Pediatrics

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?

  1. Cyclic neutropenia.

  2. HIV/AIDS.

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

  4. Systemic lupus erythematosus, relapsing polychondritis.

  5. ANCA-mediated vasculitis, including Wegener's granulomatosis and microscopic polyangiitis.

  6. Takayasu's arteritis.

  7. Other systemic autoinflammatory diseases.

  8. HLA B27-associated juvenile spondyloarthropathies.

  9. Sarcoidosis.

  10. Malignancies, including leukemia and lymphoma.

  11. Acute intermittent porphyria.

  12. Surgical emergencies, including appendicitis, intussusception.

  13. Relapsing pancreatitis.

Systemic autoinflammatory syndromes that mimic Muckle-Wells syndrome:

  1. Systemic onset juvenile idiopathic arthritis, adult Still's disease.

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

  3. Familial cold autoinflammatory syndrome (FCAS).

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

  5. TNF receptor associated periodic fever syndrome (TRAPS).

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

  7. Familial Mediterranean fever (FMF).

  8. Behcet's disease.

  9. Crohn's disease.

  10. Macrophage activation syndrome.

  11. Hereditary or acquired angioedema.

  12. Gout.

  13. 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

Table I.

Advantages and Disadvantages of Treatment Options
Drug Advantages Disadvantages
Anakinra Recombinant IL-1 antagonist that competitively inhibits binding of IL-1 to the cell-surface IL-1 receptor Daily painful injections; short term efficacy without long term benefit after discontinuation
Rilonacept Recombinant IL-1beta decoy receptor that binds IL-1 before it can bind cell-surface IL-1 receptor Weekly injections; relatively new with less long term safety data known
Canakinumab Monoclonal Ab to IL-1 beta that blocks IL-1 activity Every 8 wk injections; relatively new with less long term safety data known
Infliximab Monoclonal Ab to TNFalpha, another proinflammatory cytokine that participates in inflammation; long term safety data >15 yr available Frequent infusion reactions; requires medical setting to administer; adverse events common

What are the adverse effects associated with each treatment option?

Table II. Adverse effects of treatment option

Table II.

Adverse effects of treatment option
NSAIDS Gastritis, gastric ulcer, gastroesophageal reflux, rash, edema, liver/renal toxicity -uncommon in children
Corticosteroids Infection, weight gain, muscle atrophy, adrenocortical insufficiency, osteopenia, growth delay, avascular necrosis, emotional lability, rash, edema, hypertension, diabetes
Infliximab Infection, allergic reaction, anaphylaxis, nausea, diarrhea, abdominal pain, fatigue, elevated LFTs, serum sickness, ANA positivity, CNS/demyelinating disease, increased heart failure, cytopenias, future malignancy
Anakinra Infection, severe injection site reaction/pain, future malignancy
Rilonacept Infection, injection site reaction, hypersensitivity reaction, hyperlipidemia, future malignancy
Canakinumab Infection, injection site reaction, diarrhea, nausea, vertigo, weight gain, myalgias, headache, future malignancy

What are the possible outcomes of Muckle-Wells syndrome?

What will you tell the family about prognosis?

  1. Unlike some inherited periodic fever syndromes, not a benign self-limited disease.

  2. Of the CAPS syndromes, greatest disease severity: NOMID > MWS >> FCAS.

  3. Frequency of 2° amyloidosis: MWS > NOMID > FCAS.

  4. Progressive profound sensioneural hearing loss in >70% patients not on a biologic.

  5. Significant chronic fatigue in all patients, remits with therapy.

  6. Amyloidosis in 25%, which improves with IL-1 blockade but not colchicine.

  7. IL-1 blockade relieves acute symptoms, but effect on long term morbidities less clear.

Table III. What will you tell the family about risks/benefits of the available treatment options

Table III.

