Targeting the B Cell in Rheumatoid Arthritis

There has been renewed interest in the B cell as a target for the treatment of rheumatoid arthritis (RA) over the past decade. Efficacy with rituximab has been demonstrated in randomised clinical trials (RCTs) resulting in regulatory approval for patients failing tumour necrosis factor (TNF) inhibitors. Although the actual mechanism of action has not been clearly delineated, several molecules are under development to modify B cell number/function in hope of superior efficacy/safety or ease of administration. The safety of rituximab over the intermediate time point has been comparable to that seen with other biologic disease-modifying anti-rheumatic drugs (DMARDs). The recent report of cases of progressive multifocal leukoencephalopathy in three patients receiving rituximab for RA is a concern and, for now, limits rituximab to salvage therapy for the treatment-resistant patient. How this impacts on other B-cell inhibitors under development is not yet clear. Development of biomarkers that will assist our therapeutic decisions to enhance the benefit/risk ratio for our patients are needed as we move forward with further selective targeted therapies.

Over the past decade, therapies targeting B-cell activity have been demonstrated to be effective in RA. In 2001, Edwards et al. reported significant clinical improvement in five RA patients refractory to multiple DMARDs treated with rituximab plus cyclophosphamide and high-dose corticosteroids . Significant sustained improvement was reported and this small study received great publicity in the lay press. This observation led to a development programme that resulted in the regulatory approval of rituximab for RA patients failing TNF inhibitors. RCTs over the past several years have been conducted to evaluate the efficacy and safety of rituximab in different populations of patients, including those with early RA, which have helped to define the efficacy and safety of the treatment. Several other approaches to B-cell modulation such as monoclonal antibodies and soluble receptors for B-cell-activating factor of the TNF family (BAFF) have been and are presently being evaluated in RCTs. This article will review the published data on B cell modulation in RA.

Why the B Cell?

B cells have been considered to play a role in the pathogenesis of RA for over 60 years since the discovery of rheumatoid factor activity and since the more recent discovery of antibodies to citrullinated proteins. However, there was limited interest in the B cell as a target as the prevailing theory over the past 20 years was that RA was a T-cell dependent disease despite initial limited success in modifying T-cell activity in clinical trials. Subsequent recognition of the importance of cytokines in the pathogenesis of RA and the success of inhibitors to tumour necrosis factor (TNF) alpha and interleukin 1 resulted in a paradigm shift in RA treatment.

With the Edwards report and recognition that 50% of patients treated with TNF inhibitors fail to demonstrate a clinically significant response, interest in basic B cell biology in RA was renewed. Preclinical studies demonstrated that B cells were necessary for several animal models of inflammatory arthritis and murine lupus . Synovial infiltration with B cells and plasma cells is common with extra-lymphatic germinal centres found in rheumatoid synovium in approximately 30% of patients. These germinal centres have been demonstrated to be B cell dependent. Cell transfer experiments in severe combined immunodeficiency (SCID) mice demonstrated the failure of development of germinal centres after B-cell depletion with rituximab, suggesting a critical role of the B cell in CD4 + T-cell activation in the germinal centres.

Edwards and colleagues have suggested that RA may be mediated by self-perpetuating B cell clones that may explain the disease persistence . Using surface B-cell receptors that have rheumatoid factor activity binding to immune complexes, it was postulated that T-cell tolerance to autoantigens could be breached, resulting in ongoing B-cell-induced T-cell activation. In addition, direct binding of complexed IgG RF to the Fc receptor Fc gamma 111a on macrophages could generate TNF alpha production.

How does B-cell modulation or depletion impact the pathogenesis of RA? Although it is not clear which is the most important mechanism in the inflammatory process, three pathways have been postulated . As described above, B-cell differentiation to plasma cells producing RF and anti-cyclic citrullinated peptide (CCP) antibodies is found in 70–80% of RA patients and treatment with rituximab can result in a decrease in titres of these autoantibodies . In addition to autoantibody production, B cells are efficient antigen-presenting cells (APCs), resulting in T cell activation. An antigen-specific B cell has a specific antigen membrane bound Ig that can process and present antigens with ≥1000-fold more efficiency than other APCs such as dendritic cells . In addition, activated B cells express co-stimulatory molecules, CD80/86 and CD40, necessary for T-cell activation. B cells also produce cytokines such as lymphotoxin that is crucial for the development of tertiary lymphoid structures as well as IL10, IL4 and IL 6, which have both anti-inflammatory and pro-inflammatory capabilities .

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