Hemophagocytic lymphohistiocytosis and macrophage activation syndrome: two rare sides of the same devastating coin.

Hemophagocytic lymphohistiocytosis (HLH) is a rare genetic hyperinflammatory syndrome that occurs early in life. Macrophage activation syndrome (MAS) usually refers to a secondary form of HLH associated with autoimmunity, although there are other causes of secondary HLH, such as infections and malignancy. In this article, we reviewed the concepts, epidemiology, clinical and laboratory features, diagnosis, differential diagnosis, prognosis, and treatment of HLH and MAS. We also reviewed the presence of MAS in the most common autoimmune diseases that affect children. Both are severe diseases that require prompt diagnosis and treatment to avoid morbidity and mortality.

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.

Rowell syndrome complicated with macrophage activation syndrome in a child.

Rowell syndrome (RS) is a rare disease characterized by the association of systemic lupus erythematosus (SLE) or cutaneous lupus with lesions similar to erythema multiforme and the presence of autoantibodies including ANA, SSA, SSB, or rheumatoid factor. Due to the low incidence of this disease, the epidemiology of RS is not clear. So far there are 95 cases reported in the literature; of these, only seven cases are pediatric patients. Macrophage activation syndrome (MAS) is an increasingly recognized complication of SLE, although its true prevalence in childhood is still unknown. We describe a unique pediatric patient with RS who developed MAS.

Precordial pain, leukocytosis and bicytopenia in a teenager with systemic juvenile idiopathic arthritis under immunosuppressive therapy / Dor precordial, leucocitose e bicitopenia em adolescente com artrite idiopática juvenil sistêmica em terapia imunossupressora

ABSTRACT Objective: To highlight the importance of the new classification criteria for the macrophage activation syndrome (MAS) in systemic juvenile idiopathic arthritis in order to reduce morbidity and mortality outcome related to this disease. Case description: A 12-year-old female patient with diagnosis of systemic juvenile idiopathic arthritis under immunosuppression therapy for two years developed cough, acute precordial chest pain, tachypnea, tachycardia and hypoxemia for two days. Chest tomography showed bilateral laminar pleural effusion with bibasilar consolidation. The electrocardiogram was consistent with acute pericarditis and the echocardiogram showed no abnormalities. Laboratory exams revealed anemia, leukocytosis and increased erythrocyte sedimentation rate, as well as C-reactive protein rate and serum biomarkers indicative of myocardial injury. Systemic infection and/or active systemic juvenile idiopathic arthritis were considered. She was treated with antibiotics and glucocorticoids. However, 10 days later she developed active systemic disease (fever, evanescent rash and myopericarditis with signs of heart failure) associated with macrophage activation syndrome, according to the 2016 Classification Criteria for Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis. She was treated for five days with pulse therapy, using glucocorticoids, immunoglobulin and cyclosporine A, with improvement of all clinical signs and laboratory tests. Comments: Myopericarditis with signs of heart failure associated with MAS is a rare clinical presentation of systemic juvenile idiopathic arthritis. Macrophage activation syndrome occurs mainly during periods of active systemic juvenile idiopathic arthritis and may be triggered by infection. Knowledge about this syndrome is crucial to reduce morbidity and mortality.

RESUMO Objetivo: Destacar a importância do conhecimento sobre os novos critérios de classificação para síndrome de ativação macrofágica (SAM) na artrite idiopática juvenil sistêmica para reduzir a morbidade e mortalidade desse desfecho. Descrição do caso: Adolescente do sexo feminino de 12 anos de idade, em terapia imunossupressora por diagnóstico de artrite idiopática juvenil sistêmica há 2 anos, com quadro de tosse, dor precordial aguda, taquipneia, taquicardia e hipoxemia há 2 dias. A tomografia de tórax evidenciou efusão pleural laminar bilateral com consolidação bibasal. O eletrocardiograma foi compatível com pericardite aguda, e o ecocardiograma foi normal. Os exames laboratoriais revelaram anemia, leucocitose e aumento da velocidade de hemossedimentação, proteína C-reativa e marcadores séricos de lesão miocárdica. Infecção sistêmica e/ou doença sistêmica em atividade foram consideradas. A paciente foi tratada com antibióticos e glicocorticoide. Entretanto, dez dias depois, evoluiu com doença sistêmica em atividade (febre, exantema e miopericardite com insuficiência cardíaca) associada à SAM, de acordo com o 2016 Classification Criteria for Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis, e necessitou de cinco dias de pulsoterapia com glicocorticoide, imunoglobulina e ciclosporina A, com melhora de todos os parâmetros clínicos e laboratoriais. Comentários: A miopericardite com sinais de insuficiência cardíaca associada à SAM é uma apresentação clínica rara da artrite idiopática juvenil sistêmica, que ocorre principalmente em períodos de atividade sistêmica da doença e pode ser deflagrada por infecções. O conhecimento sobre essa síndrome é fundamental para reduzir morbidade e mortalidade desse grave desfecho.

