TUMOR-NECROSIS FACTOR RECEPTOR-ASSOCIATED PERIODIC SYNDROME (TRAPS): NEW INSIGHTS INTO THE PATHOGENESIS OF THE DISEASE AND RESPONSE TO ANTI-IL-1 TREATMENT IN CHILDHOOD

TRAPS is associated to a mutation of a gene coding for the type I receptor for one of the most important pro-inflammatory cytokines, called TNF. The disease is characterized by fever episodes lasting several weeks associated with abdominal pain, arthralgia, myalgia and cutaneous rash. A severe impairment of quality of life is registered during fever episodes. Fiveteen to 25% of patients develop renal amyloidosis and may undergo to severe kidney impairment. At present, at least 30 families carrying mutations of the TNFRSF1A are know in Italy. Fever episodes are partially controlled by the use of steroid, that is not able to influence disease course and possible progression to amyloidosis. Immunosuppressive drugs commonly used in chronic inflammatory conditions has been proved to be ineffective. A partial and transient effect has been observed with the use of biologics anti-TNF treatment. The beneficial effect of the recombinant IL-1 receptor antagonist (Anakinra) has been recently reported. The same dramatic effects has been also preliminarily observed in two children affected with severe TNFRSF1A mutations in the Coordinator’s Center. This research plan integrates the competences of doctors and geneticists that deal with these diseases with those of basic scientists with a particular knowledge on the mechanisms governing the control of inflammation. The aims are: i) to understand the intracellular mechanisms related to the defect of TNF-induced apoptosis in TRAPS patients, ii) to investigate the regulation of IL-1b secretion TRAPS patients and to identify new strategies for its inhibition; iii) to analyze the efficacy and safety of treatment with Anakinra ; iv) to identify new genes possible involved in patients affected by a TRAPS-like disorders.