Health & Medical Rheumatoid Arthritis

Treating Rheumatoid Arthritis When Methotrexate Fails

Treating Rheumatoid Arthritis When Methotrexate Fails

Abstract and Introduction


Objectives To compare the effectiveness of adding synthetic disease-modifying antirheumatic drugs (sDMARDs) versus tumour necrosis factor α inhibitors (TNFi) to methotrexate (MTX) in patients with rheumatoid arthritis (RA) who were MTX inadequate responders (IR). Second, to examine outcomes in patients receiving MTX+TNFi for whom the MTX+sDMARD combination had also failed.
Methods Patients with RA (disease duration ≤ 5 years, MTX IR and naïve to other DMARDs) starting treatment with MTX+TNFi or MTX+sDMARDs were included. From the latter group a subgroup of patients who went on to receive MTX+TNFi was identified.
Results Patients receiving MTX+TNFi (n=98) and MTX+sDMARDs (n=129) had similar baseline disease activity when starting combination therapy (mean Disease Activity Score 28 (DAS28) = 4.90 and 4.96, respectively). Three- and 6-month effectiveness and 2-year drug survival were better for MTX+TNFi than for MTX+sDMARDs: mean ΔDAS28 was −1.61 versus −0.85 after 3 months (p<0.001) and −1.91 versus −1.03 after 6 months (p=0.01); DAS28<2.6 was reached by 29.0% versus 11.6% after 3 and 34.5% versus 12.9% after 6 months. Effectiveness was somewhat better with triple therapy than other MTX+sDMARD combinations but was generally inferior compared with MTX+TNFi. For the patients who received MTX+TNFi as a third step after MTX+sDMARDs had failed (n=38) there was a tendency towards lower remission rates, worse disease activity states and inferior drug survival compared with patients who received MTX+TNFi directly after the failure of MTX.
Conclusions Effectiveness was better for MTX+TNFi than for MTX+sDMARDs. Patients who started MTX+TNFi after two synthetic DMARD regimens had failed had a tendency to less favourable disease states after 3 months than patients who switched directly from MTX to MTX+TNFi.


Methotrexate (MTX) is currently the cornerstone in the treatment of rheumatoid arthritis (RA) and recommended as first-line therapy. Both the treatment recommendations from the European League Against Rheumatism (EULAR) and recently published recommendations for the use of MTX in rheumatic diseases advocate MTX monotherapy as the first choice rather than combinations of MTX with other synthetic disease-modifying antirheumatic drugs (sDMARDs), whereas the American College of Rheumatology recommends MTX or other DMARDs as monotherapy or MTX in combination with other DMARDs, depending on the disease duration and level of disease activity.

The efficacy of adding a tumour necrosis factor α inhibitor (TNFi) to MTX in patients who are MTX inadequate responders (IR) is well established, whereas evidence for the efficacy of adding sDMARDs in MTX IR is less robust. In many countries it is currently required that two or more sDMARDs must have failed before initiation of TNFi therapy. In Norway the general requirement is moderate to high disease activity level and inadequate response to MTX in patients with RA.

The objective of this real-life register-based study was to compare the effectiveness of adding sDMARDs versus adding a TNFi to MTX in patients with RA who were MTX IR. A second objective was to examine the clinical outcomes in the subgroup of patients who received delayed MTX+TNFi after the sDMARD combination.

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