TNF Receptor-Associated Periodic Fever Syndrome

In: GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993.


Clinical characteristics: TNF receptor-associated periodic fever syndrome (TRAPS) is characterized by episodes of inflammation typically occurring every four to six weeks and lasting between five and 25 days. Flares may be prompted by stress, infection, trauma, hormonal changes, and vaccination. Symptoms may include fever, abdominal pain, arthralgia, myalgia, migratory rash, and eye inflammation, with variable severity. Symptoms often begin in early childhood (median age 4.3 years), though symptom onset can occur later in life. During a flare, acute-phase reactants such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and serum amyloid A are typically elevated. Generally, acute-phase reactants stabilize between flares but may remain somewhat elevated even in the absence of clinical symptoms. AA amyloidosis, the most severe sequela of TRAPS, can largely be avoided with adequate treatment. Proteinuria and kidney failure occur in 80%-90% of affected individuals with amyloidosis, while intestinal, thyroid, myocardium, liver, and spleen deposits are less common.

Diagnosis/testing: The diagnosis of TRAPS is established in a proband with at least one suggestive clinical feature and a heterozygous pathogenic (or likely pathogenic) variant in TNFRSF1A identified by molecular genetic testing.

Management: Treatment of manifestations: Interleukin-1 (IL-1) inhibitors (anakinra or canakinumab) are considered first-line therapies. Another treatment option is the use of TNF inhibitors (most commonly etanercept), which may be considered in refractory situations. The use of corticosteroids may be useful as needed during an acute attack but is not sufficient for long-term management or for preventing amyloidosis. Standard treatment (including low-vision services) by an ophthalmic subspecialist may be considered in those who experience retinal infarcts and/or optic nerve damage.

Prevention of secondary manifestations: IL-1 inhibitors and the TNF inhibitor etanercept control the severity of disease flares and are effective in preventing AA amyloidosis.

Surveillance: Complete physical examination with blood pressure and other vital signs, full skin examination, assessment for the presence of lymphadenopathy and hepatosplenomegaly, and musculoskeletal evaluation should be performed yearly, or more frequently if clinically indicated. The following are also recommended on an annual basis (or more frequently if indicated): measurement of CRP, ESR, serum level of AA amyloid, fibrinogen, haptoglobin, and complete blood count with differential, liver and renal function tests, urinalysis, quantitative immunoglobulins, QuantiFERON® to screen for tuberculosis (for those on biologic treatment), ophthalmologic evaluation, and assessment of the Autoinflammatory Diseases Activity Index (AIDAI). Imaging of the abdomen to assess for splenomegaly/hepatomegaly may also be considered if there are findings of serum AA amyloid or suspected spleen or liver enlargement on physical exam.

Agents/circumstances to avoid: For affected individuals managed with continuous biologic agents, consideration should be given to whether live-attenuated versus non-live vaccines should be administered. Data on the effect of live-attenuated vaccines is limited, and risks/benefits should be considered. It should be noted that affected individuals may have severe, paradoxical reactions that have been associated with anti-TNF monoclonal antibodies.

Pregnancy management: To date, no pattern of birth anomalies with either the anti-IL-1 or TNF inhibitor medication classes has been reported. The use of corticosteroids during human pregnancy has been associated with an increased risk of cleft lip with or without cleft palate in exposed fetuses.

Genetic counseling: TRAPS is inherited in an autosomal dominant manner. Most individuals diagnosed with TRAPS have an affected parent. Each child of an individual with TRAPS has a 50% chance of inheriting the TNFRSF1A pathogenic variant. Once the TNFRSF1A pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

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