Pediatrics

Hereditary Pediatric Fever Syndromes

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OVERVIEW: What every practitioner needs to know

Are you sure your patient has a hereditary periodic fever syndrome? What are the typical findings for this disease?

Hereditary periodic fever (PFS) syndromesare rare defects of innate immunity characterized by inappropriate, uncontrolled and often spontaneous inflammation in the absence of autoimmunity or infection.

The most common findings include the following:

  1. Lifelong recurrent episodes of fever and systemic illness.

  2. The attacks are characterized by fever ≥ 38°C and at least 2 associated symptoms:

    • Chest pain

    • Abdominal pain or other gastrointestinal manifestations

    • Arthralgias or arthritis

    • Lymphadenopathy

    • Splenomegaly

    • Rashes

  3. Attacks of fever and inflammation lasts for days to weeks and are separated by intervals of good health for weeks to months.

  4. Between febrile attacks, symptoms and acute phase response often improve, but may be chronic. In individual patients, the fever pattern becomes predictable with similar associated symptoms and illness course.

  5. The symptom complex results from uprovoked ongoing systemic inflammation in the absence of clinical infection or evidence for autoimmunity.

Other findings include:

  1. PFS may present in infancy, but may also be delayed until adolescence or adulthood.

  2. Genotyping is now use to confirm diagnosis, guide treatment decision and for long term prognosis.

  3. There is an increased risk of disease and secondary (2°) amyloidosis in certain ethnicities.

Clinical parameters most predictive of inherited PFS:

  1. Young age (< 2 yr) at onset of symptoms

    • Family history of periodic fever

    • Chest pain

    • Abdominal pain

    • Diarrhea

    • Oral aphthae

Classification of Hereditary Periodic Fever Syndromes

  1. Familial Mediterranean Fever (FMF)

  2. Hyper-immunoglobulinemia D with periodic fever syndrome (HIDS)

  3. Tumor necrosis factor (TNF) receptor 1 associated periodic syndrome (TRAPS)

Cryopyrin-associated periodic syndromes (CAPS):

  • Muckle-Wells syndrome (MWS)

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

  • Familial cold autoinflammatory syndrome (FCAS)

Table I. Clinical Features of Hereditary Pediatric Fever Syndromes

Table I.

FMF TRAPS HIDS FCAS NOMID MWS
Age at Onset <20 yr <1-50 yr;avg 3 yr <1 yr;avg 6 mo <6 mo variable <6 mo
Attack Duration 1-3 d 1-6 wk 3-7 d 12-24 hr chronic with flares 1-3 d to chronic
Attack Frequency 3-8 wk 1-3 mo 4-8 wk <1 d chronic with flares 1 mo-chronic
Triggers - - vaccines cold - -
Ethnic/geographic Arab, Turkish, Armenian, Jewish, Italians Irish, Scottish Dutch, French, European European European European
Target Organs Skin, joints, peritoneum, pleura Skin, eyes, joints, pleura, peritoneum Skin, eyes, joints, lymph nodes, serosa Skin, eyes, joints Skin, brain, eyes, ears, joints, bones Skin, eyes, ears, joints
Amyloidosis <20% on colchicine 10-25% <3% <5% 10-25% 25%

Inheritance Pattern of Hereditary Periodic Fever Syndromes

Autosomal Dominant

  1. TRAPS

  2. CAPS: FCAS, MWS, NOMID

Autosomal Recessive

  1. FMF

  2. HIDS

What other diseases/conditions share some of these symptoms?

  1. Cyclic neutropenia

  2. Fever of unknown origin

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

  4. HIV/AIDS

  5. Tuberculosis, CMV, brucellosis, rat-bite fever, relapsing fever or other chronic viral, bacterial or parasitic infections, Systemic lupus erythematosus, relapsing polychondritis

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

  7. Takayasu's arteritis

  8. Other systemic autoinflammatory diseases

  9. HLA B27-associated juvenile spondyloarthropathies

  10. Sarcoidosis

  11. Malignancies, including leukemia and lymphoma

  12. Autoimmune lymphoproliferative syndrome (ALPS)

  13. Acute intermittent porphyria

  14. Surgical emergencies, including appendicitis, intussusception

  15. Relapsing pancreatitis

Systemic autoinflammatory syndromes that mimic hereditary periodic fever syndromes:

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

  2. Behcet's disease

  3. Crohn's disease

  4. Macrophage activation syndrome

  5. Pyogenic sterile arthritis, pyoderma gangrenosum and acne (PAPA)

  6. Pediatric granulomatous arthritis (PGA) or Blau syndrome (chronic granulomatous synovitis with uveitis and cranial neuropathy)

  7. Hereditary or acquired angioedema

  8. Gout

  9. Autoimmune bone diseases: CRMO (chronic recurrent multifocal osteomyelitis), SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis)

What caused this disease to develop at this time?

Triggers may include cold, heat, stress, surgery, concurrent infection, pregnancy, vaccines. In many cases, no specific trigger is identified.

These conditions are the result of single gene defects for proteins involved in control of inflammatory, cytokine and cell death pathways mediating the innate immune response.

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

Additional laboratory studies that may be helpful in confirming diagnosis

  • CMV, EBV, Brucella IgM & IgG

  • CMV, EBV DNA PCR

  • ANA panel, ANCAs

  • ACE (angiotensin converting enzyme)

  • C3, C4, C1 inhibitor activity

  • HLA typing (specifically for HLA B27, B51)

  • Serum IgD

  • Analysis of synovial fluid for cell count, crystals and culture

  • 24 hr urine collection for protein and creatinine clearance

  • Renal or rectal biopsy and staining for amyloid deposition

  • Genotyping for FMF, HIDS, TRAPS, CAPS, PAPA

Interpretation of Laboratory Tests

  • Marked leukocytosis with left shift in association with ESR >80 and CRP >80 suggest infection.

  • Positive IgM serologies, PCR or cultures suggest infection.

  • Elevated ACE suggests sarcoidosis.

  • Positive PPD suggests tuberculosis.

  • Elevated uric acid especially if there is associated leukocytosis or thrombocytopenia suggests leukemia.

