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Macrophage activation syndrome associated with systemic onset juvenile rheumatoid arthritis.

To the Editor: Coagulation abnormalities in systemic onset juvenile rheumatoid arthritis (JRA) could be due to two different pathogenic mechanisms; one caused by vasculitis and the other induced by macrophage activation syndrome (MAS). MAS is now widely recognized as a severe, potentially life-threatening complication of systemic onset JRA; therefore, early diagnosis and immediate treatment are indispensable for a good outcome. In patients with systemic onset JRA, MAS needs to be differentiated from an acute exacerbation of the underlying disease through clinical and laboratory findings, including pancytopenia, persistent fever, coagulation abnormalities, bleeding, liver and neurologic abnormalities, and phagocytosis of bone marrow-derived elements (hematoph-agocytic histiocytes).

Different authors have reported on patients with systemic onset JRA who developed clinical and laboratory abnormalities compatible with MAS, which were associated with viral infections or drugs, including gold, nonsteroidal anti-inflammatory drugs, methotrexate, and aspirin. (1,2) However, MAS may occur without any identifiable precipitating factor.

Although the cause of MAS is unknown, dysregulation of macrophage-lymphocyte interactions with a subsequent increase in the levels of both T-cell-derived and macrophage-derived cytokines, particularly TNF alpha and interferon gamma, could be involved in this syndrome. (3) Treatment of MAS in patients with systemic onset JRA has included a variety of chemotherapeutic and immunosuppressive agents such as high-dose corticosteroids, cyclosporin, cyclophosphamide, antithymocyte globulin and IV immunoglobulin. (2,4) Cyclosporin A has been successful in patients refractory to corticosteroid therapy. (1) These results support the role of T-cells in the pathogenic mechanism of MAS. In contrast, IV immunoglobulin therapy has been used to treat severe flares of systemic JRA in patients with MAS with different rheumatic diseases with modest or no efficacy. (1) However, in a personal observation, a patient with systemic onset JRA who developed a severe case of MAS was successfully treated with IV immunoglobulin. (5) The anti-inflammatory effect of IV immunoglobulin has been well recognized. The mechanism proposed is through the ability of the immunoglobulins to induce the expression of the inhibitor Fc[gamma]RIIB receptor on effectors cells, counteracting the activation responses triggered by Fc[gamma]RIIB engagement in macrophages and other immune competent cells. (6) This receptor could mediate inhibitory intracellular signaling that may be responsible for shutting down the exacerbated responses in macrophages.

In conclusion, MAS is a severe, potentially life-threatening complication of chronic rheumatic diseases especially in systemic onset JRA. Therefore, it is essential for clinicians to have a high threshold of suspicion, make an early diagnosis, and start prompt treatment. Although there is no standard treatment, it should begin with high doses of steroids, followed by cyclosporin A in steroid-resistant cases. However, IV immunoglobulin may be the next logical step to treat this severe condition.

Antonio G. Tristano, MD, MSc

Pharmaceutical and Administrative Sciences Department

College of Pharmacy, Nova Southeastern University

Fort Lauderdale, FL


1. Stephan JL, Kone-Paut I, Galambrun C, et al. Reactive hemophagocytic syndrome in children with inflammatory disorders: a retrospective study of 24 patients. Rheumatology (Oxford) 2001;40:1285-1292.

2. Sawhney S, Woo P. Murray KJ. Macrophage activation syndrome: a potentially fatal complication of rheumatic disorders. Arch Dis Child 2001;85:421-426.

3. Henter J. Elinder G, Soder O, et al. Hypercytokinemia in familial hemophagocytic lymphohistiocytosis. Blood 1991;78:2918-2922.

4. Grom A, Passo M. Macrophage activation syndrome in systemic juvenile rheumatoid arthritis. J Pediatr 1996;129:630-632.

5. Tristano A, Casanova-Escalona L, Torres A, et al. Macrophage activation syndrome in a patient with Still's disease rescue with intravenous immunoglobulin therapy. J Clin Rheumatol 2003;9:253-258.

6. Samuelsson A, Towers TL, Ravetch JV. Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science 2001;291:484-486.
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Title Annotation:Letters to the Editor
Author:Tristano, Antonio G.
Publication:Southern Medical Journal
Article Type:Letter to the editor
Date:Jul 1, 2006
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