Pediatrics

NOMID/CINCA

OVERVIEW: What every practitioner needs to know

Are you sure your patient has NOMID/CINCA? What are the typical findings for these diseases?

Neonatal-onset multisystem inflammatory disease (NOMID) or chronic infantile neurologic cutaneous and articular syndrome (CINCA) is an inherited periodic fever syndrome characterized by inappropriate, uncontrolled and often spontaneous inflammation in the absence of autoimmunity or infection.

The most common symptoms of NOMID / CINCA are bouts of urticarial rash, with or without fever, with onset noted at birth or in early infancy. NOMID/ CINCA is the most severe cryoprin-associated periodic syndrome (CAPS) with chronic rash, continuous symptoms and frequent flares not necessarily accompanied by fever. Ninety-nine percent of untreated patients will have severe CNS manifestations that include:

  1. Chronic aseptic meningitis.

  2. Progressive profound sensorineural hearing loss in >70%.

  3. Increased intracranial pressure.

  4. Papilledema.

  5. Headache.

  6. Ventriculomegaly.

  7. Cerebral atrophy.

  8. Seizures.

  9. Significant developmental delay.

Characteristic epiphyseal overgrowth and arthropathy is pathognomonic of this disease and develops in 30-60% patients. The next most common symptoms include prematurity or small for gestational age in 30%, chronic intraocular inflammation in 50% (manifested by treatment resistant anterior/posterior uveitis, optic atrophy, and blindness or severe vision loss in 25%).

Patients have chronically elevated inflammatory markers.

The diagnosis is frequently delayed until overgrowth arthropathy or CNS disease is observed.

Complications vary in severity and age of onset, but also include:

1. Early growth retardation, delayed puberty.

2. Skull abnormalities, frontal bossing.

3. Progressive joint contractures and limited mobility due to arthritis or overgrowth arthropathy.

4. 2° amyloidosis in 10-25% patients.

Other features:

  1. Due to autosomal dominant mutations in the NLRP3 gene encoding cryopryin/NLRP3.

    • NLRP3 is a component protein of the inflammasome.

    • Inflammasome activation is required for initiation of the innate inflammatory response.

  2. Mutations in NLRP3 also cause other cryopyrin-associated periodic syndromes:

    • Familial cold autoinflammatory syndrome (FCAS).

    • Muckle-Wells syndrome (MWS).

  3. Diagnosis may be suspected based on constellation of symptoms including fever pattern, associated symptoms, acute phase response, family history.

  4. Therapeutic agents that block IL-1 eliminate most systemic inflammatory symptoms and may decrease or prevent long term complications.

What other disease/conditions share 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. Autoimmune lymphoproliferative syndrome (ALPS).

  12. Acute intermittent porphyria.

  13. Surgical emergencies, including appendicitis, intussusception.

  14. Relapsing pancreatitis.

Systemic autoinflammatory syndromes that mimic NOMID/CINCA

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

  2. Muckle-Wells syndrome (MWS).

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

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

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

  6. Familial Mediterranean fever (FMF).

  7. Behcet's disease.

  8. Crohn's disease.

  9. Macrophage activation syndrome.

  10. Hereditary or acquired angioedema.

  11. Gout.

  12. 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, or concurrent infection. In many cases, no specific trigger is identified.

The clinical flares of the disease are due to inappropriate activation and control of antigen-independent inflammation (activation of the innate immune system).

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, fibrinoge.

  • Quantitative immunoglobulins (IgG, IgA, IgM)

  • Urinalysis

  • Blood, urine cultures

  • PPD

  • Genotyping for CAPS

Additional laboratory studies or diagnostic testing 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

  • Synovial fluid analysis for cell count and culture

  • Annual or biannual audiologic evaluations

  • Annual slit lamp examinations to rule out papilledema, chronic uveitis or vision loss

Interpretation of results:

  • Marked leukocytosis with bandemia, ESR >80, CRP >80 may suggest infectious rather than autoinflammatory process

  • A positive PPD suggest tuberculosis

  • Elevated uric acid suggests leukemia or lymphoma

  • Proteinuria or 24 hr urine protein >500 mg suggests possible amyloidosis

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

A chest radiograph (x-ray) is indicated when pulmonary infection, non-infectious inflammatory lung disease, or serositis is suspected.