  • ANA ≥1:320, positive lupus serologies or ANCA suggests possible systemic autoimmune disease.

  • Hypogammaglobulinemia suggests infection secondary to a primary immunodeficiency.

  • Hypergammaglobulinemia suggests HIV or systemic autoimmune disease.

  • Suspect HIDS if elevated serum IgD with or without elevated IgA and normal IgG and IgM.

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

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

  • Abdominal x-ray or ultrasound 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.

  • Chest, abdomen, pelvis computed tomography (CT) to evaluate lymphadenopathy, inflammatory or interstitial lung disease.

  • Bone gallium scan to evaluate bone pain for infection, osteitis.

  • Magnetic resonance imaging (MRI) with and without contrast of specific joints to evaluate arthritis.

  • Neck, chest, abdomen, pelvis MR angiogram for evaluation of carotid or abdominal bruits or asymmetric peripheral pulses.

  • Head MRI with and without contrast to evaluate CNS vasculitis, hearing loss.

Confirming the diagnosis

  1. IF documented recurrent episodes of fever ≥38’C.

  2. FOR at least 4-12 months:

  3. WITHOUT concurrent infectious symptoms,

  4. ASK 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 (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

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

If you are able to confirm that the patient has an inherited periodic fever syndrome, what treatment should be initiated?

  • Are there some therapies that should be instituted immediately?

Table II. Therapies for Initial or Acute Management of Hereditary Pediatric Fever Syndromes

Table II.

Therapies for Initial or Acute Management of Hereditary Pediatric Fever Syndromes
FMF IVFs or supportive therapy
TRAPS NSAIDS alonePrednisone 0.5-2 mg/kg/day for severe symptoms; taper and discontinue as improve         ORMethylprednisolone 30 mg/kg (max 1 g) IV q.24 hr times 3, then prednisone
HIDS Avoid unnecessary surgeryNSAIDSPrednisone 0.5-2 mg/kg/day times 3-7 days for severe symptoms; taper and discontinue as improve (often without benefit)
NOMID NSAIDSRilonacept 4.4 mg/kg (max 320 mg) SQ on day 1, then 2.2 mg/kg (max 160 mg) SQ q. wk ORAnakinra 1-2 mg/kg (max 100 mg) SQ dailyPrednisone 0.5-2 mg/kg/day for severe symptoms; taper and discontinue as improve
FCAS Cold avoidance
MWS Prednisone 0.5-2 mg/kg/day for severe symptoms; taper and discontinue as improve
  • What about longer term treatment? (see Table III)

Table III.

FMF     1. Colchicine 1 mg daily if symptoms are severe or patient is known to carry a M694V mutation.     2. Dose may be increased until remission achieved (usually no more than 1.8 mg/day is needed).     3. Smaller dose (0.3-0.6 mg) sometimes prescribed for children < 5 yr.         •May be sufficient to prevent attacks, but may or may not prevent renal amyloidosis.     3. There is controversy regarding risk versus benefit of chronic colchicine use if MEFV mutations identified by genotyping are considered:         •  Standard treatment is chronic daily colchicine regardless of MEFV mutation.         •  Alternatively, management depends on genotyping since amyloidosis is associated with particular MEFV mutations:             1. Patients homozygous for M694V mutation or compound heterozygous for M694V and another disease-causing mutation (V726A-E148Q) should start chronic daily colchicine as soon as diagnosis is confirmed.             2. Patients homozygous for V726A-E148Q or compound heterozygous for V726A-E148Q and another non-M694V disease-causing mutation should receive colchicine at onset of attacks and not chronic colchicine unless attacks severe and/or develop amyloidosis.             3. Patients without M694V or V726A-E148Q mutations and mild clinical symptoms many not need colchicine unless attacks severe or has amyloidosis.         •  Treatment with colchicine should not be excluded in individuals with typical clinical symptoms who lack an identifiable MEFV mutation.
TRAPS NSAIDS alone for mild symptomsPrednisone 0.25-2 mg/kg/day for chronic symptomsEtanercept 0.4 mg/kg (max 25 mg) SQ b.i.w. - t.i.w. OR 0.8 mg/kg (max ;75 mg) SQ q. wk for severe symptoms
HIDS NSAIDSPrednisone 0.25-2 mg/kg/day for chronic symptoms or bursts as needed (often no benefit)consider Anakinra 2 mg/kg (max 100 mg) SQ daily at symptom onset as needed
NOMID Rilonacept 4.4 mg/kg (max 320 mg) SQ on day 1, then 2.2 mg/kg (max 160) mg SQ q. wkORCanakinumab 150 mg SQ q.8 wk (>4y&>40 kg); 2-3 mg/kg (max 150 mg) SQ q.8 wk (<40 kg)ORAnakinra 1-6 mg/kg (max 300 mg) SQ daily
FCAS Cold avoidanceNSAIDS alone if minimal symptomsRilonacept 4.4 mg/kg (max 320 mg) SQ on day 1, then 2.2 mg/kg (max 160) mg SQ q. wkORCanakinumab 150 mg SQ q.8 wk (>4 y&>40 kg); 2-3 mg/kg (max 150 mg) SQ q.8 wk (<40 kg)ORAnakinra 0.5-1.5 mg/kg (max 100 mg) SQ daily
MWS Rilonacept 4.4 mg/kg (max 320 mg) SQ on day 1, then 2.2 mg/kg (max 160 mg) SQ q. wk ORCanakinumab 150 mg SQ q.8 wk (>4 y&>40 kg); 2-3 mg/kg (max 150 mg) SQ q.8 wk (<40 kg)ORAnakinra 1-3.5 mg/kg (max 300 mg) SQ daily (case report of successful use at 10 m/kg/day)
  • What about alternative treatments if standard therapy fails? (see Table IV)

Table IV.

