Update οn the diagnosis and management of systemic lupus erythematosus.

Clinical heterogeneity, unpredictable course and flares are characteristics of systemic lupus erythematosus (SLE). Although SLE is-by and large-a systemic disease, occasionally it can be organ-dominant, posing diagnostic challenges. To date, diagnosis of SLE remains clinical with a few cases being negative for serologic tests. Diagnostic criteria are not available and classification criteria are often used for diagnosis, yet with significant caveats. Newer sets of criteria (European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019) enable earlier and more accurate classification of SLE. Several disease endotypes have been recognised over the years. There is increased recognition of milder cases at presentation, but almost half of them progress overtime to more severe disease. Approximately 70% of patients follow a relapsing-remitting course, the remaining divided equally between a prolonged remission and a persistently active disease. Treatment goals include long-term patient survival, prevention of flares and organ damage, and optimisation of health-related quality of life. For organ-threatening or life-threatening SLE, treatment usually includes an initial period of high-intensity immunosuppressive therapy to control disease activity, followed by a longer period of less intensive therapy to consolidate response and prevent relapses. Management of disease-related and treatment-related comorbidities, especially infections and atherosclerosis, is of paramount importance. New disease-modifying conventional and biologic agents-used alone, in combination or sequentially-have improved rates of achieving both short-term and long-term treatment goals, including minimisation of glucocorticoid use.

Sudden Hypotension and Increased Serum Interferon-γ and Interleukin-10 Predict Early Macrophage Activation Syndrome in Patients with Systemic Juvenile Idiopathic Arthritis.

OBJECTIVE: To identify clinical and laboratory predictors for early macrophage activation syndrome (MAS) associated with systemic juvenile idiopathic arthritis (sJIA). STUDY DESIGN: This is a retrospective cohort study of 149 patients with sJIA, of whom 27 had 31 episodes of MAS. We evaluated the clinical and laboratory features of patients with sJIA and MAS and compared them with those without MAS. We focused our analysis on the overall process of MAS development, especially MAS onset. RESULTS: As shown in previous studies, we found a high percentage of fever, absence of arthritis, and central nervous system dysfunction at MAS onset in our study cohort. We also found that 35% of patients with MAS had hypotension although not shock, and 22.6% of patients with MAS had gastrointestinal involvement at MAS onset. Compared with patients with MAS without hypotension, patients with MAS and hypotension had greater rates of admission to the intensive care unit; presented with more arthritis, serositis, pneumonia, and gastrointestinal involvement; and had greater white blood cell and absolute neutrophil counts and serum bilirubin levels and lower serum total protein. We confirmed laboratory markers such as platelet counts, lactate dehydrogenase, and aspartate aminotransferase can help to identify early MAS and that ferritin/erythrocyte sedimentation rate ratio of approximately 20.0 had a high diagnostic sensitivity and specificity for MAS. In addition, we discovered that the combination of interferon-γ >17.1 pg/mL and interleukin-10 >7.8 pg/mL appeared to be a good cytokine pattern for the recognition of MAS onset. CONCLUSIONS: Sudden hypotension, elevated ferritin/erythrocyte sedimentation rate ratio, and the cytokine pattern of significantly increased interferon-γ and interleukin-10 levels are important markers for early identification of MAS in addition to the traditional characteristics of sJIA-associated MAS.

Thrombotic Microangiopathy Associated with Macrophage Activation Syndrome: A Multinational Study of 23 Patients.

OBJECTIVE: To describe the clinical characteristics, treatment, and outcomes of a multinational cohort of patients with macrophage activation syndrome (MAS) and thrombotic microangiopathy (TMA). STUDY DESIGN: International pediatric rheumatologists were asked to collect retrospectively the data of patients with the co-occurrence of MAS and TMA. Clinical and laboratory features of patients with systemic juvenile idiopathic arthritis (sJIA)-associated MAS and TMA were compared with those of an historical cohort of patients with sJIA and MAS. RESULTS: Twenty-three patients with MAS and TMA were enrolled: 17 had sJIA, 2 systemic lupus erythematosus, 1 juvenile dermatomyositis, 1 mixed connective tissue disease, and 2 undifferentiated connective tissue disease. Compared with the historical cohort of MAS, patients with sJIA with coexistent MAS and TMA had higher frequencies of renal failure and neurologic involvement, hemorrhage, jaundice, and respiratory symptoms, as well as more severe anemia and thrombocytopenia, higher levels of alanine aminotransferase, lactate dehydrogenase, bilirubin and D-dimer, and lower levels of albumin and fibrinogen. They also required admission to the intensive care unit more frequently. Among patients tested, complement abnormalities and reduced ADAMTS13 activity were observed in 64.3% and 44.4% of cases, respectively. All patients received glucocorticoids. Treatment for TMA included plasma-exchange, eculizumab, and rituximab. CONCLUSIONS: The possible coexistence of MAS and TMA in rheumatic diseases may be underrecognized. This association should be considered in patients with MAS who develop disproportionate anemia, thrombocytopenia, and lactate dehydrogenase increase, or have multiorgan failure.

