Ailevi Akdeniz Ateşi Hastalığında Aksiyel Spondiloartrit Alt Grupları Arasında Klinik Bulguların ve Patojen Mutasyonların Karşılaştırılması

Öz

Bu çalışmada, Ailevi Akdeniz ateşi (FMF) hastalığı olan radyografik olan ve olmayan aksiyel spondiloartrit (aks-SpA) hastaları arasında, Akdeniz Ateşi (MEFV) gen mutasyonlarının ve FMF ilişkili klinik bulguların karşılaştırılması amaçlanmıştır. Çalışmada Ocak 2015-Temmuz 2020 tarihleri arasında FMF hastalığı tanısı ile takip edilmekte olan hastaların dosyaları retrospektif olarak incelendi. Hastaların genetik tetkikleri, klinik bulguları ve sakroilyak eklemin röntgen ve manyetik rezonans görüntüleme tetkikleri incelendi. Uluslararası Spondiloartrit Değerlendirme Birliği (ASAS) kriterlerine göre aks-SpA hastaları radyografik olan ve olmayan şeklinde gruplandırılarak çalışmaya dahil edildi ve bulgular gruplar arasında karşılaştırıldı. Aks-SpA tespit edilen toplam 36 hasta (24 radyografik, 12 radyografik olmayan) çalışmaya dahil edildi. Test sonuçlarına ulaşılabilen 11 aks-SpA hastasının hepsinde insan lökosit antijeni (HLA)B27 genetik test sonucu negatif bulundu. Radyografik olan ve olmayan aks-SpA hastaları arasında klinik bulgular, kolşisin yanıtı ve aile öyküsü farklı değildi. M694V mutasyonunun fenotipik frekansı radyografik olan ve olmayan aks-SpA grupları arasında sırasıyla, %91,7 ve %50,0 bulundu (p=0,005). V726A mutasyonunun fenotipik frekansı radyografik olan ve olmayan aks-SpA grupları arasında sırasıyla, %0 ve %25,0 bulundu (p=0,011). Sonuç olarak FMF’ye eşlik eden aks-SpA’nın alt grupları arasında FMF klinik bulguları farklı değildir. M694V mutasyonu röntgen bulgularının belirgin olduğu SpA alt grubunda, V726A mutasyonu da röntgen bulguları belirgin olmayan SpA alt grubunda daha sıktırlar ve bu mutasyonlar sık görüldükleri SpA alt gruplarının etyolojisinde rol oynuyor olabilirler.

Anahtar Kelimeler

• Ailevi Akdeniz ateşi
• M694V
• Spondiloartrit
• Sakroileit
• V726A

Comparison of Clinical Findings and Pathogenic Mutations Among Axial Spondyloarthritis Subgroups in Familial Mediterranean Fever Disease

Öz

In this study, it was aimed to compare the Mediterranean Fever (MEFV) gene mutations and familial Mediterranean fever (FMF)-related clinical findings between radiographic and non-radiographic axial spondyloarthritis (ax-SpA) patients with FMF disease. In the study, the charts of the patients who were followed up with a diagnosis of FMF disease between January 2015 and July 2020 were retrospectively examined. Genetic examinations, clinical findings and x-ray graphs and magnetic resonance imaginations of the sacroiliac joints were examined. According to The Assessment of Spondyloarthritis International Society (ASAS) criteria, ax-SpA patients were grouped as radiographic and non-radiographic, and the findings were compared between the groups. A total of 36 patients (24 radiographic, 12 non-radiographic) with ax-SpA were included in the study. Human leukocyte antigen (HLA) B27 genetic test results were negative in all 11 patients with ax-SpA whose test results were available. Clinical findings, colchicine response, and family history were not different between radiographic and non-radiographic ax-SpA patients. The phenotypic frequency of the M694V mutation was 91.7% and 50.0% among the radiographic and non-radiographic ax-SpA groups, respectively (p = 0.005). The phenotypic frequency of the V726A mutation was 0% and 25.0%, among the radiographic and non-radiographic ax-SpA groups, respectively (p = 0.011). As a result, FMF clinical findings are not different among subgroups of ax-SpA accompanying FMF. M694V mutation is more common in the SpA subgroup where X-ray findings are evident, and the V726A mutation is more common in the SpA subgroup with no X-ray findings, and these mutations may play a role in the etiology of the SpA subgroups in which they are common.

