Macrophage Activation Syndrome In sJIA Research Articles

Expansion of CD4dimCD8+ T cells characterizes macrophage activation syndrome and other secondary HLH

AbstractCD8+ T-cell activation has been demonstrated to distinguish patients with primary and infection-associated hemophagocytic lymphohistiocytosis (HLH) from patients with early sepsis. We evaluated the activation profile of CD8+ T cells in patients with various forms of secondary HLH (sHLH), including macrophage activation syndrome (MAS). Peripheral blood mononuclear cells from children with inactive systemic juvenile idiopathic arthritis (sJIA, n = 17), active sJIA (n = 27), MAS in sJIA (n = 14), infection-associated HLH (n = 7), and with other forms of sHLH (n = 9) were analyzed by flow cytometry. Compared with patients with active sJIA, in patients with MAS and sHLH of different origins, beside a significant increase in the frequency of CD38high/HLA-DR+CD8+ T cells, we found a significant increase in the frequency of CD8+ T cells expressing the CD4 antigen (CD4dimCD8+ T cells). These cells expressed high levels of the activation markers CD38 and HLA-DR, suggesting they were a subset of CD38high/HLA-DR+CD8+ T cells, as well as of the activation/exhaustion markers CD25, PD1, CD95, and interferon-γ. The frequency of CD4dimCD8+ T cells strongly correlated with most of the laboratory parameters of MAS severity and with circulating levels of CXCL9 and interleukin-18. These findings were confirmed in a prospective replication cohort in which no expansion of any particular T-cell receptor Vβ family in CD3+ T cells of patients with sHLH was found. Finally, frequency of CD4dimCD8+, but not of CD38high/HLA-DR+CD8+ T cells, significantly correlated with a clinical severity score, further supporting the involvement of these cells in MAS/sHLH pathogenesis.

The performance of the diagnostic scoring system or criteria for macrophage activation syndrome in systemic juvenile idiopathic arthritis for adult-onset Still's disease. A multicentre case-control study in China.

To evaluate the performance of the diagnostic scoring system/criteria for macrophage activation syndrome (MAS) used in systemic juvenile idiopathic arthritis (sJIA) for adult-onset Still's disease (AOSD). This retrospective case-control study included AOSD patients with and without MAS from six hospitals in China. The cut-off values that best discriminated MAS from active AOSD were determined by receiver operating characteristic (ROC) curve analysis. The performance of the present diagnostic scoring system/criteria for sJIA-MAS was evaluated in AOSD-associated MAS. The optimal critical value of the ROC curve replaces the relevant indicators of the existing scoring system and different models were tested for sensitivity/specificity. A total of 56 AOSD-associated MAS patients (AOSD-MAS) and 112 AOSD patients without MAS matched with age and sex treated at six centres between 2007 and 2017 were enrolled. The 2016 MAS in sJIA classification criteria had an overall sensitivity of 100.0% and specificity of 80.4% for classifying AOSD-MAS. Excluding hypertriglyceridemia and substituting some other criteria with newly obtained cut-off values could increase specificity. An MS score ≥-2.1 yielded a sensitivity of 95.2% and a specificity of 76.6% in classifying AOSD-MAS. ROC curve analysis revealed that a score of -1.74 could best discriminate AOSD-MAS from AOSD without MAS. An MS score ≥-1.74 yielded a sensitivity of 93.5% and a specificity of 92.6% in diagnosing AOSD-MAS (AUC=0.96, 95%CI: 0.93-0.99, p<0.0001). The diagnostic tool for MAS in sJIA with modification appears to apply to AOSD-MAS.

Ferritin to Erythrocyte Sedimentation Rate Ratio: Simple Measure to Identify Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis.

ObjectiveMacrophage activation syndrome (MAS) is a life‐threatening complication of systemic juvenile idiopathic arthritis (sJIA). Early diagnosis is critical. Classification criteria for MAS in sJIA perform less well in the setting of cytokine‐directed therapies. The goal herein was to explore a simple ratio of serum ferritin to the erythrocyte sedimentation rate (ESR) for diagnosis of MAS in the setting of sJIA, and to assess ferritin alone as a screening tool for identifying MAS of multiple etiologies.MethodsData from a large international cohort of sJIA patients with and without MAS, and from hospitalized patients with systemic infection (SI), were assessed for the ferritin:ESR ratio and ferritin alone to identify MAS among sJIA patients. Moreover, data from a smaller cohort of MAS patients associated with multiple etiologies and febrile hospitalized controls were explored. For both cohorts and controls, receiver operating characteristic curves (ROCs) for the ferritin:ESR ratio and ferritin alone were constructed, and areas under the curves (AUCs) were calculated. The Youden index was used to determine the optimal ferritin:ESR ratio and ferritin alone cut points for diagnosis.ResultsA ferritin:ESR ratio of 21.5 was 82% sensitive and 78% specific for diagnosing sJIA‐MAS versus active sJIA without MAS. Ferritin alone with a set sensitivity of 95% (screening tool) had an 89.3% specificity of identifying all‐cause MAS versus febrile hospitalized children.ConclusionThe ferritin:ESR ratio is a practical tool for diagnosing MAS among sJIA patients, and serum ferritin alone is a remarkable screening tool for identifying MAS among febrile hospitalized children.

