Advertisement

Rheumatology International

, Volume 36, Issue 10, pp 1421–1429 | Cite as

Macrophage activation syndrome in children with systemic juvenile idiopathic arthritis and systemic lupus erythematosus

  • Selin Aytaç
  • Ezgi Deniz Batu
  • Şule Ünal
  • Yelda Bilginer
  • Mualla Çetin
  • Murat Tuncer
  • Fatma Gümrük
  • Seza ÖzenEmail author
Observational Research

Abstract

Macrophage activation syndrome (MAS) is a hyper-inflammatory disorder secondary to a rheumatic disease such as systemic juvenile idiopathic arthritis (SJIA) and systemic lupus erythematosus (SLE). We aimed to present the characteristics of our pediatric MAS patients. Clinical features, laboratory parameters, treatment, and outcome of 34 patients (28 SJIA; six SLE; 37 MAS episodes) followed at a tertiary health center between 2009 and 2015 were retrospectively reviewed. The median age at MAS onset was 11 years. More SJIA patients had MAS at disease onset than SLE patients (53.6 vs. 16.7 %). Fever, high C-reactive protein and hyperferritinemia were present in all MAS episodes. Rash was less (p = 0.03), and fatigue was more frequent (p = 0.042) in SLE than SJIA patients. All received corticosteroids. Cyclosporine was given in 74.2 % of SJIA-MAS; 66.7 % of SLE-MAS episodes. Intravenous immunoglobulin, anakinra, or etoposide was administered during 67.7; 41.9; 32.3 % of SJIA-MAS and 33.3; 33.3; 50 % of SLE-MAS episodes, respectively. Plasmapheresis was performed during 41.9 % of SJIA-MAS and 33.3 % of SLE-MAS episodes. The mortality rate was 11.8 % (n = 4;3 SJIA, 1 SLE). Hepatosplenomegaly was more frequent (p = 0.005), and plasmapheresis was performed more frequently (p = 0.021) in the patients who died compared to the cured patients. The median duration between symptom onset and admission to our hospital was longer among the patients who died (16.5 vs. 7 days; p = 0.049). Our patients’ characteristics were similar to the reported cases, but our mortality rate is slightly higher probably due to late referral to our center. Early diagnosis and effective treatment are crucial to prevent mortality.

Keywords

Macrophage activation syndrome Systemic juvenile idiopathic arthritis Systemic lupus erythematosus Child 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

The study was approved by the ethics committee of Hacettepe University and was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki (1964). All these patient files were evaluated retrospectively, and all patients were anonymous. When the patients admitted to the hospital, the parents gave a general consent approving anonymous data use for academic purpose.

Supplementary material

296_2016_3545_MOESM1_ESM.docx (15 kb)
Supplementary material 1 (DOCX 15 kb)
296_2016_3545_MOESM2_ESM.docx (14 kb)
Supplementary material 2 (DOCX 14 kb)
296_2016_3545_MOESM3_ESM.docx (14 kb)
Supplementary material 3 (DOCX 14 kb)