Anahtar Kelimeler

• Familial Mediterranean fever
• M694V
• Spondyloarthritis
• Sacroiliitis
• V726A

Kaynakça

1. 1. Dilsen N (1963) [Familial Mediterranean fever (periodic disease) associated with ankylopoietic spondylitis. (Apropos of a case)]. Turk Tip Cemiyeti mecmuasi 29:160-167
2. 2. Langevitz P, Livneh A, Zemer D, Shemer J, Pras M (1997) Seronegative spondyloarthropathy in familial Mediterranean fever. Seminars in arthritis and rheumatism 27 (2):67-72. doi:10.1016/s0049-0172(97)80007-8
3. 3. Kasifoglu T, Calisir C, Cansu DU, Korkmaz C (2009) The frequency of sacroiliitis in familial Mediterranean fever and the role of HLA-B27 and MEFV mutations in the development of sacroiliitis. Clinical rheumatology 28 (1):41-46. doi:10.1007/s10067-008-0980-3
4. 4. Akar S, Soysal O, Balci A, Solmaz D, Gerdan V, Onen F, Tunca M, Akkoc N (2013) High prevalence of spondyloarthritis and ankylosing spondylitis among familial Mediterranean fever patients and their first-degree relatives: further evidence for the connection. Arthritis research & therapy 15 (1):R21. doi:10.1186/ar4154
5. 5. Akkoc N, Sari I, Akar S, Binicier O, Thomas MG, Weale ME, Birlik M, Savran Y, Onen F, Bradman N, Plaster CA (2010) Increased prevalence of M694V in patients with ankylosing spondylitis: additional evidence for a link with familial mediterranean fever. Arthritis and rheumatism 62 (10):3059-3063. doi:10.1002/art.27598
6. 6. Cosan F, Ustek D, Oku B, Duymaz-Tozkir J, Cakiris A, Abaci N, Ocal L, Aral O, Gul A (2010) Association of familial Mediterranean fever-related MEFV variations with ankylosing spondylitis. Arthritis and rheumatism 62 (11):3232-3236. doi:10.1002/art.27683
7. 7. Sieper J, Rudwaleit M, Baraliakos X, Brandt J, Braun J, Burgos-Vargas R, Dougados M, Hermann KG, Landewe R, Maksymowych W, van der Heijde D (2009) The Assessment of SpondyloArthritis international Society (ASAS) handbook: a guide to assess spondyloarthritis. Annals of the rheumatic diseases 68 Suppl 2:ii1-44. doi:10.1136/ard.2008.104018
8. 8. Kiltz U, Baraliakos X, Karakostas P, Igelmann M, Kalthoff L, Klink C, Krause D, Schmitz-Bortz E, Florecke M, Bollow M, Braun J (2012) Do patients with non-radiographic axial spondylarthritis differ from patients with ankylosing spondylitis? Arthritis care & research 64 (9):1415-1422. doi:10.1002/acr.21688

