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Advances in Clinical Medicine
Vol. 12  No. 12 ( 2022 ), Article ID: 59501 , 14 pages
10.12677/ACM.2022.12121666

炎症性肠病中的银屑病：一项系统评价与荟萃分析

李露1，陈钰琪1，张传栋1，潘文胜2*

1青岛大学医学院，山东 青岛

2浙江省人民医院，浙江 杭州

收稿日期：2022年11月21日；录用日期：2022年12月15日；发布日期：2022年12月26日

摘要

背景：银屑病是炎症性肠病最常见的免疫介导的皮肤表现。目前关于共存的银屑病对炎症性肠病自然史的影响的数据很少且相互矛盾。本研究旨在确定炎症性肠病患者中银屑病的临床特征和相关风险因素。方法：对电子数据库(PubMed和Embase)进行了搜索，从开始到2022年3月12日，以确定报告炎症性肠病患者中银屑病的研究。从纳入的研究中提取了相关数据，包括无法进行荟萃分析的数据。采用随机和固定效应模型来总结临床信息。本研究遵循流行病学观察研究的Meta分析指南。结果：这项荟萃分析包括34项研究。在累计453,917名IBD患者中，总共有9487例银屑病患者。斑块状银屑病占总数的60.4% (95% CI 0.544~0.665)。50.7%的银屑病患者(95% CI 0.489~0.525)发生在被诊断为炎症性肠病之前。在荟萃分析中，银屑病与女性(RR = 1.145, 95% CI 1.110~1.180)、克罗恩病(RR = 1.128, 95% CI 1.056~1.205)、吸烟者(RR = 1.280, 95% CI 1.130~1.450)、其他肠外表现(RR = 1.907, 95% CI 1.588~2.290)和IBD相关手术史(RR = 2.083, 95% CI 1.203~3.607)有关。结论：大约一半的银屑病在炎症性肠病诊断前出现，抗肿瘤坏死因子治疗诱发的矛盾性银屑病不是停药的指征。临床医生应针对这一特殊人群制定个性化的治疗方案。

关键词

银屑病，炎症性肠病，肠外表现，抗肿瘤坏死因子

Psoriasis in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis

Lu Li1, Yuqi Chen1, Chuandong Zhang1, Wensheng Pan2*

1Medical College, Qingdao University, Qingdao Shandong

2Zhejiang Provincial People’s Hospital, Hangzhou Zhejiang

Received: Nov. 21st, 2022; accepted: Dec. 15th, 2022; published: Dec. 26th, 2022

ABSTRACT

Background: Psoriasis is the most common immune-mediated cutaneous manifestation of inflammatory bowel disease. The current data on the impact of coexistent psoriasis on natural history of inflammatory bowel diseases are scarce and contradictory. This study aimed to identify the clinical features and associated risk factors of psoriasis in patients with inflammatory bowel disease. Methods: The search of electronic databases (PubMed and Embase) was conducted from inception to March 12, 2022 to identify studies reporting psoriasis among inflammatory bowel disease patients. We extracted relevant data from included studies, including data not able to be meta-analysis. Random and fixed effect models were used to summarize clinical information. This study followed meta-analysis of Observational Studies in Epidemiology guidelines. Results: This meta-analysis included 34 studies. In total, there were 9487 cases of psoriasis in the cumulative 453,917 IBD patients. Plaque psoriasis accounted for 60.4% of the total (95% CI 0.544~0.665). 50.7% of patients with psoriasis (95% CI 0.489~0.525) occurred before they were diagnosed with inflammatory bowel disease. In meta-analysis, psoriasis was associated with female (RR = 1.145, 95% CI 1.110~1.180), Crohn’s disease (RR = 1.128, 95% CI 1.056~1.205), smokers (RR = 1.280, 95% CI 1.130~1.450), other extraintestinal manifestations (RR = 1.907, 95% CI 1.588~2.290), and IBD-related surgery history (RR = 2.083, 95% CI 1.203~3.607). Conclusions: About half of psoriasis appear before inflammatory bowel disease diagnosis, and gastroenterology consultation may be required when a patients with psoriasis present with intestinal symptoms. Clinicians should make personalized treatment plans for this specific population.

