【背景】 噬血细胞性淋巴组织细胞增多症（hemophagocytic lymphohistocytosis, HLH）又称 为噬血细胞综合征（hemophagocytic syndrome, HPS）是一组少见的内科急危重症，临 床上以发热、血细胞减少、器官肿大、高铁蛋白血症及骨髓等组织发现噬血现象等为 主要特征。继发性 HLH（secondary HLH, sHLH）主要发生在成人，常见的三大病因 为感染、恶性肿瘤和自身免疫病，且未发现 HLH 相关基因异常。由自身免疫病所引 起的 HLH 亦称为巨噬细胞活化综合征（macrophage activation syndrome, MAS）。目前 国内外关于 sHLH 的相关研究较少，临床存在认识不足、诊断困难等问题。本研究拟 对 sHLH 的疾病特征、预后预测及早期诊断作进一步探讨。 第一部分 继发性噬血细胞综合征预后相关预测模型的研究 由于 sHLH 是一类少见、高异质性的临床综合征，不同原发病所致 sHLH 的临床 特征、治疗选择及预后均不尽相同，然而，由于 sHLH 患病率较低，目前研究报道尚 缺乏针对 sHLH 原发病的临床特征及 sHLH 危险因素的预后预测。 【目的】 探讨不同原发病继发 HLH 的临床特征及其预后情况，寻找疾病死亡相关的危险 因素，为提高疾病的早期认知、改善预后提供帮助。 【方法】 连续收集 2016 年 1 月 1 日至 2022 年 12 月 31 日期间在北京大学人民医院明确诊 断 sHLH 的病例。纳入标准为年龄≥18 岁、临床资料完整及符合 HLH-2004 诊断标 准，进行如下分析：（1）按照原发病将 sHLH 病例分为恶性肿瘤组、自身免疫病组、 感染组及其他疾病组，分析不同病因 sHLH 的临床特征；（2）依据患者的预后情况， 分为病情缓解组及死亡组，应用 SPSS 25.0 软件对数据进行分析，组间比较采用卡方 检验、独立样本 t 检验或方差分析、Mann-Whitney 检验等检验方法，P＜0.05 为组间 差异有统计学意义，依据预后不同将单因素组间比较 P＜0.05 的变量纳入多因素 Logistic 回归分析，最终得到 sHLH 死亡相关的独立危险因素，经计算各因素的比值 比（odds ratio, OR），建立 sHLH 预后的预测模型。 【结果】 1. 本研究共纳入 220 例 sHLH 患者，按照原发病因将 sHLH 进行分类后，疾病临床特 征如下：自身免疫病继发 HLH（MAS）组患者的血细胞下降程度最轻，sCD25 表 达水平最低，PT 及 APTT 延长少，合并感染比例低，以 CMV 感染多见达 32.6%，仅 5.4%合并 EBV 感染，死亡率为 18.5%；恶性肿瘤继发 HLH 组患者的血 细胞减少程度最严重，伴 PT 及 APTT 延长，血培养阳性率及合并真菌感染者最 多，28.8%合并 EBV 感染，死亡率为 42.5%；感染继发 HLH 组患者的 sCD25 升高 最为明显，伴 PT 及 APTT 显著延长，噬血现象检出率最高达 54.8%，50.0%合并 EBV 感染，死亡率为 50.0%。 2. 依据预后情况，将 sHLH 分为病情缓解组及死亡组进行分析，多因素 Logistic 回归 显示：年龄≥38 岁、两系及以上血细胞减少、PLT≤50×10 9 /L、AST≥135U/L、 PT≥14.9s、APTT≥38.5s、合并 EBV 及真菌感染是 sHLH 死亡的危险因素；该模 受试者工作特征曲线下面积（area under receiver operating characteristic curve, AUC）为 0.857（95%CI: 0.801~0.914, P），预测 sHLH 死亡的敏感度、特异 性分别为 0.716 和 0.866；Hosmer-Lemeshow 拟合优度法检验 P=0.256；参考 Logistic 回归方程中各危险因素的 OR 值，以此为基础建立预测模型，创建 sHLH 预后预测的评分模型如下：① 2 分：年龄≥38 岁；② 2.5 分：AST≥135U/L；真 菌感染；每项评 2.5 分；③ 3 分：PLT≤50×10 9 /L；PT≥14.9s；APTT≥38.5s； EBV 感染；每项评 3 分；④ 6 分：两系及以上血细胞减少。本预后预测模型总分 为 25 分，依据约登指数，预测 sHLH 患者死亡风险的最佳分界点为 9.5 分，评分 ＜10 分时死亡风险为 10.1%，≥10 分为 47.3%。随着评分增加，sHLH 患者死亡风 险呈进行性增高，按照整体评分将 sHLH 分为低危组（分）、中危组（10~16 分）、高危组（≥16 分），三组患者的死亡率分别为 10.1%、29.5%和 73.6%。 【结论】 1. 在 sHLH 中，自身免疫病继发 HLH 患者病情较轻，预后最好；恶性肿瘤继发 HLH 与感染继发 HLH 患者病情严重，预后较差。 2. 多因素 Logistic 回归分析显示：年龄、两系及以上血细胞减少、血小板≤50× 10 9 /L、AST≥135U/L、PT 和 APTT 延长、合并 EBV 感染及真菌感染是 sHLH 死 亡的危险因素，其 AUC 为 0.857（95%CI，0.801~0.914），预测 sHLH 死亡的敏感 度、特异性分别为 0.716 和 0.866。依据 Logistic 回归方程创建的 sHLH 预后预测模 型，经验证具有良好的判别能力与校正能力。第二部分 系统性红斑狼疮继发噬血细胞综合征中转录组标志物的筛选 与验证 巨噬细胞活化综合征（macrophage activation syndrome, MAS）是指由自身免疫病 所引起的 HLH，系统性红斑狼疮（systemic lupus erythematosus, SLE）是最常继发 HLH 的自身免疫病之一。然而，由于 SLE 的系统症状与 HLH 临床表现重叠，导致临 床诊断困难，漏诊率及误诊率高，在 SLE 中探索继发 HLH 敏感度和特异性高的早期 诊断标志物具有重要临床意义。 【目的】 利用全转录组测序技术，基于 SLE 患者相关的外周血单个核细胞（peripheral blood mononuclear cells, PBMC），筛选 SLE 继发 HLH 的转录组差异分子，并进行临 床验证，以期寻找对于诊断 HLH 敏感度和特异性高的生物标志物。 【方法】 研究招募在北京大学人民医院急诊科及风湿免疫科就诊的 2021 年 1 月 1 日至 2024 年 1 月 31 日的活动 SLE 患者，入选标准：SLE 患者 SLEDAI 评分≥5 分；排除 标准：（1）肝硬化 Child 分级≥B 级；（2）慢性肾脏病 3b-5 期。根据 HLH-2004 诊断 标准或 HScore 评分≥169 分诊断 HLH。首先纳入中度活动以上 SLE、SLE 继发 HLH 和健康对照（healthy control, HC）各 3 例，提取各自的 PBMC，用于全转录组测序。 基于全转录组结果，筛选 mRNA、lncRNA 及 miRNA 差异分子，构建 lncRNAmiRNA-mRNA 互作网络，利用 Real-time PCR 检测 mRNA 及 lncRNA 差异分子在活动 SLE 患者 PBMCs 的相对表达水平，分成有无继发 HLH 组后，验证其预测 SLE 继发 HLH 的诊断价值。应用 SPSS 25.0 软件对数据进行分析，组间比较采用卡方检验、独 立样本 t 检验或方差分析、Mann-Whitney 检验等检验方法，P＜0.05 为组间差异有统 计学意义，根据受试者工作特征曲线下面积（area under receiver operating characteristic, AUC）来评估生物标志物的预测能力。 【结果】 1. 基于全转录组测序结果，筛选差异分子如下： (1) mRNA：微小染色体维持复合物 2（minichromosome maintenance complex 2, MCM2），染色质装配因子 1 亚基 B（chromatin assembly factor 1 subunit B, CHAF1B），unc-51 样自噬激活激酶 2（unc-51 like autophagy activating kinase 2, ULK2），杀伤细胞凝集素样受体 C3（killer cell lectin like receptor subfamily C member 3, KLRC3）及杀伤细胞凝集素样受体 G1（killer cell lectin-like receptor G1, KLRG1）； (2) lncRNA：DCAF8-DT，抑制蛋白β2（arrestin beta2, ARRB2），颗粒蛋白前体 （granulin precursor, GRN）； (3) miRNA ： hsa-miR-514a-3p 、 hsa-miR-582-5p 、 has-miR-181a-2-3p 及 has-miR1291。 2. 纳入 14 例 HC 及 50 例 SLE 患者，SLE 按照有无 HLH，分为 SLE 组（36 例）， SLE 继发 HLH 组（14 例），验证 mRNA 及 lncRNA 差异分子的相对表达水平，结 果如下： (1) 与 HC 及 SLE 组相比，SLE 继发 HLH 中 DCAF8-DT 的 lncRNA 与 ULK2、KLRC3 及 KLRG1 mRNA 的相对表达水平显著下降；其他分子在三组之间表达无差异； (2) KLRG1 诊断 SLE 继发 HLH 效能最佳，AUC 为 0.927（95%CI: 0.854-0.999），敏感 度 0.889，特异性 0.929；KLRC3 诊断 SLE 继发 HLH 的 AUC 为 0.885（95%CI: 0.793-0.977），敏感度 0.806，特异性 0.929；ULK2 诊断 SLE 继发 HLH 的 AUC 为 0.843（95%CI: 0.714-0.972），敏感度 0.806，特异性 0.857。 【结论】 KLRG1、KLRC3 及 ULK2 是预测 SLE 继发 HLH 的潜在生物标志物，其中， KLRG1 预测 SLE 继发 HLH 敏感度、特异性最高，分别为 0.889 和 0.929，是诊断 SLE 继发 HLH 的最佳生物标志物。

