**1. Introduction**

78 Autoimmune Disorders – Current Concepts and Advances from Bedside to Mechanistic Insights

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Hemophagocytic syndrome (HPS), also known as hemophagocytic lymphohistiocytosis (HLH) encompasses an infrequent group of non-malignant, yet potentially life-threatening disorders caused by massive cytokine release from activated lymphocytes and macrophages (Filipovich, 2009; Henter et al., 1998, 2007; Janka et al., 1998; Janka, 2009). This multisystem inflammatory syndrome is associated with a range of genetic and acquired factors. Hectic and persistent fever, cytopenias, hepatitis, jaundice, edema, splenomegaly, neurological symptoms and hemophagocytosis in bone marrow (BM), liver or lymph nodes are common clinicopathological features of HLH.

#### **2. Historical background and terminology of HLH**

The first published report on HLH is presumably an observation of hemophagocytosis in malignancy (Tschistowitsch & Bykova, 1928). In 1939, Scott and Robb-Smith reported four similar cases of adults with an HLH-like picture and proposed to call this condition histiocytic medullary reticulosis (HMR) (Scott & Robb-Smith, 1939). The term HMR was later succeeded by the disease entity known as malignant histiocytosis (MH) (Rappaport, 1966). The familial form of HLH (named FHL or FHLH) was first described in a family with two affected siblings (Farquhar & Claireaux, 1952). Risdall et al. later reported a series of 19 patients with active viral infection, whose bone marrow smears disclosed histiocytic hyperplasia with prominent hemophagocytosis (Risdall et al., 1979). Of note, 14 of 19 patients in this study were immunosuppressed and active infection with herpes group viruses was documented in 74% (14/19) of patients. They proposed to term this condition virus-associated hemophagocytic syndrome (VAHS). Some authors argue that this paper by Risdall and colleagues is the first well documented report of acquired (or secondary) HLH (sHLH) (Kumakura, 2005). Five years later, Risdall et al. also reported HPS in three patients with bacterial sepsis (Risdall et al., 1984). This condition was named bacteria-associated

Autoimmune-Associated Hemophagocytic Syndrome/Macrophage Activation Syndrome 81

literature, whereas syndromes described in the hematology and infectious disease literature often describe a similar phenomenon as secondary HLH (Deane et al., 2010). Some authors suggest that the terms MAS and HLH are interchangeable (Behrens, 2008; Behrens et al., 2008; Emmenegger et al., 2005; Ramanan & Baildam, 2002), whereas others describe MAS as a distinct subset of sHLH (Arceci, 2008; Janka, 2007, 2009), and still others highlight the heterogeneity of disorders described by both terms and call for revised terminology based

According to the aforementioned historical background and current progress in understanding of its pathophysiology, HLH is generally divided into two distinct forms: an inherited, familial form and an acquired, secondary form (Arceci 2008; Janka, 2009; Henter et al., 2007). FHL has an autosomal recessive inheritance pattern, and usually arises in infants (80% cases), however in rare cases it can also occur in adults (Gupta & Weitzman, 2010; Henter et al., 1991b, 1998, 2007; Nagafuji et al., 2007). Acquired HLH can develop at any age, from childhood to the elderly, as a result of intensive immunological activation due to severe infections, autoimmune inflammatory disorders or malignancies (Janka, 2009; Henter et al., 2007). HLH as a serious complication of autoimmune diseases is commonly called macrophage activation syndrome or autoimmune-associated hemophagocytic syndrome. Macrophage activation syndrome as a severe complication of the systemic form of juvenile idiopathic arthritis (sJIA) is a prototype of AAHS. Nowadays MAS is considered a special form of acquired HLH by most rheumatologists. However, it should be emphasized that in the literature dealing with HLH in adults, MAS is sometimes used synonymously with acquired HLH regardless of its cause (Janka, 2009). The contemporary

Until recently, it was widely believed that FHL because of genetic causes arose during infancy and early childhood. In a retrospective Swedish study the incidence of FHL was estimated to be 0.12/100,000 children per year (Henter et al., 1991b). With the more widespread availability of genetic testing, it is apparent that the first significant episode of HLH can occur throughout life from prenatal presentations through to the seventh decade. There is no exact data on the incidence of any form of the acquired HLH. In 2007, a retrospective study was published analyzing HLH cases diagnosed in Japan between 2001 and 2005 (Ishii et al., 2007). The most frequent form of HLH in all age groups in Japan was EBV-associated HLH (35%; 163/469 pts), followed by other infection–associated HLH (29%; 138/469 pts), lymphoma–associated HLH (18%; 84/469 pts), autoimmune–associated HLH (11%; 53/496), FHL (4.5%; 20/469 pts) and post-HSCT (hematopoietic stem cell transplantation) HLH (2.5%; 11/469 pts). The authors estimated that the annual incidence of all types of HLH and in all age groups of Japanese patients was 1 case in 800,000 individuals per year (Ishii et al., 2007). However, this number is probably underestimated, due to the retrospective nature of the study, certain diagnostic difficulties and overlooking or misdiagnosing of some HLH cases. In the same study, the reported 5-year overall survival was highest in EBV- or other infection-associated HLH (> 80%) and in autoimmuneassociated HLH (almost 90%), intermediate in FHL or B-cell lymphoma-associated HLH

more precisely on pathophysiology (Grom et al., 2003; Grom & Mellins, 2010).

