TNF Receptor Associated Periodic Syndrome

Overview

TNF Receptor Associated Periodic Syndrome (TRAPS) is a rare, inherited autoinflammatory disorder characterized by recurrent episodes of fever, rash, abdominal pain, muscle aches, and joint inflammation. It belongs to a group of disorders known as hereditary periodic fever syndromes. TRAPS is caused by mutations in the TNFRSF1A gene, which encodes the type 1 tumor necrosis factor receptor (TNFR1), a protein involved in regulating inflammation. The disease typically begins in childhood or early adulthood and can vary significantly in severity. Without appropriate treatment, TRAPS may lead to complications such as amyloidosis, which can damage vital organs like the kidneys.

Causes

TRAPS is caused by mutations in the TNFRSF1A gene located on chromosome 12. This gene encodes the tumor necrosis factor receptor 1 (TNFR1), a key component in controlling the body’s inflammatory response. Mutations in TNFRSF1A result in dysfunctional receptors that fail to properly regulate inflammation, leading to uncontrolled inflammatory episodes.

The condition follows an autosomal dominant inheritance pattern, meaning that only one copy of the altered gene inherited from an affected parent is sufficient to cause the disorder. However, some individuals may develop TRAPS as a result of a new (de novo) mutation with no prior family history.

Symptoms

The symptoms of TRAPS are episodic, lasting from a few days to several weeks, and typically recur every few weeks or months. The frequency, duration, and severity of episodes can vary widely. Common symptoms include:

Systemic and Inflammatory Symptoms:

• Recurrent high fevers – Often the first and most consistent symptom, lasting more than a week.

• Fatigue and malaise – General feelings of illness and low energy during flare-ups.

Musculoskeletal and Abdominal Symptoms:

• Severe muscle pain (myalgia) – Often affecting one area, such as a limb, and may be migratory.

• Joint pain and swelling – Arthritis-like symptoms, particularly during attacks.

• Abdominal pain – Frequently due to inflammation of the abdominal lining (peritonitis).

Skin and Eye Involvement:

• Red, painful rash – Typically on the trunk or limbs, may feel warm to the touch.

• Periorbital edema – Swelling around the eyes, particularly during fevers.

• Conjunctivitis – Redness and irritation of the eyes.

Over time, chronic inflammation in TRAPS may lead to long-term complications such as amyloidosis, which involves deposition of amyloid proteins in organs and can lead to organ failure, particularly in the kidneys.

Diagnosis

Diagnosing TRAPS can be challenging due to its rarity and overlapping features with other periodic fever syndromes. Diagnosis is based on clinical evaluation, family history, and genetic testing. Diagnostic steps include:

• Detailed medical history – Including pattern, duration, and triggers of fever episodes and associated symptoms.

• Physical examination – To assess signs such as rash, joint swelling, and eye involvement during flares.

• Laboratory tests – Elevated markers of inflammation such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and serum amyloid A (SAA) during episodes.

• Genetic testing – Confirms mutations in the TNFRSF1A gene and rules out other periodic fever syndromes like FMF, HIDS, or CAPS.

• Urinalysis – Monitors for proteinuria, which may signal amyloidosis.

Treatment

Treatment of TRAPS focuses on controlling symptoms, reducing inflammation, and preventing long-term complications such as amyloidosis. Treatment options include:

1. Anti-inflammatory Medications:

• Non-steroidal anti-inflammatory drugs (NSAIDs) – May provide symptomatic relief for fever and pain.

• Corticosteroids – Often effective in reducing symptoms during acute flares, though long-term use is limited by side effects.

2. Biologic Agents (Targeted Therapy):

• Etanercept – A TNF receptor fusion protein that has shown some benefit in TRAPS, though response can be variable.

• Anakinra or canakinumab – Interleukin-1 (IL-1) inhibitors used off-label to control inflammation when TNF-blockers are ineffective.

• Tocilizumab – An IL-6 inhibitor that may help in refractory cases.

3. Monitoring and Preventive Care:

• Regular monitoring of SAA levels – To assess ongoing inflammation and risk of amyloidosis.

• Kidney function tests and urinalysis – To detect early signs of organ involvement.

• Genetic counseling – For affected individuals and family members regarding inheritance and reproductive options.

Prognosis

The prognosis of TRAPS depends on the severity of symptoms and whether complications such as amyloidosis develop. Key points include:

• Variable disease course – Some individuals have mild, infrequent symptoms, while others experience frequent and severe episodes.

• Risk of amyloidosis – If left untreated, chronic inflammation can lead to amyloidosis, most commonly affecting the kidneys, potentially resulting in kidney failure.

• Improved outcomes with treatment – Early diagnosis and use of biologic therapies have greatly improved symptom control and reduced the risk of complications.

• Normal life expectancy – With appropriate treatment and monitoring, many individuals with TRAPS can live a normal lifespan and maintain good quality of life.

Continued research and advancements in biologic therapies are helping improve the outlook for patients with TNF Receptor Associated Periodic Syndrome. Lifelong management and regular medical follow-up are essential to prevent long-term damage and ensure optimal health outcomes.