Familial Mediterranean fever: an animated, cited guide

This page needs JavaScript for its animations. The outline and key answers are below, and every claim in the full version carries a numbered citation.

Not medical advice. FMF Companion is an educational synthesis of published literature. It does not replace a clinician.

What is in it

What FMF is Who gets it, the numbers, and what an attack looks like.
The gene and inheritance MEFV, pyrin, the common variants and an animated Punnett square.
Pyrin, animated How pyrin guards RhoA, and what FMF variants change.
An attack, hour by hour 72 hours of fever, pain, CRP and SAA, site by site.
Colchicine inside the cell From the pill to the neutrophil to the microtubule.
Colchicine over months Why the benefit builds slowly, and what it prevents.
Dosing, safety and interactions What the guidelines and the label publish.
AA amyloidosis Serum amyloid A to fibril to kidney, over years.
Diagnosis and criteria Tel Hashomer, Livneh and the Eurofever/PRINTO calculator.
The differential TRAPS, MKD, CAPS, PFAPA, Behçet and the surgical abdomen.
The treatment ladder Colchicine first, then IL-1 blockade.
Living with FMF Pregnancy, surgery, school, triggers and monitoring.
Toward a cure What a cure would need, and the evidence for each route.
History and people 1908 to the discovery that pyrin senses RhoA.
Flashcards, quiz and glossary Revision for students.
Sources Every reference behind the app.

Part 3 · Complications & diagnosis

AA amyloidosis

The most serious complication of uncontrolled FMF builds silently over years. The liver keeps making serum amyloid A (SAA), a fragment of it misfolds into fibrils, and the fibrils clog the kidney's filters. Press play to watch two decades, then switch to "SAA brought below 10 mg/L" to see what controlling inflammation changes.

SAA between attacks

Years

Schematic. The time axis follows the reported median of about 17 years from onset of inflammation to diagnosis, which varies greatly between people. Deposits are drawn in Congo-red colour. The controlled mode reflects Lachmann 2007 (deposits regressed in 60% of patients with median SAA below 10 mg/L), not a prediction for anyone.

Organs fill in with the timeline above (schematic shading). Frequencies from EULAR 2016 and a 2024 review. ^177,199

Under the microscope: Congo red

Sample

Polarizer angle

Schematic colours. Real slides vary with section thickness, stain quality and fibril orientation.

Who is at risk

Log scale. Each bar is an odds ratio (or risk ratio, for M694V in Kasifoglu 2014) from a different study, population and statistical model. They are not comparable with each other and cannot be multiplied into a personal risk. The SAA1 and male-sex figures come from one mainly Armenian cohort; a separate study of 124 M694V homozygotes put male sex lower, at OR 2.37, alongside arthritic attacks at OR 3.27. ^{34,78,121,262,273}

Factors without a single number

Family history of amyloidosisDelayed diagnosisPoor adherenceInadequate doseArthritisInfectionsMICA allelesBeing the first diagnosed in the familyLonger disease duration

These are listed as risk factors in reviews and cohorts without an effect size attached. ^{89,121,262,273}

Delayed diagnosis raised amyloidosis frequency from 2.6% to 10% in one cohort, and M694V homozygotes develop amyloidosis earlier (about age 27) than heterozygotes (about age 41). ⁸⁹

Why country matters most

In 2,482 genetically confirmed patients from 35 centres in 14 countries, country of recruitment was the strongest risk factor, ahead of M694V homozygosity. Country risk tracked infant mortality, which points to an environmental factor. Amyloidosis was reported in about 24% of Armenians in Armenia but was essentially absent among Armenian Americans in California. ^231,262

How common, then and now

Year

What else to know

Why colchicine prevents it even if attacks persist

Amyloid is built from SAA, so risk follows how much SAA is made over years, not just how many attacks occur. SAA can stay raised between attacks. In 26 children with no attacks in the previous year but high SAA, raising the colchicine dose lowered median SAA from 244 to 35.5 mg/L by the 2-month recheck. In Zemer's 1,070-patient cohort, cumulative proteinuria was 1.7% at 11 years in adherent patients versus 48.9% at 9 years in those who said they were not taking it regularly. ^58,141,286

Treating established amyloidosis

EULAR 2016 advises intensifying to the maximum tolerated colchicine dose plus biologics as needed; the 2024 update frames add-on therapy the same way, with IL-1 blockers the best supported. In 68 patients with FMF amyloidosis followed at least 5 years, proteinuria regressed in 15, and worsening was linked to starting creatinine ≥1.5 mg/dL and to doses ≤1.5 mg/day. A 2025 systematic review found the evidence for treating established disease observational but judged it reassuring; retrospective data suggest tocilizumab may help selected patients. ^{158,172,199,203,229}

Amyloid storm

A rapid deterioration, often set off by infection: creatinine and proteinuria at least double and CRP rises more than tenfold within 2 weeks. In a 20-patient series, 16 reached end-stage kidney disease or death within a year (3 of 20 controls); infection triggered 17 of the 20 storms. ^89,139

Eprodisate Mixed evidence

A drug that interferes with fibril formation. In the 183-patient EFAST trial, worsening kidney function or death occurred in 27% vs 40% on placebo (P = 0.06; HR 0.58), with slower clearance decline but no significant effect on dialysis or death. The 261-patient confirmatory phase 3 trial missed its primary endpoint in 2016. ^48,126

Kidney transplantation

Egypt, living donors (23 amyloid recipients, 16 FMF): graft survival like controls; 10-year patient survival 68% vs 87%; recurrence in 1. ²³⁷
Turkey, 17 FMF recipients: about 89–90% graft and patient survival at 5 years; recurrence in 2. ¹²⁴
Israel: survival 73% vs 84% at 5 years and 39% vs 63% at 15 years. ⁸⁸

Cardiovascular disease drives post-transplant deaths; recurrence in the graft has become rare. ¹⁷⁷

Phenotype II

Amyloidosis before, or instead of, typical attacks. It is uncommon: among 461 relatives of FMF-amyloidosis patients, only 2 had significant proteinuria without symptoms, and their rectal biopsies showed no amyloid. Estimates differ: at most 0.3% of the 2,838-patient Turkish registry, and about 0.6% in a later review, whose authors also doubt it is a separate entity. ^89,171,264

Monitoring

EULAR 2016: urinalysis at every visit to exclude proteinuria. ¹⁹⁹
In amyloidosis, frequent SAA with a target below 10 mg/L, plus proteinuria and GFR; CRP is an imperfect substitute. ¹⁹⁹
The 2024 update asks for complete, sustained control of biochemical inflammation. ^203,222
Amyloid kidneys are sensitive to low blood flow, high blood pressure, nephrotoxic drugs and surgery. ¹⁹⁹

Why it matters

Leading cause of deathIn a Turkish cohort of 587 patients, amyloidosis was the leading cause of death and the only significant predictor of mortality. In an Israeli cohort of 1.25 million adolescents (1,225 with FMF), mortality was higher with FMF, and kidney amyloidosis caused 35% of deaths in men and 60% in women with FMF. ^2,266

Exam hookAA amyloid = SAA (122 aa) → AA (76 aa) → cross-β fibrils. Kidney first shows as proteinuria. Diagnosis: Congo red + apple-green birefringence, anti-SAA immunohistochemistry. Target: SAA < 10 mg/L.

In plain wordsYears of hidden inflammation let a blood protein pile up in the kidneys as sticky threads. Keeping inflammation fully switched off, even between attacks, stops the pile-up and can let some of it clear slowly. That is why urine and blood tests matter even when someone feels well.