Rather, it is perhaps more appropriately considered a syndrome with a common clinical phenotype arising from diverse pathways operating variably, albeit often with overlap, in individual patients ( Firestein, 2014).ĭepicting the sequence of events leading to the development of clinically detectable rheumatoid arthritis – at least two potential models are depicted. Based on the diversity of clinical responses to highly targeted therapeutic agents, we propose that RA probably does not comprise a single entity. In this review, we will posit that RA starts with a high-risk genetic background that, in combination with epigenomic marks that contribute to heritability and disease chronicity, and stochastic environmental exposures that create neo-epitopes, launches a cascade of events inducing synovitis and ultimately chronic destructive arthritis ( Figure 1). Thus, RA is characterized by evidence of disordered innate immunity, including immune complex-mediated complement activation, adaptive immune responses against ‘self’-antigens comprising predominantly post-translationally modified proteins, dysregulated cytokine networks, osteoclast and chondrocyte activation and imprinting of resident stromal cells that in turn develop semi-autonomous features that support disease progression ( Arend & Firestein 2012 Firestein 2003).īased on substantial new data identifying the immunologic and metabolic events that precede onset of clinical disease, even by years (i.e., “pre-RA”), and the increasing impact of the application of the advanced molecular ‘omics’ revolution to disease investigation, an integrated hypothesis for disease pathology is emerging ( Catrina et al 2016 Tan & Smolen 2016). Autoreactivity as a pivotal step dominates the conceptual landscape, although other mechanisms, both immunologic and tissue derived clearly contribute to disease pathogenesis. However, concepts of how immune responses contribute to disease have evolved dramatically over the last 50 years. Immune dysregulation was first implicated in the pathogenesis of rheumatoid arthritis (RA) by the discovery of anti-immunoglobulin G (IgG) antibodies known as rheumatoid factors, initially by Erik Waaler and then more fully described by H. This target represents a bold vision for the future of RA therapeutics. They allude to the possibility of restoration of immunologic homeostasis and thus a state of tolerance associated with drug free remission. Herein we review recent data that support intriguing models of disease pathogenesis. Targeted immune therapeutics, and aggressive treatment strategies have substantially improved clinical outcomes, and informed pathogenetic understanding, but no cure as yet exists. Clinical disease onset comprises synovitis and systemic comorbidities affecting the vasculature, metabolism and bone. 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. 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. Rheumatoid arthritis (RA) is the most common inflammatory arthropathy.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |