Dermatology Online Journal

A Systematic Review of Adverse Effects Associated with Topical Treatments for Psoriasis
Christine R. Bruner, MD, Steven R. Feldman, MD, PhD, Madhuri Ventrapragada, BS, Alan B. Fleischer, Jr., MD
Dermatology Online Journal 9 (1): 2

Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, North Carolina. sfeldman@wfubmc.edu

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Abstract

Mild to moderate psoriasis is a disease that can often be treated with topical medications. The diversity of topical therapies and their disparate side effects complicates treatment planning. Our purpose is to compare the rates of adverse events associated with different topical psoriasis treatments. A review of medical literature from 1996 to March, 2002 was conducted using guidelines set by QUORUM statement criteria. In monotherapy studies, corticosteriods caused fewer adverse reactions compared to vitamin D analogues and tazarotene. In combination studies adverse event rates were higher than in monotherapy studies, except for the combination of topical steroid and calcipotriene which decreased irritation. Irritant contact dermatitis was the main side effect with vitamin D analogues, tazarotene, dithranol or coal tar, while side effects of topical corticosteriods included headache, viral infection and skin atrophy. Topical agents for psoriasis are usually well-tolerated without severe side effects. Formulating a patient's medication regimen should take into account the needs for short-term management and long-term control of psoriasis. Since clearance is not a realistic expectation, reasonable goals should be set as excessive use of topical treatments may increase the risk of both cutaneous and systemic side effects.

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Introduction

Psoriasis is a disease that has long been a challenge for clinicians to treat. The complexity of treating psoriasis may be attributed to both the chronic and persistent nature of the disease itself, as well as to the numerous therapies available to the physician. The choice of the appropriate treatment must take into account many factors, including the characteristics and locations of the lesions and extent of involvement.

It is estimated that 75% of patients with psoriasis have mild to moderate clinical severity of disease (<20% of body surface area affected or a Psoriasis Area Severity Index (PASI) score of <10) and can be satisfactorily managed on an outpatient basis with topical therapy.[1] Yet 100% clearance of lesions is not a realistic expectation for patients treated with topical medications. Reported complete clearance rates range from 2% with tazarotene gel to 45% with a combination of 0.005% calcipotriol ointment and 0.1% betamethasone ointment.[2] In addition, topical therapies for psoriasis have significant side effects that must be weighed by both physician and patient when developing a treatment program.

The challenge of selecting the best topical anti-psoriatic therapy for the patient with limited or mild disease is compounded by a lack of uniformity in the reporting of adverse events associated with the different treatments. Previous reviews of topical therapies have only been descriptive in nature, and have not systematically reviewed randomized controlled trials or compared their reported rates of adverse events.[3,4,5] The purpose of this systematic review is to compare the rates of adverse events associated with the currently available topical treatments for psoriasis.

Methods

Searching

A systematic review of the medical literature was performed according to the QUORUM statement criteria for the reporting of randomized controlled trials.[6] A search of Medline from 1966 to March 4, 2002 was conducted to identify studies reporting the rate of adverse events associated with various topical treatments for psoriasis (Table 1). Inclusion and exclusion criteria were set before the search of medical literature was conducted. Two searches were performed: the terms "psoriasis" and "safety" were crossed, and the terms "psoriasis" and "adverse events" were crossed in order to maximize relevant findings. The results of these searches were then limited to English language and human subject randomized, controlled trials. The search findings were verified against the Cochrane Controlled Trials Register using the same search strategy and limited only to English publications in order to identify additional trials (Table 1). Hand searching of the resultant pool of articles was then used to extract studies involving clinical trials of topical monotherapies or combination therapies for psoriasis. Most subjects described in these selected trials had mild-to-moderate plaque-type psoriasis.

Selection

Inclusion and exclusion criteria were predetermined to minimize bias and to assist in identifying studies appropriate for comparing rates of adverse events associated with different treatments of psoriasis. Inclusion and exclusion criteria were as follows:

Inclusion Criteria:

• The study was a randomized and/or double blind clinical trial in which the proportion of subjects experiencing adverse events was indicated, or could be calculated from given data.
• The specific adverse events associated with each treatment were described.
• The sample size was at least 50 subjects.
• Enrolled subjects received at least 14 days of active treatment.

Exclusion Criteria:

• There was no pre-established maximum duration of treatment (i.e. a study in which the subject received drug until cured).
• Following the active treatment period, subjects were re-administered the treatment in the follow-up phase of the trial.
• Maintenance studies were excluded.
• Subjects received other active topical psoriasis agents within 1 week prior to study entry, or systemic agents within 1 month prior to study (insufficient washout period).
• Studies that exclusively concerned guttate psoriasis, pustular psoriasis, or scalp psoriasis were excluded.
• Experimental agents were excluded.

Validity assessment and data extraction

Trials were considered to be valid if they met the inclusion criteria and contained sufficient data for further analysis. One study of each monotherapy or combination therapy for psoriasis was included; more than one was included if variations in the frequency or duration of treatment were reported. Duplicate publications were excluded. All comparable data were extracted and recorded in tables. For each treatment group in each study, the frequency of application of the treatment, the design of the study and the duration of treatment, and the number of subjects included in the intention to treat analysis were identified and recorded. The proportion of subjects with treatment-related adverse events, a description of the specific treatment-related adverse events and the proportion of subjects affected, as well as the proportion of subjects who withdrew from the study due to treatment-related adverse events were recorded. Whenever exact numbers were presented in the published papers, these were preferentially used in the subsequent analysis. When these numbers were not available, we calculated the rate of treatment-related adverse events from the proportions provided. Our initial Medline search identified 321 referenced reports. After duplicate publications were excluded, studies involving topical therapies for psoriasis were identified by hand searching, and records were limited to English language, human, randomized controlled trials, 55 studies remained. A search of the Cochrane Controlled Trials Register yielded an additional 22 studies, for a total of 77 articles that were retrieved for more detailed evaluation (Table 1). On the basis of the predetermined inclusion and exclusion criteria, 23 studies were ultimately identified and selected (Table 2).[7-29] Among these studies, 70% were double blind, 70% were comparison studies, and 78% were multicenter trials.

