Macrophage activation syndrome

Macrophage activation syndrome (MAS) is a term used by rheumatologists to describe a potentially life-threatening complication of systemic inflammatory disorders, most commonly systemic juvenile idiopathic arthritis (sJIA) and its adult equivalent adult onset Still disease and systemic lupus erythematosus (SLE) 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.

A majority of clinical data available involves macrophage activation syndrome as a complication of systemic juvenile idiopathic arthritis (sJIA). The prevalence of fulminant macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis is reported to be about 10%; however, subclinical macrophage activation syndrome may be present in as many as 30% of children with known or suspected systemic juvenile idiopathic arthritis ³. As macrophage activation syndrome becomes more clinically recognized, an increasing frequency of occurrence in other systemic inflammatory disorders [i.e., systemic lupus erythematosus (SLE), Kawasaki disease, and periodic fever syndromes] has been reported ⁴. While macrophage activation syndrome is known to complicate a variety of inflammatory conditions, including but not limited to malignancy, infection (i.e., Epstein-Barr virus [EBV]), and primary immunodeficiencies, it is most commonly reported as a well-recognized complication of systemic juvenile idiopathic arthritis (sJIA), and therefore, much of the understanding of the genetics, pathology, and subsequently immunology is derived from this specific cohort ⁵.

Because macrophage activation syndrome (MAS) is a serious condition that can follow a rapidly fatal course, prompt recognition of its clinical and laboratory features and immediate therapeutic intervention are critical. However, because it lacks a single distinguishing characteristic and is clinically heterogeneous, early diagnosis can be difficult.

Early recognition of macrophage activation syndrome remains diagnostically challenging as there is no diagnostic test or even a set of disease uniform diagnostic criteria to differentiate macrophage activation syndrome from the underlying systemic inflammatory condition ¹. Clinical and laboratory features of macrophage activation syndrome include sustained fever, hyperferritinemia, pancytopenia, fibrinolytic consumptive coagulopathy, and liver dysfunction. In 2016, an expert consensus panel published a set of validated diagnostic criteria to help distinguish a systemic juvenile idiopathic arthritis (sJIA) flare from macrophage activation syndrome. The final macrophage activation syndrome criteria for children with systemic juvenile idiopathic arthritis (sJIA) proved to be both sensitive (0.73) and specific (0.99). The diagnosis of macrophage activation syndrome can be made in a febrile patient with systemic juvenile idiopathic arthritis (sJIA), or suspected systemic juvenile idiopathic arthritis (sJIA), who has a serum ferritin level > 684 ng/ml plus any 2 of the following: platelet count ≤ 181 × 109/l, aspartate aminotransferase > 48 units/l, triglyceride concentration > 156 mg/dl, or fibrinogen ≤ 360 mg/dl ⁶. These relatively few total criteria are routinely readily available and timely. To date, these criteria have yet to prove diagnostic in other autoimmune diseases and remain limited to children with known or suspected systemic juvenile idiopathic arthritis (sJIA), with the possible exception of adult onset Still disease ⁷.

Macrophage activation syndrome causes

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) ⁸ and Kawasaki disease ⁹ and, occasionally, polyarticular juvenile idiopathic arthritis ¹⁰.

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 ¹¹. One report described a young girl with systemic juvenile idiopathic arthritis (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 methotrexate toxicity ¹².

The shortness of the time interval between methotrexate dosing and onset of macrophage activation syndrome (24 hours) 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.

Recently, instances of macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis (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 systemic juvenile idiopathic arthritis (sJIA) refractory to conventional therapy ¹³. 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 ². 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 ¹³. The development of hemophagocytosis in 3 patients with systemic juvenile idiopathic arthritis (sJIA) who received fludarabine as part of the conditioning regimen has been reported ¹⁴.

Macrophage activation syndrome symptoms

The clinical presentation of macrophage activation syndrome (MAS) is generally acute and occasionally dramatic. Typically, patients 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.

