Erythematosus plaques with macrophage infiltration as an initial manifestation of macrophage activation syndrome in a patient with systemic lupus erythematosus

The diagnosis of macrophage activation syndrome (MAS) in patients with systemic lupus erythematosus (SLE) may be challenging as it can mimic the clinical features of the underlying disease or be confused with an infectious complication. In this report, a Japanese woman in her forties had diverse clinical features of MAS at initial presentation of SLE, where erythematosus plaques with histiocytic infiltrates focally surrounding degenerated collagen might be the earliest indicator of MAS.     

Macrophage activation syndrome II/II

Macrophage activation syndrome (MAS) is a rare systemic disorder which results from uncontrolled activation and proliferation of T cells and excessive activation of macrophages. Primary haemophagocytic lymphohistiocytosis (HLH) is recognized as having a genetic basis, but the secondary haemophagocytic syndrome (HS), also referred to as MAS, occurs in a number of autoimmune disorders including systemic onset juvenile idiopathic arthritis, systemic lupus erythematosus (SLE), adult onset Still's disease and other disorders. In this second of the two part series, the clinical features and management are described.     

Macrophage activation syndrome in systemic lupus erythematosus: a multicenter,case-control study in China

The objective of this study was to describe the clinical and laboratory characteristics, precipitating factors, treatment, and outcome of macrophage activation syndrome (MAS) complicating systemic lupus erythematosus (SLE). A multicenter case-control study was performed across six tertiary hospitals from 1997 to 2014. A total of 32 patients with SLE-associated MAS were enrolled. Sixty-four age- and sex-matched SLE patients diagnosed in the same period without MAS episodes were selected as controls. The most frequent clinical feature was fever, followed by splenomegaly. Hyperferritinemia, hypoalbuminemia, and hyper-lactate dehydrogenase (LDH)-nemia were among the most common laboratory abnormalities. Compared with pre-MAS visit, patients at the onset of MAS had greater frequencies of renal involvement, liver dysfunction, and cytopenia. Receiver operating characteristic (ROC) analysis identified optimal cutoff values of ferritin (>662.5 ng/mL) and LDH (>359 U/mL) to predict the occurrence of MAS in SLE. SLE flare and infection were the common triggers of MAS in SLE. Abortion and parturition were recorded as well. The overall mortality rate was 12.5%. All patients received corticosteroids. Cyclosporine A, cyclophosphamide, and etoposide were the three most commonly used immunosuppressants. Rituximab was given to one patient. Intravenous immunoglobulin (IVIG) was added for 46.9% patients. MAS is a potentially fatal complication of SLE. Its occurrence is most frequently associated with active SLE disease or infection. The presentation of unexplained fever, cytopenia, or liver dysfunction, with high levels of ferritin and LDH, in patients with SLE should raise the suspicion of MAS. Corticosteroids with immunosuppressants and IVIG may be an appropriate treatment.     

Macrophage activation syndrome in children with systemic lupus erythematosus and children with juvenile idiopathic arthritis

Objective

To describe patient demographics, interventions, and outcomes in hospitalized children with macrophage activation syndrome (MAS) complicating systemic lupus erythematosus (SLE) or juvenile idiopathic arthritis (JIA).

Methods

We performed a retrospective cohort study using data recorded in the Pediatric Health Information System (PHIS) database from October 1, 2006 to September 30, 2010. Participants had International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes for MAS and either SLE or JIA. The primary outcome was hospital mortality (for the index admission). Secondary outcomes included intensive care unit (ICU) admission, critical care interventions, and medication use.

Results

A total of 121 children at 28 children's hospitals met the inclusion criteria, including 19 children with SLE and 102 children with JIA. The index admission mortality rate was 7% (8 of 121 patients). ICU admission (33%), mechanical ventilation (26%), and inotrope/vasopressor therapy (26%) were common. Compared to children with JIA, those with SLE had a similar mortality rate (6% versus 11%, respectively; exact P = 0.6). More patients with SLE than those with JIA received ICU care (63% versus 27%; P = 0.002), received mechanical ventilation (53% versus 21%; P = 0.003), and had cardiovascular dysfunction (47% versus 23% received inotrope/vasopressor therapy; P = 0.02). Children with SLE and those with JIA received cyclosporine at similar rates, but more children with SLE received cyclophosphamide and mycophenolate mofetil, and more children with JIA received interleukin‐1 antagonists.

