Pediatrics

Periodic Fever Syndromes

OVERVIEW: What every practitioner needs to know

Are you sure your patient has a periodic fever syndrome? What are the typical findings for these diseases?

Periodic fever syndromes (PFS) are a group of rare autoinflammatory diseases characterized by inappropriate, uncontrolled, and often spontaneous signs and symptoms of inflammation. Recurrent fever ≥ 38°C is the cardinal feature in each PFS. The recurrent febrile episodes occur in the absence of infection or evidence of active autoimmunity. Fevers in PFS are due to abnormalities in activation of the innate immune system.

Attacks of fever and inflammation may last for days to weeks separated by intervals of good health for weeks to months. The fever pattern (duration and periodicity) and clinical features are variable between syndromes and patients. Associated symptoms usually spontaneously resolve when the patient becomes afebrile. However, in severe cases of inherited disease, inflammation can be chronic with persistent symptoms and development of long-term complications.

The onset of symptoms is usually in infancy, but may be delayed until adolescence or later. For an individual patient, there is often a predictable fever pattern, a common constellation of associated symptoms and a similar course of the acute illness.

Most PFS are inherited and share the following features:

  1. Constellation of symptoms including fever pattern, associated symptoms, acute phase response, family history, and ethnicity suggest diagnosis which can be confirmed by genotyping.

  2. Significant long-term morbidities and increased mortality occurs in untreated patients.

  3. Increased risks of disease and secondary amyloidosis in certain ethnicities.

  4. Due to single gene defects encoding proteins involved in control of inflammatory, cytokine and apoptosis pathways mediating innate immune responses.

  5. Genotyping may guide treatment and long-term prognosis.

Classification of periodic fever syndromes

Hereditary PFS:

  • Familial Mediterranean fever (FMF)

  • Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS)

  • Tumor necrosis factor (TNF) receptor associated periodic syndrome (TRAPS)

  • Cryopyrin-associated periodic syndromes (CAPS):

    • Muckle-Wells syndrome (MWS)

    • Neonatal onset multisystem inflammatory disorder (NOMID) or chronic infantile neurologic cutaneous and articular syndrome (CINCA)

  • Familial cold autoinflammatory syndrome (FCAS)

Idiopathic PFS:

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

Inheritance pattern of hereditary periodic fever syndromes

Autosomal Dominant

  1. TNF receptor-associated periodic syndrome (TRAPS)

  2. Cryopyrin-associated periodic syndromes: NOMID/CINCA, MWS, FCAS

Autosomal Recessive

  1. Familial Mediterranean fever (FMF)

  2. Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS)

What other disease/condition shares some of these symptoms?

  1. Cyclic neutropenia

  2. Fever of unknown origin

  3. HIV/AIDS

  4. Tuberculosis, cytomegalovirus (CMV), brucellosis, rat-bite fever, relapsing fever or other chronic viral, bacterial or parasitic infections

  5. Systemic lupus erythematosus, relapsing polychondritis

  6. Anti-neutrophil cytoplasmic antibodies (ANCA)-mediated vasculitis, including Wegener's granulomatosis and microscopic polyangiitis

  7. Takayasu's arteritis

Other systemic autoinflammatory diseases

  1. HLA B27-associated juvenile spondyloarthropathies

  2. Sarcoidosis

  3. Malignancies, including leukemia and lymphoma

  4. Autoimmune lymphoproliferative syndrome (ALPS)

  5. Acute intermittent porphyria

  6. Surgical emergencies, including appendicitis, intussusception, testicular or ovarian torsion

  7. Relapsing pancreatitis

Other systemic autoinflammatory syndromes that mimic PFS

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

  2. Chronic granulomatous synovitis with uveitis and cranial neuropathy (Blau syndrome)

  3. Pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome

  4. Behçet's disease

  5. Crohn's disease

  6. Macrophage activation syndrome

  7. Hereditary or acquired angioedema

  8. Gout

  9. Autoinflammatory bone diseases:

    • CRMO (chronic recurrent multifocal osteomyelitis)

    • SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis)

    • Chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia (Majeed syndrome)

    • Deficiency of the IL-1 receptor antagonist (DIRA)

What caused this disease to develop at this time?

