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Key messages A subgroup of rheumatoid arthritis (RA) cases can have a mixed autoimmune-autoinflammatory overlapping clinical phenotype which has implications for choice of appropriate therapy.
This points to innate immunity or autoinflammatory mechanisms as underpinning flare or relapse in some autoantibody positive RA cases.
These findings point to the marked genetic heterogeneity in RA cases that is thus far poorly recognised.
Introduction
Rheumatoid arthritis (RA) is genetically, phenotypically and molecularly heterogeneous. Most cases have an autoimmune phenotype as indicated by the major histocompatibility complex Class 2 (MHC-II) association, shared autoantibodies and responses to B cell depletion and co-stimulatory blockade therapies. However, there is growing evidence that innate immunity plays an important role in the pathogenesis of this disorder. 1 We and others have also observed that some RA cases clinically resemble patients with so-called systemic autoinflammatory disorders (SAIDs), 2 which would support this idea.
Broadly speaking SAIDs are diseases of the innate immunity caused by the mutations in genes including TNFRSF1A, NLRP3, MEFV and NOD2, which control the release of the proinflammatory cytokines, mainly interleukin (IL)-1ß, and IL-6 and Tumor necrosis factor (TNF). 3 Typically, the patients experience abrupt systemic inflammatory attacks characterised by fever, prominent joint swelling, erythema and a raised C-Reactive protein (CRP). Furthermore, patients with SAID respond to therapies such as colchicine and anti-IL-1 biologics, which target the innate immune system. We present a series of five patients who have overlapping clinical features of RA and SAID.
Materials and methods
For detailed information regarding patients' clinical assessment, and methods used for genetic and cytokine studies, please see online supplementary file 1 .
Case 1
A 54-year-old man presented at the age of 35 years with episodic night sweats, fever, erythematous skin rash and bilateral symmetrical synovitis suggestive of RA ( figure 1 ). Investigations showed elevated CRP and negative rheumatoid factor (RF), and skin biopsy had features in keeping with urticarial vasculitis. Over the next decade, he continued to suffer with episodic skin rashes and synovitis associated with systemic inflammation. He failed numerous empirical treatments including combinations of methotrexate and etanercept and methotrexate and tocilizumab ( table 1 ). At the age of 47 years he was found to have a known pathogenic missense variant in the NLRP3 gene...