Pediatrics

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:

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

  2. 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.

  3. 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?

  1. Cyclic neutropenia

  2. HIV / AIDS

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

  4. Systemic lupus erythematosus (SLE), relapsing polychrondritis

  5. Takayasu's arteritis

  6. Other systemic autoinflammatory diseases

  7. HLA B27-associated juvenile spondyloarthropathies

  8. Sarcoidosis

  9. Autoimmune lymphoproliferative syndrome (ALPS)

  10. Acute intermittent porphyria

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

  12. Relapsing pancreatitis

Systemic autoinflammatory syndromes that mimic TRAPS

  1. Systemic onset juvenile idiopathic arthritis, adult Still's disease

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

  3. Other hereditary periodic fever syndromes:

    • Hyper-immunoglobulinemia D with periodic fever (HIDS)

    • Familial Mediterranean fever (FMF)

    • Muckle-Wells syndrome (MWS)

  4. Behcet's disease

  5. Crohn's disease

  6. Macrophage activation syndrome

  7. Hereditary or acquired angioedema

  8. Gout

  9. 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.

Table I.

Adverse effects of treatment options for TRAPS
NSAIDS Gastritis, gastric ulcer, gastroesophageal reflux, rash, edema, liver/renal toxicity uncommon in children
Corticosteroids Infection, weight gain, muscle atrophy, adrenocortical insufficiency, osteopenia, growth delay, avascular necrosis, emotional lability, rash, edema, hypertension, diabetes
Etanercept Infection, injection site reaction, CNS/demyelinating disorder, ANA positivity, malignancy (very low risk)
Anakinra Infection, severe injection site reaction/pain, future malignancy
Tocilizumab Infection, thrombocytopenia, allergic reaction, anaphylaxis, CNS/demyelinating disorder, GI perforation, elevated LFTs, hyperlipidemia, future malignancy

What are the possible outcomes of TRAPS?

What will you tell the family about prognosis?

  1. Age at initial presentation highly variable: < 1 to > 50 years; median age of onset: 3 years.

  2. Usually normal lifespan.

  3. Earlier mortality due to 2° amyloidosis in 10% of patients; no colchicine benefit.

  4. Significant morbidities include:

    • Monoarticular arthritis

    • Rashes

    • Migratory myalgias

    • Ocular inflammation

    • Abdominal pain.

What will you tell the family about risks/benefits of the available treatment options? These are listed in Table II.

Table II.

Risks and Benefits of Treatment Options for TRAPS
Drug Indication Risks Benefits
NSAIDS Arthritis; pain, fever Adverse reactions Reduce fever, pain, arthritis
Corticosteroids Fever, arthritis, serositis, urticaria, lymphadenopathy Adverse reactions; efficacy wanes over time requiring increasing doses Relieve fever, rash; improve adenopathy, arthritis; lessen organ involvement, serositis
Etanercept Treatment for TRAPS; arthritis, aphthous stomatitis, fever, 2°amyloidosis & other complications Adverse reactions; may trigger flare of TRAPS (but less risk than of infliximab) Controls fever, arthritis, aphthous stomatitis; improve inflammatory markers; reduces 2°amyloidosis & other complications in TRAPS
Anakinra Fever, urticaria, rash, arthritis, elevated ESR/CRP; TRAPS unresponsive to conventional therapy Adverse reactions; may trigger flare; no long-lasting disease control off treatment Remits fever, rash, arthritis & laboratory abnormalities in TRAPS
Tocilizumab Treatment of TRAPS unresponsive to etanercept or anakinra; arthritis, elevated ESR/CRP Adverse reactions Normalizes CRP, ESR; effect on 2° amyloidosis unknown

What causes this disease and how frequent is it?

  • Detailed epidemiology:

    • Incidence: rare (5-6 cases per 10 million persons in the population in Germany), but most common autosomal dominant HPFS.

    • Many of Scottish or Irish ancestry; as a result, initially called Familial Hybernian Fever.

    • Affects males and females equally.

  • What's known about the genetics?

    • Autosomal dominant missense mutations in the TNFRSF1A gene encoding the 55 kDa TNF receptor.

    • >50 mutations described; R92P/Q are most common mutations.

    • Incomplete disease penetrance.

    • T50M mutation seems to be associated with suboptimal responses to etanercept and anakinra.

How do these pathogens/genes/exposures cause the disease?

  • Cell surface and soluble TNF receptors bind the proinflammatory cytokine, TNF, with opposing effects on TNF receptor signaling and TNF secretion during inflammatory responses.

  • Some mutations affect receptor shedding, permitting sustained membrane-bound TNF receptor stimulation and decreased availability of soluble TNF receptors (shed extracellular portions) that function to inhibit further TNF signaling.

  • Most mutations affect TNR receptor folding and trafficking to the cell membrane, leading to intracellular accumulation of mutant receptors that spontaneously induce activation of protein kinases in several inflammatory pathways.

  • Other mutations decrease TNF binding to membrane bound receptor, inhibiting TNF-dependent apoptosis pathways involved in control of inflammation.

