Systematic literature review of long-term efficacy data for topical psoriasis treatments

Abstract Objective To identify long-term efficacy evidence that supports use of topical therapies as regular maintenance therapy in the prevention of psoriasis relapse. Methods A systematic literature review identified clinical trials and observational studies that reported efficacy outcomes for topical psoriasis therapies with treatment durations of at least 12 weeks. For therapies with long-term data, the approved treatment schedules in product labels were reviewed. Results Forty-six studies with at least 12-week efficacy outcomes were identified. Eight randomized controlled trials and six observational studies or single-arm open-label studies reported efficacy data for >12-week treatment periods. Most studies used treatment regimens that reflect current standard of care of repeated treatment of relapses. The PSO-LONG study is the only identified randomized controlled trial to have compared regular proactive maintenance use of a topical treatment (calcipotriol/betamethasone foam) with reactive management in response to psoriasis relapses. Conclusions Limited high-quality long-term efficacy data are available for topical psoriasis therapies. While some product labels mention clinical experience of up to 12 months, they do not provide specific recommendations on the optimal long-term regimen. Calcipotriol/betamethasone foam is the only treatment for which the approved label allows either reactive treatment of relapse or regular (twice weekly) maintenance use.


Introduction
Psoriasis is a chronic inflammatory disease characterized by a fluctuating pattern of remission and flare (1). Plaque psoriasis accounts for 90% of cases and manifests as sharply demarcated scaly, erythematous lesions commonly affecting the knees, elbows, scalp and trunk (2). Psoriasis has an impact on the physical, psychological and social wellbeing of patients (3). Due to the chronic nature of psoriasis, long-term treatment strategies are needed to reach the treatment goals of achieving remission and maintaining clear, or almost clear, skin and restoring normal daily functional ability and quality of life (4).
Topical therapy is the standard of care for treatment of the majority of patients with mild to moderate disease (88% of all patients with psoriasis, (5)), whilst patients with more severe disease may use topical therapies in conjunction with conventional systemic treatments and biologics (6,7). Effective management with topical therapies offers several advantages over conventional systemic and biologic treatment including a more favorable side effect profile, significantly lower cost and the possibility for patients to manage their psoriasis without the need for specialist treatment (4,8). Vitamin D analogues (such as calcipotriol) and corticosteroids (such as betamethasone dipropionate and clobetasol propionate) are commonly used topical treatments and are often prescribed in combination.
While topical steroids play a key role in psoriasis treatment, potent and very potent agents are not recommended for periods of longer than 4-8 weeks because of potential adverse effects (3), this is reflected in approved labels. Current long-term management (>6 months) often follows a reactive approach in response to flares (9) without precise guidance on how or when to stop and re-start topical therapy, or the frequency and duration of treatment (8).
Alternative long-term management approaches include proactive maintenance treatment with long-term, low frequency (e.g. twice weekly) treatment. This proactive approach is well established for atopic dermatitis with topical calcineurin inhibitors for up to a year (8,10,11), and has been shown to reduce, prevent and delay disease exacerbations (12). There is a growing consensus amongst dermatologists for a proactive approach to long-term management of psoriasis with topical therapies in order to maintain remission, increase adherence and improve long-term outcomes (8,9,13).
In a recent review, Segaert et al. (8) described 'long-term maintenance' as aiming to maintain remission once achieved, with the possibility of continuous treatment on a less frequent basis. We use this terminology to distinguish between current, reactive long-term management approaches to treat relapse, and proactive treatment strategies to maintain remission.
Long-term maintenance with topical therapies has been recommended in psoriasis treatment guidelines, based on review of published literature and expert opinion. In France, twice weekly maintenance treatment with a vitamin D analogue and corticosteroid was recommended by a panel of experts (14). The joint US guideline from the American Association of Dermatology and the National Psoriasis Foundation describes proactive management as treatment of quiescent areas (typically twice weekly) to reduce the frequency of flares (15). German and Swiss consensus guidelines agree that successful once daily induction therapy for 4-8 weeks may be followed by twice weekly proactive management to reduce the risk of relapse (16,17).
Previous reviews of topical psoriasis treatments have defined studies of <6 months duration as short-term and those >6 months as long-term (18,19). Long-term studies of topical psoriasis treatments have focused on demonstrating the safety and tolerability of treatments originally approved for short-term use (based on 4-12-week studies) when used over longer periods on a continuous basis, or intermittently in response to relapses (20,21). There is a lack of controlled evidence of high quality on the efficacy of topical treatments under a long-term maintenance regimen compared to the current standard of care (18,19). Such evidence is needed to support a change in product labeling and consequently clinical practice, and to provide patients with an alternative treatment strategy that could offer improved long-term disease control while also limiting the issues associated with continuous steroid use (3). Currently, only the fixed-dose combination of calcipotriol and betamethasone in foam formulation (EnstilarV R ) is indicated for long-term maintenance treatment in addition to short-term flare treatment (22).
The aims of this systematic review were to evaluate the available long-term efficacy evidence that supports the use of topical psoriasis treatments under long-term maintenance regimens, (i.e. alternative treatment strategies to the current practice of reactive treatment in response to flare), and to compare this evidence with recommendations on long-term use of topical treatments from the Summaries of Product Characteristics (SmPCs) of available topical treatments.

