Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: Diagnosis, genetics, pathophysiology and treatment

Department of Pediatrics, Università degli Studi di Genova, Genova, Italy.
Genes and immunity (Impact Factor: 2.91). 03/2012; 13(4):289-98. DOI: 10.1038/gene.2012.3
Source: PubMed


Macrophage activation syndrome (MAS) is a severe, frequently fatal complication of systemic juvenile idiopathic arthritis (sJIA) with features of hemophagocytosis leading to coagulopathy, pancytopenia, and liver and central nervous system dysfunction. MAS is overt in 10% of children with sJIA but occurs subclinically in another 30-40%. It is difficult to distinguish sJIA disease flare from MAS. Development of criteria for establishing MAS as part of sJIA are under way and will hopefully prove sensitive and specific. Mutations in cytolytic pathway genes are increasingly being recognized in children who develop MAS as part of sJIA. Identification of these mutations may someday assist in MAS diagnosis. Defects in cytolytic genes have provided murine models of MAS to study pathophysiology and treatment. Recently, the first mouse model of MAS not requiring infection but rather dependent on repeated stimulation through Toll-like receptors was reported. This provides a model of MAS that may more accurately reflect MAS pathology in the setting of autoinflammation or autoimmunity. This model confirms the importance of a balance between pro- and anti-inflammatory cytokines. There has been remarkable progress in the use of anti-pro-inflammatory cytokine therapy, particularly against interleukin-1, in the treatment of secondary forms of MAS, such as in sJIA.

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Available from: Alexei A Grom, Jan 13, 2015
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    • "Her low haptoglobin level provided evidence of bleeding and liver impairment, resulting in poor coagulation profile and markedly elevated liver enzymes. Furthermore, our initial suspicion that the patient was having HPS as a possible complication was supported by laboratory findings of elevated levels of serum ferritin, sCD163 and sCD25 typical of HPS (Ravelli et al. 2012; Bleesing et al. 2007). Although observation of hemophagocytosis is the gold standard for identifying macrophage activation syndrome, specific biomarkers are needed for its early detection. "
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    ABSTRACT: HPS is a potentially life-threatening histiocytic disorder that has been described in various viral infections including dengue. Its involvement in severe and fatal dengue is probably more common but is presently under recognized. Case description A 38-year-old female was admitted after 5 days of fever. She was deeply jaundiced, leukopenic and thrombocytopenic. Marked elevation of transaminases, hyperbilirubinemia and hypoalbuminemia were observed. She had deranged INR values and prolonged aPTT accompanied with hypofibrinogenemia. She also had splenomegaly. She was positive for dengue IgM. Five days later she became polyuric and CT brain image showed gross generalized cerebral edema. Her conditions deteriorated by day 9, became confused with GCS of 9/15. Her BMAT showed minimal histiocytes. Her serum ferritin level peaked at 13,670.00 µg/mL and her sCD163 and sCD25 values were markedly elevated at 4750.00 ng/mL and 4191.00 pg/mL, respectively. She succumbed to the disease on day 10 and examination of her tissues showed the presence of dengue virus genome in the bone marrow. Discussion and evaluation It is described here, a case of fatal dengue with clinical features of HPS. Though BMAT results did not show the presence of macrophage hemophagocytosis, other laboratory features were consistent with HPS especially marked elevation of ferritin, sCD163 and sCD25. Detection of dengue virus in the patient’s bone marrow, fifteen days after the onset of fever was also consistent with the suggestion that the HPS is associated with dengue virus infection. The findings highlight HPS as a possible complication leading to severe dengue and revealed persistent dengue virus infection of the bone marrow. Detection of HPS markers; ferritin, sCD163 and sCD25, therefore, should be considered for early recognition of HPS-associated dengue.
    SpringerPlus 11/2015; 4(665). DOI:10.1186/s40064-015-1463-z
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    • "Macrophage activation syndrome (MAS) is a severe, potentially life-threatening complication of systemic juvenile idiopathic arthritis (s-JIA) [1]. MAS occurs in approximately 7%–13% patients with s-JIA [2]. "
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    ABSTRACT: To assess the role of IL-6/IL-18 in the pathogenesis of systemic juvenile idiopathic arthritis (s-JIA) and to investigate the clinical significance of serum IL-18 levels for predicting macrophage activation syndrome (MAS) development, we measured the serum IL-6/IL-18 levels in 76 s-JIA patients, including 15 with MAS, and compared them with the clinical features. We identified 2 distinct subsets on the basis of serum IL-6/IL-18 levels. The IL-18-dominant subset had more patients who developed MAS. Serum IL-18 levels during active phase in patients with MAS were significantly higher than those without MAS. The cutoff value of serum IL-18 levels for predicting MAS development was 47750pg/ml. The patients with IL-18 dominant subset at their disease onset were significantly more likely to develop MAS after TCZ therapy started. IL-18 might have a key role in the pathogenesis of MAS. Serum IL-18 levels >47750pg/ml might be useful to predict MAS development. Copyright © 2015. Published by Elsevier Inc.
    Clinical Immunology 06/2015; 160(2). DOI:10.1016/j.clim.2015.06.005 · 3.67 Impact Factor
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    • "Because of the similarities between MAS and hemophagocytic lymphohistiocytosis (HLH), some authors believed that the MAS was a secondary or acquired form of HLH [10] [11]. Like HLH, the patients with MAS and juvenile idiopathic arthritis (JIA) had genetic defects in the cytolytic pathway [12] [13]. Also, late onset primary HLH in adult has the specific genetic features [14]. "
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    ABSTRACT: Purpose: To compare the laboratory data and changes in these data between patients with MAS and patients with flare-up of the autoimmune diseases. Methods: In a prospective study, the static laboratory data and dynamic changes in the selected data in 17 consecutive patients with MAS and 53 patients with active disease of SJIA, PJIA, Kawasaki disease, and SLE were compared. The ROC curve analysis was used to evaluate cut-off points, sensitivity, and specificity of the static and dynamic laboratory data to differentiate between MAS and active disease. Results: In the MAS group, the mean CRP3, ALT, AST, total bilirubin, ferritin, LDH, PT, PTT, and INR were significantly higher and the mean WBC2, PMN2, Lymph2, Hgb1, 2, 3, ESR2, serum albumin, and sodium were significantly lower than in control group. Some of the important cut-off points were PLT2 < 209000/microliter, AST > 38.5, ALT > 38, WBC < 8200 × 103/UL, ferritin > 5277 ng/mL. Conclusion: The dynamic changes in some laboratory data, especially PLT, can differentiate between MAS and active disease. The changes in WBC, PMN, and ESR and the levels of the liver enzymes may also be helpful in the early differentiation. Very high levels of ferritin may also help the diagnosis along with other clinical and laboratory signs.
    Disease markers 04/2015; 2015. DOI:10.1155/2015/424381 · 1.56 Impact Factor
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