The two-compound formulation of calcipotriol and betamethasone dipropionate for treatment of moderately severe body and scalp psoriasis – an introduction

Abstract

Psoriasis is a common chronic inflammatory skin disease and many patients require lifelong treatment. Characteristic scaly, itchy, unsightly psoriatic lesions affect many body areas and most patients commonly experience scalp involvement. The cosmetic embarrassment of visible body lesions, inaccessibility of scalp skin to application of therapies and proximity of sensitive facial skin add to the challenges of most patients managing their psoriasis long term. Psoriasis can severely impact patients’ quality of life.

This can impact significantly on the patient. In economic terms patients may incur increased out-of-pocket expenditure or extended time away from work as a direct consequence of psoriasis, particularly in severe cases; In many countries, specialist review of patients provides pressures on hard-pressed services and the costs of psoriasis care are substantial, particularly in patients with severe recalcitrant psoriasis which may require lengthy inpatient admission.

Around 80% of patients with psoriasis have mild to moderately severe disease and the majority are treated with topical medicines by their physician in primary care. Despite the availability of a wide range of treatment options, regimens have been unsatisfactory, associated with patient dissatisfaction, poor compliance and often safety concerns with long-term use. Evidence-based clinical guidelines aim to improve healthcare of patients and while there are such guidelines for psoriasis, to date the challenges of (and recommendations for) managing scalp psoriasis are often limited or missing from these treatment guidelines.

In the following in-journal supplement, a connected suite of five papers focus on the use of topical therapies for the treatment of the person afflicted with psoriasis. This work harnesses robust evidence from randomised clinical trials (RCTs) of topical therapies commonly used in psoriasis patients and translates this into recommendations for the most appropriate treatment of patients with body or scalp psoriasis, from an efficacy, safety and cost-effectiveness perspective. Based upon systematic review and harnessing ‘state of the art’ evidence assessment methodologies, the modelling work suggests that the use of a two-compound formulation (TCF) product of calcipotriol and betamethasone dipropionate is the most appropriate treatment option for both body and scalp psoriasis. This Editorial acknowledges the results of any modelling exercise have limitations; indeed such limitations are acknowledged in each modelling contribution in this issue. With these caveats in mind, this introductory paper considers the implications of this research and distillation of the evidence. This work should guide cost-effective treatment choices for body and scalp psoriasis, assist in recommendations for management of scalp psoriasis in future iterations of psoriasis clinical guidelines and help primary care physicians striving to attain best outcomes in the care of the person with psoriasis.

Key words::

• Body psoriasis
• Cost effectiveness
• Mixed treatment comparison
• Scalp psoriasis
• Systematic review
• Topical treatment

Introduction

Psoriasis is a common inflammatory life-long skin condition affecting some 2% of the population1–3 (with estimates of prevalence worldwide ranging from 0.5 to 4.6%4) and most patients suffering with scalp involvement5–7. While signs and symptoms vary immensely between patients8, itching and scaling7 are the most common and distressing in the majority. Physically disfiguring, these afflictions can significantly impact on a patient’s quality of life, restricting daily living7,9–12 often due to loss of self-esteem and confidence. As a consequence, dermatological conditions, including psoriasis, comprise a high proportion of the general practitioners’ (GP) caseload in clinical practice13. Although most patients are cared for in the community, some recalcitrant cases require inpatient care and incur significant costs14,15. Internationally, demands upon dermatology specialist services continue to escalate16–20, increasing outpatient referrals, pressure and waiting times for specialist consultations. In 2005 there were more GP referrals to dermatology clinics in the UK than to all other medical specialties combined21 and in England now there are more than 9 million referrals annually22.