Results

The minimum reported rate of treatment-related adverse events of any monotherapy was 3.2%, associated with fluticasone propionate cream. Among the non-corticosteroids, tacalcitol ointment 4 µg/g was the least irritating, with 4.8% of subjects experiencing adverse events. Calcitriol 3 µg/g had a similarly low reported rate of adverse events (5.0%), and in another recent study, was found to be extremely well tolerated as it did not give rise to any cumulative irritancy or sensitization.[30] The maximum reported rate of adverse events of 72% was observed with dithranol cream. In general, the corticosteroids demonstrated a lower percentage of subjects experiencing treatment-related adverse events (range of 3.2% to 23%) compared with the newer topical therapies such as the vitamin D analogues (4.8% to 35%) and tazarotene (13% to 50%). Furthermore, the corticosteroid trials had the lowest proportion of subjects who withdrew due to treatment-related adverse events, with a maximum of 2.5% withdrawn from a fluocinonide trial. By contrast, treatment was more frequently discontinued with dithranol, vitamin D analogues, and tazarotene (maximums of 5.4%, 4.6%, 18%, respectively).

With combination therapy, the minimum proportion of subjects with treatment-related adverse events, 12%, was associated with mometasone furoate 0.1%/salicylic acid 5%, whereas the maximum rate of adverse events for combination therapies of 24% was associated with calcipotriene cream/clobetasone 17-butyrate cream. Other studies have found less irritation with calcipotriene combined with a potent topical corticosteroid than with calcipotriene monotherapy, however.[31,32] A very low proportion of subjects using combination treatments discontinued therapy (ranges of 0% with mometasone furoate/salicylic acid, to a maximum of 5.3% with coal tar/allantoin/hydrocortisone cream).

For all topical therapies, burning, pruritus, and erythema were the most commonly recorded adverse events. They were most frequent in subjects using vitamin D analogues and tazarotene, and were the predominant drug-related effects reported by patients receiving both corticosteroids given as monotherapies or in combination therapies. However while patients treated with vitamin D analogues, tazarotene, dithranol, or coal tar combination treatments primarily experienced an irritant contact dermatitis, subjects receiving topical corticosteroids reported a broad spectrum of adverse events, ranging from viral infection, headache, and hypertrichosis to skin atrophy.

Discussion

A controlled clinical trial is a very effective means to demonstrate the efficacy of therapies compared to placebo. A controlled clinical trial is also valuable for identifying common side effects of medications. The incorporation of a control population allows one to tell if observed side effects are due to the treatment or are simply common adverse events that occur in any population over time. Our search of well-designed clinical trials finds that topical agents for psoriasis are generally quite safe, with the major common side effects being more bothersome than severe.

A limitation of controlled, clinical trials that are powered to detect efficacy is that they may not be large enough to detect rare side effects or side effects that occur outside the strict limitations of the study design. This limits how representative they are of true clinical use. Despite the relatively low rates of adverse events we report with the use of topical corticosteroids in the short-term treatment of psoriasis, the cutaneous side effects that develop when corticosteroids are used for long periods of time are well known. Such side effects include cutaneous atrophy, telangiectasia, and striae.[3] In clinical studies that are carefully designed to detect decrease in skin thickness, such decreases occur within a six-week topical corticosteroid treatment course. Prednicarbate, betamethasone 17-valerate, and mometasone furoate all cause skin thinning when used for 6 weeks.[33] Topical corticosteroids clearly cause more atrophy and have greater effects on collagen synthesis than the non-corticosteroid topical anti-inflammatory agent, tacrolimus ointment.[34] Vitamin D analogues and tazarotene also have potential side effects (hypercalcemia/uricemia and teratogenicity, respectively) that were not addressed by the short-term studies in our review; nevertheless, these effects need to be considered in treatment planning. The lack of long-term clinical trials that examine the safety and tolerance of topical psoriasis treatments is a significant limitation of our comparison of the side effect profiles of these agents.

We would have liked to develop a risk/benefit ratio for the reviewed therapies, but there was a lack of uniformity among the studies in the reporting of the improvement or clearance of psoriasis. The definition of clearance, resolution, or improvement was not the same in all studies, nor were PASI scores used in every trial, making a direct comparison of safety in relation to efficacy impossible. Similarly, the risks, or adverse events, associated with the topical treatments differ from one agent to another. The side effects of retinoids, for example, differ from those related to use of topical corticosteroids. Furthermore, a lack of complete homogeneity in patient populations from study to study also complicates the formulation of a reliable summary risk/benefit ratio for each study.

Until reliable risk/benefit ratios or standardized safety profiles of the various topical therapies are available to help guide physicians, the optimal treatment of psoriasis should include attention to both short-term management of the disease and the development of a safe long-term approach to maintain control of the condition. Given that complete clearance is usually not a realistic expectation with topical therapy, recognizing the limitations of therapy is essential.[2] Patients should be aware that even topical medications have their safety limitations; excessive use in an attempt to obtain full resolution of their condition may result in increased treatment-related effects.

Conflicts of interest: Dr. Feldman has received funding for studies from Bristol Meyer Squibb-Dermatology, Allergan, Galderma and Connetics corporation. Dr. Fleischer has received funding for studies and speaker's bureaus from Bristol Meyer Squibb, Fujisawa, Novartis, Galderma, Schering-Plough and Berlex.

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