Methotrexate

Since 2003, 2 randomized, control trials (RCT) have been published. In the first, Scarpa and colleagues randomized 35 patients with early oligoarthritis (<12 weeks’ disease duration) to nonsteroidal antiinflammatory drugs (NSAIDs) alone or NSAIDs plus MTX for 3 months; thereafter, all patients continued with the combination. A significant improvement was noted at 3 and 6 months compared with baseline in both groups. However, at 3 months, patients on the MTX/NSAIDs combination had a significantly better joint response than patients with NSAIDs alone, although no differences were noted between the 2 groups at 6 on MTX/NSAIDs. In this study, patients with early oligoarthritis demonstrated an improved response to MTX compared with NSAIDs, and that delay of 3 months in the administration of MTX did not significantly lower treatment response at 6 months, although differences in radiographic progression were not addressed in the study.

In the Methotrexate In Psoriatic Arthritis (MIPA) trial, 221 patients were randomized to MTX (target dose 15 mg/wk) or placebo and outcomes assessed at 6 months with the PsA response criteria (PsARC) as the primary one. At 6 months, no differences in any of the individual outcomes (PsARC, American College of Rheumatology 20/50/70 Response [ACR20/50/70], Disease Activity Score C-reactive protein) were noted, except for patient global and physician global assessments, which were higher in the MTX compared with the placebo group. The results of this trial indicate that MTX is not effective for PsA, but several flaws in this trial emerged. First, despite the study’s short duration, only 65% and 69% of patients in the active and placebo groups, respectively, completed the trial, which might bias results toward a null effect. Second, patient recruitment lasted 5 years, which might reflect an element of selection bias. Third around 35% of the patients included had oligoarticular disease and the maximum dose of MTX was 15 mg/wk a dose achieved by only 78% of patients.

Most of the evidence to support use of MTX in PsA is based on observational study data. In the reevaluation of the efficacy of MTX in the University of Toronto PsA registry, they reported that patients in the 1994 to 2004 cohort had shorter disease duration and received higher MTX doses (16.2 vs 10.8 mg/wk) compared with the 1978 to 1993 cohort. In this cohort, 68% had 40% or greater decrease in swollen joint counts and less radiographic progression, compared with the earlier cohort (1.5 [SD, 1.8] vs 2.3 [SD, 1.2] increase in radiographic damage score as assessed by the modified Steinbrocker method, respectively), suggesting that, with higher MTX doses, there may be better response with less progression of damage. Cantini and colleagues reported a remission rate (using very strict remission criteria) of 19%, and ACR20/50/70 responses in 34%, 23%, and 10%, respectively, in 121 patients with peripheral PsA treated with MTX monotherapy. In the Norwegian DMARD registry, effectiveness and retention rate of MTX was compared in 430 patients with PsA and 1280 patients with rheumatoid arthritis (RA). After 6 months of MTX treatment, both PsA and RA patients improved in most disease activity measures and patient-reported outcomes. MTX retention rates at 2 years, providing indirect evaluation of efficacy and toxicity, were 65% and 66% in PsA and RA patients, respectively.

In an open-label study, 115 patients with mild PsA were randomized to MTX or MTX plus infliximab. Although patients on combination therapy achieved significantly better response, ACR20/50/70 responses were observed in 67%, 40%, and 19%, respectively of patients treated with MTX monotherapy. Recently, a study in Japanese patients was published. Fifty-one PsA patients treated with TNFi plus MTX or MTX alone were investigated retrospectively. Both treatments were equally effective in reducing clinical activity.

One of the intriguing issues with MTX is the difference in toxicities observed between patients with RA compared with patients with psoriasis or PsA. A recent cross-sectional study confirmed that pulmonary toxicity was more common in RA patients compared with patients with PsA, and that hepatotoxicity was more common in PsA patients. A metaanalysis of long-term MTX treatment studies in RA and psoriatic disease showed a 3-fold greater risk of hepatic fibrosis in patients with psoriatic disease. The reasons for such differences may be related to higher rates of obesity and fatty liver, and these results may justify different toxicity monitoring protocols for patients with psoriatic disease. This subject was discussed at the 2007 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) meeting related to MTX toxicity. The attendees reached the following consensus. Insufficient data exist to recommend or not recommend serial liver biopsies, but the presence of other risk factors may help to guide decision making. Although data are insufficient to form strong recommendations, in practice small amounts of alcohol are probably safe. Three months off treatment before conception for both female and male partner is appropriate. The combination of MTX with SSZ or with an anti-TNF agent is safe; much less consensus existed regarding the combination of MTX with leflunomide or with cyclosporine.

Leflunamide

Leflunamide was significantly superior to placebo in a 24 week RCT in 186 patients based on improvements in PsARC, tender and swollen joint scores, Health Assessment Questionnaire, and Dermatology Life Quality Index. More recently, the results on a multinational observational study in 440 patients with active PsA treated with leflunamide were reported. At 24 weeks, 86% of patients achieved a PsARC response with significant improvements also seen in tender and swollen joint count, patient and physician global assessments, fatigue, skin disease, dactylitis, and nail lesions. Results on 85 patients followed at the University of Toronto PsA Clinic who received leflunamide (43 patients) alone or in combination with MTX (42 patients) were published. Of the 55 patients who continued the drug, 38%, 48%, and 56% achieved a 40% or greater reduction of actively inflamed joint count at 3, 6, and 12 months, respectively. Although MTX did not modify arthritis response, psoriasis did improve. Patients taking MTX in combination with leflunomide were more likely to achieve a Psoriasis Area and Severity Index (PASI50) response than patients taking leflunomide alone.

Sakellariou and colleagues found that, among 11 patients who received leflunamide in combination with MTX owing to inadequate MTX response, 7 demonstrated moderate improvement and 1 was a nonresponder based on the European League Against Rheumatism (EULAR) response criteria.

Related to safety, withdrawal owing to toxicity was almost 4 times more frequent with leflunomide than with placebo in a published metaanalysis. In the European study, 13% of patients experienced adverse events; the more frequent ones included diarrhea (16.3% of all ADR), alopecia (9.2%), hypertension (8.2%), and pruritus (5.1%). Only 3 adverse events were serious, affecting 2 patients, and none of the unexpected adverse events was considered serious by the investigator. Importantly, addition of leflunomide to concomitant DMARDs (93 patients, most of them with leflunamide plus MTX, followed for 24 weeks) did not lead to an increase in adverse events.

Sulfasalazine

In a systematic review, 6 RCT compared SSZ with placebo. SSZ demonstrated efficacy in PsA, although effect size was very low, and there is no effect on other manifestations such as enthesitis.

SSZ does not seem to halt radiographic progression in PsA. In a case-control study, 20 patients who received SSZ for more than 3 months were compared with 20 control patients. The mean change in the radiographic score at 24 months between the 2 groups was not significant. A trend has been observed in most of the RCT toward higher withdrawal rates in the SSZ group compared with the placebo group, mostly related to adverse events, such as gastrointestinal intolerance, dizziness, and liver toxicity, which have been observed in up to one-third of patients receiving SSZ.

Cyclosporine is rarely used for the treatment of PsA and is not included in this review.