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.

Keywords: A proliferation inducing ligand protein; B-cell activating factor; Sjogren’s syndrome; biologic treatment; myositis; rheumatoid arthritis; systemic lupus erythematosus.

Figure 1.

BAFF and APRIL signalling. BAFF and APRIL are type II transmembrane proteins of the TNF superfamily. BAFF and APRIL become active as homotrimers, although BAFF can also act as a transmembrane form. BAFF binds to three receptors: BAFF-R, BCMA and TACI, mainly during the initial stages of B-cell development. It binds strongly to BAFF-R and TACI. APRIL binds strongly to BCMA and weakly to TACI. Both these cytokines are essential for B-cell survival and maturation, as well as class-switch recombination. Several monoclonal antibodies have been developed to block these pathways. Belimumab (green) is an anti-BAFF that acts only on the soluble form. Tabalumab (blue) and blisibimod (purple) bind to both soluble and transmembrane forms of BAFF, but they differ in their constitution; tabalumab is a monoclonal antibody and blisibimod is a fusion protein composed of four BAFF binding domains assembled on an Fc fragment. Atacicept (orange) is a recombinant fusion protein that blocks BAFF and APRIL interaction with TACI. Modified from Vincent et al. [2014]. APRIL, A proliferation inducing ligand; BAFF, B-cell activating factor; BCMA, B-cell maturation antigen; TACI, transmembrane activator and cyclophillin ligand interactor; TNF, tumour necrosis receptor.