国家银屑病基金会医学董事会：伴炎症性肠病的银屑病患者的治疗

Scott M. Whitlock, MD, Clinton W. Enos, MD, April W.Armstrong, MD, MPH, Alice Gottlieb, MD, Richard G. Langley, MD, Mark Lebwohl,MD, Joseph F. Merola, MD, MMSc, Caitriona Ryan, MD, Michael P. Siegel, PhD,Jeffrey M. Weinberg, MD, Jashin J. Wu, MD, and Abby S. Van Voorhees, MD

主题负责人：吴文育  上海华山医院

审校：贾雪松  新疆石河子大学医学院第一附属医院

翻译：唐教清  四川大学华西医院

摘要

背景：银屑病与炎症性肠病（inflammatory bowel disease，IBD）有密切关联，众多针对银屑病和银屑病性关节炎的治疗同样可用于IBD。

目的：评估伴IBD的银屑病患者的治疗。

方法：对银屑病、银屑病性关节炎、溃疡性结肠炎和克罗恩病系统用药和生物制剂的临床研究进行系统文献检索，检索时间限定为1947年1月1日至2017年2月14日。优先选择随机对照双盲研究，若没有则选择证据级别最高者。

结果：共检索2282篇文献，最终选定其中的132篇。英夫利昔单抗和阿达木单抗对银屑病、银屑病性关节炎、溃疡性结肠炎和克罗恩病有效。赛妥珠单抗对银屑病性关节炎和克罗恩病有效。依那西普、苏金单抗、布罗达单抗和艾克司单抗对银屑病和银屑病性关节炎有效，但可能加重或诱发IBD。古塞库单抗对银屑病有效。

不足：尚无临床试验专门评估银屑病合并IBD的治疗。

结论：英夫利昔单抗和阿达木单抗对银屑病、银屑病性关节炎、溃疡性结肠炎和克罗恩病有效，其他药物对上述部分（非所有）疾病有效。（J Am Acad Dermatol 2018;78:383-94.）

关键词：克罗恩病；炎症性肠病；银屑病；银屑病性关节炎；溃疡性结肠炎

内容提要

• 银屑病与炎症性肠病存在密切关联。

• 英夫利昔单抗和阿达木单抗对银屑病、银屑病性关节炎、溃疡性结肠炎和克罗恩病有效。

• 炎症性肠病可能与IL-17抑制剂相关，或可考虑使用此类药物治疗炎症性肠病患者。

缩略词表

炎症性肠病：inflammatorybowel disease，IBD

白细胞介素：interleukin，IL

美国食品药品监督管理局：US Food andDrug Administration，FDA

肿瘤坏死因子：tumor necrosisfactor，TNF

引言

银屑病与炎症性肠病（inflammatorybowel disease，IBD）存在密切关联^1-3。尽管银屑病确切发生率不明，据估计克罗恩病患者出现银屑病的比例为9.6%（一般人群出现银屑病的比例为2.2%）²，而银屑病患者中出现克罗恩病的比例预估为0.5%（一般人群出现克罗恩病的比例为0.2%）。溃疡性结肠炎情况类似³。重度银屑病患者中，出现克罗恩病的相对风险为2.85，出现溃疡性结肠炎的相对风险为1.96⁴。银屑病和IBD均为上皮组织的多因性慢性炎症性疾病，均涉及细胞免疫活化。IL-23R的基因多态性可转变IL-22/23信号通路，均可见于银屑病和IBD^5-7。银屑病和克罗恩病还共有众多其他易感位点⁸。

尽管有众多药物可治疗银屑病和IBD，但某些银屑病治疗药物可能诱发或加重IBD。有大量病例报道显示TNF抑制剂治疗IBD时会诱发银屑病样皮损^9,10。尽管IBD常会系统应用糖皮质激素，但指南并不推荐此药用于银屑病，因停药后会致疾病反弹^11,12。当为合并银屑病和IBD患者制定治疗计划时，需了解哪些药物对IBD有改善作用，哪些药物又有加重作用。治疗IBD时，与患者的内科医生或消化科医生合作将有助于优化相关疾病的治疗策略。本综述旨在总结各种用于银屑病和银屑病性关节炎的药物，并简要讨论相应药物在IBD的证据级别。