Materials and methods
A systematic literature review (SLR) was conducted to identify clinical trials and observational studies that assessed long-term efficacy of topical treatments for psoriasis in adult patients.
PubMed, Embase and the Cochrane Library were searched from January 01, 2000 to November 05, 2020 for published articles, without language restriction. Search strategies included index and text terms for psoriasis, the relevant interventions, clinical trials and observational studies. The full search strategy can be found in Supplementary Table 1. All identified titles and abstracts were assessed for inclusion by one reviewer. Full texts were then assessed, with a second reviewer checking those articles excluded by the first reviewer. Discrepancies were resolved by discussion.
Clinical trials and observational studies of vitamin D analogues, corticosteroids and other marketed topical therapies for psoriasis with a treatment period of at least 12 weeks that reported at least one efficacy outcome were eligible for inclusion. Details of inclusion and exclusion criteria are presented in Supplementary Table 2.
For studies meeting the eligibility criteria, details of the study design, patient population, interventions, treatment regimens and outcomes were extracted.
Based on the review findings, studies were categorized based on treatment duration: 12 weeks, >12 weeks to 26 weeks and >26 weeks, which allowed for studies with a duration of 6 months and studies with duration 1 year to be clustered together. Within each treatment duration category, randomized controlled trials (RCTs) were considered separately from openlabel and observational studies.

Results
Electronic database searches identified 3,586 articles. Following removal of duplicates, a total of 2,086 records were screened at title and abstract stage; of these 102 articles were assessed at the full text screening stage. The SLR included 55 articles reporting on 46 studies that included treatment periods of at least 12weeks ( Figure 1).
Many of the trials reporting 12-week efficacy data were small (fewer than 100 patients), non-randomized, non-controlled studies. Twelve of the studies were RCTs including more than 100 patients (described in Table 1). These studies demonstrate that a range of treatments can be used safely and effectively for up to 12 weeks, but do not address the long-term management of psoriasis to prevent relapse. In the open-label study, patients were treated for 6 months with once daily tacalcitol used "as needed" in response to disease relapse (61). After 6 months treatment, mean Psoriasis Area and Severity Index (PASI) score was significantly improved compared to baseline and there was a reduction in total body surface involvement of 33%.
The four RCTs each included an initial treatment period of between 2 and 12 weeks for the induction of remission with a combination regimen of topical corticosteroid with either vitamin D analogue or tazarotene, and follow-on treatment period of between 8 and 24 weeks during which treatment was used either continuously (once daily or less frequently), or on an as needed basisdetails of the regimens are provided in Table 2. In three studies, patients were required to have responded to initial treatment in order to progress to follow-on therapy (62)(63)(64). In the fourth study, this requirement was not stated but it was noted that all patients achieved at least 50% global improvement (i.e. "moderate" global response to treatment) at the end of the initial treatment phase (65).
Studies by Lebwohl et al. and Koo et al. showed respectively that tazarotene þ clobetasol and calcipotriol þ clobetasol could be used without steroid-specific side effects over 24 and 26 weeks and that combination treatment was more effective than monotherapy (with tazarotene (65) or either calcipotriol or clobetasol (63)) during follow-on treatment. A comparison of once daily treatment with calcipotriol alone or calcipotriol þ clobetasol reported by Katoh and Kishimoto (62) showed that switching from combination therapy during the initial phase to monotherapy with calcipotriol resulted in exacerbations of psoriasis during the long-term phase.
A multicenter, open-label RCT by Lee et al. (64) evaluated the optimal follow-on treatment regimen with calcipotriol/betamethasone gel following an initial eight week once daily treatment phase. In this trial, patients who responded to initial once daily treatment with calcipotriol/betamethasone gel were randomized to receive one of three follow-on calcipotriol/betamethasone gel regimens: once daily as needed, once daily every day and twice weekly (Saturday and Sunday, 'weekend group'). At the end of the induction phase, patients who met the response criteria of a rating of 'clear' or 'almost clear' by Investigator's Global Assessment of disease severity (IGA) progressed to follow-on treatment. At the end of the follow-on treatment phase (week 16), response rate was significantly lower in the twice weekly ('weekend') group compared to either the 'as needed' or 'continuous daily' treatment groups; 31% in the 'weekend' group compared with 64% in the 'as needed' group and 68% in the 'continuous treatment' group (p ¼ .0109 and p ¼ .0015).

Studies reporting >26-week efficacy data
One observational study, four open-label, non-controlled trials and four RCTs with efficacy data for treatment periods of between 52 weeks and 18 months were identified. (Results of an additional long-term open-label study of the fixed combination of tazarotene and halobetasol propionate used on an as-needed basis, which was excluded from the review as a research letter have recently been published in full).
The prospective, observational study (PRO-LONG) compared patient-reported outcomes with calcipotriol/betamethasone gel or calcipotriol/betamethasone ointment over a 52-week treatment period using a once daily, as needed regimen (66). The four open-label clinical trials were of vitamin D analogues (calcitriol, calcipotriol and tacalcitol) and all used an as needed treatment approach (67)(68)(69)(70)(71). The study designs are presented in Table 3.
Of the four RCTs, two studied once daily, as needed treatment regimens, in one study the treatment regimen was not  Patients were randomized to either tazarotene monotherapy once daily or tazarotene once daily (PM) þ high potency corticosteroid (fluticasone (continued) specified, and one studied a proactive twice weekly treatment regimen. Two of the studies evaluated the effects of nonpharmacological interventions aimed at improving patient adherence during long-term treatment when used in combination with calcipotriol/betamethasone or fluocinonide (72)(73)(74). The remaining two RCTs included an investigation of the safety of calcipotriol/betamethasone ointment over 52 weeks compared to alternating 4-week treatment periods with calcipotriol then betamethasone or calcipotriol alone (75), and a comparison of the efficacy and safety of twice weekly, proactive management with calcipotriol/betamethasone foam against vehicle foam for the prevention of psoriasis relapse (76). An overview of the RCT designs is provided in Table 4.
The first of the studies evaluating non-pharmacological interventions (PSO-TOP) compared standard of care treatment with calcipotriol/betamethasone gel with and without the addition of a topical treatment optimization program (TTOP; patient support including visit checklists for conversations between dermatologists, nurses and patients, patient information, telephone/e-mail helpdesks and treatment reminders) (73,74). Study medication was applied once daily for 8 weeks, followed by as needed application for 56 weeks. Greater improvement in mean Patients were randomized to either 1% coal tar cream or 5% coal tar lotion three times daily. Swinkels et al. (58) 250 Dithranol vs UVB 12-week parallel group RCT. Open-label.
Patients were randomized to UVB three times per week for 12 weeks, short contact dithranol treatment (daily, either at home or outpatient clinic) for 12 weeks or inpatient dithranol treatment (daily) for up to 8 weeks. Physician's Global Assessment of psoriasis severity (PGA) during the 'as needed' period was achieved in the calcipotriol/betamethasone gel þ TTOP arm compared to calcipotriol/betamethasone gel without TTOP (p ¼ .0343). One small RCT (n ¼ 40) evaluated adherence over a 52-week period in patients treated with topical fluocinonide with or without weekly self-reporting of the state of their psoriasis via an internet survey (72). Fluocinonide was applied in the intervention and control groups twice daily. The authors note that by month 12, 42.8% of patients had breaks in treatment of 7 days or longer and that missed dosing was common in patients who still had psoriasis. No clear statement was made on whether treatment was used continuously or as needed during the trial.
The internet reporting intervention improved adherence (50% vs 35%, p ¼ .08) and there was an improvement in PASI at 52 weeks (3.32 vs 0.34, p ¼ .038) but no difference in IGA between the groups.
