DEFINITION
Muckle Wells Syndrome is a dominantly inherited autoinflammatory disease characterized by rashes, fever, arthralgia, progressive sensorineural deafness, and the frequent development of systemic amyloidosis.
EPIDEMIOLOGY
MWS is a rare disorder. Although it has been reported in many regions of the world, the exact prevalence of this disorder is not known properly. MWS is a autosomal dominant pathology that has variable age of onset.
SYMPTOMS
People suffering from this syndrome have recurring “flare-ups” which begin during babyhood or among children. These episodes may appear to arise instinctively or be actuated by cold, heat, fatigue or stresses. Individuals getting affected develop non itchy rash, fever which varies from mild to moderate range, swollen or at times painful joints and redness in the white portions of the eyes which is commonly known as Conjunctivitis. Hearing loss and kidney damage are also associated with this disorder.
Individuals affected with MWS generally begin to have its symptoms from birth. Occasionally, the symptoms may occur later in childhood. This condition is generally inherited in an autosomal dominant pattern, which means that a copy of the altered gene in each cell is enough to cause the disorder. In certain cases, the inheritance pattern is not known. This syndrome mostly affects Europeans below 20 years of age. MWS is another cause of Acute Anterior Uveitis.
The overproduction of IL-1β can give rise to inflammation in some parts of the body. The symptoms tend to worsen at night. The problems usually last for one to two days, although there may also be days when these cannot be felt.
The principal symptoms of MWS are:amyloidosis, arthralgia, joint pain, eye redness/pain, fatigue, fever/chills, hives, pins and needles sensation, limb pain, clawfoot, skin thickening, infertility, nephrotic syndrome, small kidney glaucoma, shriveled kidney, polycythemia, muscle pain, protein deposit in kidney, excessive glycine levels in urine, atrophy of cochlear nerve.
DIAGNOSIS
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.
PATHOGENESIS
Mutations in the NLRP3 gene (also known as CIAS1) cause Muckle-Wells syndrome. The NLRP3 gene provides instructions for making a protein called cryopyrin. (Genetic Linkage of the Muckle-Wells Syndrome to Chromosome 1q44, 1999)
Cryopyrin belongs to a family of proteins called nucleotide-binding domain and leucine-rich repeat containing (NLR) proteins. These proteins are involved in the immune system, helping to regulate the process of inflammation. Inflammation occurs when the immune system sends signaling molecules and white blood cells to a site of injury or disease to fight microbial invaders and facilitate tissue repair. When this has been accomplished, the body stops (inhibits) the inflammatory response to prevent damage to its own cells and tissues.
Cryopyrin is involved in the assembly of a molecular complex called an inflammasome, which helps trigger the inflammatory process. Researchers believe that NLRP3 gene mutations that cause Muckle-Wells syndrome result in a hyperactive cryopyrin protein and an inappropriate inflammatory response. Impairment of the body's mechanisms for controlling inflammation results in the episodes of fever and damage to the body's cells and tissues seen in Muckle-Wells syndrome.
PATIENT RISK FACTORS
MWS patients at high risk for severe disease can be identified at the time of diagnosis. Female patients presenting with hearing loss have the highest likelihood of manifesting severe MWS and should be considered a high-risk group. Muckle-Wells syndrome (MWS) is one of the inherited cryopyrin-associated periodic fever syndromes (CAPS), which are caused by mutations in the NLRP3 gene, leading to alterations of the gene product cryopyrin (also known as NALP3). The protein is part of the inflammasome, a multiprotein complex crucial for intracellular host defense. CAPS encompass the mildest form, familial cold autoinflammatory syndrome (FCAS), MWS, and the most severe form, neonatal-onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous, articular syndrome (NOMID/CINCA syndrome). All 3 diseases are characterized by seemingly unprovoked inflammation as a consequence of excessive production of the proinflammatory cytokine interleukin-1β (IL-1β)
Secondary amyloidosis is common, and may occur in 1/3 to 1/4 of patients.
COMPLICATIONS
Quite a few complications arise due to this syndrome. These include:
• Abdominal pain
• Peritonitis
• Urticaria
• AA amyloidosis
• Sensorineural hearing loss
Urticaria in patient with MWS
THERAPY
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 follow-up 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.
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.
MWS can have severe consequences due to chronic high levels of inflammation in the body. This can be life-threatening if Generalized Amyloidosis of the AA type develops, due to long-term buildup of amyloid protein products from the chronic inflammation in MWS.
Over 25% of MWS patients have elevated Serum Amyloid, and at least 25% have Amyloidosis. Serum AA testing is essential to follow, along with C-reactive protein (CRP), Erythrocyte Sedimentation Rate (ESR) and other lab tests. Amyloidosis is also a risk to some FCAS and NOMID/CINCA patients, but is not seen at the same level of frequency as in MWS. Generalized Amyloidosis is due to a permanent buildup of amyloid in the kidneys, liver and elsewhere, that can be fatal.
