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World's first biopsy-driven RA trial finds tocilizumab superior to rituximab
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ATLANTA — Tocilizumab is more effective than rituximab at achieving significant reductions in disease activity in patients with rheumatoid arthritis who demonstrate low B-cell levels in synovial tissue and are unresponsive to conventional synthetic DMARDs or TNF inhibitors, according to a presenter at ACR/ARP 2019.
“This is the world’s first biopsy-driven randomized clinical trial in patients with rheumatoid arthritis,” Costantino Pitzalis, MD, PhD, FRCP, of Queen Mary University of London and St. Bartholomew’s Hospital, said in a press conference. “The rationale for the study comes from a previous study, in which we demonstrated that about 50% of patients have a very low level of B cells in the synovial biopsy. Why would you give rituximab to patients who have a very low level of infiltration when clearly the disease is active and the cells which are driving the inflammation in those patients are alternative cell types?”
Hypothesizing that alternative B-cell-independent pathways drive inflammation among these patients, and that alternative biologic drugs could be superior to rituximab (Rituxan, Genentech), Pitzalis and colleagues conducted a 48-week, phase 4, open-label, randomized controlled trial. Specifically, the researchers evaluated whether stratifying patients with RA based on synovial B-cell levels could help predict response to rituximab. They recruited 164 patients who had not responded or were intolerant to conventional synthetic DMARDs or at least one TNF inhibitor, from 19 European centers.
Pitzalis and colleagues collected synovial tissue samples at the start of the trial, and histologically classified each patient as either B-cell rich or poor. Patients were randomly assigned to receive either standard therapy with rituximab or tocilizumab (Actemra, Genentech) based on this B-cell classification. The researchers then tested the superiority of tocilizumab compared with rituximab among patients with low B-cell levels at 16 weeks.
The primary endpoint was 50% clinical disease activity index (CDAI) improvement, or better, from baseline, with a co-primary outcome of major treatment response, defined as 50% or better improvement of CDAI as well as a CDAI of 10.1 or lower. Secondary endpoints included CDAI response in patients who were B-cell rich, testing the noninferiority of rituximab compared with tocilizumab. Safety outcomes were reported up to week 48. At total of 81 patients in the rituximab group, and 73 patients who received tocilizumab, completed the trial to week 16.
According to the researchers, 56.1% of patients with low B-cell levels achieved the primary outcome with tocilizumab, compared with 44.7% who responded to rituximab. In addition, 46.3% achieved the coprimary endpoint while taking tocilizumab, compared with 23.7% with rituximab. Proportions of patients in remission were 36.6% among patients treated with tocilizumab and 15.8% in those who received rituximab. Approximately 87.8% of those treated with tocilizumab reached moderate or good EULAR response, compared with 65.8% of those in treated with rituximab.
There were no significant differences found among the cohort of patients with high B-cell levels, across the majority of endpoints. Patients who received tocilizumab demonstrated more adverse and serious adverse events, including infections, compared with those treated with rituximab.
“The implications of this can be massive,” Pitzalis said. “In terms of trying to determine from the synovial biopsy, as it happens, for example, in breast cancer or other types of disease in which you don’t give tamoxifen to every patient with breast cancer — you give it to patients who are estrogen-receptor positive, but not to the patients who are estrogen-receptor negative, the same applies to monoclonal antibodies. So, why should we continue in rheumatoid arthritis to give drugs on a trial basis in this fashion?”
He added that the study highlights the importance of integrating molecular pathology into clinical practice.
“Making the diagnosis is not sufficient,” he said. We really need to know what the pathology of the patient is, so we can give the right drug to the right patient. This has major socioeconomic implications as well, as rheumatoid arthritis is a common inflammatory condition affecting 1% of the world’s population.”
“The biologic drugs are very expensive indeed, and cost between $15,000 and $30,000 a year for a patient,” he added. “Therefore, giving the wrong drug when you start a treatment has implications both in terms of wasting important resources, but also, more importantly, if the patient doesn’t respond, the disease remains uncontrolled, the damage of the disease progresses and the disability increases. Therefore, the long-term consequences of society are very significant.” – by Jason Laday
Reference:
Pitzalis C. #Abstract 2911. 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. Presented at: American College of Rheumatology/Association of Rheumatology Professionals Annual Meeting; Nov. 9-13, 2019; Atlanta.
Disclosure: McCormick reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.