PSORIATIC ARTHRITIS: A QUANTITATIVE OVERVIEW OF THERAPEUTIC OPTIONS

British Journal of Rheumatology 1997;36:95 99 PSORIATIC ARTHRITIS: A QUANTITATIVE OVERVIEW OF THERAPEUTIC OPTIONS G. JONES, M. CROTTY,* P. BROOKS* and THE PSORIATIC ARTHRITIS META-ANALYSIS STUDY GROUP Menzies Centre for Population Health Research, GPO Box 252C, Hobart, Tasmania, 7001 and *Medical Professorial Unit, St Vincents Hospital, Victoria Street, Darlinghurst, Sydney, Australia, 2010 SUMMARY The objective of this study was to use the technique of meta-analysis to undertake a systematic review of published and unpublished randomized controlled trials of pharmacological agents to determine their relative efficacy and toxicity in the treatment of psoriatic arthritis. The main outcome measure was the change in pooled disease index with component variables derived from OMERACT. Nineteen randomized trials were identified, of which 12 were included in the quantitative analysis with data from 792 subjects. Although all agents were better than placebo, parenteral high-dose methotrexate, salazopyrin, azathioprine and etretinate were the agents that achieved statistical significance (although it should be noted that only one component variable was available for azathioprine and only one trial with a high dropout rate was available for etretinate suggesting some caution is necessary in interpreting these results). In all trials, the placebo group improved over baseline (pooled improvement 0.43 disease index (DI) units, 95% CI 0.28 0.59). There were insufficient data to examine toxicity. In conclusion, parenteral high-dose methotrexate and salazopyrin are the only two agents with well-demonstrated published efficacy in psoriatic arthritis. The magnitude of the effect seen with etretinate, oral low-dose methotrexate, azathioprine and perhaps colchicine suggests that they may be effective, but that further multicentre clinical trials are required to establish their efficacy. Furthermore, the magnitude of the improvement observed in the placebo group strongly suggests that uncontrolled trials should not be used to guide management decisions in this condition. KEY WORDS: Meta-analysis, Psoriatic arthritis, Treatment. IT has been estimated that arthritis occurs in 5 7% of those with psoriasis [1]. However, this figure becomes much higher in those who are hospitalized with psoriasis [2]. Certainly, psoriatic arthritis is commonly encountered by rheumatologists and can, on occasion, be difficult to manage. Its overall natural history appears somewhat better than that of rheumatoid arthritis [3], although not all agree with this optimism [4]. Relatively few clinical trials of treatment are available for this condition and data presentation in these trials is far from uniform, making comparison difficult. Often, management is extrapolated from trials in rheumatoid arthritis, but there is some evidence in the literature to suggest that this may not be appropriate [5]. In this study, we used the technique of meta-analysis to attempt to answer the following question: how do various treatments compare in terms of both efficacy and toxicity in the treatment of psoriatic arthritis? METHODS Search strategy A computerized literature search was conducted in May 1994 and updated regularly until November 1995. Data bases utilized were Medline (1966 95) and Excerpta Medica (June 1974 95). Search terms were psoriasis, arthritis, therapy and/or controlled trial. The search strategy was supplemented by manually searching bibliographies of previously published Submitted 1 February 1996; revised version accepted 15 July 1996. Correspondence to: P. Brooks. reviews and papers, as well as the conference proceedings of the American Rheumatology Association. We also contacted drug companies who might be involved in clinical trials. Inclusion criteria For inclusion in the meta-analysis, studies had to have had at least two treatment groups, and the allocation to these must have been by formal randomization. Only articles published in English were included due to the necessity of full text evaluation for quality assessment. Data extraction Data were extracted from the published reports by two of the authors independently. Disagreements were resolved by discussion. For each trial, we