Abstract：
In 1979, it became recognized in the literature that what we call hemophagocytic lymphohistiocytosis (HLH) was a nonmalignant disease of histiocytes. Subsequently a familial form and a secondary form of HLH were differentiated. When HLH is secondary to an autoimmune disease, rheumatologists refer to this entity as macrophage activation syndrome (MAS) to differentiate it from HLH itself. Although the first cases of MAS likely appeared in the literature in the 1970s, it was not until 1985 that the term activated macrophages was used to describe patients with systemic juvenile idiopathic arthritis (sJIA) complicated by MAS and the term macrophage activation syndrome first appeared in the title of a paper in 1993.MAS is one of the many types of secondary HLH and should not be confused with primary HLH. Experience has taught that MAS secondary to different autoimmune diseases is not equal. In the 30 years since initial description in patients with sJIA, the clinical spectrum, diseases associated with MAS, therapy, and understanding the pathogenesis have all made significant gains. The diagnostic/classification criteria for MAS secondary to sJIA, SLE, RA, and KD differ based on the different laboratory abnormalities associated with each (Ahn et al., J Rheumatol 44:996-1003, 2017; Han et al., Ann Rheum Dis 75:e44, 2016; Ravelli et al., Ann Rheum Dis 75:481-489, 2016; Borgia et al., Arthritis Rheumatol 70:616-624, 2018). These examples include the thrombocytosis associated with sJIA, a chronic generalized activation of the immune system, leading to elevations of fibrinogen and sIL-2R, low platelet count associated with SLE, and more acute inflammation associated with KD. Therefore, individual diagnostic criteria are required, and they all differ from the diagnostic criteria for HLH, which are based on a previously non-activated immune system (Ahn et al., J Rheumatol 44:996-1003, 2017; Han et al., Ann Rheum Dis 75:e44, 2016; Ravelli et al., Ann Rheum Dis 75:481-489, 2016; Borgia et al., Arthritis Rheumatol 70:616-624, 2018; Henter et al., Pediatr Blood Cancer 48:124-131, 2007). This helps to explain why the HLH diagnostic criteria do not perform well in MAS.The initial treatment remains high-dose steroids and IVIG followed by the use of a calcineurin inhibitor for resistant cases. IVIG can be used if there is a concern about malignancy to wait for appropriate investigations or with steroids. Interluekin-1 inhibition is now the next therapy if there is a failure to respond to steroids and calcineurin inhibitors. Advances in understanding the mechanisms leading to MAS, which has been greatly aided by the use of mouse models of MAS and advances in genome sequencing, offer a bright future for more specific therapies. More recent therapies are directed to specific cytokines involved in the pathogenesis of MAS and can lead to decreases in the morbidity and mortality associated with MAS. These include therapies directed to inhibiting the JAK/STAT pathway and/or specific cytokines, interleukin-18 and gamma interferon, which are currently being studied in MAS. These more specific therapies may obviate the need for nonspecific immunosuppressive therapies including high-dose prolonged steroids, calcineurin inhibitors, and etoposide.
摘要：
1979年，文献中认识到，我们所说的噬血细胞性淋巴组织细胞增生症（HLH）是组织细胞的非恶性疾病。随后区分家族形式和次要形式的HLH。当HLH继发于自身免疫性疾病时，风湿病学家将此实体称为巨噬细胞活化综合征（MAS），以将其与HLH本身区分开。尽管MAS的第一批病例可能出现在20世纪70年代的文献中，直到1985年,术语“活化的巨噬细胞”才被用于描述系统性幼年特发性关节炎(sJIA)合并MAS的患者,而术语“巨噬细胞活化综合征”首次出现在1993年的一篇论文标题中.MAS是许多类型的继发性HLH之一，不应与原发性HLH混淆。经验告诉我们，MAS继发于不同的自身免疫性疾病是不相等的。在sJIA患者最初描述的30年里，临床谱，与MAS相关的疾病，治疗,和对发病机制的理解都取得了重大进展。sJIA继发MAS的诊断/分类标准，SLE,RA,和KD根据与每个相关的不同实验室异常而有所不同(Ahn等人。,JRheumatol44：996-1003，2017；Han等人。,AnnRheumDis75：e44，2016；Ravelli等人。,AnnRheumDis75：481-489，2016；Borgia等人。,关节炎Rheumatol70:616-624,2018)。这些例子包括与sJIA相关的血小板增多症，免疫系统的慢性全身激活，导致纤维蛋白原和sIL-2R升高，与SLE相关的低血小板计数，和更多与KD相关的急性炎症。因此,需要个人诊断标准，它们都不同于HLH的诊断标准，这是基于以前未激活的免疫系统(Ahn等人。,JRheumatol44：996-1003，2017；Han等人。,AnnRheumDis75：e44，2016；Ravelli等人。,AnnRheumDis75：481-489，2016；Borgia等人。,关节炎Rheumatol70：616-624，2018；Henter等人。,Pediatr血癌48:124-131,2007)。这有助于解释为什么HLH诊断标准在MAS中表现不佳。最初的治疗仍然是高剂量类固醇和IVIG，然后在耐药病例中使用钙调磷酸酶抑制剂。如果担心恶性肿瘤，可以使用IVIG等待适当的检查或使用类固醇。如果对类固醇和钙调磷酸酶抑制剂没有反应，则抑制Interluekin-1现在是下一个疗法。在理解导致MAS的机制方面取得的进展，通过使用MAS的小鼠模型和基因组测序的进步，为更具体的疗法提供光明的未来。最近的疗法针对与MAS的发病机理有关的特定细胞因子,并且可以导致与MAS相关的发病率和死亡率的降低。这些包括针对抑制JAK/STAT途径和/或特定细胞因子的疗法。白细胞介素-18和γ干扰素，目前正在MAS进行研究。这些更具体的疗法可以消除对非特异性免疫抑制疗法的需要，包括高剂量延长类固醇。钙调磷酸酶抑制剂，和依托泊苷。