Macrophage activation syndrome in children with Kawasaki disease: an experience from a tertiary care hospital in northwest India.

OBJECTIVES: To carry out a review of clinical characteristics, laboratory profiles, management and outcomes of patients with Kawasaki disease (KD) and macrophage activation syndrome (MAS). METHODS: Medical records of patients treated for KD and MAS between January 1994 and December 2019 were reviewed. Patient demographics, clinical signs, laboratory values, coronary artery abnormalities, treatments and outcomes of patients with KD and MAS were recorded. We also performed a review published studies on the subject. RESULTS: Of the 950 cases with KD, 12 (1.3%; 10 boys, 2 girls) were diagnosed with MAS. The median age at diagnosis was 4 years (range 9 months-7.5 years). The median interval between onset of fever and diagnosis of KD was 11 days (range 6-30). Thrombocytopenia was seen in 11 patients. The median pro-brain natriuretic peptide value was 2101 pg/ml (range 164-75 911). Coronary artery abnormalities were seen in 5 (41.7%) patients; 2 had dilatation of the left main coronary artery (LMCA), 1 had dilatation of both the LMCA and right coronary artery (RCA), 1 had dilatation of the RCA and 1 had bright coronary arteries. All patients received IVIG as first-line therapy for KD. MAS was treated with i.v. methylprednisolone pulses followed by tapering doses of oral prednisolone. Additional therapy included i.v. infliximab (n = 4), second-dose IVIG (n = 1) and oral ciclosporin (n = 1). CONCLUSION: MAS is an unusual and underrecognized complication of KD. In our cohort of 950 patients with KD, 1.3% had developed MAS. KD with MAS is associated with an increased propensity towards development of coronary artery abnormalities.

Current Understanding of Multisystem Inflammatory Syndrome (MIS-C) Following COVID-19 and Its Distinction from Kawasaki Disease.

PURPOSE OF REVIEW: In this article, I have reviewed current reports that explore differences and similarities between multisystem inflammatory syndrome in children (MIS-C) and other known multisystem inflammatory diseases seen in children, particularly Kawasaki disease. RECENT FINDINGS: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a human coronavirus causing the COVID-19 disease which emerged in China in December 2019 and spread rapidly to the entire country and quickly to other countries. Currently, there is a pandemic of SARS-CoV-2 infection that results in 20% of patients admitted to hospital with illness, with 3% developing intractable acute respiratory distress syndrome (ARDS) with high mortality. However, pediatric COVID-19 is still reported to be a mild disease, affecting only 8% of children. Pathogenesis in children is comparable to adults. There are suggested impaired activation of IFN-alpha and IFN regulator 3, decreased cell response causing impaired viral defense, yet the clinical course is mild, and almost all children recover from the infection without major complications. Interestingly, there is a subset of patients that develop a late but marked immunogenic response to COVID-19 and develop MIS-C. Clinical features of MIS-C resemble certain pediatric rheumatologic diseases, such as Kawasaki disease (mucocutaneous lymph node syndrome) which affects small-medium vessels. Other features of MIS-C resemble those of macrophage activation syndrome (MAS). However, recent research suggests distinct clinical and laboratory differences between MIS-C, Kawasaki disease, and MAS. Since the start of the SARS-CoV-2 pandemic, MIS-C has become the candidate for the most common cause of acquired heart disease in children.

Performances of the "MS-score" And "HScore" in the diagnosis of macrophage activation syndrome in systemic juvenile idiopathic arthritis patients.

