Kevin D. Deane, MD, PhD
Stopping Tumor Necrosis Factor Inhibitor Therapy in Patients With Established Rheumatoid Arthritis in Remission or With Stable Low Disease Activity: A Pragmatic Multicenter, Open-Label Randomized Controlled Trial
Ghiti Moghadam M, Vonkeman HE, Ten Klooster PM, et al; Dutch National POET Collaboration
Arthritis Rheumatol. 2016;68:1810-1817
In this study, Ghiti Moghadam and colleagues from The Netherlands used a pragmatic trial design to investigate rates of rheumatoid arthritis (RA) flare after cessation of anti-tumor necrosis factor (anti-TNF) therapy. They analyzed 817 patients, all of whom had a Disease Activity Score in 28 joints (DAS28) < 3.2 for 6 months before inclusion.
Individuals with RA were randomized in a 2:1 ratio to stop or continue anti-TNF therapy (531 and 286 patients, respectively). The primary outcome was flare of disease, as determined by a DAS28 ≥ 3.2 over 12 months of follow-up or an increase in score ≥ 0.6.
At 12 months, the anti-TNF discontinuation group had more flares (approximately 51% vs 18%; P < .001) and a higher mean DAS28 (P < .001). Of the 195 patients who restarted anti-TNF therapy, around 85% regained a DAS28 < 3.2 after 6 months. Besides stopping anti-TNF therapy, predictors of time to a flare were a higher baseline DAS28 and disease duration > 10 years at the time of study entry. In terms of safety, there was one death due to an infection in the continuation group, and 34 hospitalizations in the discontinuation group compared with seven in the continuation group (P = .012)
Increasing numbers of studies have been investigating the possibility that individuals with RA can decrease therapy and yet continue to have excellent disease control. These studies were reviewed in an outstanding article by Schett and colleagues that was published in the May 2016 edition of the Annals of Rheumatic Diseases. Results have been variable, although there has been substantial heterogeneity across the studies.
In the current large pragmatic-design trial, investigators found that there were significantly more flares in the anti-TNF discontinuation group. Given that such trials can perhaps provide more “real-world” information than randomized controlled trials,[2,3] these findings may be more reflective of routine clinical practice. One can therefore envision that on the basis of this trial, practitioners may inform their patients that ~50% of individuals will have their RA flare within 12 months of stopping anti-TNF therapy. However, the fact that higher rates of sustained disease control have been observed after tapering therapy in other studies, and that approximately one half of patients in this study that maintained remission, suggests that some individuals with RA can indeed taper therapy and maintain disease control.
The trick is how to pick the individuals who can taper their RA therapy and continue to have good disease control. On the basis of current knowledge, it is highly likely that such a choice will include evaluating several factors that have been associated in other studies with maintained RA control after taper. These factors include shorter disease duration; deeper remission, as determined by lower DAS28 scores; biomarkers, including autoantibodies and inflammatory measures; imaging; and even factors that are yet to be determined. Given that pragmatic trials are becoming increasingly popular, we will also need to see how such trials can influence the field.