Once a rheumatoid arthritis patient maintains relatively long-term remission on a regimen that combines a synthetic and a biologic disease-modifying drug, temptation mounts to try withdrawing one of the two drugs. Cost considerations alone can make it irresistible to patients to taper down or stop an expensive biologic drug to see whether the patient’s remission can sustain dose reduction or elimination.
But several American experts cautioned that despite growing evidence that at least some rheumatoid arthritis (RA) patients will stay in remission after their biologic disease-modifying antirheumatic drug (DMARD) is gone, the overall efficacy and safety of this approach remain uncertain and it’s not fully clear which patients are the best candidates. Biologic-drug withdrawal has not repeatedly been shown to be fully safe and worth attempting with results from rigorously controlled and adequately powered studies, an evidence base that may still be several years off.
Dr. Eric L. Matteson
"We can try withdrawing a drug," and many American RA patients do just that, a step more often than not initiated by the patient. "But we don’t know if it’s benign for radiographic progression or for cardiovascular disease events," said Dr. Arthur Weinstein, director of rheumatology at Washington (D.C.) Hospital Center. Even though RA patients in remission who taper down or fully stop their biologic DMARD are usually closely monitored for flare, "there is some evidence for a disconnect between radiographic progression and clinical status," raising the danger that a patient may appear to remain in remission when off the biologic drug while joint deterioration occurs. That, coupled with concern that an RA patient’s cardiovascular risk may worsen off their biologic, can make patients and physicians hesitate when faced with the prospect of messing with a stable remission on a combined biologic and synthetic DMARD regimen, Dr. Weinstein said in an interview.
Biologic withdrawal can succeed
Despite that, it’s undeniable that a substantial minority or even a majority in some series of RA patients in remission or low disease activity on both a biologic and synthetic DMARD can taper down or stop the biologic without a flare occurring. The flip side of that is, of course, that in many series a good number of patients who stop their biologic have a flare and need to have the drug restarted. The good news for these scenarios is that prompt restart of the biologic once a flare occurs generally seems capable of restoring remission with no long-term deleterious effects.
In its 2013 RA treatment guidelines, the European League Against Rheumatism (EULAR) said that "if a patient is in persistent remission after having tapered glucocorticoids, one can consider tapering biologic DMARDs, especially if this treatment is combined with a synthetic DMARD" (Ann. Rheum. Dis. 2014;73:492-509). The most recent RA management guidelines from the American College of Rheumatology, published in 2012, don’t address tapering down or withdrawing biologics. Dr. Weinstein noted that the EULAR recommendation is largely based on consensus expert opinion without a definitive evidence base to justify this approach.
Recent evidence documenting the success of biologic withdrawal includes a report earlier this year from a prespecified analysis in the OPTIMA (Optimal Protocol for Treatment Initiation with Methotrexate and Adalimumab) trial that detailed the outcomes of 207 patients who had stable, low disease activity on combined treatment with adalimumab (Humira) and methotrexate and were randomized to either adalimumab withdrawal or continuation. A year later, 70% of patients who maintained the two-drug regimen and 54% of those randomized to stop adalimumab remained at low disease activity and had no sign of radiographic progression, a between-group difference that was not statistically significant (Lancet 2014;383:321-32).
But in other studies, patients withdrawn from a biologic did not fare nearly as well. The PRESERVE (Maintenance, induction, or withdrawal of etanercept after treatment with etanercept and methotrexate in patients with moderate rheumatoid arthritis) trial randomized 604 RA patients with low disease activity on a combination of etanercept (Enbrel) and methotrexate to continue to receive 50 mg of etanercept plus methotrexate weekly, step down to 25 mg of etanercept plus methotrexate weekly, or completely stop etanercept and continue on methotrexate alone. A year later, the percentage of patients who remained in low disease activity tallied 83% in those who received at least one dose of 50 mg etanercept, 79% of patients in the 25-mg etanercept group, and 43% in the group maintained on methotrexate monotherapy, statistically significant differences between each of the two etanercept groups and the monotherapy arm (Lancet 2013;381:918-29).
Dr. Arthur Weinstein
A more real-world assessment included 717 RA patients at low disease activity who discontinued their first biologic drug while enrolled in the CORRONA (Consortium of Rheumatology Researchers of North America) registry. The results showed that after 1 year on monotherapy without a biologic, 73% of patients remained free from a flare, and that state persisted in 56% to 18 months, 42% after 2 years, and 28% after 3 years on monotherapy, Dr. Arthur F. Kavanaugh and his associates reported last year at the annual meeting of the American College of Rheumatology (Arthritis Rheum. 2013;65:S603).