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Objective Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a rare autosomal dominantly inherited autoinflammatory disease caused by mutations of the TNFRSF1A gene. To address the association between TNFRSF1A mutations and clinical phenotype, we analyzed four pedigrees of TRAPS patients. Methods Four Greek patients with TRAPS-like clinical features were screened for TNFRSF1A mutations by sequencing exons 2, 3 and 4. Following positive testing, twenty-two members of their families were also genetically and clinically screened. Results Twenty-six members of four unrelated Greek families were investigated. The C73Y (c.305G>A) mutation of the TNFRSF1A gene was identified in five patients, with two of the five carrying a concomitant R92Q variation. We also identified seven C73W (c.306C>G), two T50M (c.236C>T) and seven R92Q (c.362G>A) carriers. Symptoms varied and the C73Y, C73W and T50M mutations were associated with the most severe clinical manifestations. The R92Q phenotype ranged from asymptomatic to mild disease. Molecular modelling linked pathogenicity with aberrant TNFRSF1A disulphide bond formation. Conclusion In this first pedigree analysis of TRAPS in Greece, we identified the rare C73Y TNFRSF1A mutation. A wide clinical spectrum was observed with the C73Y, C73W and T50M mutations that affect TNFRSF1A disulphide bonds and are associated with worse symptoms.

Rheumatoid arthritis is a common autoimmune disease leading often to joint destruction and reduced quality of life. We report a case of a young woman with rheumatoid arthritis with fever and rapid, destructive joint involvement verified with magnetic resonance imaging. She had failed therapy with methotrexate and leflunomide, anti-TNF, IL-6 inhibitor, B cell depletion and IL-1RA. Her laboratory results remained insignificant despite the aggressiveness of her disease. In this case, the patient only partly responded to anakinra but developed side effects, and therefore was switched to Canakinumab that led to sustained remission. There are no clear biomarkers or other clues in order to separate early in the beginning of the disease course if a polyarticular inflammatory spectrum can be IL-1β driven. The young age of the patient at onset of disease, its aggressive course, inflammatory fever without significant laboratory inflammatory markers but with polyarthritis affecting small joints, may raise the suspicion of an IL-1β-driven disease and alert the treating rheumatologist to the use of IL-1β inhibitors early in the disease course.