Other clinical manifestations that might help with diagnosis and management

Secondary amyloidosis:

  1. Medical management focused on prevention of 2° amyloidosis.

  2. Amyloid deposition in kidneys in > 90% patients and usually presents as proteinuria without renal insufficiency.

  3. Amyloidosis in GI tract in 20% patients; presents as diarrhea and malabsorption.

  4. Amyloid deposition also in liver, spleen, thyroid, and nervous system.

  5. Cardiac involvement from 2° amyloidosis due to chronic inflammation is rare, unlike other types of amyloidosis.

  6. Amyloidosis diagnosed by biopsy of kidney or rectum.

  7. Serum amyloid A (SAA) level may reflect active amyloid deposition.

  8. Serial SAA measurements may help guide therapy.

  9. Colchicine prevents renal amyloidosis in FMF, but not in HIDS or TRAPS.

What complications might you expect from the disease or treatment of the disease?

  1. Most complications self-limited, but some do affect health and quality of life.

  2. Most worrisome disease complication is 2° amyloidosis.

  3. Treatment complications may be as common or more common than from TRAPS itself, including worsening inflammation, organ toxicity, infection, and future malignancy.

Are additional laboratory studies available; even some that are not widely available?

  1. Serum amyloid A protein (SAA)

  2. Soluble TNF receptor level

How can TRAPS be prevented?

  1. No known prevention.

  2. Genetic counseling important if TRAPS is suspected.

  3. Prenatal diagnosis requires identification of disease-causing mutation(s).

What is the evidence?

Periodic Fever Syndrome (PFS):

Simon, A, van der Meer, JW. "Pathogenesis of familial periodic fever syndromes or hereditary autoinflammatory syndromes". Am J Physiol Regul Integr Comp Physiol. vol. 292. 2007. pp. R86-98.

Bodar, EJ, Drenth, JP, van der Meer, JW, Simon, A. "Dysregulation of innate immunity: hereditary periodic fever syndromes". Br J Haematol. vol. 144. 2009. pp. 279-302.

Glaser, RL, Goldbach-Mansky, R. "The spectrum of monogenic autoinflammatory syndromes: understanding disease mechanisms and use of targeted therapies". Curr Allergy Asthma Rep. vol. 8. 2008. pp. 288-98.

Goldbach-Mansky, R, Kastner, DL. "Autoinflammation: the prominent role of IL-1 in monogenic autoinflammatory diseases and implications for common illnesses". J Allergy Clin Immunol. vol. 124. 2009. pp. 1141-9.

Masters, SL, Simon, A, Aksentijevich, Kastner, DL. "Horror Autoinflammaticus: The molecular physiology of autoinflammatory disease". Ann Rev Immunol. vol. 27. 2009. pp. 621-68.

Kastner, DL, Aksentijevich, A, Goldbach-Mansky, R. "Autoinflammatory disease reloaded: a clinical perspective". Cell. vol. 140. 2010. pp. 784-90.

Henderson, C, Goldbach-Mansky, R. "Monogenic autoinflammatory diseases: new insights into clinical aspects and pathogenesis". Curr Opin Rheumatol. vol. 22. 2010. pp. 567-78.

Ombrello, MJ, Kastner, DL. "Autoinflammation in 2010: expanding clinical spectrum and broadening therapeutic horizons". Nat Rev Rheumatol. vol. 7. 2011. pp. 82-4.

van der Hilst, JCH, Simon, A, Drenth, JPH. "Hereditary periodic fever and reactive amyloidosis". Clin Exp Med. vol. 5. 2005. pp. 87-98.

Bilginer, Y, Akpolat, T, Ozen, S. "Renal amyloidosis in children". Pediatr Nephrol. vol. 26. 2011. pp. 1215-27.

TNF Receptor-Associated Periodic Syndrome (TRAPS):

McDermott, MF, Aksentijevich, I, Galon, J. "Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes". Cell. vol. 7. 91999. pp. 133-44.

Hull, KM, Drewe, E, Aksentijevick, I. "The TNF receptor-associated periodic syndrome (TRAPS)". Medicine (Baltimore). vol. 81. 2002. pp. 349-68.

Rezaei, N. "TNF-receptor-associated periodic syndrome (TRAPS): an autosomal dominant multisystem disorder.". vol. 25. 2006. pp. 773-7.

Vaitla, PM, Radford, PM, Tighe, PJ. "Role of interleukin-6 in a patient with tumor necrosis factor receptor-associated periodic syndrome". Arthritis Rheum. vol. 63. 2011. pp. 1151-5.

Pettersson, T, Kantonen, J, Matikainen, S, Repo, H. "Setting up TRAPS". Ann Med. vol. 44. 2012. pp. 109-18.

Ongoing controversies regarding etiology, diagnosis, treatment

Long-term risks/benefits of treatment with biologics, given uncertain future risks, particularly for malignancies, opportunistic infections, autoimmune diseases, organ toxicity.

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