Expert consensus on dynamics of laboratory tests for diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis

ObjectiveTo identify which laboratory tests that change over time are most valuable for the timely diagnosis of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (sJIA).MethodsA multistep process, based...

Evidence-based diagnosis and treatment of macrophage activation syndrome in systemic juvenile idiopathic arthritis.

BackgroundMacrophage activation syndrome (MAS) is a severe and potentially lethal complication of several inflammatory diseases but seems particularly linked to systemic juvenile idiopathic arthritis (sJIA). Standardized diagnostic and treatment guidelines for MAS in sJIA are currently lacking. The aim of this systematic literature review was to evaluate currently available literature on diagnostic criteria for MAS in sJIA and provide an overview of possible biomarkers for diagnosis, disease activity and treatment response and recent advances in treatment.MethodsA systematic literature search was performed in MEDLINE, EMBASE and Cochrane. 495 papers were identified. Potentially relevant papers were selected by 3 authors after which full text screening was performed. All selected papers were evaluated by at least two independent experts for validity and level of evidence according to EULAR guidelines.Results27 papers were included: 7 on diagnosis, 9 on biomarkers and 11 on treatment. Systematic review of the literature confirmed that there are no validated diagnostic criteria for MAS in sJIA. The preliminary Ravelli criteria, with the addition of ferritin, performed well in a large retrospective case-control study. Recently, an international consortium lead by PRINTO proposed a new set of diagnostic criteria able to distinguish MAS from active sJIA and/or infection with superior performance.Other promising diagnostic biomarkers potentially distinguish MAS complicating sJIA from primary and virus-associated hemophagocytic lymphohistiocytosis.The highest level of evidence for treatment comes from case-series. High dose corticosteroids with or without cyclosporine A were frequently reported as first-line therapy. From the newer treatment modalities, promising responses have been reported with anakinra.ConclusionMAS in sJIA seems to be diagnosed best by the recently proposed PRINTO criteria, although prospective validation is needed. Novel promising biomarkers for sJIA related MAS are in need of prospective validation as well, and are not widely available yet. Currently, treatment of MAS in sJIA relies more on experience than evidence based medicine. Taking into account the severity of MAS and the scarcity of evidence, early expert consultation is recommended as soon as MAS is suspected.

Cytokines in systemic juvenile idiopathic arthritis and haemophagocytic lymphohistiocytosis: tipping the balance between interleukin-18 and interferon-γ.

To study the role of IFN-γ in the pathogenesis of systemic JIA (sJIA) and haemophagocytic lymphohistiocytosis (HLH) by searching for an IFN-γ profile, and to assess its relationship with other cytokines. Patients with inactive (n = 10) and active sJIA (n = 10), HLH [n = 5; of which 3 had sJIA-associated macrophage activation syndrome (MAS)] and healthy controls (n = 16) were enrolled in the study. Cytokines and IFN-γ-induced genes and proteins were determined in plasma, in patient peripheral blood mononuclear cells (PBMCs) and in lymph node biopsies of one patient during both sJIA and MAS episodes. IFN-γ responses were investigated in healthy donor PBMCs, primary fibroblasts and endothelial cells. Plasma IFN-γ, IL-6 and IL-18 were elevated in active sJIA and HLH. Levels of IFN-γ and IFN-γ-induced proteins (IP-10/CXCL-10, IL-18BP and indoleamine 2,3-dioxygenase) in HLH were much higher than levels in active sJIA. Free IL-18 and ratios of IL-18/IFN-γ were higher in active sJIA compared with HLH. HLH PBMCs showed hyporesponsiveness to IFN-γ in vitro when compared with control and sJIA PBMCs. Endothelial cells and fibroblasts expressed IFN-γ-induced proteins in situ in lymph node staining of a MAS patient and in vitro upon stimulation with IFN-γ. Patients with active sJIA and HLH/MAS show distinct cytokine profiles, with highly elevated plasma levels of IFN-γ and IFN-γ-induced proteins typically found in HLH/MAS. In addition to PBMCs, histiocytes, endothelial cells and fibroblasts may contribute to an IFN-γ profile in plasma. Increasing levels of IFN-γ compared with IL-18 may raise suspicion about the development of MAS in sJIA.

