白塞氏病病因和发病机制ppt课件VIP

Behets Disease 1 白塞病 (Behets Disease ， BD)又称贝赫切 特病、口 眼 生殖器三联征等。是一种慢性 全身性血管炎症性疾病，主要表现为复发性口 腔溃疡、生殖器溃疡、眼炎及皮肤损害，也可 累及血管、神经系统、消化道、关节、肺、肾 、附睾等器官，大部分患者预后良好，眼、中 枢神经系统及大血管受累者预后不佳。 白塞病诊断和治疗指南 .中华医学会风湿病学分会 20112 本病因 1937 年由土耳其皮肤病医师 Behet 报道而命名。 本病在东亚、中东和地中海地区发病率 较高，又被称为丝绸之路病。好发年龄为 16 40 岁。北美和北欧人少见。 3 病因和发病机制 1. 感染学说 链球菌、丙型肝炎病毒 2. 免疫机制学说 患者血清中可检出抗口腔黏膜细胞抗体。 患者脑脊液中淋巴细胞增多，补体 C3、 IgG 升高。 4 3. 遗传因素学说 本病具有地区性发病倾向，主要见于日本、 中国、伊朗及地中海东部一些国家，其原因可 能与上述地区存在具有某种 HLA抗原的人种 有关。 4. 其他 性激素分泌、锌元素缺乏 5 临床表现 1. 皮肤粘膜损伤 : 在颊粘膜和外阴部由于淋巴细胞和浆细胞 浸润其表皮痛感细胞层 ,造成局部组织溶解、变 性和脱落 ,而使该部出现肉眼可见的 3 15 mm圆 型或椭圆型溃疡 ,亦可出现在唇、舌、咽、扁桃 体部，伴有疼痛。 6 Multiple aphthous ulcers on the buccal membrane, gingiva, and labial mucosal membrane 7 Active genital ulcer (short arrow) and scars (long arrows) on the scrotum. 8 2. 眼部病变 : 双侧前色素膜炎常伴前房积脓和玻璃体炎 。 视网膜动脉和静脉损伤与失明有密切关系。这 些损伤可用眼底镜检出 ,而在病变早期可用静脉 荧光造影检出。由于视网膜病变而导致失明的 病因为动脉、静脉血管炎。 炎症尚可累及巩膜、角膜、结膜，引起眼 底出血、玻璃体浑浊和青光眼等。 9 Hypopyon and deformity of the iris 10 Uveitis 11 3. 神经系统损害： Neuro- Behets Disease（ NBD） 发生率约占 BD患者的 10-25%，男女比例 约为 4:1。 NBD一般 在 BD基本症状出现后数月或数年 发病，但亦可表现为首发症状。 NBD一般 为急性起病，可呈缓解与复发或 持续进展病程。 12 Neuro- Behets Disease（ NBD） 13 1. 好发部位： 中枢神经系统受累较周围神经系统为多， 中枢神经系统任何部位均可受累，白质多于 灰质 。 14 2. 临床表现： A. 脑膜脑炎型； B. 脑干型，主要表现为脑血管意外； C. 脊髓型； D. 周围神经型； E. 小脑病变型，表现为小脑性共济失调； F. 颅神经麻痹型。 15 3. 辅助检查： 3.1 实验室检查： 80%患者 CSF中淋巴细胞增多，但总数常 少于 60个 /dL， 33-65%的患者总蛋白量高于正 常，但多低于 100mg/dL。部分患者髓鞘碱性 蛋白增高。 。 Akma-Demir G, Serdaroglu P, Tasci B. (The Neuro-Behcets Study Group). Clinical patterns of neurological involvement in Behcets disease: evaluation of 200 patients. Brain 1999;122:217182. 16 血清和脑脊液中抗髓鞘因子（ AMSF）增 多，提示疾病的活动性。 血清血清和脑脊液中可见 C3、 IgA、 IgM 和 IgG等免疫因子水平升高。 17 CSF IL-6 and IL-8 play important roles in the pathogenesis of NB. However, the data also suggest that the mechanisms underlying the elevation of CSF IL-6 and IL-8 might be different in patients with acute NB and those with chronic progressive NB. Changes in Biomarkers Focused on Differences in Disease Course or Treatment in Patients with NBD. Intern Med 51: 3359- 3365, 2012 18 3.2 针刺反应试验 (pathergy test)： 用 20号无菌针头在前臂屈面中部斜行刺入 约 0.5 cm沿纵向稍作捻转后退出， 24-48h后局 部出现直径 2 mm的毛囊炎样小红点或脓疱疹 样改变为阳性。此试验特异性较高且与疾病活 动性相关，阳性率约 60-78。静脉穿刺或皮 肤创伤后出现的类似皮损具有同等价值。 International Team for the Revision of the International Criteria for Behcets Disease (ITR-ICBD), Davatchi F, Assaad-Khalil Set al (2013) The international criteria for Behcets disease (ICBD): a collaborative study of 27 countries on the sensitivity and specificity of the new criteria. J Eur Acad Dermatol Venereol. 19 Neuro-Behets Disease Presenting as Hypertrophic Pachymeningitis. Exp Neurobiol. 2015 Sep;24(3):252-255. 20 3.3 CT： CT诊断 NBD敏感性较差，部分患者可见脑 干、丘脑或大脑半球低密度病灶。 21 3.4 MRI： MRI是目前观察 NBD脑损害最敏感的方 法。 MRI的改变反映了神经白塞氏病的组织 学变化。急性期是一个急性炎症过程 , 病灶呈 T1 加权低信号 , T2 加权高信号 , 常常位于桥 脑、中脑、小脑、基底节区 , 脑室周围白质 (通常不靠近脑室壁 ) ;锥体束最常受累 , 尤其 是脑桥及中脑的锥体束。 MRI的 表现有 “可逆性 ”的特点 , 急性期 过后病灶的体积可缩小或消失。 