Hemophagocytic lymphohistiocytosis (HLH), alternatively termed hemophagocytic syndrome (HPS) is a rare acute critical clinical syndrome, featuring fever, organomegaly, pancytopenia, hyperferriinemia, and hemophagocytosis which could be observed in bone marrow and other tissues. HLH is categorized into primary HLH and secondary HLH (sHLH), contingent upon the presence or absence of genetic aberration. sHLH predom inantly afflicts adults and is chiefly instigated by infection, malignancy, or autoimmune disorders. Autoimmune diseases induced HLH is also recognized as macrophage activation syndrome (MAS). sHLH remains under-researched both domestically and internationally, characterized by insufficient clinical comprehension and diagnostic challenges. This investigation seeks to delve into the disease attributes, prognostic indicators, and early diagnostic modalities of sHLH. Part I. Research on Prognostic Prediction Model of Secondary Hemophagocytic Syndrome As sHLH represents a rare and remarkably heterogeneous array of clinical syndromes, the clinical manifestations, treatment modalities, and prognostic outcomes of sHLH stemming from distinct primary pathologies exhibit notable variations. However, owing to the low incidence of sHLH, there exists a dearth of literature delineating the clinical features and prognostic determinants subsequent to etiological classification of sHLH. Objective The aim of this study is to elucidate the disease characteristics of sHLH, delineate corresponding clinical and laboratory features post-etiological categorization, and discern the risk factors associated with mortality in sHLH, thereby augmenting comprehension and improving prognosis of the disease.Methods A comprehensive compilation of consecutive cases diagnosed definitively with sHLH at Peking University People's Hospital spanning from January 1, 2016, to December 31, 2023, was undertaken. Cases involving individuals aged above 18 years, those with complete clinical data, and instances meeting the HLH-2004 diagnostic criteria upon reassessment were systematically enrolled. Subsequently, all sHLH cases were subjected to the following analyses: (1) stratification of sHLH cases into distinct groups based on primary diseases, namely the malignancy group, autoimmune disease group, infections group and other etiologies, followed by comparative assessment of clinical characteristics and in-hospital mortality across the three groups; (2) stratification of cases based on prognosis into remission and death groups for subsequent analysis and comparison. SPSS 25.0 software was used to analyze the data, between-group comparisons were conducted using chi-square test, independent samples t-test, analysis of variance (ANOVA) or Mann-Whitney tests. P<0.05 was considered statistically significant. Variables with P<0.05 were included in the multiple logistic regression analysis to identify independent risk factors for mortality of sHLH. The odds ratios (OR) for each factor were calculated to establish a prognostic prediction model for sHLH. Results 1. A total of 220 patients with sHLH were included in this study, upon categorization of sHLH based on primary disease, the clinical features were as follows: autoimmune disease associated HLH (MAS) was characterized by: mildest hematocrit decrease, and relative lower sCD25 expression, minimal prolongation of PT and APTT, low coinfection rate, high prevalence of CMV infection (32.6%) and low EBV infection detection rate (5.4%), and with a mortality of 18.5%. Patients with malignancyassociated HLH was presented with severe cytopenia or pancytopenia, prolonged PT and APTT, the highest rate of positive blood cultures and fungal infections, an EBV infection rate of 28.8%, and with a mortality of 42.5%. Infections associated HLH is characterized by significant prolongation of PT and APTT, significant sCD25 elevation, a high prevalence of hemophagocytosis(54.8%), a high rate of EBV infection at 50.0% and whose mortality is 50.0%. 2. Prognostic analysis categorized sHLH into remission and death groups: (1) Logistic regression identified age ≥38 years, cytopenia or pancytopenia, PLT ≤50*10 9 /L, AST ≥135 U/L, PT ≥14.9s, APTT ≥38.5s, EBV and fungal infections as risk factors for in-hospital death. The regression model demonstrated good discriminative ability with an AUC of 0.857 (95% CI: 0.801~0.914, P<0.001), sensitivity and specificity of 0.716 and 0.866 respectively. (2) A prognostic scoring system was developed, with scores assigned based on identified risk factors. The mortality rates in low-risk, intermediate-risk, and high-risk groups were 10.1%, 29.5%, and 73.6% respectively, demonstrating progressive mortality risk with increasing scores. Conclusion 1. Autoimmune diseases associated HLH presented a relatively mild clinical condition and the most favorable prognosis. Malignancy and infections associated HLH exhibited severe clinical condition and poor prognosis 2. Logistic regression analysis identified several risk factors associated with mortality in sHLH patients, including age, cytopenia or pancytopenia, thrombocytopenia, elevated AST (≥135 U/L), prolonged PT and APTT, EBV infection and fungal infection, with an AUC of 0.857 (95% CI, 0.801-0.914), and sensitivity and specificity of 0.716 and 0.866, respectively. A prognostic prediction model for sHLH was developed based on the OR derived from the logistic regression model, which demonstrated robust discriminative and calibration abilities.Part II. Screening and Validation of Biomarkers in Transcriptome for Systemic Lupus Erythematosus induced Secondary Hemophagocytic Syndrome Macrophage activation syndrome represents a subtype of hemophagocytic lymphohistioc ytosis (HLH) associated with autoimmune diseases. Systemic lupus erythematosus (SLE) is one of the most common autoimmune diseases that induce HLH. The overlapping systemic symptoms of SLE and clinical manifestations of HLH pose challenges in clinical diagnosis, contributing to significant rates of underdiagnosis and misdiagnosis, warranting further investigation. And exploring early diagnostic biomarkers with high sensitivity and specificity for HLH in autoimmune diseases holds significant clinical importance.Objective The aim of this study is to identify biomarkers with high sensitivity and specificity for HLH through whole transcriptome sequencing by utilizing peripheral blood mononuclear cells (PBMC) from SLE patients, and clinically validate their utility. Methods Active SLE patients were recruited from January 1, 2021, to January 31, 2024, from the emergency, rheumatology and immunology department of Peking University People’s Hospital. Inclusion criteria comprised a SLE Disease Activity Index (SLEDAI) score ≥5 for SLE patients, while exclusion criteria encompassed cirrhosis with Child-Pugh classification ≥B or stage 3b-5 chronic kidney disease. HLH was diagnosed according to HLH-2004 diagnostic criteria or HScore ≥169. Initially, three cases each of moderately active SLE (SLEDAI score ≥ 10), SLE-HLH, and healthy controls (HC) were included, and their PBMC were extracted for whole transcriptome sequencing. Following transcriptome analysis, mRNA, lncRNA and miRNA differential molecules were identified, and an interaction network was constructed. Relative mRNA and lncRNA expression levels of the differential molecules were assessed in PBMC of the SLE cohorts using Real-time PCR. SPSS 25.0 software was used to analyze the data, between-group comparisons were conducted using chi-square test, independent samples t-test, analysis of variance (ANOVA) or Mann-Whitney tests. P<0.05 was considered statistically significant. Subsequently, the diagnostic value of these differential molecules in predicting HLH was verified by stratifying SLE patients into groups with or without HLH. Results 1. Following whole transcriptome sequencing, the identified differential genes were: (1) mRNA: minichromosome maintenance complex 2 (MCM2), chromatin assembly factor 1 subunit B (CHAF1B), unc-51 like autophagy activating kinase 2 (ULK2), killer cell lectin like receptor subfamily C member 3 (KLRC3) and killer cell lectin-like receptor G1 (KLRG1)； (2) lncRNA: DCAF8-DT, arrestin beta2 (ARRB2), granulin precursor (GRN). (3) miRNA: hsa-miR-514a-3p, hsa- miR-582-5p, has-miR-181a-2-3p and has-miR-1291 2. In a cohort comprising 14 HC and 50 SLE patients, the latter further stratified into SLEHLH (14 patients) and SLE (36 patients) groups: (1) Relative expression levels of lncDCAF8-DT, ULK2, KLRC3, and KLRG1 significantly ABSTRACT V decreased in SLE-HLH group compared to HC and non-HLH groups. (2) KLRG1 exhibited the highest diagnostic efficacy for SLE-HLH (AUC: 0.927, 95%CI: 0.854-0.999), followed by KLRC3 (AUC: 0.885, 95%CI: 0.793-0.977) and ULK2 (AUC: 0.843, 95%CI: 0.714-0.972). Conclusion KLRG1, KLRC3, and ULK2 are potential biomarkers for predicting secondary HLH in SLE patients. Among them, KLRG1 has the highest sensitivity (0.889) and specificity (0.929) for predicting SLE induced HLH, which is considered the optimal biomarker for diagnosing secondary HLH in SLE.

