TRAPS (Hybernian fever)

OVERVIEW: What every practitioner needs to know

Are you sure your patient has TRAPS? What are the typical findings for this disease?

Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is one of the hereditary periodic fever syndromes (HPFSs), now commonly called systemic autoinflammatory disorders, characterized by inappropriate, uncontrolled, and often spontaneous activation of the innate immune system in the absence of infection or autoimmunity.

The most common symptoms are recurrent prolonged episodes of fever, musculoskeletal pain, and systemic inflammation. The onset of symptoms occurs most commonly in early childhood. Episodic fevers >38° to 41°C are experienced for at least 3 days and possibly 2 to 6 weeks that recur on average every 5 to 6 weeks, but often in no predictable pattern. Focal myalgias, which may precede onset of fever, are a cardinal feature ot this disease.

The next most common symptoms are serositis (with recurrent abdominal pain due to sterile peritonitis in >90%, chest pain due to pleurisy in 50%, eye involvement with periorbital edema or conjunctivitis in 80%, arthralgia or large joint arthritis, migratory erythematous rash with underlying muscle tenderness, migratory lymphedema, and scrotal pain.

Lymphadenopathy is not usually a prominent feature and distinguishes TRAPS from HIDS (hyper-immunoglobulinemia D with periodic fever).

The most worrisome complication is secondary amyloidosis leading to renal failure in 10% of patients.

Other findings include:

• Median age of onset is 3 years, but can present for the first time even in middle age.

• During inflammatory attacks, marked leukocytosis, elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), increased serum amyloid A and ferritin, which may persist when fever-free.

• Symptoms usually resolve when afebrile.The disease is due to a single gene defect with incomplete penetrance, accounting for the variable age of onset. TRAPS arises from autosomal dominant mutations in the gene TNFRSF1A encoding the 55 kDa receptor for TNF alpha, TNFR1. More than 25% of patients have a clinically affected parent. Genotyping may be used to confirm diagnosis.

What other disease/condition shares some of these symptoms?

• Cyclic neutropenia

• HIV / AIDS

• Tuberculosis, cytomegalovirus (CMV), brucellosis, rat-bite fever, relapsing fever or other chronic viral, bacterial or parasitic infection.

• Systemic lupus erythematosus (SLE), relapsing polychrondritis

• Takayasu’s arteritis

• Other systemic autoinflammatory diseases

• HLA B27-associated juvenile spondyloarthropathies

• Sarcoidosis

• Autoimmune lymphoproliferative syndrome (ALPS)

• Acute intermittent porphyria

• Surgical emergencies, including appendicitis, intussusception, testicular torsio.

• Relapsing pancreatitis

Systemic autoinflammatory syndromes that mimic TRAPS

• Systemic onset juvenile idiopathic arthritis, adult Still’s disease

• Periodic fever with aphthous stomatitis, pharyngitis and adenitis (PFAPA syndrome)

• Other hereditary periodic fever syndromes:

  Hyper-immunoglobulinemia D with periodic fever (HIDS)

  Familial Mediterranean fever (FMF)

  Muckle-Wells syndrome (MWS)

• Behcet’s disease

• Crohn’s disease

• Macrophage activation syndrome

• Hereditary or acquired angioedema

• Gout

• Autoimmune bone diseases:

  CRMO (chronic recurrent multifocal osteomyelitis)

  SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis)

What caused this disease to develop at this time?

Triggers for flares may include stress, surgery, or concurrent infection, but in many cases, no specific trigger is identified.

The clinical symptoms are due to inappropriate activation and control of antigen-independent inflammation (innate immunity).

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Initial screening tests:

• CBC, differential during fever and when symptom-free

• ESR, CRP during fever and when symptom-free

• Complete metabolic panel

• Uric acid, lactic dehydrogenase (LD)

• Ferritin, fibrinoge.

• Quantitative immunoglobulins (IgG, IgA, IgM)

• Urinalysis

• Blood, urine cultures

• PPD (tuberculosis skin test)

Additional tests as needed:

• IgD

• CMV, Epstein-Barr virus (EBV), Brucella serologies

• CMV, EBV polymerase chain reaction (PCR)

• ACE (angiotensin converting enzyme)

• HLA B27 typing

• 24-hour urine collection for protein & creatinine clearance

• Bone marrow aspiration and biopsy for histology, cytogenetics, culture

Confirmatory studies:

Genotyping for TRAPS, FMF, HIDS, MWS

Renal or rectal biopsy for histology and stains for amyloid depositio.

Interpretation of results:

• Marked leukocytosis with left shift in association with ESR>80 and CRP>80 suggest infection.

• Positive PPD suggests tuberculosis.

• Suspect HIDS if elevated serum IgD and IgA.

Would imaging studies be helpful? If so, which ones?

• Chest x-ray for infection, inflammatory lung disease or serositis (pleuritis, pericarditis)

• Abdominal x-ray, ultrasound and/or CT to evaluate abdominal pain, rule out peritonitis or a surgical emergency

• Consider chest, abdomen, and pelvis CT to evaluate lymphadenopathy or splenomegaly

• Echocardiogram to evaluate chest pain and rule out pericarditis

Confirming the diagnosis

Pertinent history:

Peak fever temperature

Pattern of fever (hectic, quotidian, recurrent, relapsing/periodic, continuous, intermittent, remittent)

Duration of fever

Antecedent or prodromal symptoms prior to onset of fever

Associated symptoms (rash, arthritis, diarrhea, etc)

Pattern of appearance of associated symptoms

Duration of associated symptoms

Predictability of symptoms and illness course

Duration of fever-free intervals

Overall health and persistent or chronic symptoms when afebrile

Family history of similar febrile illnesses and response to treatment

Ethnicity of parents

Number and type of infections in lifetime and response to antibiotics

Suspect diagnosis if:

• Recurrent fevers without history of infectious symptoms.

• Family history, especially in first degree relative, of similar constellation of symptoms or with diagnosis of TRAPS by genotyping.

• Protracted fevers that remit and recur in association with serositis, conjunctivitis, arthritis.

• Fevers associated with focal muscle tenderness, sometimes with overlying rash.

• Amyloidosis observed.

If you are able to confirm that the patient has TRAPS, what treatment should be initiated?

• Are there some therapies that should be instituted immediately?

  NSAIDs for joint pain: Naproxen 10 mg/kg/dose b.i.d., celecoxib 50-100 mg b.i.d., or meloxicam 0.125 mg/kg (max 15 mg) daily.

  Prednisone 0.5-2 mg/kg/day for severe symptoms, taper & discontinue with symptomatic improvement.

• What about longer term treatment?

  NSAIDs for joint pain: Naproxen 10 mg/kg/dose b.i.d., celecoxib 50-100 mg b.i.d., OR meloxicam 0.125 mg/kg (max 15 mg) daily.

  Prednisone 0.5-2 mg/kg/day for severe symptoms, taper & discontinue with symptomatic improvement.

  Etanercept 0.4 mg/kg (max 25 mg) SQ b.i.w. – t.i.w. OR
  0.8 mg/kg (max 75 mg) SQ weekly for more severe symptoms.

• What about alternative treatments if fails standard therapy?

  Anakinra 1-2 mg/kg (max 100 mg ) SQ daily OR

  Tocilizumab 4-12 mg/kg IV q. 2-4 wk.

What are the adverse effects associated with each treatment option?

The adverse effects associated with each treatment option for TRAPS are shown in Table I.