Background ReFIRST is an exploratory, multi-center, open label, uncontrolled phase IIIb study evaluating the efficacy of re-treatment with Rituximab (RTX). It is the extension of the FIRST study that included 302 RA patients. In a substudy, it was intended to investigate B cell biomarkers and to identify B cell populations predictive of response.
Objectives Combining data of both studies, correlations between the course of RF or anti-CCP (aCCP) with the observed EULAR response after each course were analysed.
Methods 302RA patients (pts) fulfilling ACR criteria on stable methotrexate (MTX) but with inadequate response to a single TNFi were treated with 1000 mg RTX on days 1 and 15 and observed up to 2 years (FIRST). Thereof 193 pts entered ReFIRST starting with a 2nd similar treatment course. Up to 2 further courses could be added 24 weeks to 12 months after start of the preceding course. EULAR response was determined at weeks 4, 8, 16, and 24 after each course. In a substudy (n=154) RF, B cell subpopulations, RF-isotypes (RF IgA, RF IgM) and aCCP antibodies were measured at indicated time points.
Results 193 patients (pts) received a 2nd rituximab course 114 pts had 3 courses and 42 pts 4 courses.EULAR response (ER) at week 16 after 1, 2, 3 or 4 courses was observed in 68.0% of 291, 78.0% of 191, 92.0% of 113, and 92.9% of 42 pts. Long/short courseswere defined as a time interval of more/less than 240 days to a next course or end of study. 86 pts had only short, 58 pts only long courses (50 pts mixed).In the substudy (n=154), we analysed the course of RF and aCCP as concomitant factors. RF and aCCP values remained always positive (stable+) in 50% (RF) or in 68% (aCCP) of pts. In 24% RF and in 22% aCCP were constantly negative (stable-) while changes from positive to negative occurred less frequently (RF: 18%, aCCP: 4%). Mean baseline values for RF and aCCP were for stable+: RF=327 U/ml, aCCP=1114; for stable-: RF=10, aCCP=8; for changers: RF=62, aCCP=380. ER after 1, 2, 3 or 4 courses was higher for stable+ pts (RF: 79.2% of 77, 80.7% of 57, 100.0% of 34, 100.0% of 14 pts, aCCP: 75.0% of 104, 88.4% of 78, 98.2% of 54, 90.9% of 22pts) than for stable- pts (RF: 51.3% of 37, 64.0% of 25, 75.0% of 16, 87.5% of 8 pts, aCCP: 64.7% of 34, 65.4% of 26, 66.7% of 15, 100.0% of 7 pts). Categorizing the dose intensity (DI = cumulative dosis/observation time) by tertiles, increased DI was observed for stable- pts (high DI: RF: 43.2%, aCCP: 50%) compared to stable+ pts (high DI: RF: 28.6%, aCCP: 26.0%). Safety: Related to the number of courses the number of SAEs or special AEs (infections or infusion site reactions) did not increase over time.
Conclusions Concerning aCCP status most patients show no seroconversion during multiple courses of RTX. EULAR responses are higher in stable aCCP positive or stable RF positive patients compared to stable RF or aCCP negative patients although dose intensity is higher for stable negative patients. No new safety signal could be detected during long-term treatment.
Disclosure of Interest H.-P. Tony Speakers Bureau: Roche Pharma AG, Grenzach Wyhlen, P. Roll: None Declared, H. Mei: None Declared, L. Gnuegge Employee of: Roche Pharma AG, Grenzach Wyhlen, J. Kandenwein Employee of: Roche Pharma AG, Grenzach Wyhlen, E. Blümner Employee of: EcronAcunovaGmbH Frankfurt, A. Hammes Employee of: EcronAcunova GmbH, Frankfurt, T. Dörner Speakers Bureau: Roche Pharma AG, Grenzach Wyhlen
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