The coagulation profile is often abnormal, with prolongation of prothrombin time (PT) and partial thromboplastin time (aPTT), hypofibrinogenemia, and detectable fibrin degradation products. In children with systemic juvenile idiopathic arthritis, the clinical picture may mimic sepsis or an exacerbation of the underlying disease. However, the pattern of nonremitting fever is different from the remitting high-spiking fever seen in systemic juvenile idiopathic arthritis. Moreover, patients may show a paradoxical improvement in the underlying inflammatory disease at the onset of macrophage activation syndrome, with disappearance of signs and symptoms of arthritis and a precipitous fall in the erythrocyte sedimentation rate (ESR). The latter phenomenon probably reflects the degree of hypofibrinogenemia secondary to fibrinogen consumption and liver dysfunction ¹⁵.

Physical findings include the following:

• Mucocutaneous findings
  • Purpura
  • Easy bruising
  • Mucosal bleeding
• Hepatomegaly
• Splenomegaly
• Lymphadenopathy
• Central nervous system dysfunction
  • Lethargy
  • Irritability
  • Disorientation
  • Headache
  • Seizures
  • Coma
• Other findings: Renal, pulmonary, and cardiac involvement have been reported in some patients.

Macrophage activation syndrome complications

Macrophage activation syndrome is characterized by a highly stimulated but ineffective immune response. Sepsis is an important complication due to the profound depression of white blood cells. The abnormal coagulation profile may lead to hemorrhagic manifestations like purpura, easy bruising and mucosal bleeding.

Macrophage activation syndrome diagnosis

The recognition that macrophage activation syndrome is clinically similar to hemophagocytic lymphohistiocytosis (HLH) has led many clinicians to use the diagnostic guidelines for hemophagocytic lymphohistiocytosis (HLH) in the diagnosis of macrophage activation syndrome ¹⁶. However, the use of HLH criteria in patients with macrophage activation syndrome is associated with several problems; the chief problem is the requirement for tissue confirmation. A 2014 retrospective analysis concluded that HLH-2004 guidelines are likely not appropriate for identification of macrophage activation syndrome in children with systemic juvenile idiopathic arthritis (sJIA), and that preliminary macrophage activation syndrome guidelines showed the strongest ability to identify macrophage activation syndrome in systemic juvenile idiopathic arthritis (sJIA) ¹⁷.

The pathognomonic feature of macrophage activation syndrome (MAS) is bone marrow examination that reveals numerous well-differentiated macrophages actively phagocytosing hematopoietic cells. Such cells may be found in various other organs as well and may account for many of the systemic manifestations. However, in patients with HLH and macrophage activation syndrome, the bone marrow aspirate sample does not always reveal hemophagocytosis ¹⁸. Furthermore, hemophagocytosis is not always demonstrable at onset. In HLH, hemophagocytosis may be detected more frequently in liver, lymph node, or splenic biopsy samples than in bone marrow samples. However, performing a biopsy of these organs is contraindicated in children with macrophage activation syndrome in the presence of intravascular coagulopathy. Moreover, the failure to document hemophagocytosis does not exclude the diagnosis of HLH. A 2014 study concluded that hyperinflammation, rather than hemophagocytosis, is the common link between macrophage activation syndrome andhemophagocytic lymphohistiocytosis ¹⁹. These problems emphasize the need to identify criteria that obviate the need for tissue diagnosis.

To identify criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis (sJIA), the diagnostic sensitivity and specificity of the clinical and laboratory features of macrophage activation syndrome were recently scrutinized ²⁰. Based on these results, preliminary diagnostic guidelines for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis (sJIA) were established.

