Prevention of clinically manifest rheumatoid arthritis by B cell directed therapy in the earliest phase of the disease

Rheumatoid Arthritis (RA) is a prototype immune-mediated inflammatory disease, with important consequences for the individual patient as well as for society. RA is characterized by inflammation of the synovial membrane, leading to invasion of synovial tissue into the adjacent cartilage matrix with degradation of articular cartilage and bone as a result. The past few years, research in the field of RA has focused on the earliest stages of disease, leading to the discovery that circulating auto-antibodies, increased acute phase reactants, and asymptomatic synovitis precede the clinical onset of the disease. Recent work has also shown that there is a therapeutic window of opportunity. B cell-directed treatment, known to be effective in later stages of RA, could possibly lead to a delay of disease onset or prevention of the development of symptomatic RA when administered in the earliest phase of the disease. This randomized, double-blind, placebo-controlled study aims at the delay/prevention of clinically manifest RA in patients with pre-clinical RA, using B cell-targeted therapy. Ninety patients with pre-clinical RA, defined by arthralgia with elevated serum IgM-RF and/or ACPA together with increased acute phase reactants and/or synovitis on MRI or ultrasound, will be randomized to receive a single infusion with rituximab (1000 mg iv) or placebo in a 1:1 ratio. All patients will be followed for 4 years to assess the development of arthritis and efficacy outcome measures, such as the disease activity score evaluated in 28 joints (DAS28), ESR, CRP, joint destruction, disability, and quality of life. In addition, we will perform detailed molecular studies to determine the effects on the inflammatory process and the underlying mechanisms. We will monitor the B and T cell receptor repertoire at single-clone resolution and perform sophisticated transcriptomics. In addition to clinical and molecular studies, we will perform a cost-effectiveness study.