Conclusion

Organ system dysfunction is common in children with rheumatic diseases complicated by MAS, and more organ system support is required in children with underlying SLE than in children with JIA. Current treatment of pediatric MAS varies based on the underlying rheumatic disease.

     

Autologous hemopoietic stem-cell transplantation for children with refractory autoimmune disease

Autologous stem cell transplantation (ASCT) has been proposed as a possible treatment for severe autoimmune diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS), systemic sclerosis, and systemic lupus erythematosus (SLE). To date, more than 250 patients with various autoimmune disorders have undergone an ASCT since 1996. Among them, there is a very limited number of children. This review summarizes the experience with ASCT for pediatric rheumatic diseases. Most reported cases concern juvenile idiopathic arthritis (JIA). Experience with ASCT for childhood SLE, Scleroderma, or Dermatomyositis is very limited. To date, 12 children with severe systemic or polyarticular JIA, all with progressive disease activity despite the use of corticosteroids, MTX, CsA, or Cyclophosphamide were treated in our center with ASCT. Rheumatologic follow-up at 3-month intervals up to 36 months showed a marked decrease in arthritis severity as expressed by the core-set criteria for juvenile chronic arthritis (JCA) activity. However, these children remain at risk for severe viral infections due to the prolonged lymfopenia. ASCT in this severely ill patient group induces a very significant and drug-free remission of the disease, but carries a significantly risk of developing fatal MAS.     

Macrophage activation syndrome resistant to medical therapy in a patient with systemic lupus erythematosus and its remission with splenectomy

Macrophage activation syndrome (MAS) is a rare, but potentially life-threatening complication of systemic lupus erythematosus (SLE). A bone marrow biopsy often provides pathologic evidence of MAS, and MAS usually responds to corticosteroids alone or with the addition of cyclosporine A. We describe a case of MAS developing in a pregnant patient with SLE, who presented with fever and pancytopenia. Extensive investigations could not find the evidence of infection. Although intensive medical treatment was performed with a suspicion of MAS based on clinical grounds, no response was observed and bone marrow biopsy showed no evidence of hemophagocytosis. Positron emission tomography/computed tomography (PET/CT) suggested the possible cause of fever was in the spleen where fluorodeoxyglucose uptake was markedly increased. After splenectomy, the patient was improved and numerous hemophagocytic macrophages were proved in the splenic tissue. With this unique case, we would like to emphasize that bone marrow biopsy cannot always be relied on in making a diagnosis of MAS and PET/CT can provide helpful information in the diagnosis of MAS.     

Macrophage activation syndrome in children with systemic juvenile idiopathic arthritis and systemic lupus erythematosus

Macrophage activation syndrome (MAS) is a hyper-inflammatory disorder secondary to a rheumatic disease such as systemic juvenile idiopathic arthritis (SJIA) and systemic lupus erythematosus (SLE). We aimed to present the characteristics of our pediatric MAS patients. Clinical features, laboratory parameters, treatment, and outcome of 34 patients (28 SJIA; six SLE; 37 MAS episodes) followed at a tertiary health center between 2009 and 2015 were retrospectively reviewed. The median age at MAS onset was 11 years. More SJIA patients had MAS at disease onset than SLE patients (53.6 vs. 16.7 %). Fever, high C-reactive protein and hyperferritinemia were present in all MAS episodes. Rash was less (p = 0.03), and fatigue was more frequent (p = 0.042) in SLE than SJIA patients. All received corticosteroids. Cyclosporine was given in 74.2 % of SJIA-MAS; 66.7 % of SLE-MAS episodes. Intravenous immunoglobulin, anakinra, or etoposide was administered during 67.7; 41.9; 32.3 % of SJIA-MAS and 33.3; 33.3; 50 % of SLE-MAS episodes, respectively. Plasmapheresis was performed during 41.9 % of SJIA-MAS and 33.3 % of SLE-MAS episodes. The mortality rate was 11.8 % (n = 4;3 SJIA, 1 SLE). Hepatosplenomegaly was more frequent (p = 0.005), and plasmapheresis was performed more frequently (p = 0.021) in the patients who died compared to the cured patients. The median duration between symptom onset and admission to our hospital was longer among the patients who died (16.5 vs. 7 days; p = 0.049). Our patients’ characteristics were similar to the reported cases, but our mortality rate is slightly higher probably due to late referral to our center. Early diagnosis and effective treatment are crucial to prevent mortality.     