All healthcare systems are increasingly tasked to deliver quality services, with best possible health outcomes, typically within challenging budgets. While traditionally the field of dermatology has not been an area where costs have been studied in great depth, except perhaps more recently in the case of the higher cost biologics in recalcitrant or more severe psoriasis23, this situation is set to change. Dermatology and chronic lifelong diseases such as psoriasis will become one of a number of areas of focus. In the UK for example, in an National Health Service (NHS) tasked to look for savings in the years ahead24, GP commissioners want to ensure optimal health outcomes for their population through efficiencies and provision of cost-effective services25. In so doing, GP commissioners might wish to focus on referrals in dermatology, including psoriasis.

Apart from the inpatient care or use of higher-cost biological therapies in recalcitrant or more severe psoriasis, the economic burden of psoriasis has not been a huge focus of attention1,23. There is a paucity of literature describing the cost effectiveness of topical therapies in body psoriasis26–29 and in scalp psoriasis this too has been lacking.

Clinical and cost effectiveness of commonly used topical therapies to treat the person with mild to moderately severe body or scalp psoriasis

The broad-based research summarised in the five publications in this in-journal supplement (two papers featuring body psoriasis and three papers scalp psoriasis) has a focus upon the person with psoriasis and the provision of optimal psoriasis services in a healthcare system reconfiguring its health services to meet ever-present challenges24. This endeavour was undertaken by building upon an understanding of current clinical management of the person affected by psoriasis, then making an informed interpretation of best available robust clinical and economic data in order to provide optimal health services for patients. Headline observations from the five studies are summarised in Table 1. This paper gauges whether these recent initiatives will assist physicians in provision of optimal care for the person with moderately severe psoriasis.

Table 1.  Overview of findings from five studies.

1.	Freeman et al.30 [body psoriasis]
	Aim: To develop an interactive psoriasis model to compare the longer-term outcomes of topical treatment strategies in patients with moderately severe body psoriasis in real-world setting.
	Results: Topical treatment with high PASI 75 efficacy first-line is a cost-effective treatment strategy. The model predicts potential savings in psoriasis care for a UK population of £126 million over 2 years if all psoriasis patients received the TCF in a community setting.
	Conclusion: The authors’ psoriasis disease model could facilitate collaboration between budget holders and healthcare professionals to optimise healthcare in the UK based on best data available. This model is adaptable to tailor inputs to reflect local situation, providing an attractive tool to GP commissioners.
2.	Van de Kerkhof et al.31 [body psoriasis]
	Aim: To compare the efficacy of once-daily use of the TCF product relative to other commonly used topical in plaque psoriasis using a Bayesian MTC.
	Results: The licensed TCF once daily showed a higher efficacy based on PASI 75 and percentage CFB in PASI score compared to other commonly used topicals.
	Conclusion: Among topical therapies evaluated, the TCF once daily can be considered the most efficacious treatment for plaque psoriasis.
3.	Smith et al.49 [scalp psoriasis]
	Aim: To conduct a survey to understand typical patient management to support the development of a model estimating the cost effectiveness of a new treatment for moderately severe scalp psoriasis in Scotland.
	Results: Significant variation in stated patient pathways but also some common themes. Most patients were treated initially with coal tar preparations and shampoos, then often progressing to topical potent corticosteroids. There was no consensus on the order patients might receive topicals thereafter although if referred for specialist review they would typically have been treated with three topicals in primary care first.
	Conclusion: There was a large variety in first, second and third-line agents in primary care in scalp psoriasis although our interview programme and prescribing data confirmed which treatments were most frequently prescribed. Experts agreed ‘current standard practice’ in Scotland was best described as an average across five plausible treatment pathways.
4.	Bottomley et al.50 [scalp psoriasis]
	Aim: To evaluate effectiveness of the TCF gel versus other topical therapies for scalp psoriasis in adults using direct and indirect comparisons.
	Results: TCF gel was statistically significantly more effective than other topicals in terms of achieving a response defined according to both IGA and TSS criteria. TCF gel was generally associated with a statistical significant lower risk of AEs, skin AEs or patients withdrawing from RCTs due to AEs.
	Conclusion: TCF gel has significant benefits over other topicals considered in the routine management of patients with moderate scalp psoriasis. These results were consistent, using a number of efficacy and tolerability outcome measures.
5.	Affleck et al.51 [scalp psoriasis]
	Aim: To compare the cost-effectiveness of the TCF gel used first-, second- or third-line to standard topical treatments for moderately severe scalp psoriasis from a Scottish NHS perspective.
	Results: TCF gel used first-, second- or third-line was projected to increase QALYs (around 0.0025) with cost savings per patient (£20–30) over 1 year. Our results showed that TCF gel was the dominant treatment strategy; these results were stable across a broad range of scenarios.
	Conclusion: Where cosmetic properties are important for patient acceptability and compliance is a major issue contributing to treatment failure, the once daily TCF gel offers patients with scalp psoriasis an attractive, cost-saving treatment option. While per patient annual cost savings and QALY benefit seem modest, the authors consider such benefits will be attractive to GP consortia tasked with commissioning care for their population with scalp psoriasis.