References

  1. 1.
    Janka GE (2012) Familial and acquired hemophagocytic lymphohistiocytosis. Annu Rev Med 63:233–246. doi: 10.1146/annurev-med-041610-134208 CrossRefPubMedGoogle Scholar
  2. 2.
    Dhote R, Simon J, Papo T, Detournay B, Sailler L, Andre MH, Dupond JL, Larroche C, Piette AM, Mechenstock D, Ziza JM, Arlaud J, Labussiere AS, Desvaux A, Baty V, Blanche P, Schaeffer A, Piette JC, Guillevin L, Boissonnas A, Christoforov B (2003) Reactive hemophagocytic syndrome in adult systemic disease: report of twenty-six cases and literature review. Arthritis Rheum 49:633–639. doi: 10.1002/art.11368 CrossRefPubMedGoogle Scholar
  3. 3.
    Rouphael NG, Talati NJ, Vaughan C, Cunningham K, Moreira R, Gould C (2007) Infections associated with haemophagocytic syndrome. Lancet Infect Dis 7:814–822. doi: 10.1016/S1473-3099(07)70290-6 CrossRefPubMedGoogle Scholar
  4. 4.
    Stephan JL, Zeller J, Hubert P, Herbelin C, Dayer JM, Prieur AM (1993) Macrophage activation syndrome and rheumatic disease in childhood: a report of four new cases. Clin Exp Rheumatol 11:451–456PubMedGoogle Scholar
  5. 5.
    Lehmberg K, Pink I, Eulenburg C, Beutel K, Maul-Pavicic A, Janka G (2013) Differentiating macrophage activation syndrome in systemic juvenile idiopathic arthritis from other forms of hemophagocytic lymphohistiocytosis. J Pediatr 162:1245–1251. doi: 10.1016/j.jpeds.2012.11.081 CrossRefPubMedGoogle Scholar
  6. 6.
    Minoia F, Davi S, Horne A, Demirkaya E, Bovis F, Li C, Lehmberg K, Weitzman S, Insalaco A, Wouters C, Shenoi S, Espada G, Ozen S, Anton J, Khubchandani R, Russo R, Pal P, Kasapcopur O, Miettunen P, Maritsi D, Merino R, Shakoory B, Alessio M, Chasnyk V, Sanner H, Gao YJ, Huasong Z, Kitoh T, Avcin T, Fischbach M, Frosch M, Grom A, Huber A, Jelusic M, Sawhney S, Uziel Y, Ruperto N, Martini A, Cron RQ, Ravelli A, Pediatric Rheumatology International Trials O, Childhood A, Rheumatology Research A, Pediatric Rheumatology Collaborative Study G, Histiocyte S (2014) Clinical features, treatment, and outcome of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a multinational, multicenter study of 362 patients. Arthritis Rheumatol 66:3160–3169. doi: 10.1002/art.38802 CrossRefPubMedGoogle Scholar
  7. 7.
    Grom AA, Mellins ED (2010) Macrophage activation syndrome: advances towards understanding pathogenesis. Curr Opin Rheumatol 22:561–566. doi: 10.1097/01.bor.0000381996.69261.71 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Ravelli A, Grom AA, Behrens EM, Cron RQ (2012) Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment. Genes Immun 13:289–298. doi: 10.1038/gene.2012.3 CrossRefPubMedGoogle Scholar
  9. 9.
    Behrens EM, Canna SW, Slade K, Rao S, Kreiger PA, Paessler M, Kambayashi T, Koretzky GA (2011) Repeated TLR9 stimulation results in macrophage activation syndrome-like disease in mice. J Clin Invest 121:2264–2277. doi: 10.1172/JCI43157 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Strippoli R, Caiello I, De Benedetti F (2013) Reaching the threshold: a multilayer pathogenesis of macrophage activation syndrome. J Rheumatol 40:761–767. doi: 10.3899/jrheum.121233 CrossRefPubMedGoogle Scholar
  11. 11.
    Strippoli R, Carvello F, Scianaro R, De Pasquale L, Vivarelli M, Petrini S, Bracci-Laudiero L, De Benedetti F (2012) Amplification of the response to Toll-like receptor ligands by prolonged exposure to interleukin-6 in mice: implication for the pathogenesis of macrophage activation syndrome. Arthritis Rheum 64:1680–1688. doi: 10.1002/art.33496 CrossRefPubMedGoogle Scholar