Alternative Therapies for Management of Hereditary Pediatric Fever Syndromes
FMF Anakinra 1-2 mg/kg (max 100 mg) SQ daily ORCanakinumab 150 mg SQ q.8 wk (>4 y&>40 kg); 2-3 mg/kg (max 150 mg) SQ q.8 wk (<40 kg)Thalidomide 100-300 m g daily
TRAPS Anakinra 1-2 mg/kg (max 100 mg) SQ dailyORTocilizumab 4-12 mg/kg IV q.2-4 wk
HIDS Etanercept 0.4 mg/kg (max 25 mg) SQ b. i. w. - t.i.w. OR 0.8 mg/kg (max 75 mg) SQ wkORAnakinra 2 mg/kg (max 100 mg) SQ daily as prophylaxisORInfliximab 3-7.5 mg/kg IV q.4-8 wkconsider simvastatin 10-20 mg (max 80 mg) dailyconsider colchicine 0.3-1.2 mg dailyconsider azathioprine 1-2 mg/kg/dayconsider cyclosporine 3 mg/kg/day
NOMID Infliximab 5-10 mg/kg IV q.4-8 wkconsider thalidomide 100-300 mg daily
FCAS Infliximab 3-7.5 mg/kg IV q.4-8 wk
MWS Infliximab 3-10 mg/kg

Table V. Dosing Considerations for Alternative Therapies for Hereditary Pediatric Fever Syndromes

Table V.

Dosing Considerations for Alternative Therapies for Hereditary Pediatric Fever Syndromes
Rilonacept 4.4 mg/kg (max 320 mg) SQ on day 1, then 2.2 mg/kg (max 160) mg SQ q. wkORCanakinumab 150 mg SQ q.8 wk (>4 y&>40 kg); 2-3 mg/kg (max 150 mg) SQ q.8 wk (<40 kg)ORAnakinra 0.5-1.5 mg/kg (max 100 mg) SQ daily Anakinra is a recombinant IL-1 receptor antagonist (IL-1Ra) and a competitive inhibitor of IL-1. Rilonacept (IL-1 TRAP) blocks IL-1 signaling by acting as a soluble decoy receptor to bind IL-1 and prevent its interaction with cell surface IL-1 receptors. Canakinumab is a monoclonal antibody to IL-1 and prevents its binding to the IL-1 receptor.Anakinra and rilonacept are given as frequent SQ injections and canakinumab administered intravenously. Cost, dosing schedule and patient age affect choice of drug for treatment of CAPS.

What are the adverse effects associated with each treatment option?

Table VI. Adverse effects of Therapies for Hereditary Pediatric Fever Syndromes

Table VI.

Adverse effects of Therapies for Hereditary Pediatric Fever Syndromes
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
Colchicine Nausea, vomiting, diarrhea, abdominal pain, anorexia, peripheral neuropathy, muscle weakness, rhabdomyolysis, renal/liver toxicity, rash
Etanercept Infection, injection site reaction, CNS/demyelinating disorder, ANA positivity, malignancy (very low risk)
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, future malignancy
Canakinumab Infection, injection site reaction, diarrhea, nausea, vertigo, weight gain, myalgias, headache, future malignancy
Tocilizumab Infection, thrombocytopenia, allergic reaction, anaphylaxis, CNS/demyelinating disorder, GI perforation, elevated LFTs, hyperlipidemia, future malignancy
Azathioprine Infection, leukopenia, pancytopenia with low thiopurine S-methyl transferase (TPMT) activity, liver toxicity, nausea, vomiting, secondary malignancy
Simvastatin Constipation, dyspepsia, rhabdomyolysis, hepatitis, acute renal failure
Thalidomide Infection, peripheral neuropathy, somnolence, teratogenicity, rash,dizziness, mood changes
Cyclosporine Infection, hypertension, renal toxicity, renal failure, hirsutism, GI upset, malignancy, CNS toxicity, gingival hyperplasia

What are the possible outcomes of inherited pediatric fever syndromes?

Significant morbidities and increased mortality seen in some untreated patients with certain types of inherited PFS.

Cryopyrin-Associated Periodic Syndromes (CAPS)

  1. Although due to mutations in a single gene, phenotypes and complications differ, but may overlap.

  2. All have characteristic urticarial rash, but fever may or may not be present.

  3. Greatest disease severity: NOMID >> MWS > FCAS.

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

FCAS

  1. Diagnosis at birth or in first 6 months with acute onset of urticarial rash and fever triggered by cold exposure.

  2. Cold-induced attacks of urticaria and fevers < 24 hr.

  3. Chronic symptoms even without cold exposure:

    • Daily fatigue

    • Headache

    • Myalgias.

  4. No long term complications except 2° amyloidosis in < 5% patients.

  5. Normal lifespan.

MWS

  1. Age of onset variable, but often < 6 months and not always with cold trigger.

  2. Unpredictable acute febrile attacks usually for < 3 days, but some symptoms may persist for weeks.

  3. ESR, CRP and white blood count increase during fever and may or may not normalize completely inbetween attacks.

  4. Since fever pattern less predictable than in FCAS, diagnosis often delayed until hearing loss noted in adolescence.

  5. Originally described as triad of urticaria, deafness and amyloidosis, but only 25% patients develop 2° amyloidosis.

  6. Conjunctivitis and progressive sensioneural hearing loss are pathognomonic.

  7. Symptoms other than fever include:

    • Conjunctivitis, episcleritis.

    • Arthralgias more than chronic arthritis.

    • Myalgia.

    • Abdominal pain.

    • Recurrent headaches.

    • Recurrent oral aphthae.

    • Significant chronic fatigue affecting quality of life.

  8. Morbidities include:

    • Progressive profound sensioneural hearing loss in 70%.

    • Uveitis rarely.

    • Amyloidosis.

NOMID

  1. Urticaria without fever often present at birth or in newborn period.

  2. Prematurity or small for gestational age in 30%.

  3. Rash and illness are continuous with flares; fever often not present.

  4. Inflammatory markers are chronically elevated.

  5. Diagnosis may be delayed until epiphyseal overgrowh arthropathy or CNS disease is observed.

  6. Serious complications, poor prognosis and shortened lifespan seen in patients not on IL-1 inhibitors.

  7. 2° amyloidosis in 10-25% patients.

  8. Early diagnosis and treatment with IL-1 blockade improves quality of life.

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

  • Early growth retardation, delayed puberty.