documented the following: the number of subjects, the outcome measures used, the type of treatment, the dose regimen used, the nature of the control group, the method of allocation, the extent of blinding, the duration of the treatment, the method of analysis and the adverse effects. In trials where the results were not expressed in a form that allowed extraction of all the necessary data, we approached the investigators by letter for more information. Nine investigators were approached, eight responded and six provided data. Quality assessment Each of the trials included in the meta-analysis was assessed for quality by using a modified version of 95 1997 British Society for Rheumatology

96 BRITISH JOURNAL OF RHEUMATOLOGY VOL. 36 NO. 1 previously published work [6]. For this purpose, quality is defined in terms of the measures taken by the investigators to minimize bias in each trial. The trials were scored independently of the method of data extraction and were rated in the range 0 3 on each of the following features: (a) degree to which randomization was truly blind; (b) inclusion of data from subjects who subsequently withdrew from the study (intention to treat); (c) degree to which assessors of outcome were blind to treatment allocation; (d) whether subjects were assessed to determine if they had accurately guessed their treatment status; (e) whether an appropriate range of clinical outcome measures had been used. Scores for the individual quality items were summed for the purposes of analysis. The total possible score was 15 points. Outcome measures The trials reported a wide variety of outcome measures, including joint index, pain score, global assessments and blood parameters. No consensus exists on the appropriate endpoints to be reported in psoriatic arthritis clinical trials; however, a core set of outcome measures has been developed to measure disease activity for rheumatoid arthritis clinical trials. These measures (acute-phase reactants, disability, pain, patient global assessment, physician global assessment, swollen joint count, tender joint count and radiographic changes of joints in any trial of 1 yr or longer) known as the OMERACT measures [7] have been selected on the basis of validity and we accepted any of these measures as an outcome. We chose to examine one summary measure of treatment effect the pooled disease index [8]. This index basically weights each component variable equally, allowing them to be combined. We modified this to allow comparison between agents by dividing by the number of component variables (which varied between studies) so that the index generated has a mean of zero and a S.D. of one. Thus, unlike the normal disease index, a change in disease index (DI) of 1 unit approximates a 1 S.D. change in each of the component variables (if the component variables are highly correlated). Statistical methods Where there was only one trial looking at an agent, results were generated as a disease index value listed with a 95% confidence interval (CI). The variance of the change in the disease index was calculated by assuming that baseline and follow-up measurements for both the treatment and placebo arms were unpaired. This was necessary as data were only available as group means and S.D. at baseline and follow-up, rather than individual data. Also, because of drop-outs, patient numbers were often not the same in the two groups. This represents a conservative approach, in terms of type 1 error, to estimation of the variance. In cross-over trials, the treatment placebo difference was a paired comparison rather than a comparison of two independent groups. When there was more than one trial looking at the same agent, a pooled DI was calculated by the weighted average of the individual disease indices with the weighting inversely proportional to the variance of each individual disease index again listed with 95% CIs [9]. Thus a study with a larger sample size will have a disproportionately higher weighting than a smaller study. We also adapted the conventional 2 test for homogeneity which was applied where there was one more trial for an individual agent as well as for placebo versus baseline. This test is to check the assumption TABLE I Overview of double-blind, placebo-controlled