Muckle-Well Syndrome

Muckle-Wells syndrome is a disorder characterized by periodic episodes of skin rash, fever, and joint pain. Progressive hearing loss and kidney damage also occur in this disorder.

People with Muckle-Wells syndrome have recurrent “flare-ups” that begin during infancy or early childhood. These episodes may appear to arise spontaneously or be triggered by cold, heat, fatigue, or other stresses. Affected individuals typically develop a non-itchy rash, mild to moderate fever, painful and swollen joints, and in some cases redness in the whites of the eyes (conjunctivitis).
Hearing loss caused by progressive nerve damage (sensorineural deafness) typically becomes apparent during the teenage years. Abnormal deposits of a protein called amyloid (amyloidosis) cause progressive kidney damage in about one-third of people with Muckle-Wells syndrome; these deposits may also damage other organs. In addition, pigmented skin lesions may occur in affected individuals.

Mutations in the NLRP3 gene (also known as CIAS1) cause Muckle-Wells syndrome. The NLRP3 gene provides instructions for making a protein called cryopyrin.

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.
Read more about the NLRP3 gene.

Muckle-Wells syndrome (MWS) is one of the cryopyrin associated periodic syndromes (CAPS) caused by mutations in the CIAS1/NLRP3 gene.
In some MWS cases amyloidosis develops later in life, a disease in which an abnormal accumulation of the protein amyloid occurs in a patient’s tissues and organs. Accumulation of amyloid in the kidneys results in damage and often kidney failure if untreated.

FACT SHEET
what it is
mws is one of the cryopyrin-associated periodic syndromes (caps) generally caused by mutations in the cias1/nlrp-3 gene. these syndromes are characterized by recurrent attacks of rash, fever/chills, joint pain, fatigue, and eye pain/redness. mws symptoms are triggered by unknown random factors and possibly by stress, exercise, or cold.
in most cases, muckle-wells syndrome (mws) patients develop progressive hearing loss. in some mws cases amyloidosis, a disease in which an abnormal accumulation of the protein, amyloid, occurs in a patient’s tissues and organs, develops later in life.
causes and symptoms

mws is generally caused by a mutation in a gene identified as the cold-induced auto-inflammatory syndrome 1 (cias1) gene, more recently named the nod-like receptor protein-3 (nlrp-3) gene. the cias1/nlrp-3 gene mutation is passed on in an autosomal dominant manner. the mutation also can occur spontaneously. the mutation in the cias1/nlrp-3 gene causes increased activity of cryopyrin, a protein that regulates inflammation in the body. the increased activity of cryopyrin results in an overproduction of a protein knows as interleukin-1ß (il-1ß), which leads to symptoms of inflammation such as fever and joint pain. common symptoms of mws, which are generally first experienced during early childhood or adolescence, include recurrent rash, fever/chills, joint pain, fatigue, eye pain/redness, progressive hearing loss, and amyloidosis. symptoms can vary between individuals.

mws symptoms are triggered by unknown random factors and possibly by stress, exercise, or cold. episodes generally last between 24 to 48 hours.

incidence and prevalence
mws is thought to be a very rare condition. since mws is a newly discovered condition, the actual incidence and prevalence of the disease is difficult to determine.
living with mws
the symptoms and complications related to mws can sometimes be quite debilitating.
diagnosis
diagnosis of mws is determined through an evaluation of a patient’s symptoms. confirmation of the diagnosis is sometimes, but not always achieved through genetic testing and the identification of a cias1/nlrp-3 gene mutation.

