Topic Editor: Robert Giles, MBBS, BPharm

Review Date: 9/7/2012

Definition

TNF-receptor-associated periodic syndrome (TRAPS) is an autosomal dominant inherited auto-immune/inflammatory condition which is characterized by recurrent febrile attacks and localized inflammation.

Description

• Originally termed Familial Hibernian Fever
• Recurrent fever without infection is the hallmark of a group of disorders known as periodic fever syndromes. TRAPS is one of six periodic fever syndromes which have been described.
• TRAPS is caused by mutations in the gene encoding the TNF receptor super family, member 1A (TNFRSF1A) on chromosome 12p13
• Hypothetical pathogenesis of TRAPS is felt to be due to defective TNFRSF1A shedding from cell membranes in response to a stimulus including TNF alpha. However, this may only account for the minority of TRAPS patients
• Other reported mechanisms include "resistance to apoptosis, TNFRSF1A internalization, or TNFRSF1A misfolding and aggregation leading to NF-kappaB activation and apoptosis"
• Clinical and genetic features of TRAPS are distinct from those of familial Mediterranean fever, hyperimmunoglobulinemia D syndrome, and other periodic fever syndromes
• Recurrent episodes of inflammatory symptoms usually last >5 days and include fever, abdominal pain, myalgia with migratory erythematous macular rashes, conjunctivitis with periorbital edema, chest pain, arthralgia and/or monoarticular synovitis
• Approximately 15% of patients develop amyloidosis. Unfortunately, this usually involves nephropathy, which can be life-threatening

Epidemiology

Incidence/Prevalence

• Epidemiologic data is limited. This condition is felt to be the most prevalent autosomal-dominant recurrent fever syndrome (ADRF). Familial Mediterranean Fever is the second most common inherited periodic fever
• TRAPS is most commonly seen in Europeans, many of Irish-Scottish descent, however, it has been seen in patients from many other ethnic backgrounds, such as Ashkenazi and Sephardic Jews, the Maghrebian population, Arabs, Puerto Ricans, and Dutch Indonesians
• Worldwide more than 1,000 people have been diagnosed with TRAPS since the condition was first described
• In a prospective surveillance of children (aged 16 years) conducted in Germany (2003 to 2006) the incidence of TRAPS was 6 per 107 person years. This corresponds to 6-10 newly diagnosed children per year in Germany

Age

• Median age of onset is 3 years but ranges from age 2 weeks to the sixth decade of life
• Age of onset is also noted to vary both within families and between families

Gender

• Male-to-female ratio is 3:2

Genetics

• TRAPS is an autosomal dominant disease caused by mutations in the TNFRSF1A gene
• As of August 2012, 120 mutations have been reported. The identified mutations are generally missense mutations affecting the first 2 cysteine-rich domains of the extracellular portion of the receptor
• Carriers of cysteine mutations are more severely affected are more likely to develop life threatening amyloidosis

Risk factors

• Family history of this condition
• Triggers for an attack:
  • Exercise
  • Hormonal changes
  • Infection
  • Injury/Trauma
  • Stressors (emotion/physical)

Etiology

• Caused by mutations in the gene encoding TNFRSF1A on chromosome 12p13

History

• History may include affected family members as this is an autosomal dominant condition
• Patients with TRAPS have recurrent episodes of fever which most commonly last 3 weeks. The range of episodes are from days to a few months
• The frequency of febrile episodes also varies between as little as 6 weeks, to several years
• Temperature >38^oC (100.4^oF) - 41^oC (105.8^oF), with 3 or more days duration generally indicates the onset an episode, along with other inflammatory symptoms
• Myalgias usually affect a single body area. These symptoms wax and wane throughout an attack. Pain migrates centrifugally over the course of several days. When joints are involved, a swollen joint with temporary contracture of the affected limb is common
• Episodes of fever usually occur due to no clear precipitant; however, some cases appear to be due to triggering factors such as:
  • Exercise
  • Hormonal changes
  • Infection
  • Injury/Trauma
  • Stressors (emotion/physical)
• Additional signs and symptoms:
  • Abdominal pain (present in 92%) may reflect inflammation of the peritoneum or muscular wall
  • Aphthous stomatitis
  • Arthralgias
  • Calf pain
  • Chest pain (present in 60%) - either musculoskeletal or pleural in origin
  • Conjunctivitis (often with periorbital edema)
  • Dyspnea
  • Fatigue
  • Lymphadenopathy
  • Myalgias
  • Ptosis
  • Rigors
  • Skin lesions (migratory patches, erysipelas-like erythema, edematous plaques, and/or urticaria)
  • Testicular pain
  • Vomiting and constipation (with or without bowel obstruction)
• Long-term inflammatory response can lead to serum amyloid A protein amyloidosis with common involvement of the kidneys and liver