What will you tell the family about risks/benefits of the available treatment options?
Drug Indication Risks Benefits
NSAIDS Arthritis; pain, fever Adverse reactions Reduce fever, pain, arthritis
Corticosteroids Fever, arthritis,serositis, urticaria, vasculitis Adverse reactions Relieve fever, rash, arthritis, serositis
Infliximab Chronic arthritis, fever & inflammation resistant to IL-1 blockade, chronic uveitis Adverse reactions Controls fever, arthritis, aphthous stomatitis, uveitis; improves inflammatory markers
Anakinra Treatment of CAPS; fever, urticaria, rash, arthritis, acute phase response Adverse reactions; may trigger flare of inflammation; no longlasting disease control off treatment Remits fever, rash, arthritis & laboratory abnomalities, reduces amyloidosis & other complications
Rilonacept Treatment of CAPS; fever, rash, arthritis, acute phase response Adverse reactions Remits fever, rash, arthritis & laboratory abnomalities
Canakinumab Treatment of CAPS; fever, rash, arthritis, acute phase response Adverse reactions Full remission in > 95% patients; normalizes SAA; reduces 2° amyloidosis & other longterm complications

What causes this disease and how frequent is it?

  • Detained epidemiology:

    • More frequently reported in Europe and North America, but limited data from other areas.

    • Incidence: rare, usually familial cases.

    • Males and females equally affected.

  • What is known about the genetics?

    • Due to autosomal dominant mutations in the NLRP3 gene encoding cryopyrin/NLRP3, which is highly expressed in neutrophils, monocytes and chrondrocytes.

    • 25% patients with characteristic clinical features lack identifiable NLRP3 mutations.

How do these pathogens/genes/exposures cause the disease?

How does the NLRP3 gene cause the disease?

NLRP3 is required for assembly of the intracellularmulti-protein complex or "inflammasome" in phagocytic cells that linksinitial sensing of danger from microbial products and metabolicstress to activation of the innate immune system via production ofthe pleiotrophic pyrogen and alarm cytokine IL-1beta.

  • The inflammasome is comprised of NLRP3, caspase-1 and ASC (apoptosis-associatedspeck-like protein).

  • Inflammasome activation is essential for production of bioactive IL-1beta and initiation of inflammation.

  • Gain-of-function mutations in NLRP3 causeconstitutive inflammasome activation and increase caspase-1 activityresulting in excessive IL-1beta release, uncontrolled inflammation andtissue injury.

  • Considered an "intrinsic inflammasomopathy."

Other clinical manifestations that might help with diagnosis and management

Secondary amyloidosis:

The medical management of Muckle-Wells syndrome is focused on prevention of acute symptoms and minimizing the long term complications, including 2° amyloidosis. Amyloid deposition is primarily in the kidneys and typically presents initially as proteinuria without renal insufficiency. Proteinuria or >500 mg protein in 24 hr urine sample suggest amyloid-related nephropathy. Amyloidosis in GI tract presents as diarrhea and malabsorption. Renal or rectal biopsy is used to confirm the diagnosis of amyloidosis.

Amyloidosis may be prevented by IL-1 blockade, but long term data is lacking.

What complications might you expect from the disease or treatment of the disease?

  1. One of the most worrisome disease complications is 2° amyloidosis, leading to renal failure and early death unless renal transplantation is available.

  2. Another significant complication is severe sensioneural deafness.

  3. Treatment complications include organ toxicity, infection and future malignancy.

Are additional laboratory studies available; even some that are not widely available?

  1. Serum amyloid A protein (SAA).

How can Muckle-Wells syndrome be prevented?

  1. No known prevention.

  2. Genetic counseling is important if Muckle-Wells syndrome is suspected.

  3. Prenatal diagnosis requires identification of disease-causing mutation(s).

What is the evidence?

PFS:

Reviews of Autoinflammatory Diseases:

Kastner, DL, Aksentijevich, A, Goldbach-Mansky, R. "Autoinflammatory Disease Reloaded: A Clinical Perspective". Cell. vol. 140. 2010. pp. 784.

(A review of current thinking about the etiology of autoinflammatory diseases and recent advances that offer new opportunities for therapeutic intervention.)