** This content was written by Dr. Hal Hoffman. Content is from http://www.capscommunity.com/caps_fact_mws_pat.html

Effect of anakinra therapy with those that have MWS
DISCUSSION
The complete and rapid clinical and serologic response to rHuIL-1Ra in Muckle-Wells syndrome con- firms that IL-1’ has a fundamental role in the patho- genesis of inflammation associated with mutations in the NALP3 gene. These findings support studies of anakinra in patients with FCAS and in children with the much more severe NOMID/CINCA syndrome phenotype, given the similar nature of the underlying molecular defect in all of these entities. Therapy with anakinra has the potential to be life saving in patients with Muckle- Wells syndrome complicated by AA amyloidosis, and the response to treatment also raises the possibility that inhibition of IL-1 might be beneficial in other pyrinopa- thies, potentially including acute attacks of FMF itself. These studies also illustrate the potential for elucidating disease processes, using highly specific biologic drugs.
Anakinra is a recombinant nonglycosylated ho- molog of human IL-1Ra that competitively inhibits binding of IL-1’ and IL-1’ to the IL-1 receptor type 1, which is expressed in a wide variety of tissues and organs (14). Anakinra has been evaluated most extensively in patients with rheumatoid arthritis, in whom it is safe and well tolerated (15,16). IL-1, originally named endoge-
nous pyrogen, is a key proinflammatory cytokine that has many actions, including a contribution to increased synthesis of SAA by hepatocytes during the acute-phase response.
The availability of rHuIL-1Ra enabled us to undertake an empirical therapeutic trial of this agent in 2 patients with Muckle-Wells syndrome in whom ne- phrotic syndrome due to AA amyloidosis had developed, and in whom many drugs had been unable to suppress their inflammatory disease and abundant production of SAA. These unrelated patients both had the NALP3 R262W variant (also annotated as R260W) (2) and had failed to respond to treatment with colchicine, cortico- steroids, chlorambucil, antihistamines, dapsone, azathio- prine, mycophenolate mofetil, and infliximab. In both patients, symptoms of inflammation ceased within hours of the first injection of rHuIL-1Ra, and plasma SAA concentrations normalized within 3 days and have re- mained normal for 6 months (11). Even during this relatively short treatment period, the amyloid-related proteinuria level fell from 11.2 gm/day to 4.9 gm/day in one of these patients, and from 10.2 gm/day to 2.3 gm/day in the other. The glomerular filtration rate has remained normal in both patients. Anakinra is modestly effective in rheumatoid arthritis (15,16), whereas its remarkable effect in small doses in patients with Muckle-Wells syndrome indicates that IL-1’ has a piv- otal role in the pathogenesis of this disorder.
AA amyloidosis develops in 5% of patients with chronic inflammatory diseases overall, but it eventually occurs in approximately one-fourth of patients with MWS, reflecting the very intense and prolonged acute- phase response in this particular disorder. AA amyloid fibrils are derived from the circulating acute-phase pro- tein SAA. This is the most responsive and dynamic marker of the acute-phase response, with the plasma concentration of SAA increasing from normal values of 10 mg/liter up to as much as 2,000 mg/liter in response to a wide range of inflammatory stimuli (17). Frequent monitoring of the plasma SAA concentration is vital in patients with AA amyloidosis in order to guide antiin- flammatory therapy in a rational manner (18), and SAA is also an extremely sensitive and objective marker of disease activity in MWS. AA amyloidosis cannot occur in the absence of an acute-phase SAA response, and the rapid normalization of the SAA concentration observed in members of this family reflects the completeness of their response to anakinra therapy.
Elucidation of the molecular basis of MWS, FCAS, and NOMID/CINCA syndrome is providing in- sights into some of the distinctive features of these
disorders. Approximately 20 NALP3 mutations have been identified, mostly within the NACHT domain (6,9,10). This gene is expressed in peripheral blood leukocytes, and it is possible that NALP3 mutations lead to defective apoptosis of neutrophils, leading to their persistence and inappropriate activation. The gene is also expressed in chondrocytes, which may account for the joint pain that occurs in MWS and FCAS, and the premature patellar and long bone ossification with re- sultant bony overgrowth in NOMID/CINCA syndrome (5). Expression of this gene in cartilage might also account for the deafness in patients with MWS. It remains to be determined whether early and prolonged treatment with rHuIL-1Ra may prevent deafness and abnormal bone development. Induction of systemic in- flammation by exposure to cold in FCAS remains in- triguing and unexplained at the present time.
The fact that NALP3 mutations cause MWS, FCAS, and NOMID/CINCA syndrome—3 diseases pre- viously regarded as distinct—prompted us to look for clinical features that characteristically occur in FCAS and NOMID/CINCA syndrome in our patients with MWS. Inflammatory disease activity was markedly ex- acerbated by exposure to cold in all 3 members of this family and in both of our patients with MWS associated with NALP3 R262W, who also responded to anakinra. Neurologic manifestations, including chronic aseptic meningitis, hearing loss, and mental retardation, are features of children with NOMID/CINCA syndrome, many of whom die before reaching adulthood. Each member of the present family had papilledema, and one experienced daily headaches with features suggestive of raised intracranial pressure, which resolved after initia- tion of anakinra therapy.
We suspect that the clinical features of patients with NALP3 mutations overlap much more than has previously been recognized, and that the correlation of phenotype and NALP3 genotype may prove to be quite broad in terms of disease characteristics, penetrance, and severity. For example, in a previous study, we identified the V200M variant in 1 of 130 healthy Cau- casian controls and in 2 of 47 healthy Indian controls, and a cousin in the present family who has this variant does not have clinical evidence of MWS (3). The same variant (annotated as V198M) was reported by Hoffman et al to be associated with FCAS (1). Certain variants such as D305N (also annotated as D303N) underlie NOMID/CINCA syndrome in some individuals but un- derlie MWS in others (2,4,6), and R262W (also anno- tated as R260W) can be associated with MWS and FCAS in different families. These diseases are some-
times caused by de novo mutations in the NALP3 gene, and, indeed, this is usually the case among patients with NOMID/CINCA syndrome, who typically are too sick to parent families of their own. A lack of family history should therefore not discourage analysis of this gene in any patient with features that are suggestive of this spectrum of disease, nor should a lack of periodicity of such symptoms, which tend to be much more constant in MWS and NOMID/CINCA than in other inherited periodic fever syndromes such as FMF.
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© 2004, American College of Rheumatology