**3. Classification of HLH**

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

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

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).

Simonini et al., 2010; Titze et al., 2009; Tristano, 2008).

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;

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

al., 2004).

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 classification of HLH is presented in Table 1.
