Familial Mediterranean Fever (FMF) and hereditary periodic fever syndromes

What changes during this transition

Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease — autosomal recessive (with some heterozygotes manifesting), caused by mutations in MEFV on chromosome 16p13.3 encoding pyrin. Pyrin normally regulates the inflammasome; loss-of-function and gain-of-function MEFV variants release IL-1β production from its normal restraint, producing recurrent self-limited attacks of 12-72 hours with the cardinal features: fever, SEROSITIS (peritonitis, pleuritis, synovitis, scrotal pain in males), and erysipelas-like erythema typically on the lower leg or ankle. Between clinically apparent attacks patients carry SUBCLINICAL INFLAMMATION with elevated CRP and serum amyloid A (SAA), and that subclinical inflammation drives the leading long-term complication of untreated disease — AA AMYLOIDOSIS — which causes progressive renal failure historically and remains the dominant mortality driver in patients without adequate disease control. The entire standard-of-care framework since Goldfinger's 1972 discovery has been built around suppressing this subclinical inflammation, not just controlling attacks. Colchicine has been first-line therapy since 1972 — lifelong daily dosing that prevents both attacks and AA amyloidosis. Adherence is the dominant clinical issue. True colchicine-resistant FMF (~5-10% of patients) is now managed with IL-1 blockade, and the field was transformed by CANAKINUMAB (Ilaris, Novartis), an anti-IL-1β monoclonal antibody FDA-approved in 2016 for colchicine-resistant FMF, HIDS, and TRAPS (and originally CAPS) — SC every 4-8 weeks. ANAKINRA (Kineret, Swedish Orphan Biovitrum) is an IL-1 receptor antagonist used SC daily widely off-label for colchicine-resistant FMF with strong real-world evidence in Turkish, Israeli, and Armenian cohorts. RILONACEPT (Arcalyst, Regeneron) is an IL-1 trap SC weekly, FDA-approved for CAPS. The transformation of colchicine-resistant FMF since canakinumab's 2016 approval has been substantial — a population that historically progressed to AA amyloidosis and renal failure now achieves disease control with biologic IL-1 blockade. Related periodic fever syndromes share IL-1β biology and overlapping therapeutic options: CAPS (NLRP3 inflammasome gain-of-function — FCAS, MWS, NOMID/CINCA spectrum); TRAPS (TNFRSF1A); HIDS / mevalonate kinase deficiency (MVK); PFAPA (polygenic pediatric periodic fever, often self-limited through adolescence). Diagnosis: clinical criteria (Tel Hashomer / Livneh, Yalcinkaya pediatric) plus MEFV genotyping. Common variants: M694V (most severe, highest AA amyloidosis risk), M680I, V726A, E148Q (controversial). Workup covers CRP, SAA (load-bearing marker for subclinical inflammation surveillance), ESR, CBC, CMP with renal function, urinalysis with proteinuria screen and spot urine protein-to-creatinine ratio. FMF is fundamentally a multi-jurisdictional disease — concentrates in populations of Mediterranean ancestry (Sephardic Jewish carrier rate ~1/5-7, Armenian ~1/7, Turkish, Arab across Levant and Middle East, Italian especially southern Italian), with largest clinical cohorts and research programs in Turkey, Israel, Armenia. International FMF Foundation + Eurofever registry + INSAID consortium + Autoinflammatory Alliance + National Stem Cell Foundation coordinate research and advocacy. EULAR 2016 + 2024 recommendations anchor clinical standard-of-care. Cascade family screening, preconception MEFV testing, and PGT options are part of the conversation in carrier-rich communities. No peptide in the Juno library has a discovery-card-defensible FMF case. BPC-157 is the sharpest mechanism-vs-disease contradiction in the substrate — 'gut healing' community framing collides directly with FMF peritonitis attacks (serositis IS the disease), uncharacterized in autoinflammatory disease, pro-angiogenic VEGF / NO signaling against IL-1β-driven cytokine biology has no honest evidence base. NMN reaches the population through the general-aging channel in the aging-FMF demographic that emerged from sustained colchicine adherence + IL-1 blockade era. The GH-axis trio overlaps with chronic inflammatory disease body-composition framing and a more specific pediatric-FMF growth question where disease control with colchicine + IL-1 blockade is the lever, not community GH-axis stimulation; somatropin under pediatric endocrinology is the supervised pathway. Tesamorelin Rule 6 non-propagation is sharpest in the GH-axis trio. Semaglutide is the coordination-of-care conversation for obesity in long-term colchicine + biologic patients with GI-side-effect-versus-peritonitis-attack disambiguation as the load-bearing titration consideration. Eighty-sixth deliberate non-elevation.