Muckle-Wells syndrome

Author: Dr Delwyn Dyall-Smith FACD, Dermatologist, Australia, 2011.


What is Muckle-Wells syndrome?

Muckle-Wells syndrome (MWS, MIM 191900) is a rare genetic autoinflammatory syndrome and the intermediate-severity form of cryopyrin-associated periodic syndrome (CAPS). As with other forms of this syndrome, it presents with recurrent episodes of fever, skin rash, joint pain, abdominal pain and conjunctivitis, but in addition sufferers typically develop a progressive sensorineural deafness and amyloidosis.

Familial cold autoinflammatory syndrome (FCAS) and NOMID/CINCA are closely related conditions. Families and individuals have been reported with MWS triggered by exposure to cold (a feature of FCAS) and also showing mild features of NOMID/CINCA such as early morning headaches, short stature, forehead prominence, flattening of the nasal bridge or papilloedema (swelling of the optic disc in the eye).

Who gets Muckle-Wells syndrome and why?

Muckle-Wells syndrome predominantly affects Europeans, presenting before the age of 20 years.

Muckle-Wells syndrome is inherited as an autosomal dominant condition, meaning each child of a sufferer has a 50% chance of developing the syndrome. Rarely cases with no family history are identified. This can mean a parent is an asymptomatic carrier of the mutation, a spontaneous mutation has occurred or no mutation has been identified on DNA sequencing.

Molecular biology and genetics

The protein affected in Muckle-Wells syndrome is cryopyrin, produced from the NLRP3 gene located on chromosome 1. The gene is expressed in white blood cells (mainly neutrophils) and chondrocytes (cartilage cells). Cryopyrin is an essential component of the inflammasome, an intracellular protein complex involved in the innate immune system. The abnormal inflammasome in Muckle-Wells syndrome allows unrestricted activation of the enzyme caspase-1, which in turn causes overproduction of active interleukin-1beta, switching on the inflammatory cascade in an uncontrolled manner.

The same point mutation can be identified in MWS and familial cold autoinflammatory syndrome (FCAS) eg R260W, V198M, V262G, and less commonly MWS with mild NOMID/CINCA.

What are the clinical features of Muckle-Wells syndrome

The febrile episodes in Muckle-Wells syndrome are very similar to those seen in familial cold-associated syndrome (FCAS) but persisting for 1-3 days (or longer) and without the close and definite association with exposure to cold. Characteristically Muckle-Wells syndrome is associated with the early development of progressive sensorineural hearing loss.

The clinical features of the acute attacks of Muckle-Wells syndrome may include:

  • Fever – not present in all cases, but when present is usually higher than in FCAS (39-40C)
  • Skin rash – atypical urticaria (hive)-like
  • Joint pain – ranges from short episodes of arthralgia to recurrent swelling of large joints with possible joint destruction or polyarticular arthritis. It can be exacerbated by exercise and minor trauma. Improvement in the arthralgia has been reported after the bones stop growing. There may be associated muscle pain (myalgia).
  • Conjunctivitis – frequent
  • Other inflammatory conditions of the eyes, episcleritis, uveitis and iridocyclitis, have been reported.
  • Headaches – severe, indicate an aseptic meningitis or raised intracranial pressure.
  • Fatigue – can be persistent and severe, impacting on quality of life
  • Abdominal pain – reported during flares
  • Mouth ulcers

Overlap features with FCAS or NOMID/CINCA are often present in Muckle-Wells syndrome when looked for. Cold as a trigger for attacks, frequent headaches and asymptomatic papilloedema (swelling at the back of the eye) are examples. Even within the one family with the same gene mutation, the features can range from ‘pure’ MWS in one member to overlap in another, and ‘pure’ FCAS in a third.

What triggers attacks?

Symptoms may worsen towards evening. Some patients have intermittent rare acute episodes whereas others have daily or continuous symptoms. The duration of attacks is generally longer than for FCAS lasting from several days to continuous.