PFS are considered autoinflammatory, not autoimmune, diseases that may or may not have specific triggers. When present, triggers may include cold, heat, stress, surgery, concurrent infection, pregnancy, and vaccines.

The clinical manifestations of PFS are due to inappropriate activation and regulation of antigen-independent inflammation (innate immunity).

Most PFS are due to single gene defects encoding proteins in pathways involved in control of inflammation, cytokine production, or cell death.

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

Initial screening tests:

  • CBC, differential during fever and when symptom-free

  • ESR, CRP during fever and when symptom-free

  • Complete metabolic panel

  • Uric acid, lactate dehydrogenase (LD)

  • Ferritin, fibrinogen

  • Quantitative immunoglobulins (IgG, IgA, IgM)

  • Urinalysis

  • Blood, urine, throat cultures

  • PPD

Additional tests as needed:

  • IgD

  • Cytomegalovirus (CMV), Epstein-Barr virus (EBV), Brucella IgM and IgG

  • CMV, EBV DNA PCR

  • Antinuclear antibody (ANA) panel, anti-neutrophil cytoplasmic antibodies (ANCAs)

  • Angiotensin-converting enzyme (ACE)

  • C3, C4, C1 inhibitor activity

  • HLA typing (specifically for HLA B27, B51)

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

  • 24-hour urine collection for protein and creatinine clearance

  • Bone marrow aspirate and biopsy for histology, cytogenetics, cultures

Confirmatory tests:

  • Genotyping for FMF, HIDS, TRAPS, CAPS

  • Renal or rectal biopsy and staining for amyloid deposition

Interpretation of results:

  • 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 can be helpful when infection, inflammatory lung disease, or serositis (pleuritis, pericarditis) is suspected.

  • Abdominal x-rays or ultrasound may be indicated to evaluate abdominal pain, or help rule out peritonitis or a surgical emergency.

  • CT scan of the neck, chest, abdomen or pelvis may be needed to evaluate lymphadenopathy, inflammatory lung disease, serositis, or splenomegaly.

  • Echocardiogram is indicated to evaluate chest pain and rule out pericarditis.

  • Consider bone gallium scan to rule out osteomyelitis.

  • Consider joint MRI with and without contrast for arthritis.

  • Consider head MRI with and without contrast, and MRA to evaluate for CNS vasculitis and causes of headache, developmental delay, or hearing loss.

Confirming the diagnosis

Pertinent history:

  1. Document recurrent episodes of fever ≥38°C.

  2. FOR at least 4-12 months.

  3. WITHOUT concurrent infectious symptoms.

  4. Fever characteristics:

  • 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

  • Family history of similar febrile illnesses and response to treatment

  • Ethnicity of parents

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

Suspect diagnosis of PFS if:

  • Recurrent fevers without history of infectious symptoms or response to antibiotics.

  • Fever-free intervals of generally good health.

  • Family history, especially in first degree relative, of similar symptoms

  • Amyloidosis, chronic uveitis, hearing loss, serositis, or arthritis are also present.

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

  • Therapies that should be instituted immediately are shown in Table I.

Table I.

