Gülçin OTAR YENER, Selcuk YUKSEL, Zahide EKİCİ TEKİN, Hülya TÜRKMEN

Ailesel Akdeniz ateşi hastalarında romatizmal hastalıkların sıklığı

Amaç: Ailesel Akdeniz ateşine (FMF) neden olan Mediterranean FeVer (MEFV) genindeki mutasyonlarbaşka spesifik romatizmal hastalıkların da ortaya çıkmasına neden olabilir. Bu çalışmanın amacı pediatrikFMF hastalarında diğer romatizmal hastalıkların sıklığını belirlemek, eşlik eden romatizmal hastalığı olan veolmayanlar arasında klinik ve genetik farklılık olup olmadığını değerlendirmek ve verileri önceki çalışmalarlakarşılaştırmaktır.Gereç ve yöntem: Çocuk romatoloji bölümünde takip edilen FMF hastalarının dosyaları retrospektif olarakincelendi. Dosyalardan demografik veriler, MEFV mutasyonları, tedavi, hastalık şiddet skorları ve eşlik edenromatizmal hastalıkları kaydedildi.Bulgular: 303 FMF hastası (154 kadın/149 erkek) vardı. Ortalama tanı yaşı 7,04±3,9 idi. Ortalama hastalıksüresi 5,33±3,13 yıldı. Kohortta 41 FMF hastasına (%13,5) başka bir romatizma hastalığı teşhisi kondu. 22juvenil idiyopatik artrit (%53,6), yedi vaskülit (%17), altı periyodik ateş aftöz stomatit ve adenit sendromu(%14,6), üç Behçet hastalığı (%7,3), iki akut romatizmal ateş (%4,8) ve bir sistemik lupus eritematozus (%2,4)olgusu vardı. Bu 41 FMF hastasının 32'sinde (%78) M694V mutasyonu vardı (11’i homozigot, 21’i heterozigot).Hastalık şiddet skorları Pras ve ISSF skorları romatizmal hastalığı olan FMF hastalarında daha yüksekti(sırasıyla p=0.002 ve p<0.001).Sonuç: FMF hastalarında diğer romatolojik hastalıklar da değerlendirilmelidir. Eşlik eden diğer romatizmalhastalıklarda ise M694V mutasyonu ve hastalık şiddet skorları önemli faktörlerdir.

Anahtar Kelimeler:

Ailesel Akdeniz ateşi, romatizmal hastalık, MEFV mutasyonu

Frequency of rheumatic diseases in patients with familial Mediterranean fever

Purpose: Mutations in the Mediterranean FeVer (MEFV) gene, which causes familial Mediterranean fever(FMF), may also cause the emergence of other specific rheumatic diseases. This study aims to determine thefrequency of other rheumatologic diseases in paediatric FMF patients, evaluate whether there are clinical andgenetic differences between those with and without concomitant rheumatologic diseases, and compare the datawith previous studies.Materials and methods: The files of FMF patients who were followed up at the paediatric rheumatologydepartment were reviewed retrospectively. Demographic data, MEFV mutations, treatment, disease severityscores, and concomitant rheumatic diseases were recorded from the files.Results: There were 303 FMF patients (154 female/149 male). The mean age at diagnosis was 7.04±3.9 years.The mean disease duration was 5.33±3.13 years. In the cohort, 41 FMF patients (13.5%) were diagnosed withanother rheumatic disease. There were 22 cases of juvenile idiopathic arthritis (53.6%), seven cases of vasculitis(17%), six cases of periodic fever aphthous stomatitis and adenitis syndrome (14.6%), three cases of Behçet’sdisease (7.3%), two cases of acute rheumatic fever (4.8%), and one case of systemic lupus erythematosus(2.4%). Thirty-two of these of these 41 FMF patients (78%) had the M694V mutation (homozygous in 11,heterozygous in 21). Disease activity scores Pras and ISSF scores were higher in FMF patients with rheumaticdiseases (p=0.002 and p<0.001, respectively).Conclusion: Other rheumatologic diseases should be evaluated in FMF patients. Regarding other accompanyingrheumatic diseases, the M694V mutation and disease severity scores are notable factors.