PRECORDIAL PAIN, LEUKOCYTOSIS AND BICYTOPENIA IN A TEENAGER WITH SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS UNDER IMMUNOSUPPRESSIVE THERAPY.

OBJECTIVE: To highlight the importance of the new classification criteria for the macrophage activation syndrome (MAS) in systemic juvenile idiopathic arthritis in order to reduce morbidity and mortality outcome related to this disease. CASE DESCRIPTION: A 12-year-old female patient with diagnosis of systemic juvenile idiopathic arthritis under immunosuppression therapy for two years developed cough, acute precordial chest pain, tachypnea, tachycardia and hypoxemia for two days. Chest tomography showed bilateral laminar pleural effusion with bibasilar consolidation. The electrocardiogram was consistent with acute pericarditis and the echocardiogram showed no abnormalities. Laboratory exams revealed anemia, leukocytosis and increased erythrocyte sedimentation rate, as well as C-reactive protein rate and serum biomarkers indicative of myocardial injury. Systemic infection and/or active systemic juvenile idiopathic arthritis were considered. She was treated with antibiotics and glucocorticoids. However, 10 days later she developed active systemic disease (fever, evanescent rash and myopericarditis with signs of heart failure) associated with macrophage activation syndrome, according to the 2016 Classification Criteria for Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis. She was treated for five days with pulse therapy, using glucocorticoids, immunoglobulin and cyclosporine A, with improvement of all clinical signs and laboratory tests. COMMENTS: Myopericarditis with signs of heart failure associated with MAS is a rare clinical presentation of systemic juvenile idiopathic arthritis. Macrophage activation syndrome occurs mainly during periods of active systemic juvenile idiopathic arthritis and may be triggered by infection. Knowledge about this syndrome is crucial to reduce morbidity and mortality.

Macrophage activation syndrome: A severe and frequent manifestation of acute pancreatitis in 362 childhood-onset compared to 1830 adult-onset systemic lupus erythematosus patients.

OBJECTIVE: We previously reported a case series of acute pancreatitis (AP) and macrophage activation syndrome (MAS) in childhood (cSLE) patients; however, there are no data regarding the comparison of AP and MAS in large populations of cSLE and adult SLE (aSLE). METHODS: A study included 362 cSLE and 1830 aSLE patients. MAS was diagnosed according to preliminary diagnostic guidelines and AP according to the presence of abdominal pain or vomiting associated to an increase of pancreatic enzymes and/or pancreatic radiological abnormalities. Demographic data, clinical features, SLEDAI-2K, SLICC/ACR-DI, and treatment were assessed. RESULTS: Age in MAS patients was significantly lower compared with those without this complication [15 (8.8-55) vs. 33.5 (10.2-45.7) years, p = 0.007]. The frequencies of fever (94% vs. 37%, p = 0.001), leucopenia (82% vs. 19%, p = 0.0001), thrombocytopenia (65% vs. 19%, p = 0.013), hypertriglyceridemia (87% vs. 42%, p = 0.037), and hyperferritinemia (93% vs. 37%, p = 0.011) were also more frequently observed in AP patients with MAS compared in AP patients without MAS. Fever and hyperferritinemia concomitantly were more frequent in the former group (86% vs. 12%, p = 0.0015). Higher and significant frequency of AP in cSLE compared to aSLE patients [12/362 (3.3%) vs. 20/1830 (1.1%), p = 0.003], with similar AP duration [22 (6-60) vs. 15 (4-90) days, p = 0.534]. MAS (85% vs. 30%, p = 0.003) and death by MAS complication (31% vs. 0%, p = 0.017) were significantly higher in children compared with aSLE. CONCLUSIONS: This study provides novel data demonstrating that MAS occur in the majority of cSLE with AP with a higher mortality compared to aSLE. In addition, we identified in AP patients, a cluster of MAS clinical and laboratorial parameters more associated with this complication.