Immediate therapies for periodic fever syndromes
FMF Colchicine 1 mg p.o. daily regardless of age or weightIntravenous fluids as neededIf significant serositis: consider prednisone 0.5-2 mg/kg/day or methylprednisolone 10-30 mg/kg (max 1 gm) IV daily times 1-3 doses; taper and discontinue with symptomatic improvementAvoid unnecessary surgery
TRAPS NSAIDs for pain: Naproxen 10 mg/kg b.i.d.; celecoxib 50-100 mg b.i.d.; meloxicam 0.125 mg/kg (max 15 mg) daily; or indomethacin 1 mg/kg b.i.d.Consider prednisone 0.5-2 mg/kg/day for severe symptoms, taper and discontinue with symptomatic improvement or methylprednisolone 10-30 mg/kg (max 1 gm) IV daily times 1-3 days
HIDS Avoid unnecessary surgeryNSAIDS for fever or pain: Naproxen 10 mg/kg b.i.d.; celecoxib 50-100 mg b.i.d.; meloxicam 0.125 mg/kg (max 15 mg) daily; or indomethacin 1 mg/kg b.i.d.For severe or NSAID-resistant symptoms: Consider prednisone 0.5-2 mg/kg/day, taper and discontinue with symptomatic improvement or methylprednisolone 10-30 mg/kg (max 1 gm) IV daily times 1-3 days
NOMID 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, ORCanakinumab 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, ORAnakinra 1-10 mg/kg (max 300 mg) SQ dailyNSAIDS: Naproxen 10 mg/kg b.i.d.; celecoxib 50-100 mg b.i.d.; meloxicam 0.125 mg/kg (max 15 mg) daily; or indomethacin 1 mg/kg b.i.d.Consider prednisone 0.5-2 mg/kg/day for severe symptoms; taper and discontinue with symptomatic improvementOmeprazole 10-20 mg daily
FCAS Cold avoidance
MWS 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, ORCanakinumab 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, ORAnakinra 1-3.5 mg/kg (max 300 mg) SQ dailyPrednisone 0.5-2 mg/kg/day for severe symptoms; taper and discontinue with symptomatic improvementNSAIDs: Naproxen 10 mg/kg b.i.d.; celecoxib 50-100 mg b.i.d.; or meloxicam 0.125 mg/kg (max 15 mg) dailyOmeprazole 10-20 mg daily
FPAPA None
  • Table II lists longer term treatment for periodic fever syndromes.

Table II.

Longer term treatment for periodic fever syndromes
FMF Colchicine 0.3-1.8 mg a day depending on mutation genotyping
TRAPS NSAIDS alone for mild symptomsPrednisone 0.5-2 mg/kg/day for chronic symptomsEtanercept 0.4-1 mg/kg (max 25 mg) SQ 2-3 times wk or 0.8-1 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)IL-1 blockade: Anakinra 1-2 mg/kg (max 100 mg) SQ daily at symptom onset as needed or chronically OR TNF inhibition: Etanercept 0.4-1 mg/kg (max 25 mg) SQ 2-3 times a wk or 0.8-1 mg/kg (max 75 mg) SQ q.wk.
NOMID 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 ORCanakinumab 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 dailyNSAIDsOmeprazole 10-20 mg q.day-b.i.d.
FCAS Cold avoidanceNSAIDS alone if minimal symptomsIntermittent or 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 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 0.5-1.5 mg/kg (max 100 mg) SQ daily
MWS 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 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
FPAPA No treatmentPrednisone 1-2 mg/kg/day (max 60 mg) times 1-2 days at onset of symptomsConsider cimetidine 20-40 mg/kg/dayConsider tonsillectomy (controversial as first-line treatment)
  • Table III lists alternative treatments if standard therapy fails.

Table III.

Alternative treatments for periodic fever syndromes if standard therapy fails
FMF IL-1 blockade: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 mg daily if IL-1 blockade does not remit symptoms
TRAPS IL-1 blockade: Anakinra 1-2 mg/kg (max 100 mg) SQ daily ORIL-6 blockade: Tocilizumab 4-12 mg/kg IV q.2-4 wk
HIDS Other 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 ORCanakinumab 150 mg SQ q.8 wk (>4 y & >40 kg); 2-3 mg/kg (max 150 mg) SQ q.8 wk (<40 kg) TNF blockade: Infliximab 3-7.5 mg/kg IV q.4-8 wk Consider simvastin 10-20 mg (max 80 mg) daily ORColchicine 0.3-1.2 mg daily (controversial) ORAzathioprine 1-2 mg/kg/day (max 150-200 mg)Cyclosporine 1-3 mg/kg/day for trough level 100-200 ng/ml
NOMID TNF blockade: Infliximab 5-10 mg/kg IV q.4-8 wkConsider thalidomide 100-300 mg daily
FCAS TNF blockade: Infliximab 3-7.5 mg/kg IV q.4-8 wk
MWS TNF blockade: Infliximab 3-10 mg/kg IV q.4-8 wk
FPAPA Intermittent IL-1 blockade: Anakinra 1 mg/kg (max 100 mg) SQ within 48 hr of attack onset; may repeat onceColchicine 0.3-1.2 mg dailyTonsillectomy
  • Table IV gives advantages and disadvantages of the medication options for treating periodic fever syndromes.

