Autoinflammatory Periodic Fever Syndromes

Autoinflammatory periodic fever syndromes (PFS) are a heterogeneous group of rare, predominantly monogenic disorders characterised by recurrent episodes of systemic inflammation without evidence of infection, autoimmunity, or malignancy. They result from dysregulation of the innate immune system — particularly abnormal inflammasome activation or cytokine signalling — rather than adaptive immune dysfunction. In Australia, diagnosis is often delayed due to the rarity of these conditions and overlap with more common inflammatory disorders.

Classification is evolving with the discovery of novel monogenic syndromes. The Eurofever/PRINTO classification criteria (2019) provide validated clinical and genetic criteria for the major PFS. In Australia, genetic testing for monogenic PFS is available through specialised metabolic and immunogenetics laboratories, and management should involve a paediatric or adult rheumatologist with expertise in autoinflammatory diseases.

Autoinflammatory PFS result from mutations in genes encoding components of the innate immune system, particularly those involved in inflammasome assembly, cytokine processing, and the NF-κB pathway. The key pathways involved differ by syndrome, leading to distinct clinical phenotypes and informing targeted therapies.

Genetic and Pathophysiological Basis of Major Periodic Fever Syndromes

Inflammasome Activation — Central Mechanism

The NLRP3 inflammasome is central to most PFS pathophysiology. Normally, it assembles in response to danger signals (PAMPs/DAMPs), activating caspase-1 which cleaves pro-IL-1β and pro-IL-18 into their active forms. In CAPS, gain-of-function NLRP3 mutations allow constitutive activation. In FMF, mutant pyrin fails to suppress the pyrin inflammasome. In MKD, mevalonate kinase deficiency impairs protein prenylation, reducing Rho GTPase activity and activating the NLRP3 inflammasome. The resulting excess IL-1β drives fever, serositis, and systemic inflammation.

Amyloidosis Risk

Each PFS has a characteristic fever pattern, duration, associated features, and age of onset. Recognising these patterns is key to directing genetic testing and avoiding unnecessary investigations for infection or malignancy. Most syndromes begin in childhood or early adulthood.

Clinical Features of Major Periodic Fever Syndromes

FMF — Specific Features

• Acute peritonitis: severe abdominal pain mimicking surgical abdomen, abdominal wall rigidity — most common presentation (~90%)
• Pleuritis: unilateral pleuritic chest pain, often with transient pleural effusion
• Febrile arthritis: monoarthritis or oligoarthritis (usually large joints — knee, ankle, hip)
• Erysipelas-like erythema: well-demarcated, hot, painful erythema of lower limb (ankle/foot) — pathognomonic when present
• Pericarditis (rare): recurrent episodes; risk of constrictive pericarditis
• Strong ethnic predisposition: Sephardic Jewish, Turkish, Armenian, Arab populations; increasingly recognised in non-Mediterranean backgrounds

PFAPA — Specific Features (Paediatric Focus)

• Classic triad: aphthous stomatitis + pharyngitis + cervical adenitis — not all features present in every episode
• Extremely regular periodicity: caregivers can often predict dates of next fever episode
• Child is completely well between episodes with normal growth and development
• No genetic mutation identified; negative genetic testing for FMF/TRAPS/MKD should prompt PFAPA consideration
• Diagnosis of exclusion: after ruling out infection, immunodeficiency, and other autoinflammatory conditions
• Single dose of prednisolone (1–2 mg/kg) at fever onset rapidly terminates episodes (diagnostic and therapeutic)
• Usually resolves spontaneously by mid-adolescence; tonsillectomy is curative in many cases

Investigation during acute episodes typically shows a dramatic acute phase response (elevated CRP, ESR, SAA, neutrophilia) with complete normalisation between attacks. A persistently elevated SAA between attacks suggests inadequate disease control. Genetic testing is the cornerstone of diagnosis for monogenic PFS.

