Abstract
Differences in clinical presentation, response to treatment, and long-term outcomes between autoantibody-positive and -negative rheumatoid arthritis (RA) highlight the need for a better comprehension of the immunopathogenic events underlying the two disease subtypes. Whilst the drivers and perpetuators of autoimmunity in autoantibody-positive RA have started to be disclosed, autoantibody-negative RA remains puzzling, also due its wide phenotypic heterogeneity and its possible misdiagnosis. Genetic susceptibility appears to mostly rely on class I HLA genes and a number of yet unidentified non-HLA loci. On the background of such variable genetic predisposition, multiple exogeneous, endogenous, and stochastic factors, some of which are not shared with autoantibody-positive RA, contribute to the onset of the inflammatory cascade. In a proportion of the patients, the immunopathology of synovitis, at least in the initial stages, appears largely myeloid driven, with abundant production of proinflammatory cytokines and only minor involvement of cells of the adaptive immune system. Better understanding of the complexity of autoantibody-negative RA is still needed in order to open new avenues for targeted intervention and improve clinical outcomes.
Highlights
Rheumatoid arthritis (RA) is a multifactorial chronic immune-inflammatory disease characterized by significant heterogeneity in clinical presentation and outcomes among different individuals with the same formal diagnosis
Intensive research into the etiopathogenesis of anti-citrullinated protein antibodies (ACPAs)-positive rheumatoid arthritis (RA) over the last years has substantially clarified the complex interplay between genetic risk factors and environmental susceptibility resulting in dysregulated adaptive immunity with the generation of pathogenic autoantibodies [6,7]
Larger evidence exists for omega-3 fatty acids, which have been associated with lower risk of developing ACPA [66] and lower odds of developing inflammatory arthritis in ACPA-positive healthy subjects [67]
Summary
Rheumatoid arthritis (RA) is a multifactorial chronic immune-inflammatory disease characterized by significant heterogeneity in clinical presentation and outcomes among different individuals with the same formal diagnosis. The pathophysiological basis underlying the clinical diversity of RA is only partially understood It is at present poorly defined whether autoantibody-positive and -negative RA are sustained by heterogeneous immune mechanisms operating variably, albeit with some overlap, in individual patients. Intensive research into the etiopathogenesis of ACPA-positive RA over the last years has substantially clarified the complex interplay between genetic risk factors and environmental susceptibility resulting in dysregulated adaptive immunity with the generation of pathogenic autoantibodies [6,7]. RA is currently managed the same way irrespective of the autoantibody profile, a better understanding of the pathophysiological heterogeneity of the disease would definitively improve personalized approaches more focused on specific risk factors and immune pathways. We will revise current advancements in the understanding of the genetic, environmental, and immunopatogenetic complexity of autoantobody-negative RA
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