Topical treatments for chronic plaque psoriasis
Chronic plaque psoriasis is the most common type of psoriasis, and it is characterised by redness, thickness, and scaling. First‐line management of chronic plaque psoriasis is with topical treatments, including vitamin D analogues, topical corticosteroids, tar‐based preparations, dithranol, salicylic acid, and topical retinoids.
To compare the effectiveness, tolerability, and safety of topical treatments for chronic plaque psoriasis, relative to placebo, and to similarly compare vitamin D analogues (used alone or in combination) with other topical treatments.
We updated our searches of the following databases to February 2011: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library (2011, Issue 2), MEDLINE (from 1948), EMBASE (from 1980), Science Citation Index (from 2008), Conference Proceedings Citation Index ‐ Science (from 2008), BIOSIS (from 1993), Dissertation Abstracts via DialogClassic (all publication years), and Inside Conferences (all publication years).
We identified ongoing and unpublished studies from the UK Clinical Research Network Study Portfolio and the metaRegister of Controlled Trials. We checked the bibliographies of published studies and reviews for further references to relevant trials, and we contacted trialists and companies for information about newly published studies.
A separate search for adverse effects was undertaken in February 2011 using MEDLINE and EMBASE (from 2005).
Final update searches for both RCTs and adverse effects were undertaken in August 2012. Although it has not been possible to incorporate RCTs and adverse effects studies identified through these final searches within this review, we will incorporate these into the next update.
Randomised trials comparing active topical treatments against placebo or against vitamin D analogues (used alone or in combination) in people with chronic plaque psoriasis.
Data collection and analysis
One author extracted study data and assessed study quality. A second author checked these data. We routinely contacted trialists and companies for missing data. We also extracted data on withdrawals and on local and systemic adverse events. We defined long‐term trials as those with a duration of at least 24 weeks.
This update added 48 trials and provided evidence on 7 new active treatments. In total, the review included 177 randomised controlled trials, with 34,808 participants, including 26 trials of scalp psoriasis and 6 trials of inverse psoriasis, facial psoriasis, or both. The number of included studies counted by Review Manager (RevMan) is higher than these figures (190) because we entered each study reporting a placebo and an active comparison into the 'Characteristics of included studies' table as 2 studies.
When used on the body, most vitamin D analogues were significantly more effective than placebo, with the standardised mean difference (SMD) ranging from ‐0.67 (95% CI ‐1.04 to ‐0.30; 1 study, 119 participants) for twice‐daily becocalcidiol to SMD ‐1.66 (95% CI ‐2.66 to ‐0.67; 1 study, 11 participants) for once‐daily paricalcitol. On a 6‐point global improvement scale, these effects translate into 0.8 and 1.9 points, respectively. Most corticosteroids also performed better than placebo; potent corticosteroids (SMD ‐0.89; 95% CI ‐1.06 to ‐0.72; I² statistic = 65.1%; 14 studies, 2011 participants) had smaller benefits than very potent corticosteroids (SMD ‐1.56; 95% CI ‐1.87 to ‐1.26); I² statistic = 81.7%; 10 studies, 1264 participants). On a 6‐point improvement scale, these benefits equate to 1.0 and 1.8 points, respectively. Dithranol, combined treatment with vitamin D/corticosteroid, and tazarotene all performed significantly better than placebo.
Head‐to‐head comparisons of vitamin D for psoriasis of the body against potent or very potent corticosteroids had mixed findings. For both body and scalp psoriasis, combined treatment with vitamin D and corticosteroid performed significantly better than vitamin D alone or corticosteroid alone. Vitamin D generally performed better than coal tar, but findings relative to dithranol were mixed. When applied to psoriasis of the scalp, vitamin D was significantly less effective than both potent corticosteroids and very potent corticosteroids. Indirect evidence from placebo‐controlled trials supported these findings.
For both body and scalp psoriasis, potent corticosteroids were less likely than vitamin D to cause local adverse events, such as burning or irritation. Combined treatment with vitamin D/corticosteroid on either the body or the scalp was tolerated as well as potent corticosteroids, and significantly better than vitamin D alone. Only 25 trials assessed clinical cutaneous dermal atrophy; few cases were detected, but trials reported insufficient information to determine whether assessment methods were robust. Clinical measurements of dermal atrophy are insensitive and detect only the most severe cases. No comparison of topical agents found a significant difference in systemic adverse effects.
