RARE DISEASE
Tumor necrosis factor receptor 1 associated periodic syndrome
Tumor necrosis factor receptor 1 associated periodic syndrome
Tumor necrosis factor receptor 1 associated periodic syndrome
Synonyms: Familial Hibernian fever, TNF receptor 1-associated periodic syndrome, TRAPS syndrome
Synonyms: Familial Hibernian fever, TNF receptor 1-associated periodic syndrome, TRAPS syndrome
Synonyms: Familial Hibernian fever, TNF receptor 1-associated periodic syndrome, TRAPS syndrome
Drug discovery
2
drugs
With orphan designations
Overview
Tumor necrosis factor receptor 1-associated periodic syndrome (TRAPS) is a rare autosomal dominant autoinflammatory disorder caused by TNFRSF1A gene mutations, leading to dysregulated NF-κB signaling and systemic inflammation. It features recurrent fever episodes (1–3 weeks) with migratory myalgia, erythematous rash, serosal inflammation, and periorbital edema. Complications include AA amyloidosis (∼10% of cases) and increased cardiovascular risk [1][2][5][8].
Burden
Chronic inflammation increases amyloidosis risk (renal/hepatic involvement) [1][2][6]
Recurrent hospitalizations, reduced quality of life, and treatment-resistant pericarditis in severe cases [4][8][14]
Lifetime management required; mortality linked to amyloidosis complications and cardiovascular events [1][4][8]
Therapies
First-line: IL-1 inhibitors (anakinra, canakinumab) for long-term control [3][6][14]
Second-line: TNF inhibitors (etanercept) with variable response; avoid monoclonal anti-TNF agents (infliximab) due to paradoxical flares [3][7][14]
Adjunctive: Corticosteroids for acute flares, NSAIDs for symptom relief [1][14]
Categories: rare genetic diseases, rare immunological diseases, rare skin diseases, rare systemic and rheumatological diseases, rare systemic or rheumatologic diseases of childhood
Research Papers
141 drug discovery papers about Tumor necrosis factor receptor 1 associated periodic syndrome, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
141 drug discovery papers about Tumor necrosis factor receptor 1 associated periodic syndrome, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-01 | A Novel TNFRSF1A Gene Variant in a Patient with Recurrent Fevers and Amyloidosis: A Case Report
Background TNF Receptor Associated Periodic Syndrome (TRAPS) is a rare autosomal dominant autoinflammatory disorder. It is caused by pathogenic variants in the TNFRSF1A gene which encodes the TNF receptor 1. These mutations impair receptor shedding and disrupt TNFα signaling, leading to uncontrolled inflammation with recurrent fever, serositis, and myalgia.[1] Left untreated, chronic inflammation may result in AA amyloidosis and end-stage renal disease (ESRD). Early recognition and treatment with IL-1 inhibitors can mitigate deterioration and prevent irreversible complications such as amyloidosis. Here we present a case of TRAPS complicated by amyloidosis and associated with a novel variant in TNFRSF1A. Case Report A 48-year-old male was referred for early childhood onset, recurrent 3-5-day febrile episodes accompanied by severe abdominal pain, large joint arthralgias and myalgias. He was treated intermittently with corticosteroids and NSAIDs, with incomplete response. At 43 years old he developed chronic kidney disease with renal biopsy compatible with amyloidosis. This eventually progressed to ESRD requiring hemodialysis. Genetic testing was performed when he was 48 years old and revealed a heterozygous missense variant in TNFRSF1A (c.214_215delinsCT, p.Cys72Leu). The mutation resides in exon 3 within the extracellular cysteine-rich domain, and was predicted to disrupt disulfide bond formation, resulting in misfolded receptor protein and defective TNFα signaling. Substitutions at the same residue (Cys72Arg, Cys72Ser) had been previously demonstrated to be causative for TRAPS.[2] His asymptomatic parents did not carry the mutation. As such, this de novo Cys72Leu variant was classified as Likely Pathogenic, and the patient was diagnosed with TRAPS. Anakinra 100 mg SC daily was started which prevented further attacks. However, he remains on hemodialysis and is on the waitlist for renal transplant. Conclusion In summary, our case highlights the importance of early recognition of autoinflammatory diseases like TRAPS, in order to initiate targeted treatment and prevent life altering complications such as amyloidosis and ESRD. We report a novel variant in the TNFRSF1A gene, adding to the literature of mutations causing TRAPS. Further studies are needed to functionally characterize the biological impact of Cys72Leu, as well as to elucidate the complex mechanisms between TNF receptor dysfunction and IL-1 signaling. References [1.] Gaggiano C. Mediators Inflamm 2020;7:8562485. [2.] Lachmann HJ. Ann Rheum Dis 2014;73:2160-7.
