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Canakinumab in Children with Familial Mediterranean Fever: A Single-Center, Retrospective Analysis

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Abstract

Introduction

Familial Mediterranean fever (FMF) is an autoinflammatory disease characterized by interleukin (IL)-1 overproduction. Colchicine is the mainstay drug in the treatment of FMF; however, a minority of patients do not respond despite the highest tolerated doses. We aimed to share our experience with canakinumab, a human monoclonal antibody against IL-1β, in pediatric FMF patients.

Methods

This historical, single-cohort study retrospectively evaluated the disease characteristics, indications, and treatment responses of 14 pediatric FMF patients treated with canakinumab in our pediatric rheumatology department.

Results

The median age at onset and diagnosis of 14 FMF patients (9 females, 5 males), were 3.5 (range 0.5–10) years and 6 (range 3–16) years, respectively. Indications for canakinumab treatment were renal amyloidosis (n = 1), colchicine resistance (n = 11), and persistent arthritis (n = 2). Only two (14.3%) patients had colchicine intolerance. Complete response was obtained in 10/14 (71.5%) among all patients and 10/12 (86%) in patients with typical phenotype. The patient with chronic oligoarthritis had a complete response, whereas the patient with rheumatoid factor (RF)-positive polyarthritis demonstrated an initial partial response to canakinumab treatment. We found that attack frequency, proteinuria, and acute phase reactants, including erythrocyte sedimentation rate and C-reactive protein, were significantly decreased after canakinumab treatment in children with FMF.

Conclusion

Canakinumab may be an effective treatment option for pediatric FMF patients with colchicine resistance, renal amyloidosis, and chronic oligoarthritis. Further studies are needed to clarify the efficacy of canakinumab in patients with a second disease, RF-positive polyarticular juvenile idiopathic arthritis.

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References

  1. Ben-Chetrit E, Levy M. Familial Mediterranean fever. Lancet. 1998;351:659–64.

    Article  CAS  PubMed  Google Scholar 

  2. Barut K, Sahin S, Adrovic A, Sinoplu AB, Yucel G, Pamuk G, Aydın AK, Dasdemir S, Turanlı ET, Buyru N, Kasapcopur O. Familial Mediterranean fever in childhood: a single-center experience. Rheumatol Int. 2018;38:67–74.

    Article  CAS  PubMed  Google Scholar 

  3. Ozen S, Demirkaya E, Erer B, Livneh A, Ben-Chetrit E, Giancane G, et al. EULAR recommendations for the management of familial Mediterranean fever. Ann Rheum Dis. 2016;75:644–51.

    Article  CAS  PubMed  Google Scholar 

  4. Kisla 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;33:282–7.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Pathak S, McDermott MF, Savic S. Autoinflammatory diseases: update on classification diagnosis and management. J Clin Pathol. 2017;70:1–8.

    Article  CAS  PubMed  Google Scholar 

  6. Chae JJ, Cho YH, Lee GS, Cheng J, Liu PP, Feigenbaum L, et al. Gain-of-function Pyrin mutations induce NLRP3 protein-independent interleukin-1β activation and severe autoinflammation in mice. Immunity. 2011;34:755–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. de Jesus AA, Canna SW, Liu Y, Goldbach-Mansky R. Molecular mechanisms in genetically defined autoinflammatory diseases: disorders of amplified danger signaling. Annu Rev Immunol. 2015;33:823–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Meinzer U, Quartier P, Alexandra JF, Hentgen V, Retornaz F, Koné-Paut I. Interleukin-1 targeting drugs in familial Mediterranean fever: a case series and a review of the literature. Semin Arthritis Rheum. 2011;41:265–71.

    Article  CAS  PubMed  Google Scholar 

  9. Özçakar ZB, Özdel S, Yılmaz S, Kurt-Şükür ED, Ekim M, Yalçınkaya F. Anti-IL-1 treatment in familial Mediterranean fever and related amyloidosis. Clin Rheumatol. 2016;35:441–6.

    Article  PubMed  Google Scholar 

  10. Gül A, Ozdogan H, Erer B, Ugurlu S, Kasapcopur O, Davis N, et al. Efficacy and safety of canakinumab in adolescents and adults with colchicine-resistant familial Mediterranean fever. Arthritis Res Ther. 2015;17:243.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cetin P, Sari I, Sozeri B, Cam O, Birlik M, Akkoc N, et al. Efficacy of interleukin-1 targeting treatments in patients with familial mediterranean Fever. Inflammation. 2015;38:27–31.

    Article  CAS  PubMed  Google Scholar 

  12. Sozeri B, Gulez N, Ergin M, Serdaroglu E. The experience of canakinumab in renal amyloidosis secondary to Familial Mediterranean fever. Mol Cell Pediatr. 2016;3:33.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Başaran Ö, Uncu N, Çelikel BA, Taktak A, Gür G, Cakar N. Interleukin-1 targeting treatment in familial Mediterranean fever: an experience of pediatric patients. Mod Rheumatol. 2015;25:621–4.

    Article  CAS  PubMed  Google Scholar 

  14. Yazılıtaş F, Aydoğ Ö, Özlü SG, Çakıcı EK, Güngör T, Eroğlu FK, et al. Canakinumab treatment in children with familial Mediterranean fever: report from a single center. Rheumatol Int. 2018;38:879–85.