trials of pharmacological treatments for psoriatic arthritis No. of No. of subjects OMERACT Quality Year of (treated/ Follow-up variables Treatment score Agent First author publication control) period Dosage available characteristics (0 15) Methotrexate Black [10] 1962 10 80 days 1 3 mg/kg i.v. 2 Steroids permitted 5 Willkens [12] 1984 16t/21c 12 weeks 7.5 15 mg/week 4 Steroids not permitted 9 Colchicine Seideman [15] 1987 15* 16 weeks 0.5 mg TDS 4 7 McKendry [23] 1993 25* 23 weeks 0.6 1.8 mg/day 2 Methotrexate and 11 steroids permitted Sulphasalazine Farr [19] 1990 15t/15c 24 weeks 2 g/day 3 Intra-articular steroids 8 only permitted Fraser [22] 1993 20t/19c 24 weeks 2 g/day 3 8 Combe [25] 1995 64t/53c 24 weeks 2 g/day 4 11 Dougados [26] 1995 70t/66c 24 weeks 2 g/day 3 Steroids not permitted 13 Clegg [24] 1995 221 36 weeks 2 g/day 5 13 Etretinate Hopkins [13] 1985 20t/20c 24 weeks 0.5 mg/kg/day 3 Steroids permitted 7 Fumaric acid Peeters [21] 1992 13t/14c 16 weeks 120 mg/day 4 6 Azathioprine Levy [11] 1972 6* 26 weeks 3 mg/kg/day 1 6 Penicillamine Price [14] 1986 11t/8c 16 weeks 750 mg/day 3 Auranofin Carette [16] 1989 238 24 weeks 3 mg/day 3 Steroids permitted 11 Auranofin, i.m. Palit [20] 1990 82 24 weeks i.m. gold 50 mg/week, 3 Steroids not permitted 9 gold Auranofin 3 mg BD Ceftriaxone Caperton [17] 1990 8 6 months 2 g i.v./day for 2 weeks 4 6 -Interferon Fierlbeck [18] 1990 24 28 days 100 g/day for 2 weeks 3 7 *Cross-over trials.

JONES ET AL.: TREATMENT OF PSORIATIC ARTHRITIS 97 that all trials are samples from the same population of studies (the central limit theorem) and thus their 95% CIs should all overlap. FIG. 1. Efficacy of treatment vs placebo. For each agent, trials are ranked by the pooled effect size, not the statistical significance. In this case, a change in pooled disease index of one unit is roughly equivalent to a 1 S.D. improvement in each of the components of the index compared to placebo. The vertical line represents the null point. In general, trials showed a beneficial effect of treatment. Individual trials of azathioprine, colchicine, etretinate and salazopyrin (one out of four) reach statistical significance as does the pooled result for salazopyrin. In the case of colchicine, the overall result was not significant and there was marked heterogeneity. RESULTS Description of the studies A total of 19 randomized controlled trials were identified [10 28]. Complete or near complete data were available on 12 trials which included 792 subjects. There were inadequate data to consider toxicity. Randomized controlled trials were not available for antimalarials, cyclosporin or alkylating agents. Table I summarizes descriptive information for each study and quality scores. Combinable data could not be extracted from papers by Black (parenteral methotrexate) [10], Price (D-penicillamine) [13], Caperton (ceftriaxone) [17], Fierlbeck (interferon) [18] and the work by Clegg (salazopyrin) [24] was still in progress so complete data were not available. A further trial of gold versus auranofin was not included as there was no placebo comparison [27] and a trial of efamol marine was not included as it was not regarded as a pharmacologic agent [28]. Of the included trials, the effects of colchicine and auranofin were each examined by two trials, etretinate, fumaric acid, i.m. gold, azathioprine and oral methotrexate by one trial, and salazopyrin by four trials. The quality scores varied widely (Table I). There was a weak inverse correlation between trial quality and the magnitude of improvement (Spearman s = 0.3, P = 0.20). However, trial quality was strongly associated with year of publication (Spearman s = 0.65, P = 0.01). There were considerable differences in the inclusion and exclusion criteria of the individual trials. For example, one of the trials looking at the efficacy of gold and auranofin excluded patients who had previously received gold or other suppressive anti-rheumatic therapy [20], while the other accepted patients who had had prior gold [16]. Wash-out periods of between 2 and 3 months were required by five trials [12, 13, 16, 22, 26]. TABLE II Change in outcome (expressed as change in disease index) in studies of the use of pharmacological treatments for psoriatic arthritis