  12. 12.
    Canna SW, Wrobel J, Chu N, Kreiger PA, Paessler M, Behrens EM (2013) Interferon-gamma mediates anemia but is dispensable for fulminant toll-like receptor 9-induced macrophage activation syndrome and hemophagocytosis in mice. Arthritis Rheum 65:1764–1775. doi: 10.1002/art.37958 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Zhang M, Behrens EM, Atkinson TP, Shakoory B, Grom AA, Cron RQ (2014) Genetic defects in cytolysis in macrophage activation syndrome. Curr Rheumatol Rep 16:439. doi: 10.1007/s11926-014-0439-2 CrossRefPubMedGoogle Scholar
  14. 14.
    Barut K, Yucel G, Sinoplu AB, Sahin S, Adrovic A, Kasapcopur O (2015) Evaluation of macrophage activation syndrome associated with systemic juvenile idiopathic arthritis: single center experience over a one-year period. Turk Pediatri Ars 50:206–210. doi: 10.5152/TurkPediatriArs.2015.3299 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Bennett TD, Fluchel M, Hersh AO, Hayward KN, Hersh AL, Brogan TV, Srivastava R, Stone BL, Korgenski EK, Mundorff MB, Casper TC, Bratton SL (2012) Macrophage activation syndrome in children with systemic lupus erythematosus and children with juvenile idiopathic arthritis. Arthritis Rheum 64:4135–4142. doi: 10.1002/art.34661 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Yokota S, Imagawa T, Mori M, Miyamae T, Takei S, Iwata N, Umebayashi H, Murata T, Miyoshi M, Tomiita M, Nishimoto N, Kishimoto T (2014) Longterm safety and effectiveness of the anti-interleukin 6 receptor monoclonal antibody tocilizumab in patients with systemic juvenile idiopathic arthritis in Japan. J Rheumatol 41:759–767. doi: 10.3899/jrheum.130690 CrossRefPubMedGoogle Scholar
  17. 17.
    Yokota S, Itoh Y, Morio T, Sumitomo N, Daimaru K, Minota S (2015) Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis under treatment with tocilizumab. J Rheumatol 42:712–722. doi: 10.3899/jrheum.140288 CrossRefPubMedGoogle Scholar
  18. 18.
    Zeft A, Hollister R, LaFleur B, Sampath P, Soep J, McNally B, Kunkel G, Schlesinger M, Bohnsack J (2009) Anakinra for systemic juvenile arthritis: the Rocky Mountain Experience. J Clin Rheumatol 15:161–164. doi: 10.1097/RHU.0b013e3181a4f459 CrossRefPubMedGoogle Scholar
  19. 19.
    Chiossone L, Audonnet S, Chetaille B, Chasson L, Farnarier C, Berda-Haddad Y, Jordan S, Koszinowski UH, Dalod M, Mazodier K, Novick D, Dinarello CA, Vivier E, Kaplanski G (2012) Protection from inflammatory organ damage in a murine model of hemophagocytic lymphohistiocytosis using treatment with IL-18 binding protein. Front Immunol 3:239. doi: 10.3389/fimmu.2012.00239 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Ohyagi H, Onai N, Sato T, Yotsumoto S, Liu J, Akiba H, Yagita H, Atarashi K, Honda K, Roers A, Muller W, Kurabayashi K, Hosoi-Amaike M, Takahashi N, Hirokawa M, Matsushima K, Sawada K, Ohteki T (2013) Monocyte-derived dendritic cells perform hemophagocytosis to fine-tune excessive immune responses. Immunity 39:584–598. doi: 10.1016/j.immuni.2013.06.019 CrossRefPubMedGoogle Scholar
  21. 21.
    Bracaglia CPG, Gatto A, Pardeo M, Lapeyre G, Raganelli L, Marasco E, Insalaco A, Ferlin W, Nelson R, de Min C, De Benedetti F (2015) Anti interferon gamma monoclonal antibody treatment in a child with NLRC4-related disease and severe hemophagocytic lymphohistiocytosis (HLH). Arthritis Rheumatol Suppl 10:67Google Scholar
  22. 22.
    Janka GE, Lehmberg K (2014) Hemophagocytic syndromes–an update. Blood Rev 28:135–142. doi: 10.1016/j.blre.2014.03.002 CrossRefPubMedGoogle Scholar
  23. 23.
