Muckle-Wells syndrome

OVERVIEW: What every practitioner needs to know

Are you sure your patient has Muckle-Wells syndrome? What are the typical findings for this disease?

Muckle-Wells syndrome is an inherited periodic fever syndrome characterized by lifelong recurrent episodes of fever and illness due to seemingly unprovoked inflammation in the absence of autoimmunity or infection.

The most common symptoms are recurrent but unpredictable acute attacks of fever >38.5°C and urticaria lasting 1-3 days at a time. The age of onset is often <6 months. All patients suffer from significant chronic fatigue. Musculoskeketal symptoms are very common with arthralgias present in nearly 100%, chronic polyarthritis in 65%, and myalgia in 50%. Conjunctivitis is present in >90% of patients and chronic uveitis occurs in 15-20% patients.

In a patient with periodic fever and urticaria, the concomitant presence of conjunctivitis and progressive sensioneural hearing loss are pathognomonic of this disease. Abdominal pain and headaches are noted in 50-80% of patients during febrile attacks, but these symptoms are not as severe as in Familial Mediterranean Fever. Recurrent oral aphthae can be seen in >50% during fevers.

The next most common symptoms include the triad of urticaria, deafness and amyloidosis. Amyloidosis actually less common, occurring in only 25% patients.

Cold exposure is not necessary as a trigger for clinical exacerbations in Muckle Wells, distinguishing it from Familial Cold Autoinflammatory Syndrome.

In the typical patient, laboratory studies demonstrate leukocytosis, elevated ESR and CRP during fevers, which may or may not normalize completely in-between attacks. Some inflammatory symptoms persist for weeks or more, leading to long term complications that affect quality of life. Since the fever pattern is less predictable than in FCAS, the diagnosis of Muckle-Wells syndrome is often delayed until hearing loss is noted during adolescence (in >70% patients).

The clinical features are thought to be due to mutations in the NLRP3 gene encoding cryopyrin/NLRP3. NLRP3 is a component protein of the inflammasome. Inflammasome activation is required for initiation of the innate inflammatory response. Mutations in NLRP3 also cause other cryopyrin-associated periodic syndromes (CAPS): Familial cold autoinflammatory syndrome (FCAS) and some cases of neonatal-onset multisystem inflammatory disease (NOMID). Genotyping may be used to confirm diagnosis. Therapeutic agents that block IL-1 eliminate most systemic inflammation and may decrease long term complications.

What other disease/conditions shares some of these symptoms?

• Cyclic neutropenia.

• HIV/AIDS.

• Tuberculosis, CMV, brucellosis, rat-bite fever, relapsing fever or other chronic viral, bacterial or parasitic infections.

• Systemic lupus erythematosus, relapsing polychondritis.

• ANCA-mediated vasculitis, including Wegener’s granulomatosis and microscopic polyangiitis.

• Takayasu’s arteritis.

• Other systemic autoinflammatory diseases.

• HLA B27-associated juvenile spondyloarthropathies.

• Sarcoidosis.

• Malignancies, including leukemia and lymphoma.

• Acute intermittent porphyria.

• Surgical emergencies, including appendicitis, intussusception.

• Relapsing pancreatitis.

Systemic autoinflammatory syndromes that mimic Muckle-Wells syndrome:

• Systemic onset juvenile idiopathic arthritis, adult Still’s disease.

• Neonatal onset multisystem inflammatory disorder (NOMID), also known as chronic infantile neurologic cutaneous and articular syndrome (CINCA).

• Familial cold autoinflammatory syndrome (FCAS).

• Periodic fever with aphthous stomatitis, pharyngitis and adenitis (PFAPA syndrome).

• TNF receptor associated periodic fever syndrome (TRAPS).

• Hyper-immunoglobulinemia D with periodic fever (HIDS).

• Familial Mediterranean fever (FMF).

• Behcet’s disease.

• Crohn’s disease.

• Macrophage activation syndrome.

• Hereditary or acquired angioedema.

• Gout.

• Autoimmune bone diseases:

  CRMO (chronic recurrent multifocal osteomyelitis).

  SAPHO (synovitis, acne, pustulosis, hyperostosis, osteiitis).

What caused this disease to develop at this time?

Triggers may include cold, heat, stress, surgery, concurrent infection, but in many cases no specific trigger is identified. The symptoms are due to inappropriate activation and control of antigen-independent inflammation (innate immunity).