缩略词 .......................... VIII
第一章 文献综述 ........... 1
第二章 引言 ................ 25
第三章 继发性噬血细胞综合征预后相关预测模型及其生物标记物的研究 ........ 27
第一部分 继发性噬血细胞综合征预后相关预测模型的研究 ........ 27
前言 ................. 27
材料与方法 ........... 29
结果 ..................... 33
一.继发性噬血细胞综合征的临床及原发疾病的分布特征 ................. 33
1. sHLH 患者的临床特征 ................. 33
2. sHLH 合并症的情况 ....................... 34
3. sHLH 治疗的选择 .............................. 34
4. 确诊 sHLH 的科室分布 ................... 35
5. sHLH 原发病的分布 ........................ 36
6. 不同原发疾病继发 HLH 的预后 ...... 36
二.不同原发病继发噬血细胞综合征的临床特征..... 37
1. 不同原发病组的 sHLH 患者临床特征比较 ......... 37
2. 不同原发病组的 sHLH 患者合并症特征分析 .... 38
3. 不同原发病组的 sHLH 患者实验室特征分析 .... 39
4. 不同原发病组的 sHLH 患者治疗选择分析 ........... 42
三．sHLH 的死亡相关危险因素分析 .......................... 43
1. sHLH 不同预后组患者的临床特征分析 ................ 43
2. sHLH 不同预后组患者的合并症特征分析 .......... 44
3. sHLH 不同预后组患者的实验室特征分析 .......... 45
4. sHLH 不同预后组患者治疗选择的比较 ............... 48
四. sHLH 预后相关预测模型的建立 .............................. 48
1. sHLH 死亡风险相关的多因素 Logistic 回归模型 ........ 48
2. sHLH 预后相关评分预测模型 .................................. 50
讨论 ............ 52
小结 ............ 56
第二部分 系统性红斑狼疮继发噬血细胞综合征中转录组标志物的筛选与验证 .. 57
前言 ....................... 57
材料和方法 ............. 59
结果 ................... 77
一. SLE 继发 HLH 患者 PBMC 转录组的差异基因分析 ................... 77
1. SLE 继发 HLH 患者 PBMC 转录组差异基因的分布 ..... 77
2. SLE 继发 HLH 患者 PBMC 转录组差异基因的功能分析 .... 78
3. SLE 继发 HLH 患者 PBMC 转录组差异基因的信号通路分析 ..... 82
4. SLE 继发 HLH 患者 PBMC 转录组差异分子的筛选 ........... 87
5. SLE 继发 HLH 患者 PBMC 的 lncRNA-miRNA-mRNA 互作基因网络构建 ... 89
二. SLE 继发 HLH 患者转录组中 mRNA 与 lncRNA 候选分子的验证........... 92
1. 研究对象 ............. 92
2. 两组 SLE 患者的一般临床资料比较 ......................... 92
3. 两组 SLE 患者的合并症比较 ..................................... 93
4. 两组 SLE 患者的常规实验室指标比较 ................... 93
5. 两组 SLE 患者的 HLH 相关指标比较 ................... 94
6. 两组 SLE 患者的病情活动相关指标比较 ............. 95
7. 两组 SLE 患者的 PBMC 中 mRNA 候选分子的表达量比较 ........... 96
8. 两组 SLE 患者的 PBMC 中 lncRNA 候选分子的表达量比较 ........... 97
9. SLE 患者的 PBMC 中 mRNA 候选分子在继发 HLH 中诊断价值的初探 ........ 97
10. 转录组 mRNA 候选分子与 SLE 临床指标的相关性分析 .............. 99
11. 转录组 mRNA 候选分子与 SLE 实验室指标的相关性分析 ........ 100
讨论 ............................ 101
小结 ........................... 104
结论与展望 ................................... 105
参考文献 .................. 106
致谢 ............................ 120
北京大学学位论文原创性声明和使用授权说明 .......... 122
个人简历、在学期间发表的学术论文与研究成果 ..... 123

[1] Al-Samkari H, Berliner N. Hemophagocytic Lymphohistiocytosis. Annu Rev Pathol, 2018, 13: 27-4

9.

[2] Risma KA, Marsh RA. Hemophagocytic Lymphohistiocytosis: Clinical Presentations and Diagnosis.

J Allergy Clin Immunol Pract, 2019, 7(3):824-832.

[3] Ponnatt TS, Lilley CM, Mirza KM. Hemophagocytic Lymphohistiocytosis. Arch Pathol Lab Med, 20

22, 146(4):507-519.

[4] Anna Hayden, Sujin Park, Dean Giustini, et al. Hemophagocytic syndromes (HPSs) including

hemophagocytic lymphohistiocytosis (HLH) in adults: A systematic scoping review. Blood Rev, 201

6, 30(6): 411-420.

[5] Scott RB, Robb-Smith AHT. Histiocytic medullary reticulosis. Lancet,1939, 2: 194-198.

[6] Farquhar JW, Claireaux AE. Familial haemophagocytic reticulosis. Arch Dis Child, 1952, 27: 519-5

25.

[7] Henter JI, Elinder G, Ost A, and the The FHL Study Group of the Histiocyte Society. Diagnostic gui

delines for hemophagocytic lymphohistiocytosis. Semin Oncol, 1991, 18: 29-33.

[8] Ramos-Casals M, Brito-Zeron P, Lopez-Guillermo A, et al. Adult haemophagocytic syndrome. Lan

cet, 2014, 383:1503-1516.

[9] Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and immune

suppression. Lancet, 2020, 395(10229):1033-1034.

[10] 中国噬血细胞综合征诊断与治疗指南(2022 年版). 中华医学杂志, 2022, 102(20): 1492-1499.

[11] Hadchouel M, Prieur A M, Griscelli C. Acute hemorrhagic, hepatic, and neurologic manifestations in

juvenile rheumatoid arthritis: possible relationship to drugs or infection. J Pediatr, 1985, 106(4):56 1-

566.

[12] Parikh SA, Kapoor P, Letendre L, et al. Prognostic factors and outcomes of adults with hemo

phagocytic lymphohistiocytosis. Mayo Clin Proc, 2014, 89:484-492.

[13] 裴瑞君, 王昭, 王旖旎, 等. 全国多中心噬血细胞性淋巴组织细胞增多症 601 例病因分析. 中华医

学杂志, 2015, 54(12): 1018-1022.

[14] Yuanyuan Pei, Jihong Zhu, Ranran Yao, et al. Prognostic factors in patients with secondary

hemophagocytic lymphohistiocytosis in a Chinese cohort. Ann Hematol, 2024, 103(3):695-703.

[15] Ellen Brisse, Carine H Wouters, Patrick Matthys. Hemophagocytic lymphohistiocytosis (HLH): A

heterogeneous spectrum of cytokine-driven immune disorders. Cytokine Growth Factor Rev, 2015,

26(3):263-280.

[16] Bseiso O, Zahdeh A, Isayed O, et al. The role of immune mechanisms, inflammatory pathways, and

macrophage activation syndrome in the pathogenesis of hemophagocytic lymphohistiocytosis. Cure

us, 2022, 14(12): e33175.

[17] Ishii E. Hemophagocytic Lymphohistiocytosis in Children: Pathogenesis and Treatment. Front Pedi atr, 2016, 4:47.

[18] Steen EA, Nichols KE, Meyer LK. Insights into the cellular pathophysiology of familial hemophago

cytic lymphohistiocytosis. Front Immunol, 2023, 14:1147603.

[19] Griffin G, Shenoi S, Hughes GC. Hemophagocytic lymphohistiocytosis: An update on pathogenesis,

diagnosis, and therapy. Best Pract Res Clin Rheumatol, 2020, 34(4):101515.

[20] Ammann S, Lehmberg K, Zur Stadt U, et al. Primary and secondary hemophagocytic lymphohistio

cytosis have different patterns of T-cell activation, differentiation and repertoire. Eur J Immuno, 2017,

47:364-373.

[21] Jordan MB, Hildeman D, Kappler J, et al. An animal model of hemophagocytic lymphohistiocytosis

(HLH): CD8+ T cells and interferon gamma are essential for the disorder. Blood, 2004, 104(3): 735 -

743.

[22] An D Billiau, Tania Roskams, Rita Van Damme-Lombaerts, et al. Macrophage activation syndrome:

characteristic findings on liver biopsy illustrating the key role of activated, IFN-gamma-producing

lymphocytes and IL-6- and TNF-alpha-producing macrophages. Blood, 2005, 105(4):1648-1651.

[23] Behrens EM, Canna SW, Slade K, et al. Repeated TLR9 stimulation results in macrophage ac

tivation syndrome-like disease in mice. J Clin Invest, 2011, 121(6):2264-2277.

[24] Ohyagi H, Onai N, Sato T, et al. Monocyte-derived dendritic cells perform hemophagocytosis to

fine-tune excessive immune responses. Immunity, 2013, 39(3):584-598.

