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Review
. 2021 Nov 17;22(22):12386.
doi: 10.3390/ijms222212386.

The Genetic, Environmental, and Immunopathological Complexity of Autoantibody-Negative Rheumatoid Arthritis

Ludovico De Stefano  1   2 , Bernardo D'Onofrio  1   2 , Antonio Manzo  1   2 , Carlomaurizio Montecucco  1   2 , Serena Bugatti  1   2
Affiliations
Review

The Genetic, Environmental, and Immunopathological Complexity of Autoantibody-Negative Rheumatoid Arthritis

Ludovico De Stefano et al. Int J Mol Sci. .

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.

Keywords: anti-citrullinated protein antibodies; pathogenesis; rheumatoid arthritis; rheumatoid factor; seronegative.

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Conflict of interest statement

S.B. reports grant/research support from: Pfizer, and personal fees from: AbbVie, Bristol-Myers Squibb, Eli Lilly, Gilead, Pfizer, Sanofi. C.M. reports personal fees from: AbbVie, Bristol-Myers Squibb, Eli Lilly, Gilead, Pfizer, Roche, Sanofi.

Figures

Figure 1
Figure 1
Proposed model of disease pathogenesis in autoantibody-negative rheumatoid arthritis.
See this image and copyright information in PMC

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