Too Much Inflammation: Muckle-Wells Syndrome
““Muckle-Wells is usually present in the first few years of a child’s life; the diagnosis is still considered even with no family history of CAPS.””
Brief Summary of Disease
Inflammation is our body’s way of signalling to the immune system to heal damaged tissue or fight off pathogens (a bacteria or virus that can cause disease), but what happens when that inflammation becomes excessive? Muckle-Wells Syndrome (MWS) falls under cryopyrin-associated periodic syndrome (CAPS), which is a group of rare autoinflammatory diseases (usually caused by a genetic mutation that causes immune cells to attack body cells like they would pathogens).1
It is a rare autosomal dominant disorder, which affects both males and females equally. This means that a single copy of the mutated NLRP3 gene is all that is needed to cause MWS; it can either be inherited from one parent or result from a spontaneous mutation.
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Etiology and Pathology
It is caused due to a mutation in the NLRP3 gene, which encodes for the protein cryopyrin. This protein is essential to the inflammasome, which is a complex (a group of proteins that work together) that detects pathogens and then activates immune responses. Cryopyrin controls the activation of the cytokine protein (proteins secreted by immune cells with the purpose of having effects on other cells) interleukin 1-beta (IL-1β) which stimulates inflammation. The abnormal inflammasome leads to increased and uncontrolled production of the proinflammatory cytokine, IL-1β, causing excessive inflammation.3
Symptoms
Since the disease leads to excessive inflammation, all symptoms are as a result of the inflammation. They include skin rashes during early childhood, fevers, joint pain, conjunctivitis (pink eye) – inflammation of the outer layer of the eye – and progressive hearing loss. Amyloidosis, accumulation of the insoluble protein amyloid in various organs, can also occur in about 25% of untreated Muckle-Wells sufferers, which leads to organ dysfunction (the organ does not perform the way it’s supposed to).2
Muckle-Wells is usually present in the first few years of a child’s life; the diagnosis is still considered even with no family history of CAPS. Tests that show a high erythrocyte sedimentation rate (measures how quickly erythrocytes settle at the bottom of a test tube, high values indicate inflammation), C-reactive protein ( a plasma protein that increases in concentration during inflammation) and serum amyloid A (levels increase during tissue damage or inflammation) levels are indicative of an acute attack. Low red blood cell count and a high white blood cell count are also observed in blood tests.4
High red blood cell count indicates possible internal and environmental conditions that limit oxygen supply or conditions that directly increases red blood cell production.
Several other tests can be performed at different times to measure symptom progression: an audiogram tests for progressive hearing loss, urinary protein measurements test for amyloidosis (amyloid build-up in organs), a kidney biopsy confirms the presence of any amyloid deposits, and genetic testing looks for a mutation in the NLRP3 gene on exon 3.3
Treatment
Non-steroidal anti-inflammatory drugs (NSAIDs) can be used for joint pain but long-term use isn’t recommended since it can cause intestinal issues and heart problems. Patients experiencing hearing loss are often provided hearing aids.
There are currently a few drugs available to treat the effects of IL-β. Anakinra counters the effects of IL-β. While many symptoms are found to normalize in one week,2 the deafness seemed persistent. When the drug is used as part of early intervention, it is more helpful compared to late treatment. It has also been able to reverse amyloid deposition in some individuals. Younger children may need a higher dose to body weight compared to older children and adults in order to control the symptoms. Due to the increased volume in the injection, the child can experience pain at the site of the injection. Weight gain is also seen, typically within females.4
Rilonacept is another FDA approved drug; it is a protein that directly binds to IL-β, preventing it from binding to its receptor and blocking its effects. It is administered to patients over the age of 12 years (effectiveness of the drug in children below the age of 12 has not been established yet).6
Canakinumab, another FDA approved drug, is used to treat patients over 4 years old. It is a monoclonal antibody against IL-β. A monoclonal antibody is produced in a laboratory and acts as substitute antibodies to mimic the immune system response.6
The drug is given by injection every 8 weeks. Vertigo (dizziness or loss of balance) has been noted as a side effect, specifically in patients with deafness as well. 4 The cost of a yearly treatment would approximate to $96,000 per patient.7
Since it is an autosomal dominant disorder, there is a 50% chance that a parent will pass the gene mutation to their child and only one copy of the gene is needed for the disease to be expressed. Genetic counselling is available for individuals who choose to identify whether a copy of the mutated gene is passed to the child. Rareconnect.org is a patient hosted website that offers an online community platform for those battling rare diseases. It connects people around the world with similar diseases and experiences.
Gianna Olive
Works Cited:
Muckle-Wells syndrome - Genetics Home Reference - NIH. U.S. National Library of Medicine. https://ghr.nlm.nih.gov/condition/muckle-wells-syndrome#genes. Accessed October 11, 2019.
Muckle-Wells Syndrome. NORD (National Organization for Rare Disorders). https://rarediseases.org/rare-diseases/muckle-wells-syndrome/. Accessed October 11, 2019.
Elder M. Muckle-Wells syndrome. Cancer Therapy Advisor. https://www.cancertherapyadvisor.com/home/decision-support-in-medicine/pediatrics/muckle-wells-syndrome/. Published January 17, 2019. Accessed October 11, 2019.
Muckle-Wells syndrome. Muckle-Wells syndrome | DermNet NZ. https://www.dermnetnz.org/topics/muckle-wells-syndrome/. Accessed October 11, 2019.
Inserm. Orphanet: Muckle Wells syndrome. Orphanet: Muckle Wells syndrome. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=575. Accessed October 11, 2019.
Kuemmerle-Deschner JB, Wittkowski H, Tyrrell PN, et al. Treatment of Muckle-Wells syndrome: analysis of two IL-1-blocking regimens. Arthritis Research and Therapy. 2013;15(3). doi:10.1186/ar4237.
Single Escalating Dose Pilot Trial of Canakinumab (ILARIS®) in Duchenne Muscular Dystrophy. Case Medical Research. March 2019. doi:10.31525/ct1-nct03936894.
Cite This Article:
Olive G. Too much inflammation: Muckle-Wells Syndrome. Illustrated by R. Jeong. Rare Disease Review. November 2019. DOI:10.13140/RG.2.2.30450.25287.
