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PRIORITY PRESS - 18th Congress of the European Academy of Dermatology and Venereology

Berlin, Germany / October 7-11, 2009

The disease-modifying antirheumatic drug (DMARD) methotrexate (MTX) has demonstrated efficacy in the treatment of moderate to severe psoriasis for more than 40 years. A recent National Psoriasis Foundation Consensus Conference reaffirmed its value in psoriasis. However, the consensus conference task force also noted that its long history of clinical experience has limited support from evidence-based clinical studies (J Am Acad Dermatol 2009;60:824-37).

RESTORE1 Trial

In RESTORE1, one of the largest-ever evidence-based clinical studies of psoriasis therapy, European investigators conducted a randomized, open-label comparison of the tumour necrosis factor-a (TNF-a) inhibitor infliximab and MTX. The study involved adult patients aged 18 to 75 who had plaque-type psoriasis of moderate to severe classification, characterized by a Psoriasis Area and Severity Index (PASI) score <u>></u>12, an involvement of <u>></u>10% of body surface area (BSA) and a duration of <u>></u>6 months.

“The trial provided an opportunity to compare infliximab and MTX as the first treatment for patients with psoriasis who had not responded adequately to topical treatment,” noted Dr. Kristian Reich, Dermatologikum Hamburg, Germany.

Investigators randomized patients 3:1 to the TNF-a inhibitor administered at a dose of 5 mg/kg weekly at baseline and on weeks 2, 6, 14 and 22 or MTX started at a weekly oral dose of 15 mg/week, which could be increased to 20 mg/week for patients who did not have at least a 25% reduction from baseline in PASI score by week 6.

The primary end point was the proportion of patients who achieved at least 75% improvement in the PASI (PASI 75) by week 16. Patients who had less than a PASI 50 response at 16 weeks were switched to the opposite therapy and follow-up continued to week 26.

Dr. Reich presented findings for a total of 868 patients, 653 randomized to infliximab and 215 to MTX. About 70% of the patients were male, their mean age was about 43 and their disease duration averaged about 18 years. The BSA affected by psoriasis averaged about 31% in both groups, and baseline PASI score averaged 21.

Findings

At 16 weeks of treatment and follow-up, 77.7% of patients in the TNF-a inhibitor-treated group had achieved a PASI 75 response compared with 41.8% of the MTX patients (P<0.001). The proportion of patients who had at least PASI 90 clearance of skin lesions by week 16 was 54.5% with the biologic and 20% with MTX (P<0.001) (Figure 1).

Figure 1.

Dr. Reich reported, “Infliximab had a significantly more rapid onset of action as determined by early response rates. More infliximab-treated patients had objective responses at all time points, and significant differences between the treatment groups were apparent as early as week 2.” A continued advantage in favour of the biologic was reported at 26 weeks with 77% of patients achieving PASI 75 responses compared with about 31% of the MTX group (P<0.001). Notably, PASI 90 response rates were 51% and 15% with infliximab and MTX, respectively (P<0.001).

Patients who switched to infliximab because of inadequate response also benefited. Among patients switched to the TNF-a inhibitor at week 16, 73% had achieved PASI 75 responses by week 26.

“The discontinuation rates for the study were 17% with infliximab and 41% with MTX,” observed Dr. Reich. “The principal reasons for discontinuation were infusion-site reactions in the infliximab group and lack of response in the MTX group.”

Comparable Safety

Rates of adverse events were similar between the biologic and the DMARD at 72% and 67%, as were serious adverse events (7% and 3%), respectively. Liver abnormalities leading to discontinuation occurred in 1% to 2% of patients in each group. Infusion-site reactions led to discontinuation of 4% of patients in the TNF-a inhibitor group. “The patients were treated in community clinics, so these are real-world numbers,” Dr. Reich told delegates. “The results of this trial demonstrate early and sustained superiority of infliximab over MTX for the treatment of moderate to severe plaque-type psoriasis,” he concluded. “Both drugs were used safely and no unanticipated safety events were observed.”

Quality of Life Findings

Studies have shown that psoriasis significantly and adversely affects quality of life (QoL). Placebo-controlled clinical trials have shown that TNF-a inhibitors significantly improved QoL in psoriasis patients (Reich et al. Br J Dermatol 2006;154:1161-8; Feldman et al. JAAD 2005; 53:887-9). However, the relative effects of infliximab and MTX on QoL had not been compared previously. Dr. Reich and colleagues presented data from a separate analysis of the randomized clinical trial, focusing on health-related QoL, as assessed by the Dermatology Life Quality Index (DLQI). Patients’ baseline DLQI scores averaged 13.5 in the infliximab group and 13.8 in the MTX group.

Consistent with the response data, DLQI scores revealed a significant advantage in favour of the biologic. Change from baseline in the TNF-a inhibitor group averaged -11.4 at week 10, -11.6 at week 16 and -11.3 at week 26. Mean changes in the MTX group at the same time points were -7.9 (P<0.001), -8.95 (P<0.001), and -9.14 (P=0.004). Both treatments improved health-related QoL. The mean DLQI score at 26 weeks had decreased to 2.24 with infliximab and 5.25 with MTX.

Scores on the short-form 36 (SF-36) health assessment instrument also revealed improvement in health-related QoL. An improvement of <u>></u>5 points on the physical or mental component of the SF-36 was considered a clinically meaningful improvement in health-related QoL. The physical component of the SF-36 improved significantly more with infliximab compared with MTX at week 10 (5.5 vs. 3.0, P<0.001) and week 16 (5.53 vs. 3.76, P=0.002) and was numerically superior at week 26 (4.38 vs. 3.68). The TNF-a inhibitor group had significantly more improvement in the SF-36 mental component at week 10 (7.94 vs. 5.63, P=0.011) and numerically greater improvement at weeks 16 (7.85 vs. 6.12) and 26 (8.03 vs. 6.72).

A third measure of QoL also showed a significant advantage for treatment with infliximab. The EuroQoL 5D (EQ-5D) index is a standardized, non-disease-specific scale of health outcomes applicable to a variety of clinical settings.

The EQ-5D score averaged about 0.7 in both groups at baseline. The mean value was significantly greater in the MTX group at all time points: week 10, 0.86 vs. 0.81, P<0.001; week 16, 0.86 vs. 0.84, P=0.005; week 26, 0.86 vs. 0.81, P=0.002. “Improvements in quality of life were consistently greater in the infliximab group compared with the MTX group, as confirmed in the DLQI, SF-36 and EQ-5D analyses,” Dr. Reich and colleagues concluded in a poster presentation.

Summary

The QoL improvement reflected the clinical response data which showed that significantly more patients treated with the TNF-a inhibitor achieved a PASI 75 response by week 16 (the primary end point), as confirmed by investigators here at the EADV. The advantage in favour of infliximab emerged early in the course of the trial and persisted to the end of follow-up at 26 weeks. Also, a significant proportion of inadequate responders to MTX who switched to the biologic at week 16 achieved a PASI 75 response at week 26.