The BAFF-var Polymorphism as a Biomarker of Response to B-depletive Treatment in Patients Affected by Systemic Lupus Erythematosus and Rheumatoid Arthritis: a Prospective Study

BACKGROUND

Systemic lupus erythematosus (SLE) and Rheumatoid Arthritis (RA) are multisystem immune-mediated disease characterized by a complex pathogenesis, where an abnormal activation of the humoral immune response, with overproduction of autoantibodies, demonstrated to have a pivotal role.

B lymphocyte stimulator (BAFF) is a cytokine and drug target that is primarily produced by monocytes and neutrophils. It is essential for B-cell activation, differentiation and survival. Overexpression of BAFF was demonstrated to be associated with more severe pattern of SLE and correlate to more frequent positivity for anti-Sm (OR 1.7; 95% CI 1.3, 2.2), high titre anti-dsDNA (OR 1.5; 95% CI 1.1, 2.2), lower C3 (OR 1.3; 95% CI 1.0, 1.8), higher proteinuria (OR 1.8; 95% CI 1.4, 2.4) and increased risk of flare (HR 1.86; 95% CI 1.29, 2.68). Similarly, high levels of BAFF have been observed in blood and synovial fluid of RA patients and were demonstrated to correlate with higher disease activity in RA.

Belimumab and rituximab are the prototypical form of B-cell targeted therapies currently approved for SLE and RA, respectively.

Belimumab, a fully humanized monoclonal antibody directed against BAFF, is the first biological drug licensed and approved for use in combination with standard immunosuppressants in SLE. Data from RCTs demonstrated that higher disease activity, anti-dsDNA positivity, low complement and corticosteroid treatment may predict a higher benefit to belimumab. However, around 40% of subjects did not achieve an adequate response.