An International Consensus Survey of Diagnostic Criteria for Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis

Istituto di Ricovero e Cura a Carattere Scientifico G. Gaslini, Genova, Italy.
The Journal of Rheumatology (Impact Factor: 3.19). 02/2011; 38(4):764-8. DOI: 10.3899/jrheum.100996
Source: PubMed


To identify candidate diagnostic criteria for macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (sJIA) using international consensus formation through a Delphi questionnaire survey.
A questionnaire listing 28 clinical, laboratory, and histopathologic features of MAS elicited by literature review was sent to 505 pediatric rheumatologists worldwide. Respondents were asked to select the 10 features that they felt were most important and useful in the diagnosis of MAS, and to order the 10 selected features by assigning the number 10 to the most important, and ending with 1 as the least important.
The response rate was 46% (232 physicians from 47 countries). The items selected by more than 50% of respondents were, in order of frequency, falling platelet count, hyperferritinemia, evidence of macrophage hemophagocytosis in the bone marrow, increased liver enzymes, falling leukocyte count, persistent continuous fever ≥ 38°C, falling erythrocyte sedimentation rate, hypofibrinogenemia, and hypertriglyceridemia.
Our process led to identification of features that were felt to be most important as candidate diagnostic criteria for MAS by a large sample of international pediatric rheumatologists.

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    • "Hemofagocytoza nie jest stałym i obligatoryjnym do rozpoznania objawem HLH. W MAS ferrytyna jest zwykle > 5000 mg/ml, występują podwyższone wskaźniki stanu zapalnego (z wyjątkiem obniżającego się OB, co wynika z hipofibrynogenemii), nie muszą występować cytopenie, natomiast charakterystyczny jest nagły spadek liczby leukocytów, trombocytów i/lub erytrocytów w ostrej fazie choroby [15] [16] [17]. HLH jest stanem zagrożenia życia, leczenie immunosupresyjne mające na celu zahamowanie ,,burzy cytokinowej'' powinno być wdrożone jak najszybciej. "
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    ABSTRACT: Macrophage activation syndrome (MAS), a secondary hemophagocytic lymphohistiocytosis (HLH), may be diagnosed in the course of the systemic inflammatory connective tissue diseases, especially systemic onset juvenile idiopathic arthritis (so-JIA). The pathological hyperactivation of the immune system results from a defective cytotoxicity of T lymphocytes and NK cells, leading to organ infiltration by these cells, hypercytokinemia and multiorgan failure. The classic clinical symptoms of this syndrome include fever, hepatosplenomegaly, bleeding. The most typical laboratory findings are hyperferritinemia, hypofibrinogenemia, a decrease of erythrocyte sedimentation rate, cytopenias or sudden drop in blood cells count and hemophagocytosis in the bone marrow or in tissues. The clinical course may be rapid and fatal. In the last decade, the biological agents against inflammatory cytokines – particularly inhibitors of tumor necrosis factor (TNF) and interleukin 1 and 6 (IL-1, IL-6) – are more widely used in the treatment of JIA. In Poland, etanercept and adalimumab are registered for use in children with polyarthritis JIA and tocilizumab (anti-IL-6) in so-JIA. Some casuistic reports on biological therapy, both as a risk factor of MAS and about its high efficiency in the treatment of this disease, have been found in medical literature recently. This article presents a review of the literature related to the treatment of secondary HLH with biological agents and a case report of a boy diagnosed with so-JIA and MAS after third dose of etanercept.
    No preview · Article · Jan 2013 · Pediatria polska
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    • "Specific diagnostic criteria for MAS have been suggested. They include falling leukocyte and platelet counts, hyperferritinemia, hypofibrinogenemia, hemophagocytosis in bone marrow, elevated liver enzymes, elevated erythrocyte sedimentation rate, and hypertriglyceridemia [40,41]. MAS can be the presenting feature of patients with autoinflammatory and autoimmune diseases and features of such diseases (such as arthritis or rash) should there-fore be carefully looked for in HLH patients in the course of their disease. "
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    ABSTRACT: Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening disease of severe hyperinflammation caused by uncontrolled proliferation of activated lymphocytes and macrophages secreting high amounts of inflammatory cytokines. It is a frequent manifestation in patients with predisposing genetic defects, but can occur secondary to various infectious, malignant, and autoimmune triggers in patients without a known genetic predisposition. Clinical hallmarks are prolonged fever, cytopenias, hepatosplenomegaly, and neurological symptoms, but atypical variants presenting with signs of chronic immunodeficiency are increasingly recognized. Impaired secretion of perforin is a key feature in several genetic forms of the disease, but not required for disease pathogenesis. Despite progress in diagnostics and therapy, mortality of patients with severe HLH is still above 40%. Reference treatment is an etoposide-based protocol, but new approaches are currently explored. Key for a favorable prognosis is the rapid identification of an underlying genetic cause, which has been facilitated by recent immunological and genetic advances. In patients with predisposing genetic disease, hematopoietic stem cell transplantation is performed increasingly with reduced intensity conditioning regimes. Current research aims at a better understanding of disease pathogenesis and evaluation of more targeted approaches to therapy, including anti-cytokine antibodies and gene therapy.
    Full-text · Article · Jun 2012 · Arthritis research & therapy
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    • "Factors potentially differentiating HLH from MAS include: 1.) change from quotidian to persistent fever pattern; 2.) sudden change from cytosis to cytopenia; 3.) coagulopathy; and 4.) decreasing ESR. Preliminary diagnostic criteria have been examined for MAS in sJIA, which may help to improve diagnosis of this condition in these patients [13,15]. "
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    ABSTRACT: Hemophagocytic lymphohistiocytosis is a potentially fatal disease characterized by excessive macrophage and lymphocyte activity. Patients can be affected following immune activation after an oncologic, autoimmune or infectious trigger. An associated gene mutation may be found which impairs cytolytic lymphocyte function. We describe a pediatric case of hemophagocytic lymphohistiocytosis with a novel mutation of MUNC 13-4 whose diagnosis was confounded by concurrent immunosuppression. Clinical reassessment for hemophagocytic lymphohistiocytosis is necessary in persistently febrile patients with laboratory derangements in the setting of immunosuppressive agent exposure.
    Full-text · Article · May 2012 · Pediatric Rheumatology
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