Macrophage activation syndrome (MAS) is a rare but po- tentially fatal disorder, characterized by combinations of pancytopoenia, liver failure, coagulopathy and organ dys- function. It is thought to be caused by the activation and uncontrolled proliferation of CD8 + lymphocytes and well- differentiated macrophages, leading to haemophagocytosis and a so-called cytokine storm [1-3]. The term MAS describes a condition occurring in a broad spectrum of diseases, which belong to the histiocytic disorders, e.g. haemophagocytic lymphohistiocytosis (HLH). Familial or primary haemophagocytic lymphohistiocytosis has a known and well-characterized genetic basis, namely a mu- tation in the perforin gene . It results in the inability of cytotoxic T lymphocytes (CTLs) or natural killer (NK) cells to lyse target cells. Secondary HLH can be found in patients with infections, malignancies and inflammatory diseases such as juvenile idiopathic arthritis (JIA) or it may be an adverse effect of certain drugs .
Macrophage activation syndrome (MAS) is an auto- inflammatory phenomenon. An immunogenic trigger over-activates macrophages, resulting in an uncontrolled release of cytokines, and phagocytosis of the body’s own cell lines. While most common in pediatrics , it has been documented in adults as well. This disease is most prevalent in patients with preexisting rheumatological conditions, especially systemic juvenile idiopathic arthritis (sJIA/pediatric Still’s disease), systemic lupus erythematosus (SLE), and adult-onset Still’s disease (AOSD) . Due to significant clinical, laboratory and pathophysiological overlap, the taxonomy of AOSD, hemophagocytic lymphohistiocytosis (HLH) and MAS is unclear, and the classification criteria for MAS have been debated. An expert working-group released new classification criteria in 2016, focusing on the presence of (1) a fever PLUS (2) ferritin levels >684 ng/ml, and any two of the following:
ABSTRACT. Kawasaki disease (KD) patients are known to be at increased risk for coronary artery lesions. We present evidence of another possible complication associated with KD: macrophage activation syndrome (MAS). In this case, a patient with KD and prolonged fever developed MAS. This case is of particular interest because of the late age of onset and recurrent nature of KD as well as the complication of MAS. We also present a review of the literature that supports the inclusion of MAS as an infrequent complication of KD. Pediatrics 2003;112:e495–e497. URL: http://www.pediatrics.org/cgi/ content/full/112/6/e495; Kawasaki disease, macrophage activation syndrome, hemophagocytosis, intravenous im- munoglobulin.
Macrophage activation syndrome (MAS) is a potentially fatal condition. It is a rare complication of several autoimmune disorders, including systemic lupus erythematosus (SLE) and systemic juvenile idiopathic arthritis (sJIA). The incidence of MAS associated with SLE is about 0.9–4.6% . MAS is a multifarious disease, presenting with several signs and symp- toms, including high fever, hepatomegaly, splenomegaly, hemorrhagic manifestations (e.g., purpura), and dysfunction of the central nervous system, like lethargy. Furthermore, MAS is characterized by several alterations in laboratory tests, including pancytopenia, hypofibrinogenemia, hypertriglyc- eridemia, and hyperferritinemia.
Copyright © 2016 Eri Watanabe et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. We report the case of a 71-year-old Japanese woman with adult-onset Still’s disease (AOSD) in whom macrophage activation syndrome (MAS) developed despite therapy with oral high-dose prednisolone and intravenous methylprednisolone pulse therapy twice. She was successfully treated with tocilizumab (TCZ). Soon afterward, her fever ceased and high levels of both ferritin and C-reactive protein levels decreased. Her course was complicated by disseminated intravascular coagulation, cytomegalovirus infection, and Pneumocystis jirovecii pneumonia. After these were resolved, AOSD-associated MAS was well controlled. She was discharged on hospital day 87. Although biologics such as TCZ are becoming established for the treatment of AOSD, there is no recommended therapy for AOSD-associated MAS. Several biologics have been tried for this complication, but their efficacy and safety remain controversial. We reviewed reported cases of AOSD-associated MAS successfully treated with various biologics. TCZ initiation after adequate nonselective immunosuppressive therapy, such as methylprednisolone pulse therapy or a prednisolone- based combination of immunosuppressants, can be an effective treatment for AOSD-associated MAS. On the other hand, biologics given after insufficient immunosuppressive therapy may cause MAS. A strategy combining adequate immunosuppression and a biologic could be safe if special attention is given to adverse events such as opportunistic infections or biologic-associated MAS.