    Behrens EM, Beukelman T, Paessler M, Cron RQ (2007) Occult macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis. J Rheumatol 34:1133–1138PubMedGoogle Scholar
  24. 24.
    Sawhney S, Woo P, Murray KJ (2001) Macrophage activation syndrome: a potentially fatal complication of rheumatic disorders. Arch Dis Child 85:421–426CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Stephan JL, Kone-Paut I, Galambrun C, Mouy R, Bader-Meunier B, Prieur AM (2001) Reactive haemophagocytic syndrome in children with inflammatory disorders. A retrospective study of 24 patients. Rheumatology (Oxford) 40:1285–1292CrossRefGoogle Scholar
  26. 26.
    Bleesing J, Prada A, Siegel DM, Villanueva J, Olson J, Ilowite NT, Brunner HI, Griffin T, Graham TB, Sherry DD, Passo MH, Ramanan AV, Filipovich A, Grom AA (2007) The diagnostic significance of soluble CD163 and soluble interleukin-2 receptor alpha-chain in macrophage activation syndrome and untreated new-onset systemic juvenile idiopathic arthritis. Arthritis Rheum 56:965–971. doi: 10.1002/art.22416 CrossRefPubMedGoogle Scholar
  27. 27.
    Vilaiyuk S, Sirachainan N, Wanitkun S, Pirojsakul K, Vaewpanich J (2013) Recurrent macrophage activation syndrome as the primary manifestation in systemic lupus erythematosus and the benefit of serial ferritin measurements: a case-based review. Clin Rheumatol 32:899–904. doi: 10.1007/s10067-013-2227-1 CrossRefPubMedGoogle Scholar
  28. 28.
    Correll CK, Binstadt BA (2014) Advances in the pathogenesis and treatment of systemic juvenile idiopathic arthritis. Pediatr Res 75:176–183. doi: 10.1038/pr.2013.187 CrossRefPubMedGoogle Scholar
  29. 29.
    Arici ZS, Batu ED, Ozen S (2015) Reviewing the recommendations for lupus in children. Curr Rheumatol Rep 17:17. doi: 10.1007/s11926-014-0489-5 CrossRefPubMedGoogle Scholar
  30. 30.
    Gupta A, Tyrrell P, Valani R, Benseler S, Weitzman S, Abdelhaleem M (2008) The role of the initial bone marrow aspirate in the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 51:402–404. doi: 10.1002/pbc.21564 CrossRefPubMedGoogle Scholar
  31. 31.
    Francois B, Trimoreau F, Vignon P, Fixe P, Praloran V, Gastinne H (1997) Thrombocytopenia in the sepsis syndrome: role of hemophagocytosis and macrophage colony-stimulating factor. Am J Med 103:114–120CrossRefPubMedGoogle Scholar
  32. 32.
    Strauss R, Neureiter D, Westenburger B, Wehler M, Kirchner T, Hahn EG (2004) Multifactorial risk analysis of bone marrow histiocytic hyperplasia with hemophagocytosis in critically ill medical patients—a postmortem clinicopathologic analysis. Crit Care Med 32:1316–1321CrossRefPubMedGoogle Scholar
  33. 33.
    Suster S, Hilsenbeck S, Rywlin AM (1988) Reactive histiocytic hyperplasia with hemophagocytosis in hematopoietic organs: a reevaluation of the benign hemophagocytic proliferations. Hum Pathol 19:705–712CrossRefPubMedGoogle Scholar
  34. 34.
    Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S, Ladisch S, McClain K, Webb D, Winiarski J, Janka G (2007) HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 48:124–131. doi: 10.1002/pbc.21039 CrossRefPubMedGoogle Scholar
  35. 35.
    Parodi A, Davi S, Pringe AB, Pistorio A, Ruperto N, Magni-Manzoni S, Miettunen P, Bader-Meunier B, Espada G, Sterba G, Wright D, Magalhaes CS, Khubchandani R, Michels H, Woo P, Iglesias A, Guseinova D, Bracaglia C, Hayward K, Wouters C, Grom A, Vivarelli M, Fischer A, Breda L, Martini A, Ravelli A, Lupus Working Group of the Paediatric Rheumatology European S (2009) Macrophage activation syndrome in juvenile systemic lupus erythematosus: a multinational multicenter study of thirty-eight patients. Arthritis Rheum 60:3388–3399. doi: 10.1002/art.24883 CrossRefPubMedGoogle Scholar