[25] Cron RQ, Goyal G, Chatham WW. Cytokine Storm Syndrome. Annu Rev Med, 2023, 74: 32 1-337.

[26] Fajgenbaum DC, June CH. Cytokine Storm. N Engl J Med, 2020, 383(23):2255-2273.

[27] Ravelli A, Minoia F, Davì S, et al. 2016 Classification Criteria for Macrophage Activation Sy ndrome

Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism/ Amer

ican College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collabor

ative Initiative. Arthritis Rheumatol, 2016, 68(3):566-576.

[28] Komp DM, McNamara J, Buckley P. Elevated soluble interleukin-2 receptor in childhood he

mophagocytic histiocytic syndromes. Blood, 1989, 73:2128-2132.

[29] Komp DM, Buckley PJ, McNamara J, et al. Soluble interleukin-2 receptor in hemophagocytic

histiocytoses: searching for markers of disease activity. Pediatr Hematol Oncol, 1989, 6:253-264.

[30] Takada H, Nomura A, Ohga S, et al. Interleukin-18 in hemophagocytic lymphohistiocytosis. Leuk Ly

mphoma, 2001, 42:21-28.

[31] Fujiwara F, Hibi S, Imashuku S. Hypercytokinemia in hemophagocytic syndrome. Am J Pediatr Hem

atol Oncol, 1993, 15:92-98.

[32] Debaugnies F, Mahadeb B, Nagant C, et al. Biomarkers for early diagnosis of hemophagocytic

lymphohistiocytosis in critically ill patients. J Clin Immunol, 2021, 41(3):658-665.

[33] Zhang HQ, Yang SW, Fu YC, et al. Cytokine storm and targeted therapy in hemophagocytic

lymphohistiocytosis. Immunol Res, 2022, 70(5):566-577.

[34] Ou W, Zhao Y, Wei A, et al. Serum cytokine pattern in children with hemophagocytic lympho

histiocytosis. Ann Hematol, 2023, 102(4):729-739.

[35] Osugi Y, Hara J, Tagawa S, et al. Cytokine production regulating Th1 and Th2 cytokines in he mophagocytic lymphohistiocytosis. Blood, 1997, 89:4100-4103.

[36] Cannella S, Santoro A, Bruno G, et al. Germline mutations of the perforin gene are a frequent

occurrence in childhood anaplastic large cell lymphoma. Cancer, 2007, 109:2566-2571.

[37] Setiadi A, Zoref-Lorenz A, Lee CY, et al. Malignancy associated haemophagocytic lymphohi

stiocytosis. Lancet Haematol, 2022, 9(3): e217-e227.

[38] Smith MC, Cohen DN, Greig B, et al. The ambiguous boundary between EBV-related hemop

hagocytic lymphohistiocytosis and systemic EBV-drivenTcell lymphoproliferative disorder. Int J Clin

Exp Pathol, 2014, 7:5738-5749.

[39] Imashuku S, Morimoto A, Ishii E. Virus-triggered secondary hemophagocytic lymphohistioc ytosis.

Acta Paediatr, 2021, 110(10):2729-2736.

[40] Henter JI, Horne A, Arico M, et al. HLH-2004: diagnostic and therapeutic guidelines for hem

ophagocytic lymphohistiocytosis. Pediatr Blood Cancer, 2007, 48:124-131.

[41] Fardet L, Galicier L, Lambotte O, et al. Development and validation of the HScore, a score for the

diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol, 2014, 66:2613-2620.

[42] Henter J I, Elinder G, Ost A. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The

FHL Study Group of the Histiocyte Society. Semin Oncol, 1991,18(1):29-33.

[43] Henter J I, Elinder G, Soder O, et al. Incidence in Sweden and clinical features of familial hemop

hagocytic lymphohistiocytosis. Acta Paediatr Scand, 1991,80(4):428-435.

[44] Yenan T Bryceson, Daniela Pende, Andrea Maul-Pavicic, et al. A prospective evaluation of

degranulation assays in the rapid diagnosis of familial hemophagocytic syndromes. Blood, 2012,

119(12):2754-2763.

[45] Shakoory B, Geerlinks A, Wilejto M, et al. The 2022 EULAR/ACR points to consider at the early

stages of diagnosis and management of suspected haemophagocytic lymphohistiocyt osis/

macrophage activation syndrome (HLH/MAS). Ann Rheum Dis, 2023, 82(10):1271-1285.

[46] Debaugnies F, Mahadeb B, Ferster A, et al. Performances of the H-score for diagnosis of hem

ophagocytic lymphohistiocytosis in adult and pediatric patients. Am J Clin Pathol, 2016, 14 5:862-

870.

[47] Sandrine Valade, Grégoire Monseau , Eric Mariotte, et al. Diagnostic performance of hemop

hagocytic lymphohistiocytosis criteria and HScore in critically ill patients with severe hemop

hagocytic syndrome. Crit Care Med, 2021, 49(9): e874-e879.

[48] Knaak C, Nyvlt P, Schuster FS, et al. Hemophagocytic lymphohistiocytosis in critically ill patients:

diagnostic reliability of HLH-2004 criteria and HScore. Crit Care, 2020, 24(1):244.

[49] Lisa Bilston, Jennifer Croden, Minakshi Taparia, et al. Validation of the HScore and the HLH-2004

diagnostic criteria for the diagnosis of hemophagocytic lymphohistiocytosis in a mul ticenter cohort.

Eur J Haematol, 2022, 109(2):129-137.

[50] Batu ED, Erden A, Seyhoglu E, et al. Assessment of the HScore for reactive haemophagocytic

syndrome in patients with rheumatic diseases. Scand J Rheumatol, 2017, 46:44-48.

[51] Ravelli A, Magni-Manzoni S, Pistorio A, et al. Preliminary diagnostic guidelines for macrophage

activation syndrome complicating systemic juvenile idiopathic arthritis. J Pediatr, 2005,146(5):59 8-604.

[52] Ahn S S, Yoo B W, Jung S M, et al. In-hospital mortality in febrile lupus patients based on 2016

EULAR/ACR/PRINTO classification criteria for macrophage activation syndrome. Semin Arthritis

Rheum, 2017,47(2):216-221.

[53] Tada Y, Inokuchi S, Maruyama A, et al. Are the 2016 EULAR/ACR/PRINTO classification criteria

for macrophage activation syndrome applicable to patients with adult-onset Still’s disease? Rh

eumatology International, 2019,39(1):97-104.

[54] Minoia F，Bovis F，Davl S，et a1．Development and initial validation of the MS score for

diagnosis of macrophage activation syndrome in systemic juvenile idiopathic arthritis．Ann Rheum

Dis, 2019, 78(10): 1357-1362．

[55] Henter JI, Samuelsson-Horne A, Arico M, et al. Treatment of hemophagocytic lymphohistiocytosis

with HLH-94 immunochemotherapy and bone marrow transplantation. Blood, 2002, 100: 2367-2373.

[56] Trottestam H, Horne A, Arico M, et al. Chemoimmunotherapy for hemophagocytic lymphoh

istiocytosis: long-term results of the HLH-94 treatment protocol. Blood, 2011, 118:4577-45 84.

[57] Bailly C. Etoposide: A rider on the cytokine storm. Cytokine, 2023, 168:156234.

[58] Ambruso DR, Hays T, Zwartjes WJ, et al. Successful treatment of lymphohistiocytic reticulosis with

phagocytosis with epipodophyllotoxin VP 16-213. Cancer, 1980, 45:2516-2520.

[59] Böhm S, Wustrau K, Pachlopnik Schmid J, et al. Survival in primary hemophagocytic lymph

ohistiocytosis, 2016 to 2021: etoposide is better than its reputation. Blood, 2024, 143(10): 872-881.

[60] Arca M, Fardet L, Galicier L, et al. Prognostic factors of early death in a cohort of 162 adult haem

ophagocytic syndrome: impact of triggering disease and early treatment with etoposide. Br J Hae

matol, 2015, 168(1):63-68.

[61] Imashuku S, Kuriyama K, Teramura T, et al. Requirement for etoposide in the treatment of Epste inBarr

virus-associated hemophagocytic lymphohistiocytosis. J Clin Oncol, 2001,19(10):2665-26 73.

[62] Imashuku S, Teramura T, Tauchi H, et al. Longitudinal follow-up of patients with Epstein-Barrvi rusassociated

hemophagocytic lymphohistiocytosis. Haematologica, 2004, 89(2):183-188.

[63] Song Y, Wang Y, Wang Z. Requirement for etoposide in the initial treatment of Epstein-Barrv irusassociated

haemophagocytic lymphohistiocytosis. Br J Haematol, 2019, 186(5):717-723.

[64] Kikuta H, Sakiyama Y. Etoposide (VP-16) inhibits Epstein-Barr virus determined nuclear antigen

(EBNA) synthesis. Br J Haematol, 1995, 90(4):971-973.

[65] M. Meazza Prina, F. Martini, F. Bracchi, et al. Hemophagocytic syndrome secondary to SARS-Co v2

infection: a case report, BMC Infect Dis, 2021, 21: 811.