方法

对PubMed数据库进行系统文献检索（图1），时间为1947年1月1日至2017年2月14日，检索词为“infliximab”、“adalimumab”、“golimumab”、“certolizumab”、“etanercept”、“ustekinumab”、“secukinumab”、“ixekixumab”、“acitretin”、“cyclosporine”、“methotrexate”、“apremilast”、“mycophenolate”、“mofetil”、“sulfasalazine”、“hydroxyurea”、“azathioprine”、 “6-thioguanine”、“tacrolimus”、“leflunomide”和“fumaric acid esters”。

文章类型为临床试验（clinical trial）。这些药物分别与“psoriasis”、“psoriatic arthritis”、“inflammatory boweldisease”、“Crohn’s disease”和“ulcerativecolitis”配对检索。其他文章来自初始检索中的参考文献。

后续综述优先选择随机对照双盲试验，其次选择Ⅲ期单药临床试验，若均无上述类型试验则选择Ⅱ期临床试验或证据级别最高的试验类型。另外会剔除针对药物输送技术的临床试验，会纳入每个药物和疾病相关的Meta分析，方法为上述检索词分别与“meta-analysis”进行联合检索。

根据Shekelle等人的指南¹³，记录每种药物对于每种疾病的最高证据级别。ⅠA级指证据来自随机对照试验的Meta分析；ⅠB级证据指来自随机对照试验；ⅡA级指证据来自非随机的对照试验；ⅡB级提示证据来自其他准实验研究（quasi-experimental study）；Ⅲ级指证据来自非实验的观察性研究，例如对比研究、相关性研究和病例对照研究；Ⅳ级指专家会议报道、观点或权威临床经验。有效性推荐强度分为“强”、“中”和“弱”。

结果

共检索2282篇文献，2164篇文献不满足纳入标准，最终选定132篇文献，其中包括15篇Meta分析。

FDA获批的银屑病和/或银屑病性关节炎生物制剂

英夫利昔单抗（Infliximab）。英夫利昔单抗（商品名为Remicade和Inflectra）是抗TNF的单克隆抗体，由FDA获批用于治疗银屑病（2006年）、银屑病性关节炎（2005年）、溃疡性结肠炎（2006年）、克罗恩病（1998年）、儿童克罗恩病（2006年）、儿童溃疡性结肠炎（2011年）及其他疾病（表Ⅰ）^14-47。Ⅲ期临床试验证实英夫利昔单抗对银屑病¹⁴和银屑病性关节炎¹⁵有效。另有Ⅲ期临床试验证实英夫利昔单抗对克罗恩病患者^16,48,49和溃疡性结肠炎患者¹⁷的维持缓解治疗有效。

总之，英夫利昔单抗对银屑病⁵⁰和银屑病性关节炎⁵¹疗效（有效性推荐强度均为强推荐）证据为ⅠA级。同时对克罗恩病^52,53和溃疡性结肠炎⁵⁴的有效（均为强推荐）证据亦为ⅠA级。

阿达木单抗（Adalimumab）。阿达木单抗（商品名Humira）是另外一种抗TNF的单克隆抗体，FDA批准用于银屑病（2008年）、银屑病性关节炎（2005年）、溃疡性结肠炎（2012年）、克罗恩病（2007年）、儿童克罗恩病（2014年）、儿童溃疡性结肠炎（2011年）及其他疾病⁵⁵。Ⅲ期临床试验证实阿达木单抗对银屑病^18,56和银屑病性关节炎^19,57有效。另有Ⅲ期临床试验证实阿达木单抗对克罗恩病^20,58,59和溃疡性结肠炎^21,60有效。

总之，阿达木单抗对银屑病⁵⁰和银屑病性关节炎⁵¹疗效（均为强推荐）证据为ⅠA级。同时对克罗恩病⁵³（强推荐）和溃疡性结肠炎⁵⁴（中推荐）的有效证据亦为ⅠA级。

戈利木单抗（Golimumab）。戈利木单抗（商品名为Simponi）也是抗TNF的单克隆抗体，FDA批准用于银屑病性关节炎（2009）、溃疡性结肠炎（2013年）及其他疾病，但不包括银屑病和克罗恩病⁶¹。尽管无发表的临床试验评估此药对银屑病的疗效，但有Ⅲ期临床试验证实此药对银屑病性关节炎和银屑病均有效²²。仅有一项非对照的超适应证研究证实戈利木单抗对难治性克罗恩病有一定疗效²³。Ⅲ期临床试验证实戈利木单抗对溃疡性结肠炎患者的诱导治疗和维持治疗均有效^24,62,63。

