Periodic fever and autoinflammatory syndromes — formative SAQs

SAQ 1 (10)

A six-year-old boy of Lebanese background has had fevers every four to five weeks for two years. Each attack lasts two days, with severe central abdominal pain and a tender right knee that swells for a day. Between attacks he is completely well and grows along the fiftieth centile. His father had a renal transplant at thirty-two for amyloidosis. [3]

1. Give the most likely diagnosis and the clinical criteria you would apply. (3) [3]
2. Outline your definitive management, naming the first-line agent, its purpose, and the long-term complication you must prevent. (4) [4]
3. Explain why this disease is classified as autoinflammatory rather than autoimmune, and how that distinction guides the treatment. (3) [1]

Model answer

Diagnosis and criteria. The most likely diagnosis is familial Mediterranean fever. The one-to-two-day attacks of fever with serositis (abdominal pain from peritonitis and a transient monoarthritis), the Mediterranean ethnic background, the family history of amyloidosis leading to a renal transplant, and the complete wellness with normal growth between attacks, are the classical phenotype. I would apply the Livneh 1997 clinical criteria, which combine the typical attack pattern with the ethnic predisposition and the family history, and a response to colchicine supports the diagnosis. I would confirm with MEFV gene testing and exclude the surgical abdomen at the first presentation. [3]

Definitive management. The first-line treatment is colchicine, taken orally, lifelong. Colchicine reduces both the frequency and the severity of the attacks, and it is the only treatment proven to prevent the AA amyloidosis that caused his father's renal failure. I would start it at a low dose and titrate to the response, and I would build the adherence and the surveillance from the outset. The long-term complication I must prevent is the AA amyloidosis, monitored with a regular urinalysis for proteinuria and a serum creatinine, and the serum amyloid A can guide the titration. For the colchicine-resistant disease I would add an interleukin-one blockade such as canakinumab. [4]

Autoinflammatory versus autoimmune. Familial Mediterranean fever is autoinflammatory because it is driven by the innate immune system, the pyrin inflammasome and the interleukin-one-beta, in an antigen-independent manner, with no autoantibodies. Autoimmune disease, by contrast, is adaptive and self-antigen-driven. The distinction guides the treatment: the disease responds to the colchicine and the interleukin-one blockade, which target the innate pathway, rather than to the autoantibody-directed immunosuppression that governs the autoimmune diseases. [1]

SAQ 2 (10)

A two-year-old has had fevers every five weeks for a year. Each attack lasts four days, with a high fever, a red inflamed throat, mouth ulcers, and tender swollen cervical glands. Between attacks she is entirely well and grows normally. Her parents keep a diary showing the clockwork regularity. [7]

1. Give the most likely diagnosis, and name the single most important alternative you must exclude before confirming it. (3) [7]
2. Outline your management for the acute attacks and for the refractory case, and state the prognosis. (4) [7]
3. Explain why the corticosteroid-abort, though effective, must not be used to confirm the diagnosis before the hereditary syndromes are excluded. (3) [1]

Model answer

Diagnosis and the exclusion. The most likely diagnosis is PFAPA, the periodic fever with aphthous stomatitis, pharyngitis and adenitis. The clockwork five-week interval, the four-day attacks with the triad of pharyngitis, aphthae and cervical adenitis, the high fever, and the complete wellness with normal growth between attacks, are the classical phenotype described by Marshall and refined by Thomas. The diagnosis is clinical, made after exclusion, and the most important alternative I must exclude is the hereditary periodic fever syndrome, because the same phenotype can be the presentation of a monogenic disease such as mevalonate kinase deficiency or familial Mediterranean fever. [7]

Management and prognosis. The abortive management of the acute attack is a single dose of an oral corticosteroid, such as prednisolone, given at the very start of the attack, which aborts it within hours in most children. For the severe and refractory cases that disrupt the family life and the schooling despite the corticosteroid, the option is the tonsillectomy, which is supported by the randomised trials. The prognosis is excellent: PFAPA resolves spontaneously over years, with no long-term sequelae and no amyloidosis, and the family can be reassured that the child will outgrow it. [7]

Why the corticosteroid must not confirm the diagnosis. A single dose of corticosteroid will abort a PFAPA attack, but it will also transiently quieten a hereditary periodic fever, masking the phenotype and delaying the diagnosis of a monogenic disease. If I label the child as PFAPA and treat the attacks with the corticosteroid before excluding the hereditary syndromes, the underlying gene defect goes untreated, and the amyloidosis risk of familial Mediterranean fever or the organ damage of the cryopyrin spectrum accumulates silently. The defence is to exclude the hereditary syndromes, with the fever diary, the targeted gene panel and the ethnic and family history, before the diagnosis of PFAPA is made. [1]