Periodic fever and autoinflammatory syndromes

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Target exams

Red flags

• A child with familial Mediterranean fever who develops new proteinuria or a rising creatinine has AA amyloidosis until proven otherwise; colchicine adherence and renal surveillance are non-negotiable
• An infant with recurrent fever plus a urticaria-like rash, conjunctivitis and failure to thrive from the first months of life has a cryopyrin-associated periodic syndrome, and untreated Muckle-Wells syndrome causes irreversible sensorineural deafness and renal amyloidosis
• The single most common mistake is to label every recurrent fever as recurrent infection; a clockwork interval with complete wellness between attacks is the signature of a periodic fever syndrome, not infection
• Never delay empiric broad-spectrum antibiotics in a febrile child on biologic therapy, because sepsis is clinically indistinguishable from an autoinflammatory flare
• PFAPA can be diagnosed only after the hereditary periodic fevers are excluded, because the corticosteroid that aborts a PFAPA attack will also mask and delay the diagnosis of a monogenic syndrome

Life stages

Care settings

Clinical exam formats

Board mappings

• Names the hereditary periodic fever syndromes as monogenic autoinflammatory diseases driven by innate immune activation, antigen-independent and without autoantibodies
• Recognises that familial Mediterranean fever is treated with colchicine to prevent both attacks and AA amyloidosis
• States that a child with clockwork fevers who is completely well between attacks, with normal growth, has a periodic fever syndrome such as PFAPA rather than recurrent infection
• Explains the inflammasome and interleukin-one pathophysiology that links the NLRP3, MEFV, MVK and TNFRSF1A gene defects to recurrent self-limited inflammatory attacks
• Applies the Gattorno 2019 Eurofever classification criteria and the Livneh criteria for familial Mediterranean fever to sort the hereditary recurrent fevers
• Coordinates the pathway-targeted biologic therapy and the multidisciplinary, transition and amyloidosis-surveillance plan for a child with a lifelong autoinflammatory disease
• The Livneh 1997 criteria for familial Mediterranean fever combine a typical attack pattern with ethnic predisposition and family history, and colchicine response supports the diagnosis
• Colchicine is the first-line treatment for familial Mediterranean fever, titrated to a usual maintenance of one to two milligrams daily, and it prevents AA amyloidosis
• The Gattorno 2019 Eurofever classification separates the hereditary recurrent fevers by the discriminating clinical features of each syndrome
• Synthesises the recognition, investigation and pathway-targeted management of the periodic fever syndromes into a single bedside plan shared with paediatric rheumatology and clinical immunology
• Counsels the family of a child with familial Mediterranean fever on the lifelong colchicine, the amyloidosis surveillance, and the genetic and reproductive implications
• Distinguishes PFAPA from the hereditary periodic fevers and builds the corticosteroid-abort and tonsillectomy pathway with an honest prognosis
• Level 1: Recognition of the clinical phenotype of the periodic fever syndromes and the clockwork fever signature
• Level 2: Application of the classification criteria and the colchicine and interleukin-one treatment pathways
• Level 3: Coordination of biologic therapy, amyloidosis surveillance and transition for the severe monogenic syndromes
• The distinction between autoinflammatory and autoimmune disease, with the periodic fever syndromes as the archetype of innate, antigen-independent inflammation
• The inflammasome and interleukin-one-beta pathway as the unifying mechanism across the NLRP3, MEFV, MVK and TNFRSF1A defects
• The colchicine treatment of familial Mediterranean fever and the interleukin-one blockade of the cryopyrin-associated periodic syndromes and mevalonate kinase deficiency
• Structured assessment of the child with recurrent fever for the clockwork interval, the attack features and the complete wellness between attacks
• Recognition that familial Mediterranean fever presents with short serositis attacks and a Mediterranean ethnic background, and that colchicine prevents amyloidosis
• Communication of the lifelong nature of the disease, the biologic therapy and the safety-net for sepsis to the child and family
• The hereditary periodic fever syndromes as monogenic autoinflammatory diseases with recurrent self-limited inflammatory attacks and no autoantibodies
• The inflammasome and interleukin-one pathophysiology and the gene defects of NLRP3, MEFV, MVK and TNFRSF1A
• Colchicine for familial Mediterranean fever and interleukin-one blockade for the cryopyrin-associated periodic syndromes and mevalonate kinase deficiency
• Recognition of the clinical features of the periodic fever syndromes and the clockwork fever signature
• The distinction between autoinflammatory and autoimmune disease and the role of the inflammasome
• Coordination of the diagnostic pathway and the pathway-targeted therapy with the specialist centre
• Canadian approach to the recognition and treatment of the periodic fever syndromes with colchicine and interleukin-one blockade
• The Gattorno 2019 Eurofever classification criteria and the Livneh criteria for familial Mediterranean fever
• The management of refractory disease with biologics and the amyloidosis surveillance for familial Mediterranean fever