Macrophage activation syndrome (MAS) is a serious complication of autoimmune disease with epidemiological reports of 4.2% in known cases of Juvenile Idiopathic Arthritis (JIA) and Systemic Lupus Erythematosus (SLE) . Multiple reports have described MAS complicating a number of other autoimmune and auto-inflammatory dis- eases such as Kawasaki Disease [2, 3], Periodic fever syn- dromes  and inflammatory bowel disease [5, 6]. The significant mortality associated with the condition makes early diagnosis and early management important. Even with treatment using high dose steroids and biologics, pa- tients with MAS complicating systemic-onset JIA (SoJIA) required intensive care in 34.9% and had an associated mortality of 8.1% . A number of epidemiological studies have shown that MAS may be more common in auto- immune disease than previously thought [8–10].
Macrophage activation syndrome (MAS) is a complication in a variety of rheumatoid disorders (1). It is most notably associated with systemic onset juvenile idiopathic arthritis (SoJIA), where studies have found evidence of frequent subclinical episodes that often progress to overt, potentially fatal disease (2–4). It also occurs in Kawasaki disease and systemic lupus erythematosus and sporadically in a myriad of other syndromes (5). MAS is the result of an uncontrolled, hyperactive immune response, often to an identifiable infection but in many cases lacking a known trigger (6). High levels of T cell–produced cytokines such as IFNγ, TNFα, and GM-CSF result, activating macrophages and other myeloid cells. These activated macrophages attack cells and tissues directly through phagocytosis and contribute to persistent systemic inflammation via release of IL-1 and IL-6, as well as other proinflammatory cytokines. This unchecked cytokine production leads to a cytokine storm, resulting in widespread organ damage, and is believed to be a key factor in progression of the disease. MAS occurs along a broad spectrum of intensity, with many mild cases likely going undiagnosed while severe cases lead to life-threatening complications.
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Background: Macrophage 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. Methods: A 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.
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This was a 5-year retrospective review of children re- ferred to paediatric rheumatology at Great Ormond Street Hospital National Health Service Foundation Trust between 1 st January 2007 (when the CD107a assay became routinely available at our institution) and December 31 st 2011. We included all patients who under- went protein screening assays during this time period for the work up of MAS due to suspected but as yet un- defined rheumatological cause. Patients were identified Table 1 Haemophagocytic Lymphohistiocytosis (HLH) 2004 clinical trial B diagnostic (clinical) criteria from 21 patients who had investigative work up for macrophage activation syndrome at presentation and underwent protein-based and degranulation screening tests for primary HLH from a single United Kingdom Paediatric Rheumatology centre
Macrophage activation syndrome (MAS) is a potentially fatal complication of systemic inflammation. High mobility group box 1 (HMGB1) is a nuclear protein extensively leaked extracellularly during necrotic cell death or actively secreted by natural killer (NK) cells, macrophages and additional cells during infection or sterile injury. Extracellular HMGB1 orchestrates key events in inflam- mation as a prototypic alarmin. The redox states of its three cysteines render the molecule mutually exclusive functions: fully re- duced “all-thiol HMGB1”exerts chemotactic activity; “disulfide HMGB1” has cytokine-inducing, toll-like receptor 4 (TLR4)- mediated effects—while terminally oxidized “sulfonyl HMGB1” lacks inflammatory activity. This study examines the kinetic pattern of systemic HMGB1 isoform expression during therapy in four children with severe MAS. Three of the four patients with underlying systemic rheu- matic diseases were treated with biologics and two suffered from triggering herpes virus infections at the onset of MAS. All pa- tients required intensive care unit therapy due to life-threatening illness. Tandem mass-spectrometric analysis revealed dramati- cally increased systemic levels of the cytokine-inducing HMGB1 isoform during early MAS. Disease control coincided with supplementary etoposide therapy initiated to boost apoptotic cell death, when systemic HMGB1 levels drastically declined and the molecule emerged mainly in its oxidized, noninflammatory isoform. Systemic interferon (IFN)- γ and ferritin peaked concomi- tantly with HMGB1, whereas interleukin (IL)-18 and monocyte chemotactic protein (MCP)-1 levels developed differently. In con- clusion, this work provides new insights in HMGB1 biology, suggesting that the molecule is not merely a biomarker of inflammation, but most likely also contributes to the pathogenesis of MAS. These observations encourage further studies of disulfide HMGB1 an- tagonists to improve outcome of MAS.
