Introduction
Cryopyrin-associated periodic syndrome (CAPS), a rare hereditary periodic fever illness caused by genetic mutations in the NOD-like receptor 3 (NLRP3) gene, has three clinical manifestations, one of which is Muckle-Wells syndrome (MWS). Familial cold urticaria (FCAS) is the mild type of CAPS, Chronic Infantile Neurological Cutaneous and Articular syndrome (CINCA) is the intermediate form, and MWS is the severe form with a mental and physical handicap. The primary clinical symptoms of CAPS are an urticarial rash, fever, arthralgia, and exhaustion. The pro-inflammatory interleukin 1 (IL-1) overproduction that causes CAPS symptoms is caused by the NLRP3 gene mutation. Since IL-1 inhibitors have been approved for treating MWS, patients' quality of life has significantly increased.
What Is the Epidemiology of Muckle-Wells Syndrome?
According to estimates, there are 1–10 cases of CAPS for every million people. There is no gender predominance. However, Caucasians appear more affected than other races.
What Is the Pathogenesis of Muckle-Wells Syndrome?
The NLRP3 gene, situated on chromosome 1q44, has three CAPS phenotypes, each brought on by either dominantly inherited or de novo gain-of-function mutations, with varying degrees of penetrance. The NALP3 protein (also known as cryopyrin), which belongs to the family of intracellular nucleotide-binding oligomerization domain NOD-like receptors NLRs, is produced by the NLRP3 gene. NLRs are members of the PRR (pattern-recognition receptor) family. The various danger- and pathogen-associated molecular pattern molecules (DAMPs and PAMPs) are recognized by PRRs. The NACHT domain, which allows NLRs to cluster and oligomerize, is present in all NLRs. Increased inflammation may result from NALP3 NACHT domain mutations.
Although a particular mutation may be linked to various phenotypes of varying severity, these mutations show a strong genotype-phenotype association. Only a small number of people with plausible CAPS profiles have no mutation. Somatic mosaicism in some of them may indicate a function for somatic mutations.
What Are the Clinical Manifestations of Muckle-Wells Syndrome?
Without a known cause, MWS is characterized by recurrent or intermittent fever, headache, urticarial rash, arthralgia, or arthritis. The median age of beginning for febrile attacks is 0.8 years, and they typically begin in infancy. The intense weariness that causes social isolation affects 40 % to 80 % of patients. Attacks may intensify at night, accompanied by a general feeling of malaise, chills, sweating, severe myalgia, and heaviness in the lower limbs, occasionally with edema. Most attacks end within 24 hours, although a percentage linger over three days. 40 % of patients have more than 24 attacks per year, compared to 50% who have fewer than 12 per year.
90% of migraine, intracranial hypertension, or chronic meningitis are accompanied by headaches and irritation, severely affecting everyday life. Patients may have a livedoid appearance to their skin, and urticarial rashes that are not pruritic may develop during bouts. The lesions are consistent with neutrophilic urticaria histologically. Rarer symptoms include mouth ulcers, folliculitis, or erythema nodosum.
Arthralgia and clubbing of the nails are the two primary osteoarticular symptoms. Only CINCA patients exhibit arthritis and cartilaginous proliferation at growth plates and epiphyses. After age 10, patients with MWS may experience progressive sensorineural hearing loss, which is most likely the result of chronic internal ear inflammation.
Conjunctivitis is common, and severe cases of episcleritis and uveitis can also be detected. Up to 25% of instances of amyloidosis result in proteinuria and renal failure. Blood levels of serum amyloid A (SAA), C-reactive protein (CRP), and absolute neutrophil count may all rise during an incident.
What Is the Differential Diagnosis of Muckle-Wells Syndrome?
Other periodic inflammatory diseases such as familial Mediterranean fever (FMF), hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), juvenile systemic granulomatosis, juvenile idiopathic arthritis, tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), and Behçet disease are differentially diagnosed. Still, illness was frequently accompanied by fever, rash, arthralgia, and chronic inflammatory signs. Hypocomplementemia vasculitis or systemic lupus could also be symptoms of other autoimmune disorders. The symptoms of CAPS, in general, and MWS, in particular, are similar to those of other auto-inflammatory illnesses such as HIDS, TRAPS, or FMF. The illness linked with NALP 12 mutations, which also includes adenomegaly, stomach pain, mouth ulcers, headache, and deafness in some individuals, is the hereditary recurrent fever disease that most closely resembles MWS.
What Is the Treatment Given for Muckle-Wells Syndrome?
Painkillers and antihistamines had been demonstrated to be unsuccessful in lowering CAPS symptoms prior to the discovery of biological therapies. However, high-dose corticosteroids were partially effective. In addition to exhaustion, chronic discomfort, hearing and vision impairments, and learning challenges, patients experienced a lower quality of life. They encountered a lack of understanding in their academic or professional environments, which resulted in social and emotional exclusion. They might gradually acquire various psychiatric issues, such as drug addictions or severe depression, that result in suicide. The etiology of CAPS has been clarified, enabling effective IL-1 treatment.
Three IL-1 inhibitors have proven effective in CAPS: canakinumab, a fully human monoclonal IgG1 targeted at IL-1; Rilonacept, a chimerical protein made up of the IL-1-binding domains of human IgG1 and IL-1RI fused to the Fc portion of the protein. Anakinra is a recombinant non-glycosylated form of the human IL-1RA. In Europe, all CAPS phenotypes are approved for using Anakinra and Canakinumab. For all CAPS traits, only Canakinumab is authorized in Japan. In the USA, Rilonacept is approved for use in adults and children over 12 who have FCAS and MWS, while Canakinumab is approved for use in adults and children over two who have FCAS and MWS. Anakinra is approved for use in CINCA.
Anakinra injections daily caused symptoms to quickly subside and CRP and SAA levels to return to normal. By clinical severity, Anakinra may be administered in babies as young as eight months old at doses between 1 and 8 mg/kg/day and in adults as old as 300 mg. Because Anakinra has a very short half-life (6 hours), if the medication is stopped, symptoms quickly return. As it can enter the cerebral fluid, Anakinra has substantial advantages for treating systemic symptoms and may impact chronic conditions such as aseptic meningitis, uveitis, and cochlear inflammation.
Conclusion
With a better understanding of CAPS pathophysiology and therapy utilizing anti-IL-1, clinical profiles and outcomes of MWS patients have significantly improved. Patients can now resume their everyday lives. Advanced research is still required to accurately predict phenotype from genetics for early therapy. For a more accurate diagnosis and application of anti-IL-1, further research is still required on the pharmacokinetics and diffusion of the medicines into CSF in young children. It's essential to evaluate how long-term usage of IL-1-antagonists affects children who receive treatment early in life regarding how they grow, develop, and mature sexually.
