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Rheumatoid arthritis (RA) patients in remission who had tumor necrosis factor (TNF) inhibitors withdrawn stepwise still faced markedly increased risk of disease flares compared with a control group who continued on stable doses, a randomized trial showed.

Some 63% of patients in the anti-TNF withdrawal group experienced symptom resurgence during the 12-month trial, versus just 5% of patients who stayed on their regular treatment, according to Siri Lillegraven, MD, MPH, PhD, of Diakonhjemmet Hospital in Oslo, Norway, and colleagues in .

Although remission was restored in most of the intervention group when they resumed their regular anti-TNF agents, the researchers were forced to conclude that gradual withdrawal didn't work as well as they hoped.

"The tapering strategy was not non-inferior to continued stable treatment," Lillegraven and colleagues wrote.

TNF inhibitors have been remarkably successful in reducing RA symptoms over the long term. But their inconvenience (all such agents are injectable or infusion drugs) and expense have left clinicians and patients wondering whether, when disease activity is all but eliminated, it's possible to maintain low disease activity solely with cheap oral medications such as methotrexate -- or perhaps even nothing at all.

Some such attempts have been considered successful, to the point that allow for dose reduction when patients meet formal criteria for remission for at least 6 months. But evidence supporting anti-TNF withdrawal in this population is mixed, Lillegraven's group observed. Thus, they believed their randomized trial, dubbed , would help resolve the lingering uncertainties.

The researchers recruited 99 adult RA patients who had been in remission for at least 1 year while taking anti-TNF drugs, randomizing them 1:1 to withdrawal or continued stable treatment. Fifteen patients were deemed ineligible after randomization or quit the study early, such that 84 were included in the final analysis.

As is typical in RA, most participants were women, with disease duration of about 11 years. Mean age was about 57. Disease Activity Score (DAS) at recruitment averaged 0.8; other measures of disease activity also reflected a near-total absence of symptoms. Just over 40% of participants were using etanercept (Enbrel) as their anti-TNF agent; certolizumab pegol (Cimzia) was next most common at roughly 30%. Only about 10% were taking adalimumab (Humira).

In the withdrawal group (n=43), TNF inhibitor doses were cut in half for the first 4 months, and stopped completely if remission was still maintained at month 4. Participants who experienced disease flares -- defined as a combination of DAS greater than 1.6, an increase of at least 0.6 DAS points from baseline, and developing at least two swollen joints -- had their anti-TNF doses restored to baseline levels. Those patients then remained on normal doses for the remainder of the trial. Patients who were also using methotrexate or other conventional drugs stayed on them during the trial.

Most flares occurred between months 4 and 8 when TNF inhibitor treatment was stopped entirely. But resumption of normal doses was very effective in bringing flares under control, such that 88% of the withdrawal group versus 85% of controls met remission criteria when examined at month 12.

Another encouraging finding was the radiographic progression was not significantly greater in the withdrawal group (mean change in van der Heijde score 0.3 vs 0.1 points, difference 0.2, 95% CI -0.2 to 0.6), although the 12-month trial duration might not have been adequate to fully evaluate this aspect of RA pathology.

Other limitations to the study included the small number of patients (the investigators had planned to enroll 126, but encountered difficulty in recruiting patients in full remission), the open-label design, and the relatively abrupt tapering strategy. There were also too few patients for meaningful subgroup analyses, such as stratifying by type of anti-TNF drug.

Lillegraven and colleagues emphasized that the trial was not a failure, in that it did provide solid evidence that clinicians can use in daily practice.

"Our results demonstrate excellent long-term outcomes in patients with RA who have reached remission on TNF [inhibitor] treatment, and show that most patients need continuous TNF inhibition to maintain remission," they wrote. The group also argued that treatment withdrawal can still be considered for patients in remission, given that remission restored easily following flares in the trial.

"Both information about increased flare risk and the possibility of regaining control of the disease are important aspects to address in shared decision making, as tapering of [anti-TNF] should be decided by the patient and clinician based on the total situation of the patient," Lillegraven and colleagues noted. "There is a need for further research to personalize medicine within this patient group."

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