AA amyloidosis in familial Mediterranean fever: a comparative study of clinical and genetic features between Algerian probands and their relatives.

AA amyloidosis is the most severe complication of familial Mediterranean fever (FMF). Why some patients develop amyloidosis while genotype-identical relatives remain unaffected is unknown. We assessed whether genetic counseling helps to identify at-risk relatives and whether inflammatory activity, rather than MEFV genotype, drives amyloidosis. We conducted a single-center comparative study (1998-2025) including 52 Algerian FMF probands with biopsy-proven AA amyloidosis and 30 first- or second-degree relatives with biallelic MEFV mutations who also had FMF but no amyloidosis. All underwent clinical, laboratory and MEFV genotyping (exons 2,3,5,10). Only individuals with two MEFV mutations (homozygous or compound heterozygous) were included. Multivariable logistic regression identified independent predictors of amyloidosis. The M694I/M694I genotype was equally frequent in both groups (71.2% vs. 66.7%, p = 0.67). In univariable analysis, it was not associated with amyloidosis (OR 1.23, 95% CI 0.48-3.16, p = 0.67). Independent drivers of amyloidosis were identified by multivariable logistic regression: attack duration > 72 h (adjusted odds ratio [aOR] 3.21, 95% CI 1.41-7.31, p = 0.006), attack interval < 3 months (aOR 4.12, 95% CI 1.77-9.58, p < 0.001), and baseline CRP > 100 mg/L (aOR 2.91, 95% CI 1.23-6.88, p = 0.014). Only 9.6% of amyloidosis patients achieved normalised CRP (< 5 mg/L) under colchicine, compared to 86.7% of relatives (p < 0.001). Strikingly, among amyloidosis patients who achieved CRP normalisation, 57.7% required 1.5 mg/day of colchicine and 7.7% required 2 mg/day, whereas 86.7% of amyloid-free relatives achieved normalisation with only 1 mg/day, highlighting the higher inflammatory burden in patients who develop amyloidosis despite carrying the same MEFV genotype. Genetic counseling allowed screening of 30 relatives without amyloidosis. Inflammation, not MEFV genotype, dictates AA amyloidosis in FMF. Genetic counseling is essential to identify at-risk relatives. Treatment should target complete CRP normalisation regardless of genotype.