AE, adverse event; CFB, change from baseline; IGA, investigator global assessment; MTC, mixed treatment comparison; PASI, Psoriasis Area and Severity Index; RCT, randomised clinical trial; TCF, two-compound formulation; TSS, total sign score.

In the first paper, Freeman and co-workers30 developed an interactive body psoriasis model to compare the longer-term outcomes of topical treatment strategies in patients with moderately severe psoriasis in real-world settings by adapting a previously published 1-year economic analysis of the two-compound formulation (TCF) calcipotriol plus betamethasone dipropionate and other commonly used topical agents in plaque psoriasis29. The beauty of this 2-year disease model is its flexibility, its adaptability to realistic clinical situations, its ability to accommodate new evidence as the evidence base in body psoriasis matures and the harnessing of best evidence to relevant outcomes, such as numbers of referrals avoided, or local budget impact, which resonate with today’s commissioners of healthcare. This work, undertaken in collaboration with the National Association of Primary care (NAPC) is an example of improving care using best available psoriasis evidence, by applying what we know to what we do. For now, the current evidence-base demonstrates convincingly the clinical and economic benefits to patients, physicians and commissioners of care for the use of a topical with high PASI 75 efficacy and safety, such as the TCF, which predicts potential savings in psoriasis care for a UK population of £126 million over 2 years if all psoriasis patients received the TCF, rather than other topical therapies, in a community setting.

The second body psoriasis publication in this supplement by van de Kerkhof et al.31 compares the available efficacy of once daily use of the TCF product relative to other commonly used topicals in plaque psoriasis. Numerous quality randomised controlled studies (RCTs) show that the TCF applied once daily for body psoriasis is more effective than its individual constituents (calcipotriol and betamethasone dipropionate – both of which are used to treat the disease) and is associated with less skin irritation than calcipotriol monotherapy32–36. No published head-to-head comparisons between the TCF, other commonly used treatments, or the non-fixed combination of calcipotriol and BDP are available to inform prescribing or purchasing decisions. In reality, such a study would be impossible to conduct and it would not reflect clinical practice. It is well known that the cosmetic properties of psoriasis treatments are important for patient acceptability and poor compliance is a major issue contributing to treatment failure37,38. The smell, texture and staining of white or grey hair or skin (which limit the use and appeal of tar preparations39) make blinding commonly used treatments impossible. The logistics of administering multiple daily applications of blinded topical treatments in such a study would influence the study outcomes and would not reflect compliance in clinical practice.

In the absence of the ideal head-to-head RCTs or head-to-head observational studies, the conduct of a Bayesian mixed treatment comparison (MTC), essentially an extension of traditional meta-analysis, is considered a credible and accepted alternative (for example by bodies such as the National Institute for Health and Clinical Excellence (NICE) or the Scottish Medicines Consortium (SMC)) to assess the relative value of one technology versus another. Considered the method of choice, the Bayesian approach allows for a probabilistic interpretation which informs decision making. The ensuing ranking of technology (e.g., in terms of their efficacy) is useful in the decision making context40,41.

