TNF受容体関連周期性症候群

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a rare autoinflammatory disorder, and adult-onset cases caused by somatic mosaic TNFRSF1A variants are exceptionally rare. A man in his 60s developed recurrent febrile episodes with rash and polyarthralgia and was initially misdiagnosed with a biliary infection and adult-onset Still's disease. Hybrid capture-based next-generation sequencing identified a somatic mosaic TNFRSF1A variant with a variant allele frequency of 19%, thus establishing the diagnosis of TRAPS. Treatment with canakinumab resulted in complete clinical remission and successful glucocorticoid tapering.

Autoinflammatory diseases are characterized by dysregulation of the innate immune system. This article provides an updated overview of autoinflammatory diseases with gastrointestinal manifestations and outlines the clinical situations in which gastroenterologists should consider these conditions. The most prevalent form worldwide is familial Mediterranean fever (FMF), which is associated with mutations in the MEFV (MEditerranean FeVer) gene and presents with recurrent episodes of serositis, primarily peritonitis, accompanied by systemic inflammation. From a biological standpoint, a peripheral inflammatory syndrome is typically observed during acute attacks; however, in some cases inflammation may persist chronically. At the molecular level, these diseases involve numerous genes encoding proteins that participate in the activation or regulation of inflammatory pathways within innate immune cells. Initially, four monogenic disorders were described FMF, TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), and cryopyrin-associated periodic syndromes (CAPS) collectively referred to as the four historical autoinflammatory diseases. Each year, new monogenic autoinflammatory diseases are identified thanks to rapid advances in genetic sequencing technologies. The recent identification of somatic forms of monogenic diseases, including certain cryopyrinopathies and, in 2020, VEXAS syndrome, has added a new level of complexity to the field.

INTRODUCTION: Autoinflammatory diseases are inherited disorders of innate immunity, broadly classified into inflammasomopathies, interferonopathies, and complement-mediated disorders. They are characterized by dysregulated cytokine signaling - particularly IL-1, IL-6, TNF, type I interferon, and the JAK-STAT pathway-and are increasingly managed with molecular targeted therapies. Prototypical entities include familial Mediterranean fever (FMF), TNF receptor - associated periodic syndrome (TRAPS), and cryopyrin-associated periodic syndromes (CAPS). Other conditions - notably mevalonate kinase deficiency (MKD/HIDS), deficiency of adenosine deaminase 2 (DADA2), haploinsufficiency of A20 (HA20), OTULIN-related autoinflammatory syndromes, and proteasome-associated autoinflammatory syndromes (PRAAS) - are now recognized as biologic-responsive diseases. AREAS COVERED: This review summarizes molecular mechanisms and therapeutic strategies, focusing on IL-1 blockade with anakinra, canakinumab, and rilonacept, as well as IL-6 and TNF inhibitors, integrating evidence from clinical trials and real-world studies. EXPERT OPINION: IL-1 inhibition has transformed the management of inflammasome-mediated diseases, enabling glucocorticoid-free remission and reducing amyloidosis risk. TNF inhibitors remain standard for vasculopathic disorders such as DADA2, while IL-6 blockade and JAK inhibitors are options in selected refractory cases. The recognition of novel syndromes, including HA20, OTULIN deficiency, and PRAAS, has broadened the therapeutic landscape, and next-generation biologics may further enable personalized treatment.

BACKGROUND: Rare diseases (RD) have progressively emerged as public health priority in many countries. Epidemiological data are still lacking and the extraction of data from the public health system remains insufficient. In France, RD database set up in 2013 as Banque Nationale de Données de Maladies Rares (BNDMR). Patients’ information is provided by physician at each consultation and RD are classified according ORPHAcode. The status of each diagnosis can be entered as ‘confirmed’, ‘probable’ or ‘under investigation’, as well as related families. OBJECTIVES AND METHODS: We aimed to test the reliability and quality of data for epidemiology by analyzing the data from a RD caused by autosomal dominant inheritance and with a univocal genetic diagnosis: TNF receptor-associated periodic syndrome (TRAPS). Patients were extracted on January 2023 and genetic files were retrieved from January to march 2023. All patients registered with a diagnosis of TRAPS were included. RESULTS: We identified 132 patients who fulfilled inclusion criteria, among which 31 were excluded (missing data and duplicates). We analyzed 101 patients and their sequences of TNFSRSF1A gene. Pathogenic and likely pathogenic variants were found in 69% of patients, while the remaining 31% may rather represent undetermined systemic autoinflammatory disease. The main pathogenic variant found was T50M (c.236 G > T) while the main VUS was R92Q (c.362 G > A). For the patients entered as ‘confirmed’, only 44% of them had a pathogenic/likely pathogenic variant. We identified eight different families. We therefore estimated the minimum prevalence of TRAPS in France: 1/1 156 711. CONCLUSION: In the French National Rare Disease Registry, the quality of data remains a challenge, especially in monogenic diseases where the knowledge of the pathogenicity of variants and the number of gene involved is constantly increasing. Our study suggests that the data exported from the BNDMR needs important data correction to allow reliable epidemiologic studies in these diseases.

Background/Aims: Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant systemic autoinflammatory disease caused by mutations in the TNFRSF1A gene. The clinical presentation of TRAPS is heterogeneous, which can complicate its diagnosis. This study aimed to characterize the clinical and genetic features of patients with TRAPS diagnosed and treated in Slovakia, as well as to evaluate their therapeutic response to canakinumab. Materials and Methods: A retrospective analysis of clinical data from the Slovak national database of patients with periodic fever syndromes was performed, including 7 TRAPS patients diagnosed between 2019 and 2022 in Slovakia. These data were compared with findings from available cohorts from Europe, China, and Japan. Results: All 7 patients were female, with a median age at clinical disease onset of 6 years (range: 8 months to 30 years); 1 patient had adult-onset disease. The most frequent symptoms were recurrent episodes of fever (6/7), skin rash (6/7), arthralgia (6/7), myalgia (5/7), abdominal pain (4/7), chest pain (4/7), and general fatigue (4/7). Notably, 1 patient exhibited central nervous system (CNS) involvement manifesting as seizures and aseptic CNS inflammation. Genetic analysis identified 4 variants in TNFRSF1A, including the N145S variant (also referred to as N116S), a variant only rarely reported in the literature. Treatment with canakinumab resulted in a significant reduction in flare frequency and decreases in inflammatory markers. Conclusion: This study underscores the phenotypic diversity of TRAPS, as shown by the identification of the rare TNFRSF1A N145S variant and a case with CNS involvement. The estimated prevalence of TRAPS in Slovakia is approximately 1 : 780 000, and the clinical features of these patients are comparable to those reported in European cohorts. Furthermore, the favorable therapeutic response to canakinumab supports its potential as an effective treatment option for TRAPS.