Macrophage Activation Syndrome

Definition

Macrophage activation syndrome (MAS) is a severe, potentially fatal complication of rheumatic diseases caused by excessive activation and expansion of macrophages and T cells, leading to an overwhelming inflammatory reaction. The main manifestations of MAS include fever, hepatosplenomegaly, lymphadenopathy, severe cytopenias, liver enzyme elevation, and coagulopathy consistent with disseminated intravascular coagulation (DIC). Striking hyperferritinemia is another characteristic laboratory finding. Numerous, well-differentiated macrophage phagocytosing hematopoietic elements are often found in bone marrow, liver, spleen, or lymph nodes ( Fig. 42.1 ). These hemophagocytic macrophages can infiltrate almost any organ in the body and may account for many of the systemic features of this syndrome. Although often considered the pathognomonic feature of MAS, pathological hemophagocytosis is neither highly specific nor sensitive for the overall diagnosis of MAS. Although MAS has been reported to occur with many other rheumatic diseases, it is most common in the systemic form of juvenile idiopathic arthritis (JIA) and its adult form adult-onset Stills disease (AOSD). Systemic lupus erythematosus (SLE) and Kawasaki disease are also conditions in which MAS appears to occur more frequently than in other rheumatological diseases. ^,

MAS bears a close resemblance to a group of histiocytic disorders known as hemophagocytic lymphohistiocytosis (HLH ), ^, a term that describes a spectrum of disease processes characterized by accumulations of well-differentiated mononuclear cells with a macrophage phenotype. ^, Because the macrophages represent a subset of histiocytes distinct from Langerhans cells, this entity should be distinguished from Langerhans cell histiocytosis and other dendritic cell disorders. In the current classification of histiocytic disorders, HLH is further subdivided into primary or familial HLH (pHLH or FHL) and secondary or reactive HLH (ReHLH). ^, Clinically, however, it may be difficult to distinguish one from the other. Primary HLH is a constellation of rare autosomal recessive immune disorders linked to genetic defects in various genes all affecting the cytolytic pathway. Its clinical symptoms usually become evident within the first months of life. Reactive HLH tends to occur in older children and is more often associated with an identifiable infectious episode, most notably Epstein–Barr virus (EBV) or cytomegalovirus infection. The group of secondary hemophagocytic disorders also includes malignancy-associated HLH. The distinction between primary and secondary HLH is becoming increasingly blurred as new genetic causes are identified, some of which are associated with less severe and somewhat more distinct clinical presentations. Some of these may present later in life because of heterozygous or compound heterozygous mutations in cytolytic pathway genes that reduce cytolytic function.

As with MAS, the clinical course for HLH is characterized by persistent fever and hepatosplenomegaly. ^, Neurological symptoms can complicate and sometimes dominate the clinical course. Hemorrhagic rash and lymphadenopathy are observed somewhat less frequently. The laboratory findings—cytopenias (particularly thrombocytopenia), elevated liver enzymes, hypertriglyceridemia, hyperferritinemia, and hypofibrinogenemia—also overlap with MAS. As with MAS, hemophagocytosis in bone marrow is a hallmark of HLH. Despite all these clinical similarities, the exact pathophysiological relationship between MAS and HLH is unclear.

Epidemiology

Epidemiological studies of MAS have been limited mainly to single center retrospective chart reviews. Approximately 7% to 17% of patients with systemic JIA develop profound disease, ^, whereas mild “subclinical” MAS may be seen in as many as one-third of patients with active systemic JIA. ^, In subclinical MAS, bone marrow examination typically reveals extensive expansion of enlarged foamy macrophages with only a few of them exhibiting overt hemophagocytic activity. In SLE, MAS can be seen in about 1% to 9% of patients.

MAS occurs with equal frequency in boys and girls. There appears to be no racial predilection, and it may occur at almost any age. The youngest MAS patient reported to date was 12 months old. Although most patients develop this syndrome sometime during the course of their primary rheumatic disease, MAS occurring at the initial presentation is not uncommon. ^{, ,} Thus in the retrospective single center study of MAS in SLE by Borgia et al., the majority of these patients developed MAS concomitantly with SLE diagnosis, and the presence of MAS was strongly associated with a higher risk of death.

The vast majority of patients have an active primary rheumatic disease prior to developing MAS. However, in the recent phase III clinical trials of the biologics inhibiting either interleukin (IL)-1 or IL-6, MAS occurred in several patients despite an excellent control of the underlying systemic JIA. Infectious triggers were identified in almost all of these cases. ^,

Triggers

A triggering event, such as infection or modification in the drug therapy, can be identified in about half of MAS episodes. It is now evident that development of MAS can be precipitated by virtually any infectious agent: viral, bacterial, fungal, and even parasitic. Viral illnesses, particularly EBV and other members of the herpes family, appear to be the most commonly reported. ^, In several reports, the triggering of MAS coincided with modifications in drug therapy, most notably administration of gold preparations, methotrexate, and sulfasalazine. These associations, however, should be interpreted cautiously because many of the described patients had very active underlying rheumatic disease and might have been developing MAS as the drugs were started. In many patients, MAS appears to be triggered by a flare of the underlying rheumatic disease.

Genetic Background

As discussed later in this chapter, the pathological mechanisms of MAS are not fully understood. In clinically similar primary HLH, the uncontrolled proliferation of T cells and macrophages has been linked to decreased natural killer (NK) cell and cytotoxic T cell (CTL) function. In about 30% of pHLH patients, the cytolytic dysfunction is due to mutations in the gene encoding perforin ( PRF1 ), a protein that cytolytic cells normally utilize to induce apoptosis of target cells, such as cells infected with viruses. The proteins encoded by several other pHLH-associated genes are involved in the intracellular transport of perforin-containing granules to the cell surface interface with the target cell ( MUNC13-4, Syntaxin 11 [ STX11 ], and syntaxin binding protein 2 [ STXBP2, also known as MUNC18-2 ]). Although the cytolytic cells in these patients with pHLH produce sufficient amounts of perforin, the reduced ability to release perforin into the immunological synapse with the target cell leads to profoundly decreased cytolytic activity. Similar defects have also been implicated in other genetic diseases associated with hemophagocytic syndromes. Mutations in the gene encoding RAB27A , one of the MUNC13-4 effector molecules, have been linked to the development of Griscelli syndrome type 2, and mutations in the LYST gene have been identified as a cause of Chédiak–Higashi syndrome. Similarly, mutations in both the gene encoding SH2D1A (an adaptor protein critical for lymphocyte activation, including granule-mediated cytotoxicity) and the gene encoding X-linked inhibitor of apoptosis (XIAP) have been associated with X-linked lymphoproliferative disease. ^, As in HLH, systemic juvenile idiopathic arthritis (sJIA) patients with MAS have profoundly depressed NK cell function, although this impairment tends to improve after MAS resolution and better control of the underlying systemic JIA. Compared with healthy controls, sJIA patients with MAS carry “an increased burden” of rare protein-altering variants in the cytolytic pathway, with about 30% of these patients carrying heterozygous hypomorphic variants in the pHLH-associated genes. In addition, noncoding variants that may affect MUNC13-4 expression have been reported in children with MAS.