Tapering TNF Inhibitors: A Good Strategy for Rheumatoid Arthritis?

A recent year-long, 2-phase study demonstrated that lowering tumor necrosis factor inhibitor (TNFi) dosage by one-third yielded excellent results in terms of safety, clinical effectiveness, and tolerability in patients with rheumatoid arthritis (RA) already responding well to maintenance doses of a TNFi and 1 or more disease-modifying antirheumatic drugs (DMARDs).

The Optimizing Treatment With Tumour Necrosis Factor Inhibitors in Rheumatoid Arthritis (OPTTIRA) trial, which featured a 6-month proof-of-principle phase followed by a 6-month exploratory phase, was a randomized, open-label study evaluating whether TNFi dosage could safely and effectively be reduced in patients with demonstrated low disease activity or remission for ≥3 months. This study was conducted to assess the potential to improve cost-effectiveness of RA treatment via TNFi dosage reduction. The study authors state, “TNFi are expensive…such biologic treatments will never become inexpensive,” indicating the need for a successful tapering strategy in good responders.

A total of 97 patients with RA receiving etanercept or adalimumab plus 1 or more DMARDs were enrolled in the study. All study participants had sustained disease reduction for 3 months, as evidenced by Disease Activity Scores in 28 joints (DAS28) ≤3.2, without any elevations >0.6 during this period. For the first phase of the study (from 0 to 6 months), study participants were randomly assigned to receive constant TNFi (n=50; control group) or 33% or 66% TNFi dose reduction (n=26 and n=21, respectively; experimental group). In the second phase (from 7 to 12 months), participants in the control group from phase 1 were randomly assigned to receive 33% or 66% TNFi dose reduction, and participants in the experimental group from phase 1 were prolonged on the same dosage (either 33% or 66% taper from starting dose) at increasingly large intervals, with the ultimate goal of discontinuing the TNFi therapy completely.

The primary endpoint was time to first flare, defined as a ≥0.6 increase in DAS28 score accompanied by an increase in number of swollen joints on exam, an increase in DAS28 ≥1.2, irrespective of swollen joint count. Secondary outcomes included Health Assessment Questionnaire, EuroQol 5-dimension scale, Medical Outcomes Study 36-Item Short Form Health Survey (SF-36), and Functional Assessment of Chronic Illness Therapy at 0, 3, 6, and 12 months. Additional secondary indices were X-rays of hands and feet at 0, 6 and 12 months, evaluation of swollen/tender joints (28), erythrocyte sedimentation rate, and assessment of pain (using a 100-mm visual analogue scale) every 3 months.

In the first phase, 8 patients in the control group (16%), 3 patients in the 33% taper group (12%), and 6 patients in the 66% taper group (29%) experienced flares. Statistical analysis demonstrated no significant reduction in time to flare for the 33% taper group (adjusted hazard ratio [HR], 0.87; 95% CI, 0.22-3.88; P =.835), but showed a substantial decrease in time to flare in the 66% taper group (adjusted HR, 2.81; 95% CI, 0.99-7.94; P =.051) when compared with controls.

During the exploratory phase, 40 rerandomized participants from the control group experienced a total of 11 flares: 3 participants in the 33% taper group (14%) and 8 participants in the 66% taper group (44%). Analysis showed a significant increased risk for flare in the latter group when compared with those whose medication had been cut by one-third (adjusted HR, 5.10; 95% CI, 1.81-21.95; P =.029).

In assessing the combined tapering groups over the course of the full year, investigators found flares in 13% of patients from the 33% taper group vs 36% of patients in the 66% taper group. Analysis revealed that tapering by two-thirds produced significantly higher flare risk than doing so by one-third (adjusted HR, 3.47; 95% CI, 1.26-9.58; P =.016).