Tocilizumab More Effective than Rituximab in RA Patients with Low B-Cell Levels in Synovial Tissue

ATLANTA —New research discovered that tocilizumab is more effective than rituximab in achieving low disease activity in patients with rheumatoid arthritis whose synovial tissue show a low level of B cell infiltration and did not respond to conventional synthetic disease-modifying anti-rheumatic drugs (conventional synthetic DMARDs) or tumor necrosis factor (TNFi) inhibitors first (Abstract# 2911).

Rheumatoid arthritis (RA) is the most common type of autoimmune arthritis. It is a chronic disease that causes joint pain, stiffness, swelling and decreased movement of the joints. Small joints in the hands and feet are most commonly affected. Sometimes RA can affect your organs, such as eyes, skin or lungs.

“Approximately half of RA patients lack treatment responses to expensive biologic therapies that also carry the risk of side effects. Predictive markers of response could help stratify RA,” said Costantino Pitzalis MD, PhD, FRCP, director of the Center for Experimental Medicine and Rheumatology at Barts and the London School of Medicine and Dentistry, and the study’s lead author. “This leaves a major unmet clinical need and an urgent necessity to identify markers of treatment response to avoid delays in disease control, unnecessary exposure to potentially toxic drugs and considerable waste of resources.”

B-cells are pivotal to RA pathogenesis, validated by the efficacy of the B cell-depleting agent rituximab, which is approved for use in RA patients after inadequate response to conventional synthetic DMARDs and TNFi. However, only 30 percent of these difficult to treat patients achieve a 50 percent improvement (ACR50 response) in disease activity, at six months after starting rituximab. 

In a previous trial, the study’s researchers found that, in patients with early RA, more than 50 percent had low levels or an absence of B-cell infiltration in their synovial tissue. For this study being presented at the 2019 ACR/ARP Annual Meeting, we hypothesized that alternative B cell independent pathways drive inflammation in this subgroup, and that alternative biologic agents to rituximab should work more effectively in these patients.

This 48-week, phase four, open-label randomized controlled trial evaluated whether or not stratifying RA patients according to synovial B-cell rich or poor status would help predict response to rituximab. Patients were recruited from 19 European medical centers who did not respond, or were intolerant, to conventional synthetic DMARD therapy and at least one TNFi l. Researchers obtained synovial tissue samples at the beginning of the trial, and histologically classified them as either B-cell rich or B-cell poor to balance the randomization of 164 patients in equal groups to receive either rituximab or tocilizumab

The researchers tested the superiority of tocilizumab over rituximab at 16 weeks in the B-cell poor patient population. The study’s primary endpoint was a Clinical Disease Activity Index (CDAI) improvement of 50 percent or higher from baseline. The co-primary endpoint was the Major Treatment Response, which was equal to CDAI improvement of 50 percent or higher along with a CDAI of 10.1 or lower. The secondary outcomes included an assessment of CDAI response in the B-cell rich patient cohort, where they evaluated the non-inferiority of rituximab compared to tocilizumab. They also reported safety data for the therapies up to week 48 of the trial.

The researchers found that 81 of 83 patients who received rituximab and 73 of 81 patients who received tocilizumab completed treatment to week 16 of the trial. Baseline characteristics among the two treatment groups were similar. In the B-cell poor cohort, a numerically higher proportion of patients responded to tocilizumab (56.1 percent) compared to rituximab (44.7 percent) considering the primary outcome. A significantly greater proportion of patients responded to tocilizumab (46.3 percent) compared to rituximab (23.7 percent) considering the co-primary outcome as well as several additional secondary endpoints including the proportion of patients in remission at 36.6 percent versus 15.8 percent. The number of patients reaching moderate or good EULAR response was 87.8 percent versus 65.8 percent, respectively.

In the B-cell rich cohort, the researchers found no significant difference in the majority of endpoints. Patients treated with tocilizumab also had a higher number of adverse and serious adverse events, such as infections, compared to those treated with rituximab.

Overall, tocilizumab was more effective than rituximab at achieving both low levels and significant falls in disease activity in RA patients classified as B-cell poor who have failed conventional synthetic DMARDs and TNFi therapy, the study’s findings show. 

