Diagnostic Considerations

Because macrophage activation syndrome (MAS) is a serious condition that can follow a rapidly fatal course, prompt recognition of its clinical and laboratory features and immediate therapeutic intervention are critical. However, because it lacks a single distinguishing characteristic and is clinically heterogeneous, early diagnosis can be difficult. Differential diagnosis between macrophage activation syndrome and a lupus flare or between macrophage activation syndrome and infections^[30], such as leishmaniasis may be particularly challenging.

Differential Diagnoses

Flare of underlying disease (eg, systemic juvenile idiopathic arthritis [SJIA], systemic lupus erythematosus [SLE])
Infection (eg, visceral leishmaniasis, brucellosis)
Sepsis
Side effects of medications

Workup

Ravelli A, Minoia F, Davì S, et al. 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. 2016 Mar. 75 (3):481-9. [QxMD MEDLINE Link].
Grom AA, Passo M. Macrophage activation syndrome in systemic juvenile rheumatoid arthritis. J Pediatr. 1996 Nov. 129(5):630-2. [QxMD MEDLINE Link].
Jordan MB, Hildeman D, Kappler J, Marrack P. An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder. Blood. 2004 Aug 1. 104(3):735-43. [QxMD MEDLINE Link].
Prieur AM, Stephan JL. [Macrophage activation syndrome in rheumatic diseases in children]. Rev Rhum Ed Fr. 1994 Jun. 61(6):447-51. [QxMD MEDLINE Link].
Ravelli A. Macrophage activation syndrome. Curr Opin Rheumatol. 2002 Sep. 14(5):548-52. [QxMD MEDLINE Link].
Zhang K, Biroschak J, Glass DN, Thompson SD, Finkel T, Passo MH. Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis is associated with MUNC13-4 polymorphisms. Arthritis Rheum. 2008 Sep. 58(9):2892-6. [QxMD MEDLINE Link]. [Full Text].
Weiss ES, Girard-Guyonvarc'h C, Holzinger D, de Jesus AA, Tariq Z, Picarsic J, et al. Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome. Blood. 2018 Mar 29. 131 (13):1442-1455. [QxMD MEDLINE Link].
Yasin S, Schulert GS. Systemic juvenile idiopathic arthritis and macrophage activation syndrome: update on pathogenesis and treatment. Curr Opin Rheumatol. 2018 Sep. 30 (5):514-520. [QxMD MEDLINE Link].
Billiau AD, Roskams T, Van Damme-Lombaerts R, Matthys P, Wouters C. Macrophage activation syndrome: characteristic findings on liver biopsy illustrating the key role of activated, IFN-gamma-producing lymphocytes and IL-6- and TNF-alpha-producing macrophages. Blood. 2005 Feb 15. 105(4):1648-51. [QxMD MEDLINE Link].
Mazodier K, Marin V, Novick D, Farnarier C, Robitail S, Schleinitz N. Severe imbalance of IL-18/IL-18BP in patients with secondary hemophagocytic syndrome. Blood. 2005 Nov 15. 106(10):3483-9. [QxMD MEDLINE Link].
Maeno N, Takei S, Nomura Y, Imanaka H, Hokonohara M, Miyata K. Highly elevated serum levels of interleukin-18 in systemic juvenile idiopathic arthritis but not in other juvenile idiopathic arthritis subtypes or in Kawasaki disease: comment on the article by Kawashima et al. Arthritis Rheum. 2002 Sep. 46(9):2539-41; author reply 2541-2. [QxMD MEDLINE Link].
Maeno N, Takei S, Imanaka H, Yamamoto K, Kuriwaki K, Kawano Y. Increased interleukin-18 expression in bone marrow of a patient with systemic juvenile idiopathic arthritis and unrecognized macrophage-activation syndrome. Arthritis Rheum. 2004 Jun. 50(6):1935-8. [QxMD MEDLINE Link].
Grom AA. Natural killer cell dysfunction: A common pathway in systemic-onset juvenile rheumatoid arthritis, macrophage activation syndrome, and hemophagocytic lymphohistiocytosis?. Arthritis Rheum. 2004 Mar. 50(3):689-98. [QxMD MEDLINE Link].
Grom AA, Villanueva J, Lee S, Goldmuntz EA, Passo MH, Filipovich A. Natural killer cell dysfunction in patients with systemic-onset juvenile rheumatoid arthritis and macrophage activation syndrome. J Pediatr. 2003 Mar. 142(3):292-6. [QxMD MEDLINE Link].
Villanueva J, Lee S, Giannini EH, Graham TB, Passo MH, Filipovich A. Natural killer cell dysfunction is a distinguishing feature of systemic onset juvenile rheumatoid arthritis and macrophage activation syndrome. Arthritis Res Ther. 2005. 7(1):R30-7. [QxMD MEDLINE Link].
Wouters CH, Ceuppens JL, Stevens EA. Different circulating lymphocyte profiles in patients with different subtypes of juvenile idiopathic arthritis. Clin Exp Rheumatol. 2002 Mar-Apr. 20(2):239-48. [QxMD MEDLINE Link].