Ombrello, MJ, Kastner, DL. "Expanding clinical spectrum and broadening therapeutic horizons". Nat Rev Rheumatol. vol. 7. 2011. pp. 82.

Pathogenesis of Autoinflammatory Diseases:

Simon, A, van der Meer. "Pathogenesis of familial periodic fever syndromes or hereditary autoinflammatory syndromes". Am J Physiol Regul Integr Comp Physiol. vol. 292. 2006. pp. R86.

Bodar, EJ, Drenth, JPH, van der Meer, JWM, Simon, A. "Dysregulation of innate immunity: hereditary periodic fever syndromes". Brit J Hematol. vol. 144. 2008. pp. 279.

Glaser, RL, Goldbach-Mansky, R. "The Spectrum of Monogenic Autoinflammatory Syndromes: Understanding Disease Mechanisms and Use of Targeted Therapies". Curr Allergy Asthma Rep. vol. 8. 2008. pp. 288.

Goldbach-Mansky, Kastner, DL. "Autoinflammation: The prominent role of IL-1 in monogenic autoinflammatory diseases and implications for common illnesses". J Allergy Clin Immunol. vol. 124. 2009. pp. 1141.

Masters, SL, Simon, A, Aksentijevich, Kastner, DL. "Horror Autoinflammaticus:The Molecular Physiology of Autoinflammatory Disease". Ann Rev Immunol. vol. 27. 2009. pp. 621.

Henderson, C, Goldbach-Mansky, R. "Monogenic autoinflammatory diseases: new insights into clinical aspects and pathogenesis". Curr Opin Rheumatol. vol. 22. 2010. pp. 567.

Complications of hereditary periodic fever syndromes and autoinflammatory diseases:

van der Hilst, JCH, Simon, A, Drenth, JPH. "Hereditary periodic fever and reactive amyloidosis". Clin Exp Med. vol. 5. 2005. pp. 87.

Bilginer, Y, Akpolat, T, Ozen, S. "Renal amyloidosis in children". Pediatr Nephrol. vol. 26. 2011 Aug. pp. 1215-27.

Therapy of MWS:

Mitroulis, M, Skendros, P, Ritis, K. "Targeting IL-1beta in disease; the expanding role of NLRP3 inflammasome". Eur J Int Medicine. vol. 21. 2010. pp. 157.

Kubota, T, Koike, R. "Cryopyrin-associated periodic syndromes: background and therapeutics". Mod Rheumatol. vol. 20. 2010. pp. 213.

Aganna, E, Martinon, F, Hawkins, PN, Ross, JB, Swan, DC, Booth, DR. "Association of Mutations in the NALP3/CIAS1/PYPAF1 gene with a Broad Phenotype Including Recurrent Fever, Cold Sensitivity, Sensioneural Deafness, and AA Amyloidosis". Arthritis Rheum. vol. 46. 2002. pp. 2445.

Lepore, L, Paloni, G, Caorsi, R, Alessio, M, Rigante, D, Ruperto, N. "Follow-up and quality of life of patients with cryopyrin-associated periodic syndrome treated with Anakinra". J Pediatr. vol. 157. 2010. pp. 310.

Church, LD, McDermott, MF. "Canakinumab: a human anti-IL-1beta monoclonal antibody for the treatment of cryopyrin-associated periodic syndromes". Expert Rev Clin Immunol. vol. 6. 2010. pp. 831.

Kuemmerle-Deschner, JB, Tyrrell, PN, Koetter, I, Wittkowski, H, Bialkowski, A, Tzaribachev, N. "Efficacy and Safety of Anakinra Therapy in Pediatric and Adult Patients with the Autoinflammatory Muckle-Wells Syndrome". Arthritis Rheum. vol. 63. 2011. pp. 840.

Ongoing controversies regarding etiology, diagnosis, treatment

  1. Long term risks/benefits of treatment with biologics, given uncertain future risks, particularly for maligancies, opportunistic infections, autoimmune diseases, organ toxicity.

  2. Pharmacological options for management of MWS given difficulty distinguishing between CAPS syndromes in some patients and thus long term prognosis.

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