C-OPERA Study: Certolizumab Combo Therapy Effective for Methotrexate-naïve Patients with Rheumatoid Arthritis

Timing is everything in the treatment of patients with rheumatoid arthritis (RA). Once joint damage begins, it is often irreversible, so earlier effective treatment is the key. The recent emergence of biological agents targeting inflammatory cytokines such as tumor necrosis factor (TNF) has opened up new and important avenues of research and added to what is emerging as a potent therapeutic toolbox.

Disease-modifying anti-rheumatic drugs (DMARDS) still have an important role to play; methotrexate (MTX) as either monotherapy or in combination with other DMARDS is still the first-line treatment. But evidence continues to emerge that biologics—in combination with DMARDS—offer a solid line of defense for patients at risk of rapid disease progression.

A study in Annals of the Rheumatic Diseases looked at certolizumab pegol (CZP), a humanized anti-TNF antibody fragment conjugated to polyethylene glycol, and found that in MTX-naive early RA patients with poor prognostic factors, CZP+MTX significantly inhibited structural damage and reduced RA signs and symptoms. The finding is just the latest in a series of research showing the promising potential of DMARDS and biologics together.CZP had previously been shown safe and effective in the treatment of established RA, but this study confirms similar action in MTX-naïve early RA.

The study details the Certolizumab—Optimal Prevention of joint damage for Early RA (C-OPERA) study. The study was double-blind (DB) for 1 year, with either CZP or placebo administered concomitantly with MTX. Following this, the trial was open label for another year, whereby completers of the double-blind period were maintained on MTX monotherapy after discontinuing CZP.

The study took place at 73 sites in Japan; half of the 316 patients were given CZP + MTX, and the other half placebo + MTX.The CZP+MTX group showed significantly greater inhibition of radiographic progression relative to placebo +MTX at week 24 and week 52. Clinical remission rates of the CZP+MTX group were significantly higher compared with those of the placebo +MTX group, at weeks 24 and 52. Safety results in both groups were similar, with no new safety signals observed with addition of CZP to MTX.

The study authors note that, “…as far as we know, this is the first randomized controlled trial to employ the 2010 ACR/EULAR classification criteria as the main inclusion criteria. Thus, patients enrolled in C-OPERA had very early stages of disease, strictly defined as the time from initiation of persistent arthritic symptoms identified by medical interview (RA duration ≤12 months). Approximately 35% of patients had no joint damage (mTSS ≤0.5) in baseline radiographs… Second, we intentionally enrolled only patients with high anti-CCP antibody titres, which is highly specific for RA, compensating for a relatively low specificity of classification criteria. Since positive anti-CCP antibody predicts poor prognosis and rapid progression, these patients are more likely to require and benefit from aggressive treatment during early disease.”

The study also sheds some light on a frequent open question in RA treatment: are increased dosages of MTX more effective than lower doses? The results of C-OPERA suggest that higher doses of MTX may not always be necessary when administered with concomitant anti-TNF agents, although the study authors caution that “this [result] is far from conclusive, requires further investigation and may be limited to effects on joint damage progression.”

Study limitations included not assessing the effect of CZP monotherapy.