22 Brain computed tomography (axial images). Left temporoparietal hypodensity extending into left cerebral peduncle with faint central hyperdensity with mass effect and midline shift of 5mm 23 Brain MRI. Apparent diffusion coefficient (ADC) and T2 images showed altered signal in the left basal ganglia extending to the left thalamus, midbrain and pons with the lesion causing mild fullness of the ipsilateral lateral ventricle due to compression of the left foramen of Monro 24 A brain mass in a patient with Behcets disease: a case report. Alfedaghi et al. Journal of Medical Case Reports (2015) 9:209 Normal MRA and MRV Follow-up CT image (after 1 month) with more than 50% reduction in the size of the mass with minimal brain edema 25 Brain MRI shows lesions in the pons extending to bilateral middle cerebellar peduncles, which are hypointense on T1- weighted imaging (A), hyperintense on T2-weighted imaging (B), with heterogeneous contrast enhancement (C). 26 (A) DWI shows low signal intensity in central part of pons (arrow), high signal intensity on left side of the pons (arrowhead). (B) ADC map shows vasogenic oedema in central part of pons (arrow), cytotoxic oedema on left side of the pons (arrowhead). 27 Different diffusion-weighted MRI findings in brainstem neuro- Behets disease. BMJ Case Rep 2013. doi:10.1136/bcr-2013-200738 Follow-up T2-weighted imaging (T2WI) shows (A) high signal intensity in the pons (arrow), (B) brain stem and cerebellar atrophy and (C) apparent diffusion coefficient map shows gliosis/demyelination on the of pons. 28 3.5 脑血管造影： 以脑血管意外为主要表现的患者脑血管 造影可显示血管广泛狭窄和血栓形成，其中， 大血管狭窄以大脑前、中动脉多见。 29 4. 诊断： 目前诊断以临床表现为主，反复性溃疡性 口腔炎 ,伴两种或更多的以下症状 :生殖器溃疡 、色素膜炎、皮肤结节或皮肤小脓疱、滑囊炎 即可诊断 BD。 在 BD诊断的前提下如出现神经系统症状 和体征即可诊断 NBD。 30 国际白塞病研究组 1989年诊断标准 31 International consensus recommendation (ICR) criteria for NBD diagnosis 2013 32 Consensus classification of neuro-Behcets disease Central nervous system Parenchymal Multifocal/diffuse Brainstem Spinal cord Cerebral Asymptomatic (silent) Optic neuropathy Non-parenchymal Cerebral venous thrombosis: intracranial hypertension Intracranial aneurysm Cervical extracranial aneurysm/dissection Acute meningeal syndrome Peripheral nervous system (relation to BD uncertain) Peripheral neuropathy and mononeuritis multiplex Myopathy and myositis Mixed parenchymal and non-parenchymal disease 33 5. 治疗： 5.1 全身药物治疗 5.1.1 非甾体抗炎药 (NSAIDs) 具消炎镇痛作用，对缓解发热、皮肤结节 红斑、生殖器溃疡疼痛及关节炎症状有一定疗 效。多种 NSAIDs可供选用 (见类风湿关节炎治 疗 )。 34 5.1.2 秋水仙碱 (Colchicine) 可抑制中性粒细胞趋化，对关节病变、结 节红斑、口腔和生殖器溃疡、眼色素膜炎均有 一定的治疗作用，常用剂量为 0.5 mg，每日 2 3 次。应注意肝肾损害、粒细胞减少等不良 反应。 35 5.1.3 沙利度胺 (Tllalidomide) 用于治疗口腔、生殖器溃疡及皮肤病变。 剂量为 25 50mg/次，每日 3次。妊娠妇女禁 用，可导致胎儿畸形 (详见强直性脊柱炎用药 ) ，另外有引起神经轴索变性的不良反应。 36 5.1.4 氨苯砜 (Dapsone) 具有抑菌及免疫抑制作用，抑制中性粒细 胞趋化。用于治疗口腔、生殖器溃疡，假性毛 囊炎，结节红斑。常用剂量 100m /次。不良反 应有血红蛋白降低、肝损害、消化道反应等。 37 5.1.5 糖皮质激素 根据脏器受累及病情的严重程度酌情使用 ，突然停药易导致疾病复发。重症患者如严重 眼炎、中枢神经系统病变、严重血管炎患者可 静脉应用大剂量甲泼尼龙冲击， 1000 m /次， 35 d 为 1个疗程，与免疫抑制剂联合效果更 好。长期应用糖皮质激素有不良反应 (见系统性 红斑狼疮用药 )。 38 5.2 免疫抑制剂 重要脏器损害时应选用此类药，常与糖皮质 激素联用。此类药物不良反应较大，用药期间 应注意严密监测。 5.2.1 硫唑嘌呤 (azathioprine， AZA)：是白塞病 多系统病变的主要用药。用量为 2-2.5 mg/kg/d,口服。可抑制口腔溃疡、眼部病变、 关节炎和深静脉血栓，改善疾病的预后。停药 后容易复发。可与其他免疫抑制剂联用，但不 宜与干扰素 -联用，以免骨髓抑制。