  36. 36.
    Kostik MM, Dubko MF, Masalova VV, Snegireva LS, Kornishina TL, Chikova IA, Likhacheva TS, Isupova EA, Glebova NI, Kuchinskaya EM, Balbotkina EV, Buchinskaya NV, Kalashnikova OV, Chasnyk VG (2015) Identification of the best cutoff points and clinical signs specific for early recognition of macrophage activation syndrome in active systemic juvenile idiopathic arthritis. Semin Arthritis Rheum 44:417–422. doi: 10.1016/j.semarthrit.2014.09.004 CrossRefPubMedGoogle Scholar
  37. 37.
    Ravelli A, Minoia F, Davi S, Horne A, Bovis F, Pistorio A, Arico M, Avcin T, Behrens EM, De Benedetti F, Filipovic L, Grom AA, Henter JI, Ilowite NT, Jordan MB, Khubchandani R, Kitoh T, Lehmberg K, Lovell DJ, Miettunen P, Nichols KE, Ozen S, Pachlopnik Schmid J, Ramanan AV, Russo R, Schneider R, Sterba G, Uziel Y, Wallace C, Wouters C, Wulffraat N, Demirkaya E, Brunner HI, Martini A, Ruperto N, Cron RQ, Paediatric Rheumatology International Trials Organisation tCA, Rheumatology Research Alliance tPRCSG, The Histiocyte S (2016) 2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative. Ann Rheum Dis 75:481–489. doi: 10.1136/annrheumdis-2015-208982 CrossRefPubMedGoogle Scholar
  38. 38.
    Demirkaya E, Ozen S, Bilginer Y, Ayaz NA, Makay BB, Unsal E, Erguven M, Poyrazoglu H, Kasapcopur O, Gok F, Akman S, Balat A, Cavkaytar O, Kaya B, Duzova A, Ozaltin F, Topaloglu R, Besbas N, Bakkaloglu A, Arisoy N, Ozdogan H, Bakkaloglu S, Turker T (2011) The distribution of juvenile idiopathic arthritis in the eastern Mediterranean: results from the registry of the Turkish Paediatric Rheumatology Association. Clin Exp Rheumatol 29(1):111–116PubMedGoogle Scholar
  39. 39.
    Ravelli A, Minoia F, Davi S, Horne A, Bovis F, Pistorio A, Arico M, Avcin T, Behrens EM, De Benedetti F, Filipovic A, Grom AA, Henter JI, Ilowite NT, Jordan MB, Khubchandani R, Kitoh T, Lehmberg K, Lovell DJ, Miettunen P, Nichols KE, Ozen S, Pachlopnik Schmid J, Ramanan AV, Russo R, Schneider R, Sterba G, Uziel Y, Wallace C, Wouters C, Wulffraat N, Demirkaya E, Brunner HI, Martini A, Ruperto N, Cron RQ (2016) Expert consensus on dynamics of laboratory tests for diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. RMD Open 2:e000161. doi: 10.1136/rmdopen-2015-000161 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Granata G, Didona D, Stifano G, Feola A, Granata M (2015) Macrophage activation syndrome as onset of systemic lupus erythematosus: a case report and a review of the literature. Case Rep Med 2015:294041. doi: 10.1155/2015/294041 PubMedPubMedCentralGoogle Scholar
  41. 41.
    Boom V, Anton J, Lahdenne P, Quartier P, Ravelli A, Wulffraat NM, Vastert SJ (2015) Evidence-based diagnosis and treatment of macrophage activation syndrome in systemic juvenile idiopathic arthritis. Pediatr Rheumatol Online J 13:55. doi: 10.1186/s12969-015-0055-3 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Singh S, Chandrakasan S, Ahluwalia J, Suri D, Rawat A, Ahmed N, Das R, Sachdeva MU, Varma N (2012) Macrophage activation syndrome in children with systemic onset juvenile idiopathic arthritis: clinical experience from northwest India. Rheumatol Int 32:881–886. doi: 10.1007/s00296-010-1711-z CrossRefPubMedGoogle Scholar
  43. 43.
    Cortis E, Insalaco A (2006) Macrophage activation syndrome in juvenile idiopathic arthritis. Acta Paediatr 95:38–41. doi: 10.1080/08035320600649713 CrossRefGoogle Scholar
