CAPS consists of three different diseases that are classified in terms of clinical pictures, organ involvement, severity, as well as triggers. They share similar features as well.

MWS manifests in infancy or childhood and continues onwards. Its symptoms include intermittent mild-to-moderate fever, recurrent non-itchy rashes, arthritis/arthralgia, malaise, and chills. Additionally, eye pathology such as conjunctivitis, uveitis, and episcleritis are observed in these patients. Furthermore, progressive bilateral sensorineural hearing loss is common and develops in adolescence, early adulthood or beyond. Headaches as a result of aseptic meningitis can occur as well. Amyloidosis of the organs such as the kidneys may develop in approximately one-third of patients. Finally, pigmented skin lesions are observed in individuals with MWS.

These attacks can occur spontaneously or may be a consequence of triggers such as cold weather, exercise, or stress. Note that while exposure to cold temperatures is a common trigger of FCAS, it is an infrequent precipitating factor in MWS. Moreover, the episodes are usually random and last for a duration of less than 36 hours although they can continue for five days. The patient usually feels well between these acute relapses.

Physical exam

Remarkable findings include lymphadenopathy and/or hepatosplenomegaly. Also, arthritis of the large joints, skin rashes, skin discoloration, and inflammatory eye conditions such as conjunctivitis are remarkable on the exam during flare-ups.

The clinical workup consists of an evaluation of the overall clinical presentation, a thorough history including that of the patient's family, a physical examination, and relevant studies.

Laboratory tests

Diagnosis of MWS is definitively proven through genetic testing that reveals the NLRP3 mutation. However, the mutation is not always present in individuals with MWS.

There are numerous abnormal studies in patients with acute episodes. The nonspecific findings include an increase in the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and SAA, which are collectively considered to be acute phase reactants. Additionally, the complete blood count depicts leukocytosis and anemia of chronic disease. Finally, the cerebrospinal fluid (CSF) may demonstrate the presence of neutrophils and eosinophils in the absence of infection.

Special consideration

The workup should be tailored to evaluate the complications associated with MWS. For example, an audiogram is useful to assess the progressive sensorineural deafness. Additionally, a renal biopsy and an evaluation of the urinary protein should be performed to detect the presence of amyloidosis. Note that an initial sign of amyloidosis is proteinuria without red or white blood cells.

The main therapeutic approach for MWS and other CAPS diseases is the inhibition of IL-1 especially in patients with an earlier onset and more severe manifestations [9]. It is paramount to initiate treatment early in order to control the risk of developing hearing loss [8] and amyloidosis.

The IL-1 antagonist known as Rilonacept is a dimeric fusion protein that is FDA approved for MWS patients 12 years and older. Another drug in the same category, Kineret, is not FDA approved yet for MVS but has demonstrated success in many MWS patients. Overall, IL-1 inhibitors are associated with a good prognosis as they reduce the risk for developing sensorineural deafness.

Another medication used in children and adults with this disease is Canakinumab, an FDA-approved monoclonal antibody against IL-1β. This drug elicits good control in patients but may require dose adjustments throughout treatment [10].

Other

Hearing loss can be improved with hearing aids and other similar medical technologies.

Arthralgia and arthritis can be alleviated with non-steroidal anti-inflammatory drugs (NSAIDS). Moreover, corticosteroids administered in high doses can be useful but they place the patients at risk for adverse effects both in short and long-term.

If present, renal failure secondary to amyloidosis will be managed accordingly.

Progressive deafness and renal failure are serious complications in this disease. However, the prognosis is promising in those treated with IL-1 inhibitors. Specifically, sensorineural deafness responds well to this class of drugs [9]. Additionally, therapy with IL-1 antagonists can decrease the risk of amyloidosis as untreated individuals have a 25% risk of developing this sequela. Since amyloidosis nephropathy is associated with mortality, early recognition and treatment are essential.

The etiology of MWS is attributed to mutations in the NLRP3 gene (found on chromosome 1), which is transmitted in an autosomal dominant pattern. This gene codes for the cryopyrin protein [3], which is a component of the NLRP3 inflammasome along with procaspase 1. The NLRP3 inflammasome plays a key role in the activation of caspase 1, which induces the cleavage of pro-IL-1β to produce IL-1β [4]. The latter is released from cells. In this disease, there is an occasional excessive production of IL-1β that accounts for the acute inflammatory attacks consisting of fever, rash, conjunctivitis, and musculoskeletal involvement.

The prevalence of CAPS is approximately 1 per population of 400,000 [5].

The CAPS are caused by a mutation in the NLRP3 gene, which codes for cryopyrin, a protein with an integral role in the regulation of inflammation and apoptosis. This mutation activates the NLRP3 inflammasome [6], which stimulates a series of cellular mechanisms that ultimately release inflammatory cytokines such as IL-1. The latter is spontaneously secreted by macrophages in these patients [7].

IL-1 has numerous functions which include increasing the production of serum amyloid A (SAA) by the liver. SAA can deposit in organs such as the kidneys, resulting in amyloidosis and amyloidosis-induced renal failure.