[66] M. Patel, E. Dominguez, D. Sacher, et al. Temple university COVID-19 research group. Etoposide as

salvage therapy for Cytokine Storm Due to Coronavirus Disease 2019. Chest, 2021, 159(1): e7-e11.

[67] Y. Miao, L. Fan, J.Y. Li. Potential treatments for COVID-19 related cytokine storm- beyond corticost

eroids. Front Immunol, 2020, 11:1445

[68] Song Y, Wang J, Wang Y, et al. Requirement for containing etoposide in the initial treatment of

lymphoma associated hemophagocytic lymphohistiocytosis. Cancer Biol Ther, 2021, 22(10-12):59 8-

606.

[69] Wang YH, Ba JH, Shi XW, et al. Successful treatment of mycobacterial infection associated hemo

phagocytic lymphohistiocytosis with etoposide and anti-tuberculous therapy: a case report. BMC

Infect Dis, 2020, 20(1): 321.

[70] Machelart I, Lapoirie J, Viallard JF, et al. Visceral leishmaniasis with hemophagocytic lymphohist

iocytosis in an immunocompetent adult. Med Mal Infect, 2019, 49(7):548-550.

[71] Sourya Acharya, Samarth Shukla, Tushar Sontakke et al. A case report of hemophagocytic lympho

histiocytosis (HLH) - An unusual complication of dengue infection. Cureus, 2022, 14 (7): e26504.

[72] Wang R, Li T, Ye S, et al. Short-term, low-dose etoposide in refractory adult-onset Still's dis easeassociated

macrophage activation syndrome. Clin Rheumatol, 2022, 41(9):2817-2823.

[73] Palmblad K, Schierbeck H, Sundberg E, et al. Therapeutic administration of etoposide coinci des

with reduced systemic HMGB1 levels in macrophage activation syndrome. Mol Med, 2021, 27

(1):48.

[74] Gavand PE, Serio I, Arnaud L, et al. Clinical spectrum and therapeutic management of syste mic

lupus erythematosus-associated macrophage activation syndrome: A study of 103 episod es in 89

adult patients. Autoimmun Rev, 2017, 16(7):743-749.

[75] Lingbo He, Shuyan Yao , Ruoxi Zhang, et al. Macrophage activation syndrome in adults: Cha

racteristics, outcomes, and therapeutic effectiveness of etoposide-based regimen. Front Immunol, 20

22, 13:955523.

[76] Naymagon L, Tremblay D, Mascarenhas J. The efficacy of etoposide-based therapy in adult second

dary hemophagocytic lymphohistiocytosis. Acta Haematol, 2021, 144(5):560-568.

[77] Thompson P A, Allen C E, Horton T, et al. Severe neurologic side effects in patients being treated for

hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer, 2009,52(5):621-625.

[78] 姚海红, 王旖旎, 张霞,等. 67 例成人巨噬细胞活化综合征的临床特征及治疗转归.北京大学学报

医学版, 2019, 06:996-1002.

[79] Keenan C, Nichols KE, Albeituni S. Use of the JAK inhibitor Ruxolitinib in the treatment of

hemophagocytic lymphohistiocytosis. Front Immunol, 2021, 12:614704.

[80] Wei A, Ma H, Li Z, et al. Short-term effectiveness of ruxolitinib in the treatment of recurrent or

refractory hemophagocytic lymphohistiocytosis in children. Int J Hematol, 2020, 112(4):568-576.

[81] O’Shea JJ, Schwartz DM, Villarino AV, et al. The JAK-STAT pathway: impact on human disease and

therapeutic intervention. Annu Rev Med, 2015, 66:311-328.

[82] Gadina M, Le MT, Schwartz DM, et al. Janus kinases to jakinibs: from basic insights to clinical

practice. Rheumatology (Oxford), 2019, 58(Suppl. 1): i4-i16.

[83] Joly JA, Vallée A, Bourdin B, et al. Combined IFN-γ and JAK inhibition to treat hemophagocytic

lymphohistiocytosis in mice. J Allergy Clin Immunol, 2023, 151(1):247-259.e7.

[84] Wang H, Gu J, Liang X, et al. Low dose ruxolitinib plus HLH-94 protocol: A potential choice for

secondary HLH. Semin Hematol, 2020, 57(1):26-30.

[85] Wang J, Wang Y, Wu L, et al. Ruxolitinib for refractory/relapsed hemophagocytic lymphohis

tiocytosis. Haematologica, 2020, 105(5): e210-e212.

[86] Schäfer EJ, Jung W, Korsten P. Combination Immunosuppressive Therapy Including Rituximab for Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis in Adult-Onset Still's Disease.

Case Rep Rheumatol, 2016, 2016:8605274.

[87] Louise Gillard, Jacques Pouchot, Fleur Cohen-Aubart, et al. JAK inhibitors in difficult-to-treat adultonset

Still's disease and systemic-onset juvenile idiopathic arthritis. Rheumatology (Oxford), 2023,

62(4):1594-1604.

[88] Jessica Slostad, Patrick Hoversten, Candace L Haddox, et al. Ruxolitinib as first-line treatment in

secondary hemophagocytic lymphohistiocytosis: A single patient experience. Am J Hematol, 2018,

93(2): E47-E49.

[89] Inuk Zandvakili, Caitlin B Conboy, Ayed O Ayed, et al. Ruxolitinib as first-line treatment in second

ary hemophagocytic lymphohistiocytosis: A second experience. Am J Hematol, 2018, 93(5): E123-E

125.

[90] Ahmed A, Merrill SA, Alsawah F, et al. Ruxolitinib in adult patients with secondary haemop

hagocytic lymphohistiocytosis: an open-label, single-centre, pilot trial. Lancet Haematol, (2019) 6:

e630-e637.

[91] 徐晓军,汤永民.以细胞因子谱指导噬血细胞综合征的精准诊治.中华医学杂志, 2022, 1 2 (28):

2142-2147.

[92] 王晶石, 王昭.开启噬血细胞综合征精准诊断新时代. 中华医学杂志, 2022, 102(28): 2137-2142.

[93] Grom AA, Horne A, De Benedetti F. Macrophage activation syndrome in the era of biologic therapy.

Nat Rev Rheumatol, 2016, 12(5):259-268.

[94] Schulert GS, Grom AA. Pathogenesis of macrophage activation syndrome and potential for cytoki

ne-directed therapies. Annu Rev Med, 2015, 66:145-159.

[95] Zhang HQ, Yang SW, Fu YC, et al. Cytokine storm and targeted therapy in hemophagocytic

lymphohistiocytosis. Immunol Res, 2022, 70(5):566-577.

[96] He L, Yang C, Wang Y. Biological therapies for hemophagocytic lymphohistiocytosis: current

knowledge and future perspectives. Expert Opin Biol Ther, 2023, 23(10):1005-1013.

[97] Schroder K, Hertzog P J, Ravasi T, et al. Interferon-gamma: an overview of signals, mechanisms and

functions. J Leukoc Biol, 2004, 75(2):163-189.

[98] Mosser DM. The many faces of macrophage activation. J Leukocyte Biol, 2003, 73:209-212.

[99] Mantovani A, Sica A, Sozzani S, et al. The chemokine system in diverse forms of macrophage

activation and polarization. Trends Immunol, 2004, 25:677-686.

[100] Josée-Anne Joly, Alexis Vallée, Benoîte Bourdin, et al. Combined IFN-γ and JAK inhibition to treat

hemophagocytic lymphohistiocytosis in mice. J Allergy Clin Immunol, 2023, 151(1): 247-259.e7.

[101] Gao DK, Salomonis N, Henderlight M, et al. IFN-gamma is essential for alveolar macrophage-d

riven pulmonary inflammation in macrophage activation syndrome. JCI Insight, 2021, 6(17): e1475

93.

[102] Prencipe G, Caiello I, Pascarella A, et al. Neutralization of IFN-γ reverts clinical and laboratory

features in a mouse model of macrophage activation syndrome. J Allergy Clin Immunol, 2018,

141:1439-1449.

[103] Al-Salama ZT. Emapalumab: First Global Approval. Drugs, 2019, 79(1):99-103.

[104] Locatelli F, Jordan MB, Allen C, et al. Emapalumab in children with primary hemophagocytic

lymphohistiocytosis. N Engl J Med, 2020, 382:1811-1822.

[105] Jacqmin P, Laveille C, Snoeck E, et al. Emapalumab in primary haemophagocytic lymphohistio

cytosis and the pathogenic role of interferon gamma: a pharmacometrics model-based ap proach. Br J

Clin Pharmacol, 2022, 88:2128-2139.

[106] Vallurupalli M, Berliner N. Emapalumab for the treatment of relapsed/refractory hemophagocytic

lymphohistiocytosis. Blood, 2019,134(21):1783-1786.

[107] De Benedetti F, Grom AA, Brogan PA, et al. Efficacy and safety of emapalumab in macrophage

activation syndrome. Ann Rheum Dis, 2023, 82(6):857-865.

[108] Dinarello CA. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood, 201

1, 117(14):3720-3732.

