vehicle and the vehicle alone in the treatment of psoriasis vulgaris: a randomised, parallel group, double-blind, exploratory study. Eur J Dermatol 2010; 20: 465–471. 19 Affleck AG, Bottomley JM, Auland M et al. Cost effectiveness of the twocompound formulation calcipotriol and betamethasone dipropionate gel in the treatment of scalp psoriasis in Scotland. Curr Med Res Opin 2011; 27: 269–284. 20 Jemec GB, Ganslandt C, Ortonne J-P et al. A new scalp formulation of calcipotriene plus betamethasone compared with its active ingredients and the vehicle in the treatment of scalp psoriasis: a randomized, doubleblind, controlled trial. J Am Acad Dermatol 2008; 59: 455–463. 21 van de Kerkhof PC, Hoffmann V, Anstey A et al. A new scalp formulation of calcipotriol plus betamethasone dipropionate compared with each of its active ingredients in the same vehicle for the treatment of scalp psoriasis: a randomized, double-blind, controlled trial. Br J Dermatol 2009; 160: 170–176. 22 Langley RG, Gupta A, Papp K et al. Calcipotriol plus betamethasone dipropionate gel compared with tacalcitol ointment and the gel vehicle alone in patients with psoriasis vulgaris: a randomized, controlled clinical trial. Dermatology 2011; 222: 148–156. 23 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: 321–328. 24 Jemec GB, van de Kerkhof PC, Enevold A et al. Significant one week efficacy of a calcipotriol plus betamethasone dipropionate scalp formulation. J Eur Acad Dermatol Venereol 2011; 25: 27–32. 25 Silver S, Tuppal R, Gupta AK et al. Effect of calcipotriene plus betamethasone dipropionate topical suspension on the hypothalamic-pituitaryadrenal axis and calcium homeostasis in subjects with extensive psoriasis vulgaris: an open, non-controlled, 8-week trial. J Drugs Dermatol 2013; 12: 882–887. 26 Buckley C, Hoffmann V, Shapiro J, Saari S, Cambazard F, Milsgaard M. Calcipotriol plus betamethasone dipropionate scalp formulation is effective and well tolerated in the treatment of scalp psoriasis: a phase II study. Dermatology 2008; 217: 107–113. 27 Kragballe K, Hoffmann V, Ortonne JP, Tan J, Nordin P, Segaert S. Efficacy and safety of calcipotriol plus betamethasone dipropionate scalp formulation compared with calcipotriol scalp solution in the treatment of scalp psoriasis: a randomized controlled trial. Br J Dermatol 2009; 161: 159–166. 28 Tyring S, Mendoza N, Appell M et al. A calcipotriene/betamethasone dipropionate two-compound scalp formulation in the treatment of scalp psoriasis in Hispanic/Latino and Black/African American patients: results of the randomized, 8-week, double-blind phase of a clinical trial. Int J Dermatol 2010; 49: 1328–1333. 29 Saraceno R, Camplone G, D’Agostino M et al. Efficacy and maintenance strategies of two-compound formulation calcipotriol and betamethasone dipropionate gel (Xamiolâ gel) in the treatment of scalp psoriasis: results from a study in 885 patients. J Dermatolog Treat 2014; 25: 30–33. 30 McDonald HP, Garg AX, Haynes RB. Interventions to enhance patient adherence to medication prescriptions: scientific review. JAMA 2002; 288: 2868–2879. 31 Feldman SR, Levi E, Pathak P et al. Using a single product (calcipotriene/ betamethasone topical suspension) vs. multiple products to manage body and scalp psoriasis: comparisons in resource utilization and costs. J Med Econ 2013; 16: 1405–1413. 32 Lambert J, Griekspoor M, Vink J. Patient-reported effectiveness for calcipotriol and betamethasone dipropionate gel and ointment formulations in psoriasis vulgaris: 4- and 12-week interim results from PRO-long. 22nd Congress of the European Academy of Dermatology and Venereology (EADV). Istanbul, Turkey, 2–6 October 2013.
© 2014 European Academy of Dermatology and Venereology
32
33 Queille-Roussel C, Hoffmann V, Ganslandt C et al. Comparison of the antipsoriatic effect and tolerability of calcipotriol-containing products in the treatment of psoriasis vulgaris using a modified psoriasis plaque test. Clin Drug Investig 2012; 32: 613–619. 34 Simonsen L, Hoy G, Didriksen E et al. Development of a new formulation combining calcipotriol and betamethasone dipropionate in an ointment vehicle. Drug Dev Ind Pharm 2004; 30: 1095–1102. 35 Storm A, Andersen SE, Benfeldt E et al. One in 3 prescriptions are never redeemed: primary nonadherence in an outpatient clinic. J Am Acad Dermatol 2008; 59: 27–33.
JEADV 2014, 28 (Suppl. 2), 22–32
n et al. Daude
36 Linder D, Dall’olio E, Gisondi P et al. Perception of disease and doctorpatient relationship experienced by patients with psoriasis: a questionnaire-based study. Am J Clin Dermatol 2009; 10: 325–330. 37 Thorneloe RJ, Bundy C, Griffiths CE et al. Adherence to medication in patients with psoriasis: a systematic literature review. Br J Dermatol 2013; 168: 20–31. 38 Lora V, Gisondi P, Calza A et al. Efficacy of a single educative intervention in patients with chronic plaque psoriasis. Dermatology 2009; 219: 316–321.
© 2014 European Academy of Dermatology and Venereology