Further to extensive systematic literature review, RCTs of commonly used topicals of relevance to clinical practice in Europe were evaluated and compared using the same outcome measure31. The PASI 75 (percentage of patients with at least 75% improvement in Psoriasis Area and Severity Index (PASI) score), is the recognised benchmark endpoint used in clinical trials42,43 and importantly this allows relevant, accepted comparisons across the evidence base. Traditionally, the percentage change from baseline (CFB) in PASI score has been used as a measure of efficacy in clinical studies and this measure enabled a larger number of RCTs to be included in this comparison.

The topical treatments of interest were selected based on published treatment guidelines44 and included the TCF product, vitamin D analogues (tacalcitol, calcitriol, calcipotriol), steroids (betamethasone valerate, betamethasone dipropionate, clobetasol, mometasone and fluocinolone), any non-fixed combination of a vitamin D analogue and a corticosteroid, coal tar, tazarotene, dithranol, pimecrolimus, tacrolimus. This analysis indicated that relative to all the commonly used topicals studied [except for the unlicensed twice daily application of the TCF], the TCF once daily was considered to be the most efficacious treatment for plaque psoriasis since robust evidence and state of the art evidence assimilation techniques showed a higher efficacy based on PASI 75 and CFB in PASI score. The MTC observations are consistent with results of two meta-analyses that did not include the TCF, which demonstrated that the non-fixed combination of a potent topical corticosteroid plus calcipotriol was more efficacious than calcipotriol45,46, and in accord with an indirect unadjusted comparison which indicated that the TCF provided higher PASI 75 response rates than the non-fixed combination and other commonly used topicals29.

There are few national clinical guidelines for the management of scalp psoriasis; the issues relating to treatment of scalp lesions are often neglected in psoriasis treatment guidelines47 although its challenges are mentioned in the recent British Association of Dermatologists and Primary Care Dermatology Society recommendations for the initial management of psoriasis48. These recommend that tar-based shampoos are used first-line for scalp psoriasis, combined potentially with either a coconut oil/tar/salicylic acid combination ointment, a 2–5% salicylic acid preparation, calcipotriol scalp application or a potent topical steroid. Many therapies have been used to treat scalp psoriasis in the last four decades, itself testimony to the dearth of satisfactory treatment options available47. In Scotland there were no guidelines to assist clinicians in managing scalp psoriasis and the peer-reviewed literature provided no information on the current management of scalp psoriasis. This was an evidence gap which needed to be addressed in order for Leo Pharma to demonstrate the value for money of their TCF gel formulation in scalp psoriasis to the Scottish Medicines Consortium (SMC). The three remaining papers in the supplement describe the efforts to fill this evidence need.

The third publication by Smith et al.49 describes what the authors believe to be the largest survey of GP (n = 33) and specialist (n = 10) management of scalp psoriasis in Scotland. This research which reflected the national picture (embraced almost all Health Boards in Scotland (and one specialist in the North East of England)) confirmed which topicals were commonly prescribed (based on national prescribing statistics which were endorsed in bespoke interviews) and hence relevant in scalp psoriasis management and gave an insight into the typical resources incurred in managing these patients (e.g., frequency of GP consultations and triggers for specialist referrals). Commonly used topicals prescribed in mild to moderately severe scalp psoriasis in Scotland did not include use of very potent steroids such as clobetasol propionate but typically the use of medicated shampoos (e.g., Polytar Liquid) and/or coal tar preparations, potent corticosteroids such as betamethasone valerate (BMV) (e.g., Betnovate), or coal tar preparations such as Polytar, or Capasal and vitamin D analogues (e.g., Dovonex scalp solution) were cited by interviewees. These findings informed subsequent activities which are reported in the fourth paper (the conduct of a systematic review of RCTs of commonly used topicals in scalp psoriasis, and an indirect comparison of available efficacy and safety data)50 and the fifth paper in this in-journal supplement51 (a Scottish TCF gel cost utility analysis where the economic model structure and assumptions reflected the Scottish patient pathways observed in the survey49 and efficacy and safety were informed by the indirect comparison50). The TCF gel has since been recommended for use by the SMC in 200952.