Keywords:

Familial Mediterranean fever, rheumatic disease, MEFV mutation.,

PDF

___

1. Ben-Chetrit E, Levy M. Familial Mediterranean fever. Lancet 1998;351:659-664. https://doi.org/10.1016/S0140-6736(97)09408-7
2. French FMF Consortium. A candidate gene for familial Mediterranean fever. Nat Genet. 1997;17:25-31. https://doi.org/10.1038/ng0997-25
3. Chae JJ, Cho YH, Lee GS, et al. Gain-of-function Pyrin mutations induce NLRP3 protein-independent interleukin-1β activation and severe autoinflammation in mice. Immunity. 2011;34:755-768. https://10.1016/j.immuni.2011.02.020
4. Baykal Y, Saglam K, Yilmaz MI, Taslipinar A, Akinci SB, Inal A. Serum sIL-2r, IL-6, IL-10 and TNF-alpha level in familial Mediterranean fever patients. Clin Rheumatol. 2003;22:99-101. https://10.1007/s10067-002-0682-1
5. Kiraz S, Ertenli I, Arici M, et al. Effects of colchicine on inflammatory cytokines and selectins in familial Mediterranean fever. Clin Exp Rheumatol. 1998;16:721-724.
6. Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study. Medicine (Baltimore). 2005;84:1-11. https://10.1097/01.md.0000152370.84628.0c
7. Özçakar ZB, Çakar N, Uncu N, Çelikel BA, Yalçinkaya F. Familial Mediterranean fever-associated diseases in children. QJM. 2017;110:287-290. https://10.1093/qjmed/hcw230
8. Kişla Ekinci RM, Balci S, Ufuk Altintaş D, Yilmaz M. The Influence of Concomitant Disorders on Disease Severity of Familial Mediterranean Fever in Children. Arch Rheumatol. 2017;33:282-287. https://10.5606/ArchRheumatol.2018.6488
9. Yildiz M, Adrovic A, Tasdemir E, et al. Evaluation of co-existing diseases in children with familial Mediterranean fever. Rheumatol Int. 2020;40:57-64. https://10.1007/s00296-019-04391-9
10. Balcı-Peynircioğlu B, Kaya-Akça Ü, Arıcı ZS, et al. Comorbidities in familial Mediterranean fever: analysis of 2000 genetically confirmed patients. Rheumatology (Oxford). 2020;59:1372-1380. https://10.1093/rheumatology/kez410
11. Ayaz NA, Tanatar A, Karadağ ŞG, Çakan M, Keskindemirci G, Sönmez HE. Comorbidities and phenotype-genotype correlation in children with familial Mediterranean fever. Rheumatol Int. 2021;41:113-120. https://10.1007/s00296-020-04592-7
12. Yalçinkaya F, Ozen S, Ozçakar ZB, et al. A new set of criteria for the diagnosis of familial Mediterranean fever in childhood. Rheumatology (Oxford). 2009;48:395-398. https://10.1093/rheumatology/ken509
13. Ozen S, Ruperto N, Dillon MJ, et al. EULAR/PReS endorsed consensus criteria for the classification of childhood vasculitides. Ann Rheum Dis. 2006;65:936-941. https://10.1136/ard.2005.046300
14. Guidelines for the diagnosis of rheumatic fever. Jones Criteria, 1992 update. Special Writing Group of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young of the American Heart Association JAMA. 1992;268:2069-2073.
15. Petty RE, Southwood TR, Manners P, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004;31:390-392. 16. Thomas KT, Feder HM Jr, Lawton AR, Edwards KM. Periodic fever syndrome in children. J Pediatr. 1999;135:15-21. https://10.1016/s0022-3476(99)70321-5
17. Koné-Paut I, Shahram F, Darce-Bello M, et al. Consensus classification criteria for paediatric Behçet's disease from a prospective observational cohort: PEDBD. Ann Rheum Dis. 2016;75:958-964. https://10.1136/annrheumdis-2015-208491
18. Petri M, Orbai AM, Alarcón GS, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012;64:2677-2686. https://10.1002/art.34473
19. Pras E, Livneh A, Balow JE Jr, et al. Clinical differences between North African and Iraqi Jews with familial Mediterranean fever. Am J Med Genet. 1998;75:216-219. https://10.1002/(sici)1096-8628(19980113)75:2<216::aid-ajmg20>3.0.co;2-r