9. 9. Livneh A, Langevitz P, Zemer D, Zaks N, Kees S, Lidar T, Migdal A, Padeh S, Pras M (1997) Criteria for the diagnosis of familial Mediterranean fever. Arthritis and rheumatism 40 (10):1879-1885. doi:10.1002/art.1780401023
10. 10. van der Linden S, Valkenburg HA, Cats A (1984) Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis and rheumatism 27 (4):361-368. doi:10.1002/art.1780270401
11. 11. Lambert RG, Bakker PA, van der Heijde D, Weber U, Rudwaleit M, Hermann KG, Sieper J, Baraliakos X, Bennett A, Braun J, Burgos-Vargas R, Dougados M, Pedersen SJ, Jurik AG, Maksymowych WP, Marzo-Ortega H, Ostergaard M, Poddubnyy D, Reijnierse M, van den Bosch F, van der Horst-Bruinsma I, Landewe R (2016) Defining active sacroiliitis on MRI for classification of axial spondyloarthritis: update by the ASAS MRI working group. Annals of the rheumatic diseases 75 (11):1958-1963. doi:10.1136/annrheumdis-2015-208642
12. 12. Atas N, Armagan B, Bodakci E, Satis H, Sari A, Bilge NSY, Salman RB, Yardimci GK, Babaoglu H, Guler AA, Karadeniz H, Kilic L, Ozturk MA, Goker B, Haznedaroglu S, Kalyoncu U, Kasifoglu T, Tufan A (2020) Familial Mediterranean fever is associated with a wide spectrum of inflammatory disorders: results from a large cohort study. Rheumatology international 40 (1):41-48. doi:10.1007/s00296-019-04412-7
13. 13. Touitou I (2001) The spectrum of Familial Mediterranean Fever (FMF) mutations. European journal of human genetics : EJHG 9 (7):473-483. doi:10.1038/sj.ejhg.5200658
14. 14. Yildiz M, Tunc SE, Sahin M, Okudan B, Aydin O, Suslu H, Ozbek M (2006) Evaluation of joints using Tc 99m-MDP bone scintigraphy in patients with familial Mediterranean fever: should bone scans be used for diagnosis and follow-up? Rheumatology international 26 (3):220-223. doi:10.1007/s00296-004-0555-9
15. 15. French FMFC (1997) A candidate gene for familial Mediterranean fever. Nature genetics 17 (1):25-31. doi:10.1038/ng0997-25
16. 16. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. The International FMF Consortium (1997). Cell 90 (4):797-807. doi:10.1016/s0092-8674(00)80539-5
17. 17. Schnappauf O, Chae JJ, Kastner DL, Aksentijevich I (2019) The Pyrin Inflammasome in Health and Disease. Frontiers in immunology 10:1745. doi:10.3389/fimmu.2019.01745
18. 18. Korkmaz C, Ozdogan H, Kasapcopur O, Yazici H (2002) Acute phase response in familial Mediterranean fever. Annals of the rheumatic diseases 61 (1):79-81. doi:10.1136/ard.61.1.79
19. 19. Guncan S, Bilge NS, Cansu DU, Kasifoglu T, Korkmaz C (2016) The role of MEFV mutations in the concurrent disorders observed in patients with familial Mediterranean fever. European journal of rheumatology 3 (3):118-121. doi:10.5152/eurjrheum.2016.16012
20. 20. Ozdogan H, Arisoy N, Kasapcapur O, Sever L, Caliskan S, Tuzuner N, Mat C, Yazici H (1997) Vasculitis in familial Mediterranean fever. The Journal of rheumatology 24 (2):323-327
21. 21. Borman P, Gokoglu F, Tasbas O, Yilmaz M, Yorgancioglu ZR (2009) Familial Mediterranean fever-related spondyloarthropathy. Singapore medical journal 50 (3):e116-119
22. 22. Li Z, Akar S, Yarkan H, Lee SK, Cetin P, Can G, Kenar G, Capa F, Pamuk ON, Pehlivan Y, Cremin K, De Guzman E, Harris J, Wheeler L, Jamshidi A, Vojdanian M, Farhadi E, Ahmadzadeh N, Yuce Z, Dalkilic E, Solmaz D, Akin B, Donmez S, Sari I, Leo PJ, Kenna TJ, Onen F, Mahmoudi M, Brown MA, Akkoc N (2019) Genome-wide association study in Turkish and Iranian populations identify rare familial Mediterranean fever gene (MEFV) polymorphisms associated with ankylosing spondylitis. PLoS genetics 15 (4):e1008038. doi:10.1371/journal.pgen.1008038
23. 23. Poddubnyy D, Rudwaleit M, Haibel H, Listing J, Marker-Hermann E, Zeidler H, Braun J, Sieper J (2011) Rates and predictors of radiographic sacroiliitis progression over 2 years in patients with axial spondyloarthritis. Annals of the rheumatic diseases 70 (8):1369-1374. doi:10.1136/ard.2010.145995
24. 24. Lopez-Medina C, Ramiro S, van der Heijde D, Sieper J, Dougados M, Molto A (2019) Characteristics and burden of disease in patients with radiographic and non-radiographic axial Spondyloarthritis: a comparison by systematic literature review and meta-analysis. RMD open 5 (2):e001108. doi:10.1136/rmdopen-2019-001108
25. 25. Aydin SZ, Maksymowych WP, Bennett AN, McGonagle D, Emery P, Marzo-Ortega H (2012) Validation of the ASAS criteria and definition of a positive MRI of the sacroiliac joint in an inception cohort of axial spondyloarthritis followed up for 8 years. Annals of the rheumatic diseases 71 (1):56-60. doi:10.1136/ard.2011.153064
26. 26. Wang R, Gabriel SE, Ward MM (2016) Progression of Nonradiographic Axial Spondyloarthritis to Ankylosing Spondylitis: A Population-Based Cohort Study. Arthritis & rheumatology 68 (6):1415-1421. doi:10.1002/art.39542
27. 27. Grossman C, Kassel Y, Livneh A, Ben-Zvi I (2019) Familial Mediterranean fever (FMF) phenotype in patients homozygous to the MEFV M694V mutation. European journal of medical genetics 62 (6):103532. doi:10.1016/j.ejmg.2018.08.013
28. 28. Rudwaleit M, van der Heijde D, Landewe R, Listing J, Akkoc N, Brandt J, Braun J, Chou CT, Collantes-Estevez E, Dougados M, Huang F, Gu J, Khan MA, Kirazli Y, Maksymowych WP, Mielants H, Sorensen IJ, Ozgocmen S, Roussou E, Valle-Onate R, Weber U, Wei J, Sieper J (2009) The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part II): validation and final selection. Annals of the rheumatic diseases 68 (6):777-783. doi:10.1136/ard.2009.108233