Etanercept (Enbrel^®)
Adalimumab (Humira™)
Infliximab (Remicade™)

Etanercept (Enbrel^®)
WYETH SATELLITE SYMPOSIUM (no abstract available)

In a satellite symposium, data were presented from the TEMPO comparing a combination of entanercept (Enbrel^®) and methotrexate (MTX) with either therapy alone in patients with established rheumatoid arthritis.

Methods: TEMPO is a multicenter, double-blind, placebo-controlled study conducted in 92 centers in Europe and Australia. 682 patients with active RA with an average disease duration of 6 years who were TNF inhibitor nave and had failed at least one DMARD agent not including methotrexate were randomized to one of three arms:

• etanercept (25 mg 2x weekly) plus MTX (mean dose 17 mg 1x weekly);
• etanercept (25 mg 2x weekly) plus placebo pills (1x weekly);
• placebo injections (2x weekly) plus MTX (mean dose 17 mg 1x weekly).

Results: In the 682 patients recruited, mean duration of disease was 6.6 years (1-26). 43% of patients had been on methotrexate in the past; all patients were TNF inhibitor nave per protocol.

The ACR response data and Sharp score data are presented below:

The ACR responses for etanercept + methotrexate were statistically signifcant by comparison with etanercept alone and methotrexate alone.

No radiographic progression was detected in 80% of patients treated with combination therapy compared with 68% of patients treated with etanercept alone and 57% of patients treated with methotrexate alone.

Conclusion: These data suggest that for the treatment established rheumatoid arthritis, the combination of etanercept and methotrexate provides greater symptom relief and reduction in radiographic progression than monotherapy of either etanercept or methotrexate.

Editorial Comment: This study is the best study to date demonstrating the benefits of combination therapy with a TNF inhibitor plus methotrexate over either agent alone . Previous studies of combination therapy added a TNF inhibitor to patients with an inadequate response to methotrexate. The infliximab Aspire trial also reported at Eular (see below) could not compare the combination with a TNF inhibitor alone because of the need to use infliximab with methotrexate. The comparison of etanercept alone with methotrexate alone reproduces the results seen in the etanercept ERA trial , in which methotrexate compared favorably both clinically and radiographically to etanercept in early RA patients at one year. However in this trial, unlike the ERA trial, radiographic progression clearly favored etanercept. However there are some caveats. This is an unusual patient population and difficult to reproduce in the U.S. because so many patients were methotrexate nave despite many years of disease. In addition, patients could not have failed methotrexate because of lack of tolerance, side effects or lack of efficacy, yet 43% of patients had prior exposure to methotrexate. What was the reason for discontination? Nonetheless the study is well designed and the numbers are indeed impressive. This clearly adds credibility to the approach of combination methotrexate and TNF inhibitor therapy.

The current dosing regimen for Etanercept is 25mg, twice weekly (biw). The purpose of this double-blind study was to compare a one weekly dose (qw) of 50 mg Etanercept to placebo and to compare its safety and efficacy to the 25 mg biweekly dosing.

Methods: 420 patients with active RA were randomized to one of 3 arms: 50mg qw Etanercept (n=214) for 16 weeks; placebo for 8 weeks followed by 8 weeks of 25mg biw Etanercept (n=53); 25mg biw Etanercept for 16 weeks. All patients received the same number of weekly injections. ACR 20 response was the primary endpoint.

Results: There was no significant difference in the number of patients achieving ACR 20 between the two Etanercept dosing groups.

Additionally at weeks 8 and 16, all other disease activity measurements were comparable between the two Etanercept dosing groups and significantly improved when compared to the placebo group. The following table shows data for week 16 assessments.

A single weekly injection of 50mg of Etanercept has comparable safety and efficacy to biweekly injections of 25mg Etanercept and is significantly more effective than placebo in treated patients with RA.

Conclusion: Serious adverse events were similar in both Etanercept groups, 1.9% in patients treated with 50mg qw and 5.2% in patients treated with 25mg biw. No serious adverse events occurred in the placebo group.

Editorial Comment: The demonstrated equivalence of once weekly and twice weekly dosing will bring added convenience for our patients on etanercept. We await a single syringe 50 mg dose.

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Adalimumab (Humira™)
THU0271 ADALIMUMAB INHIBITS RADIOGRAPHIC DISEASE PROGRESSION IN LONG-STANDING, RAPIDLY PROGRESSIVE RHEUMATOID ARTHRITIS
R Rau, G Herborn, LBA van de Putte

The data reported in the study are results from an open label extension period (year 2) following a double blind, placebo controlled trial (year 1). (see results from year 1 data). The purpose of the study was to investigate the effects of adalimumab monotherapy on radiographic disease progression over a 2-year period in patients with active RA.

Methods: 284 patients were entered in the initial Phase II study. Of these, 163 patients participated in the second year and received open-label treatment of weekly 40 mg adalimumab s.c. injections with methotrexate (MTX). Primary endpoints included change in Total Sharp Score and Ratingen score.

Results: Inhibition of the progression of structural joint damage in patients receiving adalumimab treatment in the first year was maintained throughout the second year of treatment. Ratingen scores were 30% (year 1) and 25% (year 2) of predicted progression rate. Basically, the improvements observed during the first year of treatment (see data) remained unchanged during the second year of treatment.

