Immunopathogenesis of Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is the most common inflammatory arthropathy. The majority of evidence, derived from genetics, tissue analyses, models, and clinical studies, points to an immune-mediated etiology associated with stromal tissue dysregulation that together propogate chronic inflammation and articular destruction. A pre-RA phase lasting months to years may be characterized by the presence of circulating autoantibodies, increasing concentration and range of inflammatory cytokines and chemokines, and altered metabolism. Clinical disease onset comprises synovitis and systemic comorbidities affecting the vasculature, metabolism, and bone. Targeted immune therapeutics and aggressive treatment strategies have substantially improved clinical outcomes and informed pathogenetic understanding, but no cure as yet exists. Herein we review recent data that support intriguing models of disease pathogenesis. They allude to the possibility of restoration of immunologic homeostasis and thus a state of tolerance associated with drug-free remission. This target represents a bold vision for the future of RA therapeutics.

Figure 1

Depicting the sequence of events leading to the development of clinically detectable rheumatoid arthritis – at least two potential models are depicted. In model A, a pre-RA phase comprises early generation of autoantibodies (ACPAs) that can bind post-translationally modified self-proteins, particularly via citrullination. This is followed by amplification of the range of specificities of ACPA and by the elaboration of cytokines and chemokines, complement, and metabolic disturbance in the months prior to clinical development of disease. A transition event that requires a ‘second hit’, as yet poorly understood permits the development of synovitis. The latter is characterized by frank inflammation, stromal compartment changes and tissue modification leading to articular damage. In model B, which is not mutually exclusive, there is an early interaction between innate immune activation and stromal factors that lead to stromal cell alteration, including epigenetic modifications that initiate a cycle of inflammatory stromal mediated damage. Autoimmunity can arise as a result of these interactions that in turn can conrtibtue directly or in an amplification loop to disease perpetuation.

Figure 2

Myeloid cells, particularly macrophages are central to the perpetuation of disease pathogenesis. Pathways that can activate macrophages in RA synovitis are shown that promote cytokine release – IL-6 and TNF in particular, and probably GM-CSF, are of central importance as defined by the clear therapeutic benefits achieved upon their inhibition.

Figure 3

Mechanisms that drive the chronicity of RA. Distinct pathways combine to mediate failed resolution of disease – these include adaptive, innate and stromal components with additional impact of the systemic features of disease. The latter may be both consequence of the chronic inflammation or could promote the chronicity e.g. via creation of pro-inflammatory lipid profiles, promotion of bone remodeling and secondary osteoarthritis.