应用期间 应定期复查血常规和肝功能等。 39 5.2.2 甲氨蝶呤 (metbotrexate， MTX)：每周 7.5 15 mg，口服或静脉注射。用于治疗神经系 统、皮肤黏膜等病变，可长期小剂量服用。不 良反应有骨髓抑制、肝损害及消化道症状等。 40 5.2.3 环孢素 A(cyclosporine A， csA)：对秋水 仙碱或其他免疫抑制剂疗效不佳的眼白塞病效 果较好。剂量为每日 3 5mg kg。因其神经 毒性可导致中枢神经系统的病变，一般不用于 白塞病合并中枢神经系统损害的患者。应用时 注意监测血压，肾功能损害是其主要不良反应 。 41 柳氮磺吡啶 (sulfasalazine， SSZ)：剂量 34 g ， d，分 3-4次口服。可用于肠白塞病或关节炎 患者，应注意药物的不良反应。 苯丁酸氮芥 (chlorambucil， CB1348)：由于不 良反应较大，目前应用较少。可用于治疗视网 膜、中枢神经系统及血管病变。用法为 2 mg， 每日 3次。持续使用数月直至病情稳定后减量 维持。眼损害应考虑用药 23 年以上，以免复 发。不良反应有继发感染，长期应用有可能停 经或精子减少、无精。 42 5.3 生物制剂 5.3.1 干扰素 -2a：对关节损伤及皮肤黏膜病变 有效率较高，有治疗难治性葡萄膜炎、视网膜 血管炎患者疗效较好的报道。起始治疗为干扰 索 -2a每日 600万 u皮下注射，治疗有效后逐 渐减量，维持量为 300万 u每周 3次，部分患者 可停药。不良反应有抑郁和血细胞减少，避免 与硫唑嘌岭联用。 43 5.3.2 肿瘤坏死因子 (TNF) -拮抗剂：英夫利西 单抗 (infliiximab)、依那西普 (etanercept)和阿 达木单抗 (adalimumab)均有治疗白塞病有效 的报道。可用于白塞病患者的皮肤黏膜病变、 葡萄膜炎和视网膜炎、关节炎、胃肠道损伤以 及中枢神经系统受累等。 TNF-拮抗剂起效迅 速，但停药易复发，复发患者重新应用仍有效 。要注意预防感染，尤其是结核感染。 44 6. 预后 NBD预后不佳，死亡率可高达 40%，部分 病例在出现症状后一年内死亡。从临床类型看 ，脊髓型和周围神经型预后相对较好，脑膜脑 炎型和脑干型预后较差。早期诊断及治疗有助 于改善预后。 NBD is a severe condition in which patients with the HLAB51 allele appear to experience a worse prognosis. Long-Term Outcome of Neuro-Behc竐 ts Disease. ARTHRITIS these might be elevated at the neurological presentation, but are of limited value in the differential diagnosis of NBD Recommendation 4 We recommend considering MRI study including contrast and MRV in suspected NBD. This commonly demonstrates characteristic features especially in acute/sub-acute parenchymal involvement and can confirm CVT. The distinct MRI findings are helpful in the differentiation from the other CNS inflammatory disorders 50 Recommendation 5 (a) We recommend CSF examination in suspected NBD, as it has a supportive role in the diagnosis, in addition to looking for mimics and especially CNS infections (b) Parenchymal NBD is usually associated with CSF pleocytosis (either neutrophilic or lymphocytic, but rarely as florid as seen in bacterial meningitis), and/or raised protein. Oligoclonal bands are frequently absent. A completely normal CSF does not exclude parenchymal NBD. Non-parenchymal NBD is associated withelevated CSF pressure only. The role of CSF abnormalities in prognosis and monitoring of the disease needs further research 51 Recommendation 6 Raised CSF IL-6 is an indicator of ongoing disease activity in NBD, usually in association with raised CSF constituents. While we recommend considering CSF IL -6 for disease monitoring, especially in the absence of other raised inflammatory CSF constituents, its use in monitoring therapeutic response needs further research. 52 Recommendation 7 The pathergy test is simple and has a well-established role in BD diagnosis. We recommend pathergy testing in suspected NBD, since a positive result, especially with other systemic BD eatures, would contribute significantly toward NBD diagnosis. A negative test, however, will not exclude NBD 53 Recommendation 8 BD is associated with the HLA-B5 allele and, more specifically, with HLA-B51. It is not clear if HLA- B51/B5 testing has a role in