Modulating proximal cell signaling by targeting Btk ameliorates humoral autoimmunity and end-organ disease in murine lupus.

INTRODUCTION: Systemic lupus erythematosus is a chronic autoimmune disease characterized by an abundance of autoantibodies against nuclear antigens. Bruton's tyrosine kinase (Btk) is a proximal transducer of the BCR signal that allows for B-cell activation and differentiation. Recently, selective inhibition of Btk by PCI-32765 has shown promise in limiting activity of multiple cells types in various models of cancer and autoimmunity. The aim of this study was to determine the effect of Btk inhibition by PCI-32765 on the development of lupus in lupus-prone B6.Sle1 and B6.Sle1.Sle3 mice. METHODS: B6.Sle1 or B6.Sle1.Sle3 mice received drinking water containing either the Btk inhibitor PCI-32765 or vehicle for 56 days. Following treatment, mice were examined for clinical and pathological characteristics of lupus. The effect of PCI-32765 on specific cell types was also investigated. RESULTS: In this study, we report that Btk inhibition dampens humoral autoimmunity in B6.Sle1 monocongenic mice. Moreover, in B6.Sle1.Sle3 bicongenic mice that are prone to severe lupus, Btk inhibition also dampens humoral and cellular autoimmunity, as well as lupus nephritis. CONCLUSIONS: These findings suggest that partial crippling of cell signaling in B cells and antigen presenting cells (APCs) may be a viable alternative to total depletion of these cells as a therapeutic modality for lupus.

Biomarkers of rheumatoid arthritis: recent progress.

IMPORTANCE OF THE FIELD: Biomarkers are emerging as vital tools for early diagnosis, prognostication and disease management in chronic diseases, including rheumatoid arthritis (RA). AREAS COVERED IN THIS REVIEW: This review discusses diagnostic, prognostic and theranostic biomarker candidates for RA that are being studied at present. WHAT THE READER WILL GAIN: The reader will gain a better understanding of the different classes of markers being proposed as potential biomarkers for RA, and how they compare with each other. TAKE HOME MESSAGE: At present, several molecules are showing varying degrees of promise as potential biomarkers in RA. These include serum rheumatoid factors and anti-cyclic citrullinated protein antibodies, a couple of acute phase proteins and pro-inflammatory cytokines expressed in the serum and/or diseased joints, notably IL-1, IL-6, TNF-α, MCP-1 and MIP-α, as well as molecules released by damaged synovial tissue, cartilage and bone. Continuing proteomic and metabolomic efforts are rapidly expanding this repertoire of potential biomarker candidates. Large-scale longitudinal trials are clearly needed where several biomarker candidates can be assessed in parallel, relative to current yardsticks. The ultimate goal is to distill out a subset of informative biomarkers, presumably representing distinct pathogenic pathways, which will enable the rheumatologist to prognosticate, predict and actively manage the disease course in RA.