Smith and coworkers49 consider that the significant treatment heterogeneity observed likely reflects the limitations in current therapies, an aging literature for topical treatments used in clinical practice (and consequent paucity of evidence-based effectiveness data) and lack of clinical guidelines in Scotland. While significant variation in stated patient pathways was reported (essentially there was no gold standard for the management in Scotland) some common themes were evident. Most patients were treated initially with shampoos and coal tar preparations, then typically receiving topical potent corticosteroids and while there were differences in the order patients might receive topicals thereafter, expert agreement on a ‘current standard practice’ in terms of probable treatment pathways in primary care enabled the impact of use of the TCF gel in clinical practice for scalp psoriasis to be simulated in the fifth publication51.

Bottomley and co-workers50 undertook a systematic review of the effectiveness of topical treatments for scalp psoriasis used in clinical practice in Scotland49 and undertook a meta-analysis to obtain estimates of clinical effectiveness of these topical using recommended efficacy and safety outcome measures for scalp psoriasis. The recommended efficacy measures were responders based upon Investigator Global Assessment (IGA) and Total Sign Score (TSS) criteria, where the definition of a responder was agreed to be representative of how patients are managed and judged to have responded to a topical treatment in clinical practice. Tolerability was evaluated in terms of percentages of patients experiencing all adverse events (AEs), skin AEs and withdrawals due to AEs. Direct comparisons or head-to-head comparisons of TCF gel to another topical agent were sought. In the absence of direct comparisons, the use of formal adjusted indirect comparison methods, as advocated by NICE53, were employed. Although evidence in the network was sparse, the meta-analysis and indirect comparison suggested that the TCF gel had significant efficacy and tolerability benefits over other topicals considered in the routine management of patients with moderate scalp psoriasis. The consistency of the beneficial TCF gel findings across IGA and TSS efficacy outcomes and three safety outcomes reassured the authors as to the robustness of their findings. This analysis50 was also in accord with general findings from the MTC of the TCF product in body psoriasis31

Reassuringly, in both these comparisons in body31 and scalp50 psoriasis, the authors strove to improve the quality of their analysis by including all available evidence (of standard therapies) via robust systematic review, using accepted clinical outcome measures to pool the data, and adopting conservative methodologies throughout (e.g., the use of random effect models to account for heterogeneity across the RCTs) in their deliberations to infer credible conclusions from their analyses.

The fifth paper by Affleck et al.51 builds upon the findings from the third and fourth papers to describe the cost effectiveness of the TCF gel used first-, second- or third-line compared to standard topical treatments for moderately severe scalp psoriasis. A 1-year Markov model included 12 different topical treatment pathways, each simulating three lines of therapy, where the topical treatment pathways in primary care (typically comprising three topical therapies before applying a risk of outpatient referral), usual resource use and costs were determined from the Scottish survey49. Relative efficacy and safety of topical were derived from the formal adjusted indirect comparison50. Populated by Scottish-relevant clinical practice data and robust assessment of efficacy and safety data, the model indicated that the TCF gel used first-, second- or third-line was the ‘dominant’ strategy (being associated with added benefits and cost savings relative to competing treatment lines). Importantly, these findings were consistent across a broad range of credible scenarios.