• Essential
  Full blood count + differential

  Neutrophilia during acute attacks; normal between episodes. Sustained leucocytosis between attacks raises concern for infection or alternative diagnosis.
• Essential
  CRP and ESR

  Markedly elevated during attacks (CRP may exceed 200 mg/L). Should normalise between episodes. Baseline elevated CRP between attacks suggests inadequate control.
• Essential
  Serum Amyloid A (SAA)

  Most sensitive marker of PFS activity and amyloidosis risk. Target: maintain SAA <10 mg/L between attacks. Available at major Australian reference laboratories.
• Essential
  Genetic panel — PFS gene panel

  PCR/next-generation sequencing panel covering MEFV (FMF), TNFRSF1A (TRAPS), MVK (MKD), NLRP3 (CAPS), and other PFS genes. Available at major Australian pathology labs (SA Pathology, VCGS, Melbourne Pathology). Results take 4–8 weeks. A negative result does not exclude PFS — clinical diagnosis remains important.
• Essential
  Urinalysis (protein)

  Screen for proteinuria — early indicator of AA amyloidosis affecting the kidneys. Perform at every specialist review. 24-hour urine protein if proteinuria detected.
• Recommended
  Renal function (eGFR, creatinine)

  Baseline and annual monitoring for AA amyloidosis nephropathy. Renal biopsy (Congo red stain) for definitive diagnosis of AA amyloidosis if suspected.
• Recommended
  Liver function tests

  Elevated LFTs during attacks (especially MKD); baseline before commencing IL-1 biologics.
• Recommended
  Mevalonate in urine (MKD)

  Elevated urinary mevalonate during acute attacks (MKD/HIDS). Can be detected at specialist metabolic labs. Levels between attacks may be normal.
• Recommended
  IgD level

  Elevated IgD (>100 IU/mL) was historically used for MKD/HIDS diagnosis. Unreliable in young children and elevated in other conditions; positive in only ~80% of MKD patients. IgD testing is now supplementary to genetic testing.
• Recommended
  Ophthalmological review (CAPS)

  Annual review for papilloedema, optic disc swelling, cataracts, and uveitis — particularly in CAPS/NOMID patients. Baseline MRI brain for CAPS to assess CNS inflammation and CSF pressure.
• Recommended
  Audiogram

  Baseline and annual audiological assessment in MWS and NOMID — sensorineural hearing loss is progressive and requires early intervention (hearing aids, cochlear implant consideration).
• Specialist
  Bone marrow biopsy / Congo red stain

  For suspected AA amyloidosis — rectal, abdominal fat pad, or affected organ biopsy with Congo red stain under polarised light showing apple-green birefringence. Renal biopsy if renal involvement suspected.
• Specialist
  Lumbar puncture (CAPS/NOMID)

  In NOMID/CINCA: elevated CSF white cells and protein indicate aseptic meningitis. Baseline LP before IL-1 blockade; repeat to assess treatment response.

Severity assessment in PFS guides treatment intensity — from symptom management with NSAIDs for mild FMF to urgent IL-1 blockade in NOMID/CINCA. Risk of AA amyloidosis is the primary long-term concern requiring aggressive SAA suppression. The Eurofever/PRINTO classification criteria provide validated diagnostic and severity frameworks for major PFS.

Severity Indicators and Amyloidosis Risk by Syndrome

SAA Monitoring Target

Treatment is syndrome-specific. Colchicine remains first-line for FMF and is lifelong. IL-1 pathway blockade (anakinra or canakinumab) is the treatment of choice for CAPS, refractory FMF, TRAPS, and MKD. NSAIDs provide symptomatic relief for acute attacks across syndromes. Corticosteroids have a role in PFAPA and acute flares but are not appropriate long-term for amyloidosis-prone syndromes.

Colchicine — FMF First-line

IL-1 Blockade — CAPS, Refractory PFS

Symptomatic and Adjunct Therapies

Acute attacks of PFS are usually self-limiting but can be very distressing and severely impact quality of life. Management aims to shorten attack duration, control symptoms, and — in the context of known diagnosis — administer targeted therapy. In patients presenting acutely without prior diagnosis, exclusion of serious infection is the first priority.

New Diagnosis Presenting Acutely

• Full sepsis workup if febrile and unwell: blood cultures, urine cultures, CXR, consider LP if meningism
• Detailed history: ethnicity, family history of similar attacks, duration, periodicity, associated features
• Initiate fever diary from this admission
• Refer to paediatric or adult rheumatology/immunology for outpatient evaluation
• Do NOT start colchicine or IL-1 biologics in the emergency setting without specialist input

Long-term monitoring in PFS is directed at two goals: assessing disease control (attack frequency, SAA suppression) and detecting organ damage (AA amyloidosis, sensorineural hearing loss, CNS complications in CAPS). All patients on biologic therapy require additional infection screening and vaccination review.

