Muckle Wells syndrome
๐ฅ During attacks, levels of C-reactive protein (CRP), serum amyloid A (SAA), and the absolute neutrophil count often rise โ reflecting systemic inflammation.
๐ About
- A rare autoinflammatory disorder belonging to the cryopyrin-associated periodic syndromes (CAPS).
- Part of a spectrum that also includes familial cold autoinflammatory syndrome and chronic infantile neurological cutaneous articular syndrome (CINCA).
- First described in the 1960s by Dr. Thomas J. Muckle and Dr. Michael A. Wells.
๐งฌ Aetiology & Pathophysiology
- Caused by mutations in the NLRP3 gene on chromosome 1q44.
- This results in uncontrolled activation of the NLRP3 inflammasome โ excessive caspase-1 activity โ overproduction of interleukin-1ฮฒ (IL-1ฮฒ).
- IL-1ฮฒ drives fever, neutrophilia, and tissue inflammation โ leading to systemic and organ-specific manifestations.
๐ฉบ Clinical Features
- ๐ก๏ธ Recurrent fever and flu-like malaise.
- ๐ฟ Urticarial rash (non-pruritic, migratory, unlike typical allergy).
- ๐๏ธ Conjunctivitis and sometimes episcleritis.
- ๐ฆด Arthralgia and fatigue, often worsening with cold exposure.
- ๐ Progressive sensorineural hearing loss (a hallmark feature).
- โ ๏ธ AA amyloidosis โ due to persistent high SAA, leading to nephrotic syndrome and renal failure.
- Occasional: oral ulcers, folliculitis, erythema nodosum.
๐ฌ Investigations
- ๐ Raised inflammatory markers (CRP, SAA, ESR) during flares.
- ๐งช Urine protein: screen for amyloidosis-related proteinuria.
- ๐งฌ Genetic testing: confirmation of NLRP3 mutation.
- ๐ Audiometry: monitor hearing loss progression.
๐ Management
The mainstay of treatment is IL-1 blockade, which transforms prognosis by preventing attacks and protecting against amyloidosis:
- ๐ Anakinra: recombinant IL-1 receptor antagonist (daily subcutaneous injection). Produces rapid relief and normalisation of CRP/SAA.
- ๐ Rilonacept: a fusion protein โIL-1 trapโ (weekly injection).
- ๐ Canakinumab: fully human monoclonal antibody targeting IL-1ฮฒ (monthly injection) โ increasingly preferred for long-term disease control.
โ ๏ธ Complications
- ๐ง Irreversible sensorineural hearing loss.
- ๐ง Renal amyloidosis โ proteinuria, nephrotic syndrome, chronic kidney disease.
- ๐ง CNS involvement (rare): headache, papilloedema, chronic meningitis.
๐ Teaching Pearls
- CAPS are autoinflammatory (innate immune dysregulation) not autoimmune (no autoantibodies) โ a key exam distinction.
- UK renal clinics often pick up MuckleโWells late, when patients present with unexplained proteinuria/amyloidosis.
- Early recognition + IL-1 blockade prevents renal failure and disability.
๐ References