[109] Dinarello CA. IL-1: discoveries, controversies and future directions. Eur J Immunol, 2010, 40

(3):599-606.

[110] Bami S, Vagrecha A, Soberman D, et al. The use of anakinra in the treatment of secondary hemo

phagocytic lymphohistiocytosis. Pediatr Blood Cancer, 2020, 67(11): e28581.

[111] Patoulias D. Anakinra for macrophage activation syndrome. Eur J Intern Med, 2023, 111:133-13 4.

[112] Mehta P, Cron RQ, Hartwell J, et al. Silencing the cytokine storm: the use of intravenous anakinra

in haemophagocytic lymphohistiocytosis or macrophage activation syndrome. Lancet Rheumatol,

2020, 2(6): e358-e367.

[113] Sonmez HE, Demir S, Bilginer Y, et al. Anakinra treatment in macrophage activation syndrome: a

single center experience and systemic review of literature. Clin Rheumatol, 2018, 37(12):3329-3335.

[114] Leonard Naymagon. Anakinra for the treatment of adult secondary HLH: a retrospective experience.

Int J Hematol, 2022, 116(6):947-955.

[115] Nigrovic PA, Mannion M, Prince FH, et al. Anakinra as first-line disease-modifying therapy in

systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter

series. Arthritis Rheum, 2011, 63(2):545-555.

[116] Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and

immunosuppression. Lancet, 2020, 395: 1033-1034.

[117] Hardman SJ, Tukur G, Waruiru C. Enterovirus-Associated HLH: Addition of Anakinra to IVIG and

Corticosteroids. J Clin Immunol, 2019, 39(4):373-375.

[118] Philipp Wohlfarth, Hermine Agis, Guido A Gualdoni, et al. Interleukin 1 receptor antagonist

anakinra, intravenous immunoglobulin, and corticosteroids in the management of critically Ill adult

patients with hemophagocytic lymphohistiocytosis. J Intensive Care Med, 2019, 34(9): 723-731.

[119] Galea J, Ogungbenro K, Hulme S, et al. Intravenous anakinra can achieve experimentally effective

concentrations in the central nervous system within a therapeutic time window: results of a dose-ran

ging study. J Cereb Blood Flow Metab, 2011, 31: 439-447.

[120] Gueorguieva I, Clark SR, McMahon CJ, et al. Pharmacokinetic modelling of interleukin-1 receptor

antagonist in plasma and cerebrospinal fluid of patients following subarachnoid haemorrhage. Br J

Clin Pharmacol, 2008, 65: 317-325.

[121] Nicolino Ruperto, Hermine I Brunner, Pierre Quartier, et al. Two randomized trials of canakinumab

in systemic juvenile idiopathic arthritis. N Engl J Med, 2012, 367(25): 2396-2406.

[122] Lovell D J, Giannini E H, Reiff A O, et al. Long-term safety and efficacy of rilonacept in patients

with systemic juvenile idiopathic arthritis. Arthritis Rheum, 2013,65(9):2486-2496.

[123] Ilowite NT, Prather K, Lokhnygina Y, et al. Randomized, double-blind, placebo-controlled trial of

the efficacy and safety of rilonacept in the treatment of systemic juvenile idiopathic arthritis. Arthritis

Rheumatol, 2014,66(9):2570-2579.

[124] Strippoli R, Carvello F, Scianaro R, et al. Amplification of the response to Toll-like receptor ligands

by prolonged exposure to interleukin-6 in mice: implication for the pathogenesis of macrophage

activation syndrome. Arthritis Rheum, 2012,64(5):1680-1688.

[125] Le RQ, Li L, Yuan W, et al. FDA approval summary: tocilizumab for treatment of chimeric antigen

receptor T cell–induced severe or life-threatening cytokine release syndrome. Oncologist, 2018,

23:943-947.

[126] Shankar-Hari M, Vale CL, Godolphin PJ, et al. Association between administration of IL-6

antagonists and mortality among patients hospitalized for COVID-19: a meta-analysis. JAMA, 2021,

326:499-518.

[127] Leaf DE, Gupta S, Wang W. Tocilizumab in Covid-19. N Engl J Med, 2021, 384(1):86-87.

[128] Ju Yeon Kim, Miso Kim, Jin Kyun Park, et al. Limited efficacy of tocilizumab in adult patients with

secondary hemophagocytic lymphohistiocytosis: a retrospective cohort study. Orphanet J Rare Dis,

2022, 17(1):363.

[129] Etienne Dufranc, Arnaud Del Bello, Julie Belliere, et al. IL6-R blocking with tocilizumab in

critically ill patients with hemophagocytic syndrome. Crit Care, 2020, 24(1):166.

[130] Tsuchida Y, Sumitomo S, Shoda H, et al. Macrophage activation syndrome associated with

tocilizumab treatment in adult-onset Still's disease. Mod Rheumatol, 2017,27(3):556-557.

[131] Horiuchi T, Mitoma H, Harashima S, et al. Transmembrane TNF-alpha: structure, function and

interaction with anti-TNF agents. Rheumatology (Oxford), 2010, 49(7):1215-1228.

[132] Atiqi S, Hooijberg F, Loeff FC, et al. Immunogenicity of TNF-Inhibitors. Front Immunol, 2020,

11:312.

[133] He B, Li Y, Luo WW, et al. The risk of adverse effects of TNF-alpha inhibitors in patients with

rheumatoid arthritis:a network meta-analysis. Front Immunol, 2022, 13:814429.

[134] Makay B, Yilmaz S, Turkyilmaz Z, et al. Etanercept for therapy-resistant macrophage activation

syndrome. Pediatr Blood Cancer, 2008, 50(2):419-421.

[135] Sterba G, Sterba Y, Stempel C, et al. Macrophage activation syndrome induced by etanercept in a

patient with systemic sclerosis. Isr Med Assoc J, 2010,12(7):443-445.

[136] Puren A J, Fantuzzi G, Dinarello C A. Gene expression, synthesis, and secretion of interleukin 18

and interleukin 1beta are differentially regulated in human blood mononuclear cells and mouse

spleen cells. Proc Natl Acad Sci U S A, 1999, 96(5):2256-2261.

[137] H Takada, S Ohga, Y Mizuno, et al. Oversecretion of IL-18 in haemophagocytic lymphohist

iocytosis: a novel marker of disease activity. British Journal of Haematology, 1999, 106(1): 182-189.

[138] Miyazawa H, Wada T. Immune-mediated inflammatory diseases with chronic excess of serum

interleukin-18. Front Immunol, 2022, 13:930141.

[139] Baggio C, Bindoli S, Guidea I, et al. IL-18 in Autoinflammatory Diseases: Focus on Adult Onset

Still Disease and Macrophages Activation Syndrome. Int J Mol Sci, 2023, 24(13):111 25.

[140] Laura Chiossone, Sandra Audonnet, Bruno Chetaille, et al. Protection from inflammatory organ

damage in a murine model of hemophagocytic lymphohistiocytosis using treatment with IL-18 bindi

ng protein. Front Immunol, 2012, 3:239.

[141] Canna SW, Girard C, Malle L, et al. Life-threatening NLRC4-associated hyperinflammation

successfully treated with IL-18 inhibition. J Allergy Clin Immunol, 2017, 139(5):1698-1701.

[142] Gabay C, Fautrel B, Rech J, et al. Open-label, multicentre, dose-escalating phase II clinical trial on

the safety and efficacy of tadekinig alfa (IL-18BP) in adult-onset Still's disease. Ann Rheum Dis,

2018, 77(6):840-847.

[143] Balamuth N J, Nichols K E, Paessler M, et al. Use of rituximab in conjunction with immunos

uppressive chemotherapy as a novel therapy for Epstein Barr virus-associated hemophagocytic lymp

hohistiocytosis. J Pediatr Hematol Oncol, 2007, 29(8):569-573.

[144] Kaegi C, Wuest B, Schreiner J, et al. Systematic Review of Safety and Efficacy of Rituximab in

Treating Immune-Mediated Disorders. Front Immunol, 2019, 10:1990.

[145] Chellapandian D, Das R, Zelley K, et al. Treatment of Epstein Barr virus-induced haemophagocytic

lymphohistiocytosis with rituximab-containing chemo-immunotherapeutic regimens. Br J Haematol,

2013,162(3):376-382.

[146] Ikić Matijašević M, Kilić P, Ikić L, et al. Rituximab, intravitreal Bevacizumab and Laser Photocoag

ulation for treatment of macrophage activation syndrome and retinal vasculitis in lupus: a case report.

Int J Mol Sci, 2023, 24(3):2594.

[147] Paik J. Nivolumab Plus Relatlimab: First Approval. Drugs, 2022, 82(8):925-931.

[148] Rajapakse P, Andanamala H. Hemophagocytic lymphohistiocytosis secondary to immune checkp

oint inhibitor therapy. World J Oncol, 2022, 13(2):49-52.

[149] Liu P, Pan X, Chen C, et al. Nivolumab treatment of relapsed/refractory Epstein-Barr virus-associ

ated hemophagocytic lymphohistiocytosis in adults. Blood, 2020, 135(11):826-833.

