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In the past decade, the treatment of autoimmune diseases [such as rheumatoid arthritis (RA) and Crohn disease] has fundamentally changed with the introduction of targeted therapies. On the contrary, the treatment of Sjögren’s syndrome (SS) and especially the eye and mouth dryness that are its main manifestations has remained purely symptomatic and the systemic effects, such as inflammatory arthritis continue to be treated with nonspecific immunosuppressive medications. As our understanding of the pathophysiology has improved and new measures of disease activity have been designed, SS is poised to enter the era of biological therapies.
One of the most striking pathophysiological features of SS is the infiltration of tissues such as salivary glands with lymphocytes, both B and T cells. The CD4+ but also CD4−CD8−T cells promote local inflammation by producing proinflammatory cytokines such as interferon-γ and interleukin (IL) 17. Moreover, follicular T helper cells (Tfhs) help organize locally secondary lymphoid structures and promote B-cell activation. Although the initiating factor(s) and exact mechanisms are still unclear, T cells are attracted to the salivary glands by chemokines and encounter a locally activated epithelium that can further promote their activation. Moreover, imbalance between effector and regulatory T (Treg) cell activity may also contribute to both the local and systemic manifestations of the disease, making T cells prime therapeutic targets ( Fig. 19.1 ).
T cells bind to antigen-presenting cells (APCs), such as dendritic cells and B cells through a cognate interaction but rely on a second signal to stabilize and enhance the rather weak T-cell receptor (TCR) antigen–major histocompatibility complex (MHC) interaction. This second costimulatory signal is absolutely necessary for a productive immune response and can readily be targeted using monoclonal antibodies and soluble receptors. In the following sections, we describe the main pathways that have been targeted in SS.
One of the main costimulatory molecules that delivers this second signal to T cells is CD28. CD28 binds to its ligand B7 (CD80 or CD86) on APC and enhances the TCR-initiated T-cell activation. Then after this initial activation phase, T cells express in lieu of CD28, CTLA4 that also binds to B7 but delivers an inhibitory signal to T cells, effectively ending activation. In SS, salivary gland epithelial cells also express B7 molecules that show an increased affinity for CD28 and decrease binding for CTLA4. Capitalizing on this naturally occurring phenomenon, the antirheumatic drug abatacept was engineered. Abatacept is a fusion molecule of CTLA4 and immunoglobulin that can effectively interrupt T-cell activation and is proven to be an effective treatment for RA.
As RA patients often have secondary SS, the effect of abatacept was evaluated in 32 patients with RA and secondary SS in an open-label 1-year pilot study. Abatacept had a modest effect, primarily on eye dryness (increase in the Schirmer test result from 3.6 ± 4.6 mm/5 min at 0 weeks to 5.5 ± 7.1 mm/5 min at 24 weeks of treatment) and less on oral sicca symptoms. Interestingly, abatacept decreased the levels of rheumatoid factor (RF) and total immunoglobulin (Ig) G, but had no effect on the levels of Ro/SSA.
In a small, open label study in primary SS patients, abatacept was given subcutaneously to 15 patients for 24 weeks. The primary endpoint was the European League Against Rheumatism (EULAR) Sjögren Syndrome Disease Activity Index (ESSDAI). ESSDAI significantly decreased while the patients were receiving treatment, only to increase back to baseline 24 weeks after treatment ended. The salivary and lacrimal flows did not change significantly as in the aforementioned secondary SS study, but the RF and total IgG did decrease.
In yet another study, 11 patients with primary SS received eight doses of abatacept. Abatacept treatment led to modest decrease in salivary gland inflammation as measured by the number of lymphocytic foci. Saliva production increased modestly, with this increase being statistically significant only when adjusted for disease duration. Serum IgG decreased slightly after treatment.
Overall, these small studies showed that CD28–B7 interaction might be an important pathway for intervention in primary SS. A large, placebo control phase III clinical trial in patients with primary SS of less than 7 years’ duration is currently underway. The primary outcome of the blinded study is ESSDAI at 24 weeks, with an open label extension for another 24 weeks.
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