Clinical Features at Onset and Genetic Characterization of Pediatric and Adult Patients with TNF-<i>α</i> Receptor—Associated Periodic Syndrome (TRAPS): A Series of 80 Cases from the AIDA Network
Carla Gaggiano, Antonio Vitale, Laura Obici, Giampaolo Merlini, Alessandra Soriano, Ombretta Viapiana, Marco Cattalini, Maria Cristina Maggio, Giuseppe Lopalco, Davide Montin, Masen Abdel Jaber, Lorenzo Dagna, Raffaele Manna, Antonella Insalaco, Matteo Piga, Francesco La Torre, Virginia Berlengiero, Viviana Gelardi, Luisa Ciarcia, Giacomo Emmi, Piero Ruscitti, Francesco Caso, Rolando Cimaz, José Hernández‐Rodríguez, Paola Parronchi, Ludovico Luca Sicignano, Elena Verrecchia, Florenzo Iannone, Jurgen Sota, Salvatore Grosso, Carlo Salvarani, Bruno Frediani, Roberto Giacomelli, Maria Antonietta Mencarelli, Alessandra Renieri, Donato Rigante, Luca Cantarini
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 (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M1"><mml:mi>p</mml:mi><mml:mo><</mml:mo><mml:mn>0.05</mml:mn></mml:math>). 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 <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M2"><mml:mi>p</mml:mi><mml:mo><</mml:mo><mml:mn>0.01</mml:mn></mml:math> and <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M3"><mml:mi>p</mml:mi><mml:mo><</mml:mo><mml:mn>0.05</mml:mn></mml:math>, respectively), while abdominal pain was present in 84% of children and in 25% of adults (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M4"><mml:mi>p</mml:mi><mml:mo><</mml:mo><mml:mn>0.01</mml:mn></mml:math>). Abdominal pain was significantly associated also to the presence of HP mutations (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M5"><mml:mi>p</mml:mi><mml:mo><</mml:mo><mml:mn>0.01</mml:mn></mml:math>), while oral aphthosis was more frequently found in the LP variant group (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M6"><mml:mi>p</mml:mi><mml:mo><</mml:mo><mml:mn>0.05</mml:mn></mml:math>). Systemic amyloidosis occurred in 25% of subjects carrying HP variants. As concerns laboratory features, HP mutations were significantly associated to higher ESR values (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M7"><mml:mi>p</mml:mi><mml:mo><</mml:mo><mml:mn>0.01</mml:mn></mml:math>) and to the persistence of steadily elevated inflammatory markers during asymptomatic periods (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M8"><mml:mi>p</mml:mi><mml:mo><</mml:mo><mml:mn>0.05</mml:mn></mml:math>). 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 (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M9"><mml:mi>p</mml:mi><mml:mo><</mml:mo><mml:mn>0.05</mml:mn></mml:math>). Both NSAIDs and colchicine were used as monotherapy more frequently in the LP group compared to the HP group (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M10"><mml:mi>p</mml:mi><mml:mo><</mml:mo><mml:mn>0.01</mml:mn></mml:math>). Biologic agents were prescribed to 49 (61%) patients; R92Q subjects were more frequently on NSAIDs monotherapy than other patients (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M11"><mml:mi>p</mml:mi><mml:mo><</mml:mo><mml:mn>0.01</mml:mn></mml:math>); 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 (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M12"><mml:mi>p</mml:mi><mml:mo><</mml:mo><mml:mn>0.05</mml:mn></mml:math>). 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.