Clinical and genetic characteristics of familial Mediterranean fever-associated vasculitides in children of Armenia

Family Mediterranean fever (FMF), or a periodic disease, is the most common hereditary disease among Armenians. FMF manifests mainly in childhood, presenting a significant problem for the pediatric health care system in Armenia. The clinical presentations of FMF have much in common with that of vasculitides: fever, abdominal pains, arthritis, myalgias, and skin damage. The data available in the literature indicate the high incidence of vasculitides in patients with FMF in the ethnically significant groups compared with the general population.

Objective: to investigate the clinical and genetic characteristics of FMF-associated vasculitides in children of Armenia. Subjects and methods. The National Pediatric FMF Center, Arabkir Medical Complex, Institute of Child and Adolescent Health, examined a group of 715 children (438 boys, 277 girls; mean age, 8.64+0.17 years) with FMF. The diagnosis of FMF was confirmed using the Tel-Hashomer criteria and the MEFV gene mutation analysis. The Epi-Info 2000 program was used for statistical analysis.

Results and discussion. The rate of vasculitides was 4.3% (n=31), being generally higher than expected. In particular, the diagnoses made were Henoch-Scho nlein pirpura (HSP) in 11 (1.5%) children, protracted febrile myalgia (PFM) in 20 (2.7%), and Behcet’s disease (BD) in 1 (0.1%) patient. The patients were characterized by early-onset FMF (at an average of 3 years) with a moderate/severe course, frequent episodes, a predominance of articular syndrome, more commonly acute relapsing arthritis, with the addition of clinical presentations of vasculitis on average 5—6 years after the onset of FMF, and genetically by the M694V homozygous genotype (M694V/M694V). HSP and PFM were observed in 2.9 and 4.6% of patients with the M694V homozygous genotype, respectively (p<0.02).

Conclusion. The rate of FMF-associated vasculitides in the children of Armenia was 4.3%: HSP, PFM, and BD were diagnosed in 1.5, 2.7, and 0.1% of patients, respectively. The findings allow HSP and PFM to be considered as additional markers for the severe course of FMF and the M694V homozygous genotype as a risk factor for PFM. They also indicate the feasibility of the MEFV gene mutation screening in children with vasculitides in Armenia for an association with FMF for early diagnosis of the disease, timely administration of colchicine, and prevention of complications.

1. Torosyan Y, Aksentijevich I, Sarkisian T, et al. Role of complex allels and gender in susceptability to FMF in the Armenian population. Am JHum Genet. 2000;67(4):Suppl. 2.

2. Airapetyan AS. Geneticheskie aspektyperiodicheskoi bolezni u armyan [Genetic aspects of periodic illness in Armenians]. Avtoref. dis. ... dokt. biol. nauk. Erevan; 2002. 36 p. (In Russ.).

3. Amaryan GG. Periodicheskaya bolezn'u detei: kliniko-genetich-eskie aspekty i sovremennye podkhody k lecheniyu [Periodic disease in children: clinical and genetic aspects and modern approaches to treatment]. Avtoref. dis. ... dokt. med. nauk. Erevan; 2010. 37 p. (In Russ.).

4. Ozen S, Acar-Ozen NP. Recent advances in childhood vasculitis. Curr Opin Rheumatol. 2017;29:530-4. doi: 10.1097/B0R.0000000000000424

5. Ozdogan H, Arisoy N, Kasap Kapur O, et al. Vasculitis in FMF. J Rheumatol. 1997;24:323-7.

6. Livneh A, Langevitz P, Zewer D, et al. Criteria for the diagnosis of FMF. Arthritis Rheum. 1997;40:1879-85. doi: 10.1002/art.1780401023

7. Mor A, Rivka G, Livneh A. Abdominal and Digestive Systems associations of FMF. Am J Gastroenterol. 2003;98:2594-604. doi: 10.1111/j.1572-0241.2003.08784.x

8. Sachs D, Langevitz P, Morag B, Pras M. Polyarteritis nodosa and FMF. Rheumatology. 1987;26:139-41. doi: 10.1093/rheumatol-ogy/26.2.139

9. Kone P, Dulbuc M, Sportouch J, et al. Phenotype-genotype correlation in 91 patients with FMF reveals a high frequency of curta-neomucous features. Rheumatology. 2000;39:1275-9. doi: 10.1093/rheumatology/39.11.1275

10. Balbir-Gurman A, Menahem-Nahi A, Braun-Moscovici Y. Vasculitis in siblings with FMF: a report of three cases and revew of the literature. Clin Rheumatol. 2007;26:1183-5. doi: 10.1007/s10067-006-0323-1

11. Giese A, Wittkowski H, Ornek A, et al. Markers of inflammationin adult patients with FMF. 7th International Congress of FMF and AIDs.2013; Abstarct YPW01-007.

12. Taylan A. Leukocytoclastic vasculitis in a patinet with FMF. 7th International Congress of FMF and AIDs. 2013; Abstract YPW02-008.

13. Soyli A, Kasap B, Turkmen M, et al. Febrile myalgia syndrome in FMF. J Clin Rheumatol. 2006;12:93-6. doi: 10.1097/01.rhu.0000208635.64537.10

14. Ozcakar ZB, Yalsinkaya F, Yuksel S, Ekim M. The expanded clinical spectrum of FMF. Clin Rheumatol. 2008;26:1557-60. doi: 10.1007/s10067-006-0447-3

15. Rabinovich E, Livneh A, Langevitz P, et al. Severe disease in patients with rheumatoid arthritis carrying a mutation in the FMF gene. Ann Rheum Dis. 2005;64:1009-14. doi: 10.1136/ard.2004.029447

16. Abbara S, Grateau G, Ducharme-Benard S, et al. Association of Vasculitis and Familial Mediterranean Fever. Front Immunol. 2019;10:763. doi: 10.3389/fimmu.2019.00763

17. Ter-Kasparova MR. Organopatologiya periodicheskoi bolezni [Organopathology of a periodic disease]. Erevan; 2002. 165 p. (In Russ.)

18. Sarkisian T, Hayrapetyan H, Shahsuvaryan G. Molecular Study of FMF patients in Armenia. Curr Drug Targ Inflam Allergy. 2005;4(1):113-6. doi: 10.2174/1568010053622885

19. Dawson B, Trapp R. Basic and clinical biostatistics Lange medical Book s. McGraw Hill; 2001.

20. Lange-Sperandio B, Mohring K, Gutzler F, Mehls O. Variable expression of vasculitis in siblings with FMF. Pediatr Nephrol. 2004;19:539-43. doi: 10.1007/s00467-004-1440-1