B-cell survival factors in autoimmune rheumatic disorders

Abstract

Autoimmune rheumatic disorders have complex etiopathogenetic mechanisms in which B cells play a central role. The importance of factors stimulating B cells, notably the B-cell activating factor (BAFF) and A proliferation inducing ligand (APRIL) axis is now recognized. BAFF and APRIL are cytokines essential for B-cell proliferation and survival from the immature stages to the development of plasma cells. Their levels are increased in some subsets of patients with autoimmune disorders. Several recent biologic drugs have been developed to block this axis, namely belimumab [already licensed for systemic lupus erythematosus (SLE) treatment], tabalumab, atacicept and blisibimod. Many clinical trials to evaluate the safety and efficacy of these drugs in several autoimmune disorders are ongoing, or have been completed recently. This review updates the information on the use of biologic agents blocking BAFF/APRIL for patients with SLE, rheumatoid arthritis, Sjögren's syndrome and myositis.

Unintended Immunological Consequences of Biologic Therapy

“…BAFF is a TNF-superfamily member secreted by multiple cell types (T follicular helper cells, monocytes, and dendritic cells) that is critical for maintaining B cell homeostasis [106–108, 97]. Elevated plasma BAFF levels have been correlated with increased disease activity in SLE and return of anti-dsDNA antibodies following rituximab treatment [106, 97].…”

“…However, it remains unclear if combined anti-B cell therapy may create synergistic immunosuppressive effects such as prolonged hypogammaglobulinemia, increased incidence of PML, or other unexpected immunosuppression. Tabalumab and blisibimod (fusion peptide antagonist), two additional biologics that target soluble and membrane-bound BAFF, were examined in initial clinical trials for efficacy in SLE [108]. Despite initial positive data, further development of tabalumab was halted by its manufacturer due to perceived low therapeutic window compared to placebo.…”

“…APRIL is a TNF superfamily member of cytokines which acts in conjunction with BAFF by binding TACI, B-cell maturation antigen receptors on B cells to promote B cell development and proliferation [108]. Atacicept failed to meet 20% improvement criteria for RA, and in trials for MS, a paradoxical worsening of CNS lesions was seen [114].…”

Vaccine development for rheumatoid arthritis

“…In that regard, this vaccine design would rely on confirming that arthritogenic T-cells, which have evaded negative selection during T-cell development, would now recognize arthritogenic antigens. Increased levels of B-cell activating factor (BAFF) and a proliferation inducing ligand (APRIL) are associated with autoimmune disorders such as systemic lupus erythematosus and RA [45]. Thus, BAFF and APRIL have been linked to B-cell survival, differentiation, proliferation and antibody production which are likely to influence RA autoimmunity.…”

VNAR single-domain antibodies specific for BAFF inhibit B cell development by molecular mimicry

“…BAFF overproduction appears to play a role in a variety of autoimmune disorders and certain B cell malignancies and BAFF-blocking antibodies have been developed for their treatment, including belimumab, tabalumab, and blisibimod (peptibody) (for reviews see (Stohl, 2012; Stohl and Hilbert, 2012). While the approval of belimumab represents a major advance for mild to moderate Systemic Lupus Erythematosus (SLE), not all patients respond and the development of tabalumab was discontinued due to an insufficient level of efficacy despite evidence of BAFF inhibition (Morais et al, 2015). …”