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Copyright © 2018 Yiming Luo et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Macrophage activation syndrome (MAS) is a rare manifestation of systemic lupus erythematosus (SLE) with potentially life- threatening consequences. To the best of our knowledge, this is the ﬁrst case reported in literature for a constellation of MAS, glomerulonephritis, pericarditis, and retinal vasculitis as initial presentation of SLE. Despite extensive multisystem involvement of his disease, the patient responded well to initial steroid treatment, with mycophenolate mofetil successfully added as a steroid- sparing agent. Our case highlights the importance of multispecialty collaboration in the diagnosis and management of SLE with multisystem involvement.
both UNC13d  and PRF1 . In the context of the Italian National Registry of familial HLH we performed mutation analysis of genes involved in pHLH in 31 pa- tients with sJIA and MAS. The analysis included PRF1 , UNC13d , STX11 , STXBP2 and RAB27a , and identified monoallelic mutations in 11 of the 31 patients (35.5%). Three out of 31 patients (9.7%) carried a mutation in 2 genes. Interestingly, it has been recently reported that mice carrying heterozygous mutation in more than one gene involved in pHLH carry a significant higher risk to develop HLH following viral infection . Overall, clin- ical and laboratory feature of MAS in patients carrying the mutations were not different from those of patients who do not carry the mutation. However, recurrences of MAS seem to be more frequent in patients who carry the mutations (mutated 27% versus non-mutated 10%). In our series of patients one patient died because of MAS and she was heterozygous for a known pathogenic PRF1 mutation (N252S) . Altogether these observa- tions, far from being conclusive, point to the presence of a genetic contribution to MAS similar to that of pHLH. All together these observations suggest that events re- lated to the pathogenesis of pHLH are relevant in sHLH in general, and in MAS in particular: a) accumulation of partial genetic defect in one, or more than one, of the known pHLH related gene b) the possible dominant negative effects of some heterozygous variants [10, 18]. Defective cytotoxicity may impair clearance of infected cells, and/or prolong lymphocyte-APC interactions, both events leading to increased pro-inflammatory cytokine production (e.g. IFNγ) by T lymphocytes [10, 19].
Sepsis, hemophagocytic lymphohistiocytosis (HLH), macrophage activation syndrome (MAS), and systemic inflammatory response syndrome (SIRS, e.g., sepsis without a documented pathogen) are different clinical entities that likely represent a common immuno- pathologic state referred to as cytokine storm (1). The designation given any particular patient’s cytokine storm syndrome is generally determined by whether an underlying trigger can be found: bacte- rial infection (2), malignancy or genetic defect (3), rheumatologic disease (4), or idiopathic or drug induced (1), respectively. Despite the different names, these syndromes share more in common than not (5): massive inflammatory response, elevated serum cytokine levels, multiorgan system disease, hemophagocytic macrophages, and often death. These syndromes are often clinically indistin- guishable (5). However, the cytokines that predominate in each of these syndromes may differ; for instance, TNF-α predominates in bacterial sepsis (6), and IFN-γ predominates in HLH and MAS (7, 8). What drives the systemic toxicity in these diseases is not clear. Much attention has recently been given to primary HLH due to our increased understanding of the genetic defects involved. Pri- mary HLH is caused by genetic defects in cytotoxic granule exo- cytosis, such that CD8 + T cells are unable to kill virally infected
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systemic form, but also in systemic lupus erythematosus, adult-onset Still’s disease, Kawasaki disease, dermatomyo- sitis, mixed connective tissue disease, systemic sclerosis, and primary SS . The MAS–SS association has been rarely reported. In a systematic review analyzing 117 publications about MAS in systemic diseases, and in- cluding 421 patients, only 3 cases were associated with SS . This case is, to the best of our know- ledge, the first report of this association in Africa.