Keywords:Psoriasis, Inflammatory Bowel Disease, Extraintestinal Manifestations, Anti-Tumor Necrosis Factor

Copyright © 2022 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

炎症性肠病(Inflammatory bowel disease, IBD)包括溃疡性结肠(Ulcerative colitis, UC)、克罗恩病(Crohn’s disease, CD)和未分类的炎症性肠病，后者是一种病因不明的特发性肠道炎症性疾病。IBD的临床表现主要是肠道症状，但其他器官也常受累，如皮肤、眼睛、关节、肝脏、胆道等 [1]。由IBD引起的其他系统的症状被称为肠外表现(Extraintestinal manifestations, EIM)。皮肤受累是IBD最常见的肠外表现之一 [2] [3] [4]。其皮肤表现可按病理生理学分为4类：1) 特异性 2) 反应性 3) 相关性 4) 治疗引起的皮损 [5]。

银屑病和结节性红斑也是与IBD相关的最常见的皮肤病 [6]。银屑病是一种慢性炎症性疾病，据世界卫生组织估计，全球有0.09%~11.43%的人口受到影响 [7]，主要症状是反复出现的红斑和鳞屑，可影响身体任何部位的皮肤。它的特点是疗程长，疗效差，容易复发 [8] [9]，轻症的病例出现皮疹，而严重的病例可导致感染，甚至关节和器官损伤。

在不同的临床环境中，已经观察到银屑病和IBD的重合。为了阐明两者之间的关系，专家们提出了一些假说，如基因、肠道微生物群失衡、免疫反应的变化等 [10] [11] [12]。一项荟萃分析报告指出，IBD患者中银屑病的发病率为4.2% [13]。然而，目前关于这类患者的临床过程的数据很少，而且更多的是从皮肤病学的角度而不是从胃肠病学的角度。这两种疾病(IBD和银屑病)似乎有重叠的炎症调节途经，以前的研究表明，那些确诊为银屑病的人患IBD的风险增加 [14] [15] [16] [17]。此外，在过去的十年中，相关的研究过于关注肿瘤坏死因子(Tumor necrosis factor, TNF)抑制剂引起的皮肤不良反应，而忽略了它们之间的原始免疫联系，并且已经做了一些尝试来阐明两者之间的双向关联。虽然个别研究表明，药物使用、家族史、性别、种族等人口学因素与银屑病有关，但目前关于IBD人群中银屑病的风险因素和特征的数据并不充分，且相互矛盾，现有文献未能提供明确的定义。本文通过系统评价和荟萃分析，可以更清晰地描述IBD患者银屑病的临床特征和相关危险因素，加深对IBD并发银屑病的自然史的认识。

2. 资料和方法

2.1. 材料

根据MOOSE指南对IBD患者中的银屑病表现进行了系统评价。文献检索在PubMed和Embase的英文数据库中进行，检索时间限制为从开始到2022年3月12日。英文检索词如下：“psoriasis”“inflammatory bowel disease”“Crohn’s disease”“ulcerative colitis”和“extraintestinal manifestations”。

2.2. 纳入和排除标准

纳入标准 1) 原始临床研究；2) IBD患者，包括UC和CD；3) 根据患者临床表现或病理活检确认的银屑病；4) 对治疗手段没有限制；5) 纳入的研究必须提供关于IBD患者银屑病的详细数据。

排除标准 1) 包括综述、荟萃分析、会议摘要、短篇通讯、评论、信件、病例报告、病例系列报告、未发表的和非英语写作的研究；2) 计数与其他皮肤病(湿疹等)混杂，且未明确说明受试者的数据；3) 与作者联系后仍无法获得的数据。

2.3. 研究选择

在第一阶段，两位作者独立检查标题和摘要，评估成功通过第二阶段的论文，并选择符合纳入标准的论文进行数据提取。数据由两位作者独立提取，资深作者修改并确定所有最终的分歧。对于同一机构或数据库来源的纳入时间重叠的研究，我们只纳入时间跨度最长的文章以避免数据重复。当文章中含有尚未报道的潜在相关数据时，我们曾试图通过电子邮件与作者联系，但无法获得进一步的信息。

2.4. 数据提取和质量评估

只包括IBD人群。从每个研究中提取的信息包括。1) 识别细节：引文数据(作者，出版年份，研究时期)，研究类型，人群(国家，年龄组)。2) 流行病学特征：样本量、患者来源、IBD病例数、性别。3) 临床特征：疾病类型，结果(银屑病患者的数量)。所有提取的数据都由共同作者反复核对以确保其准确性。采用纽卡斯尔–渥太华量表(NOS)进行质量评估，对于横断面研究采用改编版本。通过人群选择、可比性、暴露评价对研究质量进行评价，满分为10分，得分 ≥ 7分为高质量研究，4~6分为中等质量研究，<4分为低质量研究。