[150] Olin R L, Nichols K E, Naghashpour M, et al. Successful use of the anti-CD25 antibody daclizumab

in an adult patient with hemophagocytic lymphohistiocytosis. Am J Hematol, 2008, 8 3(9):747-749.

[151] Machaczka M, Vaktnas J, Chiang S C, et al. Alemtuzumab treatment for hemophagocytic lymph

ohistiocytosis. Nat Rev Clin Oncol, 2010,7(10).

[152] Marsh R A, Allen C E, McClain K L, et al. Salvage therapy of refractory hemophagocytic lymphoh

istiocytosis with alemtuzumab. Pediatr Blood Cancer, 2013,60(1):101-109.

[153] Keith M P, Pitchford C, Bernstein W B. Treatment of hemophagocytic lymphohistiocytosis with

alemtuzumab in systemic lupus erythematosus. J Clin Rheumatol, 2012,18(3):134-137.

[154] Kinjo N, Hamada K, Hirayama C, et al. Role of plasma exchange, leukocytapheresis, and plasma

diafiltration in management of refractory macrophage activation syndrome. J Clin Apher, 2018, 33

(1):117-120.

[155] Yuan YH, Zhang H, Xiao ZH, et al. Efficacy of plasma exchange in children with severe hemop

hagocytic syndrome: a prospective randomized controlled trial. Zhongguo Dang Dai Er Ke Za Zhi,

2022, 24:249-254.

[156] Jesudas R, Nichols KE. Recent advances in the treatment of hemophagocytic lymphohistiocytosis

and macrophage activation syndrome. Curr Opin Allergy Clin Immunol, 2022, 22(6):364-370.

[157] Rademacher JG, Wulf G, Koziolek MJ, et al. Cytokine adsorption therapy in lymphoma-associated

hemophagocytic lymphohistiocytosis and allogeneic stem cell transplantation. J Artif Organs, 2021,

24:402-406.

[158] Bottari G, Murciano M, Merli P, et al. Hemoperfusion with CytoSorb to manage multiorgan dysfunc

tion in the spectrum of hemophagocytic lymphohistiocytosis syndrome in critically ill children. Bloo

d Purif, 2022, 51:417-424.

[159] Tristano A G, Casanova-Escalona L, Torres A, et al. Macrophage activation syndrome in a patient

with systemic onset rheumatoid arthritis: rescue with intravenous immunoglobulin therapy. J Clin

Rheumatol, 2003,9(4):253-258.

[160] Carter SJ, Tattersall RS, Ramanan AV. Macrophage activeation syndrome in adults: recent advan

ces in pathophysiology, diagnosis and treatment. Rheumatology (Oxford), 2019, 58 (1):5-17.

[161] Riviere S, Galicier L, Coppo P et al. Reactive hemophagocytic syndrome in adults: a retrospective

analysis of 162 patients. Am J Med, 2014, 127:1118-1125.

[162] Tingting Cui, Jingshi Wang, Zhao Wang. The outcome of induction therapy for EBV-related

hemophagocytic Llymphohistiocytosis: a model for risk stratification. Front Immunol, 2022, 13:8764

15.

[163] Nader Kim El-Mallawany, Choladda V Curry, Carl E Allen. Haemophagocytic lymphohistiocytosis

and Epstein-Barr virus: a complex relationship with diverse origins, expression and outcomes. Br J

Haematol, 2022, 196(1):31-44.

[164] 曾祥宗, 魏娜, 王旖旎, 等. 61 例 EBV 相关噬血细胞性淋巴组织细胞增多症患者的疗效及预后

分析. 中华血液学杂志, 2015, 36(6): 507-510.

[165] 尤亚红, 王晶石, 王昭. 非 EB 病毒病原体所致感染相关噬血细胞综合征的临床特征及预后. 中

华血液学杂志, 2022, 43(2): 128-133.

[166] Lin TF, Ferlic-Stark LL, Allen CE, et al. Rate of decline of ferritin in patients with hemophagocytic

lymphohistiocytosis as a prognostic variable for mortality. Pediatr Blood Cancer, 2011, 56:154-155.

[167] Otrock ZK, Eby CS. Clinical characteristics, prognostic factors, and outcomes of adult patients with

hemophagocytic lymphohistiocytosis. Am J Hematol, 2015, 90(3):220-224.

[168] 黄文秋, 王旖旎, 王晶石, 等. 192 例成人噬血细胞淋巴组织细胞增生症患者的临床分析. 中华血

液学杂志, 2014, 35(9): 796-801.

[169] Dongguang Wang, Xiang Tong, Sitong Liu, et al. Clinical characteristics and risk factors for 90-day

overall survival among 204 adult patients with secondary hemophagocytic lymphohistiocytosis:

Experience from a single-center retrospecti ve study. Front Med (Lausanne), 2022, 9:774959.

[170] Yanchun Zhao, Danlei Lu, Shanshan Ma, et al. Risk factors of early death in adult patients with

secondary hemophagocytic lymphohistiocytosis: a single-institution study of 171 Chinese patients.

Hematology, 2019, 24(1):606-612.

[171] Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO

clinical practice guideline for acute kidney injury. Kidney Int Suppl, 2012, 2:1-138.

[172] 急性胰腺炎急诊诊断及治疗专家共识. 中华急救医学杂志, 2021, 30(2):161-172.

[173] Glassford NJ, Schneider AG, Xu S, Eastwood GM, Young H, Peck L, et al. The nature and

discriminatory value of urinary neutrophil gelatinase associated lipocalin in critically ill patients at

risk of acute kidney injury. Intensive Care Med, 2013, 39 (10):1714-1724.

[174] 李硕, 王晶石, 王旖旎, 等．147 例噬血细胞综合征病因及预后分析．临床血液学杂志, 2014,

27(7): 559-563．

[175] Bergsten E, Horne A, Arico M, et al. Confirmed Efficacy of Etoposide and Dexamethasone in HLH

Treatment:Long-Term Results of the Cooperative HLH-2004 Study. Blood, 2017, 130(25):2728-27

38.

[176] Ai-Chun Liu, Yue Yang, Meng-Tao Li, et al. Macrophage activation syndrome in systemic lupus

erythematosus: a multicenter, case-control study in China. Clin Rheumatol, 2018, 37(1):93-100.

[177] 贾园, 栗占国. 成人巨噬细胞活化综合征诊断困境和个体化治疗. 北京大学学报(医学版), 2020,

52(6):991-994.

[178] Yokota S, Miyamae T, Imagawa T, et al. Therapeutic efficacy of humanized recombinant antiinterleukin-6

receptor antibody in children with systemic-onset juvenile idiopathic arthritis. Arthritis

Rheum, 2005, 52(3):818-825.

[179] De Benedetti F, Brunner H I, Ruperto N, et al. Randomized trial of tocilizumab in systemic juvenile

idiopathic arthritis. N Engl J Med, 2012, 367(25):2385-2395.

[180] Bannai E, Yamashita H, Kaneko S, et al. Successful tocilizumab therapy in seven patients with

refractory adult-onset Still's disease. Mod Rheumatol, 2016, 26(2):297-301.

[181] Stéphan JL, Donadieu J, Ledeist F, et al. Treatment of familial hemophagocytic lymphohistiocyto

sis with antithymocyte globulins, steroids, and cyclosporin A. Blood, 1993, 82(8):2319-2323.

[182] Malek TR. The biology of interleukin-2. Annu Rev Immunol, 2008, 26:453-479.

[183] Hanna Graßhoff, Sara Comdühr, Luisa R. Monne. Low-Dose IL-2 Therapy in Autoimmune and Rhe

umatic Diseases. Front Immunol, 2021, 12: 648408.

[184] Jing He, Ruijun Zhang, Miao Shao, et al. Efficacy and safety of low-dose IL-2 in the treatment of

systemic lupus erythematosus: a randomised, double-blind, placebo-controlled trial. Ann Rheum Dis,

2020, 79(1):141-149.

[185] He J, Chen J, Miao M, et al. Efficacy and Safety of Low-Dose Interleukin 2 for Primary Sjögren

Syndrome: A Randomized Clinical Trial. JAMA Netw Open, 2022, 5(11): e2241451.

[186] Yoon JH, Park SS, Jeon YW, et al. Treatment outcomes and prognostic factors in adult patients with

secondary hemophagocytic lymphohistiocytosis not associated with malignancy. Haematologica,

2019, 104:269-276.

[187] Jacqueline D Squire, Stephanie N Vazquez, Angela Chan, et al. Case Report: Secondary hemophag

ocytic lymphohistiocytosis with disseminated infection in chronic granulomatous disease-a serious

cause of mortality. Front Immunol, 2020, 11:581475.

[188] Edoardo Cammarata, Elia Esposto, Marco Andreassi, et al. Primary cutaneous gamma delta T-celllymphoma: a unique polymorphic cutaneous presentation with hemophagocytic lymphohistiocytosis,

and bone marrow Acremonium kiliense infection. Ital J Dermatol Venerol, 2022, 157(5):466-467.

[189] Tamir Diamond, Aaron D Bennett, Edward M Behrens. The Liver in Hemophagocytic Lympho

histiocytosis- Not an Innocent Bystander. J Pediatr Gastroenterol Nutr, 2023, 77(2):153-159.

