Characteristic elevation of soluble TNF receptor II : I ratio in macrophage activation syndrome with systemic juvenile idiopathic arthritis

To investigate the clinical significance of soluble tumour necrosis factor receptor (sTNF‐R) II/I ratio as an indicator of the diagnosis of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (s‐JIA), we measured the serum sTNF‐RI and II levels in 117 patients with s‐JIA, including 29 patients with MAS, 15 with Epstein–Barr virus‐induced haemophagocytic lymphohistiocytosis (EBV‐HLH), 15 with Kawasaki disease (KD) and 28 healthy controls (HCs). We determined their correlation with measurements of disease activity and severity. Furthermore, we measured serum interleukin (IL)‐18 levels in patients with EBV‐HLH and compared these in levels in patients with MAS. The sTNF‐RII/I ratio was elevated significantly in MAS and EBV‐HLH patients compared with those in the acute phase of s‐JIA and KD patients, whereas there were no significant differences between HCs and those in the acute phase of s‐JIA. The sTNF‐RII/I ratio increased profoundly as MAS developed and correlated positively with disease activity. Serum IL‐18 levels were elevated significantly in MAS patients compared with EBV‐HLH patients. The monitoring of serum IL‐18 and sTNF‐RII/I might be useful for the diagnosis of MAS and the differentiation between MAS and EBV‐HLH.     

Distinct cytokine profile in juvenile systemic lupus erythematosus-associated macrophage activation syndrome

Macrophage activation syndrome (MAS) has been observed in patients with systemic lupus erythematosus (SLE). Recognition of MAS in patients with SLE may be particularly challenging because it may mimic the clinical features of the underlying disease or be confused with an infectious complication. Massive hypercytokinemia is strongly associated with the pathogenesis of systemic lupus erythematosus-associated macrophage activation syndrome (SLE–MAS) but the pathogenesis and kinetics of cytokine release in SLE–MAS patients is not well studied. We present a case of SLE–MAS. The patient showed the distinct cytokine profile of SLE–MAS compared to systemic juvenile idiopathic arthritis associated MAS and Epstein–Barr virus-induced hemophagocytic lymphohistiocytosis. The observed TNF-α dominant increase appears to be characteristic of SLE–MAS. IgM type antilymphocyte antibody (ALAB) was detected on the surface of lymphocytes during the acute phase and disappeared when the patient was in remission. The patient had a heterozygous P369S-R408Q mutation in the MEFV gene. Our results suggest that ALAB and a MEFV mutation might play important roles in the pathogenesis of SLE–MAS. Furthermore, the cytokine profile of SLE–MAS differs from that of S-JIA–MAS: the TNF-α dominant increase appears to be characteristic.     

以重症肝炎为首发症状的巨噬细胞活化综合征6例临床分析及回顾

目的:提高对以重症肝炎为首发症状的巨噬细胞活化综合征的认识。方法:对6例以重症肝炎为首发症状的巨噬细胞综合征的临床表现及实验室资料进行回顾性分析。结果:6例以重症肝炎为首发症状的巨噬细胞活化综合征的患儿均有幼年特发性关节炎(全身型)病史,MAS发病时均无发热,6例患儿的肝功能ALT平均为1 927.33 U/L,TBIL平均为179.82μmol/L,6例经治疗后肝功能均好转出院,无死亡病例。结论:对于重症肝炎的患儿,应综合分析,追问有无风湿性疾病的病史,尤其是幼年特发性关节炎(全身型)病史,提高对巨噬细胞活化综合征的认识,早期诊断,早期治疗。     

Complications of systemic juvenile idiopathic arthritis: risk factors and management recommendations

Systemic juvenile idiopathic arthritis (SJIA) is an inflammatory condition characterized by fever, lymphadenopathy, arthritis, rash and serositis. Systemic inflammation has been associated with dysregulation of the innate immune system, suggesting that SJIA is an autoinflammatory disorder. IL-1 and IL-6 play a major role in the pathogenesis of SJIA, and treatment with IL-1 and IL-6 inhibitors has shown to be highly effective. However, complications of SJIA, including macrophage activation syndrome, limitations in functional outcome by arthritis and long-term damage from chronic inflammation, continue to be a major issue in SJIA patients’ care. Translational research leading to a profound understanding of the cytokine crosstalk in SJIA and the identification of risk factors for SJIA complications will help to improve long-term outcome.     

