Pharyngotonsillitis, aphthous stomatitis, and adenitis precede familial Mediterranean fever by two decades
Eli Magen, Suhail Aamar, Israel Magen, Eugene Merzon, Ilan Green, Avivit Golan‐Cohen, Shlomo Vinker, Ariel IsraelAbstract
Background
Familial Mediterranean fever (FMF) and periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome share innate‐immune features, but population‐level data on oropharyngeal morbidity before FMF recognition are lacking.
Objectives
To examine the magnitude, timing, specificity, and treatment burden of a PFAPA‐like oropharyngeal phenotype in patients later diagnosed with FMF.
Methods
Population‐based matched case–control study in Leumit Health Services, Israel. FMF patients with colchicine dispensing ( n = 3324) were matched 1:4 by birth year and sex to 13,296 controls. Oropharyngeal diagnoses, tonsil/adenoid surgery, antibiotic dispensing, and ear, nose, and throat (ENT) visits were compared across windows up to 20 and 10 years before diagnosis (30‐day blackout), using streptococcal, hypertrophy, and non‐ENT negative controls with false discovery rate (FDR) adjustment.
Results
A PFAPA diagnostic code was recorded in 2.6% of FMF patients versus 0.1% of controls (odds ratio [OR] 25.4, 95% confidence interval 14.3–48.5). Up to 20 years before diagnosis, future FMF patients had more acute tonsillitis (35.6% vs. 27.2%; OR 1.48, 1.37–1.61), viral‐labeled tonsillitis (OR 2.65), oral aphthae (OR 1.72), and cervical lymphadenitis (OR 1.62; all q < 0.05); associations persisted after diagnosis. Streptococcal sore‐throat coding was not increased (lifelong OR 1.03, 0.94–1.14). Antibiotic dispensing and ENT visits were increased; tonsillectomy alone was more frequent (OR 2.51), although surgical comparisons did not survive FDR correction.
Conclusions
FMF is associated with a non‐streptococcal, PFAPA‐like oropharyngeal phenotype detectable years before diagnosis. Recurrent pharyngotonsillitis with aphthae or cervical adenitis, without demonstrated streptococcal disease, may be a clinical cue to consider FMF in at‐risk populations.