A56: Macrophage Activation Syndrome in Patients With Systemic Juvenile Idiopathic Arthritis Treated With Tocilizumab

Background/Purpose: Macrophage activation syndrome (MAS) is a severe, potentially fatal complication of systemic juvenile idiopathic arthritis (sJIA).[1] Changes in therapies, including biologics,[2, 3] may trigger MAS. Interleukin-6 (IL-6) plays a major pathogenic role in sJIA; data in animals suggest that high IL-6 levels contribute to the triggering of MAS.[4] Treatment with the IL-6 receptor inhibitor tocilizumab (TCZ) is very effective in patients with sJIA.[2] In this study, we investigated the rates and features of MAS occurring during TCZ treatment in patients with sJIA. Methods: Data were collected from patients with sJIA treated with TCZ in the international phase 3 trial (TENDER), 4 clinical trials in Japan, and the Japanese postmarketing surveillance (JPMS) program. Reported MAS events or disease flares associated with alanine aminotransferase/aspartate aminotransferase (ALT/AST) elevations were collected. Worksheets with event information were assessed by an independent panel (2 pediatric rheumatologists, 1 pediatric hematologist with MAS expertise) overseen by the TENDER lead investigator. Cases were adjudicated as definite MAS, potential MAS, not MAS, or insufficient data. Results: The data set included 112 patients from TENDER (403.0 patient-years' [PY] exposure to TCZ), 149 patients from the Japanese trials (326 PY), and 366 patients from the JPMS program (523.9 PY). Of 31 cases reviewed, 22 events were adjudicated as definite or potential MAS: 5 from TENDER (3 definite, 2 potential), 6 from the Japanese trials (3 definite, 3 potential), and 11 from the JPMS program (5 definite, 6 potential). The rates/100 PY of definite/potential MAS were 1.24 (95% CI, 0.4–2.90) in TENDER, 1.84 (95% CI, 0.68–4.00) in the Japanese trials, and 2.10 (95% CI, 1.05–3.76) in the JPMS program. Features contributing to the adjudication of definite MAS are listed in the 1. All 11 events adjudicated as definite MAS met the preliminary MAS diagnostic guidelines.[6] All definite and potential MAS resolved with the exception of MAS in a patient from the Japanese phase 3 study who died after respiratory/cardiac arrest. Table 1. Criteria for Adjudication of Cases as Definite MAS (n = 11) Features of MAS Patients for Whom These Features Led to Adjudication of Definite MAS n (%)mg a aThresholds for abnormal values were determined according to age and local guidelines. Clinical signs Fever 6 (55) Rash 3 (27) Hemorrhage with purpura, hematuria 2 (18) Hepatomegaly 0 (0) Laboratory featuresa Elevated ALT/AST 11 (100) Thrombocytopenia 9 (82) Elevated ferritin 8 (73) Leukopenia 7 (64) Neutropenia 6 (55) Elevated lactate dehydrogenase 4 (36) Low fibrinogen 4 (36) Increased triglycerides 4 (36) Elevated D-dimers 3 (27) Low hemoglobin 4 (36) Elevated C-reactive protein 2 (18) Low erythrocyte sedimentation rate 2 (18) Conclusion: The use of TCZ does not appear to be associated with increased risk for MAS in sJIA. There were no unusual clinical or laboratory features in these MAS cases.

SP0102 Toward new diagnostic criteria for macrophage activation syndrome in systemic juvenile idiopathic arthritis

Macrophage activation syndrome (MAS) is a severe, potentially fatal complication of systemic juvenile idiopathic arthritis (sJIA) with features of hemophagocytosis, leading to coagulopathy, pancytopenia, and liver and central nervous system...

Differentiating Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis from Other Forms of Hemophagocytic Lymphohistiocytosis

