A new discontinuation strategy for infliximab in patients with rheumatoid arthritis, in which the biologic dose was determined by the serum level of tumor necrosis factor (TNF)-α, was unsuccessful for sustained biologic-free remission, say researchers recently writing in Annals of the Rheumatic Diseases.
It is well known that proinflammatory cytokines such as TNF-α play central roles in the occurrence and progression of rheumatoid arthritis. As the therapeutic effects of infliximab, an inhibitor of TNF-α, plus methotrexate have been demonstrated in several clinical studies, the goal of rheumatoid arthritis treatment has expanded from the achievement of clinical remission to sustained remission without biological disease-modifying antirheumatic drugs (bDMARDs), out of concern for adverse events or treatment cost. Several studies have suggested that few patients with established rheumatoid arthritis can discontinue bDMARDs without losing remission, while those in sustained deep remission are more likely to be able to discontinue bDMARDs. Moreover, a significant interaction has been demonstrated between the infliximab dose and TNF-α level in the clinical response, suggesting that serum levels of TNF-α could be a key indicator for optimal dosing of infliximab to achieve a clinical remission and a sustained discontinuation of infliximab for the treatment of rheumatoid arthritis. However, this hypothesis has not been confirmed in a randomized controlled trial.
“The aim of this study is to determine whether the ‘programmed’ infliximab treatment strategy (for which the dose of infliximab was adjusted based on the baseline serum TNF-α) is beneficial to induction of clinical remission after 54 weeks and sustained discontinuation of infliximab for one year,” wrote the authors of the study, led by Yoshiya Tanaka, M.D., Ph.D., of the University of Occupational and Environmental Health in Kitakyushu, Japan.
This multicenter trial, dubbed RRRR, included 337 patients with infliximab-naïve rheumatoid arthritis with inadequate response to methotrexate. Participants were randomized to receive either the programmed treatment of 3 mg/kg infliximab until week six and after 14 weeks the dose of infliximab was adjusted based on the baseline levels of serum TNF-α until week 54, or standard treatment with 3 mg/kg of infliximab. Patients who achieved a simplified disease activity index (SDAI) ≤3.3 at week 54 discontinued infliximab. The primary endpoint was the proportion of patients who sustained discontinuation of infliximab at week 106.
At week 54, 39.4 percent of the programmed group and 32.3 percent the standard group attained remission (SDAI ≤3.3). At week 106, the one-year sustained discontinuation rate was 23.5 percent and 21.6 percent, respectively, representing a nonsignificant 2.2 percent difference (95% CI −6.6 percent to 11.0 percent; p=0.631).
“In both arms, baseline SDAI <26 was a statistically significant predictor of sustained discontinuation at one year (OR=2.97 in the programmed arm and 2.83 in the standard arm),” the authors wrote. “This exploratory analysis implies that the success of sustained discontinuation of infliximab depends on disease activity at baseline, and that sufficient disease control by adequate dose of
methotrexate is required before infliximab is administered.”
There was no statistically significant difference in the proportion of deep remission (DAS28 <2.2), at the last administration of infliximab between the groups, which could result in failure of sustained discontinuation of infliximab. Still, the incidence rates of infections and other safety signals were comparable between the groups, suggesting that dose escalation was tolerated in the study.
“Thus, the fine tuning of infliximab-dose based on serum levels of TNF represents a key factor for achievement of remission defined by SDAI and DAS28-ESR, but may not be related to deep remission.
“If serum levels of rheumatoid factor are less than 45, serum levels of TNF-α are higher than 1.65, or disease activity is controlled with less than 10mg/kg of methotrexate, standard treatment may be intense enough to achieve successful discontinuation of infliximab, the authors wrote.
In order to facilitate decision-making by patients and rheumatologists, the authors suggested that more effort is needed to determine the patient profile most likely to benefit from discontinuation of bDMARDs.
"Taken together, the findings of the RRRR study (Remission induction by Raising the dose of Remicade in RA) reveal that the programmed treatment strategy using different doses of infliximab based on the baseline levels of serum TNF-α did not increase the sustained remission rate 1year after withdrawal of infliximab treatment at week 106. However, in order to facilitate decision-making by patients and rheumatologists, more efforts are needed to determine the patient profile most likely to benefit from discontinuation of biological DMARDs," the authors wrote.
Yoshiya Tanaka, Koji Oba, Takao Koike, et al. “Sustained discontinuation of infliximab with a raising-dose strategy after obtaining remission in patients with rheumatoid arthritis: the RRRR study, a randomised controlled trial.” Annals of the Rheumatic Diseases. October 19, 2019. doi: 10.1136/annrheumdis-2019-216169