Tumor Necrosis Factor Receptor Associated Periodic Syndrome

Overview

Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS) is a rare, inherited autoinflammatory disorder characterized by recurrent episodes of fever and systemic inflammation. It is part of a group of disorders known as hereditary periodic fever syndromes, which are caused by genetic mutations affecting the innate immune system. TRAPS was first described in 1982 and was previously known as familial Hibernian fever. It is the most common autosomal dominant periodic fever syndrome and typically begins in childhood, though adult-onset cases have also been reported. The duration of inflammatory episodes is often prolonged, lasting from days to weeks, and symptoms can significantly impair quality of life if left untreated.

Causes

TRAPS is caused by mutations in the TNFRSF1A gene, which encodes the tumor necrosis factor receptor 1 (TNFR1). This receptor plays a key role in the regulation of inflammation by binding tumor necrosis factor-alpha (TNF-α), a potent inflammatory cytokine. Mutations in the TNFRSF1A gene lead to improper functioning of the TNFR1 receptor, resulting in unregulated inflammation and inappropriate activation of immune pathways.

The condition follows an autosomal dominant inheritance pattern, meaning that a single copy of the mutated gene inherited from one parent is sufficient to cause the syndrome. However, not all individuals with the mutation will develop symptoms—a phenomenon known as reduced penetrance.

Symptoms

Symptoms of TRAPS are episodic and vary in severity and duration among affected individuals. Common features include:

Fever:

• Recurrent episodes of high fever, typically lasting more than a week (in contrast to other periodic fever syndromes with shorter flares).

Musculoskeletal Pain:

• Severe muscle pain, especially in the limbs, which may be migratory.

• Joint pain or arthritis during flares.

Skin Manifestations:

• Painful red rash, often appearing as erythematous patches or plaques, typically overlying affected muscles.

Ocular Symptoms:

• Periorbital edema (swelling around the eyes)

• Conjunctivitis or uveitis in some cases

Abdominal and Chest Symptoms:

• Abdominal pain, nausea, vomiting, or diarrhea

• Pleuritic chest pain (due to inflammation of the lining of the lungs)

Other Features:

• Malaise, fatigue, and weight loss during episodes

• Potential development of amyloidosis (abnormal protein buildup), particularly in the kidneys, if the condition is left untreated

Diagnosis

Diagnosis of TRAPS is based on a combination of clinical findings, family history, laboratory markers of inflammation, and confirmatory genetic testing. The diagnostic process includes:

• Clinical history: Recurrent, prolonged febrile episodes, often with muscle pain and skin rashes, especially in individuals with a family history of similar symptoms.

• Laboratory tests:

  • Elevated inflammatory markers during episodes (e.g., C-reactive protein [CRP], erythrocyte sedimentation rate [ESR], serum amyloid A)

  • Normal or mildly elevated white blood cell count

  • Screening for renal function and proteinuria to assess for amyloidosis

• Genetic testing: Identification of mutations in the TNFRSF1A gene confirms the diagnosis.

• Differential diagnosis: Conditions such as familial Mediterranean fever (FMF), mevalonate kinase deficiency (MKD), and other periodic fever syndromes should be considered.

Treatment

Treatment of TRAPS focuses on reducing the frequency and severity of flares and preventing long-term complications such as amyloidosis. Management strategies include:

1. Anti-inflammatory Medications:

• Nonsteroidal anti-inflammatory drugs (NSAIDs): Used to manage mild symptoms during flares.

• Corticosteroids: Oral or intravenous steroids can be effective in reducing inflammation but are not ideal for long-term use due to side effects.

2. Biologic Therapies:

• Etanercept: A TNF receptor fusion protein used to bind and neutralize TNF-α. This was one of the earliest biologics used in TRAPS, though not all patients respond adequately.

• Anakinra: An interleukin-1 (IL-1) receptor antagonist that has shown efficacy in many patients with TRAPS.

• Canakinumab: A long-acting IL-1β inhibitor that provides effective control for some patients.

3. Colchicine:

• Not typically effective in TRAPS (unlike in familial Mediterranean fever), but may be tried in select cases or when diagnosis is uncertain.

4. Monitoring and Prevention:

• Regular monitoring of inflammatory markers and renal function to detect amyloidosis early.

• Genetic counseling for affected families to understand inheritance patterns and reproductive options.

Prognosis

The prognosis of TRAPS is variable and depends on the severity of symptoms and the effectiveness of treatment. Key points include:

• With effective treatment: Many patients experience fewer and less severe flares and can maintain a good quality of life.

• Without treatment: Chronic inflammation can lead to systemic complications, particularly amyloidosis, which may cause irreversible kidney damage and increase mortality.

• Early diagnosis and intervention: Significantly improve long-term outcomes and reduce the risk of organ damage.

Continued follow-up with a rheumatologist or clinical immunologist is essential for managing TRAPS, adjusting therapy, and monitoring for complications over time.