Practice Essentials
Macrophage activation syndrome (MAS) is a life-threatening complication of rheumatic disease that, for unknown reasons, occurs much more frequently in individuals with systemic juvenile idiopathic arthritis (SJIA) and in those with adult-onset Still disease. [1, 2] Macrophage activation syndrome is characterized by pancytopenia, liver insufficiency, coagulopathy, and neurologic symptoms and is thought to be caused by the activation and uncontrolled proliferation of T lymphocytes and well-differentiated macrophages, leading to widespread hemophagocytosis and cytokine overproduction. [3, 4, 5, 6]
Signs and symptoms
Typically, patients with macrophage activation syndrome become acutely ill with the sudden onset of nonremitting high fever, profound depression in all 3 blood cell lines (ie, leukopenia, anemia, and thrombocytopenia), hepatosplenomegaly, lymphadenopathy, and elevated serum liver enzyme levels. High levels of triglycerides and lactic dehydrogenase and low sodium levels are consistently observed.
See Presentation for more detail.
Diagnosis
The diagnosis of macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis requires the presence of any 2 or more the following laboratory criteria or 2 or more of the following clinical criteria:
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Laboratory criteria
Decreased platelet count (< 262 x 109/L)
Elevated aspartate aminotransferase levels (>59 U/L)
Decreased white blood cell (WBC) count (< 4 x 109/L)
Hypofibrinogenemia (≤2.5 g/L)
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Clinical criteria
CNS dysfunction (eg, irritability, disorientation, lethargy, headache, seizures, coma)
Hemorrhages (eg, purpura, easy bruising, mucosal bleeding)
Hepatomegaly (≥3 cm below the costal margin)
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Histopathologic criterion: Evidence of macrophage hemophagocytosis is found in the bone marrow aspirate sample. The demonstration of hemophagocytosis in bone marrow samples may be required in doubtful cases.
See Workup for more detail.
Management
The treatment of macrophage activation syndrome is traditionally based on the parenteral administration of high doses of corticosteroids. High-dose intravenous immunoglobulins, cyclophosphamide, plasma exchange, and etoposide have also been used.
See Treatment and Medication for more detail.
Pathophysiology
Macrophage activation syndrome is characterized by a highly stimulated but ineffective immune response. However, its pathogenesis is still poorly understood and has many similarities with that of the other forms of hemophagocytic lymphohistiocytosis (HLH). HLH is not a single disease but is a hyperinflammatory syndrome that can occur in association with various underlying genetic and acquired conditions. The best known form is familial HLH (FHLH), which is characterized by a severe impairment of lymphocyte cytotoxicity. Recent studies have shown that MUNC 13-4 polymorphisms are associated with macrophage activation syndrome in some patients with SJIA. [7] A study by Weiss et al described a connection between MAS risk and interleukin-18 and suggests an interleukin-18 pathway and potential distinguishing biomarker and target of therapy. [8, 9]
The cytotoxic activity of natural killer (NK) and CD8+ T lymphocytes is mediated by the release of cytolytic granules, which contain perforin, granzymes, and other serinelike proteases, to the target cells. Several independent genetic loci related to the release of cytolytic granules have been associated with FHLH, and mutations at this level cause a severe impairment of cytotoxic function of NK cells and cytotoxic T lymphocytes (CTLs) in patients with FHLH. Through mechanisms that have not yet been well elucidated, this impairment in cytotoxic function leads to an excessive expansion and activation of cytotoxic cells, with hypersecretion of proinflammatory cytokines such as interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, and macrophage-colony-stimulating factor (M-CSF). These cytokines are produced by activated T cells and histiocytes that infiltrate all tissue and lead to tissue necrosis and organ failure.
In perforin-deficient mice, the animal model of HLH, infection with microorganisms such as lymphocytic choriomeningitis virus (LCMV) initiates a similar uncontrolled immune response. This immune response results in death and is characterized by fever, splenomegaly, hemophagocytosis, hypertriglyceridemia, and hypofibrinogenemia. Multiple cytokines, including IL-6, IL-18, IL-10, M-CSF, IFN-α and IFN-γ, are elevated; however, only the antibody to IFN-γ, and not the antibodies to other cytokines, prolongs survival and prevents the development of histiocytic infiltrates and cytopenia. Elevated IFN-γ is thought to be secondary to the increased antigen stimulation of CD8+ cells; neutralizing antibodies against LCMV lowers IFN-γ levels and prolongs survival.
These findings were supported by a recent study of hepatic biopsy samples in patients with various types of HLH, including macrophage activation syndrome. [10] The study revealed extensive infiltration of the liver by IFN-γ–producing CD8+ T lymphocytes and hemophagocytic macrophages secreting TNF-α and IL-6. The hyperproduction of IL-18, which strongly induces T helper cell 1 (Th-1) responses and IFN-γ production and enhances NK cells cytotoxicity, and an imbalance between levels of biologically active free IL-18 and levels of the IL-18–binding protein may also play a role in secondary hemophagocytic syndromes, including macrophage activation syndrome. [11]
Moreover, very high levels of IL-18 have been reported in 2 patients with SJIA and macrophage activation syndrome. [12] In a study of autopsy specimens of a child with SJIA–associated macrophage activation syndrome, the bone marrow was identified as the origin of increased serum IL-18. [13]
The mechanisms that lead to cytolytic defects in immunocompetent patients with acquired HLH are less clear. Patients with virus-associated HLH also have very low or absent cytolytic NK cell activity. However, in contrast to FHLH, this phenomenon appears to be related to a profoundly decreased number of NK cells rather than to impaired perforin expression. Notably, NK function has been found to completely recover in some patients after the resolution of the acute phase. [14]
Some evidence suggests that depressed NK activity, with or without abnormal perforin expression, may also be involved in the pathogenesis of SJIA–associated macrophage activation syndrome. Patients with active SJIA were found to have reduced perforin expression in NK cells and in cytotoxic CD8+ T lymphocytes compared with patients who had other subtypes of juvenile idiopathic arthritis and healthy control subjects. [15]
In some patients, decreased NK activity was associated with very low number of NK cells but mildly increased levels of perforin expression in NK cells and cytotoxic CD8+ T lymphocytes; this pattern was somewhat similar to that seen in virus-associated HLH. In other patients, very low NK activity was associated with only mildly decreased numbers of NK cells but very low levels of perforin expression in all cytotoxic cell types; this pattern was indistinguishable from that seen in primary HLH. Remarkably, most patients with low perforin expression had a history of multiple episodes of macrophage activation syndrome.
