Finding the right patients
Despite evidence like this, the right time and the right patient for withdrawing a biologic remain murky. "At this point it is investigational," said Dr. Kavanaugh in an interview. "In the United States, it is mostly initiated by patients. There are many factors to consider, including the duration of RA, how well the patients are doing, is the patient on another drug that should be stopped first such as prednisone, and can the synthetic DMARD like methotrexate sustain the response," said Dr. Kavanaugh, a rheumatologist who is professor of clinical medicine and director of the Center for Innovative Therapy at the University of California, San Diego.
Routinely attempting biologic taper-down or withdrawal from RA patients in remission or at low disease activity "is not yet standard practice, but many patients do it," said Dr. Joel M. Kremer, a rheumatologist and professor of medicine at Albany (N.Y.) Medical College. When he attempts withdrawing a biologic, he prefers to use a gradual taper-down of the dosage, and he said he is more reluctant to attempt this for patients who began treatment with severe RA, and that he is more likely to try it for patients who began treatment with early RA, although he admitted that this remains uncertain. Like all experts interviewed, he said the type of biologic a patient is on doesn’t seem to matter.
"I think this entire area needs more study," Dr. Kremer said in an interview. For example, "are there biomarkers associated with the ability to withdraw? I don’t believe we know much about who can or should withdraw." Once withdrawal occurs, he recommended careful follow-up to detect a flare quickly, and restarting the biologic if even a mild flare occurs.
Dr. Arthur F. Kavanaugh
Biologic withdrawal "is really more investigational" right now, said Dr. Eric L. Matteson, professor and chairman of rheumatology at the Mayo Clinic in Rochester, Minn. "No guideline establishes it as standard of practice. I like to see patients in full remission for a year before considering such a move," he said in an interview. Withdrawal depends on whether the RA is well controlled and not on whether treatment started on early or established RA, he added; nor did he think that a flare after withdrawal precludes future withdrawal attempts as long as the patient returns to a durable, full remission. But Dr. Matteson did caution about also considering extra-articular disease like vasculitis or iritis that may be active even when a patient’s joints are not. "Any evidence of recurrent disease should cause the patient and physician to consider ramping the therapy back up."
Like others, Dr. Matteson highlighted the lingering unknowns about biologic withdrawal that keep it from being standard practice. "We don’t know whether the biologic or synthetic DMARD should get withdrawn first. We don’t have a great handle on what biomarkers to use to help decide if there is subclinical disease activity that necessitates reimplementation of the biologic. We don’t know which patients may violently flare following withdrawal and which might not. We also don’t know if retreatment of the disease is as good when a biologic is withdrawn and then restarted. Finally, I think we overestimate the percent of our patients who are actually in remission or a low-disease-activity state and underestimate who really should continue their medications."
The STARA trial
Dr. Weinstein and his associates recently planned a U.S.-based trial that has come close to launching to address several of these issues, the STARA (Stopping TNF-Alpha Inhibitors in Rheumatoid Arthritis) trial.
"One aspect of STARA is to determine whether there is a profile of clinical, imaging, and laboratory factors that will reliably distinguish patients who will flare from those who will remain in remission" following withdrawal of a biologic DMARD, said Dr. Weinstein, STARA’s lead investigator and also a professor of medicine at Georgetown University in Washington. "Another aim is to find predictors of good candidates for withdrawal. The advantage of STARA is patients are drawn from real-world practice and not from a clinical trial." Dr. Weinstein faulted some of the published studies of biologic withdrawal, such as OPTIMA and PRESERVE, because they included trial patients exclusively and not patients managed in routine practice.
STARA’s design uses a sudden, full withdrawal of the biologic to allow a standardized approach to patients who could enter the study on etanercept, adalimumab, or infliximab (Remicade). For routine practice, gradual withdrawal is more common, though there is no evidence this produces better long-term outcomes. An important withdrawal question that STARA won’t address is: Which is the better drug to remove, the biologic or the synthetic DMARD? In most cases, the more expensive biologic is the patient’s choice, but ideally this issue should be addressed in a randomized trial, Dr. Weinstein said.