珍屯医学

标题: IgG4相关性疾病 IgG4 related Disease [打印本页]

作者: 大江 时间: 2019-2-26 06:10
标题: IgG4相关性疾病 IgG4 related Disease
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IgG4相关前列腺炎的低功率视图。前列腺基质表现出致密的炎性浸润和纤维化（H＆E，100x）

IgG4相关疾病（IgG4-RD），以前称为IgG4相关的全身性疾病，是一种慢性炎症性疾病，其特征是组织浸润淋巴细胞和分泌IgG4的浆细胞，各种程度的纤维化（瘢痕形成）和通常迅速的反应口服类固醇。在大约51-70％的患有此疾病的人群中，血清IgG4浓度在急性期升高[1] [2] [3]

它是一种复发缓解性疾病，与多个部位的肿块形成，组织破坏性病变有关，在任何部位都有特征性的组织病理学表现。如果不进行治疗，炎症和结缔组织在受影响的解剖部位的沉积可导致器官功能障碍，甚至器官衰竭[4]。

早期发现对于避免器官损伤和潜在的严重并发症非常重要。[5]所有有症状的IgG4-RD病例以及涉及某些解剖部位的无症状IgG4-RD都建议进行治疗[4] [6]。

目录
1 症状
1.1 个体器官表现
2 组织学
2.1 下颌下腺研究
3 诊断
4 治疗
4.1 诱导缓解
4.2 保养
4.3 复发
4.4 其他干预措施
4.5 试验
5 流行病学
6 命名
7 参考

症状
已经将IgG4相关疾病描述为惰性病症。尽管可能基于观点而非客观评估，但在医学文献中，症状（如果有的话）通常被描述为轻微的。尽管存在相当大的潜在器官破坏，但这仍然存在。人们通常被描述为在诊断时一般情况良好，尽管有些人可能会有减肥史。

疼痛通常不是炎症的特征。然而，它可能作为次要效应发生，例如由于阻塞或压缩。

通常由于存在无痛肿胀或肿块，或由于肿块的并发症（例如肿块）而进行诊断。由于胰腺，胆管系统或肝脏受累引起的黄疸。症状通常归因于其他病症，并且其他诊断可能在诊断前几年进行，例如，男性的泌尿系统症状归因于共同的前列腺疾病。病变也可能偶然在放射图像上检测到，但很容易被误诊为恶性肿瘤。

报告的病例确实包括一些重要的症状或发现：

系统罕见的症状和并发症
神经性癫痫发作，[7] [8]瘫痪或偏瘫，[7]颅神经麻痹，[7]感音神经性聋，[9]垂体激素缺乏[10]
视力丧失，[7]眼球突出[11]
心血管收缩性心包炎，[12]心脏传导阻滞，[13]主动脉瘤破裂，[14] [15]主动脉夹层，[16]颈动脉夹层，[17]颅内动脉瘤，[18]心绞痛，[19]心源性猝死[20] [21]
呼吸道阻塞，[22]胸腔积液[23] [24]
胃肠道食管阻塞，[25] [26]肠梗阻[27]
泌尿系肾功能衰竭，[28]肾积水，[28] [29]睾丸疼痛[30]
个别器官表现
IgG4-RD可涉及体内的一个或多个部位。在多机构参与的情况下，所涉及的站点可能同时（同步）或在不同的不相关时段（异步）受到影响。

多年来已知的几种不同疾病现在被认为是IgG4-RD的表现。这些包括：1型自身免疫性胰腺炎，间质性肾炎，Riedel氏甲状腺炎，Mikulicz病，Küttner肿瘤，炎性假瘤（在身体的各个部位），纵隔纤维化和一些腹膜后纤维化病例。[31] [32]

其他受影响的部位，在组织学上证实是IgG4-RD的表现，包括：心脏; [13]硬腭，[50]食道，[25] [26]胃，[51]小肠，[52]直肠，[ 53]肾上腺，[54]卵巢，[55]子宫，[23]输尿管，[56]膀胱，[57] 脐尿管，[58]和滑膜[59]。大约1/3的病例表现出血液嗜酸性粒细胞计数增加，嗜酸粒细胞增多或嗜酸性粒细胞增多。

在确诊的IgG4-RD病例中已经报道了提示上腔静脉[13]和精囊[60]受累的放射学证据。

组织学
无论身体的哪个部位涉及，IgG4-RD的标志性组织病理学特征是：[3] [31] [32]

致密的淋巴浆细胞（淋巴细胞和浆细胞）浸润富含IgG4阳性的浆细胞。
需要特异性地要求并进行IgG4免疫染色以检测IgG4阳性浆细胞。
纤维化，至少局部排列[3]为storiform模式。
“Storiform”通常被称为“具有车轮图案”，但其字面意思是“编织垫[拉丁语：storea]（匆忙或稻草）”的外观。
闭塞性静脉炎。
在静脉壁和管腔内，静脉通道被致密的淋巴浆细胞浸润所消除。[3]
与IgG4-RD相关的其他组织病理学特征是：

静脉炎没有闭塞管腔。[3]
组织中嗜酸性粒细胞的数量增加。[3] [31]
颌下腺研究
在1977年的一篇文章中，对349例Küttner肿瘤（现称为“IgG4相关性唾液腺炎”）的组织学研究确定了纤维炎症过程的四个不同阶段：[61]