[190] Pierre-Nicolas Bris, Philippe Gauchez, Raynier Devillier, et al. Hepatic haemoph agocytosis in

haematology patients with hepatic dysfunction: prognostic impact and contribution of liver biopsy

combined with the haemophagocytic syndrome diagnostic score (HScore). Br J Haematol, 2022, 199

(1):106-116.

[191] Knolle PA, Wohlleber D. Immunological functions of liver sinusoidal endothelial cells. Cell Mol

Immunol, 2016,13(3):347-353.

[192] He Y, Hwang S, Ahmed YA, et al. Immunopathobiology and therapeutic targets related to cytokines

in liver diseases. Cell Mol Immunol, 2021,18(1):18-37.

[193] Valade S, Mariotte E, Azoulay E. Coagulation disorders in hemophagocytic lymphohistiocytosis/

macrophage activation syndrome. Crit Care Clin, 2020, 36 (2):415-426.

[194] Sandrine Valade, Bérangère S Joly, Agnès Veyradier, et al. Coagulation disorders in patients with

severe hemophagocytic lymphohistiocytosis. PLoS One, 2021, 16 (8): e0251216.

[195] Bin Q, Gao JH, Luo JM. Prognostic factors of early outcome in pediatric hemophagocytic lymphoh

istiocytosis: an analysis of 116 cases. Ann Hematol. 2016, 95(9):1411-1418.

[196] Jiayu Huang, Guangli Yin, Limin Duan, et al. Prognostic value of blood-based inflammatory

biomarkers in secondary hemophagocytic lymphohistiocytosis. Journal of Clinical Immunology,

2020, 40:718-728.

[197] Jun Zhou, Jing Zhou, Zhi-Qi Wu, et al. A novel prognostic model for adult patients with hemopha

gocytic lymphohistiocytosis. Orphanet J Rare Dis, 2020, 15(1):215.

[198] M Zho, L Li, Q Zhang, et al. Clinical features and outcomes in secondary adult hemophagocytic

lymphohistiocytosis. QJM, 2018, 111(1):23-31.

[199] hoi JL, Li S, Han JY. Platelet function tests: a review of progresses in clinical application. Biomed

Res Int, 2014, 2014:456569.

[200] Paola E J van der Meijden, Johan W M Heemskerk. Platelet biology and functions: new concepts

and clinical perspectives. Nat Rev Cardiol, 2019, 16(3):166-179.

[201] 姚海红, 杨帆, 唐素玫, 等.系统性红斑狼疮及成人 Still 病合并巨噬细胞活化综合征的临床特点

及诊断指标.北京大学学报. 医学版,2023(06):966-974.

[202] R Naveen, Avinash Jain, Hafis Muhammed, et al. Macrophage activation syndrome in systemic

lupus erythematosus and systemic‑onset juvenile idiopathic arthritis: a retrospective study of

similarities and dissimilarities. Rheumatol Int, 2021, 41(3):625-631.

[203] Bartel DP. Metazoan MicroRNAs. Cell, 2018, 173(1):20-51.

[204] Bao Z, Yang Z, Huang Z, et al. LncRNA Disease 2.0: an updated database of long non-coding RN

A-associated diseases. Nucleic Acids Res, 2019, 47(D1): D1034-D1037.

[205] Aringer M, Costenbader K, Daikh D, et al. 2019 European League Against Rheumatism/American

College of Rheumatology classification criteria for systemic lupus erythematosus. Ann Rheum Dis, 2019, 78(9):1151-1159.

[206] Bombardier C, Gladman DD, Urowitz MB, et al. Derivation of the SLEDAI. A disease activity

index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum, 1992,

35(6):630-640.

[207] Child CG, Turcotte JG. Surgery and portal hypertension. Major Probl Clin Surg, 1964(1): 1-85.

[208] Stevens PE, Levin A; Kidney Disease: Improving Global Outcomes Chronic Kidney Disease

Guideline Development Work Group Members. Evaluation and management of chronic kidney

disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline.

Ann Intern Med, 2013, 158(11):825-830.

[209] Langmead B, Trapnell C, Pop M, et al. Ultrafast and memory-efficient alignment of short DNA

sequences to the human genome. Genome Biol, 2009, 10(3): R25

[210] D. W. Thomson, M. E. Dinger. Endogenous microRNA sponges: Evidence and controversy. Nat

Rev Genet, 2016, 17(5): 272-283.

[211] Henson SM, Franzese O, Macaulay R, et al. KLRG1 signaling induces defective Akt (ser473)

phosphorylation and proliferative dysfunction of highly differentiated CD8+ T cells. Blood, 2009,

113(26):6619-6628.

[212] Ibegbu CC, Xu YX, Harris W, et al. Expression of killer cell lectin-like receptor G1 on antig enspecific

human CD8+ T lymphocytes during active, latent, and resolved infection and its relation

with CD57 [published correction appears in J Immunol, 2006, 176(12):7787]. J Immunol, 2005,

174(10):6088-6094

[213] Robert Thimme, Victor Appay, Marie Koschella, et al. Increased expression of the NK cell receptor

KLRG1 by virus-specific CD8 T Cells during persistent antigen stimulation. J Virol, 2005,

79(18):12112-12116.

[214] D L Armstrong, A Reiff, B L Myones, et al. Identification of new SLE-associated genes with a twostep

Bayesian study design. Genes Immun, 2009, 10(5):446-456.

[215] Straube J, Bukhari S, Lerrer S, et al. PD-1 signaling uncovers a patho genic subset of T cell s in

inflamematory arthritis. Arthritis Res Ther, 2024, 26(1):32.

[216] Lucia Novelli, Cristiana Barbati, Cristina Capuano, et al. KLRG1 is reduced on NK cells in SLE

patients, inversely correlates with disease activity and is modulated by hydroxychloroquine in vitro.

Lupus, 2023, 32(4):549-559.

[217] Kalim H, Wahono CS, Permana BPO, et al. Association between senescence of T cells and disease

activity in patients with systemic lupus erythematosus. Reumatologia, 2021, 59 (5):292-301.

[218] Masayuki Ito, Takuma Maruyama, Naotoshi Saito, et al. Killer cell lectin-like receptor G1 binds

three members of the classical cadherin family to inhibit NK cell cytotoxicity. J Exp Med, 2006,

203(2):289-295.

[219] Gunturi A, Berg RE, Forman J. The role of CD94/NKG2 in innate and adaptive immunity. Immunol

Res, 2004, 30(1):29-34.

[220] Lazetic S, Chang C, Houchins JP, et al. Human natural killer cell receptors involved in MHC class I

recognition are disulfide-linked heterodimers of CD94 and NKG2 subunits. J Immunol, 1996,

157(11):4741-4745.

[221] Glienke J, Sobanov Y, Brostjan C, et al. The genomic organization of NKG2C, E, F, and D receptor

genes in the human natural killer gene complex. Immunogenetics, 1998, 48(3):163-173.

[222] Nakata S, Imagawa A, Miyata Y, et al. Low gene expression levels of activating receptors of natural

killer cells (NKG2E and CD94) in patients with fulminant type 1 diabetes. Immunol Lett, 2013,

156(1-2):149-155.

[223] Dalia Shalaby, Marwa Saied, Doaa Khater, et al. The Expression of Activating Receptor Gene of

Natural Killer Cells (KLRC3) in Patients with Type 1 Diabetes Mellitus (T1DM). Oman Med J, 2017,

32(4):316-321.

[224] Lee YH, Bae SC, Song GG. Meta-analysis of gene expression profiles to predict response to

biologic agents in rheumatoid arthritis. Clin Rheumatol, 2014, 33(6):775-782.

[225] Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular selfdigestion.

Nature, 2008, 451(7182):1069-1075.

[226] Klionsky DJ, Abdel-Aziz AK, Abdelfatah S, et al. Guidelines for the use and interpretation of assays

for monitoring autophagy (4th edition). Autophagy, 2021, 17(1):1-382.

[227] Sebastian Alers, Antje S Löffler, Florian Paasch, et al. Atg13 and FIP200 act independently of Ulk1

and Ulk2 in autophagy induction. Autophagy, 2011, 7(12):1423-1433.

[228] Eleni Frangou, Akrivi Chrysanthopoulou, Alexandros Mitsios, et al. REDD1/autophagy pathway

promotes thromboinflammation and fibrosis in human systemic lupus erythematosus (SLE) through

NETs decorated with tissue factor (TF) and interleukin-17A (IL-17A). Ann Rheum Dis, 2019,

78(2):238-248.

[229] Yuan-Yuan Qi, Xu-Jie Zhou, Hong Zhang, et al. Autophagy and immunological aberrations in

systemic lupus erythematosus. Eur J Immunol, 2019, 49(4):523-533.

[230] Zhi-Wei Lai, Ryan Kelly, Thomas Winans, et al. Sirolimus in patients with clinically active systemic

lupus erythematosus resistant to, or intolerant of, conventional medications: a single-arm, open-label,

phase 1/2 trial. Lancet, 2018, 391(10126):1186-1196.