Discussion

This in-journal supplement has described a number of studies to inform the evidence base relating to the management of body and scalp psoriasis and has drawn out some common themes. The findings are consistent in both body and scalp psoriasis. This is probably not surprising. Scalp and body psoriasis are different in terms of accessibility of lesions to treatment and the TCF products therefore comes in unique formulations for body and scalp. This consistency of findings may therefore qualify the once daily TCF as the optimal choice of treatment of the person with mild to moderately severe body or scalp psoriasis – attractive in terms of added benefits, cost-savings and cosmetic appeal.

Poor quality care is costly54 and we cannot afford to continue the same old ways. The author would suggest that the consistent themes emerging from this suite of papers, and of relevance to the person with psoriasis, are set to give health professionals in psoriasis a helpful steer towards implementing optimal cost-effective services for their patients with mild to moderately severe body and/or scalp psoriasis.

The gold standard source of quality clinical evidence is the head-to-head RCT or head-to-head observational study55, recommended to populate economic models56 – essentially clinical therapeutic effect data is fairly portable for inclusion on an economic model. While an RCT comparing all relevant topical treatments is always the ideal and preferable to inform an economic analysis in psoriasis, in practice such RCTs do not exist and for a host of legitimate and pragmatic reasons are not considered feasible. Real world effectiveness studies of relevant topical are ideal to appreciate the impact of these drugs in a real world setting, but the authors are not aware of any such studies. The next best option is to interrogate the evidence base using best methodologies and this in-journal supplement has done this for body and scalp psoriasis. As well as comparing the relevant outcomes, all efforts were made for the Bayesian MTC (body psoriasis)31 and the indirect comparison (scalp psoriasis)50 to include only those studies well matched regarding baseline patient characteristics (e.g., gender, age, duration of disease, baseline PASI score).

However, the acceptance of economic analyses will increase only if they approximate more closely the setting in which the intervention is used in clinical practice. All economic models must reflect the perspective and context of the decision maker with assumptions underpinning a model being regarded as credible to a specific locality or country. Decision makers are aware of country variations in terms of medical resource utilization and clinical outcomes and are increasingly challenged as to the implications of this57–59. The body psoriasis and scalp psoriasis models described in the in-journal supplement will still be populated with data from the studies by van de Kerkhof31 and Bottomley et al.50, respectively, yet may be easily customised to reflect other country situations, by conducting research analogous to that of Smith et al.49 to develop acceptable country-specific information.

Conclusion

This paper offers an overview of recent research efforts to harness credible peer-reviewed evidence using accepted methodologies to assist in defining optimal topical treatment of the patient with body or scalp psoriasis. Full details of these are seen in the following five papers in this issue. The authors are convinced that despite any limitations in their research methodologies (for example as a result of paucity of high quality information or model validation) their findings will inform and improve the treatment of the person afflicted with psoriasis.

Transparency

Declaration of funding

This work was supported by Leo Pharma A/S. The funder was invited to comment on drafts of the paper but all editorial decisions rests with the author, who takes full responsibility for the content.

Declaration of financial/other relationships

K.F. has disclosed that he is an employee of Co. Durham and Darlington NHS Foundation Trust & Sunderland Teaching Primary Care Trust. K.F. has received funding from Leo Pharma to attend dermatology conferences, to chair the North of England Psoriasis Consensus Group and to make presentations to healthcare professionals on psoriasis and dermatology service design/delivery. K.F. has received funding from Pfizer, Galderma and Abbott for similar activities. These activities have received funding from Leo Pharma A/S.

Some peer reviewers receive honoraria from CMRO for their review work. The peer reviewers of this paper have disclosed that they have no relevant financial relationships.

Acknowledgements

Medical writer Dr Julia Bottomley helped with the initial draft of the manuscript, for which she received payment from Leo Pharma A/S.

Notes

* Polytar is a registered trademark of Stiefel Laboratories Ltd.

† Betnovate Scalp Application is a registered trademark of GlaxoSmithKline.

‡ Capasal is a registered trademark of Dermal Laboratories Ltd.

§ Dovonex Scalp Solution is a registered trademark of Leo Pharma.