To identify measures distinguishing macrophage activation syndrome (MAS) in systemic juvenile idiopathic arthritis (sJIA) from familial hemophagocytic lymphohistiocytosis (FHL) and virus-associated hemophagocytic lymphohistiocytosis (VA-HLH) and to define appropriate cutoff values. To evaluate suggested dynamic measures differentiating MAS in patients with sJIA from sJIA flares. In a cohort of patients referred for evaluation of hemophagocytic lymphohistiocytosis, we identified 27 patients with sJIA and MAS (MAS/sJIA) fulfilling the criteria of the proposed preliminary diagnostic guideline for the diagnosis of MAS in sJIA. Ten measures at diagnosis were compared between the MAS/sJIA group and 90 patients with FHL and 42 patients with VA-HLH, and cutoff values were determined. In addition, 5 measures were analyzed for significant change from before MAS until MAS diagnosis. Neutrophil count and C-reactive protein were significantly higher in patients with MAS/sJIA compared with patients with FHL and patients with VA-HLH, with 1.8×10(9)/L neutrophils (sensitivity 85%, specificity 83%) and 90 mg/L C-reactive protein (74%, 89%) as cutoff values. Soluble CD25<7900 U/L (79%, 76%) indicated MAS/sJIA rather than FHL/VA-HLH. Platelet (-59%) and white blood cell count (-46%) displayed a significant decrease, and neutrophil count (-35%) and fibrinogen (-28%) showed a trend during the development of MAS. However, a substantial portion of patients had values at diagnosis of MAS within or above the normal range for white blood cells (84%), neutrophils (77%), platelets (26%), and fibrinogen (71%). Readily available measures can rapidly differentiate between MAS/sJIA and FHL/VA-HLH. The findings substantiate that a decline of measures may facilitate the distinction of MAS from flares of sJIA.

Toward the Development of New Diagnostic Criteria for Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis

Macrophage activation syndrome (MAS) is a severe, potentially 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 about 10% of children with sJIA but may occur subclinically in another 30-40% of patients. The diagnosis of MAS in sJIA can be challenging because it may mimic a flare of the underlying disease or be confounded with an infectious complication or a medication side effect. So far, universally agreed upon diagnostic criteria for MAS are not available. A multinational collaborative effort is under way that is aimed to generate new criteria for diagnosing MAS as a complication of sJIA. The first step of the project has led to the identification of, by means of a Delphi survey, the clinical, laboratory and histopatho logic features of MAS that were felt to be most important by a large sample of international pediatric rheumatologists with experience with MAS in children with sJIA. The diagnostic performance of potential criteria will be scrutinized further in the second phase of the study, through the analysis (ongoing) of real patient data. The final set of criteria is meant to be established in a consensus conference of experts using a combination of statistical and consensus formation techniques. The ultimate goal of the project is to develop a core set of criteria that is both highly sensitive and specific. These criteria will assist physicians in MAS diagnosis in children with sJIA and enable quick institution of appropriate therapy.

Hypocomplementemia Associated with Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis and Adult Onset Still’s Disease: 3 Cases: Table 1.

To the Editor: Macrophage activation syndrome (MAS) is a life-threatening complication seen in association with childhood inflammatory diseases, most commonly in systemic juvenile idiopathic arthritis (sJIA)1,2,3. MAS has also been described in the setting of adult-onset Still’s disease (AOSD), systemic lupus erythematosus, drug reactions, and viral infections4,5. Decrease in C3 has been documented in patients with lupus and MAS4; however, to our knowledge, hypocomplementemia has not been previously described as associated with MAS in sJIA or AOSD. We describe 2 patients with sJIA, and a third with AOSD, who developed MAS with hypocomplementemia during the acute phase of illness. Patient 1, a 9-year-old boy, presented with high quotidian fever, evanescent rash, and arthritis. He had leukocytosis (24 × 109/l) with elevated markers of inflammation: erythrocyte sedimentation rate (ESR) 52 mm/h and C-reactive protein (CRP) 17.3 mg/dl. Liver enzymes and renal function were normal. Ferritin was 5623 ng/ml. Serologic tests for Epstein-Barr virus, parvovirus, cytomegalovirus, Lyme disease, mycoplasma, and group A streptococcus were negative. Complement levels, obtained by the primary intensive care team, showed slightly increased C3 (166 mg/dl) and normal C4 (32 mg/dl). He was discharged with a diagnosis of new-onset sJIA and prescribed indomethacin. Several days later, he returned to clinic with worsening symptoms and petechial … Address correspondence to Dr. Gorelik; E-mail: mark.gorelik{at}chp.edu

A case of systemic-onset juvenile idiopathic arthritis complicated with sepsis -Usefulness of cytokine profile for the differentiation between macrophage activation syndrome and sepsis-

The differential diagnosis of macrophage activation syndrome (MAS) and sepsis must be considered in the clinical course of systemic-onset juvenile idiopathic arthritis (s-JIA) with sudden onset of high-grade fever and abnormal laboratory findings, including leukocytopenia, thrombocytopenia, and coagulopathy. In this report, we describe the case of a 17-month-old girl diagnosed with s-JIA complicated with sepsis. Her serum interleukin (IL)-18 level was significantly elevated throughout the clinical course. Furthermore, compared to other MAS patients, she showed a significantly elevated serum IL-6 level and procalcitonin in sepsis. Therefore, our results suggest that a patient's cytokine profile may be a useful indicator of disease activity and may thus help in the differential diagnosis of sepsis and MAS in s-JIA.