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

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.

[1]  F. Nicolás-Sánchez,et al.  p.RQ92 mutation associated with amyloidosis , 2021 .

[2]  M. van Gijn,et al.  Clinical characteristics and genetic analyses of 187 patients with undefined autoinflammatory diseases , 2019, Annals of the rheumatic diseases.

[3]  M. Sormani,et al.  Classification criteria for autoinflammatory recurrent fevers , 2019, Annals of the rheumatic diseases.

[4]  M. Swertz,et al.  New workflow for classification of genetic variants’ pathogenicity applied to hereditary recurrent fevers by the International Study Group for Systemic Autoinflammatory Diseases (INSAID) , 2018, Journal of Medical Genetics.

[5]  L. Bezrodnik,et al.  A web-based collection of genotype-phenotype associations in hereditary recurrent fevers from the Eurofever registry , 2017, Orphanet Journal of Rare Diseases.

[6]  J. Yagüe,et al.  Disease Phenotype and Outcome Depending on the Age at Disease Onset in Patients Carrying the R92Q Low-Penetrance Variant in TNFRSF1A Gene , 2017, Front. Immunol..

[7]  Q. Yao,et al.  Adult autoinflammatory disease frequency and our diagnostic experience in an adult autoinflammatory clinic. , 2016, Seminars in arthritis and rheumatism.

[8]  S. Ozen,et al.  International retrospective chart review of treatment patterns in severe FMF, TRAPS and MKD/HIDS , 2016 .

[9]  J. Yagüe,et al.  Clinical and genetic characterization of the autoinflammatory diseases diagnosed in an adult reference center. , 2016, Autoimmunity reviews.

[10]  S. Ozen,et al.  Development of the autoinflammatory disease damage index (ADDI) , 2016, Pediatric Rheumatology.

[11]  M. Sormani,et al.  Evidence-based provisional clinical classification criteria for autoinflammatory periodic fevers , 2015, Annals of the rheumatic diseases.

[12]  E. Silvestri,et al.  Key facts and hot spots on tumor necrosis factor receptor‐associated periodic syndrome , 2014, Clinical Rheumatology.

[13]  L. Punzi,et al.  The expanding spectrum of low-penetrance TNFRSF1A gene variants in adults presenting with recurrent inflammatory attacks: clinical manifestations and long-term follow-up. , 2014, Seminars in arthritis and rheumatism.

[14]  I. Touitou,et al.  The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry , 2013, Annals of the rheumatic diseases.

[15]  M. Galeazzi,et al.  Childhood versus adulthood-onset autoinflammatory disorders: myths and truths intertwined. , 2013, Reumatismo.

[16]  P. Hawkins,et al.  AA amyloidosis complicating the hereditary periodic fever syndromes. , 2013, Arthritis and rheumatism.

[17]  R. Cimaz,et al.  Tumour necrosis factor receptor-associated periodic syndrome (TRAPS): state of the art and future perspectives. , 2012, Autoimmunity reviews.

[18]  I. Touitou,et al.  Guidelines for the genetic diagnosis of hereditary recurrent fevers , 2012, Annals of the rheumatic diseases.

[19]  S. Bombardieri,et al.  Validation of a Diagnostic Score for the Diagnosis of Autoinflammatory Diseases in Adults , 2011, International journal of immunopathology and pharmacology.

[20]  M. Galeazzi,et al.  Autoinflammatory diseases and cardiovascular manifestations , 2011, Annals of medicine.

[21]  M. Sormani,et al.  Long-Term Clinical Profile of Children With the Low-Penetrance R92Q Mutation of the TNFRSF1A Gene , 2011, Arthritis and rheumatism.

[22]  J. Pouchot,et al.  Extended Report , 2022 .

[23]  C. Baldari,et al.  Role of Etanercept in the Treatment of Tumor Necrosis Factor Receptor-Associated Periodic Syndrome: Personal Experience and Review of the Literature , 2010, International journal of immunopathology and pharmacology.

[24]  R. von Kries,et al.  Incidence of TNFRSF1A mutations in German children: epidemiological, clinical and genetic characteristics. , 2009, Rheumatology.

[25]  N. Ravet,et al.  Clinical significance of P46L and R92Q substitutions in the tumour necrosis factor superfamily 1A gene , 2006, Annals of the rheumatic diseases.

[26]  I. Touitou,et al.  A decision tree for genetic diagnosis of hereditary periodic fever in unselected patients , 2006, Annals of the rheumatic diseases.

[27]  G. Hitman,et al.  Allelic variants in genes associated with hereditary periodic fever syndromes as susceptibility factors for reactive systemic AA amyloidosis , 2004, Genes and Immunity.

[28]  D. Kastner,et al.  The TNF Receptor-Associated Periodic Syndrome (TRAPS): Emerging Concepts of an Autoinflammatory Disorder , 2002, Medicine.

[29]  J. Piette,et al.  The enlarging clinical, genetic, and population spectrum of tumor necrosis factor receptor-associated periodic syndrome. , 2002, Arthritis and rheumatism.

[30]  D. Kastner,et al.  The tumor-necrosis-factor receptor-associated periodic syndrome: new mutations in TNFRSF1A, ancestral origins, genotype-phenotype studies, and evidence for further genetic heterogeneity of periodic fevers. , 2001, American journal of human genetics.

[31]  Ian Todd,et al.  Germline Mutations in the Extracellular Domains of the 55 kDa TNF Receptor, TNFR1, Define a Family of Dominantly Inherited Autoinflammatory Syndromes , 1999, Cell.