    Article  CAS  PubMed  Google Scholar 

  15. Brik R, Butbul-Aviel Y, Lubin S, Ben Dayan E, Rachmilewitz-Minei T, Tseng L, et al. Canakinumab for the treatment of children with colchicine-resistant familial Mediterranean fever: a 6-month open-label, single-arm pilot study. Arthritis Rheumatol. 2014;66:3241–3.

    Article  CAS  PubMed  Google Scholar 

  16. Laskari K, Boura P, Dalekos GN, Garyfallos A, Karokis D, Pikazis D, et al. Long-term beneficial effect of canakinumab in colchicine-resistant familial Mediterranean fever. J Rheumatol. 2017;44:102–9.

    Article  CAS  PubMed  Google Scholar 

  17. De Benedetti F, Gattorno M, Anton J, Ben-Chetrit E, Frenkel J, Hoffman HM, et al. Canakinumab for the treatment of autoinflammatory recurrent fever syndromes. N Engl J Med. 2018;378:1908–19.

    Article  PubMed  Google Scholar 

  18. Livneh A, Langevitz P, Zemer D, Zaks N, Kees S, Lidar T, et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum. 1997;40:1879–85.

    Article  CAS  PubMed  Google Scholar 

  19. van der Hilst JCh, Moutschen M, Messiaen PE, Lauwerys BR, Vanderschueren S. Efficacy of anti-IL-1 treatment in familial Mediterranean fever: a systematic review of the literature. Biologics. 2016;4(10):75–80.

    Google Scholar 

  20. Akar S, Cetin P, Kalyoncu U, Karadag O, Sari I, Cınar M, et al. Nationwide experience with off-label use of interleukin-1 targeting treatment in familial Mediterranean fever patients. Arthritis Care Res (Hoboken). 2018;70:1090–4.

    Article  CAS  PubMed  Google Scholar 

  21. Babaoglu H, Varan O, Kucuk H, Atas N, Satis H, Salman R, et al. Effectiveness of canakinumab in colchicine- and anakinra-resistant or -intolerant adult familial Mediterranean fever patients: A single-center real-life study. J Clin Rheumatol. 2018. https://doi.org/10.1097/RHU.0000000000000873.

    Article  Google Scholar 

  22. Kisla Ekinci RM, Balci S, Bisgin A, Hershfield M, Atmis B, Dogruel D, et al. Renal amyloidosis in deficiency of adenosine deaminase 2: successful experience with canakinumab. Pediatrics. 2018;142(5):e20180948.

    Article  PubMed  Google Scholar 

  23. Sargin G, Kose R, Senturk T. Anti-interleukin-1 treatment among patients with familial Mediterranean fever resistant to colchicine treatment. Retrospective analysis. Sao Paulo Med J. 2019;137:39–44.

    Article  PubMed  Google Scholar 

  24. Kucuksahin O, Yildizgoren MT, Ilgen U, Ates A, Kinikli G, Turgay M, et al. Anti-interleukin-1 treatment in 26 patients with refractory familial Mediterranean fever. Mod Rheumatol. 2017;27:350–5.

    Article  CAS  PubMed  Google Scholar 

  25. Petty RE, Southwood TR, Baum J, Bhettay E, Glass DN, Manners P, et al. Revision of the proposed classification criteria for juvenile idiopathic arthritis: Durban, 1997. J Rheumatol. 1998;25:1991–4.

    CAS  PubMed  Google Scholar 

  26. Ringold S, Angeles-Han ST, Beukelman T, Lovell D, Cuello CA, Becker ML, et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Treatment of Juvenile Idiopathic Arthritis: therapeutic approaches for non-systemic polyarthritis, sacroiliitis, and enthesitis. Arthritis Rheumatol. 2019;71:846–63.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Alten R, Gomez-Reino J, Durez P, Beaulieu A, Sebba A, Krammer G, et al. Efficacy and safety of the human anti-IL-1β monoclonal antibody canakinumab in rheumatoid arthritis: results of a 12-week, Phase II, dose-finding study. BMC Musculoskelet Disord. 2011;12:153.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Gülez N, Makay B, Sözeri B. Long-term effectiveness and safety of canakinumab in pediatric familial Mediterranean fever patients. Mod Rheumatol. 2018;17:1–13.

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Pediatric Rheumatology, Cukurova University Faculty of Medicine, Adana, 01331, Turkey

    Rabia Miray Kisla Ekinci, Sibel Balci & Mustafa Yilmaz

  2. Department of Pediatric Allergy and Immunology, Cukurova University Faculty of Medicine, Adana, Turkey

    Dilek Dogruel & Derya Ufuk Altintas

Authors
  1. Rabia Miray Kisla Ekinci
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  2. Sibel Balci
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  3. Dilek Dogruel
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  5. Mustafa Yilmaz
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Corresponding author

Correspondence to Rabia Miray Kisla Ekinci.

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Conflict of interest

Dr Kisla Ekinci, Dr Sibel Balci, Dr Dilek Dogruel, Dr Derya Ufuk Altintas, and Dr Mustafa Yilmaz declare that they have no conflicts of interest.

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None.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from parents of the participants included in the study.

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Kisla Ekinci, R.M., Balci, S., Dogruel, D. et al. Canakinumab in Children with Familial Mediterranean Fever: A Single-Center, Retrospective Analysis. Pediatr Drugs 21, 389–395 (2019). https://doi.org/10.1007/s40272-019-00354-6

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  • DOI: https://doi.org/10.1007/s40272-019-00354-6

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