B cell targeting in rheumatoid arthritis (RA)

Referent: Prof. Thomas Dörner

B cells have been shown to play a pivotal role in the pathogenesis of rheumatoid arthritis (RA), with rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies preceding the onset in approximately 50% of patients with RA. (1,2) A number of patients develop B cell aggregates or GC-like structures in the inflamed synovium further supporting their pathogenic role in RA. B cells participate in numerous inflammatory pathways and the humoral immune response, and have been shown to play a role in secretion of proinflammatory cytokines, antigen presentation, T-cell activation and autoantibody production and self-perpetuation. These cells represent a link between innate and adaptive immunity and are also of substantial importance for immune memory (3). New therapeutic strategies, including B cell depletion and indirect B cell targeting by blocking B cell survival factors/cytokines, are being developed to prevent the emergence of these autoimmune B cells. In addition, other anti-cytokine therapies, such as blocking TNF inhibition lead to a reduction of memory B cells which serve as surrogate of response.
In particular, anti-CD20 monoclonal antibodies (mAbs) are a depletion therapy that were initially shown to be effective in patients with lymphoma who also had rheumatic disease. (4,5)  The efficacy of rituximab plus methotrexate is now well established, and this therapeutic option has been integrated into the treatment of RA. (6-9)  In addition to this, the novel anti-CD20 mAbs, ofatumumab and other monoclonals have also been found to be effective in patients with RA in Phase I/II trials, confirming B-cells as a target in RA. (10,11)
While the safety and efficacy of B cell targeting has improved the treatment of difficult to treat patients with RA, it also provided unique possibilities to study the effects of anti-CD20 therapy in humans. In this context, distinct repopulation characteristics of short- versus long-term responders were identified. (12)  These studies could also demonstrate that re-establishing  of immune tolerance was associated with a predominance of naive B cells in contrast to the dominance of antigen-experienced memory B cells prior to successful therapy. Moreover, recent studies suggest that certain mucosally induced B cell subset also identified as steady state plasmablasts (13)  appeared to be resistant to rituximab therapy and do not correlate with disease actrivity. (14)
Potential new approaches to B cell depletion in RA, including IL6R-blockade, CD22 binding and SyK inhibition, have shown promise in early pre-clinical and clinical trials, with future results expected to further elucidate the role of B cell depletion in RA therapy.

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14. Mei HE et al., Blood 2010;116(24):5181−90.