  44. 44.
    Miettunen PM, Narendran A, Jayanthan A, Behrens EM, Cron RQ (2011) 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) 50:417–419. doi: 10.1093/rheumatology/keq218 CrossRefGoogle Scholar
  45. 45.
    Prahalad S, Bove KE, Dickens D, Lovell DJ, Grom AA (2001) Etanercept in the treatment of macrophage activation syndrome. J Rheumatol 28:2120–2124PubMedGoogle Scholar
  46. 46.
    Lin CI, Yu HH, Lee JH, Wang LC, Lin YT, Yang YH, Chiang BL (2012) Clinical analysis of macrophage activation syndrome in pediatric patients with autoimmune diseases. Clin Rheumatol 31:1223–1230. doi: 10.1007/s10067-012-1998-0 CrossRefPubMedGoogle Scholar
  47. 47.
    De Benedetti F, Brunner HI, Ruperto N, Kenwright A, Wright S, Calvo I, Cuttica R, Ravelli A, Schneider R, Woo P, Wouters C, Xavier R, Zemel L, Baildam E, Burgos-Vargas R, Dolezalova P, Garay SM, Merino R, Joos R, Grom A, Wulffraat N, Zuber Z, Zulian F, Lovell D, Martini A, Printo Prcsg (2012) Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med 367:2385–2395. doi: 10.1056/NEJMoa1112802 CrossRefPubMedGoogle Scholar
  48. 48.
    Kostik MM, Dubko MF, Masalova VV, Snegireva LS, Kornishina TL, Chikova IA, Isupova EA, Kuchinskaya EM, Glebova NI, Buchinskaya NV, Kalashnikova OV, Chasnyk VG (2015) Successful treatment with tocilizumab every 4 weeks of a low disease activity group who achieve a drug-free remission in patients with systemic-onset juvenile idiopathic arthritis. Pediatr Rheumatol Online J 13:4. doi: 10.1186/1546-0096-13-4 CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Ruperto N, Brunner HI, 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 SK, Uziel Y, Viola S, Nistala K, Wouters C, Cimaz R, Ferrandiz MA, Flato B, Gamir ML, Kone-Paut I, Grom A, Magnusson B, Ozen S, Sztajnbok F, Lheritier K, Abrams K, Kim D, Martini A, Lovell DJ, Printo Prcsg (2012) Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N Engl J Med 367:2396–2406. doi: 10.1056/NEJMoa1205099 CrossRefPubMedGoogle Scholar
  50. 50.
    Carvalheiras G, Anjo D, Mendonca T, Vasconcelos C, Farinha F (2010) Hemophagocytic syndrome as one of the main primary manifestations in acute systemic lupus erythematosus—case report and literature review. Lupus 19:756–761. doi: 10.1177/0961203309354906 CrossRefPubMedGoogle Scholar
  51. 51.
    Zeng HS, Xiong XY, Wei YD, Wang HW, Luo XP (2008) Macrophage activation syndrome in 13 children with systemic-onset juvenile idiopathic arthritis. World J Pediatr 4:97–101. doi: 10.1007/s12519-008-0018-6 CrossRefPubMedGoogle Scholar
  52. 52.
    Ringold S, Weiss PF, Beukelman T, DeWitt EM, Ilowite NT, Kimura Y, Laxer RM, Lovell DJ, Nigrovic PA, Robinson AB, Vehe RK, American Collge of R (2013) 2013 update of the 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: recommendations for the medical therapy of children with systemic juvenile idiopathic arthritis and tuberculosis screening among children receiving biologic medications. Arthritis Rheum 65:2499–2512. doi: 10.1002/art.38092 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Selin Aytaç
    • 1
  • Ezgi Deniz Batu
    • 2
  • Şule Ünal
    • 1
  • Yelda Bilginer
    • 2
  • Mualla Çetin
    • 1
  • Murat Tuncer
    • 1
  • Fatma Gümrük
    • 1
  • Seza Özen
    • 2
    Email author
  1. 1.Division of Hematology and Oncology, Department of PediatricsHacettepe University Faculty of MedicineAnkaraTurkey
  2. 2.Division of Rheumatology, Department of PediatricsHacettepe University Faculty of MedicineAnkaraTurkey

Personalised recommendations