Monitoring Schedule for Autoinflammatory Periodic Fever Syndromes

Colchicine Monitoring

• Gastrointestinal side effects (diarrhoea, nausea) — most common; dose reduction may be needed; usually improve over time
• Myopathy risk: elevated with concurrent statin use — monitor CK; avoid in severe renal impairment (eGFR <30)
• Azoospermia: reversible with cessation; counsel male patients on fertility implications with long-term use
• Teratogenicity: NOT a significant risk at therapeutic doses — colchicine should be continued in pregnancy in FMF patients

Pregnancy and Reproductive Health

• Colchicine in pregnancy (FMF): CONTINUE throughout pregnancy. FMF attacks in pregnancy increase risk of miscarriage, preterm labour, and preeclampsia — far greater risk than colchicine exposure. Reassure patients: extensive data confirm safety at therapeutic doses.
• Colchicine and breastfeeding: Compatible with breastfeeding. Low levels in breast milk; no adverse infant effects reported at therapeutic doses.
• IL-1 biologics in pregnancy: Limited data. Generally, anakinra and canakinumab are discontinued in the third trimester (cross placenta; potential neonatal immunosuppression). Decision individualised by rheumatologist and obstetrician — weigh risk of CAPS/NOMID flare vs foetal exposure.
• Male fertility: Colchicine may cause reversible azoospermia/oligospermia at high doses. Counsel men of reproductive age; dose reduce if semen analysis abnormal.

Paediatric PFS

• Most PFS present in childhood — PFAPA predominantly <5 years; FMF typically <20 years; CAPS from neonatal period
• Colchicine dosing is weight-based in children; children generally tolerate colchicine well
• IL-1 biologics are approved for paediatric use in CAPS (canakinumab from 2 years); off-label for other PFS in children
• Growth monitoring essential: chronic inflammation and corticosteroid exposure impair linear growth; biologic therapy often improves growth trajectory in CAPS
• School management: attack frequency may significantly impact school attendance — provide supporting medical letters; flexible attendance plans during attacks

Elderly and Late-Onset PFS

• Late-onset FMF (after age 40) is recognised, often with atypical presentations; higher amyloidosis risk at diagnosis due to longer disease duration
• TRAPS can present in adulthood — molecular diagnosis essential; high amyloidosis risk with high-penetrance mutations
• Drug interactions in elderly: colchicine interactions with CYP3A4/P-gp inhibitors (clarithromycin, ciclosporin, statins) increase toxicity risk significantly

Patients with Renal Impairment

• Colchicine: dose reduce in moderate renal impairment (eGFR 15–30 to max 0.5 mg/day); AVOID in severe renal impairment (eGFR <15) or dialysis
• AA amyloidosis nephropathy may itself reduce eGFR — distinguishing from other causes of CKD requires renal biopsy (Congo red stain)
• Biologics (anakinra/canakinumab): dose adjustment required in severe renal impairment — seek specialist/pharmacist advice

Appropriate diagnosis and treatment of PFS avoids repeated unnecessary antimicrobial courses, unnecessary surgical interventions (laparotomy for FMF peritonitis), and prolonged hospitalisation. Genetic diagnosis and specialist confirmation before initiating expensive biologic therapy is an important stewardship principle, balancing cost, safety, and clinical need.

Vaccination Principles for Patients on Biologics

• All live vaccines (MMR, varicella, yellow fever, oral typhoid, BCG) are CONTRAINDICATED while on IL-1 biologic therapy
• Ensure all indicated live vaccines are up-to-date at least 4 weeks before initiating biologic therapy
• Inactivated vaccines (influenza, COVID-19, pneumococcal, pertussis, hepatitis B) are safe and recommended — annual influenza and appropriate respiratory vaccines
• Annual vaccination review at each specialist appointment
• Children transitioning from paediatric to adult care: confirm vaccination record is complete before biologic continuation

Given the rarity of monogenic PFS, all confirmed or suspected cases should be under the care of a specialist with expertise in autoinflammatory diseases (paediatric or adult rheumatologist, clinical immunologist). Long-term shared care with the GP is appropriate for stable patients on established therapy.

Referral and Follow-up Framework for Periodic Fever Syndromes

Patient and Family Education

• Provide written information about the specific syndrome, its inheritance pattern, and long-term prognosis
• Genetic counselling: FMF is autosomal recessive (parents are carriers); TRAPS/CAPS often autosomal dominant — siblings and children may need testing
• Advise patients to carry a medical alert card/bracelet noting their diagnosis and to inform any treating clinician
• Emergency contact details for treating rheumatologist for acute flares
• Connect families with patient support organisations (e.g. FMF Australasia, Autoinflammatory Alliance)
• Register with Eurofever Registry (international patient registry) to contribute to rare disease research

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