Mechanistic immunological based classification of rheumatoid arthritis

The classical autoimmunity paradigm in rheumatoid arthritis (RA) is strongly supported by immunogenetics suggesting follicular helper T-cell responses driving high titre specific autoantibodies that pre-dates disease onset. Using the immunological disease continuum model of inflammation against self with "pure" adaptive and innate immune disease at opposite boundaries, we propose a novel immune mechanistic classification describing the heterogeneity within RA. Mutations or SNPs in autoinflammatory genes including MEFV and NOD2 are linked to seronegative RA phenotypes including some so called palindromic RA cases. However, just as innate and adaptive immunity are closely functionally integrated, some ACPA+ RA cases have superimposed "autoinflammatory" features including abrupt onset attacks, severe attacks, self-limiting attacks, relevant autoinflammatory mutations or SNPs and therapeutic responses to autoinflammatory pathway therapies including colchicine and IL-1 pathway blockade. An emergent feature from this classification that non-destructive RA phenotypes, both innate and adaptive, have disease epicentres situated in the extracapsular tissues. This mixed innate and adaptive immunopathogenesis may be the key to understanding severe disease flares, resistant disease subsets that are unresponsive to standard therapy and for therapies that target the autoinflammatory component of disease that are not currently considered by expert therapeutic recommendations.