**3. Classification of HLH** 

classification of HLH is presented in Table 1.

**4. Epidemiology of HLH** 

hemophagocytic syndrome (BAHS). To date, sHLH is known to be associated not only with viral or bacterial infections, but also with different types of other disseminated infections, including fungal or parasitic infections (Janka et al., 1998). Therefore, HLH associated with any infection type is collectively called infection-associated hemophagocytic syndrome (IAHS) or infection-associated hemophagocytic lymphohistiocytosis (I-HLH) (Kumakura et al., 2004).

The origin of the proliferating cells in MH has been thought to be the precursors of histiocytes, but then it has been clarified that the proliferating cells are lymphoma cells (Kumakura, 2005). In 1981, a case of T-cell lymphoma resembling MH was reported (Kadin, 1981). Following this report, many lymphoma cases associated with HPS have been reported worldwide (Han et al., 2007; Hasselblom et al., 2004; Ishii et al., 2007; Janka et al., 1998; Reiner & Spivak, 1988; Tong et al., 2008). In most of these cases it was proven that the proliferating cells were not of histiocytic origin, but that they were lymphoma cells. Therefore, the 'true MH', which is recognized as a neoplastic disease of immature histiocytes, is thought to be very infrequent, and secondary HLH associated with lymphoma is called lymphoma-associated hemophagocytic syndrome (LAHS) (Kumakura, 2004). Later, it has become clear that other hematological malignancies (e.g. myelodysplastic syndromes, acute and chronic leukemias, multiple myeloma) and solid cancers (e.g. thymoma, carcinoma, germ cell tumor, hepatocellular carcinoma) can be associated with HLH as well (Gupta et al., 2009; Ishii et al., 2007; Janka et al., 1998; Lackner et al., 2008; Machaczka et al., 2010; Reiner & Spivak, 1988; Shabbir et al., 2010). Thus, HLH associated with any malignancy should be collectively called malignancy-associated hemophagocytic syndrome (MAHS) or malignancy-associated hemophagocytic lymphohistiocytosis (M-HLH).

In 1991, Wong reported six patients with active systemic lupus erythematosus (SLE) who demonstrated reactive bone marrow hemophagocytosis (Wong et al., 1991). Since there was no evidence of an underlying infection, hemophagocytosis was thought to be solely associated with the activity of SLE, and the authors proposed to name this condition acute lupus hemophagocytic syndrome (ALHS). Shortly thereafter, Kumakura et al. reported cases of secondary HLH associated with autoimmune diseases other than SLE, and postulated to consider a new disease entity autoimmune-associated hemophagocytic syndrome (AAHS) (Kumakura et al., 1995, 1997). Albert et al. were the first to use the term 'macrophage activation syndrome' (MAS) in a description of the disorder (Albert et al., 1992). Shortly after, Stephan et al. used the term MAS in their description of 4 children suffering from chronic rheumatic disease characterized by a pro-inflammatory milieu (Stephan et al., 1993). MAS has been often reported in cases of systemic juvenile idiopathic arthritis (sJIA), but is also a known complication of adult onset Still's disease (AOSD), systemic lupus erythematosus (SLE), rheumatoid arthritis, Sjögren's syndrome, dermatomyositis, Kawasaki disease, mixed connective tissue disease and systemic sclerosis (Carvalheiras et al., 2010; Davi et al., 2011; Fukaya et al., 2008; Grom & Mellins, 2010; Hendricks et al., 2010; Kumakura et al., 2004; Parodi et al., 2009; Sawhney et al., 2001; Simonini et al., 2010; Titze et al., 2009; Tristano, 2008).

Recognition in recent years that MAS belongs to the class of sHLH has led to a proposal to rename it according to the contemporary classification of histiocytic disorders (Ramanan & Baildam, 2002). Some authors have suggested that the term MAS be dropped in favor of reactive HLH to reflect this similarity and to better familiarize pediatric rheumatologists with treatment options, particularly in patients not responding to frontline therapy (Grom 2003). Nevertheless, use of the term MAS still remains prevalent in the rheumatology literature, whereas syndromes described in the hematology and infectious disease literature often describe a similar phenomenon as secondary HLH (Deane et al., 2010). Some authors suggest that the terms MAS and HLH are interchangeable (Behrens, 2008; Behrens et al., 2008; Emmenegger et al., 2005; Ramanan & Baildam, 2002), whereas others describe MAS as a distinct subset of sHLH (Arceci, 2008; Janka, 2007, 2009), and still others highlight the heterogeneity of disorders described by both terms and call for revised terminology based more precisely on pathophysiology (Grom et al., 2003; Grom & Mellins, 2010).
