Can ACPA Predict Long-Term Remission in RA?

April 6, 2015

Two new studies show that ACPA-positive rheumatoid arthritis patients are substantially less likely to sustain remission after drug tapering or withdrawal.

Wevers-de Boer KV, Heimans L, Visser K, et al., Determinants of reaching drug-free remission in patients with early rheumatoid or undifferentiated arthritis after one year of remission-steered treatment.Rheumatology. 2015 doi: 10.1093/rheumatology/keu477

Haschka J, Englbrecht M, Hueber AJ, et al., Relapse rates in patients with rheumatoid arthritis in stable remission tapering or stopping antirheumatic therapy: interim results from the prospective randomised controlled RETRO study. Ann Rheum Dis. 2015 Feb 6.  doi: 10.1136/annrheumdis-2014-206439.

The presence of anti-citrullinated protein antibodies (ACPA) may help predict which rheumatoid arthritis (RA) patients can expect sustained remission, two recent studies suggest.

While almost one third of early RA patients can get to drug-free remission (DFR) on conventional DMARD therapy and can taper medications successfully, ACPA-positive patients don’t seem to stay drug-free as long as ACPA-negative patients, according to Dutch researchers.

An interim analysis of a German clinical trial of tapering or stopping both conventional and biological DMARDs finds that relapses within the first 6 months after cutting back medication are more frequent among ACPA-positive patients.

But the Dutch study surprisingly finds that ACPA-positive patients reach early remission more often than those who are ACPA-negative.

Data analysis for 375 patients in the IMPROVED study in the Netherlands finds that neither ACPA or rheumatoid factor (RF) positivity is an independent predictor of reaching drug-free remission. But ACPA-positivity is a factor in relapses.

IMPROVED is a multi-center trial of remission-steered treatment among 601 patients with RA and undifferentiated arthritis, using as a target a disease activity in 28 joints score (DAS28) below 1.6.

All patients started out on methotrexate (MTX) 25 mg/week plus prednisone 60 mg/day, tapered to 7.5 mg/day after 7 weeks.

Among the 375 (61%) patients achieving early remission at 4 months, prednisone was then tapered to zero.

After 8 months, patients remaining in remission (n=119, or 32%) were able to taper MTX to zero, while those still not in remission (n=245) restarted prednisone.

Even though ACPA-positive patients reached early remission more often than the ACPA-negative patients, they maintained DFR less often than ACPA-negatives (58% vs 80%, respectively).

After the medication was stopped, 30% of patients relapsed over the next 4 months and had to restart medication, with more ACPA-positive patients losing DFR than ACPA-negative patients.

The Reduction of Therapy in patients with Rheumatoid arthritis in Ongoing remission (RETRO) study in Germany is a multicenter, parallel-group phase 3 trial, randomizing patients in stable remission to one of three arms: stay on full dose DMARDs for 12 months, taper DMARDs by 50% for the next 12 months, or reduce the dose by half for 6 months before stopping therapy altogether.

Among the first 101 patients who completed the study 62% were women in their late 50s and 60% were ACPA-positive.

More than a third (33.7%) relapsed, with relapses more common in the drug-tapering group (39%) and in the drug stoppage group 52%. 

More than 70% of those who relapsed were ACPA-positive, compared to 53% among those remaining in remission. Significantly more ACPA-positive patients who relapsed were women.

ACPA-negative patients had a lower prevalence of relapse independent of whether treatment was continued, tapered or stopped. In contrast, ACPA-positive patients in remission showed a gradual increase of relapse rates, especially in the drug stoppage arm.

ACPA-positivity is the main risk factor for relapse, the German researchers comment.

ACPA precede the onset of RA, are associated with more severe disease and trigger pathological changes even in the absence of RA. Hence, the presence of ACPA in patients with RA in remission may indicate an underlying autoimmune process hampering successful treatment withdrawal,” they suggest.

There are concerns about leaving stable RA patients on continual long-term DMARDs considering the side effects and cost. But few clinical trials have studied the feasibility and effects of dose-tapering or stopping medication once stable remission has been reached.

This study shows that such a strategy may allow more than half of RA patients to maintain remission over 1 year, but “caution should be undertaken in patients with ACPA showing a higher risk for relapse,” the authors conclude.