Background Pathogenic variants in two regulating genes, NLRP3 and TNFRSF1A, cause two severe and early-onset autoinflammatory syndromes, CAPS and TRAPS. The spectrum of autoinflammatory syndrome, NLRP3 and TNFRSF1A mutations, clinical manifestations and response to treatment in a cohort of Russian patients with recurrent inflammatory attacks were not analyzed.
Objectives To evaluate frequent incidence, clinical manifestations of CAPS and TRAPS and response to treatment in patients with recurrent inflammatory attacks in Russia.
Methods The study included 52 children (23 boys, 29 girls) from 1 to 17 years (mean 8.2 (4.7; 11.5) with fever of unknown cause, after exclusion of infections, malignancy and autoimmune diseases. The median age at which symptoms began was 3.0 (1.5; 5.1) years, disease duration – 4.4 (1.0; 7.6) years. The commonest features were fever (100%), arthritis/arthragia (100%), rash (96%), hepato- and splenomegaly (96%), lymphadenopathy (94%), headache (62%), abdominal pain (58%) and eye manifestations (21%). The mean leukocytes level - 17 (13; 23)x109/l, platelets - 550 (470; 680)x1012/l, hemoglobin 96 (79; 108) g/l, level of CRP - 87 (52; 146) mg/l, ESR -56 (38; 68) mm/h. DNA was sequenced in all coding exons and intronic flanks of the TNFRSF1A and NLRP3 genes whose mutations cause autoinflammatory syndromes, TRAPS and CAPS, respectively.
Results 9 (17%) patients were diagnosed with autoinflammatory syndrome. In 7 patients, we found etiological mutations in TNFRSF1A. 6 patients had a mutation c.362G>A (p.R92Q) located in exon 4 and associated with the mild progression of TRAPS. Interestingly, 1 patient was homozygous for p.R92Q, others were heterozygous. The 7th TRAPS patient had a novel frameshift mutation c.792delT (p.Lys265Serfs*87) in exon 9 of TNFRSF1A. TRAPS debuted at the age of 3.7 (1.9; 7.2) years, the most often symptoms were fever (100%), arthritis or arthragia (100%), lymphadenopathy (100%), hepato- and splenomegaly (100%), rash (86%), headache (86%), abdominal pain (57%). In 2 patients, mutations in NLRP3 were detected. 6 patients with TRAPS continued preceding therapy due to the remission. 1 child was treated with methotrexate, 1 – with infliximab; 1 – with rituximab, methotrexate, cyclosporine; 1 – with tocilizumab, 1 – with canacinumab, methotrexate, cyclosporine and prednisolone, 1 – with canacinumab and prednisolone. 1 girls with TRAPS was switched from tocilizumab to etanercept and then to adalimumab, but remission was not achieved. The first CAPS patient had a NLRP3 mutation c.2113C>A (p.Gln705Lys) whereas the second contained a novel mutation c.2861C>T (p.Thr954Met). Both patients with CAPS presented fever, lymphadenopathy, hepato- and splenomegaly, abdominal pain, rash and arthragia at the age of 3.3 and 6 years accordingly. 1 girl presented periorbital oedema and headache. Cases of AA amyloidosis were not registered. 2 patients with CAPS continued preceding therapy with tocilizumab and canacinumab due to the remission at the time of diagnosis. Both girls were treated with glucocorticosteroids.
Conclusions Our results suggests for a relatively frequent incidence of CAPS and TRAPS in patients with recurrent inflammatory attacks in Russian population.
Disclosure of Interest None declared