The diagnosis of macrophage activation syndrome requires the presence of any 2 or more the following laboratory criteria or 2 or more of the following clinical criteria:

Laboratory criteria

• Decreased platelet count (< 262 x 10⁹/L)
• Elevated aspartate aminotransferase levels (>59 U/L)
• Decreased white blood cell count (< 4 x 10⁹/L)
• Hypofibrinogenemia (≤2.5 g/L)

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)

Histopathologic criterion: The pathognomonic feature of the syndrome is bone marrow examination that reveals numerous well-differentiated macrophages actively phagocytosing hematopoietic cells. Such cells may be found in various other organs, as well, and may account for many of the systemic manifestations. However, in patients with macrophage activation syndrome, the bone marrow aspirate does not always show hemophagocytosis. Moreover, failure to reveal hemophagocytosis does not exclude the diagnosis of macrophage activation syndrome.

The above criteria are of value only in patients with active systemic juvenile idiopathic arthritis (sJIA). The thresholds of laboratory criteria are provided only as an example. The clinical criteria are probably more useful as classification criteria rather than as diagnostic criteria because they often occur late in the course of macrophage activation syndrome and, therefore, may be of limited value in the early diagnosis of the syndrome.

Other abnormal clinical features in macrophage activation syndrome associated with systemic juvenile idiopathic arthritis (sJIA) not listed above include nonremitting high fever, splenomegaly, generalized lymphadenopathy, and paradoxical improvement of signs and symptoms of arthritis.

Other abnormal laboratory findings in macrophage activation syndrome associated with systemic juvenile idiopathic arthritis (sJIA) not listed above include anemia, a lowered erythrocyte sedimentation rate, elevated alanine aminotransferase levels, increased bilirubin levels, presence of fibrin degradation products, elevated lactate dehydrogenase levels, hypertriglyceridemia, low sodium levels, decreased albumin, and hyperferritinemia.

Because universally agreed on diagnostic criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis (sJIA) are not available, a multinational collaborative effort aimed to generate new criteria for diagnosing macrophage activation syndrome as a complication of systemic juvenile idiopathic arthritis (sJIA) is currently underway. The first step of the project has led to the identification of, by means of a Delphi survey, the clinical, laboratory and histopathologic features of macrophage activation syndrome that were felt to be most important by a large sample of international pediatric rheumatologists with experience with macrophage activation syndrome in children with systemic juvenile idiopathic arthritis (sJIA) ²¹.

The diagnostic performance of potential criteria will be scrutinized further in the second phase of the study, through the analysis (ongoing) of real patient data. The final set of criteria is meant to be established in a consensus conference of experts using a combination of statistical and consensus formation techniques. The ultimate goal of the project is to develop a core set of criteria that is both highly sensitive and specific. These criteria will assist physicians in macrophage activation syndrome diagnosis in children with systemic juvenile idiopathic arthritis (sJIA) and enable quick institution of appropriate therapy.

As previously reported, diagnosis of macrophage activation syndrome may be particularly challenging in patients with systemic lupus erythematosus (SLE) because it may mimic the clinical and laboratory features of the underlying disease. Recently, preliminary diagnostic guidelines for macrophage activation syndrome complicating juvenile SLE were developed ²².

The main laboratory findings of macrophage activation syndrome include the following:

• Cytopenias
• Abnormal serum hepatic enzyme levels
• Coagulopathy
• Decreased erythrocyte sedimentation rate (ESR)
• Hypertriglyceridemia
• Hyponatremia
• Hypoalbuminemia
• Hyperferritinemia

The initial laboratory evaluation should include the following:

• CBC count with platelets and reticulocyte count
• Acute phase reactants (ie, erythrocyte sedimentation rate and C-reactive protein [CRP] levels)
• Markers of liver and kidney function
• Ferritin levels: Hyperferritinemia is an important laboratory hallmark of macrophage activation syndrome that has received increasing attention; elevated ferritin levels (often >10,000 ng/mL) have been reported in the acute phase of macrophage activation syndrome. Furthermore, a good correlation between ferritin levels and response to therapy has been observed; a decrease in ferritin levels is associated with a favorable course of macrophage activation syndrome. Recent studies have shown that low levels of glycosylated ferritin, in the presence of high level of total serum ferritin, may be another helpful marker for diagnosis ²³. A retrospective analysis by Ruscitti et al that included 50 Still’s disease patients (21 pediatric and 29 adult) reported that at diagnosis, high levels of serum ferritin and an elevated systemic score were associated with macrophage activation syndrome ²⁴.