Macrophage activation syndrome (MAS) is a devastating complication of systemic JIA (sJIA), seen in approximately 10-25% of the sJIA patients. A number of criteria have been proposed to differentiate between activation of sJIA and MAS, including HScore and the recently proposed MS-score. This is the first study comparing the performances of MS-score and HScore for the diagnosis of MAS in sJIA patients. Systemic JIA patients followed at Hacettepe University Pediatric Rheumatology Unit were included in the study. Clinical features and laboratory findings at the time when the disease was most active or patients were diagnosed with MAS were recorded retrospectively. HScore and MS-score were calculated and the diagnostic performance for MAS was compared by receiver operating characteristic (ROC) curve analysis. Seventy-one sJIA patients were included (23 MAS, 48 activation). There was no difference in age of onset (median 4.7 vs. 5.0 years) and gender (73.9% vs. 54.2%) between patients who had MAS and sJIA activation. Median MS-score and HScore were higher in the MAS group. ROC curve analysis revealed that the HScore performed slightly better in diagnosing MAS, compared with the MS-score (AUC = 0.965 and 0.901 for HScore and MS-score respectively, P < 0.001). In our cohort, the optimal cut-off for the MS score was ≥ - 1.64 (sensitivity: 91.3%; specificity: 83.8%) and for the HScore it was ≥ 162.5 (sensitivity: 91.3%; specificity: 90.2%). HScore performed slightly better than MS-score for the diagnosis of MAS in our cohort.

Macrophage activation syndrome in systemic lupus erythematosus and systemic-onset juvenile idiopathic arthritis: a retrospective study of similarities and dissimilarities.

Macrophage activation syndrome (MAS) is a serious complication of rheumatic diseases. Fever and hyperferritinemia are common in active systemic-onset juvenile idiopathic arthritis (sJIA) and cytopenia in active systemic lupus erythematosus (SLE), thus recognizing MAS in them is a challenge. We compared clinical and laboratory parameters, various classification criteria, and outcomes of MAS in SLE and sJIA. Clinical and laboratory data were extracted from case records of patients with clinician diagnosed cases of SLE-MAS (adult and pediatric) and sJIA-MAS, admitted (2004-2018) at a tertiary care hospital. Ravelli, International consensus, HLH-2004, and criteria proposed by Parodi et al. were applied and compared. Among 33 patients (18 females) with MAS, 19 had SLE (7, childhood-onset SLE) and 14 had sJIA. MAS was more likely to be the presenting manifestation of disease in SLE (p < 0.05). There were no differences in the clinical features among them. Patients with SLE-MAS had lower baseline total leucocyte and platelet counts (p < 0.01), whereas patients with sJIA-MAS had significantly higher median CRP (p = 0.002), fall in TLC (p = 0.012), delta ESR/CRP ratio (p = 0.02), and lower fibrinogen level (p = 0.006). Neutrophil-to-lymphocyte ratio, ferritin/CRP ratio, and the number of patients with ferritin/ESR > 80 were similar. Only 6/33(18%) fulfilled the HLH criteria. Criteria meant for sJIA-MAS or SLE-MAS performed well for both diseases and the majority of patients could be diagnosed using them. Two patients died in each group. MAS in SLE and sJIA is more similar than dissimilar in clinical features and outcome. Criteria meant for MAS in sJIA or SLE-MAS performed equally well in both diseases.

Hemophagocytic lymphohistiocytosis: a review inspired by the COVID-19 pandemic.

