Background
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] 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. [2, 3, 4, 5]
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. [6] 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. [7, 8]
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. [9] 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. [10]
Moreover, very high levels of IL-18 have been reported in 2 patients with SJIA and macrophage activation syndrome. [11] 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. [12]
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. [13]
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. [14]
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. [15, 16] 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.
Epidemiology
Frequency
United States
The exact incidence of macrophage activation syndrome in childhood rheumatic disorders is unknown.
International
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. [4] Approximately 100 cases have been reported in the literature. [2, 4, 17, 18]
Mortality/Morbidity
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. [19]
Age
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. [17] 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.