Change in disease index P value for Agent First author (treatment vs placebo) 95% CI homogeneity Methotrexate Willkens [12] +0.66 0.001 to +1.30 Colchicine Seideman [15] +3.66 +2.84 to +4.47 McKendry [23] 0.30 0.85 to +0.25 Overall +1.70 1.90 to +5.30 0.0001 Salazopyrin Farr [19] 0.22 0.86 to +0.42 Fraser [22] +0.44 0.27 to +1.15 Dougados [26] +0.70 +0.36 to +1.03 Combe [25] +0.31 0.001 to +0.73 Overall +0.44 +0.22 to +0.66 0.41 Etretinate Hopkins [13] +0.84 +0.08 to +1.59 Fumaric acid Peeters [21] +0.41 0.36 to +1.18 Azathioprine Levy [11] +2.20 +1.06 to +3.33 I.m. gold Palit [20] +0.23 0.39 to +0.85 Auranofin Carette [16] 0.34 0.95 to +0.27 Palit [20] +0.23 0.05 to +0.51 Overall +0.12 0.13 to +0.38 0.23

98 BRITISH JOURNAL OF RHEUMATOLOGY VOL. 36 NO. 1 TABLE III Comparison between the efficacy of different agents in psoriatic arthritis and rheumatoid arthritis in terms of change in disease index* Psoriatic arthritis Rheumatoid arthritis Placebo vs baseline 0.43 (+0.28 to +0.59) 0.15 (+0.11 to +0.19) Treatment vs placebo Auranofin 0.12 ( 0.13 to +0.38) 0.30 (+0.06 to +0.54) I.m. gold 0.23 ( 0.39 to +0.85) 0.56 (+0.11 to +1.01) Methotrexate 0.66 ( 0.001 to +1.30) 0.58 (+0.10 to +1.06) Salazopyrin 0.44 (+0.22 to +0.66) 0.60 (+0.18 to +1.02) *All results are listed with 95% confidence intervals. Extracted from [29]. Similarly, trials varied according to whether they permitted the use of prednisone during the trial (Table I) and one trial permitted patients to remain on methotrexate [23]. Effects on outcome Of the 12 studies included in the quantitative analysis, the results are listed ranked by effect size and statistical significance of the improvement in disease index compared to placebo shown in Table II and Fig. 1. In patients treated with pharmacological agents, the disease index was statistically significantly improved relative to placebo in only two of the studies (Fig. 1). When the pooled indices for individual agents were examined, azathioprine, etretinate and salazopyrin were statistically better than placebo with borderline significance for low dose oral methotrexate (Table II). Data for parenteral methotrexate were unavailable for comparison purposes, but it was clearly much better than placebo (P 0.001). All pooled indices apart from colchicine were homogeneous (Table II). The heterogeneity with colchicine indicates that marked caution should be used in the interpretation of this result. In all the trials, the placebo group improved over baseline (pooled mean improvement 0.43 DI units, 95% CI 0.28 0.59). This improvement was also homogeneous (P = 0.28). Table III shows a comparison between previously published effect sizes in rheumatoid arthritis [29] and psoriatic arthritis. The outstanding difference is that the placebo group improves three times as much as the placebo group in rheumatoid arthritis (P 0.05). Gold compounds appear less efficacious in psoriatic arthritis, but these results were not statistically significant. DISCUSSION The study provides the first comprehensive overview of randomized controlled trials of psoriatic arthritis. It demonstrates well published efficacy for salazopyrin and parenteral high-dose methotrexate only. Importantly, it shows differences between rheumatoid arthritis and psoriatic arthritis not only in response to treatment, but also in the magnitude of improvement observed in the placebo arm. This latter finding, in particular, has significant implications for the interpretation of uncontrolled trials in this condition. There are a number of potential limitations in this review stemming from the methodological shortcomings in the primary trials. The trial sizes are generally small with insufficient statistical power increasing the likelihood of type II errors. This could affect the results with low-dose methotrexate and perhaps colchicine. It also should be noted that only one component variable was available for azathioprine and only one trial with a high dropout rate was available for etretinate suggesting some caution is necessary in interpreting these results. Secondly, subgroup analyses of results were not possible with this meta-analysis as the patient groups had been poorly characterized. There is some limited support in the literature for the hypothesis