Combination drug therapy had a higher remission rate than single-drug therapy for newly diagnosed rheumatoid arthritis
ACP J Club. 1999 Nov-Dec;131:57. doi:10.7326/ACPJC-1999-131-3-057
Möttönen T, Hannonen P, Leirisalo-Repo M, et al., for the FIN-RACo trial group. Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial. Lancet. 1999 May 8;353:1568-73.
For patients with newly diagnosed rheumatoid arthritis (RA), is combination therapy with sulfasalazine (SSZ), methotrexate (MTZ), hydroxychloroquine, and prednisolone as safe and effective as single-drug therapy (SSZ) for induction of remission?
Randomized (concealed), single-blind (outcome assessor for radiographs), controlled trial with 24-month follow-up.
18 hospitals in Finland.
199 patients (mean age 48 y, 61% women, mean duration of disease 8 mo) with confirmed active RA for < 2 years. Exclusion criteria included previous use of disease-modifying antirheumatic drugs (DMARDs), recent glucocorticoid therapy, serious comorbid conditions, hypersensitivity to study medications, or history of cancer. Follow-up was 89%.
99 patients were allocated to combination therapy (SSZ, 1 g/d; MTX, 7.5 mg/wk; hydroxychloroquine, 300 mg/d; and prednisolone, 5 mg/d), and drug doses were selectively increased at 3 months if improvement criteria were not met (MTX to 10 mg/wk and prednisolone to 7.5 mg/d); if remission occurred, drug doses were tapered (for all drugs) or discontinued (for prednisolone and MTX). The 100 patients allocated to the single-drug group started with SSZ, 2 g/d (with or without prednisolone), which was increased to 3 g/d at 3 months if indicated; MTX was substituted for SSZ at 6 months if needed.
Main outcome measure
Remission using American College of Rheumatology criteria with fatigue and duration criteria excluded.
More patients in the combination group achieved remission at 24 months than in the single-drug group (P = 0.003) (Table); the groups did not differ for any adverse event (70% for combination vs 71% for single-drug, P = 0.8) or serious adverse events (3% vs 5%, P = 0.7).
Combination drug therapy was more effective and just as safe as single-drug therapy for inducing remission in patients with newly diagnosed RA.
Sources of funding: Finnish Society for Rheumatology; Rheumatism Research Foundation in Finland; Medical Research Foundation of Turku University Central Hospital; Finnish Office for Health Care Technology Assessment.
For correspondence: Dr. T. Möttönen, Turku University Central Hospital, Division of Rheumatology, Paimio Hospital, FIN-21540 Paimio, Finland. FAX 358 22614300.E-mail firstname.lastname@example.org.
Table. Combination vs single-drug therapy for early rheumatoid arthritis*
|Outcome at 24 mo||Combination||Single drug||RBI (95% CI)||NNT (CI)|
|Remission||36%||18%||102% (25 to 232)||6 (4 to 17)|
*Abbreviations defined in Glossary; RBI, NNT, and CI calculated from data in article.
RA is often an aggressive, relentless disease that culminates in disability and mortality. Severe joint damage can occur early, often within 2 years of disease onset, and once established, is irreversible. Symptom control does not equal true long-term remission, which requires long-term DMARD therapy to suppress inflammation. Thus, early diagnosis and DMARD treatment are essential. Because DMARD monotherapy has limited efficacy, combination therapy has evolved despite equivocal results (1).
Möttönen and colleagues showed that about 100% more patients were in remission in the combination group than in the single-drug group at each time point from 6 to 24 months. Notably, the combination therapy group had fewer new joint erosions, needed fewer intra-articular glucocorticoid injections, and had no increase in adverse events or decrease in compliance. The authors studied patients with early RA; followed patients for long periods; and were flexible in titrating drug doses, interchanging DMARDs, and using adjunctive nonsteroidal anti-inflammatory drugs, low-dose oral prednisolone, and intra-articular glucocorticoids: These methods truly simulate clinical practice.
The findings can be adopted with a few caveats. Approximately 1 in 5 patients with RA may remit spontaneously and may not require combination therapy. MTX monotherapy replaced SSZ monotherapy in 51% of patients; if these patients had started with MTX monotherapy and had flexibility in increasing the dose, the results may have been different. However, there is no evidence that MTX works better than SSZ alone (2). Finally, despite combined treatment and intensive follow-up, it is noteworthy that 30% of patients with RA did not improve and > 60% were not in remission after 2 years. Thus, although our understanding of RA and its treatment have radically improved, more specific and active drugs for RA are needed.
Ami Schattner, MD
Joshua Friedman, MDHebrew University and Hadassah Medical SchoolJerusalem, Israel