Table IV

Advantages and disadvantages of medication options for periodic fever syndromes
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
Etanercept Soluble TNF receptor that binds TNF before it can bind to cell surface receptor Biweekly or weekly injections; best long-term safety profile
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; safety data known

What are the adverse effects associated with each treatment option?

Table V gives the adverse effects associated with each treatment option for periodic fever syndromes.

Table V

Adverse effects of treatment options for periodic 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
Cimetidine Headache, cytopenias
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
Tonsillectomy Pain/risks from surgery

What are the possible outcomes of periodic fever syndromes?

There are some significant morbidities and increased mortality rates seen in untreated patients with inherited PFS:

Cryopyrin-associated periodic syndromes, CAPS (FCAS, MWS, NOMID/CINCA):

Each of these syndromes are due to an autosomal dominant mutation in a single gene, NLRP3. Phenotypes and complications are different among FCAS, MWS, and NOMID, although significant overlap is noted. All share a characteristic urticarial rash, but fever may or may not be present. The most severe disease is seen in NOMID, followed by MWS and FCAS. The frequency of 2° amyloidosis is greatest in MWS, followed by NOMID and then FCAS.

FCAS (Familial cold autoinflammatory syndrome): Usually diagnosed at birth or within first 6 months of life, based on attacks of urticarial rash and fever triggered by cold exposure and lasting less than 24 hrs. These patients usually have a normal lifespan, but 2° amyloidosis occurs in up to 5% of patients. Daily fatigue, headache, and myalgias, even without cold exposure, contribute to considerable morbidity.

MWS (Muckle-Wells syndrome): Characterized by recurrent but unpredictable attacks of fever >38.5°C and urticaria lasting for 1-3 days, although some symptoms may persist. The age of onset is often <6 months, and triggering by cold is not necessary. MWS was originally described as a triad of urticaria, deafness and amyloidosis, but only 25% patients with identifiable NLRP3 mutations develop amyloidosis. Conjunctivitis (in >90%) and progressive sensorineural hearing loss (>70%) are pathognomonic. Since the fever pattern is less predictable than in FCAS, the diagnosis of MWS is often delayed until hearing loss is noted during adolescence. All patients suffer from severe chronic fatigue, which remits with IL-1 blockade. Abdominal pain and headaches occur in most patients during fevers, but these are not as severe as in FMF. Arthralgias are more common than chronic arthritis. Recurrent oral aphthae occur in >50% patients during fevers.

NOMID/CINCA (Neonatal-onset multisystem inflammatory disease / chronic infantile neurological cutaneous articular syndrome): This is the most severe form of CAPS, with chronic urticaria with or without fever noted at birth or in the newborn period. Continuous symptoms and frequent flares are not necessarily accompanied by fever. Unlike other PFSs, NOMID follows a chronic course with significant complications, poor overall prognosis and shortened lifespan if untreated (by IL-1 blockade therapy.) Early diagnosis and treatment with IL-1 inhibition improves quality of life and delays or prevents morbidities. Severe CNS manifestations are seen in 90% of untreated patients. The characteristic epiphyseal overgrowth arthropathy is pathognomonic and develops in 30%-60% of patients. Secondary amyloidosis develops in 10%-25% of patients. Other complications vary in severity and age of onset, but include:

  • ˚ Early growth retardation, delayed puberty

  • ˚ Skull abnormalities, frontal bossing

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

  • ˚ Chronic aseptic meningitis, often with chronic headache, papilledema, and increased intracranial pressure

  • ˚ Mild arthritis in >65%, but 30%-60% develop early severe chronic joint inflammation with characteristic epiphyseal overgrowth, especially of patellae, with progressive joint contractures and limited mobility

  • ˚ Progressive cognitive impairment.