  • Skull abnormalities, frontal bossing.

  • Progressive profound sensioneural hearing loss from early childhood in >70%.

  • Chronic aseptic meningitis in 90%, often with chronic headache, papilledema, increased intracranial pressure.

  • Mild arthritis in 65%, but 30% develop early severe chronic joint inflammation with characteristic epiphyseal overgrowth, especially of patellae, with progressive joint contracures and limited mobility.

  • Progressive cognitive impairment.

  • Chronic intraocular inflammation in 50% patients manifested by treatment resistant anterior/posterior uveitis, optic atrophy, severe vision loss in >25%, and blindness.

Hyperimmunoglobulinemia D with Periodic Fever Syndrome (HIDS)

  1. Attacks begin in 1st yr of life; median age at initial attack: 6 mo.

  2. Attacks characterized by high spiking fever ≥38.5°C for 3-7 days every 4-8 wk.

  3. Prominent cervical lymphadenopathy and splenomegaly distinct from other PFS.

  4. Diagnosis often delayed unless family history of HIDS.

  5. Suspect diagnosis if increased urinary mevalonic acid excretion and elevated serum IgD (>100 IU/ml).

  6. >70% patients also have elevated IgA.

  7. 20-25% patients, usually < 5 yr of age, have normal serum IgD and IgA.

  8. Normal lifespan with few serious complications other than 2° amyloidosis in < 3% patients.

  9. Unlike FMF, colchicine does not improve symptoms or amyloid nephropathy.

  10. Clinical symptoms include:

    • Sustained high fevers.

    • Pronounced cervical lymphadenopathy.

    • Bouts of severe abdominal pain resulting in unnecessary exploratory laparotomy or appendectomy.

    • Non-destructive recurrent arthritis.

    • Splenomegaly.

    • Chronic rashes.

    • Subset develop neurological problems similar to mevalonic aciduria.

  11. Unlikely diagnosis if age at onset of fever > 5 yr, fevers > 14 days, no joint symptoms.

Familial Mediterranean Fever (FMF)

  1. Initial attack often in early childhood; 80% are < 20 yr of age at onset of symptoms.

  2. Cardinal feature is recurrent attacks of fever and serositis, usually of peritoneum or pleura.

  3. Febrile attacks last 1-3 days and recur on average every 3-8 wk.

  4. Asymptomatic between attacks, but leukocytosis, elevated ESR and CRP, and increased serum amyloid A (SAA) may persist.

  5. Major cause of mortality is 2° amyloidosis leading to renal failure:

    • Before colchicine: 2° amyloidosis occurred in 60-75% patients > 40 yr of age.

    • Country of origin (Turkey, Armenia, Arab nations) and M694V mutation in MEFV gene associated with increased amyloidosis risk.

    • Some patients have amyloidosis as first clinical manifestation of FMF.

  6. Daily colchicine prevents amyloid-related nephropathy in most patients.

  7. On colchicine, 95% improve, 70% remit, 10-15% develop 2° amyloidosis.

  8. Diagnosis may be confirmed in symptomatic persons without identifiable MEFV mutations if 6-month trial of daily colchicine remits attacks that recur after discontinuation of colchicine.

  9. Diagnosis should not be excluded based solely on genetic testing if characteristic clinical features are present.

  10. Complications/morbidities include:

    • Recurrent peritonitis in 90%, leading to unnecessary abdominal surgery, infertility, bowel obstruction.

    • Recurrent pleuritis in 45%; pericarditis rare.

    • Mono- or oligo- arthritis in 75%.

    • Orchitis.

    • Recurrent aseptic meningitis.

    • Erysipelas-like erythema; uncommon.

  11. Diagnosis in children requires ≥2 of 5 criteria:

    • Recurrent fever.

    • Abdominal pain.

    • Chest pain.

    • Arthritis.

    • Family history of FMF.

Most common inherited periodic fever syndrome.

  1. Predominantly affects people of Mediterranean origin.

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

  3. Due to mutations in MEFV gene encoding pyrin, a protein critical to initiation of the innate immune response.

  4. Genotyping used to confirm diagnosis, but also helpful for treatment decisions and assessment of long term prognosis.

  5. Diagnosis may be confirmed in symptomatic persons without identifiable MEFV mutations if 6-month trial of daily colchicine remits attacks that recur after discontinuation of colchicine.

  6. Diagnosis should not be excluded based solely on genetic testing for MEFVmutations if characteristic clinical features are noted.

  • Major cause of mortality is renal amyloidosis.

  • Normal lifespan without amyloidosis.

  • Before colchicine, 2° amyloidosis occurred in 60-75% patients > 40 yr of age.

  • M694V mutation is associated with a severe phenotype and strongly affects prognosis:

    • Early age of disease onset

    • High frequency of arthritis and rash

    • Increased amyloidosis.

  • Daily colchicine prevents amyloid-related nephropathy in most patients:

    • On colchicine, 95% improve, 70% remit, 10-15% develop 2° amyloidosis.

Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS)

  1. Age at initial presentation highly variable: < 1 to > 50 yr; median age of onset: 3 yr.

  2. Unpredictable febrile attacks lasting 1-6 wk.

  3. Usually normal lifespan.

  4. Associated symptoms:

    • Monoarticular arthritis or arthralgias.

    • Tender migratory erythematous rash.

    • Migratory myalgias.

    • Conjunctivitis, periorbital edema.

    • Headache.

    • Abdominal pain.

    • Diarrhea or constipation.

    • Lymphadenopathy.

    • Pleuritis.

  5. Earlier mortality due to 2° amyloidosis in 10-25% patients; no colchicine benefit.

Pyogenic Sterile Arthritis, Pyodema Gangrenosum and Acne (PAPA)

  1. First clinical manifestation is usually recurrent flares of arthritis with low grade fever and often severe acne.

  2. Age at onset: between 1-16 yr of age.

  3. Trauma is common trigger for flares of arthritis lasting >1-2 wk.

  4. Characterized by recurrent destructive arthritis and muscle and skin inflammation.

  5. Arthritis does not resolve spontaneously and requires treatment with steroids or biologics for resolution.

  6. Symptoms and morbidities include:

    • Severe cystic acne in adolescence.