Hemophagocytic syndrome (HPS) or hemophagocytic lymphohistiocytosis (HLH) is an acute and rapidly progressive systemic inflammatory disorder characterized by cytopenia, excessive cytokine production, and hyperferritinemia. Common clinical manifestations of HLH are acute unremitting fever, lymphadenopathy, hepatosplenomegaly, and multiorgan failure. Due to a massive cytokine release, this clinical condition is considered as a cytokine storm syndrome. HPS has primary and acquired (secondary, reactive) forms. Its primary form is mostly seen in childhood and caused by various mutations with genetic inheritance and, therefore, is called familial HLH. Secondary HLH may be caused in the presence of an underlying disorder, that is, secondary to a malignant, infectious, or autoimmune/autoinflammatory stimulus. This paper aims to review the pathogenesis and the clinical picture of HLH, and its severe complication, the cytokine storm, with a special emphasis on the developed classification criteria sets for rheumatologists, since COVID-19 infection has clinical symptoms resembling those of the common rheumatologic conditions and possibly triggers HLH. MED-LINE/Pubmed was searched from inception to April 2020, and the following terms were used for data searching: "hemophagocytic syndrome" OR "macrophage activation syndrome" OR "hemophagocytic lymphohistiocytosis", OR "cytokine storm". Finally, AND "COVID-19" was included in this algorithm. The selection is restricted to the past 5 years and limited numbers of earlier key references were manually selected. Only full-text manuscripts, published in an English language peer-reviewed journal were included. Manuscript selection procedure and numbers are given in Fig. 2. Briefly, the database search with the following terms of "Hemophagocytic syndrome" OR "Macrophage activation syndrome" OR "Hemophagocytic lymphohistiocytosis" OR "Cytokine storm" yielded 6744 results from inception to April 2020. The selection is restricted to the past 5 years and only limited numbers of earlier key references were selected, and this algorithm resulted in 3080 manuscripts. The addition of (AND "COVID-19") resulted in 115 publications of which 47 studies, together with four sections of an online book were used in the final review. No statistical method was used. HLH is triggered by genetic conditions, infections, malignancies, autoimmune-autoinflammatory diseases, and some drugs. In COVID-19 patients, secondary HLH and cytokine storm may be responsible for unexplained progressive fever, cytopenia, ARDS, neurological and renal impairment. Differentiation between the primary and secondary forms of HLH is utterly important, since primary form of HLH requires complicated treatments such as hematopoietic stem cell transplantation. Further studies addressing the performance of HScore and other recommendations in the classification of these patients is necessary.

Macrophage activation syndrome in juvenile dermatomyositis: a systematic review.

Macrophage activation syndrome (MAS) is a potentially fatal complication of a number of rheumatological conditions, but few studies assessed it in juvenile dermatomyositis (JDM). Indeed, MAS is not considered as a frequent complication of JDM, but its occurrence could be under-estimated. In order to address this issue, we performed a revision of the available medical literature, describing and assessing patients with both MAS and JDM. After retrieving 253 records initially, 11 papers were selected as appropriate for our research objective, which provided a total of 12 patients affected with both MAS and JDM. Our pooled case series suggested that MAS in JDM may not be very rare, even though no final conclusion about its incidence and mortality rate can be made. However, JDM-related MAS seems to be difficult to treat, since methylprednisolone pulse therapy alone was not sufficient in most cases. Moreover, MAS in JDM patients often occurred at the onset of the rheumatic disease, before the final diagnosis of JDM could be established. Finally, MAS criteria validated for systemic Juvenile Idiopathic Arthritis (sJIA) resulted to be a very useful guidance to diagnose MAS in JDM patients as well, but their reliability may not be absolute. Therefore, cohort and multicenter studies are needed to assess the incidence and improve the diagnostic criteria for MAS in JDM patients.

Macrophage activation syndrome complicating rheumatic diseases in adults: case-based review.

Macrophage activation syndrome (MAS) is a life-threatening complication of rheumatologic diseases. Data regarding the clinical course, management and outcome of adults with MAS is limited. Therefore, we aimed to describe the clinical features, treatment and outcome of adult patients with MAS, and review the literature for previous cohorts. We retrospectively reviewed patients with MAS complicating rheumatologic diseases between the years 2007 and 2017. Through Pubmed, Medline and Scopus literature search we identified previous cases of adult patients with MAS. We identified 7 patients with MAS complicating rheumatologic diseases (5 females and 2 males). The median age of diagnosis was 32 (range 26-57) years. The median follow-up was 30 months (range 6.95-36.5) months. The underlying rheumatologic disease was adult onset Still's disease (AOSD) in 3 patients, systemic juvenile idiopathic arthritis (sJIA) in 2 patients, systemic lupus erythematosus (SLE) in 1 patient, and systemic vasculitis in 1 patient. Four patients developed MAS concurrently with the clinical development of the rheumatologic disease. All the patients were treated with systemic corticosteroids. Five patients were treated with cyclosporine A, one of which received combination therapy with anakinra, and one received tocilizumab. Two patients deceased during the hospitalization. We identified 92 patients from literature cohorts, 73 (79%) of them with AOSD. MAS developed concurrently with the underlying rheumatologic disease in 25 (27%) patients, and 30 (33%) patients deceased. Our cohort and previous cohorts demostrate that MAS often presents concurrently with the underlying rheumatologic disease and is associated with a high mortality rate. Further larger prospective studies are needed to determine the optimal management of MAS.

