Complex Immune Biomarkers of Treatment Response and Disease Outcomes in Rheumatoid Arthritis.

摘要

Rheumatoid arthritis (RA) is a prototypical autoimmune inflammatory disease of the diarthrodial joints and other body systems. A crucial barrier to the development of more effective, individualized treatment strategies for RA is the lack of biomarkers for predicting and monitoring the outcomes of disease-modifying antirheumatic drug (DMARD) therapy. In this thesis, we develop the novel hypothesis that an immune response signature based on the responsiveness of ex vivo multi-cytokine production by peripheral blood mononuclear cells to a panel of stimuli can be identified that will be predictive of treatment response and long-term outcomes of RA. We have tested our central hypothesis by pursuing three broad, specific aims. Our first aim was to validate the concept that immune response signatures reflect the stage and severity of RA. Our second aim was to identify an immune response signature predictive of structural joint damage, the ultimate outcome of RA. Our third aim was to identify an immune response signature that predicts the clinical treatment responses to initial DMARD therapy in patients with newly diagnosed RA. The results of the three studies reported herein and published in the peer-reviewed literature reveal a T-cell immune response signature related to cytomegalovirus (CMV) immunity that is associated with structural joint damage as well as poor response to initial DMARD therapy. This work is anticipated to inform a new direction of research into the interactions of viral immunity with autoimmune inflammatory diseases. Future studies will also be undertaken to determine if individualizing management based on CMV immunity will improve outcomes for patients with RA.