Stephan JL, Kone-Paut I, Galambrun C, et al. Reactive haemophagocytic syndrome in children with inflammatory disorders. A retrospective study of 24 patients. Rheumatology (Oxford). 2001 Nov. 40(11):1285-92. [QxMD MEDLINE Link].
[Guideline] Ravelli A, Magni-Manzoni S, Pistorio A, et al. Preliminary diagnostic guidelines for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. J Pediatr. 2005 May. 146(5):598-604. [QxMD MEDLINE Link].
Gormezano NW, Otsuzi CI, Barros DL, da Silva MA, Pereira RM, Campos LM, et al. Macrophage activation syndrome: A severe and frequent manifestation of acute pancreatitis in 362 childhood-onset compared to 1830 adult-onset systemic lupus erythematosus patients. Semin Arthritis Rheum. 2015 Nov 5. [QxMD MEDLINE Link].
Minoia F, Davì S, Horne A, Demirkaya E, Bovis F, Li C, et al. Clinical features, treatment and outcome of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis A multinational, multicenter study of 362 patients. Arthritis Rheumatol. 2014 Jul 30. [QxMD MEDLINE Link].
Ravelli A, Viola S, De Benedetti F, Magni-Manzoni S, Tzialla C, Martini A. Dramatic efficacy of cyclosporine A in macrophage activation syndrome. Clin Exp Rheumatol. 2001 Jan-Feb. 19(1):108. [QxMD MEDLINE Link].
McCann LJ, Hasson N, Pilkington CA. Macrophage activation syndrome as an early presentation of Lupus. J Rheumatol. 2006 Feb. 33(2):438-40. [QxMD MEDLINE Link].
Muise A, Tallett SE, Silverman ED. Are children with Kawasaki disease and prolonged fever at risk for macrophage activation syndrome?. Pediatrics. 2003 Dec. 112(6 Pt 1):e495. [QxMD MEDLINE Link].
Ravelli A, Caria MC, Buratti S, Malattia C, Temporini F, Martini A. Methotrexate as a possible trigger of macrophage activation syndrome in systemic juvenile idiopathic arthritis. J Rheumatol. 2001 Apr. 28(4):865-7. [QxMD MEDLINE Link].
Cate R, Brinkman DM, van Rossum MA, et al. Macrophage activation syndrome after autologous stem cell transplantation for systemic juvenile idiopathic arthritis. Eur J Pediatr. 2002 Dec. 161(12):686-6. [QxMD MEDLINE Link].
Wulffraat NM, Vastert B, Tyndall A. Treatment of refractory autoimmune diseases with autologous stem cell transplantation: focus on juvenile idiopathic arthritis. Bone Marrow Transplant. 2005 Mar. 35 Suppl 1:S27-9. [QxMD MEDLINE Link].
Sreedharan A, Bowyer S, Wallace CA, Robertson MJ, Schmidt K, Woolfrey AE. Macrophage activation syndrome and other systemic inflammatory conditions after BMT. Bone Marrow Transplant. 2006 Apr. 37(7):629-34. [QxMD MEDLINE Link].
Wedderburn LR, Abinun M, Palmer P, Foster HE. Autologous haematopoietic stem cell transplantation in juvenile idiopathic arthritis. Arch Dis Child. 2003 Mar. 88(3):201-5. [QxMD MEDLINE Link].
Jordan MB, Hildeman D, Kappler J, Marrack P. An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder. Blood. 2004 Aug 1. 104(3):735-43. [QxMD MEDLINE Link].
Rouphael NG, Talati NJ, Vaughan C, Cunningham K, Moreira R, Gould C. Infections associated with haemophagocytic syndrome. Lancet Infect Dis. 2007 Dec. 7(12):814-22. [QxMD MEDLINE Link].
Henter JI, Elinder G, Ost A. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL Study Group of the Histiocyte Society. Semin Oncol. 1991 Feb. 18(1):29-33. [QxMD MEDLINE Link].
Davì S, Minoia F, Pistorio A, Horne A, Consolaro A, Rosina S, et al. Performance of current guidelines for diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. Arthritis Rheumatol. 2014 Jul 7. [QxMD MEDLINE Link].
Janka GE. Familial hemophagocytic lymphohistiocytosis. Eur J Pediatr. 1983 Jun-Jul. 140(3):221-30. [QxMD MEDLINE Link].
Weaver LK, Behrens EM. Hyperinflammation, rather than hemophagocytosis, is the common link between macrophage activation syndrome and hemophagocytic lymphohistiocytosis. Curr Opin Rheumatol. 2014 Sep. 26(5):562-9. [QxMD MEDLINE Link].
Ravelli A, Minoia F, Davì S, et al. Expert consensus on dynamics of laboratory tests for diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. RMD Open. 2016. 2 (1):e000161. [QxMD MEDLINE Link].
Boom V, Anton J, Lahdenne P, Quartier P, Ravelli A, Wulffraat NM, et al. Evidence-based diagnosis and treatment of macrophage activation syndrome in systemic juvenile idiopathic arthritis. Pediatr Rheumatol Online J. 2015 Dec 3. 13:55. [QxMD MEDLINE Link].