Recently, gene expression profiling and determination of sIL-2R alpha and sCD163 concentration in peripheral blood have been suggested as useful tools for identifying early macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis (sJIA) ²⁵. However, the routine use of these diagnostic techniques outside of a research context is still unavailable in most laboratories worldwide.

Macrophage activation syndrome treatment

The treatment of macrophage activation syndrome (MAS) is traditionally based on the parenteral administration of high doses of corticosteroids. However, some fatalities have been reported, even among patients treated with massive doses of corticosteroids ¹⁰. The administration of high-dose intravenous immunoglobulins, cyclophosphamide, plasma exchange, and etoposide has provided conflicting results.

The use of cyclosporin A (CyA) was considered based on its proven benefit in the management of familial hemophagocytic lymphohistiocytosis (FHLH). Cyclosporin A was found to be effective in severe or corticosteroid-resistant macrophage activation syndrome ²⁶. In some patients, this drug exerted a “switch-off” effect on the disease process, leading to quick disappearance of fever and improvement of laboratory abnormalities within 12-24 hours ²⁶. Because of the distinctive efficacy of cyclosporin A, some authors have proposed using this drug as the first-line treatment for macrophage activation syndrome occurring in childhood systemic inflammatory disorders ²⁶.

Increased production of tumor necrosis factor (TNF) in the acute phase of macrophage activation syndrome has suggested the use of TNF-α inhibitors as potential therapeutic agents. However, although Prahalad et al ²⁷ reported the efficacy of etanercept in a boy who developed macrophage activation syndrome, other investigators have observed the onset of macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis (sJIA) who were treated with etanercept ²⁸. Similarly, Lurati et al reported the onset of macrophage activation syndrome in a patient with systemic juvenile idiopathic arthritis during treatment with the recombinant interleukin (IL)-1 receptor–antagonist anakinra ²⁹. Macrophage activation syndrome has also been reported in a patient with adult-onset Still disease who was receiving anakinra ³⁰.

Although the association between macrophage activation syndrome onset and treatment with etanercept or anakinra may be coincidental and not causal, the above-mentioned observations suggest that inhibition of tumor necrosis factor (TNF) or IL-1 does not prevent macrophage activation syndrome. Moreover, although macrophage activation syndrome–like symptoms are almost completely prevented by elimination of CD8+ T cells or by neutralization of INF-λ in perforin-deficient mice, the animal model of hemophagocytic lymphohistiocytosis (HLH), inhibition of IL-1 or TNF provides only mild alleviation of the symptoms.

Despite these observations, several cases of systemic juvenile idiopathic arthritis (sJIA)-associated macrophage activation syndrome dramatically benefiting from anakinra after inadequate response to corticosteroids and cyclosporin have now been reported ³¹. For those severely ill children, IL-1 blockade has been remarkably effective in a relative brief time frame.

Other forms of HLH not associated with rheumatic diseases usually require more aggressive treatment: for instance, children younger than 1 year in whom familial HLH is suspected and all patients with severe signs and symptoms are candidates for combination therapy with dexamethasone, cyclosporin A, and etoposide. Etoposide has been shown to improve prognosis for Epstein-Barr virus (EBV)–related HLH; its effectiveness may be explained by inhibition of synthesis of EBV nuclear antigen. Whether HLH therapeutic protocols are suitable for use in children with macrophage activation syndrome associated with rheumatic diseases is unclear.

Despite aggressive treatment, long-term disease-free survival in patients with familial HLH can be reached only after stem cell transplantation ³².

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