Systemic Lupus Erythematosus

Bruton's tyrosine kinase (BTK) plays a critical role in B cell development and function. We recently described a selective BTK inhibitor, RN486, that blocks B cell receptor (BCR) and Fcγ receptor signaling and is efficacious in animal models of arthritis. The aim of this study was to examine the potential efficacy of BTK in systemic lupus erythematosus (SLE), using an NZB × NZW mouse model of spontaneous SLE. Mice received RN486 or its vehicle (administered in chow) at a final concentration of 30 mg/kg for 8 weeks, starting at 32 weeks of age. The administration of RN486 completely stopped disease progression, as determined by histologic and functional analyses of glomerular nephritis. The efficacy was associated with striking inhibition of B cell activation, as demonstrated by a significant reduction in CD69 expression in response to BCR crosslinking. RN486 markedly reduced the secretion of IgG anti-double-stranded DNA (anti-dsDNA) secretion, as determined by enzyme-linked immunosorbent and enzyme-linked immunospot assays. Flow cytometric analysis demonstrated depletion of CD138(high) B220(low) plasma cells in the spleen. RN486 inhibited secretion of IgG anti-dsDNA but not IgM anti-dsDNA, suggesting that pharmacologic blockade of BTK resembles the reported transgenic expression of low levels of endogenous BTK in B cells. In addition, RN486 may also impact the effector function of autoantibodies, as evidenced by a significant reduction in immune complex-mediated activation of human monocytes in vitro and down-regulation of the expression of macrophage-related and interferon-inducible genes in both the kidneys and spleens of treated mice. Collectively, our data suggest that BTK inhibitors may simultaneously target autoantibody-producing and effector cells in SLE, thus constituting a promising therapeutic alternative for this disease.

Background: In expanding follicles the anti-Mullerian hormone (AMH) is selected from granulosa-cell secretions as the best endocrine marker that can measure ovarian reserve. Systemic Lupus Erythematosus (SLE) is an autoimmune illness of several systems. It is frequent in young women of reproductive age and may have a negative impact on their fertility due to SLE activity and therapy. Methods: This case-control retrospective study conducted on 50 patients with SLE and 50 healthy controls who fulfilled the 1997 ACR criteria. By measuring AMH levels, assessing an ovarian volume (OV) and total antral follicle count (AFC) by transvaginal sonar (TVS) in comparison to healthy controls. An analysis was carried out on the association of SLE disease activity with AMH, OV and AFC. Results: SLE patients had decreased levels of AMH, OV and AFC, correlating with age, activity and damage levels of SLE. Displaying a negative consequence of SLE. In the SLE Group, the CD4+Tcells and NK cells were significantly reduced (p<0.05). Conclusion: AMH levels and AFC were decreased in SLE women with autoimmune activity and CD8+ T cell activation, used as useful markers and accounting for a high proportion of women with low ovarian reserve.