Davì S, Consolaro A, Guseinova D, et al. An international consensus survey of diagnostic criteria for macrophage activation syndrome in systemic juvenile idiopathic arthritis. J Rheumatol. 2011 Apr. 38(4):764-8. [QxMD MEDLINE Link].
[Guideline] Parodi A, Davì S, Pringe AB, Pistorio A, Ruperto N, et al. Macrophage activation syndrome in juvenile systemic lupus erythematosus. Arthritis Rheum. (In press).
Fardet L, Coppo P, Kettaneh A, Dehoux M, Cabane J, Lambotte O. Low glycosylated ferritin, a good marker for the diagnosis of hemophagocytic syndrome. Arthritis Rheum. 2008 May. 58(5):1521-7. [QxMD MEDLINE Link].
Wang Z, Wang Y, Wang J, Feng C, Tian L, Wu L. Early diagnostic value of low percentage of glycosylated ferritin in secondary hemophagocytic lymphohistiocytosis. Int J Hematol. 2009 Aug 5. [QxMD MEDLINE Link].
Ruscitti P, Rago C, Breda L, Cipriani P, Liakouli V, Berardicurti O, et al. Macrophage activation syndrome in Still's disease: analysis of clinical characteristics and survival in paediatric and adult patients. Clin Rheumatol. 2017 Dec. 36 (12):2839-2845. [QxMD MEDLINE Link].
Fall N, Barnes M, Thornton S, Luyrink L, Olson J, Ilowite NT. Gene expression profiling of peripheral blood from patients with untreated new-onset systemic juvenile idiopathic arthritis reveals molecular heterogeneity that may predict macrophage activation syndrome. Arthritis Rheum. 2007 Nov. 56(11):3793-804. [QxMD MEDLINE Link].
Bleesing J, Prada A, Siegel DM, et al. 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. 2007 Mar. 56(3):965-71. [QxMD MEDLINE Link].
Mouy R, Stephan JL, Pillet P, Haddad E, Hubert P, Prieur AM. Efficacy of cyclosporine A in the treatment of macrophage activation syndrome in juvenile arthritis: report of five cases. J Pediatr. 1996 Nov. 129(5):750-4. [QxMD MEDLINE Link].
Ravelli A, De Benedetti F, Viola S, Martini A. Macrophage activation syndrome in systemic juvenile rheumatoid arthritis successfully treated with cyclosporine. J Pediatr. 1996 Feb. 128(2):275-8. [QxMD MEDLINE Link].
Prahalad S, Bove KE, Dickens D, Lovell DJ, Grom AA. Etanercept in the treatment of macrophage activation syndrome. J Rheumatol. 2001 Sep. 28(9):2120-4. [QxMD MEDLINE Link].
Ramanan AV, Schneider R. Macrophage activation syndrome following initiation of etanercept in a child with systemic onset juvenile rheumatoid arthritis. J Rheumatol. 2003 Feb. 30(2):401-3. [QxMD MEDLINE Link].
Lurati A, Teruzzi B, Salmaso A, et al. Macrophagic activation sindrome (MAS) during anti-IL1 receptor therapy (anakinra) in a patient affected by systemic onset idiopathic juvenile arthritis (soJIA). Pediatr Rheumatol Online J. 2005. 3(1):
Fitzgerald AA, Leclercq SA, Yan A, Homik JE, Dinarello CA. Rapid responses to anakinra in patients with refractory adult-onset Still's disease. Arthritis Rheum. 2005 Jun. 52(6):1794-803. [QxMD MEDLINE Link].
Kelly A, Ramanan AV. A case of macrophage activation syndrome successfully treated with anakinra. Nat Clin Pract Rheumatol. 2008 Nov. 4(11):615-20. [QxMD MEDLINE Link].
Miettunen PM, Narendran A, Jayanthan A, Behrens EM, Cron RQ. 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 Feb. 50(2):417-9. [QxMD MEDLINE Link].
Nigrovic PA, Mannion M, Prince FH, et al. 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 Feb. 63(2):545-55. [QxMD MEDLINE Link].
Bruck N, Suttorp M, Kabus M, et al. Rapid and sustained remission of systemic juvenile idiopathic arthritis-associated macrophage activation syndrome through treatment with anakinra and corticosteroids. J Clin Rheumatol. 2011 Jan. 17(1):23-7. [QxMD MEDLINE Link].
Kelly A, Ramanan AV. A case of macrophage activation syndrome successfully treated with anakinra. Nat Clin Pract Rheumatol. 2008 Nov. 4(11):615-20. [QxMD MEDLINE Link].
Record JL, Beukelman T, Cron RQ. Combination therapy of abatacept and anakinra in children with refractory systemic juvenile idiopathic arthritis: a retrospective case series. J Rheumatol. 2011 Jan. 38(1):180-1. [QxMD MEDLINE Link].
Janka GE. Hemophagocytic syndromes. Blood Rev. 2007 Sep. 21(5):245-53. [QxMD MEDLINE Link].
Minoia F, Davì S, Horne A, et al. Dissecting the heterogeneity of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. J Rheumatol. 2015 Jun. 42 (6):994-1001. [QxMD MEDLINE Link].