2026-07-21 | A Case of Adult-Onset TNF Receptor-Associated Periodic Syndrome (TRAPS) with Somatic Mosaicism Treated with an IL-1 Inhibitor.
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.
2026-06-18 | The use of JAK inhibitors and tocilizumab in the management of TRAPS: a sibling case study.
Tumour necrosis factor (TNF) receptor-1 associated periodic syndrome (TRAPS) is an autoinflammatory condition. Most treatment options require regular injections, posing challenges for individuals with needle phobia. We reviewed the medical records of two siblings, a now 14-year-old female, and her 10-year-old brother, both diagnosed with TRAPS in early infancy. Both children responded to on-demand oral corticosteroid therapy, but due to frequent flares, persistent biochemical inflammation and poor growth, steroid-sparing therapies were required. Non-standard first-line therapies were subsequently selected as the eldest child had developed a needle phobia, and she was commenced on an oral Janus kinase (JAK) inhibitor. The younger brother was treated with tocilizumab, reflecting parental preference to minimise frequent injections. Over the last two years, both children have demonstrated significant improvement, with almost no further TRAPS flares, normalisation of baseline inflammatory markers and improvements in their growth trajectories. No adverse effects were reported on either agent. JAK inhibitor therapy and tocilizumab were effective in our two cases of TRAPS. To our knowledge, this is the first report describing the use of a JAK inhibitor in TRAPS, while also adding to the limited published experience with tocilizumab in TRAPS.
2026-05-29 | Pediatric Rheumatic Disorders Revisited: Integrating Imaging and Pathophysiologic Insights across the Autoinflammatory-Autoimmune Continuum.
Recent advances in immunologic and molecular research on rheumatic diseases have significantly improved understanding of the diverse group of immune-mediated disorders. Rheumatic diseases were traditionally considered autoimmune diseases, caused by impaired adaptive immunity and often associated with pathogenic autoantibodies. However, in the late 20th century, certain genetic rheumatic diseases-such as tumor necrosis factor receptor-associated periodic syndrome (TRAPS) and familial Mediterranean fever (FMF)-were found to result from antigen-independent activation of innate immune cells and the subsequent cytokine-mediated inflammation. This discovery introduced the new concept of autoinflammatory diseases, characterized by dysregulation of innate immunity. Although autoimmune and autoinflammatory diseases were initially regarded as distinct categories, substantial overlap has become evident. For instance, autoantibodies can be detected in disorders primarily affecting innate immunity, while recent cytokine-targeting therapies have proven effective for classic autoimmune diseases, such as systemic lupus erythematosus (SLE) and dermatomyositis. These insights led to the concept of an autoinflammatory-autoimmune continuum, highlighting that dysregulation of the interaction between innate and adaptive immune systems contributes to the clinical symptoms of rheumatic diseases. The authors explore clinical, imaging, pathophysiologic, and therapeutic aspects of pediatric rheumatic diseases through the lens of this continuum, providing a comprehensive overview of current diagnostic and treatment strategies. © RSNA, 2026 Supplemental material is available for this article.
2026-04-04 | When to suspect monogenic autoinflammatory diseases in patients with digestive symptoms?
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.
2026-08-01 | A Novel TNFRSF1A Gene Variant in a Patient with Recurrent Fevers and Amyloidosis: A Case Report
Background TNF Receptor Associated Periodic Syndrome (TRAPS) is a rare autosomal dominant autoinflammatory disorder. It is caused by pathogenic variants in the TNFRSF1A gene which encodes the TNF receptor 1. These mutations impair receptor shedding and disrupt TNFα signaling, leading to uncontrolled inflammation with recurrent fever, serositis, and myalgia.[1] Left untreated, chronic inflammation may result in AA amyloidosis and end-stage renal disease (ESRD). Early recognition and treatment with IL-1 inhibitors can mitigate deterioration and prevent irreversible complications such as amyloidosis. Here we present a case of TRAPS complicated by amyloidosis and associated with a novel variant in TNFRSF1A. Case Report A 48-year-old male was referred for early childhood onset, recurrent 3-5-day febrile episodes accompanied by severe abdominal pain, large joint arthralgias and myalgias. He was treated intermittently with corticosteroids and NSAIDs, with incomplete response. At 43 years old he developed chronic kidney disease with renal biopsy compatible with amyloidosis. This eventually progressed to ESRD requiring hemodialysis. Genetic testing was performed when he was 48 years old and revealed a heterozygous missense variant in TNFRSF1A (c.214_215delinsCT, p.Cys72Leu). The mutation resides in exon 3 within the extracellular cysteine-rich domain, and was predicted to disrupt disulfide bond formation, resulting in misfolded receptor protein and defective TNFα signaling. Substitutions at the same residue (Cys72Arg, Cys72Ser) had been previously demonstrated to be causative for TRAPS.[2] His asymptomatic parents did not carry the mutation. As such, this de novo Cys72Leu variant was classified as Likely Pathogenic, and the patient was diagnosed with TRAPS. Anakinra 100 mg SC daily was started which prevented further attacks. However, he remains on hemodialysis and is on the waitlist for renal transplant. Conclusion In summary, our case highlights the importance of early recognition of autoinflammatory diseases like TRAPS, in order to initiate targeted treatment and prevent life altering complications such as amyloidosis and ESRD. We report a novel variant in the TNFRSF1A gene, adding to the literature of mutations causing TRAPS. Further studies are needed to functionally characterize the biological impact of Cys72Leu, as well as to elucidate the complex mechanisms between TNF receptor dysfunction and IL-1 signaling. References [1.] Gaggiano C. Mediators Inflamm 2020;7:8562485. [2.] Lachmann HJ. Ann Rheum Dis 2014;73:2160-7.
