Objective. To compare the efficacy of doxycycline plus methotrexate (MTX) versus MTX alone in the treatment of early seropositive rheumatoid arthritis (RA), and to attempt to differentiate the antibacterial and antimetalloproteinase effects of doxycycline.Methods. Sixty-six patients with seropositive RA of <1 year's duration who had not been previously treated with disease-modifying antirheumatic drugs were randomized to receive 100 mg of doxycycline twice daily with MTX (high-dose doxycycline group), 20 mg of doxycycline twice daily with MTX (low-dose doxycycline group), or placebo with MTX (placebo group), in a 2-year double-blind study. Treatment was started with an MTX dosage of 7.5 mg/week, which was titrated every 3 months until remission was reached (maximum dosage of 17.5 mg/week). The primary end point was an American College of Rheumatology 50% improvement (ACR50) response at 2 years.Results. ACR50 responses were observed in 41.6%of patients in the high-dose doxycycline group, 38.9% of those in the low-dose doxycycline group, and 12.5% of patients in the placebo group. Results of chi-square analysis of the ACR50 response in the high-dose doxycycline group versus that in the placebo group were significantly different (P ‫؍‬ 0.02). Trend analysis revealed that the ACR20 response and the ACR50 response were significantly different between groups (P ‫؍‬ 0.04 and P ‫؍‬ 0.03, respectively). MTX doses at 2 years were not different among groups. Four patients in the high-dose doxycycline group, 2 patients in the low-dose doxycycline group, and 2 patients in the placebo group were withdrawn because of toxic reactions. Conclusion. In patients with early seropositive RA, initial therapy with MTX plus doxycycline was superior (based on an ACR50 response) to treatment with MTX alone. The therapeutic responses to low-dose and high-dose doxycycline were similar, suggesting that the antimetalloproteinase effects were more important than the antibacterial effects. Further studies to evaluate the mechanism of action of tetracyclines in RA are indicated.

ReplySchned and coworkers raise an important issue. Can research done in academic settings be generalized to community practice? This is a pervasive issue in the medical literature since most clinical research is undertaken in academic settings.Indeed, the clinicians involved in the development of the SLEDAI were from teaching and research settings. The patients' profiles were generated from a center with a mix of primary, secondary, and tertiary care patients. However, primary care patients were well represented; 70% of the patients came to the clinic within 1 year of diagnosis and 50% of the patients were first diagnosed at the clinic. We believe that a significant portion of patients can be considered "primary care patients." Nonetheless, as Schned et a1 propose, the index needs to be validated in various settings to test its generalizability. We have already undertaken this process. The SLEDAI has recently been tested internationally (1-4). It was compared in 8 European and 6 American centers (on their own local patients) against two other indices, the BILAG (British Isles Lupus Assessment Group) ( 5 ) and the SLAM (Systemic Lupus Activity Measure) (6). It was also assessed by 8 rheumatologists from 4 countries who examined and evaluated the same patients. The results showed that these indices were comparable and reproducible for evaluating disease activity in SLE.The 3 instruments (SLEDAI, BILAG, and SLAM) were recently tested for their sensitivity to change in disease activity, by 8 rheumatologists from 4 countries (7). Also, the usefulness of the SLEDAI has been demonstrated not only by the expert clinicians who participated in its generation, but also by other rheumatologists who treat lupus patients as well as by less experienced clinicians such as rheumatology fellows (8).Schned and colleagues' question can only be answered by continuing the process of evaluating the SLE-DAI's feasibility and practicability in various settings. Derivation of the SLEDAI To the Editor:We enjoyed reading the recent article by Bombardier et a1 in which a nominal group technique was used to develop an index of disease activity in systemic lupus erythematosus (SLE) (Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH, and the Committee on Prognosis Studies in SLE: Derivation of the SLEDAI: a disease activity index for lupus patients. Arthritis Rheum 35:630-640, 1992). In conjunction with indices for assessing damage from disease and health status, which hopefully will be developed, the SLEDAI promises to be an important tool for outcomes assessment in clinical and research settings.As the authors explain, this index relies on a "judgmental, rather than an empirical, approach." It should be emphasized, then, that it reflects the collective clinical judgment of this particular group of academic-based rheumatologists and methodologists. The raters were described as "experienced 'lupologists' . . . engaged in the study of methods for assessing disease activity at their own institutions. " There is no question about the ex...

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