20. Ozen S, Aktay N, Lainka E, Duzova A, Bakkaloglu A, Kallinich T. Disease severity in children and adolescents with familial Mediterranean fever: a comparative study to explore environmental effects on a monogenic disease. Ann Rheum Dis. 2009;68:246-248. https://10.1136/ard.2008.092031
21. Demirkaya E, Acikel C, Hashkes P, et al. Development and initial validation of international severity scoring system for familial Mediterranean fever (ISSF). Ann Rheum Dis. 2016;75:1051-1056. https://10.1136/annrheumdis-2015-208671
22. Brik R, Shinawi M, Kasinetz L, Gershoni-Baruch R. The musculoskeletal manifestations of familial Mediterranean fever in children genetically diagnosed with the disease. Arthritis Rheum. 2001;44:1416-1419. https://10.1002/1529-0131(200106)44:6<1416::AID-ART236>3.0.CO;2-6
23. Rozenbaum M, Rosner I. Severe outcome of juvenile idiopathic arthritis (JIA) associated with familial Mediterranean fever (FMF). Clin Exp Rheumatol. 2004;22:S75-S78.
24. Sönmez HE, Batu ED, Demir S, Bilginer Y, Özen S. Comparison of patients with familial Mediterranean fever accompanied with sacroiliitis and patients with juvenile spondyloarthropathy. Clin Exp Rheumatol. 2017;35 Suppl 108:124-127.
25. Aydin F, Özçakar ZB, Çakar N, et al. Sacroiliitis in Children With Familial Mediterranean Fever. J Clin Rheumatol. 2019;25:69-73. https://10.1097/RHU.0000000000000770
26. Ozer E, Seker D, Taner E, et al. The frequency of juvenile spondyloarthropathies in childhood familial Mediterranean fever. Clin Exp Rheumatol. 2018;36:141-145.
27. Gülhan B, Akkuş A, Ozçakar L, Beşbaş N, Ozen S. Are MEFV mutations susceptibility factors in enthesitis-related arthritis patients in the eastern Mediterranean?. Clin Exp Rheumatol. 2014;32:S160-S164.
28. Bayram C, Demircin G, Erdoğan O, Bülbül M, Caltik A, Akyüz SG. Prevalence of MEFV gene mutations and their clinical correlations in Turkish children with Henoch-Schönlein purpura. Acta Paediatr. 2011;100:745-749. https://10.1111/j.1651-2227.2011.02143.x
29. Ozçakar ZB, Yalçinkaya F, Cakar N, et al. MEFV mutations modify the clinical presentation of Henoch-Schönlein purpura. J Rheumatol. 2008;35:2427-2429. https://10.3899/jrheum.080405
30. Ozdogan H, Arisoy N, Kasapçapur O, et al. Vasculitis in familial Mediterranean fever. J Rheumatol. 1997;24:323-327.
31. Adrovic A, Sahin S, Barut K, Kasapcopur O. Familial Mediterranean fever and periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome: shared features and main differences. Rheumatol Int. 2019;39:29-36. https://10.1007/s00296-018-4105-2
32. Dagan E, Gershoni-Baruch R, Khatib I, Mori A, Brik R. MEFV, TNF1rA, CARD15 and NLRP3 mutation analysis in PFAPA. Rheumatol Int. 2010;30:633-636. https://10.1007/s00296-009-1037-x
33. Pehlivan E, Adrovic A, Sahin S, Barut K, Kul Cınar O, Kasapcopur O. PFAPA Syndrome in a Population with Endemic Familial Mediterranean Fever. J Pediatr. 2018;192:253-255. https://10.1016/j.jpeds.2017.08.078 34. Gunes M, Cekic S, Kilic SS. Is colchicine more effective to prevent periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis episodes in Mediterranean fever gene variants?. Pediatr Int. 2017;59:655-660. https://10.1111/ped.13265
35. Butbul Aviel Y, Tatour S, Gershoni Baruch R, Brik R. Colchicine as a therapeutic option in periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome. Semin Arthritis Rheum. 2016;45:471-474. https://10.1016/j.semarthrit.2015.07.005
36. Kalyoncu M, Acar BC, Cakar N, et al. Are carriers for MEFV mutations "healthy"? Clin Exp Rheumatol. 2006;24:S120-S122.
37. Ozen S, Bakkaloglu A, Yilmaz E, et al. Mutations in the gene for familial Mediterranean fever: do they predispose to inflammation?. J Rheumatol. 2003;30:2014-2018.