Insight into the pathophysiology of TRAPS
Patients suffer from recurrent episodes of fever and pain with renal amyloidosis being the most serious and potentially fatal complication in nearly 20 % of the cases. The disease usually commences in infancy, and treatment mainly consists of corticosteroids, and more recently anti-TNF therapeutics but with inconsistent efficacy. A recently identified disease, there is limited information available regarding onset, pathophysiology and diagnosis of TRAPS, a disorder caused by mutations in the tumour necrosis factor receptor superfamily member 1A (TNFRSF1A) gene. To address the under-diagnosis of the disease, the EUROTRAPS (Natural course, pathophysiology, models for early diagnosis, prevention and innovative treatment of TNF receptor associated periodic syndrome TRAPS with application for all hereditary recurrent fevers) project brought together leading scientists from nine different countries. This established network generated a European patient registry with all relevant clinical information and data, thereby providing a clearer picture on disease symptoms and clinical pattern. Scientists assessed the actual prevalence of this disease, together with the distribution of cases according to age, gender and origin. Significant effort went towards improving knowledge on genetics and pathophysiology of TRAPS. Several new mutations were identified alongside new pathways implicated in the disease. Researchers observed mutant TNFR1 aggregates in the cytoplasm and discovered altered cytokine expression (IL-6, IL-1β) compared to healthy controls. In addition, reactive oxygen species production was higher in mutant cells, which exhibited impaired autophagy potential. Another important finding was the discovery that a particular genotype conferred a 5.3-fold increased risk for TRAPS patients to develop amyloidosis. From a therapeutic perspective, the consortium worked on targeting the ongoing inflammation in TRAPS patients. In this context, they designed a vehicle to specifically and efficiently trigger RNAi-mediated gene silencing within monocytes. Overall, the knowledge generated during EUROTRAPS was translated into clinical care and is expected to improve disease diagnosis. With novel therapeutic and preventive schemes, prompt treatment in childhood will undoubtedly improve the quality of life of patients with TRAPS.
Keywords
TRAPS, TNF receptor, EUROTRAPS, patient registry, cytokine