#1leading
ER retention of misfolded TNFR1 drives inflammation through the unfolded protein response (UPR), independently of TNF binding
15 studies·pathogenesis
75
evidence
TNF Receptor-Associated Periodic Syndrome
Also known asTRAPSFamilial Hibernian FeverTNFRSF1A-associated periodic syndrome
TNF Receptor-Associated Periodic Syndrome (TRAPS) is the most common autosomal dominant autoinflammatory disease, caused by heterozygous mutations in the TNFRSF1A gene encoding the type 1 TNF receptor (TNFR1). First described in 1982 as 'Familial Hibernian Fever' in an Irish family by Williamson et al.
Data sourced from 1 published studies with evidence grading (A–D). Last reviewed . Not medical advice.
Pathophysiology◐Partially understood
Treatment✓Effective options available
Genetic basis○Well characterised
Research activity
1 studies·1 active trials·2019–2019
Epidemiology
- Total cases
- 1,000
- Mean onset
- 4 years
- Onset range
- 1–63 years
- Sex ratio (M:F)
- 1.1:1
- Diagnostic delay
- ~5 years
- Discovered
- 1982 (L.M. Williamson)
- Prevalence
- ~1/1,000,000
- Classification
- Autoinflammatory, Monogenic
Cardinal Features
11 key symptoms and signs
| Feature | Frequency | Category | Sources |
|---|---|---|---|
Recurrent prolonged fever Febrile episodes lasting 1–4 weeks (longer than FMF), recurrent at irregular intervals. Temperature often >39°C. Median 70 symptomatic days per year. | 88% | systemic | |
Migratory myalgia Distinctive centrifugal migratory muscle pain, typically moving distally along a limb over hours to days. Often accompanied by overlying erythematous skin changes. A hallmark feature that helps distinguish TRAPS from other periodic fevers. | 80% | musculoskeletal | |
Abdominal pain Severe abdominal pain during febrile episodes, sometimes mimicking surgical abdomen. Caused by peritoneal inflammation (sterile peritonitis). More frequent in paediatric onset (84% in children vs 25% in adults). | 75% | gastrointestinal | |
Periorbital edema Swelling around the eyes, often unilateral. A distinctive clinical feature that helps differentiate TRAPS from other autoinflammatory diseases. Included in Eurofever classification criteria. | 40% | ophthalmic | |
Migratory erythematous rash Erythematous, often tender, migratory skin patches overlying areas of myalgia. Not urticarial (unlike Schnitzler or CAPS). Histology shows perivascular mononuclear infiltrate. | 70% | dermatologic | |
Arthralgia / arthritis Joint pain affecting large joints, sometimes with frank arthritis. Non-destructive. Typically coincides with febrile episodes. | 65% | musculoskeletal | |
Pleurisy / chest pain Pleuritic chest pain from serositis. May present with pleural effusion. Part of the serosal inflammation spectrum in TRAPS. | 40% | respiratory | |
Pericarditis Present in ~30% of TRAPS patients. Can be the presenting feature, particularly in adults. More responsive to corticosteroids than to colchicine. 6% of idiopathic recurrent pericarditis patients may carry TNFRSF1A mutations. | 30% | cardiovascular | |
Conjunctivitis / periorbital inflammation Eye redness and inflammation, often unilateral. May occur with periorbital edema. Characteristic of TRAPS attacks. | 45% | ophthalmic | |
Elevated CRP / acute phase reactants Markedly elevated CRP and ESR during attacks. Serum amyloid A (SAA) often extremely high, predisposing to AA amyloidosis. Normalises between episodes in some patients. | 95% | laboratory | |
Elevated serum amyloid A (SAA) SAA is often extremely elevated during attacks, sometimes >1000 mg/L. Persistent SAA elevation is a risk factor for AA amyloidosis. Key monitoring biomarker. | 85% | laboratory |
Hypothesis Tracker
Competing explanations ranked by evidence weight
#2leading
Mitochondrial ROS generation from misfolded TNFR1 activates NLRP3 inflammasome, driving IL-1β-mediated inflammation
10 studies·pathogenesis
70
evidence
#3leading
Wild-type and mutant TNFR1 act in concert from distinct cellular locations — both alleles are required for the inflammatory phenotype
5 studies·pathogenesis
65
evidence
#4competing
Defective TNFR1 ectodomain shedding reduces soluble receptor, leaving TNF signalling unchecked
8 studies·pathogenesis
35
evidence
Open Questions
What triggers the periodicity of TRAPS attacks?
TRAPS patients have constant genetic mutations, yet attacks come and go. The mechanism that converts constitutive ER stress and ROS elevation into episodic febrile attacks is unknown. Environmental triggers, infections, stress, and hormonal changes are suspected but unproven.