    • Pyoderma gangrenosum triggered by skin trauma.

    • Cutaneous sterile abscesses at injection sites.

    • Pathergy.

    • Adult-onset insulin-dependent diabete mellitus.

    • Proteinuria.

Pediatric Granulomatous Arthritis (PGA)

  1. Disease spectrum includes Blau syndrome (chronic granulomatous synovitis with uveitis and cranial neuropathy) and early onset sarcoidosis.

  2. Average age at presentation: 30 months; range: 3 months to 18 years; 80% < 4 years of age.

  3. Classic presentation is triad of rash, arthritis and chronic granulomatous uveitis.

  4. Ichthyosiform rash is first sign of disease in >85% patients.

  5. Clinical symptoms and complications include:

    • Non-caseating granulomas on skin and lymph node biopsy.

    • Erosive polyarticular arthritis with joint destruction in 90%.

    • Bilateral chronic granulomatous uveitis with vision loss in 40-65%,

    • Cranial neuropathies.

    • Lymphadenopathy.

    • Camptodactyly.

    • Cardiomyopathy, uncommon.

    • Large vessel vasculitis.

    • Nephritis.

    • Interstitial lung disease.

Table VII. Risks/benefits of available treatment options

Table VII.

Drug Indication Risks Benefits
NSAIDS Arthritis; pain, fever Adverse reactions Reduce fever, pain, arthritis
Corticosteroids Fever, arthritis, serositis, urticaria, vasculitis, lymphadenopathy, organ inflammation/damage Adverse reactions Relieve fever, rash; improve adenopathy, arthritis; lessen organ invovement, serositis
Colchicine Treatment of FMF; fever, aphthous stomatitis, 2°amyloidosis in FMF Adverse reactions Prevents attacks in >70% and decreases attacks in 95% of FMF (no effect in TRAPS, HIDS, CAPS); lowers SAA in FMF; prevents 2°amyloidosis in most FMF; reduces fever, oral aphthae.
Etanercept Treatment for TRAPS; arthritis, aphthous stomatitis, fever, 2°amyloidosis and other complications Adverse reactions; may trigger flares of TRAPS and MAS Controls fever, arthritis, aphthous stomatitis; improve inflammatory markers; lowers SAA; reduces 2°amyloidosis and other complications in TRAPS
Infliximab Chronic arthritis, fever and inflammation not controlled by etanercept, chronic uveitis, macrophage activation syndrome (MAS) Adverse reactions; triggers paradoxical flares of TRAPS Controls fever, arthritis, aphthous stomatitis, uveitis; improves inflammatory markers; improves MAS
Anakinra Treatment of CAPS; fever, urticaria, rash, arthritis, elevated ESR/CRP; MAS and some FMF, HIDS and TRAPS unresponsive to conventional therapy Adverse reactions; triggers flare of inflammation; no longlasting disease control off treatment Remits fever, rash, arthritis and laboratory abnomalities in FCAS, MWS (less effective in NOMID) and some FMF, HIDS, TRAPS; lowers SAA; reduces 2° amyloidosis and other complications in CAPS; remits MAS.
Rilonacept Treatment of CAPS; fever, rash, arthritis, laboratory abnormalities Adverse reactions Remits fever, rash, arthritis andlaboratory abnomalities in many CAPS patients
Canakinumab Treatment of CAPS and colchicine-resistant FMF; fever, rash, arthritis, laboratory abnormalities Adverse reactions Full remission in > 95% CAPS patients; normalizes SAA; reduces 2° amyloidosis and other longterm complications in CAPS
Tocilizumab Treatment of TRAPS unresponsive to etanercept or anakinra; arthritis, elevated ESR/CRP Adverse reactions Normalizes CRP, ESR and SAA ; effect on 2° amyloidosis unknown
Azathioprine HIDS resistant to standard therapy Adverse reactions May reduce HIDS symptoms in a few patients
Cyclosporine HIDS resistant to standard therapy Adverse reactions May reduce HIDS symptoms andepisodes in a few patients
Thalidomide Treatment of NOMID, TRAPS, FMF resistant to standard therapy; arthritis, aphthous stomatitis Adverse reactions Reduces ESR, CRP; reduce inflammation in PGA
Simvastatin HIDS resistant to standard therapy Adverse reactions; may tigger flares of HIDS May reduce HIDS episodes in a few patients

What causes this disease and how frequent is it?

Epidemiology

  • FMF:

    • Most common inherited PFS.

    • Predominantly affects people living in the Mediterranean region.

    • Incidence: 1-3/105 in Turkey, Armenia, North Africa, Arab countries, and Italy; rare elsewhere.

    • Clinical symptoms and range/frequency of individual mutations in Arabs distinctly different from other ethnicities and vary by country of birth.

    • Mutation frequency: 1:3 - 1:7 in North African and Iraqi Jews, Armenians and Turks who have severe disease and increased amyloidosis.

    • Mutation frequency: 1:5 in Ashkenazi Jews, but prevalence of disease lower since most common mutation is associated with mild disease.

    • Slight male predominance (13:10).

  • TRAPS:

    • Incidence: rare (5-6/107 person-yr in Germans).

    • Many of Scottish or Irish ancestry; as a result, initially called Familial Hybernian Fever.

    • Affects males and females equally.

  • HIDS:

    • Incidence: Very rare (<200 worldwide).

    • Mutation frequency: 1:350 in Netherlands and founder effect.

    • >60% of Dutch or French ancestry, otherwise from western Europe.

    • Affects males and females equally.

  • FCAS:

    • Many of European ancestry.

    • Incidence: rare, usually familial.

  • MWS:

    • Many of European ancestry.

    • Incidence: rare, usually familial.

  • NOMID:

    • Many of European ancestry.

    • Incidence: rare.

  • PAPA:

    • No racial or ethnic predilection.

    • Only three affected families have been described.

  • PGA:

    • No racial or ethnic predilection.

    • Very rare.

    • Affects males and females equally.