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

Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS)

Attacks may begin in the 1st year of life with a median age at initial attack of 6 mo. All patients have their disease onset before 5 years of age, although the diagnosis is often delayed unless there is a family history of HIDS. Clinical attacks are characterized by unremitting fever ≥ 38.5°C for 3-7 days, in recurring cycles every 4-8 weeks. Prodromal symptoms such as chills, fatigue and URI are common. Pronounced cervical lymphadenopathy occurs in >90% and splenomegaly is noted in 50% (distinguishing HIDS from other PFSs). Bouts of severe abdominal pain due to serositis may result in unnecessary exploratory laparotomy or appendectomy procedures. Non-destructive arthritis or arthralgias occur in 80%. Chronic rashes are noted in >80% and are variable in appearance. Patients with HIDS usually have a normal lifespan with few serious complications other than 2° amyloidosis (in <3% patients).

Familial Mediterranean fever(FMF)

The initial attack of FMF is often in early childhood; 80%-90% are < 20 years of age at onset of symptoms. The disease is characterized by recurrent attacks of fever >38°C and abdominal pain for 1-3 days repeating every 3-8 weeks. Patients are asymptomatic and in generally good health between attacks. The major cause of mortality is 2° amyloidosis leading to renal failure:

  1. Before colchicine: 2° amyloidosis occurred in 60%-75% patients > 40 years of age; in 30% of Sephardic Jews, 60% of Turks; >75% of North African Jews.

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

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

  4. Continuous colchicine prevents amyloid-related nephropathy in most patients.

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

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

  7. Complications/morbidities include:

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

    • Recurrent pleuritis in 45%; occasionally pericarditis

    • Mono- or oligo- arthritis in 75%.

    • Orchitis

    • Recurrent aseptic meningitis

    • Erysipelas-like erythema, but uncommon.

  8. Diagnosis in children requires ≥2 of 5 criteria: fever, abdominal pain, chest pain, arthritis, and family history of FMF.

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS)

TRAPS is characterized by recurrent and unpredictable bouts of prolonged fevers >38°C - 41°C, lasting for 3 days to 6 weeks. The episodes recur on average every 5-6 weeks. Age at initial presentation is highly variable: < 1 to > 50 yr; median age of onset: 3 yr. These patients usually have a normal lifespan, but earlier mortality can be due to 2° amyloidosis in 10% patients. Other significant morbidities include:

  • Monoarticular arthritis

  • Rash

  • Migratory focal myalgias, which often precede fever, are cardinal feature

  • Ocular inflammation in 80%

  • Abdominal pain

Table VI summarizes the risks and benefits of available treatment options for CAPS.

Table VI.

Risks/benefits of available treatment options for cryopyrin-associated periodic syndromes (CAPS)
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; may shorten interval between or increase frequency of PFAPA attacks in 30%. Relieve fever, rash; improve adenopathy, arthritis; lessen organ involvement, serositis
Colchicine Treatment of FMF and possible PFAPA; fever, aphthous stomatitis, 2° amyloidosis in FMF Adverse reactions; short-lived benefit in PFAPA Prevents attacks in >70% and decreases attacks in 95% of FMF (no effect in TRAPS, HIDS, CAPS); lowers serum amyloid A (SAA) in FMF; decreases/prevents 2° amyloidosis in FMF; reduces fever, oral aphthae; decreases recurrences of PFAPA in >50%.
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, consider for FPAPA. Adverse reactions; triggers flare of inflammation; no long-lasting disease control off treatment Remits fever, rash, arthritis and laboratory abnormalities in FCAS, MWS (less effective in NOMID) and some FMF, HIDS, TRAPS, FPAPA; 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 and laboratory abnormalities 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 long-term 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 and episodes in a few patients
Thalidomide Treatment of NOMID, TRAPS, FMF resistant to standard therapy; arthritis, aphthous stomatitis Adverse reactions May reduce ESR/CRP in a few HIDS patients
Simvastatin HIDS resistant to standard therapy Adverse reactions; may trigger 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.

