Methotrexate alone appears to be just as good as when it is combined with etanercept in reducing tender and swollen joints in patients with early inflammatory arthritis who have at least one joint with clinical synovitis, according to results from a randomized, controlled trial.
However, the combination of etanercept (Enbrel) and methotrexate (MTX) gave a more rapid clinical response that was maintained, along with responses on various imaging outcomes, in the majority of patients who stopped taking etanercept if they had no tender or swollen joints for 26 weeks or if they had reached week 52 of treatment when the primary outcome of no tender or swollen joints was measured.
A previous study has shown that the combination of methotrexate and etanercept produced greater rates of remission in patients with early rheumatoid arthritis of 4 months or less duration, but the current study, conducted by Dr. Jackie L. Nam, a clinical research fellow at the University of Leeds (England) Musculoskeletal Biomedical Research Unit and her associates, is the first to test the combination in early inflammatory arthritis (Ann. Rheum. Dis. 2014 March 11 [doi:10.1136/annrheumdis-2013-204882]).
The investigators enrolled a total of 110 patients at four centers into the trial during October 2006-May 2009. They had a mean age of 48.6 years and median symptom duration of 7 months, although all had been diagnosed within 3 months of receiving treatment in the trial. None had been treated with a synthetic or biologic disease-modifying antirheumatic drug. Most of the patients were female (76%) and many tested positive for rheumatoid factor (53%), anti-citrullinated peptide antibodies (77%), and shared epitope (82%). Most (94%) also met the 2010 ACR-EULAR (American College of Rheumatology–European League Against Rheumatism) classification criteria for rheumatoid arthritis (RA), whereas 41% met the 1987 ACR RA classification criteria. At baseline, the patients had a mean C-reactive protein Disease Activity Score (DAS28-CRP) of about 4.13 and a DAS44-CRP of 2.94.
Both groups received MTX starting at 10 mg weekly, which could then be increased by 5 mg every 4 weeks up to 20 mg and then up to a final dose of 25 mg/week if the primary outcome of no swollen or tender joints had not been reached by week 12 or thereafter. After week 52, patients could take other conventional disease-modifying antirheumatic drugs if there was ongoing disease activity. NSAIDs also were permitted throughout the trial. A single intramuscular or intra-articular corticosteroid injection equivalent to 120 mg methylprednisolone was permitted on one occasion during the first 9 months of the trial and as clinically indicated afterward.
MTX plus etanercept or MTX plus placebo led to similar rates of no tender or swollen joints at 52 weeks in patients with early inflammatory arthritis diagnosed within 3 months of treatment (32.5% vs. 28.1%, respectively). But in exploratory analyses, a significantly higher proportion of patients in the combination therapy group achieved a 28-joint, DAS28-CRP of less than 2.6 at 2 weeks than did those taking MTX monotherapy (38.5% vs. 9.2%) as well as for DAS28-CRP of 3.2 or lower (55.5% vs. 22.2%).
Initially, the investigators had hypothesized that the combination therapy group would have a 60% response rate in no tender or swollen joints at 52 weeks and the MTX monotherapy group would have a 30% response rate, but they noted that "It is likely that [no tender or swollen joints] was too strict a target and that the achievement of no swollen joints alone may have been a more realistic outcome."
There were no surprises in adverse events among the two groups, with comparable numbers occurring in the patients on combination therapy and in those on monotherapy (451.6/100 patient-years vs. 417.3, respectively) and more serious adverse events occurring among patients treated with etanercept (16.4/100 patient-years vs. 3.7), although the investigators said that many were related to medical or surgical procedures that the patients underwent.
Pfizer provided the study drug and unrestricted grant funding. Seven of the 13 investigators reported potential conflicts of interest with numerous pharmaceutical companies, including Pfizer and other companies marketing treatments for inflammatory arthritis.