2.5. 统计分析

数据处理使用Stata 17.0软件(Stata Corporation, Texas)。我们使用固定效应模型，使用Freeman-Tukey双弧线转换法，评估银屑病的表型和发病时间在诊断IBD之前/之后的比例。用风险比(RR)和95%置信区间(95% CI)描述相关的风险因素。通过Cochrane Q和I2检验异质性。I2 > 50%认为研究之间存在异质性，并使用随机效应模型进行分析。I2 ≤ 50%表示同质性良好，采用固定效应模型进行分析。P < 0.05被认为具有统计学意义。为了消除TNF抑制剂的影响，亚组分析包括免疫相关组和矛盾反应组。通过逐一排除研究来探索异质性和敏感性分析的来源，以检查我们结果的稳定性。使用漏斗图和Egger’s检验来获取出版偏倚。

3. 结果

3.1. 文献检索结果

初步筛选PubMed中有1785篇文章，Embase中有3369篇文章。通过标题和摘要筛选173项研究进行全文评估后，我们纳入了34篇文章，包括队列研究、病例对照研究和横断面研究。在累计的453,917名IBD患者中，共有9487例银屑病患者 [18] - [51]。其中，12项研究是关于TNF抑制剂诱导的银屑病的观察性研究 [40] - [51]。研究特点见表1。

Table 1. Characteristics of studies reporting psoriasis in IBD

表1. IBD中银屑病的研究特点。

3.2. 银屑病的表型和发病时间

本研究包括的两组受试者是有银屑病和无银屑病的IBD患者。因此，只用单臂荟萃分析法分析了银屑病的表型和发病时间。七项研究报告了IBD患者银屑病的表型。斑块状银屑病占60.4% (95% CI 0.544 −0.665, P < 0.001) [见图1]。四项研究报告了这两种疾病的发病顺序。令人惊讶的是，50.7%的银屑病患者(95% CI 0.489~0.525, P < 0.001)发生在被诊断为炎症性肠病之前[见图2]。

Figure 1. Forest plots of proportion of plaque psoriasis in IBD

图1. IBD中斑块状银屑病比例的森林图

Figure 2. Forest plots of proportion of psoriasis that occurs earlier than the diagnosis of IBD

图2. 早于IBD诊断发生的银屑病比例的森林图

3.3. 女性和克罗恩病

女性的相对风险高于男性(RR = 1.145, 95% CI 1.110~1.180, P < 0.001) [见图3]。结果包括：RR(I) = 1.128 (95% CI 1.091~1.166, P < 0.001)，RR(P) = 1.275 (95% CI 1.173~1.387, P < 0.001)。

Figure 3. Forest plots represent correlation between different gender groups

图3. 不同性别组之间的相关性的森林图

与溃疡性结肠炎相比，克罗恩病与银屑病的相对风险增加有关(RR = 1.128, 95% CI 1.056~1.205, P < 0.001) [见图4]。同时分为2个亚组：RR(I) = 1.122 (95% CI 1.022~1.231, P = 0.016)，RR(P) = 1.153 (95% CI 1.062~1.251, P = 0.001)。

按研究年份、国家和研究类型进行了亚组分析，没有明显的异质性原因。逐一排除的研究表明，Bernstein等人的研究 [30]，Protic等人的研究 [51] 和Halling等人的研究 [21] 是异质性的主要来源。我们推测，地理区域、环境和案例识别似乎导致了研究之间的异质性。

Figure 4. Forest plots represent correlation between different IBD subtype groups

图4. 不同IBD亚型组之间相关性的森林图

3.4. 吸烟者、其他EIMs和IBD相关手术

吸烟者与银屑病的风险增加有关(RR = 1.280, 95% CI 1.130~1.450, P < 0.001) [见图5]。结果包括RR(I) = 1.058 (95% CI 0.809~1.383, P = 0.682)，RR(P) = 1.425 (95% CI 1.250~1.625, P < 0.001)。逐一排除的研究表明，Lolli等人的研究 [39] 是异质性的主要来源，这可能是因为对照人群是非IBD患者。

Figure 5. Forest plots represent correlation of psoriasis between smokers and non-smokers

图5. 吸烟者和非吸烟者之间银屑病的相关性的森林图

其他EIMs与银屑病呈中度相关(RR = 1.907, 95% CI 1.588~2.290, P < 0.001) [见图6]。只有两篇文章提到IBD相关手术史，显示与银屑病明显相关(RR = 2.083, 95% CI 1.203~3.607, P = 0.009) [见图7]。