“These findings are important as they indicate that patients with low level of B cells in the synovial tissue are less likely to respond to rituximab and should be treated with alternative medications,” said Dr. Pitzalis. 

 

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About the ACR/ARP Annual Meeting

The ACR/ARP Annual Meeting is the premier meeting in rheumatology. With more than 450 sessions and thousands of abstracts, it offers a superior combination of basic science, clinical science, tech-med courses, career enhancement education and interactive discussions on improving patient care. For more information about the meeting, visit https://www.rheumatology.org/Annual-Meeting, or join the conversation on Twitter by following the official #ACR19 hashtag. 

About the American College of Rheumatology

The American College of Rheumatology (ACR) is an international medical society representing over 8,500 rheumatologists and rheumatology health professionals with a mission to empower rheumatology professionals to excel in their specialty. In doing so, the ACR offers education, research, advocacy and practice management support to help its members continue their innovative work and provide quality patient care. Rheumatologists are experts in the diagnosis, management and treatment of more than 100 different types of arthritis and rheumatic diseases.

ABSTRACT

A Randomized, Open Labelled Clinical Trial to Investigate Synovial Mechanisms Determining Response – Resistance to Rituximab versus Tocilizumab in Rheumatoid Arthritis Patients Failing TNF Inhibitor Therapy

Background/Purpose: Although biologic therapies have transformed the outlook for rheumatoid arthritis (RA), the lack of a major treatment response in over 50% of patients, the potential side effects and the high cost of these drugs have highlighted the need to define predictive markers of response and to stratify patients according to therapeutic outcome. B-cells are pivotal to RA pathogenesis, validated by the efficacy demonstrated by the B cell depleting agent rituximab (RTX). RTX is licensed for use following failure of conventional synthetic (cs)-DMARDs and TNF inhibitor (TNFi) therapy. However, in this increasing therapeutically resistant cohort only 30% of patients achieve an ACR50 response at 6 months. We have recently demonstrated in an early RA cohort1synovial heterogeneity with over 50% of patients showing low/absence of synovial B-cell infiltration. This prompted us to test the hypothesis that in these patients an alternative biologic agent targeting alternative pathways maybe more effective. We report results from the first pathobiology-driven randomized controlled trial (RCT) in RA (R4RA) evaluating whether patient stratification according to the synovial B-cell rich/poor status enriches for response/non response to RTX.

Methods: R4RA is a 48- week phase IV open-label RCT conducted in 19 European centers that recruited patients failing or intolerant to csDMARD therapy and at least one TNFi. Synovial tissue was obtained at trial entry and classified histologically as B-cell rich (BCR) or B-cell poor (BCP). Patients were randomized to receive standard therapy with RTX or tocilizumab (TCZ) stratified according to histological classification. The study was powered to test in the BCP population superiority of TCZ over RTX at 16 weeks. The primary and co-primary end-points were defined respectively as Clinical Disease Activity Index (CDAI) ≥50% improvement from baseline and Major Treatment response (MTR)= CDAI improvement ≥ 50% and CDAI ≤10.1. Secondary outcomes included assessment of CDAI response in the BCR cohort where non-inferiority of RTX compared to TOCI was evaluated. Safety data up to week 48 is reported.

Results: The trial recruited to target with a power of 89.5%. 164 patients were randomized, 83 received RTX and 81 TCZ. 81/83 RTX and 73/81 TCZ patients completed treatment to week 16 (primary endpoint). Baseline characteristics were comparable among treatment groups (Tab 1). In the BCP population a numerically higher number of patients achieved the primary outcome and a statistically significantly higher number of patients achieved co-primary endpoint (MTR) as well as in a number of additional secondary endpoints in the TCZ group (Tab 2). In the BCR population there was no significant difference in the majority of endpoints (Tab 2).  A higher number of adverse and serious adverse events such as infections in patients treated with TCZ compared to RTX were recorded (Tab 3).

Conclusions: In a RA BCP population failing csDMARDs and TNFi therapy, TCZ is more effective than RTX in achieving both low levels and significant falls in disease activity. In a BCR RA population RTX is non inferior to TCZ for the majority of outcome measures evaluated. 

1. Humby, M.Lewis et al Ann Rheum Dis. 2019 Mar 16. pii: annrheumdis-2018-214539.

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