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

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.

Anakinra and canakinumab for patients with R92Q-associated autoinflammatory syndrome: a multicenter observational study from the AIDA Network

“…It has been observed that R92Q-positive patients are successfully treated with NSAIDs, colchicine or glucocorticoids as monotherapy more frequently than those with different mutations of the same gene, probably due to the reduced expressivity of this variant. 37 – 39 Nevertheless, recent data gathered from the AIDA cohort disclose that the percentage of R92Q patients requiring cytokine blockers is up to 53%, surprisingly higher than previously reported. 39 – 43 In the present study, the efficacy rate of ANA and CAN was 68%, being ‘complete efficacy’ defined as the resolution of symptoms and normalization of ESR, CRP and SAA, which should demonstrate the absence of both manifest and subclinical inflammation.…”

“… 37 – 39 Nevertheless, recent data gathered from the AIDA cohort disclose that the percentage of R92Q patients requiring cytokine blockers is up to 53%, surprisingly higher than previously reported. 39 – 43 In the present study, the efficacy rate of ANA and CAN was 68%, being ‘complete efficacy’ defined as the resolution of symptoms and normalization of ESR, CRP and SAA, which should demonstrate the absence of both manifest and subclinical inflammation. Accordingly, the median AIDAI score, which measures the clinical activity of the disease, was significantly lower at month-1 follow-up visit, while mean values of laboratory markers of inflammation decreased more slowly reaching the statistical significance after 3 months of treatment.…”

Biotechnological Agents for Patients With Tumor Necrosis Factor Receptor Associated Periodic Syndrome—Therapeutic Outcome and Predictors of Response: Real-Life Data From the AIDA Network

“…During the last two decades, TRAPS treatment has progressively changed along with the new insights on pathogenesis, clinical presentation, and genotype-phenotype correlations. In this perspective, the increasing awareness about genotypes more prone to develop long-term complications and the identification of subgroups of patients more likely responsive to corticosteroids and/or NSAIDs has led to a more precise definition of clinical cases requiring a more aggressive treatment approach with an early use of biologic agents (3,4,17,18). In the same way, the recent advances about the pivotal role of IL-1 in TRAPS pathogenesis as well as the excellent results observed in clinical trials have increasingly enhanced the use of IL-1 antagonists at the expense of the anti-TNF-α agents (11,(19)(20)(21)(22).…”

Management of Monogenic IL-1 Mediated Autoinflammatory Diseases in Childhood

“…TRAPS patients typically present with musculoskeletal complaints, abdominal pain, maculopapular and migratory rash, and periorbital edema ( 6 ). Serositis, pericarditis, arthritis and myalgia may be more prominent in adulthood, while abdominal pain is found more typically in childhood ( 6 , 48 ). Furthermore, Gaggiano et al highlight that high penetrance variants are associated with abdominal pain, amyloidosis and subclinical inflammation, whereas oral aphthosis is frequently observed in low-penetrance variants ( 48 ).…”

“…Serositis, pericarditis, arthritis and myalgia may be more prominent in adulthood, while abdominal pain is found more typically in childhood ( 6 , 48 ). Furthermore, Gaggiano et al highlight that high penetrance variants are associated with abdominal pain, amyloidosis and subclinical inflammation, whereas oral aphthosis is frequently observed in low-penetrance variants ( 48 ). TRAPS may start in adulthood, family history may then be non-contributory.…”