Clinical Features at Onset and Genetic Characterization of Pediatric and Adult Patients with TNF-α Receptor-Associated Periodic Syndrome (TRAPS): A Series of 80 Cases from the AIDA Network.

Carla Gaggiano,Raffaele Manna,Florenzo Iannone,Piero Ruscitti,Rolando Cimaz,Matteo Piga,Giacomo Emmi,Roberto Giacomelli,Marco Cattalini,Carlo Salvarani,Bruno Frediani,Luisa Ciarcia,Masen Abdel Jaber,Alessandra Soriano,Giuseppe Lopalco,Elena Verrecchia,Francesco Caso,Antonella Insalaco,Maria Antonietta Mencarelli,Viviana Gelardi,Luca Cantarini,Jurgen Sota,Maria Cristina Maggio,Ludovico Luca Sicignano,Alessandra Renieri,Salvatore Grosso,Lorenzo Dagna,Donato Rigante,Virginia Berlengiero,Francesco La Torre,Paola Parronchi,Ombretta Viapiana,Laura Obici,Giampaolo Merlini,Davide Montin,A Vitale ,José Hernández‐Rodríguez

doi:10.1155/2020/8562485

Abstract

This study explores demographic, clinical, and therapeutic features of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) in a cohort of 80 patients recruited from 19 Italian referral Centers. Patients' data were collected retrospectively and then analyzed according to age groups (disease onset before or after 16 years) and genotype (high penetrance (HP) and low penetrance (LP) TNFRSF1A gene variants). Pediatric- and adult-onset were reported, respectively, in 44 and 36 patients; HP and LP variants were found, respectively, in 32 and 44 cases. A positive family history for recurrent fever was reported more frequently in the pediatric group than in the adult group (p < 0.05). With reference to clinical features during attacks, pericarditis and myalgia were reported more frequently in the context of adult-onset disease than in the pediatric age (with p < 0.01 and p < 0.05, respectively), while abdominal pain was present in 84% of children and in 25% of adults (p < 0.01). Abdominal pain was significantly associated also to the presence of HP mutations (p < 0.01), while oral aphthosis was more frequently found in the LP variant group (p < 0.05). Systemic amyloidosis occurred in 25% of subjects carrying HP variants. As concerns laboratory features, HP mutations were significantly associated to higher ESR values (p < 0.01) and to the persistence of steadily elevated inflammatory markers during asymptomatic periods (p < 0.05). The presence of mutations involving a cysteine residue, abdominal pain, and lymphadenopathy during flares significantly correlated with the risk of developing amyloidosis and renal impairment. Conversely, the administration of colchicine negatively correlated to the development of pathologic proteinuria (p < 0.05). Both NSAIDs and colchicine were used as monotherapy more frequently in the LP group compared to the HP group (p < 0.01). Biologic agents were prescribed to 49 (61%) patients; R92Q subjects were more frequently on NSAIDs monotherapy than other patients (p < 0.01); nevertheless, they required biologic therapy in 53.1% of cases. At disease onset, the latest classification criteria for TRAPS were fulfilled by 64/80 (80%) patients (clinical plus genetic items) and 46/80 (57.5%) patients (clinical items only). No statistically significant differences were found in the sensitivity of the classification criteria according to age at onset and according to genotype (p < 0.05). This study describes one of the widest cohorts of TRAPS patients in the literature, suggesting that the clinical expression of this syndrome is more influenced by the penetrance of the mutation rather than by the age at onset itself. Given the high phenotypic heterogeneity of the disease, a definite diagnosis should rely on both accurate working clinical assessment and complementary genotype.

Highlights

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is one of the most common autosomal dominant autoinflammatory diseases and is caused by mutations in the tumor necrosis factor receptor super family member 1A (TNFRSF1A) gene on chromosome 12p13
Provisional Eurofever score for tumor necrosis factor receptor-associated periodic syndrome (TRAPS) according to Federici et al [13] was calculated for every patient by the referring physician; classification scores for TRAPS, FMF, mevalonate kinase deficiency (MKD), and cryopyrin-associated periodic syndromes (CAPS) were subsequently derived by the authors on the basis of available data, according to Gattorno et al [9]
The present study outlines the characteristics of a large cohort of TRAPS patients resulting from a positive nationwide collaborative research experience in the field of autoinflammatory diseases

Summary

Introduction

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is one of the most common autosomal dominant autoinflammatory diseases and is caused by mutations in the tumor necrosis factor receptor super family member 1A (TNFRSF1A) gene on chromosome 12p13. Among the expanding spectrum of hereditary recurrent fevers, TRAPS remains one of the most variable as concerns clinical features, age at onset, and disease severity, ranging from the mildest phenotype often associated to low-penetrance (LP) genetic variants to a severely disabling condition in patients carrying structural high-penetrance (HP) variants; in the latter group, systemic amyloidosis represents the most threatening complication of the syndrome, affecting 10-15% of untreated subjects [3, 4]. Patients may display a relapsing-remitting course, with prolonged high-grade fever attacks accompanied by a systemic inflammatory reaction and localized flogosis of any potential site, with skin, muscles, abdomen, eye, joints, serous membranes, and lymph nodes being the most frequently targeted [5]. Patients may exhibit a chronic course, characterized by symptomatic intervals between fever attacks and/or inflammatory markers steadily elevated

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