Combination therapy in rheumatoid arthritis

Abstract

Authors' reply Sir—With respect to our comparison of single-drug disease-modifying antirheumatic drug (DMARD) with combination therapy in early rheumatoid arthritis, Maarten Boers raises several interesting points, and suggests that the benefit of combination therapy could be based on the effect of oral glucocorticoids. Before the start of the trial, three and four patients had temporarily been treated with systemic glucocorticoids in combination and single-drug therapy, respectively. Further, 27 (27%) patients in the single-drug therapy group were treated with oral glucocorticoids from baseline and in 36 further patients, low-dose glucocorticoid treatment was started later with a median of 6 (range 0–93) weeks from the onset of the trial. 20 (21%) of the patients on single-drug therapy were switched from sulphasalazine to methotrexate because of adverse effects. Most of these events occurred during the first 6 months. The other switches were mainly made because of inefficacy. 21 (41%) of these 51 cases were already on prednisolone. We stated that a treatment was discontinued due to adverse effects 23 and 22 times in combination therapy and single-drug therapy groups, respectively. These figures represent the frequencies of occurrences not the number of patients. As our table 3 indicates, 51 patients were switched to methotrexate, but 18 of them were later switched further from methotrexate to other DMARDs. No patient was treated with only glucocorticoids for long periods. In our FIN-RACo trial, remission was assessed only at given check-up visits. Thus, we do not have the information regarding the duration of remission. However, the respective frequencies of the patients in remission at every follow-up visit during the second year of the study (at 12, 18, and 24 months) were 21 (22%) and 10 (10%) in the combination therapy and single-drug therapy groups (p<0·05). The rate of radiographic destruction differed constantly in both treatment groups. The median numbers of eroded joints at 0, 12, and 24 months in the single-drug therapy and combination therapy groups were 1 (IQR 0–3) versus 0 (0–2), 3 (1–5) versus 1·5 (0–4), and 4 (2–7) versus 2 (0–5), respectively. Thus, the difference in erosiveness did not develop only during the first year of the study. Taken together, the results indicate that the addition of prednisolone in the therapy did not have a major impact on the 2-year clinical outcome of the patients. We emphasise that a total of 40% of patients on single-drug therapy not on prednisolone had a remission during the first year. At the end of the study, more patients on single-drug therapy than on combination therapy were treated with systemic prednisolone (50 vs 43). The cumulative numbers of intra-articular glucocorticoid injections in the patients on single-drug therapy and combination therapy at 3, 6, and 12 months were 218 versus 113, 275 versus 152, and 410 versus 196, respectively. The patients on single-drug therapy who were treated with prednisolone developed more erosive changes than the patients who did not receive prednisolone. The duration of symptomatic disease at baseline, which reflects the delay to the optional initiation of glucocorticoid therapy, was not a significant variable with regard to achievement of remission. The main result of our trial—the difference in the rates of remission between patients on single-drug therapy and combination therapy—increased overtime from 6 months to 2 years (see our figure 2 in the report). By contrast, the initial rather massive use of prednisolone (starting with 60 mg daily) in the COBRA trial1Boers M Verhoeven AC Markusse HM et al.Randomised comparison of combined step-down prednisolone, methotrexate versus the single components in early rheumatoid arthritis: a randomised controlled, double-blind, 52-week clinical trial in early rheumatoid arthritis.Lancet. 1997; 350: 309-318Summary Full Text Full Text PDF PubMed Scopus (997) Google Scholar seems a major contributor to the transient clinical improvement of the patients treated with the DMARD combination in that study. Combination therapy in rheumatoid arthritisTimo Möttönen and colleagues (May 8, p 1568)1 clearly show the benefit of early aggressive intervention in rheumatoid arthritis. The effects of corticosteroids are intriguing. Kirwan's2 data and the COBRA trial3 support the idea that early administration of corticosteroids is beneficial. This effect could also apply to Möttönen's trial, but the published data are insufficient to reach a firm conclusion, and may even point the other way. Full-Text PDF