function. Because of redundancy in the cytokine network, targeting a single candidate may not achieve all criteria. Therefore, for an effective therapeutic response, it may be necessary to use a combination of cytokine targets concomitantly or sequentially or target downstream effector molecules shared by several cytokines. A major limitation of these approaches is the increased risk of potentially severe side effects. Local delivery of cytokines or their inhibitors, e.g., by gene therapy, is an appealing alternative to systemic treatment that would greatly improve the risk:benefit ratio of cytokine-based therapy. This approach has been applied successfully in animal models [47, 48]. The increasing availability of biological agents and the potential of gene therapy are exciting, but identifying the right target remains a challenge that can only be overcome by a better understanding of the pathogenesis of SjS.

42.3.3B Cell Activating Factors

BAFF, also known as BLyS (for B lymphocyte stimulator), is a B cell activating factor that acts as a positive regulator of B cell function and expansion (Fig. 42.3). BAFF is a cytokine that prevents apoptosis of autoreactive cells [26]. Different forms of BAFF are present in serum due to translational modifications, principally glycosylation [49]. BAFF levels are elevated in serum and saliva in SjS patients, but no correlation could be shown between serum and saliva levels [50]. However, circulating levels of BAFF in pSjS patients are a marker for disease activity [51].

Two human BAFF antagonists have been developed. One is a human antibody (anti-BLyS, belimumab) that binds to soluble BAFF. The other is a fusion protein of one of the BAFF receptors [52, 53]. SjS patients with elevated BAFF concentrations, hypergammaglobulinemia, elevated levels of autoantibodies, and B cell lymphoma associated with SjS would be candidates for anti-BAFF treatment [54].

Belimumab has recently been shown to be modestly effective in SLE, particularly in those who are serologically active, and to have consistent effects on disease activity, serological parameters, and glucocorticoid sparing [55–57]. A belimumab trial in primary SjS is currently being performed in France.

42.3.4B and T Cell Receptors

42.3.4.1Rituximab

Anti-CD20 (rituximab) is a chimeric humanized monoclonal antibody specific for the B cell surface molecule CD20. CD20 is expressed on the surface of normal and malignant pre-B and mature B lymphocytes, but not on plasma cells. CD20 mediates B cell proliferation and differentiation. In retrospective [58, 59], prospective open-label [15, 20, 60, 61], and double-blind, randomized, placebo-controlled trials [18, 21], rituximab was shown to be effective for at least 6–9 months in patients with primary SjS who have active disease. The intervention appeared to improve