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Window of Opportunity for Treating Early Rheumatoid Arthritis

June 14, 2007

Chris Berrie

A window of opportunity exists for intensive combination therapy with the disease-modifying antirheumatic drugs (DMARDs) methotrexate (MTX) and cyclosporine and/or the corticosteroid prednisone, providing significant sustained benefits on damage and disability for patients with early rheumatoid arthritis (RA).

These data from the multicenter, randomized, double-blind, factorial Combination of Anti-Rheumatic Drugs in Early RA (CARDERA) trial were presented here by principal investigator Ernest H. Choy, MD, director, Sir Alfred Baring Garrod Clinical Trials Unit, King's College London, London, United Kingdom, at the Annual European Congress of Rheumatology (EULAR).

"Rheumatoid arthritis progresses very rapidly during the early phases, which is the reason why we inverted the treatment pyramid and argued that the patient should be started promptly on disease-modifying antirheumatic drugs," said Dr. Choy in an oral presentation on June 13th on behalf of the CARDERA investigators.

Randomized clinical trials have suggested an early window of opportunity for the treatment of patients with RA, whereby optimal conventional therapy can change the disease course by the addition of corticosteroids and DMARDs.

As there remains a lack of randomized trials that allow definition of the relative contributions of these agents, the CARDERA trial was designed to answer this through a factorial design using a 2x2 treatment box.

According to Dr. Choy, patients in the study were divided into four groups: one group received methotrexate alone, one received methotrexate and cyclosporine, a third group received methotrexate and corticosteroids, and the last group received all three agents together.

All patients were treated at a target dose methotrexate of at 15 mg/week, with the option to increase to 25 mg/week. For prednisone, the COBRA treatment regime was followed for a total of 9 months, tapered daily doses from 60 mg (weeks 1, 2) to 7.5 mg (weeks 7-28) to withdrawal (week 35). Cyclosporine was started 3 months after the start of methotrexate, in case of early toxicity problems, and it was raised from 100 mg/day to the 3-mg/kg/day target dose, again with the option to go to 5 mg/kg/day.

The inclusion criteria were early RA with active synovitis, disease no more than 2 years prior to study entry. Patients previously treated with methotrexate were excluded, as were patients with contraindications to the trial drugs.

Primary outcome was the proportion of patients with one or more new erosions on x-rays of hands and feet at 24 months. Secondary outcomes were total Larsen score, disease activity score, disability score on the Health Assessment Questionnaire (HAQ), number of serious adverse effects, and quality-of-life 36-question Short Form Questionnaire. All assessments were performed every 6 months.

From the initial 1,391 patients assessed for eligibility, 467 were randomized to one of four treatment groups: 117 to methotrexate (mean age, 54 years; male, 34%); 119 to MTX+C (mean age, 53 years; male, 34%); 115 to methotrexate + prednisone (mean age, 54 years; male, 22%); and 116 to methotrexate + cyclosporine + prednisone (mean age, 55 years; male, 33%). The groups were similar in terms of baseline clinical characteristics.

More than 60% of the patients were rheumatoid factor positive, about 20% of patients had rheumatoid nodules, and 30% of patients had erosions.

In comparison with methotrexate alone, addition of cyclosporine and prednisone either alone or in the triple combination resulted in 50% fewer new erosions.

For the disease activity score, as a scale of 1 to 9, a reduction of 1.2 provided a moderate to good response. Addition of prednisone to methotrexate resulted in a rapid decrease in disease activity, although when it was withdrawn (after 9 months) there was recurrence of disease activity, with no benefits by the end of 24 months.

"Interestingly," indicated Dr. Choy, "despite the 50% reduction in radiographic damage by cyclosporine, there was really no difference in the disease activity score between methotrexate only and methotrexate plus cyclosporine, so whatever cyclosporine achieved, it did so independently from the disease activity control of inflammation."

For the HAQ score, triple therapy was best by end of the study, and according to the factorial trial design, prednisone plus cyclosporine were significantly more beneficial according to the HAQ score than either drug alone (P =.01). The same was seen for the quality-of-life scores.

Dr. Choy also described a more detailed consideration of the progression of erosive damage over the 2-year period, indicating lower erosive damage with prednisone in year 1, and methotrexate and cyclosporine in year 2.

No differences were seen in serious adverse events across the four treatment groups, with the exception of hypertension, which was associated with cyclosporine use.

Therefore, in patients with early RA, there is this window of opportunity whereby the 50% reduction in structural damage provided by 9 months of step-down corticosteroids is maintained at 2 years. Furthermore, cyclosporine also reduced structural damage by 50% in an effect that was independent of any reduction in disease activity, and cyclosporine and prednisone showed a statistically significant positive interaction on the improvement of patient physical function.

The study drugs with placebo were provided by Novartis and Wyeth.

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