TRAPS is extremely rare, with an estimated prevalence of fewer than 1 in 1,000,000 individuals. It affects both males and females and has been identified in various ethnic backgrounds, although it is more commonly reported in people of European descent. TRAPS is the second most common periodic fever syndrome, diagnosed in over 1000 people worldwide.

TRAPS is caused by mutations in the TNFRSF1A gene, which encodes the tumor necrosis factor type 1 receptor (TNFR1). This receptor protein resides in the membrane and is exposed to the outside of the cell, where it recognizes and binds to signaling proteins called tumor necrosis factor (TNF) that signals inflammation or destruction. Mutations in this gene lead to abnormal folding of this protein so that it cannot move to the cell membrane, and it forms clumps within the cell that are thought to result in excessive or prolonged inflammatory responses. The condition is inherited in an autosomal dominant manner, meaning only one copy of the mutated gene is needed to cause the disorder (see RareShare Guide on Genetic Inheritance).

TRAPS is characterized by recurrent inflammatory episodes that can last several days to weeks. Symptoms may include:

• Recurrent fever - often lasting 3 weeks but can span anywhere from a few days to a few months

• Severe muscle pain (especially in the trunk and limbs)

• Painful, spreading skin rashes, typically migratory and erythematous (redness caused by increased blood flow to capillaries), often overlying inflamed muscles

• Abdominal pain, vomiting, or diarrhea

• Conjunctivitis or periorbital swelling (swelling around the eyes)

• Joint pain (arthralgia) or swelling

• Chest pain due to inflammation of the pleura or pericardium

• Fatigue and malaise

Without treatment, persistent inflammation can lead to complications such as amyloidosis, a condition in which abnormal protein deposits (amyloid) accumulate in organs, particularly the kidneys. About 15-20% of adults diagnosed with TRAPS develop amyloidosis.

TRAPS is suspected in patients with recurrent, prolonged inflammatory episodes without evidence of infection or autoimmune disease. A family history of similar symptoms supports a genetic cause. Definitive diagnosis is made by identifying a mutation in the TNFRSF1A gene.

• Genetic testing: Confirms mutations in the TNFRSF1A gene

• Inflammatory markers: Elevated C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) during flares

• Serum amyloid A (SAA): Often elevated and used to assess risk of amyloidosis

• Urinalysis and kidney function tests: To monitor for signs of kidney involvement from amyloid deposition

• Imaging: May be used to assess organ inflammation during acute episodes

 Treatment focuses on controlling inflammation and preventing long-term complications:

• Corticosteroids: Often effective for controlling acute flares but not ideal for long-term use due to side effects

• Biologic therapies:

  • TNF inhibitors (e.g., etanercept) may have partial benefit

  • IL-1 inhibitors (e.g., anakinra, canakinumab) are more effective in many patients and often preferred

  • IL-6 inhibitors may be considered in refractory cases

• Colchicine: May be trialed, although it is generally less effective in TRAPS than in other periodic fever syndromes

• Monitoring for amyloidosis: Routine surveillance is important to prevent or detect complications early

With appropriate treatment, individuals with TRAPS can manage symptoms and prevent severe complications. However, untreated or poorly controlled disease can lead to chronic inflammation, organ damage, and amyloidosis, particularly affecting the kidneys. The disease course can vary significantly, from mild, infrequent episodes to more severe, persistent inflammation. Lifelong monitoring and treatment adjustment are often necessary to ensure optimal outcomes. Early diagnosis and the use of targeted biologic therapies have significantly improved the long-term prognosis for many individuals with TRAPS.

1. Medline Plus - Tumor necrosis factor receptor-associated periodic syndrome

2. NIH - TNF receptor-associated periodic syndrome

3. NORD - TRAPS

4. American College of Rheumatology - TRAPS