the diagnosis or prognosis of BD or NBD. 54 Recommendation 9 Neurophysiologic tests are not routinely recommended for NBD. These may be useful if peripheral nervous system or optic nerve involvement is suspected. Asymptomatic neurophysiological findings are of doubtful clinical significance. The diagnosis of NBD should be avoided when solely based on asymptomatic neurophysiological findings 55 Recommendation 10 Nervous tissue biopsy can occasionally be useful in the diagnosis of NBD. It is usually not recommended as a part of the diagnostic process. As it is an invasive procedure, we recommend considering it when all other diagnostic avenues have been exhausted, especially for tumour-like presentation. 56 Management Recommendation 11 (a) There is no level I evidence on the treatment options of NBD. The following recommendations are mainly based on observational data (b) For acute/sub-acute parenchymal NBD attack, a course of corticosteroids is recommended, preferably IV methyl prednisolone for 310 days followed by a maintenance oral corticosteroid for a few months (up to 6 months) 57 (c) We recommend considering a disease modifying therapy (DMT) after a significant parenchymal relapse depending on severity, response to steroid, previous neurological relapses,disease course, and other associated systemic BD features (d) Azathioprine is recommended as a first-line DMT; alternatives include mycophenolate mofetil, methotrexate, and cyclophosphamide 58 (e) We recommend considering a biological agent, including TNF-alpha-blockers (infliximab, adalimumab, etanercept) or interferon alpha, when first=line therapies are ineffective or intolerable and when the disease is relapsing or showing aggressive neurological or systemic features (f) We recommend caution in using cyclosporin in BD patients because of the potential association with neurological complications. It should be avoided in patients with a history of NBD and the medication should be stopped when BD patients develop neurological features suggestive of parenchymal CNS involvement 59 Recommendation 12 (a) For CVT in BD, we recommend the use of corticosteroid for a limited period for the acute/sub- acute presentation (b) There is no convincing evidence to use or withhold the use of anticoagulants, which is a standard treatment of CVT of any aetiology. If anticoagulation is to be started, caution should be taken to rule-out a systemic aneurysm (c) We recommend considering a DMT, especially if there is a previous history of CVT, active systemic disease, or a history of associated parenchymal NBD 60 Recommendation 13 (a) Poor prognostic features of NBD include brainstem or myelopathy presentation, frequent relapses, early disease progression, and presence of CSF pleocytosis in parenchymal NBD (b) We recommend early consideration of a disease modifying treatment when one or more poor prognostic features are encountered 61 Miscellaneous Recommendation 14 (a) Headaches in BD patients are commonly due to primary headache disorders