PATIENTS, METHODS, AND RESULTS

A cohort of 93 patients with active and severe RA was observed for a mean duration of 8 months (range 1–20). The group comprised 75 women, 18 men, with an average age of 49.5 years (range 17–75), and positive rheumatoid factor in 67 (72%). All had been previously treated with a median of four disease modifying antirheumatic drugs (DMARDs). The mean disease duration was 12.4 years (range 3–42). Patients were treated with subcutaneous injections of etanercept alone, 25 mg twice weekly. Eighteen of the 93 patients had an inadequate response (did not reach the American College of Rheumatology (ACR) 20 criteria, prerequisite for inclusion in this cohort) with etanercept alone; we therefore added MTX to the treatment, no other DMARDs being allowed. The mean dose of added MTX was 15.5 mg a week. The dosage was given orally to 12 patients and intramuscularly to the remaining six. All 18 patients (16 female, two male, average age 51 years, mean disease duration 13.3 years, with a positive rheumatoid factor in 14 (78%) patients) had previously received MTX before etanercept alone, but it had produced an insufficient result. This failure with MTX was a requirement before starting etanercept. A prospective follow up of these patients took place every month for 3 months and from then on every 3 months during a 12 month period, with recording of the usual clinical and biological measures in order to obtain the ACR20, 50, and 70 and the Disease Activity Score 28 (DAS28). This enabled us to assess the efficacy of this addition. The Health Assessment Questionnaire (HAQ) was also used in this study.

Table 1 summarises the results obtained. The data show an improvement in disease activity, which was sustained through the 12 month follow up. A favourable response was obtained at 3 months with 10 (56%) achieving the ACR20, 5 (28%) the ACR50, and 2 (11%) the ACR70. At 12 months of this combination therapy, 12 (67%) had achieved the ACR20, 9 (50%) the ACR50, and 3 (17%) the ACR70. DAS28 decreased from 4.9 to 3.0 at 3 months and to 2.4 at 1 year, suggesting a significant clinical improvement in disability. The HAQ score changed from 1.7 to 1.1 at 1 year.

There was also a rapid therapeutic biological response, with a decrease in the erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) of 50% after 3 months. No serious adverse events were reported and only two patients required antibiotics (bronchitis, urinary infection).

DISCUSSION

In summary, this open study suggests that the secondary addition of MTX to etanercept produced a marked improvement among patients who had had an inadequate response to etanercept alone after a first inadequate response to MTX given alone. To our knowledge, this is the first open study to evaluate the efficacy of MTX in addition to etanercept in a two step strategy. Previous studies have demonstrated the efficacy of etanercept alone compared with MTX,² its efficacy in early RA³ or in addition to methotrexate,¹ and, in particular, in juvenile idiopathic arthritis.⁴ This suggests that when MTX is added to the etanercept regimen patients with RA improve both clinically and biologically without any increase in side effects. The addition of MTX to the treatment of patients who respond incompletely to etanercept alone may be useful in the management of RA. It will be interesting to evaluate this strategy in further studies. Therefore, the preferred treatment for RA may very well be the combination of MTX plus a TNF antagonist.