Síndrome de ativação macrofágica em paciente com artrite idiopática juvenil sistêmica / Macrophage activation syndrome in a patient with systemic juvenile idiopathic arthritis

A síndrome de ativação macrofágica (SAM) é uma doença rara e potencialmente fatal, normalmente associada às doenças reumáticas crônicas, em especial a artrite idiopática juvenil. É incluída no grupo das formas secundárias de síndrome hemofagocítica, cujas outras causas podem ser as doenças linfoproliferativas e infecções. As manifestações clínicas e laboratoriais mais importantes são a febre não remitente, esplenomegalia, hemorragias, disfunção hepática, citopenias, hipoalbuminemia, hipertrigliceridemia e hiperferritinemia. O tratamento deve ser iniciado rapidamente, e a maioria dos casos responde bem aos corticosteroides e à ciclosporina (CSA). O vírus Epstein-Barr (EBV) é descrito como possível gatilho para muitos casos de SAM, especialmente naqueles em tratamento com bloqueadores do fator de necrose tumoral (TNF). Nos casos refratários ao tratamento convencional, etoposide (VP16) deve ser administrado, em associação com corticosteroides e CSA. Nosso objetivo foi descrever um caso raro de síndrome hematofagocítica provavelmente secundária à infecção pelo vírus Epstein-Barr (EBV), em paciente com artrite idiopática juvenil sistêmica, confirmada pelas manifestações clínicas e laboratoriais típicas, mielograma e sorologia positiva contra o EBV, que atingiu remissão completa após inclusão no protocolo de tratamento HLH-04.

Machrophage activation syndrome (MAS) is a rare and potentially fatal disease, commonly associated with chronic rheumatic diseases, mainly juvenile idiopathic arthritis. It is included in the group of secondary forms of haemophagocytic syndrome, and other causes are lymphoproliferative diseases and infections. Its most important clinical and laboratorial manifestations are non-remitting fever, splenomegaly, bleeding, impairment of liver function, cytopenias, hypoalbuminemia, hypertriglyceridemia, hypofibrinogenemia and hyperferritinemia. The treatment needs to be started quickly, and the majority of cases have a good response with corticosteroids and cyclosporine. The Epstein–Barr virus is described as a possible trigger for many cases of MAS, especially in these patients in treatment with tumor necrosis factor (TNF) blockers. In these refractory cases, etoposide (VP16) should be administered, associated with corticosteroids and cyclosporine. Our objective is to describe a rare case of MAS probably due to EBV infection in a subject with systemiconset juvenile idiopathic arthritis, which achieved complete remission of the disease after therapy guided by 2004-HLH protocol.

[Macrophage activation syndrome in a patient with systemic juvenile idiopathic arthritis]. / Síndrome de ativação macrofágica em paciente com artrite idiopática juvenil sistêmica.

Machrophage activation syndrome (MAS) is a rare and potentially fatal disease, commonly associated with chronic rheumatic diseases, mainly juvenile idiopathic arthritis. It is included in the group of secondary forms of haemophagocytic syndrome, and other causes are lymphoproliferative diseases and infections. Its most important clinical and laboratorial manifestations are non-remitting fever, splenomegaly, bleeding, impairment of liver function, cytopenias, hypoalbuminemia, hypertriglyceridemia, hypofibrinogenemia and hyperferritinemia. The treatment needs to be started quickly, and the majority of cases have a good response with corticosteroids and cyclosporine. The Epstein-Barr virus is described as a possible trigger for many cases of MAS, especially in these patients in treatment with tumor necrosis factor (TNF) blockers. In these refractory cases, etoposide (VP16) should be administered, associated with corticosteroids and cyclosporine. Our objective is to describe a rare case of MAS probably due to EBV infection in a subject with systemic-onset juvenile idiopathic arthritis, which achieved complete remission of the disease after therapy guided by 2004-HLH protocol.

Alveolar hemorrhage: distinct features of juvenile and adult onset systemic lupus erythematosus.

We compared outcomes of alveolar hemorrhage (AH) in juvenile (JSLE) and adult onset SLE (ASLE). From 263 JSLE and 1522 ASLE, the AH occurred in 13 (4.9%) and 15 (1.0%) patients, respectively (p < .001). Both groups had comparable disease duration (2.6 ± 3.0 vs. 5.6 ± 7.0 years, p = .151) and median SLEDAI scores [17.5 (2 to 32) vs. 17.5 (3 to 28), p = 1.000]. At AH onset, a higher frequency of JSLE were already on a high prednisone dose ( > 0.5 mg/kg/day) compared to ASLE (54% vs. 15%, p = .042). The mean drop of hemoglobin was significantly lower in JSLE (2.9 ± 0.9 vs. 5.5 ± 2.9 g/dL, p = .006). Although treatments with methylprednisolone, plasmapheresis, intravenous immunoglobulin and cyclophosphamide were similar in both groups (p > .050), regarding outcomes, there was a trend in high frequency of mechanical ventilation use (85% vs. 47%, p = .055) and also significant mortality (69% vs. 13%, p = .006) in JSLE compared to ASLE. The sepsis frequency was comparable in both groups (50% vs. 27%, p = .433). We have identified that AH in JSLE has a worse outcome most likely related to respiratory failure. The AH onset in JSLE already treated with high-dose steroids raises the concern of inadequate response to this treatment and reinforces the recommendation of early aggressive alternative therapies in this group of patients.