2026-07-21 | A Case of Adult-Onset TNF Receptor-Associated Periodic Syndrome (TRAPS) with Somatic Mosaicism Treated with an IL-1 Inhibitor.
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.
2026-06-18 | The use of JAK inhibitors and tocilizumab in the management of TRAPS: a sibling case study.
Tumour necrosis factor (TNF) receptor-1 associated periodic syndrome (TRAPS) is an autoinflammatory condition. Most treatment options require regular injections, posing challenges for individuals with needle phobia. We reviewed the medical records of two siblings, a now 14-year-old female, and her 10-year-old brother, both diagnosed with TRAPS in early infancy. Both children responded to on-demand oral corticosteroid therapy, but due to frequent flares, persistent biochemical inflammation and poor growth, steroid-sparing therapies were required. Non-standard first-line therapies were subsequently selected as the eldest child had developed a needle phobia, and she was commenced on an oral Janus kinase (JAK) inhibitor. The younger brother was treated with tocilizumab, reflecting parental preference to minimise frequent injections. Over the last two years, both children have demonstrated significant improvement, with almost no further TRAPS flares, normalisation of baseline inflammatory markers and improvements in their growth trajectories. No adverse effects were reported on either agent. JAK inhibitor therapy and tocilizumab were effective in our two cases of TRAPS. To our knowledge, this is the first report describing the use of a JAK inhibitor in TRAPS, while also adding to the limited published experience with tocilizumab in TRAPS.
2026-05-29 | Pediatric Rheumatic Disorders Revisited: Integrating Imaging and Pathophysiologic Insights across the Autoinflammatory-Autoimmune Continuum.
Recent advances in immunologic and molecular research on rheumatic diseases have significantly improved understanding of the diverse group of immune-mediated disorders. Rheumatic diseases were traditionally considered autoimmune diseases, caused by impaired adaptive immunity and often associated with pathogenic autoantibodies. However, in the late 20th century, certain genetic rheumatic diseases-such as tumor necrosis factor receptor-associated periodic syndrome (TRAPS) and familial Mediterranean fever (FMF)-were found to result from antigen-independent activation of innate immune cells and the subsequent cytokine-mediated inflammation. This discovery introduced the new concept of autoinflammatory diseases, characterized by dysregulation of innate immunity. Although autoimmune and autoinflammatory diseases were initially regarded as distinct categories, substantial overlap has become evident. For instance, autoantibodies can be detected in disorders primarily affecting innate immunity, while recent cytokine-targeting therapies have proven effective for classic autoimmune diseases, such as systemic lupus erythematosus (SLE) and dermatomyositis. These insights led to the concept of an autoinflammatory-autoimmune continuum, highlighting that dysregulation of the interaction between innate and adaptive immune systems contributes to the clinical symptoms of rheumatic diseases. The authors explore clinical, imaging, pathophysiologic, and therapeutic aspects of pediatric rheumatic diseases through the lens of this continuum, providing a comprehensive overview of current diagnostic and treatment strategies. © RSNA, 2026 Supplemental material is available for this article.
2026-04-04 | When to suspect monogenic autoinflammatory diseases in patients with digestive symptoms?
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.
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Drug Discovery Landscape
2 orphan drug designations for Tumor necrosis factor receptor 1 associated periodic syndrome, including 1 approved therapy.
2 orphan drug designations for Tumor necrosis factor receptor 1 associated periodic syndrome, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Canakinumab [Ilaris] | antibodies | EMA | 2012-11-08 | — | Novartis Europharm Limited |
canakinumab [Ilaris] | antibodies | FDA | 2012-09-04 | 2016-09-23 | Novartis Pharmaceuticals Corporation |
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