A strategic biomarker trial to personalise biologic therapy of rheumatoid arthritis

Background. Rheumatoid arthritis (RA) is an inflammatory destructive joint disease and affects 1% of the population. Biologicals with different modes of action (MoA) are licensed for therapy, but low disease activity (LDA) or remissions (REM), today`s targeted outcomes, are seen in a similar and small proportion of patients ( 20%). No markers are known that allow to personalise the choice of a specific MoA. Hypothesis. We hypothesize that a trial employing biologicals in a parallel, randomized way, allows finding biomarkers for prediction of optimal response to each of these drugs. Patients and Method. We propose a randomised, strategic biomarker trial of RA patients with failure to methotrexate to one of the four current biological modes of action: targeting TNF (infliximab); costimulation (abatacept); IL-6R (tocilizumab); and B cells (rituximab); all agents are licensed for RA and have evidence for efficacy in this indication. Predictors of response to therapy after 6 months will be analysed, and include baseline and followup assessments of clinical, functional, structural, laboratory tests (routine, autoantibodies, cytokines, gene expression, and susceptibility genes). In a second phase, patients not achieving LDA/REM will be randomised to one of the remaining MoA. Patients will be enrolled over 18 months at four centers, which start new biologicals in 200 patients/year; 50 patients per group will be included, and studied for a period of 12 months. Expected Results. Since patients have been randomized in parallel, data obtained at baseline and followup will allow finding predictors of treatment success with different biologicals.

Background. Rheumatoid arthritis (RA) is an inflammatory destructive joint disease that affects 1% of the population. Biologicals with different modes of action (MoAs) are licensed for therapy, but low disease activity (LDA) or remissions (REM), todays targeted outcomes, are seen in a similar and small proportion of patients. Applying differential decision making when prescribing biologicals is difficult due to lack of supportive data in this respect. The purpose of the BioBio study is to identify biomarkers that would be associated with future response to the respective MoA.Methods. We performed an open label prospective clinical trial of RA patients with failure to methotrexate, who were randomized to one of the four current biological MoAs: targeting TNF by infliximab, T?cell ?stimulation by abatacept, Interleukin?(IL?)6 receptor (IL?6R) by tocilizumab, and B cells by rituximab. Patients were assessed clinically, and for function, structural damage, laboratory tests, and biomarkers at baseline, 3, 6, 9, and 12 months; biomarkers were also determined at 2 weeks. Patients could advance to one of the remaining 3 MoAs either by early escape (for patients who did not improve, or worsened, at 3 month), or by failing to reach the treatment target of low disease activity or remission at 6 months.Predictors of response to therapy after 6 months will be analysed, and include baseline and followup assessments of clinical, functional, structural, laboratory tests (routine, autoantibodies, cytokines, gene expression, and susceptibility genes). In a second phase, patients not achieving LDA/REM will be randomised to one of the remaining MoA. Patients will be enrolled over 18 months at four centers, which start new biologicals in ~200 patients/year; 50 patients per group will be included,and studied for a period of 12 months.Expected Results. Since patients have been randomized in parallel, data obtained at baseline and follow?up will allow finding predictors of treatment success with different biologicals.