总之，戈利木单抗对银屑病⁶¹（中推荐）疗效证据为ⅡB级，对银屑病性关节炎⁵¹（强推荐）疗效证据为ⅠA级。戈利木单抗对克罗恩病²³（强推荐）疗效证据为Ⅲ级，对溃疡性结肠炎⁵⁴（强推荐）的疗效证据为ⅠA级。

聚乙二醇结合赛妥珠单抗（Certolizumabpegol）。聚乙二醇结合赛妥珠单抗（商品名为Cimzia）是一种针对TNF-α的聚乙二醇化单克隆抗体片段。目前FDA批准聚乙二醇结合赛妥珠单抗用于银屑病性关节炎（2013年）、克罗恩病（2008年）及其他疾病的治疗，但不包括银屑病和溃疡性结肠炎⁶⁴。已有不同Ⅲ期临床试验证实赛妥珠单抗对银屑病性关节炎²⁶和克罗恩病^27,65,66有效。另有小型非对照的超适应证研究证实此药对溃疡性结肠炎有一定疗效²⁸。

总之，聚乙二醇结合赛妥珠单抗对银屑病⁶¹（强推荐）疗效证据为ⅠB级，对银屑病性关节炎⁶⁷（强推荐）疗效证据为ⅠA级。聚乙二醇结合赛妥珠单抗对克罗恩病⁵³（强推荐）疗效证据为ⅠA级，对溃疡性结肠炎²⁸（弱推荐）的疗效证据亦为Ⅲ级。

依那西普（Etanercept）。依那西普（商品名为Enbrel）是一种抗TNF的重组融合蛋白，FDA批准用于银屑病（2004年）、银屑病性关节炎（2002年）、儿童银屑病（2016年）及其他疾病，但不包括克罗恩病和溃疡性结肠炎⁶⁸。已有Ⅲ期临床试验证实依那西普对银屑病^29,69,70和银屑病性关节炎^30,70有效。尚无已发表文献报道依那西普用于溃疡性结肠炎。另有小型对照研究证实此药对克罗恩病无效⁷¹。

IBD是依那西普的潜在副作用⁶⁸。尽管Ⅲ期临床试验未报道使用依那西普后IBD新发或加重，但大规模回顾性研究提示依那西普可能诱发或加重部分IBD患者的病情³²。

总之，依那西普对银屑病⁵⁰（中推荐）疗效证据为ⅠA级，对银屑病性关节炎⁵¹（强推荐）疗效证据为ⅠA级。依那西普对克罗恩病⁷¹疗效（无效）证据为ⅠB级，对溃疡性结肠炎疗效无相关研究。考虑到依那西普有加重IBD的风险，IBD患者用药时需谨慎。

优特克单抗（Ustekinumab）。优特克单抗（商品名为Stelara）是一种IL-12/23抑制剂，FDA批准用于银屑病（2009年）、银屑病性关节炎（2013年）和克罗恩病（2016年），但未批准用于溃疡性结肠炎⁷²。已有Ⅲ期临床试验证实优特克单抗对中重度斑块性银屑病^33,73和银屑病性关节炎^31,34有效。同时优特克单抗对库洛恩兵的诱导缓解和维持治疗有效^35,74-76。尚无已发表文献报道优特克单抗用于溃疡性结肠炎。

总之，优特克单抗对银屑病⁵⁰（强推荐）疗效证据为ⅠA级，对银屑病性关节炎⁶⁷（中推荐）疗效证据为ⅠA级。优特克单抗对克罗恩病⁷⁴疗效（强推荐）证据为ⅠB级，对溃疡性结肠炎疗效无相关研究。

苏金单抗（Secukinumab）。苏金单抗（商品名Cosentyx）是一种IL-17A抑制剂，FDA批准用于银屑病（2015年）、银屑病性关节炎（2016年）及其他疾病⁷⁷。Ⅲ期临床试验证实苏金单抗对银屑病^36,78,79和银屑病性关节炎^37,79有效。对溃疡性结肠炎疗效无相关研究。Ⅱ期临床试验证实此药对克罗恩病无效，且与安慰剂相比可增加疾病活跃度³⁸。

