Higher-dose canakinumab therapy for refractory macrophage activation syndrome in children with systemic juvenile idiopathic arthritis: two case reports


Macrophage activation syndrome (MAS) is a life-threatening, potentially fatal complication of systemic juvenile idiopathic arthritis (sJIA) appears in non-remitted fever, cytopenia, coagulopathy, liver and CNS dysfunctions. Triggers of MAS could be disease activity, infections and medications. Known IL-1 is the key cytokine in pathogenesis of MAS and SJIA, and disease flare associated with increased amounts of different cytokines, especially IL-1β. Many cases of MAS are medically-refractory to traditional doses of cytokine inhibition and may require increased dosing of biologic cytokine blockade. Interleukin-1 (IL-1) is typically a key cytokine in the pathogenesis of sJIA and associated MAS. When MAS occurs in the setting of sJIA treated with IL-1 inhibitors, then increased dosing of IL-1 blockers may be beneficial. This has been shown for anakinra, an IL-1 receptor antagonist, but this drug is currently not available worldwide. Another IL-1 blocker, canakinumbab (CKB), is a monoclonal antibody that blocks IL-1β, but does not also block IL-1α like anakinra. Herein, we describe 2 sJIA patients who developed MAS on standard doses of CKB (4 mg/kg). Both patients received an increased dose of CKB: 150 mg (7.5 and 12.5 mg/kg, respectively) with rapid and complete resolution of MAS. Later the CKB doses was tapered to normal regimen. No side effects or adverse events were noticed during usage of increased CKB doses. Increased dosing of CKB should be considered for CKB-treated sJIA patients who develop MAS on standard dosing.

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About the authors

Mikhail Mikhaylovich Kostik

Saint Petersburg State Pediatric Medical University

Email: mikhail.kostik@gmail.com
Associate Professor, Chair of Hospital Pediatrics

Tatyana Serafimovna Likhacheva

Saint Petersburg State Pediatric Medical University

Email: tatianasl@list.ru
MD, Research Fellow, Chair of Hospital Pediatrics

Irina Aleksandrovna Chikova

Saint Petersburg State Pediatric Medical University

Email: irinachikova@gmail.com
MD, Research Fellow, Chair of Hospital Pediatrics

Natal’ya Valer’yevna Buchinskaya

Saint Petersburg State Pediatric Medical University

Email: nbuchinskaia@gmail.com
MD, Research Fellow, Chair of Hospital Pediatrics

Natal’ya Nikolaevna Abramova

Saint Petersburg State Pediatric Medical University

Email: abrnatalia@yandex.ru
MD, the physician of ICU and Anesthesiology Department

Olga Valeryevna Kalashnikova

Saint Petersburg State Pediatric Medical University

Email: koira7@yandex.ru
MD, PhD, Associate Professor, Chair of Hospital Pediatrics

Randy Q Cron

University of Alabama, School of Medicine

Email: rcron@peds.uab.edu
MD, PhD, Dr Med Sci, Professor

Vyacheslav Grigoryevich Chasnyk

Saint Petersburg State Pediatric Medical University

Email: chasnyk@gmail.com
MD, PhD, Dr Med Sci, Professor, Head of the Department of Hospital Pediatrics