上海单中心住院儿童风湿性疾病谱演变

目的:了解上海单中心风湿性疾病住院患儿疾病谱的变化趋势,提高对儿童风湿性疾病的认识。方法:回顾性分析2005—2016年复旦大学附属儿科医院5950例患者的临床资料,采用χ2检验进行发生率的比较和分析。结果:①住院例数位列前3位的分别是:川崎病2633例(44.3%),过敏性紫癜(HSP)2109例(35.4%),幼年特发性关节炎(JIA)574例(9.6%)。②除外HLP,其余病种住院人数均呈上升趋势。③近6年住院的风湿性疾病种类由原来的17种增长到目前37种。④SLE患者逐年增长(112/2348和197/3602,χ2=1.41,P=0.235),重症狼疮患者数亦较前增多(35/112和55/197,χ2=0.38,P=0.536)。⑤风湿性疾病合并巨噬细胞活化综合征(MAS)的发生率为7.2‰(43/5950),幼年型关节炎伴全身发作(sJIA)中有12.9%(26/201)出现过MAS,占风湿性疾病合并MAS总数的60.5%(26/43)。近6年风湿性疾病合并MAS(χ2=14.1,P<0.01),及sJIA合并MAS均明显增多(χ2=11.2,P<0.01)。⑥1.1%(64/5950)风湿性疾病相关肺部病变,幼年型皮肌炎(JDM)中24.4%(20/82)合并风湿性疾病相关肺部病变,占风湿性疾病相关肺部病变总人数的31.3%(20/64)。近6年风湿性疾病并发相关肺部病变及患者明显增多(χ2=5.66,P=0.017)。⑦儿童风湿性疾病病死率为3.7‰(22/5950),45.5%发生于SLE(10/22)。近6年SLE病死率有所下降(5/112和5/197,χ2=0.34,P=0.558)。结论:风湿性疾病住院患者病种及人数由多到少依次为川崎病、HSP、JIA、SLE及JDM。在每年总患者数相对稳定情况下,少见、疑难、危重病种逐年增多。虽近6年SLE仍是风湿性疾病主要死因,但病死率逐年下降。     

成人斯蒂尔病与巨噬细胞活化综合征关联性的临床分析

目的 探讨成人斯蒂尔病(AOSD)与巨噬细胞活化综合征(MAS)的关系.方法 选择AOSD组为78例资料完整的AOSD;MAS组是从26例有组织学证据的噬血细胞综合征的随访治疗中确定11例为风湿免疫疾病相关的噬血细胞综合征.对以上患者的临床表现和实验室资料进行分析.结果 在AOSD组78例中,有9例(占12%)在使用治疗之前可以诊断为MAS,但无噬血组织学依据.在11例有噬血现象的MAS中,AOSD 6例,脂膜炎2例,系统性红斑狼疮、皮肌炎、系统性血管炎各1例.脾脏肿大、白细胞减低、贫血、血小板下降、高甘油三酯是AOSD出现MAS的相关临床指标.结论 AOSD继发MAS的现象比较常见,严重者可以有组织学的噬血表现.AOSD出现脾脏增大、血细胞降低时,需要作MAS的相关检查,包括骨髓检查以及甘油三酯、纤维蛋白原、自然杀伤(NK)细胞活性等,以便及时诊断MAS.     