[Plasmapheresis for macrophage activation syndrome and multiorgan failure as first presentation of juvenile dermatomyositis]. / Plasmaféresis en el síndrome de activación macrofágica y fracaso multiorgánico como primera manifestación de una dermatomiositis juvenil.

The use of extracorporeal techniques for the treatment of paediatric diseases has expanded dramatically in the past decade. Plasmapheresis, a technique for exchanging plasma components with albumin or plasma, has been used in some rheumatologic conditions. We report the clinical course of a 7 years old boy with clinical and biological features of macrophage activation syndrome and multiorgan failure, at the time of presentation of severe juvenile dermatomyositis, and non responsive to corticosteroids, cyclosporine and immunoglobulin. After 4 days in the paediatric intensive care unit, plasmapheresis was used as rescue therapy. Repeated therapeutic plasmapheresis was effective for improving the multiorgan failure and laboratory abnormalities. The patient was discharged on the 21st hospital day with good functional condition. Plasmapheresis should be considered as rescue treatment in patients with life threatening macrophage activation syndrome and systemic onset of juvenile dermatomyositis.

Acute pancreatitis in juvenile systemic lupus erythematosus: a manifestation of macrophage activation syndrome?

Acute pancreatitis (AP) is a rare and life-threatening manifestation of juvenile systemic lupus erythematosus (JSLE). The objective of this study was to evaluate the prevalence and clinical features of AP in our JSLE population. AP was defined according to the presence of abdominal pain or vomiting associated to an increase of pancreatic enzymes and/or pancreatic radiological abnormalities. Of note, in the last 26 years, 5367 patients were followed up at our Pediatric Rheumatology Unit and 263 (4.9%) of them had JSLE diagnosis (ACR criteria). AP was observed in 4.2% (11/263) of JSLE patients. The median of age of the JSLE patients at AP diagnosis was 12.4 years (8.8-17.9). All of them had lupus disease activity at AP onset. Three patients were receiving corticosteroids before AP diagnosis. Interestingly, 10/11 JSLE patients fulfilled preliminary guidelines for macrophage activation syndrome, three of them with macrophage hemophagocytosis in bone marrow aspirate and hyperferritinemia. The hallmark of this syndrome is excessive activation and proliferation of T lymphocytes and macrophages with massive hypersecretion of proinflammatory cytokines and clinically it is characterized by the occurrence of unexplained fever, cytopenia and hyperferritinemia. AP treatment was mainly based on intravenous methylprednisolone. Four JSLE patients with AP died and two developed diabetes mellitus. In conclusion, AP was a rare and severe manifestation in active pediatric lupus. The association between AP and macrophage activation syndrome suggests that the pancreas could be a target organ of this syndrome and that pancreatic enzyme evaluation should also be carried out in all patients.

Hidden in plain sight: macrophage activation syndrome complicating Adult Onset Still's Disease.

Hemophagocytic Lymphystiocytosis is a rare and fatal complication of rheumatic diseases, particularly Adult Onset Still's Disease (AOSD). It may be precipitated with immunosuppressive drugs and with viral and bacterial infections. A diagnosis depends on a high index of suspicion associated to certain clinical manifestations (fever, rash, Splemomegaly, any cytology blood dyscrasia, hipertrigliceridemia, hiperfibrinogenemia, and others), as well as pathologic evidence of hemophagocitosis from bone marrow biopsy or tissue samples of affected organs. Therapy consists of high dose corticosteroids and immunosuppressive drugs. We present a 42 year old woman with AOSD in remission who developed HLH in spite of receiving therapy with high dose steroids and immunosuppressive drugs. She had 2 negative bone marrow aspirates. Evidence of Hemophagocytosis was detected in both bone marrow biopsies. Timely evaluation and recognition of the signs and symptoms of HLH is crucial for the prompt management and a decrease in the mortality associated with this disease.