Figure 6. Forest plots of correlation of psoriasis between other EIMs

图6. 其他EIMs之间的银屑病相关性的森林图

Figure 7. Forest plots of correlation of psoriasis between IBD-related surgical history

图7. 银屑病与IBD相关手术史相关性的森林图

3.5. 特征(蒙特利尔分类) [见表2]

IBD特征和银屑病之间没有明显的关联。

Table 2. No significant association between IBD characteristics and psoriasis

表2. IBD特征与银屑病之间无明显关联

3.6. 敏感性分析和发表偏倚

敏感性分析采用的是留一法，上述结果是稳定的。在本研究中，用Stata软件生成的漏斗图来识别是否存在发表偏倚。在各自的漏斗图和Egger’s检验中没有发现发表偏倚的证据。

4. 讨论

有关IBD患者银屑病的数据很少且分散，目前这些研究在方法和人群上的差异限制了对该主题的全面评估。就“肠外表现”而言，纳入标准有很大差异。本研究纳入的大多数研究都描述了一种以上的肠外表现，一些作者只关注选定的疾病，而另一些作者则报告了“皮肤表现”，没有进一步解释银屑病。此外，在大多数研究中，银屑病诊断标准的定义尚未完全确定，而且很少提及IBD患者中银屑病的特定风险因素的概念。所有这些都使质量评估变得困难。尽管有这些限制，在这项荟萃分析中，女性、CD、吸烟、其他肠外表现和IBD相关的肠道手术史与银屑病显著相关。这些结果有助于更好地了解两者之间的关系，并指导临床决策。

首先，IBD的延迟诊断是一个值得关注的问题，特别是在CD中，1/4的患者从最初的症状发生到诊断需要24个月以上的时间 [25]。据报道，只有14%的肠外表现是在IBD诊断之前出现的，银屑病是IBD患者中最常见的免疫介导的c-EIM [29] [52] [53]。根据我们的荟萃分析，超过一半的银屑病发生在IBD诊断之前。这一发现特别重要，因为严重的肠道损伤可能已经发生，直至疾病被诊断出来才会被发现。与其他肠外表现相比，银屑病在皮肤上更容易被发现，是对IBD早期诊断的警示。研究表明，银屑病可能引起相关的肠道症状，但两者之间的免疫关联顺序尚不清楚 [16]。如果银屑病患者出现肠道相关症状或不明原因的体重减轻，应考虑立即就医或进行相关干预，如结肠镜检查，以免错过最佳时机。

随着生物制剂的出现，TNF抑制剂被越来越多地用于治疗IBD。TNF抑制剂也被用于治疗银屑病，但在IBD患者中使用TNF抑制剂会诱发皮肤不良反应。它们之间存在着微妙的自相矛盾的关系 [54]。英夫利西单抗诱导的银屑病在2003年被首次报道 [55]。目前，银屑病已成为众所周知的TNF抑制剂皮肤不良事件，被称之为矛盾性银屑病。该领域的专家提出了一个共同的发病联系，并试图澄清病理机制，但实际上对此知之甚少 [34]。在本研究中，为了排除药物的影响，将研究对象分为两个亚组：免疫相关组和矛盾反应组，这两组都属于IBD患者的银屑病，并不影响我们的研究结果。根据两个亚组，结论是相同的：女性比男性更容易患银屑病，相对于UC，CD的风险增加。在矛盾反应组(TNF抑制剂治疗)中，这种关联更强。这表明，女性和CD是IBD患者发生银屑病的风险因素。这与女性更容易患自身免疫性疾病的传统观念相吻合。我们假设CD患者会有更严重的全身性炎症负担，导致患病的可能性增加。

吸烟是一个危险因素吗？这一点仍有争议，尽管研究证实吸烟会增加CD患者肠道外表现的风险，但仍缺乏针对IBD合并银屑病这一特定人群的专门研究。利用现有数据，有两项荟萃分析提到吸烟史是IBD患者在TNF抑制剂治疗期间患银屑病的主要风险因素 [56] [57] [58]。然而，这项研究与上述两项研究的纳入标准不同。他们纳入的一些文章主要是关于抗TNF的皮肤不良反应，计数也与湿疹等病变混合。我们对“银屑病”进行了更严格的审查，并最终纳入了“6 + 3”篇文章。我们的荟萃分析显示了不同的结果：目前，在没有TNF抑制剂治疗的IBD患者中，吸烟不能被认为是银屑病的风险因素。有趣的是，如果将两个亚组集合起来，吸烟是IBD患者银屑病的一个风险因素。过去，人们认为吸烟会增强基因的表达，使银屑病的风险增加，包括HLA-Cw6、HLA-DQA1*0201和CYP1A1。Nguyen等人提出了一个悖论：在普通人群中，吸烟与PSA风险呈正相关，但在银屑病患者中呈负相关 [59]。如果对IBD的特定人群做进一步研究，情况比他们描述的要复杂。事实上，有报道称吸烟会增加CD的风险，对UC有保护作用 [60]。如果在UC和CD中分别分析吸烟对银屑病的影响，结果会更清楚。鉴于关于这一主题的研究很少，需要进行更多的研究。