Head magnetic resonance imaging (MRI) with and without contrast to follow CNS manifestations.

Joint MRI with and without contrast to evaluate arthritis.

Confirming the diagnosis

Pertinent history:

  • Peak fever temperature if present

  • Duration and pattern of fever (hectic, quotidian, recurrent, relapsing/periodic, continuous, intermittent, remittent)

  • Antecedent or prodromal symptoms prior to onset of fever

  • Associated symptoms (rash, arthritis, diarrhea, etc)

  • Pattern of appearance and duration of associated symptoms

  • Predictability of symptoms and illness course

  • Specific triggers

  • Duration of fever-free intervals

  • Overall health and chronic symptoms

  • Family history of similar febrile illness and response to treatment

  • Ethnicity of parents

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

Suspect diagnosis if:

  • Presentation in infancy of recurrent fevers and urticarial rash

  • One or more chronic symptoms:

    • arthritis

    • growth retardation

    • developmental delay

    • chronic aseptic meningitis

    • hearing los.

  • Epiphyseal overgrowth arthropathy of patellae noted

If you are able to confirm that the patient has NOMID, what treatment should be initiated?

  • Are there some therapies that should be instituted immediately?

    • NSAIDS: choose naproxen 10 mg/kg b.i.d., meloxicam 0.125 mg/kg (max 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 if on regular NSAIDS.

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

    • Start continuous IL-1 blockade:

      • Rilonacept 4.4 mg/kg (max 320 mg) SQ on day 1, then 2.2 mg/kg (max 160 mg) SQ q.wk, OR

      • Anakinra 1-10 mg/kg SQ daily, 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

  • What about longer term treatment?

    • NSAIDS: choose naproxen 10 mg/kg b.i.d., meloxicam 0.125 mg/kg (max 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 if on regular NSAIDS.

    • Continuous IL-1 blockade:

      • Rilonacept 4.4 mg/kg (max 320 mg) SQ on day 1, then 2.2 mg/kg (max 160 mg) SQ q.wk, OR

      • Anakinra 1-10 mg/kg SQ daily, 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

  • What about alternative treatments if fails standard therapy?

    • Infliximab 5-10 mg/kg IV q.4-8 wk

    • Consider thalidomide 100-300 mg daily

See Table I.

Table I.

Treatment options
Drug Advantages Disadvantages
Anakinra Recombinant IL-1 antagonist that competitively inhibits binding of IL-1 to cell-surface IL-1 receptor thereby blocking IL-1 activity Daily painful injections; short term efficacy without long term benefit after discontinuation
Rilonacept Recombinant IL-1 decoy receptor that binds IL-1 before it can bind to cell surface receptor Weekly injections; relatively new without long term safety data
Canakinumab Monoclonal Ab to IL-1 that blocks IL-1 activity Every 8 wk injections; relatively new without long term safety data
Infliximab Monoclonal Ab to TNFalpha that blocks its activity; long term safety data available Frequent infusion reactions; requires medical setting to administer; adverse reactions fairly common

What are the adverse effects associated with each treatment option?

See Table II.

Table II.

Adverse effects of treatment options
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 (risk > etanercept), allergic reaction, anaphylaxis, nausea, diarrhea, abdominal pain, fatigue, elevated LFTs, serum sickness, ANA positivity, CNS/demyelinating disease, increased heart failure, cytopenias, future malignancy (risk > etanercept)
Anakinra Infection, severe injection site reaction/pain, future malignancy
Rilonacept Infection, injection site reaction, hypersensitivity reaction, hyperlipidemia, possible risk of future malignancy
Canakinumab Infection, injection site reaction, diarrhea, nausea, vertigo, weight gain, myalgias, headache, possible risk of future malignancy.
Thalidomide Infection, peripheral neuropathy, somnolence, teratogenicity, rash, dizziness, mood changes

What are the possible outcomes of NOMID?

What will you tell the family about prognosis?

  1. Unlike other inherited periodic fever syndromes, has chronic course with significant long term complications, poor overall prognosis and probably shortened lifespan even on IL-1 blockade therapy.

  2. However, early diagnosis and treatment with IL-1 blockers improves quality of life and delays or prevents many morbidities.

  3. Of the CAPS: greatest disease severity: NOMID >> MWS > FCAS.

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

  5. 2° amyloidosis in 10-25% patients.