Kragballe et al. (75) reported on a randomized, double-blind safety study in which patients were randomized in a 1:1:1 ratio to either: 52 weeks of combination therapy with calcipotriol/ betamethasone ointment, 52 weeks of alternating 4 week periods of the two-compound therapy and calcipotriol ointment or, 4 weeks of the two-compound therapy followed by 48 weeks of calcipotriol ointment. Thus, patients in all groups received 4 weeks treatment with calcipotriol/betamethasone ointment before different long-term treatment strategies ("two compound group", "alternating group", "calcipotriol group"). Following the initial 4-week period, all treatments were used once daily as needed, to reflect usual clinical practice. The primary objective of the study was to investigate the safety of two-compound therapy over 52 weeks. Secondary efficacy endpoints were also evaluated, and results showed a trend toward a difference in percentage of satisfactory responses by IGA (absent, very mild or mild disease) during the total study period, with a higher proportion of satisfactory responses in the two-compound and alternating groups compared to the calcipotriol group. After the first 4-week assessment the percentage of satisfactory treatment responses by IGA were similar across groups. At all subsequent visits, the proportion of patients with satisfactory responses was higher in the two-compound group than in the calcipotriol group. In the alternating group, the proportion of satisfactory responses after a two-compound treatment period was always higher than after a calcipotriol treatment period (75).
The recently published PSO-LONG study is the only longterm study identified to have compared usual clinical practice of intermittent reactive treatment with a regular twice weekly maintenance therapy (with an interval of 2-3 days between treatment) to evaluate whether proactive treatment can prevent or delay relapse and maintain time in remission (76). Following 4 weeks open-label, once daily treatment with a foam formulation of calcipotriol/betamethasone, patients who responded to treatment (defined as PGA 0/1 with at least a 2-grade improvement) were randomized to receive calcipotriol/betamethasone foam or vehicle foam twice weekly for 52 weeks (76). In case of relapse (defined as PGA 2), patients in both groups received rescue therapy with once daily calcipotriol/betamethasone foam for 4 weeks. Patients who regained a PGA score of "clear" or "almost clear" after 4 weeks of once daily treatment re-started twice weekly maintenance treatment according to prior randomization following the open-label treatment phase. Patients who did not regain response exited the trial.
Proactive management showed superior efficacy to the reactive management strategy based on prolonged time to first relapse (median time to first relapse from randomization was prolonged by 26 days for patients in the proactive group), greater number of days in remission (41 additional days over 1 year) and reduction in number of relapses (3.1 compared to 4.8 over 1 year). The incidence of adverse events was similar between treatment groups.
SmPC recommendations on use of topical psoriasis therapies for long-term management The recommendations on long-term use of topical psoriasis therapies from the SmPCs for those treatments with long-term efficacy data are summarized in Table 5.
Dosing information for calcitriol (Silkis V R ointment) (77), calcipotriol (Dovonex V R ointment) and fluocinonide (Metosyn V R ointment) (78) do not mention long-term use. For calcipotriol/ betamethasone gel and ointment (Dovobet V R /Daivobet V R gel and ointment) (7980), tacalcitol (Curatoderm V R ointment) (81) and tazarotene (Zorac V R gel) (82) the SmPCs note clinical experience up to 52 weeks, but no specific recommendation on the appropriate treatment schedule is made. In contrast, calcipotriol/betamethasone foam (Enstilar V R ) (22) is the only treatment for which the SmPC indicates the possibility of either reactive flare treatment or long-term maintenance treatment, i.e. twice weekly proactive use, as in the PSO-LONG study.