Prescribing motivations and patients' characteristics related to the use of biologic drugs in adult-onset Still's disease: analysis of a multicentre "real-life" cohort.

A growing body of evidence suggests the usability of biologic disease-modifying anti-rheumatic drugs (bDMARDs) in treating adult-onset Still's disease (AOSD). In a multicentre "real-life" cohort, the physicians' prescribing motivations and patients' predictive characteristics of being treated with bDMARDs were assessed. Patients with AOSD, who were included in GIRRCS (Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale) cohort and treated with bDMARDs, were retrospectively assessed. Relevant data were collected by a review of clinical charts. Forty-four patients treated with bDMARDs were analysed, with slight male preponderance (52.3%) and a mean age of 39.3 ± 15.2 years. All patients were treated with corticosteroids (CCSs) (38.6% with low dosage) and 93.2% were treated with synthetic DMARDs (sDMARDs). Regarding the effectiveness of the first-line bDMARD, 65.6% of patients experienced a complete remission, defined as complete disappearance of both systemic and joint symptoms and normalisation of laboratory evidence of disease. The physicians' prescribing motivations for bDMARDs were inadequate response to CCSs and/or sDMARDs, CCS-sparing effect and occurrence of macrophage activation syndrome (MAS). Analysing patients' characteristics, chronic disease course (OR 3.09; 95%CI 1.22-7.80, p = 0.017), defined as disease with persistent symptoms, was predictive of being treated with bDMARDs, whereas age (OR 0.97, 95%CI 0.93-0.99, p = 0.048) was negatively associated, suggesting younger age as a further predictive factor. Patients with AOSD were treated with bDMARDs for inadequate response to CCSs and/or sDMARDs, CCS-sparing effect and MAS occurrence. Younger age and chronic disease course were patients' predictive characteristics of being treated with bDMARDs.

Pathophysiology of Pediatric Multiple Organ Dysfunction Syndrome.

OBJECTIVE: To describe the pathophysiology associated with multiple organ dysfunction syndrome in children. DATA SOURCES: Literature review, research data, and expert opinion. STUDY SELECTION: Not applicable. DATA EXTRACTION: Moderated by an experienced expert from the field, pathophysiologic processes associated with multiple organ dysfunction syndrome in children were described, discussed, and debated with a focus on identifying knowledge gaps and research priorities. DATA SYNTHESIS: Summary of presentations and discussion supported and supplemented by relevant literature. CONCLUSIONS: Experiment modeling suggests that persistent macrophage activation may be a pathophysiologic basis for multiple organ dysfunction syndrome. Children with multiple organ dysfunction syndrome have 1) reduced cytochrome P450 metabolism inversely proportional to inflammation; 2) increased circulating damage-associated molecular pattern molecules from injured tissues; 3) increased circulating pathogen-associated molecular pattern molecules from infection or endogenous microbiome; and 4) cytokine-driven epithelial, endothelial, mitochondrial, and immune cell dysfunction. Cytochrome P450s metabolize endogenous compounds and xenobiotics, many of which ameliorate inflammation, whereas damage-associated molecular pattern molecules and pathogen-associated molecular pattern molecules alone and together amplify the cytokine production leading to the inflammatory multiple organ dysfunction syndrome response. Genetic and environmental factors can impede inflammation resolution in children with a spectrum of multiple organ dysfunction syndrome pathobiology phenotypes. Thrombocytopenia-associated multiple organ dysfunction syndrome patients have extensive endothelial activation and thrombotic microangiopathy with associated oligogenic deficiencies in inhibitory complement and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13. Sequential multiple organ dysfunction syndrome patients have soluble Fas ligand-Fas-mediated hepatic failure with associated oligogenic deficiencies in perforin and granzyme signaling. Immunoparalysis-associated multiple organ dysfunction syndrome patients have impaired ability to resolve infection and have associated environmental causes of lymphocyte apoptosis. These inflammation phenotypes can lead to macrophage activation syndrome. Resolution of multiple organ dysfunction syndrome requires elimination of the source of inflammation. Full recovery of organ functions is noted 6-18 weeks later when epithelial, endothelial, mitochondrial, and immune cell regeneration and reprogramming is completed.