Decreased absolute numbers of NK cells, depressed NK cell cytolytic activity, or both may be a feature that distinguishes patients with SJIA from those with other forms of juvenile idiopathic arthritis. [16, 17] Whether these abnormalities will help identify the disease early in the course in patients who are more prone to the occurrence of this harmful complication remains to be seen.
Etiology
Macrophage activation syndrome affects most commonly children with systemic juvenile idiopathic arthritis (SJIA) but has been observed in other rheumatic diseases, such as juvenile systemic lupus erythematosus (SLE) [18, 19] and Kawasaki disease [20] and, occasionally, polyarticular juvenile idiopathic arthritis. [21]
Macrophage activation syndrome has also been associated with multisystem inflammatory syndrome in children (MIS-C) following SARS-CoV-2 infection. A study by Buda et al reported that age (5-12 years), symptoms characteristic of atypical Kawasaki disease, skin erosions, and elevated inflammatory biomarker and troponin levels were predictive of macrophage activation syndrome in children with MIS-C. [22, 23]
Although an identifiable precipitating factor is often not identified, macrophage activation syndrome has been related to numerous triggers, including a flare of the underlying disease, toxicity of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), viral infections, a second injection of gold salts, and sulfasalazine therapy. [6] One report described a young girl with SJIA who developed macrophage activation syndrome shortly after the first methotrexate (MTX) administration without any other apparent inciting factor; this suggests that macrophage activation syndrome could have been a direct consequence of MTX toxicity. [24]
The shortness of the time interval between MTX dosing and onset of macrophage activation syndrome (24 h) and the characteristics of clinical symptoms, particularly the intense and generalized itching, suggested hypersensitivity or an idiosyncratic reaction, a mechanism similar to that hypothesized in the pathogenesis of macrophage activation syndrome secondary to gold salt injections.
Instances of macrophage activation syndrome in patients with SJIA during treatment with biologic medications, including tumor necrosis factor (TNF)-α inhibitors and interleukin (IL)-1 receptor antagonists, have been described. However, whether these drugs are responsible for the induction of macrophage activation syndrome is controversial.
Serious episodes of macrophage activation syndrome have been observed in patients who underwent autologous bone marrow transplantation for SJIA refractory to conventional therapy. [25, 26, 27, 28] In most of these cases, an infectious trigger for macrophage activation syndrome was identified; however, the complication was believed to be favored by stringent T-cell depletion, with resultant inadequate control of macrophage activation. [27, 29] After an adaptation of a protocol consisting of less profound T-cell depletion, better control of systemic disease before transplantation, and slow tapering of corticosteroids after the procedure, no further cases of macrophage activation syndrome have occurred. [27] The development of hemophagocytosis in 3 patients with SJIA who received fludarabine as part of the conditioning regimen has been reported. [26]
Epidemiology
United States statistics
The exact incidence of macrophage activation syndrome in childhood rheumatic disorders is unknown.
International statistics
Although considered a rare complication, macrophage activation syndrome is probably more common than previously thought. In a retrospective study from a tertiary care center, 7 of the 103 children (6.7%) diagnosed with SJIA over a 20-year period developed macrophage activation syndrome. [5] Approximately 100 cases have been reported in the literature. [3, 5, 21, 30]
Age-related demographics
Macrophage activation syndrome generally develops in the earlier phases of the underlying disease or may be the presenting manifestation of SJIA; however, onset has been reported as long as 14 years after the initial diagnosis. [21] In most patients, primary disease is clinically active at the onset of macrophage activation syndrome; however, the syndrome may occasionally occur in a quiescent phase.
Prognosis
The prognosis is related to the severity of CNS, renal, pulmonary or cardiac involvement. Factors that are associated with a poor prognosis include underlying malignancy, central nervous system (CNS) involvement, liver failure, multiple organ dysfunction, and prolonged active disease. [2]
Morbidity/mortality
Macrophage activation syndrome is a complication of rheumatic disease that can follow a rapidly fatal course.
A study by Gormezano et al demonstrated that MAS occur in the majority of childhood systemic lupus erythematosus patients with acute pancreatitis with a higher mortality compared to adult systemic lupus erythematosus patients. [31]
A retrospective study by Nam et al showed that the overall survival rate in adults with rheumatic disease at 6 months after a diagnosis of MAS was 64.3%. [32]
Complications
Sepsis is an important complication due to the profound depression of WBCs. The abnormal coagulation profile may lead to hemorrhagic manifestations like purpura, easy bruising and mucosal bleeding.