Discussion
This SLR was intended to identify the available efficacy evidence for long-term maintenance treatment of psoriasis with topical therapies given the lack of standard approach to long-term management of psoriasis and interest in alternative strategies to the current practice of reactive treatment of relapses. We found 8 RCTs and 6 observational studies or non-controlled trials reporting >12-week efficacy outcomes. Most of these studies used treatment regimens that reflect current standard of care of repeated treatment of relapses. Table 5. SmPC dosing recommendations for treatments with long-term efficacy data.

Recommendations on treatment duration
The recommended treatment period is 4 weeks. There is experience with repeated courses of Dovobet up to 52 weeks. If it is necessary to continue or restart treatment after 4 weeks, treatment should be continued after medical review and under regular medical supervision.
The recommended treatment period is 4 weeks for scalp areas and 8 weeks for "non-scalp" areas. If it is necessary to continue or restart treatment after this period, treatment should be continued after medical review and under regular medical supervision. Calcipotriol (Dovonex V R ointment) (86) No instruction provided on repeated courses.
There is limited clinical experience available for the use of this dosage regimen of more than 6 weeks. Tacalcitol (Curatoderm V R ointment) (81) Normally duration of treatment depends on the severity of the lesions and should be decided by the physician. There is clinical trial experience with continuous and intermittent treatment in adults up to twelve months. Fluocinonide (Metosyn V R ointment) (78) No instruction provided on repeated courses. Tazarotene (Zorac V R gel) (82) Usually, the treatment period is up to 12 weeks. Clinical experience, particularly on tolerability, is available on periods of use of up to 12 months. Calcipotriol/betamethasone foam (Enstilar V R ) (22) Flare treatment Enstilar foam should be applied to the affected area once daily. The recommended treatment period is 4 weeks. If it is necessary to continue or restart treatment after this period, treatment should be continued after medical review and under regular supervision. Long-term maintenance treatment Patients who have responded at 4 weeks' treatment using Enstilar once daily are suitable for longterm maintenance treatment. Enstilar should be applied twice weekly on two nonconsecutive days to areas previously affected by psoriasis vulgaris. Between applications there should be 2-3 days without Enstilar treatment. If signs of a relapse occur, flare treatment, as described above, should be re-initiated.
The study by Lee et al. (64) compared proactive (weekend only treatment) and reactive ('as needed') follow-on regimens but only over an 8-week period. Long-term observational and open-label uncontrolled studies provide evidence of effectiveness of repeated treatment of relapses with vitamin D analogues (67)(68)(69)(70)(71) and two non-pharmacological intervention studies suggest different strategies to improve patient adherence and subsequently treatment outcomes (72,73), however none of these trials provide information on the optimal treatment regimen for long-term maintenance. While the study by Kragballe et al. indicates that combination therapy is favored over monotherapy as reactive long-term treatment, it does not provide information on whether a proactive or reactive strategy is more effective in the long-term maintenance of remission or frequency of relapse (75).
Relapse is common in psoriasis when using a reactive management approach. Some patients find that their relapse may be worse than their initial symptoms (83). Therefore, there is need to maintain skin clearance after flare treatment for as long as possible. A long-term proactive management approach, with maintenance treatment following initial treatment success, could help sustain disease remission and improve clinical and QoL outcomes for patients.
The PSO-LONG study is the only identified RCT to have compared regular maintenance use of a topical treatment with reactive management in response to psoriasis relapses (rescue therapy). While long-term data are available for other topical psoriasis treatments, this has not resulted in updates to SmPCs to provide specific recommendations on the optimal frequency of treatment during long-term use. In contrast, evidence from the 52-week PSO-LONG study has supported a recent update to the Enstilar V R SmPC meaning that, in addition to reactive use for flare treatment, it can also be used twice weekly for proactive management, for which it is the only topical treatment with supporting efficacy data in the product label.
For completeness, 12-week studies were included in this review although they are not considered long-term from a regulatory perspective. Regulators indicate that studies of 8-12 weeks are usually required to demonstrate short-term efficacy (4 weeks for potent topical corticosteroids), and that one-year prolonged or intermittent use studies are recommended to demonstrate long-term safety and efficacy (84). In addition, previous SLRs of topical treatments for psoriasis included studies of at least 24 weeks as long-term (18,19) and have commented that longterm studies of topical treatments for psoriasis are lacking and studies such as PSO-LONG are needed to inform long-term management strategies (8,19). Such strategies have the potential to improve disease control and reduce the negative impact of psoriasis on patient's lives, without the need for continuous daily treatment.

Strengths and limitations
This study covers a more recent time period compared to previous SLRs of topical treatments for psoriasis by Augustin et al. (18,19). and Mason et al. which cover time periods to 2013 and 2011, respectively. We identified and described relevant articles published between 1, January 2000 and November 2020. Articles published prior to this and data published in abstract form only at the time of review are not included within the scope of the study.

Conclusion
Despite the chronic nature of psoriasis, there are limited highquality long-term efficacy data available for topical psoriasis therapies. Most studies have evaluated long-term reactive maintenance treatment of relapses and only the PSO-LONG study has compared regular, proactive maintenance use of a topical treatment with reactive management in response to psoriasis relapses. While some product labels mention clinical experience of up to 12 months, they do not provide specific recommendations on the optimal long-term treatment regimen. Calcipotriol/ betamethasone foam is the only treatment for which the approved label allows either reactive treatment of relapse or regular (twice weekly) maintenance use.

Disclosure statement
Claire Bark is an employee of RJW & partners, as was Chloe Brown when the work was undertaken. Per Svangren is an independent consultant at Svangren Life Science Consulting. All were consultants to LEO Pharma for this study.

Funding
This study was funded by LEO Pharma A/S.