Genetics

  • FMF:

    • Homozygous or compound heterozygous mutations (~80) in the MEFV gene encoding pyrin/marenostrin; expressed in neutrophils, eosinophils, monocytes, dendritic cells and fibroblasts.

    • Most mutations in exon 10 and decrease function.

    • 30% of symptomatic patients, including obligate carriers, have only one identifiable MEFV mutation.

    • M694V mutation most common, confers highest disease severity and risk of amyloidosis, and predominates in North African Jews due to a founder effect.

  • TRAPS:

    • Autosomal dominant mutations in the TNFRSF1A gene encoding the 55 kDa TNF receptor.

    • Mutations almost all affect extracellular domain of the TNF receptor with R92Q most common.

    • Many patients with clinical features of TRAPS do not have identified TNFRSF1A mutations:

      • identified mutations in 32-50% of familial cases.

      • only 2-10% of sporadic TRAPS have an identified mutation.

  • HIDS:

    • Homozygous or compound heterozygous mutations throughout the MVK gene encoding mevalonate kinase.

    • >25% patients with typical HIDS symptoms and elevated serum IgD lack MVK mutations.

    • V377I mutation accounts for >50% HIDS mutations, especially in patients of Dutch ancestry.

  • CAPS (FCAS, MWS, NOMID):

    • Autosomal dominant mutations in the NLRP3 (CIASI) gene encoding cryopyrin/NLRP3; highly expressed in neutrophils, monocytes and chrondrocytes.

    • 10% of FCAS, 25% of MWS and 30-50% of NOMID/CINCA lack identifiable NLRP3 mutations.

  • PAPA:

    • Autosomal dominant mutations in the PSTPIP1/CD2BP1 gene encoding PSTPIP1, which is highly expressed in neutrophils.

    • Four gain-of-function or missense mutations have been identified in multi-generational consanguineous families.

  • PGA:

    • Autosomal dominant mutations in the pathogen-sensing domain of the NOD2/CARD15 gene; highly expressed in monocytes and intestinal epithelium.

    • Familial mutations with variable penetrance in Blau syndrome; sporadic mutations in early-onset sarcoidosis.

    • R334Q and R334W most common of 12 mutations identified to date; E383K identified in severe Blau syndrome and in asymptomatic family members.

    • 50-90% of patients with arthritis, rash and chronic granulomatous uveitis have NOD2 mutations.

    • Subset of Crohn's disease patients have non-codon 334 NOD2 mutations.

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

The inflammasome and innate immunity:

  1. The hallmark of innate immuntiy is the rapid generation and release of proinflammaory cytokines, including IL-1beta, TNFalpha, and IL-6, in response to "danger signals" such as microbial products, toxins and metabolic stress.

  2. Il-1 beta is the pleiotrophic pyrogen and alarm cytokine and its activation triggers a cascade of events resulting in inflammation and production of other proinflammatory cytokines.

  3. Activation of the intracellular multi-protein complex called the "inflammasome" by danger signals in neutrophils, macrophages, dendritic and other cells is essential for release of bioactive IL-1 and initiation of inflammation.

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

  5. Inflammasome stimulation activates caspase-1, which converts IL-1beta to its bioactive form.

  6. Mutations in one or more of the proteins comprising the inflammasome and subsequent effects on IL-1 activity have been shown to cause inherited periodic fever syndromes.

In FMF:

  • Pyrin plays an intrinsic role in regulation of granulocyte and monocyte function during inflammation.

  • Pyrin interacts with ASC and disrupts NLRP3-ASC interaction, consequently inhibiting NF-kappaB activation and apoptosis.

  • Sequestration of ASC by pyrin also prevents caspase-1 activation, inhibiting inflammasome activation and production of bioactive IL-1beta.

  • Loss-of-function MEFV mutations decrease binding of pyrin to ASC, leading to inflammasome activation and increased IL-1 beta secretion.

  • FMF is considered an extrinsic "inflammasomopathy."

  • Colchicine inhibits neutrophil chemotaxis via microtubule depolymerization and reduces IL-1beta and other proinflammatory cytokine production through NF-kappaB inhibition.

The inflammasome and innate immunity:

  1. The hallmark of innate immuntiy is the rapid generation and release of proinflammaory cytokines, including IL-1beta, TNFalpha, IL-6, IFNalpha and IFNbeta, in response to "danger signals" such as microbial products, toxins and metabolic stress.

  2. Il-1 beta is the pleiotrophic pyrogen and alarm cytokine and its activation triggers a cascade of events resulting in inflammation and production of other proinflammatory cytokines.

  3. Activation of an intracellular multi-protein complex called the "inflammasome" by danger signals in neutrophils, macrophages, dendritic and other cells is essential for release of bioactive IL-1 and initiation of inflammation.

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

  5. Inflammasome stimulation activates caspase-1, which converts IL-1beta to its bioactive form.

  6. Mutations in one or more of the proteins comprising the inflammasome and subsequent effects on IL-1 activity have been shown to cause inherited PFS.

  • CAPS (FCAS, MWS, NOMID):

    • Gain-of-function mutations in NLRP3trigger inflammasome activation and enhanced caspase-1 function, resulting in overproduction of bioactive IL-1beta, uncontrolled inflammation and tissue injury.

    • Considered "intrinsic inflammasomopathies."

  • FMF:

    • Pyrin inhibits NF-kappaB activation to decrease IL-1beta and TNF production.

    • Pyrin regulates caspase-1 and may compete with NLPR3 and caspase-1 for binding to ASC, thereby inhibiting inflammasome activation and IL-1beta secretion.

    • Loss-of-function mutations decrease pyrin binding to ASC, leading to inflammasome activation and increased IL-1beta secretion.

    • Considered an "extrinsic inflammasomopathy."

    • Colchicine inhibits neutrophil chemotaxis via microtubule depolymerization and reduces proinflammatory (IL-1, TNF) cytokine production through inhibition of NF-kappaB activation.

  • HIDS:

    • Mevalonate kinase (MVK) is necessary for cholesterol synthesis.

    • Severe loss-of-function mutations cause mevalonic aciduria, an inborn error of metabolism associated with developmental delay and early death.

