Tumour necrosis factor receptor-associated periodic syndrome

What is tumour necrosis factor receptor-associated periodic syndrome?

Tumour necrosis factor receptor-associated periodic fever syndrome or TRAPS (MIM 142680) is a rare genetic autoinflammatory syndrome. It presents as recurrent, prolonged episodes of fever typically associated with serosal, synovial and cutaneous inflammation. It can be complicated by amyloidosis, resulting in kidney or liver failure.

TRAPS is the most common autosomal dominant form of periodic fever syndrome and was originally known as familial Hibernian fever (FHF).

Who gets TRAPS and why?

TRAPS was first described in families of Irish and Scottish ancestry, but over 200 cases have now been reported including other racial groups. A large kindred in Australia of Scottish descent has been described. In a prospective study, the incidence of TRAPS in Germany has been estimated to be 5.6 per 10 million person-years.

The initial clinical presentation of TRAPS has been reported to vary over a wide age range from neonates to adults over the age of 50 years. In one series however, the median age of onset was 3 years with onset usually before the age of 20 years. Other reports suggest onset in adult life in 20%.

TRAPS is due to a mutation in the gene coding for tumour necrosis factor (TNF) receptor 1 (TNFR1). TNF is a cytokine or cell messenger protein. TRAPS is inherited as an autosomal dominant condition, meaning an affected individual has a 50% chance of passing the condition on to each child. Non-familial cases have been reported and genetic studies of relatives of affected individuals have detected asymptomatic carriers, suggesting variable penetrance. However the possibility of onset of symptoms in late adulthood makes it difficult to interpret these results.

Molecular biology

The responsible gene, TNFRSF1A, is found on chromosome 12 (12p13.2). Over 80 mutations have been identified, of which at least 60 have been associated with clinical TRAPS. These are mostly point mutations, the commonest of which are R92Q and P46L. However R92Q is found in 1-2% of the general population and is associated with atypical febrile episodes. Mutations resulting in the substitution of a cysteine in TNFR1 are possibly associated with more severe disease and the development of amyloidosis.

A number of mechanisms by which abnormalities of TNFR1 causes the inflammation of TRAPS have been proposed, including impaired TNFR shedding from the cell membrane, reduced ligand binding and defective apoptotic signaling.

Clinical features of TRAPS

The clinical features of TRAPS that distinguish it from other periodic fever syndromes are:

• prolonged febrile episodes lasting 3-4 weeks
• migratory muscle pain with overlying skin redness
• conjunctivitis with or without swelling around the eye.

The characteristics of the recurrent acute episodes of TRAPS are described in the table below.

Inguinal hernias are common in affected males.

Amyloidosis has been reported to develop in up to 25% of sufferers. The risk of amyloidosis is higher with some mutations. Amyloidosis can result in kidney or liver failure and death.

What are the features of the skin rash?

The skin rash is typically a red patch that moves around over hours to days (migratory) to form annular (ring-shaped) and gyrate (whirling) patterns. It usually begins over an area of muscle pain on the proximal limb (thigh or upper arm) and moves down towards the ankle or wrist. Initially several small round-oval lesions appear which then join up and merge. The patches are of various sizes, red, warm, tender to touch and have a fuzzy edge.

In one large family series, the skin eruption lasted 4-21 days, with a mean of 13 days. Most patients report the rash first appears before the age of 2 years.

Other skin rashes described in TRAPS include:

• Urticaria (hive)-like plaques
• Dermal oedema (deeper swelling)
• Generalised serpiginous (snake-like) patches and plaques
• Red, swollen, speckled, painful patches, localised to limbs and trunk
• Migratory lymphoedema
• Exanthematous form (viral-type rash) on the trunk
• Bruising (ecchymoses)

What triggers attacks?

Reported triggers for febrile attacks include:

• Physical trauma
• Physical and emotional stress.

In one family series, the frequency of attacks ranged from every few weeks up to ten years between episodes, but the usual interval was every 3-6 months. The frequency may decrease with age.

Attacks associated with the R92Q mutation are reportedly atypical:

• Shorter duration
• Less likely to develop abdominal, chest or joint pain
• More likely to have mouth ulcers
• More likely to develop sore throat (pharyngitis).

How is TRAPS diagnosed?

A diagnosis of TRAPS should be considered clinically when acute recurrent febrile attacks occur together with the characteristic muscle pain and overlying skin changes, in the absence of infection or autoimmune disease.

During an acute episode, blood tests show:

• Increased neutrophil count (neutrophilia)
• Significant increase in acute phase reactants (ESR, CRP, etc) – may also be detected between attacks
• Hypochromic anaemia (anaemia of chronic disease)
• Increase in polyclonal immunoglobulin, especially IgA

Skin biopsy shows a nonspecific superficial and deep perivascular mononuclear cell (T-lymphocytes, monocytes) infiltrate.

Investigation of the muscle pain reveals normal levels of muscle enzymes. Muscle biopsy shows inflammation of the deep fascia rather than in the muscle itself.

Genetic testing confirms the diagnosis of TRAPS.

Treatment of TRAPS

For an attack, systemic corticosteroids taken at the start of an episode can reduce its severity and duration. But efficacy seems to decrease with time, resulting in higher doses being required. Some patients with prolonged frequent attacks become dependent on steroids, unable to cease the medication.

Nonsteroidal anti-inflammatory drugs have been reported to relieve symptoms in some cases.

Colchicine is unhelpful, a useful distinguishing feature from familial Mediterranean fever.

Biologic agents

Etanercept, a TNF-α inhibitor, can lead to a reduction in steroid dose for some steroid-dependent patients. However it is not helpful in all cases.

The use of infliximab, a monoclonal antibody that blocks TNF-α, has been reported, with variable outcomes including ‘failure to improve’ and flare of disease activity.

Anakinra, an interleukin 1 receptor antagonist, appears to be effective for etanercept-resistant patients.

The effect of biologic agents on the development of amyloidosis is not known.