Kolşisin Dirençli Ailevi Akdeniz Ateşi Hastalığı: Tek Merkez Deneyimi

Öz

Amaç: Ailevi Akdeniz Ateşi (AAA); tekrarlayan ateş ve serözit ataklarıyla karakterize genetik bir hastalıktır. Bu çalışmada kolşisin direnci olan pediatrik AAA hastaların klinik ve laboratuvar verileri ile tedavi yanıtlarını değerlendirmek amaçlanmıştır. Yöntem: Ağustos 2020 – Eylül 2023 tarihleri arasında polikliniğe başvuran ve AAA tanısı ile takipli olan 629 hastanın tıbbi kayıtları retrospektif olarak incelendi. Kolşisin direnci olan 29 hasta çalışmaya dahil edildi. Hastaların farklı farmasötik kolşisin preparat ve biyolojik ajan kullanım sonrasında atak sıklıkları ve tedavi yanıtları incelendi. Bulgular: AAA tanılı 629 hastanın 29’unda (%4,6) kolşisin direnci vardı. Hastaların %51,7’si kız, %48,3’ü erkekti, ortanca tanı yaşı 5,5 (1,5-17) yıldı. Hastalarımızın %48,3’ünde ailede AAA öyküsü ve %41,2’sinde M694V homozigot mutasyonu mevcuttu. Ataklarında tüm hastalarımızda karın ağrısı şikayeti olup ateş (%89,7) ve artralji (%72,4) sık görülen diğer şikayetlerdi. Öncelikle hastaların 27’sine (%93,1) ithal kolşisin preparatı başlandı. Hastaların ortanca ilaç başlama yaşı 7 (3-18) yıldı. Atak sayıları anlamlı olarak azaldı. İthal kolşisin kullanan 27 hastadan; tedaviye yanıt vermeyen 9 hastaya biyolojik ajan tedavisi başlandı. İki hastamızda ise direkt biyolojik ajan tedavisine geçildi. Biyolojik tedavi sonrasında atak sayısında ve atak aralarında bakılan C-reaktif protein düzeyinde anlamlı olarak düşüş saptandı. Anakinra (Interlökin-1 reseptör antagonisti) tedavisi sonrasında lokal alerjik reaksiyon dışında ciddi yan etki görülen hastamız olmadı. Sonuç: Kolşisin tedavisi altındayken atakları devam eden hastalarda biyolojik ajana geçilmeden önce kolşisinin ithal formu denenebilir. Dirençli vakalarda biyolojik ajana geçilerek hem atak sıklığı hem de atak aralarında subklinik inflamasyon bulguları azalmaktadır.

Anahtar Kelimeler

• Ailevi Akdeniz Ateşi
• Kolşisin direnci
• Interlökin 1

Colchicine-Resistant Familial Mediterranean Fever: A Single-Center Experience

Öz

Objective: Familial Mediterranean Fever (FMF) is a hereditary disease characterized by recurrent attacks of fever and serositis. This study aimed to comprehensively assess the clinical and laboratory data, as well as treatment responses in pediatric FMF patients with colchicine resistance. Method: A retrospective analysis of 629 outpatient medical records of patients diagnosed with FMF from August 2020 to September 2023 identified 29 colchicine-resistant FMF patients. The study assessed attack frequency and treatment responses to various pharmaceutical colchicine preparations and biological therapies. Results: Among 629 FMF patients, 29 (4.6%) exhibited colchicine resistance. Gender distribution was 51.7% female and 48.3% male, with a median diagnosis age of 5.5 years (1.5-17 years). Nearly half had a family history of FMF, and 41.2% had the M694V homozygous mutation. All experienced abdominal pain during attacks; common symptoms were fever (89.7%) and arthralgia (72.4%). The median age of medication initiation was 7 (3-18) years. The number of attacks decreased significantly. Among 27 patients using imported colchicine; Biological agent treatment was started in 9 patients who did not respond to treatment. In two of our patients, a biological agent was started directly. After biological treatment, a significant decrease was detected in the number of attacks and the C-reactive protein level measured between attacks. No severe side effects were reported except localized allergic reactions to Anakinra (Interleukin-1 receptor antagonist) treatment. Conclusion: For patients experiencing persistent attacks under colchicine treatment, the use of imported forms of colchicine can be considered before transitioning to biologic therapies. In cases of resistance, a switch to biological therapies demonstrates efficacy in reducing both the frequency of attacks and subclinical inflammation between episodes.