  6. Other complications in untreated patients:

    • Growth retardation and delayed puberty common.

    • Severe sensorineural hearing loss in >70% requiring close follow up and yearly audiologic evaluations.

    • Significant eye involvement requiring frequent monitoring in >50%.

    • CNS manifestations in 90%, including chronic aseptic meningitis, papilledema and developmental delay.

    • Difficult to control arthritis or epiphyseal overgrowth arthropathy in majority of patients.

See Table III.

Table III.

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, lymphadenopathy Adverse reactions Relieve fever, rash; improve adenopathy, arthritis; lessen organ involvement, serositis
Infliximab Chronic arthritis, fever and inflammation not controlled by IL-1 blockade, chronic uveitis Adverse reactions Controls fever, arthritis, aphthous stomatitis, uveitis; improves inflammatory markers
Anakinra Approved treatment for CAPS; fever, urticaria, rash, arthritis, elevated ESR/CRP Adverse reactions; triggers flare of inflammation; no longlasting disease control off treatment Remits fever, rash, arthritis and laboratory abnormalities in NOMID; lower SAA; reduces 2° amyloidosis and other complications
Rilonacept Approved treatment for CAPS; fever, rash, arthritis, laboratory abnormalities Adverse reactions Remits fever, rash, arthritis and laboratory abnormalities in many patients
Canakinumab Approved treatment for CAPS; fever, rash, arthritis, laboratory abnormalities Adverse reactions Remits fever, rash, arthritis and laboratory abnormalities in many patients; normalize SAA; reduces 2° amyloidosis & other longterm complications

What causes NOMID and how frequent is it?

  • Detailed epidemiology:

    • Reported mostly in Europe and North America; data from other areas limited.

    • Incidence: rare.

    • Less likely than FCAS or MWS to be familial.

  • What is known about the genetics?

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

    • 30-50% of NOMID lack identifiable NLRP3 mutations.

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

  • NLRP3 is required for assembly of an intracellular multi-protein complex or "inflammasome" in phagocytic cells that links initial sensing of danger from microbial products and metabolic stress to activation of the innate immune system via production of the alarm cytokine IL-1beta.

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

    • Inflammasome activation and consequently caspase-1 activation are essential for release of bioactive IL-1beta and initiation of inflammation.

    • Gain-of-function mutations in NLRP3 lead to constitutive inflammasome activation and excessive IL-1beta secretion, resulting in uncontrolled inflammation and tissue injury.

    • Considered an "intrinsic inflammasomopathy."

Other clinical manifestations that might help with diagnosis and management

Secondary amyloidosis:

  1. Medical management is focused on prevention of complications and 2° amyloidosis.

  2. Amyloid deposition 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.

    • Rectal or renal biopsy will confirm diagnosis.

  3. Amyloidosis in GI tract presents as diarrhea and malabsorption.

  4. Amyloid depositoin also in liver, spleen, thyroid, and nervous system.

  5. Cardiac involvement from 2° amyloidosis due to chronic inflammation rare, unlike other types of amyloidosis.

  6. Colchicine does not prevent renal amyloidosis in NOMID.

  7. IL-1 blockade may prevent amyloidosis, but long term data lacking.

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

  1. Many serious complications that affect quality of life including:

    • Epiphyseal overgrowth arthropathy with progressive joint contractures.

    • Developmental delay.

    • Progressive profound sensorineural hearing loss.

    • CNS manifestations, including chronic aseptic meningitis, increased intracranial pressure, seizures.

    • Chronic uveitis and vision loss.

    • Short stature.

  2. 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 NOMID be prevented?

  1. No known prevention.

  2. Genetic counseling important if suspected.

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

What is the evidence?

PFS:

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.

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

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

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

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 March. 2011.

NOMID:

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 pf 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.

Neven, B, Marvillet, I, Terrada, C, Ferster, A, Boddaert, N, Couloignier, V. "Long-Term Efficacy of the Interleukin-1 Receptor Antagonist Anakinra in Ten Patients with Neonatal-Onset Multisystem Inflammatory Disease/Chronic Infantile Neurologic, Cutaneous, Articular Syndrome". Arthritis Rheum. vol. 62. 2010. pp. 258.

Ongoing controversies regarding etiology, diagnosis, treatment

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

  2. Pharmacological options for management of NOMID.

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