Most patients do not identify any triggering factors. Emotional and physical stress, fatigue and infection are reported to precipitate acute attacks. Febrile episodes can be triggered by cold, overlapping with FCAS.

Progress

Progressive bilateral sensorineural deafness develops in two-thirds of patients with Muckle-Wells syndrome, usually appearing first in childhood through to early adultlife. High-frequency loss is the first sign. It has been suggested that chronic inflammation in the cochlea of the inner ear results in permanent loss of the Corti hair cells (and loss of the Corti organ) and cochlear nerve damage.

Amyloidosis complicates untreated Muckle-Wells syndrome in 25% of sufferers, beginning in adult life as proteinuria, progressing to kidney failure and death within 10 years. Peripheral neuropathy due to amyloidosis may develop later than the kidney impairment.

Puberty may be delayed, especially with severe disease.

How is Muckle-Wells syndrome diagnosed?

Muckle-Wells syndrome should be considered on the typical clinical features, even in the absence of a positive family history of cryopyrin-associated periodic syndrome (CAPS).

During an acute attack, tests reveal nonspecific features, including:

  • acute phase reactants (blood tests) – elevated erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum amyloid A (SAA)
  • anaemia of chronic disease
  • leukocytosis (high white cell count)
  • cerebrospinal fluid (CSF) at high pressure with neutrophils and eosinophils and no infection

The following tests may be performed at any time.

  • Audiogram – high frequency hearing loss initially, progressing to bilateral sensorineural deafness.
  • Urinary protein to detect amyloidosis – protein in the urine, without red or white blood cells is the first sign.
  • Kidney biopsy confirms the presence of amyloid deposits.
  • Genetic testing can be performed using a commercial test for an NLRP3 gene mutation in exon 3.

What is the treatment of Muckle-Wells syndrome?

Anakinra, an interleukin 1 receptor antagonist, is a biologic agent first used to treat 2 unrelated patients with Muckle-Wells syndrome in 2003 with miraculous effect on the acute episodes. The fever, skin rash and conjunctivitis responded within 4 hours and the blood markers of inflammation had normalised within 1 week. It has subsequently been used to successfully treat many patients with Muckle-Wells syndrome.

Although there have been some reports of an improvement in the deafness, others have shown continued deterioration. Possibly the reversal of hearing loss may relate to the time since onset, with earlier intervention being helpful compared to late treatment. In young children treated before the development of hearing loss, it appears this complication may be prevented. Longer followup is required to determine this.

Anakinra has also been demonstrated to reverse amyloid deposition in some cases.

Many severe cases have had residual mild symptoms of MWS with long term follow-up. These may have responded to higher doses. Young children need a higher daily dose per kg body weight than older children and adults to control symptoms. The increased injection volume can be associated with increased local discomfort and pain at the injection site. Hyperactivity has been reported with successful treatment, perhaps due to the improvement in fatigue. Weight gain can occur, particularly in females. Indefinite daily treatment is required, with rapid recurrence of symptoms within days following cessation of injections.

Note: anakinra is not registered or subsidised in New Zealand (March 2011). In other countries such as the USA and Europe, its registered indication is rheumatoid arthritis.

Two interleukin-1 antagonists have FDA approval for the treatment of Muckle-Wells syndrome. Rilonacept has been approved for the treatment of MWS for adults and children from the age of 12 years. Rilonacept is a fusion protein which prevents the binding of interleukin-1 to its receptor. It is administered weekly as a subcutaneous injection.

Canakinumab has been FDA-approved for the treatment of adults and children from the age of 4 years affected with Muckle-Wells syndrome. It is a long-acting monoclonal antibody specifically directed against interleukin-1beta. Canakinumab is given by subcutaneous injection every 8 weeks. The development of vertigo during this treatment has been reported particularly in MWS patients with sensorineural deafness.

Quality of life is markedly improved with anti-interleukin-1 treatment for patients with Muckle-Wells syndrome. Lifelong treatment should be initiated as early as possible to reduce the risk of deafness and amyloidosis.

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References

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