Macrophage Activation Syndrome
Unfortunately, the application of the HLH diagnostic criteria to systemic JIA patients with suspected MAS is problematic. Some of the HLH markers such as lymphadenopathy, splenomegaly, and hyperferritinemia are common features of active SJIA itself and, therefore, do not distinguish MAS from a conventional SJIA flare. Other HLH criteria, such as cytopenias and hypofibrinogenemia, become evident only at the late stages. This is related to the fact that systemic JIA patients often have increased white blood cell and platelet counts as well as increased serum levels of fibrinogen as a part of the inflammatory response seen in this disease. Therefore, when these patients develop MAS, they may only reach the degree of cytopenias and hypofibrinogenemia seen in HLH at the late stages of the syndrome when their management becomes challenging. The application of criteria is even more problematic for the diagnosis of MAS in patients with SLE in whom autoimmune cytopenias are common and difficult to distinguish from those caused by MAS. In these patients, the presence of extreme hyperferritinemia and lactate dehydrogenase elevation should raise suspicion for MAS. Attempts to modify the HLH criteria to increase their sensitivity and specificity for the diagnosis of MAS in rheumatic conditions have been initiated.19
Differential Diagnosis
In addition to distinguishing MAS from a flare of an underlying rheumatologic disease, one must consider in differential diagnosis other clinical entities associated with hepatic dysfunction, coagulopathy, cytopenias, or encephalopathy. In some MAS patients, the combination of hepatic dysfunction with encephalopathy may be reminiscent of Reye syndrome. The diagnosis of Reye syndrome, however, is based of the presence of a viral prodrome, unexplained vomiting, behavioral changes, and a distinctive chemical profile characterized by rapid coordinated increase in serum aminotransferase levels, blood ammonia, and prothrombin time with relatively minimal changes in serum bilirubin. The DIC-like coagulopathy seen in MAS is not a feature of Reye syndrome. Conversely, a sharp increase in blood ammonia levels, an important feature of Reye syndrome, is usually very mild in MAS. The hemorrhagic syndrome seen in MAS may resemble thrombotic thrombocytopenic purpura. However, microangiopathic anemia with emergence of fragmented red blood cells in peripheral circulation, a central feature of thrombotic thrombocytopenic purpura, is usually not seen in MAS. It is also important to differentiate MAS from malignancy-associated HLH and malignant histiocytic disorders. Some other important differential diagnoses include sepsis and drug reactions.
Treatment
MAS is a life-threatening condition associated with high mortality rates. Therefore, early recognition and of this syndrome and immediate therapeutic intervention to produce a rapid response are critical. Most clinicians start with intraveneous methylprednisolone pulse therapy (30 mg/kg for three consecutive days) followed by 2–3 mg/kg/day in four divided doses. If a response to steroids is not evident within 24–48 hours, parenteral administration of cyclosporine A (CyA; 2–7 mg/kg/day) should be initiated.1,4,20 Patients in whom MAS remains active despite the use of corticosteroids and CyA present a serious challenge. In these patients, one might consider using the HLH-2004 treatment protocol developed by the International Histiocyte Society (see Table 1, p. 23). In addition to steroids and CyA, this protocol also includes etoposide (or VP16), a podophyllatoxin derivative that inhibits DNA synthesis by forming a complex with topoisomerease II and DNA. However, potential toxicity of the drug including severe myelosuppression is a major concern, particularly in patients with hepatic impairment. Etoposide is metabolized by the liver and then both the unchanged drug and its metabolites are excreted through the kidneys. Because patients who may require the use of etoposide are very likely to have hepatic and renal involvement, caution should be exercised to properly adjust the dosage and thus limit the extent of potential side effects such as severe bone marrow suppression,which may be detrimental. Reports describing deaths caused by severe bone marrow suppression and overwhelming infection have been published.