In the research of the literature, there were several studies that reported on the clinical manifestations and the labora- tory data in all of the various MAS conditions. These were associated with the various autoimmune diseases. In the opinions of the reviewers, the following points are important clues for an early diagnosis of MAS. Nearly all patients with MAS have a fever, although they may have different underly- ing autoimmune conditions. MAS-associated SJIA tends to have more patients with hepatosplenomegaly and lymphade- nopathy than does MAS-associated SLE. This is explained by the abnormal features that are common presentations in those patients with active SJIA, more so than in those with an active SLE. The MAS-associated KD patients always present hepatosplenomegaly, whereas this is an uncommon presentation in patients with active KD. In fact, cervical lymphadenopathy is one of the clinical criteria that is found in patients with typical presentations of KD. There are only limited data describing the different characteristics of lymph nodes in the KD condition, with or without an MAS condi- tion. The CNS manifestations in SLE patients, including seizures, comas, alterations of consciousness, and headaches, are found in both active disease and MAS-associated SLE; therefore, it is difficult to differentiate between these two conditions. However, this is quite different in those patients with SJIA and KD, in that a CNS involvement is not being presented in the manifestations of the active disease in these two conditions. Therefore, MAS is suspected in those patients with an underlying SJIA and KD, who perhaps have a CNS involvement.
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After two rounds of web evaluations, the experts achieved consensus on the classi ﬁ cation of 103 (89.6%) of the 115 patient pro ﬁ les examined. Seventy patients (60.9%) were classi ﬁ ed as MAS, whereas 33 patients (28.7%) were classi ﬁ ed as non-MAS. For 12 patients (10.4%), consensus was not reached. The 45 pro ﬁ les classi ﬁ ed as non-MAS or for which consensus among the experts was not reached, were discarded. Table 1 shows the comparison of demo- graphic, clinical and histopathological features, triggers, therapeutic interventions and outcome between patients classi ﬁ ed as MAS or non-MAS by the expert panel. Compared with patients classi ﬁ ed as non-MAS, patients who had the diagnosis of MAS con ﬁ rmed by the experts were younger at onset of MAS, and had a greater fre- quency of fever and of most of the other typical clinical features of the syndrome, had more frequently under- gone a bone marrow aspiration or a lymphnode or liver biopsy, were admitted more commonly to the intensive care unit and had a greater frequency of death. The gender ratio, duration of sJIA at MAS onset, triggers and therapeutic interventions as well as the frequency of bone marrow or biopsy haemophagocytosis, were com- parable between the two groups. The comparison of the change in laboratory parameters over time between patients diagnosed as MAS or non-MAS by the experts is presented in table 2. Overall, patients who had the diag- nosis of MAS con ﬁ rmed by the experts had a greater change in laboratory values than those classi ﬁ ed as non-MAS.
AOSD is a systemic inflammatory disorder with un- known etiology, but it is hypothesized that it may be a reactive syndrome where various infectious agents may act as disease triggers in a genetically predisposed host . It is characterized by fever, arthritis and a typical skin rash (non-pruritic, salmon-pink macular lesions on the trunk and extremities) correlating with diurnal fe- vers. Important laboratory findings include leukocytosis (predominantly neutrophils) and high levels of ferritin [40,48]. Elevated serum ferritin levels were seen in 89% of these patients in some series, nearly half of whom had levels greater than five times normal . Similarly to MAS, macrophage activation may play an important role in hyperferritinemia as well as in the pathogenesis of AOSD . Heightened soluble IL-2 receptor levels, a marker of T cell activation, were also reported in two distinct studies of AOSD patients, serving as a potential marker of disease activity [66,67]. Furthermore, reactive hemophagocytic syndrome is not uncommon in AOSD [3,40]. Recent studies revealed a pivotal role of several pro-inflammatory cytokines on AOSD, such as IL-1, IL- 6, IL-8, TNF-α and IL-18 in disease pathogenesis. There are controversial statements concerning the importance of IL-18 in distinguishing AOSD from other diagnoses [68,69]. NK T cells are numerically and functionally defi- cient in AOSD, similar to those observed in SLE, RA and MAS .