Three Hypothetical Inflammation Pathobiology Phenotypes and Pediatric Sepsis-Induced Multiple Organ Failure Outcome.

OBJECTIVES: We hypothesize that three inflammation pathobiology phenotypes are associated with increased inflammation, proclivity to develop features of macrophage activation syndrome, and multiple organ failure-related death in pediatric severe sepsis. DESIGN: Prospective cohort study comparing children with severe sepsis and any of three phenotypes: 1) immunoparalysis-associated multiple organ failure (whole blood ex vivo tumor necrosis factor response to endotoxin < 200 pg/mL), 2) thrombocytopenia-associated multiple organ failure (new onset thrombocytopenia with acute kidney injury and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 activity < 57%), and/or 3) sequential multiple organ failure with hepatobiliary dysfunction (respiratory distress followed by liver dysfunction with soluble Fas ligand > 200 pg/mL), to those without any of these phenotypes. SETTING: Tertiary children's hospital PICU. PATIENTS: One hundred consecutive severe sepsis admissions. INTERVENTIONS: Clinical data were recorded daily, and blood was collected twice weekly. MEASUREMENTS AND MAIN RESULTS: Multiple organ failure developed in 75 cases and eight died. Multiple organ failure cases with any of the three inflammation phenotypes (n = 37) had higher inflammation (C-reactive protein, p = 0.009 and ferritin, p < 0.001) than multiple organ failure cases without any of these phenotypes (n = 38) or cases with only single organ failure (n = 25). Development of features of macrophage activation syndrome and death were more common among multiple organ failure cases with any of the phenotypes (macrophage activation syndrome: 10/37, 27%; death: 8/37, 22%) compared to multiple organ failure cases without any phenotype (macrophage activation syndrome: 1/38, 3%; p = 0.003 and death: 0/38, 0%; p = 0.002). CONCLUSIONS: Our approach to phenotype categorization remains hypothetical, and the phenotypes identified need to be confirmed in multicenter studies of pediatric multiple organ dysfunction syndrome.

Disruption of vascular endothelial homeostasis in systemic juvenile idiopathic arthritis-associated macrophage activation syndrome: The dynamic roles of angiopoietin-1 and -2.

To assess the role of angiopoietin (Ang)-1 and Ang-2 and to investigate the clinical significance of serum levels of them in systemic juvenile idiopathic arthritis (s-JIA)-associated macrophage activation syndrome (MAS), we determined these levels in 51 patients with s-JIA, 11 patients with polyarticular JIA (poly-JIA), 12 patients with virus associated hemophagocytic syndrome (VAHS), 12 patients with Kawasaki disease (KD), and 15 age-matched healthy controls (HC). The results were compared with clinical features of MAS. During the MAS phase, serum Ang-1 levels were significantly decreased compared with those during the active and inactive phases. Serum Ang-2/1 ratio were significantly elevated during the MAS phase, compared with those during the active and inactive phases. There was a rapid increase in the Ang-2/1 ratio at the onset of MAS. Serum Ang-1 and the Ang-2/1 ratio significantly correlated with measures of disease activity, including AST and LDH. Ang-2/1 dysregulation was also observed in patients with VAHS, whereas not observed in most cases of KD. The homeostasis of vascular endothelial function by Ang-1 and Ang-2 is disrupted in MAS. Serum Ang-1 levels and the Ang-2/1 ratio might represent promising indicators of disease activity for MAS.

Successful therapy of macrophage activation syndrome with dexamethasone palmitate.

Macrophage activation syndrome (MAS) is a severe and potential life-threatening complication of childhood systemic inflammatory disorders. Corticosteroids are commonly used as the first-line therapy for MAS. We report four patients with MAS who were successfully treated with dexamethasone palmitate (DexP), a liposome-incorporated dexamethasone, much more efficient than free corticosteroids. DexP effectively inhibited inflammation in MAS patients in whom the response to pulse methylprednisolone was not sufficient to manage their diseases. DexP was also effective as the first-line therapy for MAS. Based on these findings, DexP is an effective therapy in treating MAS patients.