  1. Behrens E. M., Beukelman T., Paessler M., Cron R. Q. Occult macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis. J Rheumatol. 2007; 34: 1133-38.
  2. Behrens E. M., Beukelman T., Gallo L., Spangler J., Rosenkranz M., Arkachaisri T., Ayala R., Groh B., Finkel T. H., Cron R. Q. Evaluation of the presentation of systemic onset juvenile rheumatoid arthritis: data from the Pennsylvania Systemic Onset Juvenile Arthritis Registry (PASOJAR). J Rheumatol. 2008; 35: 343-48.
  3. Bruck N., Suttorp M., Kabus M., Heubner G., Gahr M., Pessler F. Rapid and sustained remission of systemic juvenile idiopathic arthritis-associated macrophage activation syndrome through treatment with anakinra and corticosteroids. J Clin Rheumatol. 2011; 17: 23-7.
  4. Chakraborty A., Tannenbaum S., Rordorf C., Lowe P. J., Floch D., Gram H., Roy S. Pharmacokinetic and pharmacodynamic properties of canakinumab, a human anti-interleukin-1beta monoclonal antibody. Clin Pharmacokinet. 2012; 51: e1-18.
  5. Davi S., Consolaro A., Guseinova D., Pistorio A., Ruperto N., Martini A., Cron R. Q., Ravelli A. An international consensus survey of diagnostic criteria for macrophage activation syndrome in systemic juvenile idiopathic arthritis. J Rheumatol. 2011; 38: 764-68.
  6. Gorelik M., Fall N., Altaye M., Barnes M. G., Thompson S. D., Grom A. A., Hirsch R. Follistatin-like protein 1 and the ferritin/erythrocyte sedimentation rate ratio are potential biomarkers for dysregulated gene expression and macrophage activation syndrome in systemic juvenile idiopathic arthritis. J Rheumatol. 2013; 40: 1191-99.
  7. Henter J. I., Horne A., Arico M., Egeler R. M., Filipovich A. H., Imashuku S., Ladisch S., McClain K., Webb D., Winiarski J., Janka G. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007; 48: 124-31.
  8. Kahn P. J., Cron R. Q. Higher-dose Anakinra is effective in a case of medically refractory macrophage activation syndrome. J Rheumatol. 2013; 40: 743-44.
  9. Kelly A., Ramanan A. V. A case of macrophage activation syndrome successfully treated with anakinra. Nat Clin Pract Rheumatol. 2008; 4: 615-20.
  10. Kuemmerle-Deschner J. B., Hachulla E., Cartwright R., Hawkins P. N., Tran T. A., Bader-Meunier B., Hoyer J., Gattorno M., Gul A., Smith J., Leslie K. S., Jiménez S., Morell-Dubois S., Davis N., Patel N., Widmer A., Preiss R., Lachmann H. J. Two-year results from an open-label, multicentre, phase III study evaluating the safety and efficacy of canakinumab in patients with cryopyrin-associated periodic syndrome across different severity phenotypes. Ann Rheum Dis. 2012; 70: 2095-02.
  11. Lovell D. J., Giannini E. H., Reiff A. O., Kimura Y., Li S., Hashkes P. J., Wallace C. A., Onel K. B., Foell D., Wu R., Biedermann S., Hamilton J. D., Radin A. R. Long-term safety and efficacy of rilonacept in patients with systemic juvenile idiopathic arthritis. Arthritis Rheum. 2013; 65: 2486-96.
  12. Miettunen P. M., Narendran A., Jayanthan A., Behrens E. M., Cron R. Q. Successful treatment of severe paediatric rheumatic disease-associated macrophage activation syndrome with interleukin-1 inhibition following conventional immunosuppressive therapy: case series with 12 patients. Rheumatology (Oxford). 2011; 50: 417-19.
  13. Nigrovic P. A., Mannion M., Prince F. H., Zeft A., Rabinovich C. E., van Rossum M. A., Cortis E., Pardeo M., Miettunen P. M., Janow G., Birmingham J., Eggebeen A., Janssen E., Shulman A. I., Son M. B., Hong S., Jones K., Ilowite N. T., Cron R. Q., Higgins G. C. Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter series.Arthritis Rheum.2011; 63: 545-55.
  14. Pascual V., Allantaz F., Arce E., Punaro M., Banchereau J. Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade. J Exp Med.2005; 201: 1479-86.
  15. Quartier P., Allantaz F., Cimaz R., Pillet P., Messiaen C., Bardin C., Bossuyt X., Boutten A., Bienvenu J., Duquesne A., Richer O., Chaussabel D., Mogenet A., Banchereau J., Treluyer J. M., Landais P., Pascual V. A multicentre, randomised, double-blind, placebo-controlled trial with the interleukin-1 receptor antagonist anakinra in patients with systemic-onset juvenile idiopathic arthritis (ANAJIS trial). Ann Rheum Dis. 2011; 70: 747-54.
  16. Ravelli A., Magni-Manzoni S., Pistorio A., Besana C., Foti T., Ruperto N., Viola S., Martini A. Preliminary diagnostic guidelines for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis // J Pediatr. 2005; 146: 598-604.
  17. Ravelli A., Grom A. A., Behrens E. M., Cron R. Q. Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment. Genes Immun. 2012; 13: 289-98.
  18. Record J. L., Beukelman T., Cron R. Q. Combination therapy of abatacept and anakinra in children with refractory systemic juvenile idiopathic arthritis: a retrospective case series. J Rheumatol. 2011; 38: 180-81.
  19. Ruperto N., Brunner H. I., Quartier P., Constantin T., Wulffraat N., Horneff G., Brik R., McCann L., Kasapcopur O., Rutkowska-Sak L., Schneider R., Berkun Y., Calvo I., Erguven M., Goffin L., Hofer M., Kallinich T., Oliveira S. K., Uziel Y., Viola S., Nistala K., Wouters C., Cimaz R., Ferrandiz M. A., Flato B., Gamir M. L., Kone-Paut I., Grom A., Magnusson B., Ozen S., Sztajnbok F., Lheritier K., Abrams K., Kim D., Martini A., Lovell D. J. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012; 367: 2396-2406.
  20. Sawhney S., Woo P., Murray K. J. Macrophage activation syndrome: a potentially fatal complication of rheumatic disorders. Arch Dis Child. 2001; 85: 421-26.
  21. Stephan J. L., Kone-Paut I., Galambrun C., Mouy R., Bader-Meunier B., Prieur A. M. Reactive haemophagocytic syndrome in children with inflammatory disorders. A retrospective study of 24 patients. Rheumatology (Oxford).2001;40: 1285-92.
  22. Stoll M. L., Cron R. Q. Treatment of juvenile idiopathic arthritis in the biologic age // Rheum Dis Clin North Am. 2013; 39: 751-66.



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Copyright (c) 2014 Kostik M.M., Likhacheva T.S., Chikova I.A., Buchinskaya N.V., Abramova N.N., Kalashnikova O.V., Cron R.Q., Chasnyk V.G.

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