Clinical significance of selected endothelial activation markers in patients with systemic lupus erythematosus

OBJECTIVE: Systemic lupus erythematosus (SLE) is an autoimmune disease in which immunologically mediated vascular endothelial cell activation is regarded as a potential pathophysiological mechanism of systemic organ damage. We investigated selected endothelial cell activation markers in serum of patients with SLE and their relationships with systemic organ manifestations and disease activity. METHODS: Serum levels of endothelin-1 (ET-1), soluble E-selectin, and thrombomodulin (sTM) were determined by ELISA in 76 SLE patients and in 34 healthy controls. RESULTS: Higher serum concentrations of ET-1, sE-selectin (p < 0.05), and sTM (p < 0.001) were observed in SLE patients in comparison with controls. Significant differences of ET-1, (p < 0.01), sTM (p < 0.001), and sE-selectin serum concentrations (p < 0.01) were found between SLE patients with systemic involvement and controls. Patients with organ manifestations (n = 34) showed significantly higher serum levels of ET-1 than patients without systemic involvement (n = 42) (p < 0.05). Comparison between patients with active and inactive SLE according to SLE Disease Activity Index (SLEDAI) score showed significantly higher concentration of ET-1 in the sera of patients with active SLE compared with inactive patients and the controls (p < 0.001). CONCLUSION: Our findings suggest that the elevated serum concentrations of ET-1, sTM, and sE-selectin reflect persisting endothelial cell activation in SLE, and point to an important role of ET-1 in the pathogenesis of internal organ involvement. Moreover, elevated ET-1 concentrations are related to disease activity, suggesting a key role of endothelial cell activation in systemic manifestations in SLE patients.     

Use of Biomarkers in the Management of Children with Lupus

Childhood systemic lupus erythematosus (SLE) is known to have a worse prognosis than adult-onset disease, and monitoring and treatment of the disease are still a challenge. Thus, there is an urgent need for highly reliable, non-invasive biomarkers for early detection of relapses, to avoid long-term complications and to optimize the management of children with LN. Recent studies of pediatric patients have yielded novel specific biomarkers for SLE diagnosis which can be used for monitoring disease activity and response to treatment. The most promising biomarkers in juvenile-onset SLE include cell-bound complement activation products, some genomic profiles, and urinary proteins such as neutrophil gelatinase-associated lipocalin, monocyte chemoattractant protein-1, and alpha-1-acid glycoprotein. None of these might be suitable for use as a single SLE-biomarker. More likely a combination of novel biomarkers with traditionally used data, including autoantibodies and complement, might help to enhance sensitivity and specificity for early diagnosis, disease monitoring, and prediction of relapses.cp     

Cloak and dagger: the case for adult onset still disease and hemophagocytic lymphohistiocytosis

Adult onset Still’s disease (AOSD) is a rare systemic inflammatory disorder of unknown etiology. Systemic onset juvenile idiopathic arthritis (SoJIA) is the preferred nomenclature of Still’s disease. Strong association with so-called macrophage activation syndrome (MAS) may provide a clue to the understanding of the distinctive pathogenetic features of SoJIA. MAS is a severe, potentially life-threatening complication characterized by the excessive activation of well-differentiated macrophages. It is more appropriately named autoimmune disease associated reactive hemophagocytic lymphohistiocytosis (ReHLH), a subset of a histiocytic disorder: class II histiocytosis hemophagocytic lymphohistiocytosis (HLH). The relation of SoJIA with HLH is still under debate. We propose that MAS, HLH, SoJIA, and AOSD are indeed the same disease, in different clinical presentations that may be classified based on severity and laboratory findings, but with essentially the same physiopathogenesis. We propose that the case described by Hong & Lee (Rheumatol Int 2008) was actually an AOSD-associated MAS/RHS/ReHLH fulminant disease.     