H‐ferritin and proinflammatory cytokines are increased in the bone marrow of patients affected by macrophage activation syndrome

Macrophage activation syndrome (MAS) is hyperinflammatory life‐threatening syndrome, associated typically with high levels of serum ferritin. This is an iron storage protein including heavy (H) and light (L) subunits, categorized on their molecular weight. The H‐/L subunits ratio may be different in tissues, depending on the specific tissue and pathophysiological status. In this study, we analysed the bone marrow (BM) biopsies of adult MAS patients to assess the presence of: (i) H‐ferritin and L‐ferritin; (ii) CD68⁺/H‐ferritin⁺ and CD68⁺/L‐ferritin⁺; and (iii) interleukin (IL)‐1β, tumour necrosis factor (TNF) and interferon (IFN)‐γ. We also explored possible correlations of these results with clinical data. H‐ferritin, IL‐1β, TNF and IFN‐γ were increased significantly in MAS. Furthermore, an increased number of CD68⁺/H‐ferritin⁺ cells and an infiltrate of cells co‐expressing H‐ferritin and IL‐12, suggesting an infiltrate of M1 macrophages, were observed. H‐ferritin levels and CD68⁺/H‐ferritin⁺ cells were correlated with haematological involvement of the disease, serum ferritin and C‐reactive protein. L‐ferritin and CD68⁺/L‐ferritin⁺ cells did not correlate with these parameters. In conclusion, during MAS, H‐ferritin, CD68⁺/H‐ferritin⁺ cells and proinflammatory cytokines were increased significantly in the BM inflammatory infiltrate, pointing out a possible vicious pathogenic loop. To date, H‐ferritin and CD68⁺/H‐ferritin⁺ were associated significantly with haematological involvement of the disease, suggesting biomarkers assessing severity of clinical picture.     

Advances in immunopathogenesis of macrophage activation syndrome during rheumatic inflammatory diseases: toward new therapeutic targets?

Introduction: Macrophage activation syndrome (MAS) is a severe, hyperinflammatory life-threatening syndrome, generally complicating different rheumatic diseases. Despite the severity of the disease, little is known about the pathogenic mechanisms and, thus, possible targeted therapies in the management of these patients.

Areas covered: In this review, we aimed to update the current pathogenic knowledge of MAS, during rheumatic diseases, focusing mainly on immunologic abnormalities and on new possible therapeutic strategies.

Expert commentary: The difficult pathogenic scenario of MAS, in which genetic defects, predisposing diseases, and triggers are mixed together with the high mortality rate, make it difficult to manage these patients. Although most efforts have been focused on investigating the disease in children, in recent years, several studies are trying to elucidate the possible pathogenic mechanism in adult MAS patients. In this context, genetic and immunological studies might lead to advances in the knowledge of pathogenic mechanisms and possible new therapeutic targets. In the future, the results of ongoing clinical trials are awaited in order to improve the management and, thus, the survival of these patients.     

A hyper-ferritinemia syndrome evolving in recurrent macrophage activation syndrome,as an onset of amyopathic juvenile dermatomyositis: A challenging clinical case in light of the current diagnostic criteria

Juvenile dermatomyositis is an immune-mediated inflammatory multi-system disease involving mainly striated muscles and skin. Typical dermatological features are fundamental to establish the diagnosis, especially whenever the myopathy is very mild or absent, as it occurs in the form called as amyopathic juvenile dermatomyositis. Sometimes, systemic rheumatic diseases can develop a hyperferritinemia syndrome characterized by hemophagocytosis, namely macrophage activation syndrome, which represents a severe and life-threatening complication. Here, we describe a complex clinical history characterized by a hyper-ferritinemia syndrome after infectious mononucleosis, leading to recurrent episodes of macrophage activation syndrome. Finally, the late onset of several skin changes brought to a diagnosis of amyopathic juvenile dermatomyositis.     

The clinical implications of serum ferritin in Kawasaki disease: a helpful biomarker for evaluating therapeutic responsiveness,coronary artery involvement and the tendency of macrophage activation syndrome

IntroductionSerum ferritin (SF) is an acute-phase reactant in inflammatory diseases. Our aim was to analyze the clinical implications of SF in Kawasaki disease (KD).Methods244 KD children were divided into 6 subgroups. SF, inflammatory mediators and blood cell counts were detected.Results(1) SF dramatically increased in the acute phase of KD and maintained after IVIG therapy; (2) SF increased in IVIG-nonresponsive KD patients (AUC = 0.705; sensitivity: 57.10%; specificity: 82.90%); SF positively correlated with the internal diameter of the coronary artery (AUC = 0.603; sensitivity: 92.30%; specificity: 37.70%); (3) SF increased in 4 patients with the macrophage activation syndrome (MAS)/MAS tendency (979.03 ±474.19 μg/l).ConclusionsSF is implied to be a helpful biomarker for forecasting IVIG-nonresponsive KD, coronary artery abnormalities (CAAs) and MAS tendency.     