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level was 4680 IU/L, triglyceride level was 571 mg/dL, and ferritin level was 67 250 ng/mL. Her serum TNF- ␣ level was 44 pg/mL (reference: ⬍ 6.0 pg/mL) interleu- kin-6 (IL-6) level was 37.5 pg/mL (reference: ⬍ 4.0 pg/ mL). The bone marrow aspirate revealed macrophage hemophagocytosis. The diagnosis of MAS was made. Aspirin was discontinued, and prednisolone 2 mg/kg per day was initiated on the 21st hospital day. At this time, laboratory tests revealed the following levels: serum so- dium, 129 mEq/L; potassium, 4.6 mEq/L; calcium, 8.1 mg/dL; phosphorus, 1.4 mg/dL; uric acid, 1.4 mg/dL; bicarbonate, 26.4 mEq/L; serum creatinine, 0.3 mg/dL; and serum urea nitrogen, 13.2 mg/dL. Her body weight had decreased by ⬃ 5% since admission. Additional lab- oratory testing revealed the following levels: plasma re- nin, 21.9 pg/mL (reference: 3.6 –36.2 pg/mL); aldoste- rone, 3.6 ng/dL (reference: 5–20 ng/dL); antidiuretic hormone, 0.3 pg/mL (reference: 0.3– 4.2 pg/mL); atrial natriuretic peptide, 25.0 pg/mL (reference: ⬍ 300 pg/ mL); and brain natriuretic peptide, 17.2 pg/mL (refer- ence: ⬍ 30 pg/mL). Urinalysis was normal, and urine osmolality was 234 mOsm/kg. Other levels obtained in- cluded: urine ␤ 2 -microgloblin, 26.3 mg/L (reference: ⬍ 1
The authors of this post hoc analysis considered that pa- tients with DIC and HBD exhibited features like those of the macrophage activation syndrome (MAS), a state of catastrophic hyper-activation of the innate immune re- sponses. MAS is also known as hemophagocytotic lympho- histiocytosis (HLH) . It is a life-threatening condition of pancytopenia, tissue hemophagocytosis, and early progres- sion to multiple organ dysfunction and death within 10 days . The hallmark of pathogenesis relies on the hyper- activation of tissue macrophages, leading to excessive pro- duction of IL-1β, IL-18, and ferritin . Since MAS can also be secondary to malignancies and other autoimmune disorders, a number of criteria have been developed to identify these cases [8, 9]. Presence of bone marrow hemo- phagocytosis is one of the criteria taken into consideration for the diagnosis of MAS [6, 8, 9]. Since this criterion was investigated neither by Shakoory et al.  nor by us in the current study due to the difficulty of performance in every critically ill patient, we prefer to call this entity macrophage activation-like syndrome (MALS). The incidence of MALS in sepsis has never been studied thus far.
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We report an 11-week-old female who presented with Kawasaki disease (KD) complicated by macrophage activation syndrome (MAS). The infant presented to the hospital with persistent fever, cough, diarrhea, and emesis, among other symptoms. Her condition quickly began to decompensate, and she developed classic features (conjunctivitis, rash, cracked lips, distal extremity edema) prompting a diagnosis of acute KD. The patient was treated with standard therapy for KD including three doses of intravenous immunoglobulin (IVIG), aspirin, and high dose glucocorticoids with no change in her condition. Due to a high suspicion for MAS, high dose anakinra therapy was initiated resulting in dramatic clinical improvements. She also received one dose of infliximab for concern for coronary artery changes, and over the course of several months, anakinra and high dose glucocorticoids were tapered. Nearly complete reversal of echocardiogram changes were observed after 8 months, and the infant is now off all immunosuppressive therapy. In this case report, we briefly review the importance of early recognition of MAS in pediatric patient populations with rheumatic diseases, and we suggest early initiation of anakinra therapy as a rapid and effective treatment option.