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

      • Carrier rate: 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 named Familial Hybernian Fever.

      • Affects females and males equally.

    • HIDS:

      • Incidence: Very rare (<200 worldwide).

      • Mutation frequency 1:350 in Netherlands secondary to founder effect.

      • >60% of Dutch or French ancestry and usually Caucasian.

      • Males and females affected equally.

    • FCAS:

      • Many of European ancestry.

      • Incidence: very rare.

    • MWS:

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

      • Incidence: rare, usually familial.

      • Males and females equally affected.

    • NOMID:

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

      • Incidence: rare.

      • Less likely than FCAS or MWS to be familial.

  • Genetics:

    • FMF:

      • Autosomal recessive (homozygous or compound heterozygous) mutations (> 50) in the MEFV gene encoding pyrin/marenostrin.

      • Four missense mutations in exon 10 (M680I, M694V, M694J and V726A) and E148Q in exon 2 account for majority of mutations.

      • All mutations decrease pyrin function

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

      • Diagnosis should never be excluded based solely on genetic testing if characteristic clinical features are noted.

      • M694V mutation most common, confers highest disease severity and risk of amyloidosis, and predominates in North African and Iraqi Jews, Armenians and Turks.

      • In Ashkenazi Jews, most common mutations (V726A and E148Q) have reduced penetrance and confer a milder disease phenotype.

    • TRAPS:

      • Autosomal dominant mutations in the TNFRSF1A gene encoding the 55 kDa TNF receptor with incomplete disease penetrance.

      • >50 mutations almost exclusively affect extracellular portion of the TNF receptor.

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

    • HIDS:

      • Homozygous or compound heterozygous mutations in the mevalonate kinase (MVK) gene encoding mevalonate kinase.

      • 80% carry at least one V377I mutation.

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

    • CAPS (FCAS, MWS, NOMID):

      • Autosomal dominant (gain-of-function) mutations in the NLRP3 (CIASI) gene encoding cryopyrin/NLRP3.

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

The Inflammasome and innate immunity

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

  2. Il-1 beta is the pleiotropic pyrogen and alarm cytokine. 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-1beta activity have been shown to cause inherited periodic fever syndromes.

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

  • CAPS (FCAS, MWS, NOMID):

    • NLRP3 required for assembly of a multi-protein complex or "inflammasome" in phagocytic cells, monocytes, macrophages, dendritic cells and chondrocytes 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.

    • Considered"intrinsic inflammasomopathies" – diseases resulting from increased IL-1beta secretion.

    • Gain-of-function mutations in NLRP3 cause constitutive inflammasome activation and increase caspase-1 activity, resulting in excessive IL-1beta release, uncontrolled inflammation, and tissue injury.

  • FMF:

    • FMF is considered an extrinsic "inflammasomopathy."

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

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

    • Sequestration of ASC by pyrin prevents caspase-1 activation.

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

    • Colchicine inhibits neutrophil chemotaxis via microtubule depolymerization and reduces proinflammatory cytokine production through inhibition of NF-kappaB activation.

  • HIDS:

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

    • MVK catalyzes conversion of mevalonic acid to 5-phospho-mevalonic acid in the isoprenoid pathway.

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

    • Less severe mutations (> 60 identified) with 1%-15% residual MVK activity cause HIDS.

    • Etiology of elevated serum IgD and also IgA (in >70%) recurrent fevers from decreased MVK activity not fully understood, but includes increased inflammasome activation and IL-1beta overproduction.

  • TRAPS:

    • Cell surface and soluble TNF receptors bind the proinflammatory cytokine, 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) that function to inhibit further TNF 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 protein kinases in several inflammatory pathways.