IBD患者应慎重使用苏金单抗⁷⁷。针对斑块型银屑病的Ⅱ期和Ⅲ期临床试验显示，有9例患者出现IBD新发或加重（发生率为每0.33每100患者年），而依那西普对照组仅有1例（发生率为0.34每100患者年），作者分析认为苏金单抗和IBD无临床联系³⁹。然而，鉴于对照组依那西普本身与IBD相关（正如此前所述），目前很难给出相关与否的确切定论。一项苏金单抗用于强直性脊柱炎的Ⅲ期临床试验显示，苏金单抗治疗组共5例新发或加重的IBD病例（发生率为0.7每100患者年），对照组病例数为0⁸⁰。

总之，苏金单抗对银屑病⁵¹（强推荐）疗效证据为ⅠA级，对银屑病性关节炎⁶⁷（强推荐）疗效证据为ⅠA级。苏金单抗对克罗恩病证据为ⅠB级（无效）³⁸，对溃疡性结肠炎疗效无相关研究。考虑到苏金单抗有加重IBD的风险，IBD患者用药时需谨慎。

艾克司单抗（Ixekizumab）。艾克司单抗（商品名Taltz）是一种IL-17A抑制剂，FDA批准用于银屑病（2016年）⁸¹。Ⅲ期临床试验证实艾克司单抗对银屑病有效^40,41。尽管FDA未批准用于银屑病性关节炎，但近期有Ⅲ期临床试验证实艾克司单抗对银屑病性关节炎⁸²有效。对克罗恩病和溃疡性结肠炎疗效无相关研究。

接受艾克司单抗治疗者应密切监测IBD的情况⁸¹。一项未披露的银屑病临床试验⁴⁰显示，艾克司单抗组出现溃疡性结肠炎的病例数为7（发生率为每0.2每100患者年），克罗恩病病例数为4（发生率为0.1每100患者年），对照组病例数为0。不过，艾克司单抗与IBD的关联还未完全阐明⁸³。

总之，艾克司单抗对银屑病和银屑病性关节炎^40,41,82（均为强推荐）疗效证据为ⅠB级，对克罗恩病和溃疡性结肠炎疗效无相关研究。考虑到艾克司单抗有加重IBD的风险，IBD患者用药时需谨慎。

布罗达单抗（Brodalumab）。布罗达单抗（商品名Siliq）是一种抗IL-17受体A的IgG2单克隆靶向抗体。目前FDA批准用于中重度斑块型银屑病（2017年）⁸⁴。Ⅲ期临床试验证实布罗达单抗对银屑病有效（其中包括一项与优特克单抗的对比试验）^85-87。目前FDA未批准用于银屑病性关节炎，但近期有Ⅱ期临床试验证实布罗达单抗对银屑病性关节炎有效^88,89。布罗达单抗对溃疡性结肠炎疗效无相关研究。Ⅱ期临床试验证实布罗达单抗会加重中重度克罗恩病，并导致研究提前终止⁹⁰。

布罗达单抗有自杀意向及行为的黑框警告，由风险评估和减轻战略（Risk Evaluation and Mitigation Strategy）进行严格管束。一项Ⅲ期临床试验报道的4例致命性副作用中有2例为自杀⁹⁶。此外，患者服用布罗达单抗期间需监测IBD的情况。除了上文提到的Ⅱ期临床试验，另有一项Ⅲ期临床试验报道1例患者在治疗期间出现克罗恩病⁸⁵。

总之，布罗达单抗对银屑病（强推荐）疗效证据为ⅠA级，对银屑病性关节炎疗效证据为ⅠB级。

古塞库单抗（Guselkumab）。古塞库单抗（商品名Tremfya）是一种抗IL-23 p19亚基的IgG1单克隆抗体。FDA批准用于中重度银屑病⁹¹。Ⅲ期临床试验证实古塞库单抗有效且耐受性良好^92,93。根据检索标准来看，古塞库单抗用于银屑病性关节炎的研究还未发表。检索网址clinicaltrials.gov可见目前有正在进行的银屑病性关节炎Ⅱ期和Ⅲ期临床试验。无涉及古塞库单抗用于克罗恩病和溃疡性结肠炎的研究。

总之，古塞库单抗对银屑病（强推荐）疗效证据为ⅠB级。截止撰稿期间，有关银屑病性关节炎的临床试验还未完成。对克罗恩病和溃疡性结肠炎疗效无相关研究。

FDA批准的银屑病系统用药（非生物制剂）

阿维A。阿维A是1997年FDA批准用于银屑病（不包括银屑病性关节炎、克罗恩病及溃疡性结肠炎）的口服维A酸类药物（表Ⅱ）^{94-105,107-111}。随机对照试验证实阿维A对银屑病有效^94,112，尽管疗效常弱于其他传统系统用药（归因于剂量限制性毒性）。阿维A被认为对银屑病性关节炎无效，无临床试验对此病进行评估。对IBD无相关研究。