Thrombotic disease in systemic lupus erythematosus is associated with a maintained systemic platelet activation

Patients with systemic lupus erythematosus (SLE) have an increased risk of thrombosis. Platelet-induced extracellular phosphorylation of plasma proteins suggests that this is due to persistent activation of the platelets. We examined 30 SLE patients (15 with thrombotic disease), 18 non-SLE patients with deep vein thrombosis (DVT) and 50 healthy controls by analysing beta-thromboglobulin, activated factor XI-antithrombin complexes and fibrinogen-bound phosphate. All parameters were elevated in SLE patients, particularly those with thrombosis, but normal in DVT cases and healthy controls. We conclude that thrombotic disease in SLE patients is associated with a persistent systemic platelet activation that may lower the threshold for induction of thrombosis.     

Macrophage activation syndrome and cytokine-directed therapies

Macrophage activation syndrome (MAS) is an episode of overwhelming inflammation that occurs most commonly in children with systemic juvenile idiopathic arthritis (SJIA). It is characterized by expansion and activation of T lymphocytes and hemophagocytic macrophages and bears great similarity to hemophagocytic lymphohistiocytosis (HLH). This disorder has substantial morbidity and mortality, and there is frequently a delay in recognition and initiation of treatment. Here, we will review what is known about the pathogenesis of MAS and, in particular, its similarities to HLH. The development of MAS is characterized by a cytokine storm, with the elaboration of numerous pro-inflammatory cytokines. We will examine the evidence for various cytokines in the initiation and pathogenesis of MAS and discuss how new biologic therapies may alter the risk of MAS. Finally, we will review current treatment options for MAS and examine how cytokine-directed therapy could serve as novel treatment modalities.     

Understanding of cytokines and targeted therapy in macrophage activation syndrome

Macrophage activation syndrome (MAS) is a potentially life-threatening complication of systemic autoinflammatory/autoimmune diseases, generally systemic juvenile idiopathic arthritis and adult-onset Still's disease. It is characterized by an excessive proliferation of macrophages and T lymphocytes. Recent research revealed that cytokine storm with elevated pro-inflammatory cytokines, including IFN-γ, IL-18, and IL-6, may be central to the pathogenesis of MAS. Though the mainstream of MAS treatment remains corticosteroids and cyclosporine, targeted therapies with anti-cytokine biologics are reported to be promising for controlling systemic inflammation in MAS.     

Risk of infection in hospitalised children with systemic lupus erythematosus: a 10-year follow-up

The objective of this study was to investigate infection and sepsis in hospitalised children with systemic lupus erythematosus (SLE). Between 1991 and 2000 we reviewed 72 episodes of suspected infection in 42 children with SLE from all hospitalised children with SLE at a medical center in Taiwan. Data comprised clinical and laboratory characteristics of SLE at the time of infection. Infections were identified and categorised as minor or major. A total of 125 patients (110 girls, 15 boys) were admitted 557 times. Forty-two patients had infections, giving an infection rate of 33.6%. There were a total of 72 infections including 20 proven infections; 61 cases of these were minor infections and 11 cases of these were major infections (10 cases were sepsis). Four patients died because of sepsis. By univariate analysis, major infection (sepsis) was significantly associated with a high SLE disease activity index score, lower complement levels and higher anti-DNA titres. In conclusion, our data confirm that infection is common in hospitalised children with SLE. Sepsis, most frequent in major infections, is associated with disease activity and causes significant mortality. These facts should be borne in mind when children with SLE are hospitalised.     

Lupus headaches in childhood-onset systemic lupus erythematosus: relationship to disease activity as measured by the systemic lupus erythematosus disease activity index (SLEDAI) and disease damage

The Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) is the most commonly used measure of disease activity for children with systemic lupus erythematosus (SLE). For headaches to be scored in the SLEDAI as a symptom of active disease, they have to be nonresponsive to narcotic analgesia. This may affect the overall estimation of disease activity, especially because headaches are common among children with SLE and narcotic analgesia is rarely used for headache therapy in paediatrics. Moreover, the importance of headaches for the development of damage and their relation to other clinical parameters and outcomes has not been well described for children with SLE. We reviewed the medical charts of an inception cohort of children (n = 63) who were newly diagnosed with SLE. Information on headaches and other disease parameters was obtained. Disease activity and damage were measured using the SLEDAI and the Systemic Lupus International Collaboration Clinics/American College of Rheumatology Damage Index (SDI), respectively. It has been shown that the accumulated burden of active disease as measured by serial SLEDAI scores over time is one of the best predictors of eventual damage to children with SLE. New-onset or significant increase of severe and/or persistent headaches (LHA) were reported in 43% of the patients during a mean follow-up of 3.6 years. LHA occurred preferentially among patients with elevated levels of antiphospholipid antibodies (aPL) (P < 0.02) and only 6% of all LHA episodes were treated with narcotics and thus considered for the measurement of disease activity in the SLEDAI. LHA were unrelated to proxy-measures of disease activity, such as the need to intensify therapies. When used in children, the insensitivity of the SLEDAI to capture LHA did not seem to decrease the responsiveness of the SLEDAI to detect clinically important worsening of disease, or negatively impact on its ability to predict damage.     

Macrophage activation syndrome in juvenile systemic lupus erythematosus: an under-recognized complication?

Macrophage activation syndrome (MAS) is a life-threatening complication of rheumatic diseases that is thought to be caused by the activation and uncontrolled proliferation of T lymphocytes and macrophages, leading to widespread haemophagocytosis and cytokine overproduction. It is seen most commonly in systemic juvenile idiopathic arthritis, but is increasingly recognized also in juvenile systemic lupus erythematosus (J-SLE). Recognition of MAS in patients with J-SLE is often challenging because it may mimic the clinical features of the underlying disease or be confused with an infectious complication. This review summarizes the characteristics of patients with J-SLE-associated MAS reported in the literature or seen by the authors and analyses the distinctive clinical, diagnostic and therapeutic issues that the occurrence of MAS may raise in patients with J-SLE.     

Life threatening macrophage activation syndrome as the initial presentation of systemic lupus erythematosus: A case report and review of the literature

BackgroundMacrophage activation syndrome (MAS) is characterized by activation of hemophagocytic cells and is a very rare initial manifestation of systemic lupus erythematosus (SLE).Aim of the workTo describe the features of a challenging case of SLE initially presented with MAS.Case reportA previously healthy 20-year-old female was referred to the Rheumatology clinic with a 25-days’ history of persistent fever, general fatigue, and significant weight loss. Clinical examination revealed a high-grade fever (41 °C), significant hair loss and general malaise. Laboratory investigations revealed leucopenia (1.5 × 10⁹/L), neutropenia (0.7 × 10⁹/L), lymphopenia (0.6 × 10⁹/L), normocytic normochromic anemia (9 g/dL), thrombocytopenia (95 × 109/L), elevated liver enzymes, hyperbilirubinemia (2.6 mg/dl); hypertriglyceridemia (306 mg/dL), hyperferritinemia (16000 ng/mL), elevated D-Dimer (4.7 mg/L), elevated lactate dehydrogenase (1379 U/L) and direct and indirect Coombs' tests were positive. Erythrocyte sedimentation rate was 28 mm/1st h. Immunological screening was positive for antinuclear antibody (ANA) and anti-double stranded deoxyribonucleic acid (anti-dsDNA). Serum C3 and C4 complement factors were low and C reactive protein was negative. Soluble CD25 was elevated (9800 pg/ml). Bone marrow biopsy showed hypocellular bone marrow with normal megakaryocytes and erythroid series with evidence of hemophagocytosis. A diagnosis of SLE initially presented with MAS was made. The patient received intravenous methylprednisolone for 5 consecutive days followed by prednisolone and cyclosporine A and intravenous immunoglobulin. The condition deteriorated with progressive coagulopathy, thrombocytopenia and hyperferritinemia. Subsequently, the conscious level of the patient deteriorated, multiorgan failure developed and the patient died.ConclusionMAS is a serious condition that may be the first presentation of SLE.