that different subtypes respond differently to treatment [14]. This may indicate that bias could be introduced by maldistribution of arthritis subtypes between treatment and placebo arms. Thirdly, these studies are of short duration, with a mean duration of 6 months, and these results cannot be extrapolated beyond this period. Finally, it would be possible to criticize the outcome measure we chose for this review. In this overview, we limited the component variables to those described at OMERACT 1 [7]. We were careful to weight all variables equally and ensure that the final disease index had a variance of one for each agent to allow direct comparison. Ideally, each disease index should have had the same number of component variables, but that was not possible in this case. This would not bias our findings unless one component variable was much more sensitive to change than the others which, intuitively, appears unlikely in this case as all the variables are correlated with each other. We would contend, therefore, that this measure is among the best available and has been well validated and widely accepted in rheumatoid arthritis [7]. Additionally, the use of one outcome measure gives a global effect estimate and minimizes the risk of type I error by eradicating the need for multiple comparisons with the different possible outcome measures. With regard to the trials with incomplete data, only the trial of high-dose methotrexate showed a marked improvement in the treatment group as compared to the placebo group [10]. However, as was shown in this trial, this dose would be too toxic for use in current practice. The excluded study of Clegg et al. [24] was also positive and this would strengthen the position of salazopyrin. The other studies showed effect sizes that appeared similar in magnitude to auranofin and i.m. gold [14, 17, 18, 28]. The uniform improvement seen in the placebo arm indicates that uncontrolled trials should not be used to guide management decisions in psoriatic arthritis. The improvement may be due to a number of possible factors, but it seems most likely that it reflects the natural history of this condition. The interpretation of uncontrolled studies in this condition will be extremely difficult as virtually all would be expected to show a positive effect which may be erroneously attributed to the treatment. Our calculations suggest that further trials will require 85 subjects per treatment arm to

JONES ET AL.: TREATMENT OF PSORIATIC ARTHRITIS 99 determine a 0.5 unit improvement in DI for treatment over placebo (with 90% power and 5% significance level). Obviously, inter-drug comparisons will require much larger sample sizes. This indicates that future therapeutic trials for this condition will need to be multicentre in design. In conclusion, the results of uncontrolled trials are likely to be misleading in psoriatic arthritis. At present, parenteral high-dose methotrexate and salazopyrin are the only two agents with well demonstrated published efficacy for the treatment of this condition. However, the magnitude of the effect seen with etretinate, low-dose methotrexate, azathioprine and perhaps colchicine suggests that they may be effective, but that further multicentre clinical trials are required to establish their efficacy. ACKNOWLEDGEMENTS The Psoriatic Arthritis Meta-analysis Study Group comprises: Monica Bengtsson and Ulla Bengtsson, Kabi Pharmacia, S-751 82 Uppsala, Sweden; H. Capell, Centre for Rheumatic Diseases, Wards 14/15, Royal Infirmary, Glasgow, G40 0SF; S. Carette, Department de Rhumatologie, Centre Hospitalier Universite, 2705 Boulevard Laurier, Ste Foy PQ G1V 4G2, Canada; B. Combe, Service du Rhumatologie, Hopital Caremeau, Rue de Professeur Debre, 30900 Nimes Cedex, France; M. Farr, Department of Rheumatology, University of Birmingham, Edgbaston, Birmingham B15 2TT; H. J. Williams, Division of Rheumatology, University of Utah School of Medicine, 50 North Medical Drive, Salt Lake City, UT 84132, USA; M. Dougados, Hopital Cochin, 27 Rue de FBG, St Jacques, Paris, 75014, France. REFERENCES 1. Wright V, Moll MH. Seronegative polyarthritis. Amsterdam: North Holland Publishing Co., 1976. 2. Leonard DG, O Duffy JD, Rogers RS. 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