    • Less severe mutations (>60 identified) with 1-10% residual MVK activity cause HIDS.

    • Increased IL-1 beta production in HIDS may in part be due to loss of the inhibitory effects of isoprenoid metabolites on IL-1beta production.

    • Etiology of elevated serum IgD and recurrent fevers from decreased MVK activity not fully understood, but involves modulation of inflammasome activation.

  • TRAPS:

    • Cell surface and soluble TNF receptors bind TNF with opposing effects on TNF receptor signaling and TNF secretion during inflammatory responses.

    • Some mutations affect receptor shedding, permitting sustained membrane-bound TNF receptor stimulation and decreased availability of soluble TNF receptors (shed extracellular portions) to bind TNF and inhibit further signaling.

    • Most mutations affect TNR receptor folding and trafficking to the cell membrane, leading to intracellular accumulation of mutant receptors that spontaneously induce activation of several inflammatory pathways.

    • Other mutations decrease TNF binding to membrane bound receptors, inhibiting TNF-dependent apoptosis pathways involved in control of inflammation.

  • PAPA:

    • PSTPIP-1 co-localizes with pyrin in neutrophils.

    • Missense gain-of-function mutations in PSTPIP-1 increase avidity of binding to pyrin and reduce pyrin's inhibition of inflammasome activation, resulting in enhanced IL-1beta secretion.

  • PGA:

    • NOD2 is structurally similar to NLPR3 and functions as an intracellular sensor for microbial products.

    • NOD2 activation has pleiotrophic effects, including NF-kappaB activation.

    • Missense gain-of-function mutations in the regulatory domain of NOD2 lead to constitutive NF-kappaB activation, resulting in increased IL-1beta secretion.

Other clinical manifestations that might help with diagnosis and management

Secondary amyloidosis in hereditary PFS:

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

  2. Development of amyloidosis is highly variable among PFS, but always devastating.

  3. Amyloid deposition in kidneys in > 90% patients and usually presents as proteinuria without renal insufficiency.

  4. Renal failure due to amyloidosis may be first disease symptom.

  5. Median survival time: 24-53 months from time of diagnosis without treatment with colchicine or biologics.

  6. Amyloidosis in GI tract in 20% patients; presents as diarrhea and malabsorption.

  7. Amyloid deposition also occurs in liver, spleen, thyroid, and nervous system.

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

  9. Amyloidosis diagnosed by biopsy of kidney or rectum.

  10. SAA level may reflect active amyloid deposition.

  11. Serial SAA measurements may help guide therapy in FMF.

  12. Colchicine prevents renal amyloidosis in FMF, but not in HIDS or TRAPS.

  13. Renal failure due to amyloid-related nephropathy may be first clinical manifestation of FMF.

  14. SAA level may reflect active amyloid deposition and serial measurements may help guide therapy.

  15. Amyloid deposition in kidneys in > 90% untreated patients and usually presents as proteinuria without renal insufficiency.

  16. Proteinuria at presentation or with follow-up requires 24 hr urine collection for protein and creatinine clearance.

  17. Amyloidosis is confirmed by biopsy of kidney or rectum.

  18. Consider renal and/or rectal biopsy if >500 mg 24 hr urine protein or elevated BUN/creatinine for staging of renal involvement and presence of amyloid.

  19. Median survival time: 24-53 months from time of diagnosis without colchicine or biologic therapy.

  20. Amyloidosis in GI tract in 20% patients and presents as diarrhea and malabsorption.

  21. Amyloid also deposits in liver, spleen, thyroid, and nervous system.

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

Genotype: phenotype correlations affecting treatment decisions in FMF:

  1. Proteinuria at presentation or with follow-up requires 24 hr urine collection for protein and creatinine clearance.

  2. Consider renal and rectal biopsy if > 500 mg 24 hr urine protein or elevated BUN/creatinine for staging of renal involvement and presence of amyloid.

  3. Patients homozygous for M694V mutation or compound heterozygous for M694V and another disease-causing mutation should start chronic colchicine therapy as soon as diagnosis is confirmed by genotyping.

  4. Patients homozygous for E148Q or compound heterozygous for E148Q and another disease-causing mutation (not M694V) should be given chronic colchicine treatment if develop severe inflammation and/or proteinuria secondary to amylodosis.

  5. Patients without a M694V or a E148Q mutation and only mild clinical symptoms may not need continuous colchicine therapy unless develop severe inflammatory episodes or amyloidosis, which would be unlikely.

  6. Diagnosis and treatment with colchicine should not be excluded in individuals with typical clinical symptoms who lack an identiable MEFV mutation.

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

Most complications self-limited, but some do affect health and quality of life.

Treatment complications may be as common as from disease, including worsening inflammation, organ toxicity, infection and future malignancy.

Unnecessary abdominal surgery.

Infertility in women secondary to pelvic adhesions and defective ovulation.

Major cause of mortality is 2° amyloidosis leading to renal failure and early death unless renal transplantation is available.

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

Serum amyloid A protein (SAA).

Urine mevalonic acid level.

How can hereditary periodic fever syndromes be prevented?

No known prevention.

Genetic counseling important if inherited PFS are suspected.

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

What is the evidence?

Hereditary PFS:

Doherty, TA, Brydges, SD, Hoffman, HM. "Autoinflammation: translating mechanism to therapy". J Leuk Biol. vol. 90. 2011.

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.

TRAPS:

McDermott, MF, Aksentijevich, I, Galon, J, McDermott, EM, Ogunkolade, BW, Centola, M. "Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes". Cell. vol. 97. 1999. pp. 133.

Hull, KM, Drewe, E, Aksentijevick, I, Singh, HK, Wong, K, McDermott, EM. "The TNF receptor-Associated Periodic Syndrome (TRAPS)". Medicine (Baltimore). vol. 81. 2002. pp. 349.

Rezaei, N. "TNF-receptor-associated periodic syndrome (TRAPS): an autosomal dominant multisystem disorder". Clin Rheuamtol. vol. 25. 2006. pp. 773.