根据我们的结果，斑块状银屑病是IBD患者中最常见的表型，如同普通人群。虽然在一些观察性研究中提到，由TNF抑制剂诱导的银屑病更为严重，但根据我们的亚组分析结果，两个亚组之间的银屑病表型没有明显差异。当然，两个亚组的受试者在年龄、发病时间、治疗史、地理、环境方面存在异质性。这一结论需要仔细考虑。IBD患者的银屑病通常较轻，TNF抑制剂诱导的银屑病不一定是停止治疗的指征，因为大多数病例可以通过外用和紫外线治疗得到有效治疗 [3]。然而，如果银屑病脓疱性皮损与感染一起发展，并可能导致PsA，则应充分考虑其他治疗方案。

此外，我们发现IBD肠道手术史与银屑病之间存在适度关联。许多研究表明，维生素D的缺乏会导致银屑病患者出现更严重的炎症反应 [61] [62] [63]。一项研究表明，25-羟基维生素D(25[OH]D)水平与银屑病患者的全因死亡率呈反比关系 [64]。事实上，维生素D与许多自身免疫性疾病的发展呈负相关，如系统性红斑狼疮、甲状腺毒症、寻常性银屑病、风湿性多发性肌炎等 [65]。手术是影响IBD患者微量营养素缺乏的一个重要因素。Schäffler等人发现，CD切除术后维生素D水平明显下降 [66]。这强调了接受IBD手术的患者的易感性，以及为这一脆弱的患者群体制定术前优化策略的必要性，包括纠正贫血、营养不良管理和控制感染 [67]。IBD患者可以接受适当的术前预处理和充分的营养支持。术后患者也可以考虑补充包括维生素D在内的微量元素，以减少并发症的风险。尽管如此，基础理论还不完善，目前的决策过程主要是基于临床数据。对于临床医生来说，如何为患者量身定制最佳治疗方案仍然是一个挑战。

在UC的扩展、CD的位置和行为方面没有明显差异。在某种程度上，这表明银屑病和炎症性肠病本身与疾病的进展关系不大。与没有银屑病的IBD患者相比，患有银屑病的IBD患者的住院时间、住院费用和二次诊断相似 [38]。

荟萃分析结果表明，银屑病患者的其他肠外表现比无银屑病患者更常见。事实上，研究确实称，有一个EIM会增加出现更多EIM的可能性 [68]。一些文章剖析了银屑病与其他各种系统性疾病之间的联系 [69] [70]。然而，当试图根据这些肠外表现的类型和位置进行进一步的亚组分析时，由于可用的数据不多，因此受到限制。

此外，我们的研究有几个局限性：1) 首先，除吸烟外，我们没有评估任何可能导致疾病发展的环境或生活方式因素(饮酒、饮食、种族、居住在农村/城市地区或使用抗生素)。这是因为目前的数据只包含有限的诊断和临床信息。2) 尽管已经努力将这些银屑病区分为免疫介导的肠外表现或药物不良反应，但这种区分并不完全清楚，因为两者的免疫学影响也可能重叠在一起。3) 尽管一些研究提到了银屑病的结果和后续的治疗方案，但由于相关研究数量有限，随访时间短，无法对继续使用同一TNF抑制剂的患者的银屑病缓解或复发的风险因素作出结论。4) 到目前为止，很少有人尝试描述EIMs和IBD的顺序，包括银屑病。本研究收录的4篇文章中只有2篇是前瞻性队列研究，样本量不足。因此，未来有必要进行大样本量的多中心研究，以更好地描述两者的顺序和临床特征。

文章引用

李 露,陈钰琪,张传栋,潘文胜. 炎症性肠病中的银屑病：一项系统评价与荟萃分析
Psoriasis in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis[J]. 临床医学进展, 2022, 12(12): 11555-11568. https://doi.org/10.12677/ACM.2022.12121666

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    71. NOTES

    *通讯作者。

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