Is R92Q truly pathogenic or a benign polymorphism with coincidental inflammatory phenotype?
R92Q is the most common TNFRSF1A variant in TRAPS patients (34%) but is also found in 1.2–4% of healthy Caucasians. Patients with R92Q have milder disease and higher spontaneous resolution. Its classification as INSAID Group B (uncertain significance) reflects genuine diagnostic ambiguity.
Why do anti-TNF monoclonal antibodies worsen TRAPS while etanercept provides partial benefit?
Infliximab and adalimumab can cause paradoxical flares in TRAPS within hours. Etanercept has partial but waning efficacy. The mechanistic difference — etanercept as soluble receptor vs infliximab crosslinking membrane TNF — is hypothesised but not proven in TRAPS-specific models.
Can early biologic treatment completely prevent AA amyloidosis in high-risk patients?
Cysteine mutations carry ~24% amyloidosis risk. The Eurofever data shows no patients on anti-IL-1 developed amyloidosis, but this is observational. A prospective study of early vs delayed biologic treatment in children with cysteine mutations is needed.
Could mitochondrial antioxidants serve as adjunctive therapy in TRAPS?
Bulua 2011 showed that pharmacological blockade of mitochondrial ROS reduces inflammatory cytokine production in TRAPS cell models. No clinical trials of antioxidants in TRAPS exist.
Recent Updates
Long-term CLUSTER extension confirms sustained canakinumab efficacy in TRAPS
Gattorno et al. (2024) published the 72-week extension of the CLUSTER trial showing >94% of TRAPS patients achieved no or minimal disease activity on canakinumab, with 69.8% experiencing zero flares.
INSAID classification system validated for TRAPS treatment decisions
Papa et al. (2021) demonstrated that INSAID variant classification (Groups A/B/C) combined with Eurofever criteria reliably predicts treatment needs in 226 TRAPS patients. Anti-IL-1 drugs achieved >85% complete response in Group A.
French national series quantifies AA amyloidosis severity in TRAPS
Delaleu et al. (2021) reported that AA amyloidosis preceded TRAPS diagnosis in 96% of cases, with 47% needing renal replacement therapy and 14% mortality. Highlights the importance of early TRAPS diagnosis.
AIDA Network real-life data on colchicine in TRAPS
Rigante et al. (2020) showed colchicine achieves complete response in only 12.5% of TRAPS patients. May be appropriate for mild phenotypes with low-penetrance variants.
Tocilizumab case reports expand treatment options for refractory TRAPS
Multiple case reports have demonstrated tocilizumab efficacy in TRAPS patients refractory to anti-TNF and anti-IL-1 therapies, supporting IL-6 as a pathogenic mediator.
Canakinumab FDA/EMA-approved for TRAPS based on CLUSTER trial
Canakinumab received FDA and EMA approval for TRAPS in 2016-2017 based on the pivotal CLUSTER trial, which demonstrated that canakinumab 150 mg every 4 weeks achieved complete disease control in 45% of TRAPS patients at 16 weeks versus 8% with placebo. This was the first approved targeted therapy for TRAPS.
Misfolded TNFRSF1A protein shown to activate unfolded protein response and ROS
Bulua et al. (2011) and Simon et al. (2010) demonstrated that structural TNFRSF1A mutations cause receptor misfolding and retention in the endoplasmic reticulum, triggering the unfolded protein response and mitochondrial ROS production. This ER stress pathway activates MAPK signaling and NF-kB independent of TNF ligand, explaining why anti-TNF therapy is less effective than IL-1 blockade in TRAPS.
Eurofever/PRINTO genotype-phenotype study in 158 TRAPS patients
Ter Haar et al. (2015) analyzed 158 TRAPS patients in the Eurofever registry, confirming that cysteine-disrupting TNFRSF1A mutations cause the most severe phenotype with highest amyloidosis risk (24%), while T50M and R92Q variants present with milder, often self-limited disease. These findings established genotype-based risk stratification for clinical management.
Eurofever/PRINTO evidence-based classification criteria for TRAPS validated
Gattorno et al. (2019) published validated classification criteria for TRAPS within the Eurofever/PRINTO framework, incorporating genetic confirmation of pathogenic TNFRSF1A variants plus clinical features (duration of episodes >6 days, migratory rash, periorbital edema, myalgia). The criteria achieved 95% sensitivity and 97% specificity, enabling standardized diagnosis for clinical trials.
R92Q prevalence in inflammatory disease cohorts higher than expected
Large population screening studies revealed the low-penetrance TNFRSF1A R92Q variant is present in 1-2% of healthy controls and enriched in patients with undifferentiated inflammatory syndromes, recurrent pericarditis, and inflammatory bowel disease. This raises questions about R92Q as a disease modifier rather than a monogenic cause, influencing genetic counseling approaches.