Prognostic factors of macrophage activation syndrome,at the time of diagnosis,in adult patients affected by autoimmune disease: Analysis of 41 cases collected in 2 rheumatologic centers

Macrophage activation syndrome (MAS) is a rare, life-threatening disease in which early diagnosis and aggressive therapeutic strategy may improve the outcome. Due to its rarity, epidemiologic data are still lacking. Hyperferritinemia is frequently associated with MAS and might modulate the cytokine storm, which is involved in the development of multiple organ failure.In this paper, we investigated clinical data, treatments, and outcome of a homogeneous cohort of 41 adult MAS patients, complicating autoimmune rheumatic diseases. MAS-related death occurred in 17 patients (42.5%) during the follow-up, and older age and increased serum ferritin levels, at the time of diagnosis, were significantly associated with mortality.In conclusion, adult MAS is associated with high mortality rate. Some clinical features at diagnosis may be predictive of MAS-associated death.     

Effect of macrophage activation on killing of Listeria monocytogenes. Roles of reactive oxygen or nitrogen intermediates, rate of phagocytosis, and retention of bacteria in endosomes.

The role of macrophage activation in the killing of L. monocytogenes is unclear. Some studies suggest that activation for enhanced production of reactive oxygen and nitrogen intermediates may not be of central importance. Recent data have indicated an important role for interferon-gamma (IFN-gamma) induced retention of L. monocytogenes in endosomes. Data from the present study indicate that proteose peptone-elicited macrophages from DBA2/J, CD-1, and C3H/HeN mice are listericidal. Activation of these cells in vitro for 20 h by IFN-gamma (20 or 500 U/ml) increased H2O2 or nitrite production, but did not increase the number of L. monocytogenes killed during a subsequent 6-h or 7-h culture. Incubation of macrophages with IFN-gamma plus lipopolysaccharide (LPS) caused greater activation and increased the number of Listeria killed during a 6-h or 7-h culture. However, this seems primarily attributable to enhanced phagocytosis. Proteose peptone-elicited macrophages were significantly more effective than resident macrophages in preventing the escape of L. monocytogenes from endosomes into the cytoplasm. This capability was not significantly enhanced by IFN-gamma in vitro, but was enhanced by IFN-gamma plus LPS. This correlates well with the effects of these activation stimuli on killing of L. monocytogenes by proteose peptone-elicited macrophages. These results indicate that enhanced retention of L. monocytogenes in endosomes is induced by proteose peptone elicitation and that further macrophage activation in vitro by IFN-gamma does not improve listericidal activity.     

POEMS综合征的临床表现及诊断

目的分析POEMS综合征的临床表现及诊断标准。方法回顾性分析36例POEMS综合征患者的临床特点,并与国内、外文献进行比较。结果POEMS综合征患者除了具有多发性神经病(100%)、器官肿大(92%)、内分泌病(86%)、单克隆浆细胞增生(100%)和皮肤病变(86%)的典型临床特征外,还常常表现为血管外容量过负荷(97%)、视乳头水肿(57%)和骨病变(25%)。另外,POEMS综合征患者还常常伴发有Castleman病(25%)。结论POEMS综合征的诊断除应将多发性神经病和克隆性浆细胞疾病作为主要诊断标准外,还应该包括硬化性骨病变、Castlem an病、视乳头水肿、外周性水肿和浆膜腔积液、皮肤病变、脏器肿大及内分泌病变在内的次要诊断标准。     

特纳综合征患者的染色体核型及临床表现特点

目的:分析特纳综合征(Turner syndrome,TS)患者的染色体核型及临床特点,以提高对此病的认识和诊疗水平,为早期发现特殊核型提供临床依据.方法:对确诊患者的临床表现、性激素水平、骨龄及染色体核型等进行分析和总结.结果:24例确诊为TS患者,首发临床表现均为身材矮小,有50％骨龄比实际年龄延后;50％具有TS典型体征,83.33％有促性腺激素水平明显偏高,50％未见卵巢组织;染色体核型分析提示33.33％为45,XO,50％为45X嵌合体,其余为其他类型;16.67％的患者有垂体瘤,8.33％有心血管结构异常,部分患者心电图有异常,8.33％有促甲状腺激素水平增高;PCR检测SRY基因均阴性,未发现Y染色质.结论:TS患者因细胞核型的不同,临床表现有所差异,且各种核型与临床表现有时并不完全相对应;对于矮小症女童,应常规行染色体核型分析;对于出现不能由传统核型分析鉴定的特殊染色体或者核型为45,XO的患者尽早行Y染色体检测,有利于发现异常的Y染色体,为是否需要预防性切除性腺提供依据.     