第1阶段：局灶性输卵管（唾液导管周围）浸润淋巴细胞
第2阶段：淋巴细胞弥漫性浸润和严重的输卵管纤维化（唾液导管周围的瘢痕）
第3阶段：淋巴细胞明显浸润，薄壁组织萎缩（即由于收缩导致的功能区域丧失）和导管硬化（瘢痕形成导致唾液导管周围硬化）
第4阶段：实质（功能区）明显丧失和硬化（硬化） - 类似于肝硬化的过程，其中肝脏功能区域出现收缩和丧失
这可能反映了IgG4-RD中涉及的其他器官中发生的炎症过程和纤维化的发展。

诊断
诊断需要受影响器官的组织活检，并具有特征性的组织学发现。血清免疫球蛋白G4通常会升高，但情况并非总是如此。[引证需要]

治疗
治疗的目标是诱导和维持缓解，以防止受影响器官中纤维化和器官破坏的进展。

一个国际专家小组已经为IgG4-RD的管理提出了建议。[4] [6]他们得出结论，在所有需要治疗的有症状的活性IgG4-RD病例中。一些无症状IgG4-RD的病例也需要治疗，因为一些器官在疾病晚期之前往往不会引起症状。建议对某些器官表现进行紧急治疗，如主动脉炎，腹膜后纤维化，近端胆管狭窄，肾小管间质性肾炎，硬脑膜炎，胰腺增大和心包炎。

诱导缓解
在未治疗的活动性疾病患者中，除非存在禁忌症，否则推荐用于诱导缓解的一线药物是糖皮质激素。糖皮质激素特征性地导致临床特征的快速且通常显著的改善，并且通常解决射线照相特征。然而，在晚期纤维化病变导致不可逆损伤的情况下，对糖皮质激素和其他当前治疗选择的反应可能很差甚至不存在。

虽然在临床试验中尚未验证，但常见的诱导方案是泼尼松龙每天30-40毫克，持续2-4周，然后逐渐减量3至6个月。然而，在糖皮质激素逐渐减量期间或之后复发是常见的。根据这些药物的当地可用性，可以考虑使用类固醇保留的免疫抑制剂，从开始治疗开始与糖皮质激素联合使用。已使用的类固醇保留剂包括利妥昔单抗，硫唑嘌呤，甲氨蝶呤和环磷酰胺，但需要进行试验以确定每种药物在IgG4-RD中的有效性。

保养
在成功诱导缓解后，可能在某些情况下给予维持治疗，例如当复发风险高或患有器官威胁表现的患者时。常见的维持治疗是泼尼松龙每天2.5-5毫克，或使用类固醇保留剂代替。

复发
复发很常见，既往复发史似乎是未来复发的有力预测指标。当在停止治疗期间发生复发并且在最初的糖皮质激素诱导后存在延长的疾病缓解时，通常可以使用糖皮质激素的再诱导策略成功地控制复发。引入类固醇保留剂也可能需要考虑复发;然而，没有一项在前瞻性对照研究中进行过测试，并且其效力超过同时使用糖皮质激素治疗所提供的证据很少。[5]

在一项回顾性队列研究中，发现血清IgG4，IgE和血液嗜酸性粒细胞的基线浓度可独立预测利妥昔单抗治疗后有或没有糖皮质激素治疗后的复发风险。基线值越高，复发风险越大，复发时间越短。[62]

其他干预措施
当器官受累引起局部机械问题时，可能需要进一步的器官特异性干预。例如，当肿瘤病变导致胆管阻塞时，可能需要插入胆管支架以使胆汁自由排出。

类似地，输尿管或血管支架，手术切除或放射治疗可考虑用于各种不同的呈现问题。

试验
目前正在研究用单克隆抗体（XmAb5871）评估浆母细胞定向治疗的效果和安全性，该抗体在不消耗这些免疫细胞的情况下抑制B细胞功能[63] [64]。 XmAb5871以其可变结构域靶向CD19，并且具有对FcγRIIb具有增加的亲和力的Fc结构域。[65]

流行病学
由于IgG4-RD的识别相对较新，因此对其流行病学的研究很有限。因此很难准确估计患病率。此外，几乎不可能估计发病年龄;诊断时的年龄经常被误用为发病年龄。

2011年的一项研究估计日本IgG4-RD的发病率为2.8-10.8 /百万人，中位年龄为58岁。[66]

命名法
以前用于IgG4-RD的名称：
IgG4相关的全身性疾病（IgG4-RSD）
IgG4相关的硬化性疾病
IgG4相关的系统性硬化病
IgG4相关的自身免疫性疾病
IgG4相关的多灶性系统性纤维化
IgG4相关疾病
IgG4综合征
Hyper-IgG4疾病
系统性IgG4相关的浆细胞综合征
IgG4阳性多器官淋巴组织增生综合征
在2011年之前，IgG4-RD曾在医学文献中以各种不同的名称提及。[2] [66]

在2011年IgG4相关疾病国际研讨会上，IgG4相关疾病的共识名称得到了认可。[2] 这个名称已被作为日本研究者的共识名称达成一致，[2] [3]特别选择不使用“系统性”一词，因为这可能导致其他器官的恶性肿瘤被错误地诊断为另一种表现形式。与IgG4相关的病症。[66]

然而，国际研讨会的一些专家确实对IgG4后的疾病命名表示保留，因为其在发病机制中的作用值得怀疑，并且使用血清IgG4浓度作为生物标志物是不可靠的。[2]

有时也使用扩展术语“免疫球蛋白G4相关疾病”。[67] 然而，这个术语在2012年的命名建议中从未被引用，[2]并且它的使用似乎是错误的。

另见
IgG4-related ophthalmic disease
IgG4-related prostatitis
IgG4-related skin disease

参考
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