Anahtar Kelimeler

• Familial Mediterranean fever
• Colchicine resistance
• Interleukin-1

Kaynakça

1. Hashkes PJ, Laxer RM, Simon A. Textbook of autoinflammation. 2019;Vol 10: Springer.
2. Ben-Chetrit E, Levy MJTL. Familial mediterranean fever. Lancet. 1998;351(9103):659-664. doi: 10.1016/S0140-6736(97)09408-7.
3. Ozkan E OO, Ekmekci A, Ozcan R, Tag T. A new approach to the treatment of periodic fever. Med Bull Istanbul. 1972.
4. Eroglu FK, Beşbaş N, Topaloglu R, Ozen SJRi. Treatment of colchicine-resistant Familial Mediterranean fever in children and adolescents. Rheumatol Int. 2015;35:1733-1737. doi:10.1007/s00296-015-3293-2.
5. Hentgen V, Grateau G, Kone-Paut I, et al. Evidence-based recommendations for the practical management of Familial Mediterranean Fever. Semin Arthritis Rheum. 2013;43(3):387-391. doi:10.1016/j.semarthrit.2013.04.011.
6. Ozen S, Demirkaya E, Duzova A, et al. FMF50: a score for assessing outcome in familial Mediterranean fever. Ann Rheum Dis. 2014;73(5):897-901. doi:10.1136/annrheumdis-2013-204719.
7. Kallinich T, Haffner D, Niehues T, et al. Colchicine use in children and adolescents with familial Mediterranean fever: literature review and consensus statement. Pediatrics. 2007;119(2):e474-e483. doi:10.1542/peds.2006-1434.
8. Tomokawa T, Koga T, Endo Y, Michitsuji T, Kawakami AJMR. Efficacy and safety of canakinumab for colchicine-resistant or colchicine-intolerant familial Mediterranean fever: A single-centre observational study. Mod Rheumatol. 2022;32(4):797-802. doi: 10.1093/mr/roab048.