Corticosteroids perform at least as well as vitamin D analogues, and they are associated with a lower incidence of local adverse events. However, for people with chronic plaque psoriasis receiving long‐term treatment with corticosteroids, there remains a lack of evidence about the risk of skin dermal atrophy. Further research is required to inform long‐term maintenance treatment and provide appropriate safety data.
Anne R Mason, James Mason, Michael Cork, Gordon Dooley, Helen Hancock
Plain language summary
Skin treatments for chronic plaque psoriasis
Chronic plaque psoriasis is the most common type of psoriasis. Although any part of the body may be affected, the most commonly affected sites are the elbows, knees, and scalp. 'Topical' treatments (i.e. treatments applied to the skin) are usually tried first. These include vitamin D products, topical corticosteroids, tar‐based preparations, dithranol, salicylic acid, and vitamin A products. As chronic plaque psoriasis is a long‐term condition, it is important to find out which treatments work best and what adverse effects they have. This review describes average benefits of different treatments, while recognising that individuals will vary in their experience of each treatment.
The evidence was based on 177 studies, which, in total, included 34,808 people. Studies were typically about 7 weeks' long, but this ranged from 1 week to 52 weeks. Vitamin D products were found to work better than placebo (the base cream or ointment). Potent topical corticosteroids (strong, e.g. betamethasone dipropionate) and very potent (very strong, e.g. clobetasol propionate) topical corticosteroids were also effective.
Some studies compared vitamin D products directly with potent or very potent corticosteroids. These products had similar effects when applied to the body, but corticosteroids worked better than vitamin D for scalp psoriasis. Treatment that combined vitamin D with a corticosteroid was more effective than vitamin D alone and more effective than the topical corticosteroid alone. Vitamin D products generally performed better than coal tar, but studies found conflicting results when comparing vitamin D with dithranol.
Whether applied to the body or to the scalp, potent corticosteroids were less likely than vitamin D to cause 'local adverse events', such as skin irritation or burning, and people were therefore more likely to stop using vitamin D products. When studies examined whether topical treatments had effects within the body ('systemic adverse events'), we found no difference between placebo and any other treatment. However, this may be because many trials did not properly assess systemic adverse events, rather than because there really was no difference.
More long‐term studies would help doctors and people with psoriasis decide on the best way to treat this chronic condition.
Anne R Mason, James Mason, Michael Cork, Gordon Dooley, Helen Hancock
Implications for practice
Evidence from large numbers of trials indicates that most of the topical treatments tested in the trials reviewed here alleviate the symptoms of psoriasis. However, it was not possible to assess the performance of treatments at different levels of severity of psoriasis.
The evidence suggests that vitamin D products are more effective than emollient alone. Potent and very potent corticosteroids are also effective, and very potent corticosteroids are more effective than either potent corticosteroids or vitamin D products. The effectiveness of dithranol and tazarotene appears to be similar to that of vitamin D products. Although vitamin D and corticosteroids are equally effective for treating psoriasis of the body, corticosteroids appear to be more effective than vitamin D for treating psoriasis of the scalp. Combined treatment of vitamin D with corticosteroid is more effective than either vitamin D alone or corticosteroid alone. Vitamin D is more effective than coal tar, but findings on the relative effectiveness of vitamin D and dithranol were mixed. Occlusion enhances the effectiveness of vitamin D, as does twice‐daily rather than once‐daily application.
Compared with vitamin D alone, combined therapy that uses two products separately (vitamin D in the morning and corticosteroid at night) can achieve similar effects and be as well tolerated as using a combined product. However, some corticosteroids seem to perform better than others when used separately (see Analysis 12.5 and Analysis 12.9), and disease severity may also affect treatment performance, though poor reporting of baseline severity in trials means that we cannot confirm this. Use of a combined product may also enhance concordance, and there is evidence to suggest that adherence is higher when application time is shorter.
Potent corticosteroids are less likely than vitamin D to cause local adverse events, and treatment with corticosteroids is less likely to result in discontinued use because of these adverse events. Tazarotene is more likely than emollient to cause local adverse events. Our review found no difference between placebo and any other topical treatment in the assessment of systemic adverse events. However, this may reflect an absence of evidence (trials failing to appropriately assess these events over adequate time periods) rather than being evidence of absence.
