119 B-cells during preclinical phase of rheumatoid arthritis Introduction In rheumatoid arthritis (RA), B lineage cells play an important role in disease development. They produce characteristic autoantibodies such as rheumatoid factor (IgM-RF) and anti-citrullinated protein antibodies (ACPAs) which are linked to a more persistent and destructive disease course. Consequently, B lineage cells have been identified as a therapeutic target, and treatments like the anti-CD20 monoclonal antibody rituximab (RTX) that results in B cell depletion have been developed, are effective and are currently widely used in established RA [1,2]. RA may be preceded by a phase in which autoantibodies are detectable in peripheral blood and individuals suffer from arthralgia, with no clinically evident arthritis [3–5]. A small portion of these so-called RA-risk individuals will develop arthritis in the short term [6]. In RA-risk individuals, the PRAIRI study demonstrated that a single dose of rituximab significantly delayed onset of arthritis [7]. It is yet unclear if there is a certain risk signature associated with progression from RA-risk to RA and/or response to rituximab. We recently demonstrated in RA patients that non-response to rituximab was associated with an incomplete disruption of the B cell receptor (BCR) repertoire, with certain BCR clones persisting throughout the therapeutic effect range [8]. These findings prompted us to investigate the effects of rituximab on the BCR repertoire during the at-risk phase. We had the unique opportunity to do so, by evaluating the BCR repertoire behaviour in RA-risk individuals who were treated with RTX or placebo in the randomized controlled PRAIRI study [7]. This phase-IIb randomized controlled trial (RCT) demonstrated that treatment with a single infusion of rituximab in the pre-clinical phase of RA results in a delay in arthritis development of 12 months compared with placebo treatment at the point when 25% of the subjects had developed arthritis [7]. Additionally, we conducted a study in a novel cohort of at-risk individuals not treated with rituximab to determine the phenotype of B cells expressing the most frequent BCR signatures, allowing for detailed insight into B cell clonal changes in the RA-risk phase during the natural course of disease development. Here, we report for the first time the effects of rituximab on the BCR repertoire during the preclinical phase of RA and the dynamics and phenotype of B cells that express the most dominant BCR signatures during this time. Materials and methods Patients From 2010 until 2015 individuals with a positive ACPA and/or IgM-RF status and arthralgia, and at least one of the following features: CRP > 0.6 mg/L or subclinical synovitis assessed by ultrasound or by MRI, but no clinical signs of arthritis were 6
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