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.
"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. "
[Show abstract][Hide abstract] 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.
"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]. "
[Show abstract][Hide abstract] 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.
"Heterozygous mutations in genes involved in HLH have been described in some subsets of SoJIA patients and might play a role in the development of MAS . Specific criteria for sJIA-associated MAS have been recently proposed . Interestingly, MAS has been recently included as an individual group of autoinflammatory diseases in an updated classification proposed by Masters et al. . "
[Show abstract][Hide abstract] ABSTRACT: Systemic juvenile idiopathic arthritis (sJIA), formerly called Still's disease, is officially classified as a subset of juvenile idiopathic arthritis (JIA). Beside arthritis, it is characterized by prominent systemic features and a marked inflammatory response. Even if it is still included in the group of juvenile arthritides, sJIA is set apart from all the other forms of JIA. This disorder has markedly distinct clinical and laboratory features suggesting a different pathogenesis. sJIA does not show any association with HLA genes or with autoantibodies and is characterised by an uncontrolled activation of phagocytes with hypersecretion of IL-1 and IL-6. Based on clinical and laboratory features, as well as on new acquisitions on the pathogenesis, it seems evident that sJIA is an autoinflammatory disease related to abnormality in innate immune system. The new insights on the pathogenesis of sJIA have therefore dramatically changed the approach to treatment, with the development of targeted treatments (anti-IL-1 and anti-IL-6 agents) more effective and safer than earlier medications.
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