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

• CBC, differential during fever and when symptom-free.

• ESR, CRP during fever and when symptom-free.

• Complete metabolic panel.

• Uric acid, LD.

• Ferritin, fibrinogen.

• Quantitative immunoglobulins (IgG, IgA, IgM).

• Urinalysis.

• Blood, urine, throat cultures.

• PPD.

• Genotyping for CAPS.

When interpreting the above:

• Marked leukocytosis with bandemia, ESR >80 and CRP >80 suggest infectious rather than autoinflammatory process, which may be confirmed by pan-cultures, serologies or other studies.

• Positive PPD suggests tuberculosis.

• Elevated uric acid suggests leukemia or lymphoma.

• Hypogammaglobulinemia may suggest primary immunodeficiency and secondary infection.

Additional laboratory studies that may be helpful in confirming diagnosis or for management:

• 24 hr urine collection for protein and creatinine clearance.

• Renal or rectal biopsy and staining for amyloid deposition.

Would imaging studies be helpful? If so, which ones?

• Chest radiograph (x-ray) for infection, inflammatory lung disease or serositis.

• Abdominal x-ray, ultrasound or computed tomography (CT) to evaluate abdominal pain, rule out peritonitis or surgical emergency.

Other imaging studies that may be helpful if specific symptoms are present:

• Echocardiogram to rule out pericarditis.

• Joint magnetic resonance imaging (MRI) with and without contrast to evaluate arthritis.

• Head MRI with and without contrast to evaluate headache and hearing loss.

Confirming the diagnosis

Pertinent history:

Peak fever temperature.

Pattern of fever (hectic, quotidian, recurrent, relapsing/periodic, continuous, intermittent, remittent).

Duration of fever.

Antecedent or prodromal symptoms prior to onset of fever.

Associated symptoms (infectious, rash, arthritis, diarrhea, etc).

Pattern of appearance of associated symptoms.

Duration of associated symptoms.

Predictability of symptoms and illness course.

Duration of fever-free intervals.

Overall health and persistent or chronic symptoms when afebrile.

Famly history of similar febrile illnesses and response to treatment.

Ethnicity of parents.

Number and type of infections in lifetime and response to antibiotics.

A diagnosis of Muckle-Wells should be suspected in the following circumstances:

• Infant presenting with recurrent fevers in association with urticaria.

• Sensioneural hearing loss noted during later childhood.

• Attacks of fever are associated with conjunctivitis, arthritis and/or abdominal pain.

• Attacks do not remit on colchicine treatment.

• Family history of FCAS.

• Amyloidosis develops.

If you are able to confirm that the patient has Muckle-Wells syndrome, what treatment should be initiated?

• Therapies that should be instituted immediately include:

  Prednisone 0.5-2 mg/kg/day for severe symptoms; taper and discontinue with symptomatic improvement.

  Naproxen 10 mg/kg b.i.d., meloxicam 7.5-15 mg daily OR celecoxib 50-100 mg b.i.d. as needed for joint pain or arthritis.

  Omeprazole 10-20 mg daily OR lanseprazole 15-30 mg daily.

  Chronic IL-1 blockade:

  Rilonacept 4.4 mg/kg (max 320 mg) SQ on day 1, then 2.2 mg/kg (max 160 mg) SQ weekly, OR

  Canakinumab 150 mg SQ q.8 wk (if >4 yr & >40 kg) or 2-3 mg/kg (max 150 mg) SQ q.8 wk if <40 kg, OR

  Anakinra 1-5 mg/kg SQ daily (one case report used 10 mg/kg with success).

• Longer term treatment may include:

  Rilonacept 4.4 mg/kg (max 320 mg) SQ on day 1, then 2.2 mg/kg (max 160 mg) SQ weekly, OR

  Canakinumab 150 mg SQ q.8 wk (if >4 yr & >40 kg) or 2-3 mg/kg (max 150 mg) SQ q. 8 wk if <40 kg, OR

  Anakinra 1-5 mg/kg SQ daily (one case report used 10 mg/kg with success)

• Alternative treatments if the patient fails standard therapy?

  Infliximab 3-10 mg/kg IV q.4-8 wk.

Table I. Advantages and Disadvantages of Treatment Options