Although current evidence demonstrates that topical steroids are as effective as and at least as well tolerated as vitamin D analogues, concern remains about the potential safety problems associated with corticosteroids (Bos 2008). Concerns include the risk of rebound (a worsening of disease following treatment discontinuation), skin atrophy (skin thinning), and tachyphylaxis (decreasing response to the drug) after long‐term use (Hengge 2006). Methods to assess rebound have been developed and should be used in future research (Carey 2006). Regarding skin thinning, one problem with psoriasis is that the skin is very thick and a goal of therapy is to reduce the thickness of lesional (epidermal) skin. Damage to the surrounding normal skin may occur, and for that reason, people should use topical corticosteroids for limited periods or sparingly in delicate areas, such as the face or folds of the skin.
Although topical corticosteroids have been in use for about 50 years, there is a surprising lack of relevant evidence addressing steroid‐associated skin dermal atrophy in people with chronic plaque psoriasis requiring long‐term treatment. It is improbable that short‐term (less than three weeks) courses of topical corticosteroids cause dermal skin atrophy, except in delicate areas such as the face and flexures (groin, axillae, inframammary). However, treatment may be long‐term and continuous for people with more severe chronic psoriasis. Current assessments of cutaneous dermal atrophy within trials have largely been limited to clinical observation or symptom and sign reporting by trial participants (which will only detect severe atrophy of the dermis). More sensitive and reliable methods, such as high frequency ultrasound, are routinely available (Cossmann 2006). Dermal atrophy might be monitored in part if trials routinely adopted more robust methods, such as high frequency ultrasound, to assess dermal skin atrophy skin‐thinning, providing useful information for patients and clinicians.
Excessive use of topical corticosteroids can also cause a substantial thinning of the epidermis (Kao 2003). However, thickening of the epidermis is part of the problem in psoriasis and so thinning of the epidermis (not dermis) that has been caused by topical corticosteroids may be of benefit in psoriasis. Evidence drawn from healthy volunteers or severe long‐term cases cannot be generalised. Specifically, evidence is required concerning the frequency and spectrum of atrophy in people with chronic psoriasis requiring long‐term treatment.
Topical vitamin D analogues (calcipotriol, tacalcitol) and topical calcineurin inhibitors (tacrolimus and pimecrolimus) do not cause cutaneous atrophy. The issue may become a historical one if newer safer steroids, currently being developed and evaluated for atopic dermatitis, subsequently demonstrate efficacy and safety in chronic plaque psoriasis.
We found no evidence on tachyphylaxis, but if treatment response were to decline, this could lead to over‐use, increasing the risk of percutaneous absorption. As the evidence base on longer‐term adverse effects in psoriasis is inadequate, the preferences of people with psoriasis and their attitudes to these perceived risks should inform treatment choice. Further research is required to inform approaches to long‐term maintenance.
Implications for research
Evidence showing that treatments improve the symptoms of psoriasis has focused mainly on treatments with relatively short duration. Although improving, there is still relatively limited randomised evidence to tell us about the long‐term effect of using these treatments; good quality head‐to‐head evidence is therefore needed to quantify and compare long‐term adverse events and to explore the feasibility of long‐term treatment. There are important sources of heterogeneity in currently available trial findings, which it is not possible to explore in anything other than a qualitative sense. For example, the properties of the vehicle preparation are known to deliver wide variation in response to treatment. This is important when interpreting the findings of this review. The value of the active ingredient may be worth one point on a six‐point (IAGI) scale, but possibly one to two points are also being contributed by the vehicle. However, an analysis of vehicle performance was outside the scope of the review. Trial publications included in this review span 45 years. Reporting standards within these trials are generally suboptimal by today's standards, and it would be useful to ensure that current trials adhere to CONSORT (CONsolidated Standards of Reporting Trials) standards to help future reviews to interpret findings appropriately. For example, where trials enrol participants with a wide range of baseline severity, stratifying the randomisation by baseline severity would be a useful design feature. We are not aware of studies that have adopted this approach. Trialists might usefully consider including more homogeneous participant groups in terms of severity, so that the clinical implications of findings are clearer.
Given the importance of safety to patients and to resolve clinical uncertainties, it would be valuable to obtain reliable data on the safety of corticosteroids used long‐term at recommended doses, including step‐down or intermittent management. Historically, these uncertainties have been driven by unrepresentative case series of non‐standard use of steroids. Given the variety of methods used to assess atrophy and other sequelae, it would be valuable to reach clinical consensus about reliable assessment methods (Cossmann 2006).