THU0088 PREDICTORS OF DISEASE FLARE AFTER DISCONTINUATION OF CONCOMITANT METHOTREXATE IN JAPANESE PATIENTS WITH RHEUMATOID ARTHRITIS TREATED WITH TOCILIZUMAB

Abstract

Background:All biologics should primarily be combined with a conventional synthetic DMARD, such as methotrexate (MTX), in rheumatoid arthritis (RA) patients. However, the use of MTX may lead to the development of adverse events (AEs), and de-escalation of MTX while maintaining a favorable disease activity state may be beneficial from the perspective of reducing AEs during long-term RA treatment. Several studies have evaluated the impact of MTX discontinuation in RA patients who achieved good clinical response with tocilizumab (TCZ) plus MTX combination therapy, finding that discontinuing MTX is noninferior to continuing MTX in terms of maintaining clinical response (1-3). However, information on risk factors for disease flare after MTX discontinuation is lacking.Objectives:To investigate predictors of disease flare after MTX discontinuation in Japanese RA patients with sustained low disease activity undergoing TCZ plus MTX combination therapy.Methods:Participants of this multicenter, open-label, uncontrolled, prospective study were RA patients maintaining low disease activity (Clinical Disease Activity Index [CDAI] ≤10) for ≥12 weeks with TCZ plus MTX. Patients had to be receiving MTX orally at a stable dose of ≥6 mg/week, and TCZ at a stable dosage regimen irrespective of the route of administration, for ≥12 weeks prior to obtaining informed consent. MTX was discontinued after 12 weeks of biweekly administration while continuing TCZ therapy (Fig. 1). Disease flare was defined as a CDAI score >10 or intervention with rescue treatments for any reason. The impact of baseline characteristics on disease flare at week 64 (52 weeks after MTX discontinuation) was assessed with logistic regression models.Results:Efficacy analyses were performed in 49 patients, of whom 15 had a disease flare by week 64. The proportion [95% confidence interval (CI)] of patients who maintained low disease activity without a flare at week 64 was 69.4% (54.6 – 81.8%) (Fig. 2A). According to Kaplan-Meier estimates, the cumulative flare-free rate was 70.0% at week 64 (Fig. 2B). The dosing interval of TCZ was longer than that described on the drug label (i.e., intravenously every 4 weeks, or subcutaneously every 2 weeks) in 27% and 6% of patients with and without a flare, respectively (Table 1). Multivariate analysis revealed that male sex [odds ratio (OR): 18.00, 95% CI: 2.80-115.56] and extended dosing interval of TCZ (OR: 12.00, 95% CI: 1.72-83.80) were independent predictors of disease flare.Table 1.Impact of baseline variables on disease flareNon-flareFlareOdds ratio (95% confidence interval)(n=34)(n=15)UnivariateMultivariateAge, years62 ± 1163 ± 91.01 (0.95-1.08)aMale, %64010.67 (1.83-62.18)*18.00 (2.80-115.56)*Weight, kg54 ± 858 ± 151.03 (0.98-1.09)aDisease duration, years11 ± 813 ± 91.03 (0.95-1.11)aRF positive, %76861.85 (0.34-10.04)ACPA positive, %85100-bRoute of TCZ, intravenous, %59802.80 (0.66-11.79)Extended TCZ dosing interval, %6275.82 (0.93-36.28)†12.00 (1.72-83.80)*MTX dose, mg/week8.2±2.28.0±2.60.95 (0.73-1.25)aUse of glucocorticoids, %26331.39 (0.37-5.18)Use of csDMARDs other than MTX, %9335.17 (1.04-25.57)*-Previous biologic use, %56803.16 (0.75-13.26)CDAI remission, %65731.50 (0.39-5.75)CRP, mg/dl0.04 ± 0.060.04 ± 0.060.42 (0.00-15115.38)aMMP-3, ng/ml58.5 ± 22.476.6 ± 37.61.02 (1.00-1.05)a†-Data are shown as mean ± SD or percentage.aOdds ratio for 1-unit increase in each item.bOdds ratio was not evaluated. *P<0.05. †P<0.10.Conclusion:Male patients and those receiving TCZ at an extended dosing interval are at high risk of disease flare after discontinuation of concomitant MTX.This work was supported by Chugai Pharmaceutical Co., Ltd.