Conclusions: Adalumimab treatment (40 mg weekly) continued to significantly inhibit radiographic progression in patients with RA as measured by Sharp and Ratingen scores at 24 months.

Editorial Comments: This open-label, study is consistant with the first year data showing that adalimumab, when given in combination with MTX, inhibits the progression of structural joint damage .

This study assesses the efficacy of long-term adalumimab treatment of more than 4 years in patients with RA.

Methods: RA patients from multiple European phase I, II or III clinical trials with adalumimab were eligible to continue in an open-label extension and were offered 40 mg s.c. injections of adalumimab every other week for at least 2 more years. Dosing could be increased to 40 mg weekly depending on DAS28 response scores. 10% of patients received concomitant methotrexate therapy.

Results: Of 794 patients who entered the open-label extension, 1-, 2-, 3-, 4- and 5-year data were available for 680, 621, 306, 173 and 48 patients, respectively. The following table shows the efficacy results for patients treated with adalimumab.

The rate of serious infections was 0.037/patient years. 76% of patients who entered the study remain on therapy. Adverse events (5.9%), lack of efficacy (13.5%), and other (4.5%) were reasons for withdrawal. Rate of serious adverse events (0.20) and serious infections (0.04) for long-term therapy were comparable to those of the controlled trial (0.40 and 0.06, respectively).

Conclusions: Improvements in all measurements, including ACR response, TJC, and SJC, were sustained into the 5th year of treatment with long-term adalimumab in patients with RA.

Editorial Comments: This is strong information supporting the durability of response to adalimumab. Similar durability has also been reported with etanercept. These findings are remarkable given the long history of other DMARDs failing to provide continued therapeutic benefit over time.

Studies on treatment generally focus on sustained efficacy of therapy over time. The purpose of this study was to evaluate the impact of prolonged dose interruptions on the efficacy and safety of adalimumab upon re-initiation of therapy.

Methods: 119 RA patients receiving adalimumab in clinical trials who experienced an interruption of therapy (>70 days) were included in this evaluation. ACR responses at the visit prior to stopping treatment were compared to the responses at the two visits immediately following resumption of treatment.

Results: The mean length of adalimumab treatment prior to interruption was 214 days. The amount of time of therapy interruption was < 140 days for 99 patients and > 140 days for the remaining 20 patients. Upon reinitiating therapy, the majority of patients (65%) had no change in ACR 20 response. 9% lost their ACR 20 response. Of patients who were ACR non-responders prior to interruption, 26% became ACR 20 responders. The types and frequencies of adverse events 3 months prior to and 3 months after re-initiation of adalimumab therapy were comparable. No allergic responses were noted following resumption of therapy.

Conclusions: Adalimumab treatment can be safely resumed following a prolonged interruption in therapy.

Editorial Comments: The need to stop a DMARD agent is a common clinical situation often caused by co-morbidities, surgery or lack of insurance coverage. It is reassuring that in the case of adalimumab, interruption does not appear to adversely affect response after re-initiating therapy. It is interesting that the response actually appears to increase after the interruption, raising the question of using a drug holiday to increase effectiveness.

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Infliximab (Remicade™)
OP0001 TREATMENT OF EARLY RHEUMATOID ARTHRITIS WITH INFLIXIMAB PLUS METHOTREXATE OR METHOTREXATE ALONE: PRELIMINARY RESULTS OF THE ASPIRE TRIAL
JS Smolen, P Emery, J Bathon, E Keystone, RN Maini, J Kalden, D Baker, B Wang, K De Woody, D van der Heijde, E St Clair

Infliximab has been shown to be highly effective in reducing the signs and symptoms of rheumatoid arthritis and in preventing radiographic joint damage. Infliximab is often started only after patients have failed methotrexate therapy and have already suffered significant joint destruction and disability. This study compares the safety and efficacy of infliximab plus methotrexate versus methotrexate alone in early RA.

Methods: 1049 patients with RA of greater than 3 months duration but less than 3 years duration, with active disease (SJC > 10, TJC >12), were randomized to three treatment groups: MTX plus placebo infusions or MTX plus infliximab 3 mg/kg or 6 mg/kg administered at weeks 0, 2, 6 and every 8 weeks. MTX in all groups was titrated to 15 mg/week by week 4 and 20 mg/week by week 8. All patients were either RF positive, had erosions on x-ray or CRP > 2.0 mg/dl. Outcomes were ACR-N; ACR 20, 50, 70; disability and radiographic progression at week 54.

Results: Therapy was well tolerated in all groups. Discontinuations due to adverse events were 9% in the active infliximab arms and 3% in the MTX only arm. Discontinuations due to lack of efficacy was 9% in the MTX arm versus 1-2% in the infliximab arms.

Changes in radiographic damage as assessed by changes in Sharp scores showed a mean change of 3.5 in the MTX only arm and mean changes of less than 0.5 in the infliximab arms.

Conclusions: The addition of infliximab to methotrexate in early RA clearly improves signs and symptoms and prevents radiographic joint damage.

Editorial Comments: This is compelling evidence to support the early use of TNF inhibitors in the treatment of RA. However, similar to the etanercept early RA trial, which this trial is patterned after, MTX does well for a significant number of patients. The question is whether this information will convince rheumatologists to use a TNF inhibitor together with MTX as initial therapy or wait to add a TNF inhibitor only in those who fail MTX.

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