Intermediate uveitis associated with MS: Diagnosis, clinical features, pathogenic mechanisms, and recommendations for management

Alan Abraham; Lindsay Nicholson; Andrew Dick; Claire Rice; Denize Atan

摘要

Uveitis is a major cause of visual impairment and blindness among working-age adults, accounting for 10% of legal blindness in the United States. Among people with MS, the prevalence of uveitis is 10 times higher than among the general population, and because MS and uveitis share similar genetic risk factors and immunologic effector pathways, it is not clear whether uveitis is one of the manifestations of MS or a coincident disorder. This uncertainty raises several diagnostic and management issues for clinicians who look after these patients, particularly with regard to recognizing visual symptoms resulting from demyelination, intraocular inflammation, or the visual complications of disease modifying drugs for MS, e.g., fingolimod. Likewise, management decisions regarding patients with uveitis are influenced by the risk of precipitating or exacerbating episodes of demyelination, e.g., following anti–tumor necrosis factor biologic therapy, and other neurologic complications of immunosuppressive treatments for uveitis. In this review, we explore the similarities in the pathophysiology, clinical features, and treatment of patients with uveitis and MS. Based on the latest evidence, we make a set of recommendations to help guide neurologists and ophthalmologists to best manage patients affected by both conditions. Uveitis is a major cause of visual impairment and blindness among working-age adults, accounting for 10% of legal blindness in the United States. 1 Uveitis is traditionally defined as inflammation of the uveal tract, although inflammation is not confined to the uvea; consequently, uveitis is now defined anatomically based on the principal sites of inflammation: anterior uveitis affects the iris and ciliary body; intermediate uveitis (IU) predominantly affects the vitreous; posterior uveitis affects the retina and/or choroid; and panuveitis refers to anterior, intermediate, and posterior uveitis combined. 2 The incidence of uveitis varies between 17.4 and 52.4 cases per 100,000 person years, and the prevalence between 69.0 to 114.5 per 100,000 persons, 3 but among patients with MS, the prevalence is 1%. 4 MS is an inflammatory demyelinating disease of the CNS, affecting almost 2.5 million people worldwide. 5 It is frequently associated with visual symptoms caused by demyelinating lesions of afferent and efferent visual pathways. IU is the uveitis subtype most commonly associated with MS, but because retinal neurons are normally unmyelinated, IU is not a consequence of demyelination. Yet it is still not known whether IU is one of the manifestations of MS or a coincident disorder. This raises several diagnostic and management issues for clinicians who look after patients affected by both disorders with regard to recognizing visual symptoms resulting from demyelination, intraocular inflammation, or the complications of treatment. This review summarizes the common pathophysiology and clinical features of IU and MS to draw inferences regarding the optimal management of patients affected by both conditions. Common pathways in the pathogenesis of MS and IU The eye and brain are immune-privileged sites, created by tight junctions between vascular endothelial cells and the cytokine milieu. Inflammation occurs through breakdown of the normal immunoregulatory mechanisms in the eye and brain. Although it is still unclear what triggers inflammation in both conditions, several sources of evidence suggest that they share similar risk factors and immunologic effector pathways. 6 , 7 Common risk factors for MS and IU Environmental risk factors, including exposure to Epstein-Barr virus, smoking, northern latitude, and low vitamin D are associated with MS, 7 with evidence for an immunoregulatory role of the gut microbiome. 8 These risk factors are not linked to IU, although the etiology of uveitis varies worldwide: 30%–50% of cases are caused by infection in developing nations, whereas a greater proportion are attributed to noninfectious, immune-mediated mechanisms in higher-income countries. 3 The associations between MS and uveitis with infection support the hypothesis that they may be triggered by infectious agents in genetically susceptible individuals. Genome-wide association studies have identified loci accounting for up to 30% of an individual's risk of MS, 7 and many overlap with genetic risk factors for IU, notably, human leukocyte antigen (HLA) class II genes, HLA-DR15 and HLA-DR-51. 4 Other shared genetic risk loci provide clues to immunologic effector pathways common to both disorders: tumor necrosis factor ( TNF , rs361525, rs1800629), lymphotoxin alpha (rs909253), interleukin 6 ( IL-6 , rs1800795), IL-2/IL-21 (rs6822844), IL-2 receptor alpha (rs2104286, rs12722489), interferon regulatory factor 5 (rs10954213), 7 , 9 , 10 and through one genetic linkage study, functional variants affecting TNF receptor superfamily members 10a and 13b (B cell–activating factor), G-protein subunit gamma transducing-1, alpha-2-