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

Other clinical manifestations that might help with diagnosis and management

Secondary amyloidosis in hereditary PFS:

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

  2. Development of amyloidosis highly variable among different PFSs, 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 the first disease symptom.

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

  6. Amyloidosis diagnosed by biopsy of kidney or rectum.

  7. Consider renal and/or rectal biopsy if >500 mg protein in 24-hr urine collection or elevated BUN/creatinine.

  8. Median survival time: 24-53 mo from time of diagnosis without treatment.

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

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

  11. Serum amyloid A (SAA) level may reflect active amyloid deposition and guide therapy.

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

Genotype: phenotype correlations and controversies affecting treatment decisions in FMF:

  1. Patients homozygous for M694V mutation or compound heterozygous for M694V and another disease-causing mutation (V726A-E148Q) should start chronic colchicine therapy as soon as diagnosis confirmed by genotyping.

  2. Patients homozygous for V726A-E148Q or compound heterozygous for V726A-E148Q and another disease-causing mutation (not M694V) should receive colchicine at onset of attacks and not necessarily chronic colchicine unless severe inflammation, proteinuria or amylodosis.

  3. Patients without M694V or V726A-E148Q mutations and mild symptoms may not need colchicine unless attacks are severe or develop amyloidosis, which would be unlikely.

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

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

  1. Most complications self-limited, but some do affect health and quality of life, including unnecessary abdominal surgery and infertility secondary to pelvic adhesions, as well as morbidities unique to NOMID.

  2. Most worrisome disease complication is 2° amyloidosis, which is the major cause of morbidity and mortality.

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

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

  1. Serum amyloid A protein (SAA)

  2. Urine mevalonic acid level

  3. Soluble TNF receptor level

How can PFS be prevented?

  1. No known prevention.

  2. Genetic counseling important if inherited PFS is suspected.

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

What is the evidence?

Periodic Fever Syndromes:

Masters, SL, Simon, A, Aksentijevich, Kastner, DL. "Horror autoinflammaticus: the molecular physiology of autoinflammatory disease". Ann Rev Immunol. vol. 27. 2009. pp. 621-68.

Bodar, EJ, Drenth, JP, van der Meer, JW, Simon, A. "Dysregulation of innate immunity: hereditary periodic fever syndromes". Brit J Haematol. vol. 144. 2008. pp. 279-302.

Simon, A, van der Meer, JW. "Pathogenesis of familial periodic fever syndromes or hereditary autoinflammatory syndromes". Am J Physiol Regul Integr Comp Physiol. vol. 292. 2007. pp. R86-98.

Kastner, DL, Aksentijevich, A, Goldbach-Mansky, R. "Autoinflammatory disease reloaded: a clinical perspective". Cell. vol. 140. 2010. pp. 784-90.

Ombrello, MJ, Kastner, DL. "Autoinflammation in 2010: expanding clinical spectrum and broadening therapeutic horizons". Nat Rev Rheumatol. vol. 7. 2011. pp. 82-4.

Henderson, C, Goldbach-Mansky, R. "Monogenic autoinflammatory diseases: new insights into clinical aspects and pathogenesis". Curr Opin Rheumatol. vol. 22. 2010. pp. 567-78.

van der Hilst, JC, Simon, A, Drenth, JP. "Hereditary periodic fever and reactive amyloidosis". Clin Exp Med. vol. 5. 2005. pp. 87-98.

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

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. 288-98.

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. 1141-9.

TNF Receptor-Associated Periodic Syndrome (TRAPS)

McDermott, MF, Aksentijevich, I, Galon, J. "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. 133-44.

Hull, KM, Drewe, E, Aksentijevich, I. "The TNF receptor-associated periodic syndrome (TRAPS): emerging concepts of an autoinflammatory disorder". Medicine (Baltimore). vol. 81. 2002. pp. 349-68.

Rezaei, N. "TNF-receptor-associated periodic syndrome (TRAPS): an autosomal dominant multisystem disorder". Clin Rheumatol. vol. 25. 2006. pp. 773-7.