Clinical and laboratory features and factors predicting disease severity in pediatric patients with hemorrhagic fever with renal syndrome caused by Hantaan virus

The clinical features and factors associated with disease severity in children with hemorrhagic fever with renal syndrome (HFRS) have not been well characterized. This study analyzed the clinical and laboratory factors associated with disease severity in children with HFRS caused by Hantaan virus. Data in pediatric patients with HFRS were retrospectively collected from Xi'an Children's Hospital over a 9-year period. Independent factors associated with disease severity were identified. Nomogram predicting disease severity was constructed based on variables filtered by feature selection. In total, 206 children with HFRS were studied. Fever, digestive tract symptoms, headache, backache, bleeding, and renal injury signs were the common symptoms. Elevated white blood cell, reduced platelet, hematuria, proteinuria, coagulation abnormalities, increased blood urea nitrogen (BUN) and procalcitonin (PCT), decreased estimated glomerular filtration rate and low serum Na⁺, Cl⁻, and Ca²⁺ were the common laboratory findings. In the 206 patients, 21 patients had critical type disease and 4 patients (1.9%) died. Hydrothorax, hypotension and cerebral edema/cerebral herniation at hospital admission were independent clinical characteristics, and neutrophil %, prothrombin activity, PCT, BUN, and Ca²⁺ at hospital admission were independent laboratory factors associated with critical disease. Feature selection identified BUN, PCT and prothrombin time as independent factors related to critical disease. A nomogram integrating BUN and PCT at admission was constructed and calibration showed high accuracy for the probability prediction of critical disease. In conclusion, this study characterized the clinical and laboratory features and constructed a nomogram predicting disease severity in pediatric HFRS, providing references for disease severity evaluation in managing children HFRS.     

抗内皮细胞抗体和血小板生成素测定在ITP与SLE鉴别中的意义

目的：探讨抗内皮细胞抗体(AECA)和血小板生成素(TPO)测定在鉴别特发性血小板减少性紫癜（ITP）和系统性红斑狼疮（SLE）中的临床意义。 方法: 用ELISA法分别测定76例ITP患者、41例SLE患者及50例正常人血清中的AECA和TPO水平。 结果: SLE组、ITP组患者血清AECA水平明显高于正常对照组（P<0.01）；SLE组患者血清AECA水平显著高于ITP组（P<0.01）；ITP组患者血清TPO水平与正常对照组无显著差异(P>0.05)，而SLE组血清TPO水平显著高于ITP组患者和正常对照组(P<0.01)。 结论: 血清AECA和TPO的测定在鉴别诊断ITP和SLE中有显著的临床意义。     

12例Cronkhite Canada综合征患者临床及病理特点

 目的 分析北京协和医院CCS患者流行病学及临床病理特点、治疗策略及预后。方法 回顾性分析,非参数Spearman相关分析判断各治疗方法的短期及远期疗效。结果 12例CCS患者均存在上消化道和下消化道息肉,以及至少1项外胚层异常。1/3患者尿蛋白阳性,1例合并肾病综合征。若联合腹痛、腹泻及便潜血阳性3项指标,则灵敏度为100%。胃镜下可见多发黏膜下黑褐色素斑,息肉病理类型以增生性息肉及腺管状腺瘤最常见。平均随访44.7月,存活率100%;10例在初始或后续治疗中加用糖皮质激素,均获不同程度缓解。糖皮质激素停药后复发者再次使用仍然有效。泼尼松≥40mg/d较≤40mg/d预后更佳（n=10,R=-0.655,p＜0.05）;单用氨基水杨酸制剂、胃黏膜保护剂、肠道益生菌、息肉电切术及肠内外营养支持均无明显疗效;氨基水杨酸制剂与较差预后相关（R =0.598,p＜0.05）。结论：CCS患者可见黏膜下色素沉着及尿蛋白阳性,糖皮质激素为基础的综合治疗临床缓解率较高,提示其发病机制可能有免疫因素参与。