机译：葡萄膜炎是工作年龄成年人视觉损害和失明的主要原因，占美国法律失明的10％。在MS的人中，葡萄膜炎的患病率高于一般人群中的10倍，因为MS和葡萄膜炎股份份额相似的遗传危险因素和免疫效应途径，目前尚不清楚葡萄膜炎是否是MS的表现或重合的表现之一紊乱。这种不确定性为照顾这些患者的临床医生提高了几个诊断和管理问题，特别是关于识别脱髓鞘，眼内炎症或疾病修饰药物的视觉并发症导致的视觉症状，例如Fingolimod。同样，关于葡萄膜炎患者的管理决策受到迁移或加剧脱髓鞘发作的风险的影响，例如，抗肿瘤坏死因子生物治疗，以及免疫抑制治疗葡萄炎的其他神经系统并发症。在本次审查中，我们探讨了葡萄病毒患者病理生理学，临床特征和治疗中的相似之处。根据最新证据，我们制定一系列建议，以帮助指导神经病学家和眼科医生，以最佳管理受这两种情况影响的患者。葡萄膜炎是工作年龄成年人视觉损害和失明的主要原因，占美国法律失明的10％。 1葡萄膜炎传统上被定义为无用的炎症的炎症，尽管炎症不限于UVEA;因此，现在基于炎症的主要部位来解剖学上的葡萄膜炎：前葡萄膜炎会影响虹膜和睫状体;中间葡萄膜炎（IU）主要影响玻璃体;后葡萄膜炎会影响视网膜和/或脉络膜;和恐慌is是指前的，中间体和后葡萄炎。 2葡萄膜炎的发生率在每10万人的17.4和52.4例之间变化，每10万人的69.0至114.5次，3例，但患者患者，患病率为1％。 4毫秒是CNS的炎症脱髓鞘疾病，影响全球近250万人。 5常与由传入和传递视觉途径的脱髓鞘病变引起的视觉症状有关。 IU是最常见于MS的葡萄膜炎亚型，但由于视网膜神经元通常是未锁定的，因此IU不是脱髓鞘的结果。然而，尚不清楚IU是否是MS或重合疾病的表现之一。这为临床医生提高了几种诊断和管理问题，这些诊断和管理问题在患有由脱髓鞘，眼内炎症或治疗的并发症中识别导致的视觉症状的患者影响。本综述总结了IU和MS的常见病理生理学和临床特征，以吸引受这两种病症影响的患者的最佳管理的推论。 MS和IU发病机制中的常见途径眼睛和大脑是免疫特权位点，由血管内皮细胞和细胞因子Milieu之间的紧密连接产生。通过眼睛和脑中的正常免疫调节机制的分解发生炎症。虽然尚不清楚两种情况下触发炎症，但有几个证据来源表明它们共享类似的风险因素和免疫效应途径。 6,7 MS和IU环境风险因素的7个常见危险因素，包括暴露于Epstein-Barr病毒，吸烟，北纬和低维生素D与MS，7.具有肠道微生物组的免疫调节作用的证据。 8这些风险因素与IU无关，尽管葡萄膜炎的病因在全球范围内各不相同：30％-50％的病例是由发展中国家感染引起的，而更大的比例归因于非排感，免疫介导的更高收入机制国家。 3 MS和葡萄膜炎之间的关联与感染支持的假设支持它们可以通过转基因易感个体中的传染性药剂引发。基因组关联研究已经确定了个体占IU的遗传危险因素的个体MS，7和许多重叠的30％，特别是人白细胞抗原（HLA）II类基因，HLA-DR15和HLA - DR-51。 4其他共享遗传风险基因座为疾病常见的免疫效应途径提供线索：肿瘤坏死因子（TNF，RS361525，RS1800629），LymPhotoxinα（RS909253），白细胞介素6（IL-6，RS1800795），IL-2 / IL- 21（RS6822844），IL-2受体α（RS2104286，RS12722489），干扰素调节因子5（RS10954213），7,9,10和通过一个遗传联系研究，影响TNF受体超家族成员10A和13B的功能变体（B细胞 - 激活因子），G蛋白亚单位γ转换-1，α-2-

Intermediate uveitis associated with MS: Diagnosis, clinical features, pathogenic mechanisms, and recommendations for management

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