Another severe sequela arising from MWS is bilateral sensorineural hearing loss secondary to chronic inflammation mediated by IL-1 in the cochlea [8].

There are no preventative measures for MWS since it is an inherited disorder. But patients and their family members planning on starting families can seek prenatal care to gain understanding about what MWS entails, the probability of transmitting the disease, and further details. Additionally, genetic testing may be offered in appropriate cases.

Muckle Wells Syndrome (MWS), also referred to as urticaria-deafness-amyloidosis syndrome, is a rare autosomal dominant disorder that falls within the spectrum of hereditary periodic fever diseases [1]. Furthermore, this autoinflammatory condition is the moderate form of three clinical phenotypes that comprise the cryopyrin-associated periodic syndromes (CAPS). The two other phenotypes are known as familial cold autoinflammatory syndrome (FCAS) (mildest) and chronic infantile neurologic cutaneous articular syndrome (CINCA syndrome) or neonatal-onset multisystem inflammatory disease (NOMID) (most severe) [2]. The mutation responsible for CAPS involves the NLRP3 gene, which encodes cryopyrin. This is a pivotal protein in the pathway that synthesizes interleukin-1β (IL-1β), which is the cause of the clinical features observed in CAPS patients.

The symptomology of MWS is characterized by recurrent episodes of fevers, urticaria, headaches, and inflammatory signs such as arthralgia and ophthalmic manifestations including conjunctivitis and uveitis. The onset of MWS occurs in infancy or childhood. Serious complications include progressive bilateral sensorineural hearing loss and amyloidosis with the latter leading to nephropathy. These attacks typically last less than 36 hours.

The clinical assessment consists of the individual's personal and family history, a physical exam, and appropriate studies. The confirmatory diagnostic tool is the genetic detection of the mutation in the NLRP3 gene. Other tests include the measurements of the acute phase reactants, which are typically abnormal during the flare-ups. Additionally, an audiogram is important as is an evaluation of amyloid nephropathy with renal biopsy when indicated.

MWS (and other CAPS) is treated with IL-1 inhibitors, which is successful in controlling the progression of hearing loss and lowering the risk of developing amyloidosis. Additionally, there is a monoclonal antibody that is effective in treating MWS. Furthermore, there are other measures that can be used for symptom relief. Finally, genetic counseling is available for patients and their family members who desire to start families.

What is Muckle Wells syndrome?

Muckle Wells syndrome (MWS) is a genetic disorder, in which the affected individuals experience repeating flare-ups of fever, non-itchy rash, and joint pain/swelling along with eye problems. These episodes can occur randomly, but they also may be triggered by cold temperatures. They usually last less than three days but may continue for up to five days.

Who is affected by MWS?

This disease begins in young infants and children. It occurs because of a mutation in the NLRP3 gene that produces a protein called cryopyrin. This mutation ultimately causes an excessive production of a protein called interleukin-1β, which is responsible for the inflammatory symptoms seen in these patients.

MWS is inherited in an autosomal dominant pattern, which means that the patient receives one bad copy of the gene from the affected parent and one good copy from the nonaffected parent. To explain further, the affected patient has 50% chance of passing this disease to offspring.

What are the signs and symptoms of MWS?

The following are the main features of the flare-ups:

• Fever (mild to moderate)
• Hives
• Joint pain and swelling
• Chills
• Inflammatory conditions of the eye such as conjunctivitis and uveitis
• Headache

Complications of MWS include:

• Hearing loss in both ears due to continued damage to the nerves: this begins in early adolescence
• Kidney failure due to amyloidosis, which is the abnormal accumulation of amyloid protein in the kidneys
• Skin discoloration

How is MWS diagnosed?

The clinician will obtain the personal and family history of the patient, perform a physical exam, and run important tests. The genetic test that confirms MWS reveals the mutation in the NLRP3 genes. However, not all patients have this mutation.

Patients with MWS will have abnormal laboratory tests during their flare-ups. For example, they have an increased number of white blood cells as well anemia of chronic disease. Also, they have increased erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and serum amyloid A (SAA).

Other important studies for MWS patients include an audiogram to test for the progressive loss of hearing. Also, a urinary protein test and renal biopsy can assess for amyloidosis.

How is MWS treated?

The main treatment for MWS includes a class of drugs known as interleukin-1 inhibitors, which block interleukin-1. Two examples are Rilonacept and Kineret. These produce good results and decrease the risk of the patient developing hearing loss.

There is another drug known as Canakinumab, which acts as an antibody against interleukin-1.

Note that non-steroidal anti-inflammatory drugs (NSAIDS) are effective for joint pain and swelling. Also, corticosteroids are helpful but they are associated with side effects.

Finally, patients with hearing loss will benefit from hearing aids.

What is the prognosis?

Treatment with interleukin-1 blockers yields good results in patients.

Can it be prevented?

Since this is a genetic disease, it cannot be prevented. But affected individuals and their family members may obtain genetic counseling to gain an understanding about the disease and learn about the chances of passing it to an offspring. Also, genetic testing may be offered as well.

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