总之，阿维A对银屑病（强推荐）疗效证据为ⅠA级¹¹³。此前对银屑病性关节炎、克罗恩病和溃疡性结肠炎疗效无相关研究。

环孢素。环孢素1997年FDA批准用于银屑病（不包括银屑病性关节炎、克罗恩病及溃疡性结肠炎）的免疫抑制剂¹¹⁴。随机对照试验证实环孢素可有效治疗银屑病^95,115。同时，另有随机对照试验证实此药对银屑病性关节炎有效^96,116,117。有时环孢素会超适应证用于治疗克罗恩病，可有不同程度疗效^97,98。小规模随机对照实验提示此药可有效诱导缓解溃疡性结肠炎病情^99-101。环孢素神经毒性等有数种严重不良反应，会影响用药安全¹¹⁴。

总之，环孢素对银屑病¹¹⁸（强推荐）疗效证据为ⅠA级，对银屑病性关节炎¹¹⁹（强推荐）疗效证据为ⅠA级。环孢素对溃疡性结肠炎¹²⁰（中推荐）疗效证据为ⅠA级，对克罗恩病⁹⁸（弱推荐）的疗效证据亦为ⅠA级。

甲氨蝶呤。甲氨蝶呤由FDA批准用于治疗银屑病（1972年），已有随机对照试验证实其疗效^95,102。甲氨蝶呤有超适应证用于银屑病性关节炎，随机对照试验证实此药有不同程度的疗效^103-105。同时，随机对照试验证实此药对克罗恩病有效^107,121，对溃疡性结肠炎疗效有争议^108,122。甲氨蝶呤药品信息特别提醒有溃疡性结肠炎时用药需谨慎¹⁰³。

总之，甲氨蝶呤对银屑病¹⁰⁶（中推荐）疗效证据为ⅠA级，对银屑病性关节炎¹¹⁹（中推荐）疗效证据为ⅠA级。甲氨蝶呤对克罗恩病¹²³（强推荐）疗效证据为ⅠA级，对溃疡性结肠炎¹²⁴（弱推荐）的疗效证据亦为ⅠA级。

阿普斯特（Apremilast）。阿普斯特（商品名为Otezla）是口服的磷酸二酯酶-4抑制剂，FDA批准用于银屑病（2014年）和银屑病性关节炎（2014年）的治疗¹²⁵。Ⅲ期临床试验证实阿普斯特可有效治疗斑块型银屑病^109,126和银屑病性关节炎¹¹⁰。无涉及阿普斯特用于克罗恩病和溃疡性结肠炎的研究。最常见不良反应为恶心和腹泻，有IBD的患者服用时需留意此情况。

总之，阿普斯特对银屑病⁵⁰（中推荐）疗效证据为ⅠA级，对银屑病性关节炎⁶⁷（强推荐）疗效证据为ⅠA级。截止撰稿期间，有关银屑病性关节炎的临床试验还未完成。对克罗恩病和溃疡性结肠炎疗效无相关研究。

超适应证药物

银屑病超适应证药物及药物对银屑病性关节炎、克罗恩病及溃疡性结肠炎的使用总结于表Ⅲ^{16,96,127-161}。

结论

英夫利昔单抗和阿达木单抗对斑块型银屑病、银屑病性关节炎、克罗恩病及溃疡性结肠炎有效。优特克单抗对斑块型银屑病、银屑病性关节炎及克罗恩病有效。赛妥珠单抗对银屑病性关节炎及克罗恩病有效。戈利木单抗对银屑病性关节炎及溃疡性结肠炎有效。布罗达单抗对银屑病有效，对银屑病性关节炎可能有效。古塞库单抗对银屑病有效。尚有众多其他药物有不同程度的疗效。

布罗达单抗会加重克罗恩病症状，依那西普、艾克司单抗和苏金单抗可能加重克罗恩病症状。推断现有银屑病临床试验数据以评估IBD的加重风险存在局限性，部分临床试验并未统计IBD相关数据。此外，本身有IBD病史的患者服药后最容易出现IBD的加重。因此，一般银屑病人群与具有IBD病史的银屑病人群相比，其出现IBD的真实风险可能被低估了。未确定银屑病与IBD的潜在关联，还有必要对长期数据进行严格考察。

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