Vaitla, PM, Radford, PM, Tighe, PJ. "Role of interleukin-6 in a patient with tumor necrosis factor receptor-associated periodic syndrome: assessment of outcomes following treatment with the anti-interleukin-6 receptor monoclonal antibody tocilizumab". Arthritis Rheum. vol. 63. 2011. pp. 1151-5.

Pettersson, T, Kantonen, J, Matikainen, S, Repo, H. "Setting up TRAPS". Ann Med. vol. 44. 2012. pp. 109-18.

Familial Mediterranean Fever (FMF):

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. 108-17.

Chae, JJ, Aksentijevich, I, Kastner, DL. "Advances in the understanding of familial Mediterranean fever and possibilities for targeted fever". Br J Haematol. vol. 146. 2009. pp. 467-78.

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

Shohat, M, Halpern, GJ, Pagon, RA, Bird, TD, Dolan, CR. "GeneReviewsTM [internet]". University of Washington, Seattle. 2012 Apr 26.

Ozen, S, Bilginer, Y, Aktay Ayaz, N, Calguneri, M. "Anti-interleukin 1 treatment for patients with familial Mediterranean fever resistant to colchicine". J Rheumatol. vol. 38. 2011. pp. 516-8.

Hyperimmunoglobulinemia D with Periodic Fever Syndrome (HIDS):

van der Hilst, JC, Bodar, EJ, Barron, KS. "International HIDS Study Group. Long-term follow-up, clinical features, and quality of life in a series of 103 patients with hyperimmunoglobulinemia D syndrome". Medicine (Baltimore). vol. 87. 2008. pp. 301-10.

van der Hilst, Frenkel, J. "Hyperimmunoglobulin D syndrome in childhood". Curr Rheumatol Rep. vol. 12. 2010. pp. 101-7.

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 Paediatr. vol. 100. 2011. pp. 21-5.

Haas, D, Hoffmann, GF. "Mevalonate kinase deficiency and autoinflammatory disorders". N Engl J Med. vol. 356. 2007. pp. 2671-3.

Cryopyrin-Associated Periodic Syndromes (CAPS):

Mitroulis, M, Skendros, P, Ritis, K. "Targeting IL-1beta in disease; the expanding role of NLRP3 inflammasome". Eur J Intern Med. vol. 21. 2010. pp. 157-63.

Kubota, T, Koike, R. "Cryopyrin-associated periodic syndromes: background and therapeutics". Mod Rheumatol. vol. 20. 2010. pp. 213-21.

Aganna, E, Martinon, F, Hawkins, PN. "Association of mutations in the NALP3/CIAS1/PYPAF1 gene with a broad phenotype including recurrent fever, cold sensitivity, sensorineural deafness, and AA amyloidosis". Arthritis Rheum. vol. 46. 2002. pp. 2445-52.

Lepore, L, Paloni, G, Caorsi, R. "Follow-up and quality of life of patients with cryopyrin-associated periodic syndrome treated with Anakinra". J Pediatr. vol. 157. 2010. pp. 310-15.

Church, LD, McDermott, MF. "Canakinumab: a human anti-IL-1β monoclonal antibody for the treatment of cryopyrin-associated periodic syndromes". Expert Rev Clin Immunol. vol. 6. 2010. pp. 831-41.

Kuemmerle-Deschner, JB, Tyrrell, PN, Koetter, I. "Efficacy and safety of anakinra therapy in pediatric and adult patients with the autoinflammatory Muckle-Wells syndrome". Arthritis Rheum. vol. 63. 2011. pp. 840-9.

Neven, B, Marvillet, I, Terrada, C. "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. 258-67.

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. Best management of PFAPA: steroids vs tonsillectomy vs IL-1 blockade vs no treatment.

  3. Use of colchicine for treatment or prophylaxis in FMF patients with one identified non-M694mutation or mild presentation.

  4. Role of pharmacogenomics in management of periodic fever syndromes.

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

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

You must be a registered member of Renal and Urology News to post a comment.

Sign Up for Free e-newsletters