Elsevier

The Lancet

Volume 359, Issue 9313, 6 April 2002, Pages 1173-1177
The Lancet

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Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study

https://doi.org/10.1016/S0140-6736(02)08213-2Get rights and content

Summary

Background

Methotrexate is the most frequent choice of disease-modifying antirheumatic therapy for rheumatoid arthritis. Although results of studies have shown the efficacy of such drugs, including methotrexate, on rheumatoid arthritis morbidity measures, their effect on mortality in patients with the disease remains unknown. Our aim was to prospectively assess the effect on mortality of methotrexate in a cohort of patients with rheumatoid arthritis.

Methods

Our cohort included 1240 patients with rheumatoid arthritis seen at the Wichita Arthritis Center, an outpatient rheumatology facility. Patients' details were entered into a computerised database at the time of their first clinic visit. We also obtained and recorded demographic, clinical, laboratory, and self-reported data at each follow-up visit (average interval 3·5 months). We estimated the mortality hazard ratio of methotrexate with a marginal structural Cox proportional hazards model.

Findings

191 individuals died during follow-up. Patients who began treatment with methotrexate (n=588) had worse prognostic factors for mortality. After adjustment for this confounding by indication, the mortality hazard ratio for methotrexate use compared with no methotrexate use was 0·4 (95% CI 0·2–0·8). Other conventional disease-modifying antirheumatic drugs did not have a significant effect on mortality. The hazard ratio of methotrexate use for cardiovascular death was 0·3 (0·2–0·7), whereas that for non-cardiovascular deaths was 0·6 (0·2–1·2).

Interpretation

Our data indicate that methotrexate may provide a substantial survival benefit, largely by reducing cardiovascular mortality. This survival benefit of methotrexate would set a standard against which new disease-modifying antirheumatic drugs could be compared.

Introduction

Rheumatoid arthritis is a chronic progressive disease associated with systemic inflammation. The disease directly affects physical function and mobility and results in substantial short-term and long-term morbidity. Furthermore, individuals with rheumatoid arthritis have a substantially shorter life expectancy than does the general population.1, 2, 3 Deaths from cardiovascular disease, infection, and cancer are increased among individuals with rheumatoid arthritis.1, 2, 3, 4

A number of disease-modifying antirheumatic drugs exist, and low-dose methotrexate is the main choice.5 Although results of many clinical trials and their follow-up studies suggest that these drugs, including methotrexate, are effective in reducing morbidity measures (rheumatoid arthritis specific outcomes and relevant quality of life measures), their effect on mortality in patients with rheumatoid arthritis remains unknown. Our aim was to assess the potential survival benefit conferred by methotrexate given to individuals with rheumatoid arthritis.

Section snippets

Study data

Since 1974, we have enrolled more than 2000 consecutive individuals with rheumatoid arthritis seen at the Wichita Arthritis Center, an outpatient rheumatology facility. We entered details of participants into a computerised database at the time of their first clinic visit, and obtained and added demographic (education level, smoking history, total income, and marital status), clinical (tender joint count, grip strength, morning stiffness, health assessment questionnaire disability index score,6

Results

1240 individuals with rheumatoid arthritis met our inclusion criteria. The mean length of follow-up until death or censoring was 6 years (SD 5; 91 007 total person-months). By the end of follow-up, 588 patients had received methotrexate (mean dose 13 mg per week; maximum dose 25 mg per week) and 191 had died. Of these 191 participants, 72 had been treated with methotrexate (37 594 exposed person-months). The mean number of months between clinic visits was 3·3 (2·3) in methotrexate users and 3·6

Discussion

Our results indicate that methotrexate was initiated more often in individuals who had severe rheumatoid arthritis. After adjustment for this confounding factor, we noted a 60% reduction in risk of mortality in patients treated with methotrexate. By contrast, we did not observe a comparable reduction in mortality associated with other conventional disease-modifying antirheumatic drugs, suggesting that there might be a differential survival benefit with methotrexate.

Cardiovascular deaths were

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