Vaitla, PM, Radford, PM, Tighe, PJ, Powell, RJ, McDermott, EM, Todd, I, Drewe, E. "Role of Interleukin-6 in a Patient With Tumor Necrosis factor Receptor-Associated Periodic Syndrome". Arthritis Rheum. vol. 63. 2011. pp. 1151.

Lainka, E, Neuforf, U, Lohse, P, Timmann, C, Stojanov, S, Huss, K, von Kries, R, Niehues, T. "Incidence of TNFRSF1A mutations in German children: epidemiological, clinical and genetic characteristics". Rheumatology. vol. 48. 2009. pp. 987.

FMF:

Goldfinger, SE. "Colchicine for familial Mediterranean fever". New Engl J Med. vol. 287. 1972. pp. 1302.

Samuels, J, Ozen, S. "Familial Mediterranean fever and the other autoinflammatory syndrome: evaluation of the patient with recurrent fever". Curr Opin Rheumatol. vol. 18. 2006. pp. 108.

Chae, JJ, Aksentijevich, I, Kastner, DL. "Advances in the understanding of familial Mediterranean fever and possibilities for targeted therapy". Br J Haematol. vol. 146. 2009. pp. 467.

Yalçinkaya, F, Ozen, S, Ozçakar, ZB, Aktay, N, Cakar, N, Düzova, A. "A new set of criteria for the diagnosis of familial Mediterranean fever in childhood". Rheumatology. vol. 48. 2009. pp. 395.

Ozen, S, Bilginer, Y, Ayaz, NA, Calguneri, M. "Anti-Interleukin 1 Treatment for Patients with Familial Mediterranean Fever Resistant to Colchicine". J Rheumatol. vol. 38. 2011. pp. 516.

HIDS:

van der Hilst, JC, Bodar, EJ, Barron, KS, Frenkel, J, Drenth, JP, van der Meer, JW, Simon, A. "Long-term follow-up, clinical features, and quality of life in a series of 103 patients with hyperimmunoglobulinemia D syndrome". Medicine. vol. 87. 2008. pp. 301.

van der Hilst, Frenkel, J. "Hyperimmunoglobulin D syndrome in childhood". Curr Rheumatol Rep. vol. 12. 2010. pp. 101.

Korppi, M, van Gijn, ME, Antila, K. "Hyperimmunoglobulinemia D and periodic fever syndrome in children. Review on therapy with biologic drugs and case report". Acta Pediatrica. vol. 100. 2011. pp. 21.

Haas, D, Hoffmann, GF. "Mevalonate knase deficiency and autoinflammatory disorders". N Engl J Med. vol. 357. 2007. pp. 1871.

CAPS:

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.

Kuemmerle-Deschner, JB, Tyrrell, PN, Koetter, I, Wittkoewski, 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.

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.

PAPA:

Schellevis, MA, Stoffels, M, Hoppenreijs, EPAH, Bodar, E, Simon, A, van der Meer, JWM. "Variable expression and treatment of PAPA syndrome". Ann Rheum Dis. Feb 16, 2011.

Lindor, NM, Arsenault, TM, Solomon, H, Seidman, CE, McEvoy, MT. "A new autosomal dominant disorder of pyogenic sterile arthritis, pyoderma gangrenosum, and acne: PAPA syndrome". Mayo Clin Proc. vol. 72. 1997. pp. 611.

Brenner, M, Ruzicka, T, Plewig, G, Thomas, P, Herzer, P. "Targeted treatment of pyoderma gangrenosum in PAPA (pyogenic arthritis, pyoderma gangrenosum, and acne) syndrome with the recombinant human interleukin-1 receptor antagonist anakinra". Br J Dermatol. vol. 161. 2009. pp. 1199.

PGA:

Blau, EB. "Familial granulomatous arthritis, iritis, and rash". J Pediatr. vol. 107. 1985. pp. 689.

Micelli-Richard, C, Lesage, S, Rybojad, M, Prieur, AM, MAnouvrier-Hanu, S, Hafner, R. "CARD15 mutations in Blau syndrome". Nat Genet. vol. 29. 2001. pp. 19.

Rose, CD, Arostegui, JI, Martin, TM, Espada, G, Scalzi, L, Yague, J. "NOD2-associated pediatric granulomatous arthritis: an expanding phenotype study of an international registry and a national cohort in Spain". Arthritis Rheum. vol. 60. 2009. pp. 1797.

Saulsbury, FT, Wouters, CH, Martin, TM, Austin, CR, Doyle, TM, Goodwin, KA, Rose, CD. "Incomplete Penetrance of the NOD2 E383K Substitution Among Members of a Pediatric Granulomatous Arthritis Pedigree". Arthritis Rheum. vol. 60. 2009. pp. 1804.

Kanazawa, N, Okatfuji, I, Kambe, N, Nishikomori, R, Nakata-Hizume, M, Nagai, S. "Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-kappaB activation: common genetic etiology with Blau syndrome". Blood. vol. 105. 2005. pp. 1195.

Yasui, K, Yashiro, M, Tsuge, M, Manki, A, Takemoto, K, Yamamoto, M, Morishima, T. "Thalidomide Dramatically Improves the Symptoms of Early-Onset Sarcoidosis/Blau syndrome: Its Possible Action and Mechanism". Arthritis Rheum. vol. 62. 2010. pp. 250.

Milman, N, Andersen, CB, Hansen, A, van Overrem Hansen, T, Nielsen, FC, Fledelius, H. "Favourable effect of TNF-alpha inhibitor (infliximab) on Blau syndrome in monozygotic twins with a de novo CARD15 mutation". APMIS. vol. 114. 2006. pp. 912.

Ongoing controversies regarding etiology, diagnosis, treatment

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

Use of colchicine for treatment or prophylaxis in FMF patients with one identified mutation (not M694V) or mild presentation.

Role of pharmacogenomics in management of periodic fever syndromes.

Consensus for treatment of HIDS since conventional immunosuppression rarely of benefit, most patients do well over time, and may not need chronic biologic therapy.

Pharmacologic options for management of CAPS given difficulty distinguishing between syndromes in some patients, and thus long term prognosis.

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