Treatment of rheumatoid arthritis with methotrexate and hydroxychloroquine, methotrexate and sulfasalazine, or a combination of the three medications: Results of a two‐year, randomized, double‐blind, placebo‐controlled trial

Abstract

Objective. To compare the efficacy of combination therapy with methotrexate (MTX) and hydroxychloroquine (HCQ), MTX and sulfasalazine (SSZ), and MTX, HCQ, and SSZ in patients with rheumatoid arthritis (RA).Methods. RA patients (n ‫؍‬ 171) who had not previously been treated with combinations of the study medications were randomized to receive 1 of the 3 treatment combinations in this 2-year, double-blind, placebo-controlled protocol. HCQ was given at a dosage of 200 mg twice a day. The dosage of MTX was accelerated from 7.5 mg/week to 17.5 mg/week in all patients who were not in remission. Similarly, the dosage of SSZ was escalated from 500 mg twice a day to 1 gm twice a day in patients who were not in remission. The primary end point of the study was the percentage of patients who had a 20% response to therapy according to the American College of Rheumatology (ACR) criteria at 2 years.Results. Intent-to-treat analysis revealed that patients receiving the triple combination responded best, with 78% achieving an ACR 20% response at 2 years, compared with 60% of those treated with MTX and HCQ (P ‫؍‬ 0.05) and 49% of those treated with MTX and SSZ (P ‫؍‬ 0.002). Similar trends were seen for the ACR 50% response, with 55%, 40%, and 29% of patients in the 3 treatment groups, respectively, achieving these results at 2 years (P ‫؍‬ 0.005 for the triple combination group versus the MTX and SSZ group). All combination treatments were well-tolerated. Fourteen patients (evenly distributed among the 3 groups) withdrew from the protocol because of symptoms that were potentially related to the study medication.Conclusion. The triple combination of MTX, SSZ, and HCQ is well-tolerated, and its efficacy is superior to that of the double combination of MTX and SSZ and is marginally superior to that of the double combination of MTX and HCQ.

Retardation of joint damage in patients with early rheumatoid arthritis by initial aggressive treatment with disease‐modifying antirheumatic drugs: Five‐year experience from the FIN‐RACo study

“…The superiority of combination therapy over single therapy in the FIN-RACo trial (4) has been confirmed by other studies with regard to the short-term clinical outcome of patients with early RA (3,5). These findings have resulted in increased optimism with regard to the ability of DMARD combinations to reduce structural joint damage as well, even over the long term.…”

“…Moreover, the ESR and serum CRP levels were low, even in RA patients who were not in remission (Figure 3). The median DAS28 scores in the combination and single groups were as follows: at baseline, 5 Figure 4). The time-weighted mean Ϯ SD DAS28 area under the curve from baseline up to 5 years was 2.70 Ϯ 1.07 in the combination group and 3.40 Ϯ 1.06 in the single group (P Ͻ 0.001).…”

“…therapy (2)(3)(4)(5). In the Dutch Combinatietherapie Bij Reumatoïde Artritis (COBRA) study, the initial aggressive step-down treatment of early RA with high-dose prednisolone, methotrexate, and sulfasalazine for 6 months, in comparison with monotherapy with sulfasalazine, regardless of the subsequent antirheumatic therapy, showed sustained suppression of the rate of radiologic progression that was detectable even after the 4-5-year followup period (6).…”

Sulfasalazine is a potent inhibitor of the reduced folate carrier: Implications for combination therapies with methotrexate in rheumatoid arthritis

“…Another strategy of the rheumatologist for enhancing the efficacy of the combination of MTX plus SSZ is the addition of a third drug (e.g., hydroxychloroquine [13] or prednisone [14]) to the MTX-SSZ combination. Although the objective of this study was not to elucidate a mechanistic basis for the efficacy of the triple DMARD therapy, recent studies by our group (47) did indicate that CEM/SSZ cells displayed enhanced sensitivity to both chloroquine and dexamethasone.…”

“…In fact, addition of a third component such as hydroxychloroquine (12,13) or prednisone (14) is usually required to significantly improve clinical efficacy. Furthermore, one notable adverse effect observed was a persistent increase in plasma homocysteine levels in patients with RA who were receiving the combination of MTX and SSZ, compared with those receiving single-drug therapy (15,16).…”