Interferon-γ mediates anemia but is dispensable for fulminant toll-like receptor 9-induced macrophage activation syndrome and hemophagocytosis in mice.

OBJECTIVE: Macrophage activation syndrome (MAS) is a devastating cytokine storm syndrome complicating many inflammatory diseases and characterized by fever, pancytopenia, and systemic inflammation. It is clinically similar to hemophagocytic lymphohistiocytosis (HLH), which is caused by viral infection of a host with impaired cellular cytotoxicity. Murine models of MAS and HLH illustrate that interferon-γ (IFNγ) is the driving stimulus for hemophagocytosis and immunopathology. This study was undertaken to investigate the inflammatory contributors to a murine model of Toll-like receptor 9 (TLR-9)-induced fulminant MAS. METHODS: Wild-type, transgenic, and cytokine-inhibited mice were treated with an IL-10 receptor blocking antibody and a TLR-9 agonist, and parameters of MAS were evaluated. RESULTS: Fulminant MAS was characterized by dramatic elevations in IFNγ, IL-12, and IL-6 levels. Increased serum IFNγ levels were associated with enhanced IFNγ production within some hepatic cell populations but also with decreased numbers of IFNγ-positive cells. Surprisingly, IFNγ-knockout mice developed immunopathology and hemophagocytosis comparable to that seen in wild-type mice. However, IFNγ-knockout mice did not become anemic and had greater numbers of splenic erythroid precursors. IL-12 neutralization phenocopied disease in IFNγ-knockout mice. Interestingly, type I IFNs contributed to the severity of hypercytokinemia and weight loss, but their absence did not otherwise affect MAS manifestations. CONCLUSION: These data demonstrate that both fulminant MAS and hemophagocytosis can arise independently of IFNγ, IL-12, or type I IFNs. They also suggest that IFNγ-mediated dyserythropoiesis, not hemophagocytosis, is the dominant cause of anemia in fulminant TLR-9-induced MAS. Thus, our data establish a novel mechanism for the acute anemia of inflammation, but suggest that a variety of triggers can result in hemophagocytic disease.

Recurrent macrophage activation syndrome associated with heterozygous perforin W374X gene mutation in a child with systemic juvenile idiopathic arthritis.

BACKGROUND: Recurrent macrophage activation syndrome (MAS) is rarely reported. AIM: To describe recurrent MAS in a 2.5-year-old girl with systemic juvenile idiopathic arthritis and heterozygous perforin mutation, which may have a role in the patient's first recurrence despite use of the HLH-2004 treatment protocol. OBSERVATIONS: In the presented case, MAS was initially controlled after the addition of etoposide to the treatment regimen. However, recurrence occurred 6.5 months after cessation of the HLH-2004 protocol. Subsequent recurrences may have occurred because of the family's noncompliance with treatment. CONCLUSIONS: The patient's extremely high serum ferritin level (267,054 ng/mL) and the recurrent course of MAS may have been because of the coexistence of juvenile idiopathic arthritis and heterozygous perforin W374X mutation. We suggest to search for mutations in HLH genes in recurrent MAS cases.

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

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.

Macrophage activation syndrome: why and what should a gastroenterologist know.

We recently treated a patient with adult-onset Still's disease who developed macrophage activation syndrome (MAS) secondary to disseminated histoplasmosis while being treated with adalimumab. The gastroenterology service was consulted early, before diagnosis, as the patient presented with elevated liver enzymes and disseminated intravascular coagulation. MAS is an exaggerated immune response that can develop as a primary condition or secondary to infections, drugs and various diseases, resulting in liver dysfunction, encephalopathy, pancytopenia and disseminated intravascular coagulation. The development of MAS has also been reported in patients with inflammatory bowel disease and post-liver transplantation and has been triggered by medications used by gastroenterologists, particularly sulfasalazine and anti-tumor necrosis factor biologic modifiers. Therefore, we present a review on etiology, pathogenesis, clinical and laboratory features, and treatment of MAS with a focus on gastrointestinal aspects and presentations. MAS is a life threatening condition with a high mortality rate if untreated. Therefore it is important to recognize this condition early. As these patients may occasionally present to gastroenterologists we hope this review will increase awareness of this rare, but serious syndrome.