9. Yalçınkaya F, Özen S, Özçakar ZB, et al. A new set of criteria for the diagnosis of familial Mediterranean fever in childhood. Rheumatology (Oxford). 2009;48(4):395-398. doi:10.1093/rheumatology/ken509.
10. Ozen S, Demirkaya E, Erer B, et al. EULAR recommendations for the management of familial Mediterranean fever. Ann Rheum Dis. 2016;75(4):644-651. doi:10.1136/annrheumdis-2015-208690.
11. Kavrul Kayaalp G, Sozeri B, Sonmez HE, et al. Adherence to best practice consensus guidelines for familial Mediterranean fever: a modified Delphi study among paediatric rheumatologists in Turkey. Rheumatol Int. Jan 2022;42(1):87-94. doi: 10.1007/s00296-020-04776-1
12. Emmungil H, İlgen U, Turan S, Yaman S, Küçükşahin OJRi. Different pharmaceutical preparations of colchicine for Familial Mediterranean Fever: are they the same? Rheumatol Int. 2020;40(1):129-135. doi:10.1007/s00296-019-04432-3.
13. Baglan E, Ozdel S, Bulbul MJMr. Do all colchicine preparations have the same effectiveness in patients with familial Mediterranean fever? Mod Rheumatol. 2021;31(2):481-484. doi:10.1080/14397595.2020.1790139.
14. Türkuçar S, Yener GO, Dundar HA, et al. Comparison of Different Pharmaceutical Preparations of Colchicine in Children with Familial Mediterranean Fever: Is Colchicine Opocalcium a Good Alternative? Balkan Med J. 2021;38(1):29. doi:10.4274/balkanmedj.galenos.2020.2020.5.2205.220.
15. Tufan A, Babaoglu MO, Akdogan A, et al. Association of drug transporter gene ABCB1 (MDR1) 3435C to T polymorphism with colchicine response in familial Mediterranean fever. J Rheumatol. 2007;34(7):1540-1544.
16. Gül AJBP, Rheumatology RC. Approach to the patients with inadequate response to colchicine in familial Mediterranean fever. Best Pract Res Clin Rheumatol. 2016;30(2):296-303. doi:10.1016/j.berh.2016.09.001.
17. Öztürk K, Coşkuner T, Baglan E, et al. Real-life data from the largest pediatric familial mediterranean fever cohort. Front Pediatr. 2022;9:805919. doi:10.3389/fped.2021.805919.
18. Gursoy D, GEZER H, ÖZ N, Ozer A, Kasman S, DURUÖZ MJNCoI. Clinical features, functional status, and quality of life in patients with late-onset familial Mediterranean fever. North Clin Istanb. 2023;10(4). doi:10.14744/nci.2022.76736.
19. Bayram MT, Çankaya T, Bora E, et al. Risk factors for subclinical inflammation in children with Familial Mediterranean fever. Rheumatol Int. 2015;35:1393-1398. doi:10.1007/s00296-015-3227-z.
20. Aktay Ayaz N, Demirkan FG, Coşkuner T, et al. PREDICT-crFMF score: A novel model for predicting colchicine resistance in children with familial Mediterranean fever. Mod Rheumatol. 2023:road008. doi:10.1093/mr/road008.
21. Ayaz NA, Tanatar A, Karadağ ŞG, Çakan M, Keskindemirci G, Sönmez HEJRI. Comorbidities and phenotype–genotype correlation in children with familial Mediterranean fever. Rheumatol Int. 2021;41(1):113-120. doi:10.1007/s00296-020-04592-7.
22. Sahin N, Ozdemir Cicek S, Pac Kisaarslan A, Poyrazoglu MH, Gunduz Z, Dusunsel RJMr. The remarkable characteristics of the children with colchicine-resistant familial Mediterranean fever in Turkey. Mod Rheumatol. 2022;32(1):177-185. doi:10.1080/14397595.2021.1908502.
23. Lidar M, Yonath H, Shechter N, et al. Incomplete response to colchicine in M694V homozygote FMF patients. Autoimmun Rev. 2012;12(1):72-76. doi:10.1016/j.autrev.2012.07.025.
24. Omenetti A, Carta S, Delfino L, Martini A, Gattorno M, Rubartelli AJAotrd. Increased NLRP3-dependent interleukin 1β secretion in patients with familial Mediterranean fever: correlation with MEFV genotype. Ann Rheum Dis. 2014;73(2):462-469. doi:10.1136/annrheumdis-2012-202774.
25. Kisla Ekinci RM, Balci S, Dogruel D, Altintas DU, Yilmaz MJPD. Canakinumab in children with familial Mediterranean fever: a single-center, retrospective analysis. Paediatr Drugs. 2019;21:389-395. doi:10.1007/s40272-019-00354-6.
26. Cetin P, Sari I, Sozeri B, et al. Efficacy of interleukin-1 targeting treatments in patients with familial Mediterranean fever. Inflammation. 2015;38:27-31. doi:10.1007/s10753-014-0004-1.
27. Ozen S, Ben-Cherit E, Foeldvari I, et al. Long-term efficacy and safety of canakinumab in patients with colchicine-resistant familial Mediterranean fever: results from the randomised phase III CLUSTER trial. Ann Rheum Dis. 2020;79(10):1362-1369. doi:10.1136/annrheumdis-2020-217419.