Physical findings on examination

• Fever >38^oC (100.4^oF) - 41^oC (105.8^oF) is expected
• Palpation of areas affected by myalgia usually show warmth and tenderness
• When joints involvement occurs, there is often evidence of synovitis with a joint effusion. There may be contracture of the affected limb
• Skin manifestations show centrifugal, migratory, erythematous patches (1-28 cm in size), most commonly overlying a single region of myalgia. These lesions are typically both warm and tender on palpation, and usually blanch with pressure. Skin lesions generally occur at just a single site, but can occasionally involve more than a single site
• Skin manifestations can also include a less distinct rash, which may have urticaria or generalized erythematous serpiginous lesions
• In some patients, acute abdomen may be present (can lead to unnecessary surgical exploration)
• Ocular signs: conjunctivitis, periorbital edema, periorbital pain and ptosis
• Prominent lymphadenopathy, generally limited to single anatomic location

Blood tests findings

• Complete blood count: May reveal variable degree of hypochromic anemia, leukocytosis, and thrombocytosis
• C reactive protein (CRP): Increased during the attack
• Erythrocyte sedimentation rate (ESR): Increased during the attack (best to simply order CRP in most cases; no need to order CRP and ESR)
• Haptoglobin, fibrinogen, and ferritin: Increased during the attack
• Immunoglobulin D (IgD) level: May be elevated (>100 IU/mL)
• Polyclonal immunoglobulin levels (particularly IgA): Increased
• Serum levels of soluble TNFRSF1A: Patients with TRAPS have low blood levels of soluble TNFRSF1A (sTNFRSF1A) which does not increase above the normal range during inflammatory attacks. This contrasts with rheumatoid arthritis, where sTNFRSF1A levels start in the normal range and may increase up to twentyfold

Other laboratory test findings

• Urine screening: Urine should be screened for protein due to renal amyloidosis

Other diagnostic test findings

• Histopathological findings:
  • Renal biopsy may shows deposition of amyloid fibrils
  • Biopsy of skin lesions may show superficial and deep perivascular and interstitial infiltration with lymphocytes and monocytes
  • Muscle biopsy can show monocytic fasciitis or lymphocytic vasculitis; but should not show myositis

• Any typical or atypical viral/bacterial or other infectious process
• Acute peritonitis
• Connective tissue diseases (e.g. SLE, Still's disease)
• Cyclic Neutropenia
• Infantile-onset multisystem inflammatory disease
• Other periodic fever syndromes:
  • Familial cold auto-inflammatory syndrome
  • Familial Mediterranean fever
  • Hyperimmunoglobulinemia D syndrome
  • Muckle-Wells syndrome
  • Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAFA )

General treatment items

• Initial treatment includes non-steroidal anti-inflammatory drugs to relieve symptoms of fever
• Etanercept and prednisone are the primary treatments for TRAPS. Etanercept (a TNFRSF1B receptor–immunoglobulin fusion molecule) mimics the effect of the normal soluble TNF receptor. In TRAPS patients, use of etanercept compensates for this deficit
• Live vaccines should not be given concomitantly with etanercept
• Prednisone decreases inflammatory episodes by suppressing migration of polymorphonuclear leukocytes, suppressing the immune system and decreasing capillary permeability. When corticosteroids are used for greater than 7-10 days, they are generally withdrawn by gradual dose tapering
• Unlike other periodic fever syndromes treatment with colchicines is not effective
• Consultations, as indicated may be required with:
  • Rheumatology
  • Dermatology
  • Infectious disease
  • Nephrology
  • Orthopedics
  • Surgery/Urology

Medications indicated with specific doses

• Etanercept [SC]
• Adult dosing
• Pediatric dosing
• Ibuprofen [Oral]
• Adult dosing
• Pediatric dosing
• Prednisone
• Adult dosing
• Pediatric dosing

Dietary or Activity restrictions

• Avoid physical or emotional stress as this may provoke an episode

Complications

• Amyloidosis
• Nephropathy

Prognosis

• Prognosis is worse in those who have amyloidosis
• In cases without amyloidosis, life expectancy is normal

Synonyms/Abbreviations

Synonyms

• Familial Hibernian fever

Abbreviations

• TRAPS

ICD-9-CM

• 279.9 Unspecified disorder of immune mechanism

ICD-10-CM

• D89.9 Disorder involving the immune mechanism, unspecified

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