容加梅,羅 娟,黃 奇,繆應(yīng)雷

容加梅,羅娟,黃奇,繆應(yīng)雷,昆明醫(yī)科大學(xué)第一附屬醫(yī)院消化內(nèi)科 云南省昆明市 650032

0 引言

炎癥性腸病(inflammatory bowel disease,IBD)是一種慢性、復(fù)發(fā)性、具有一定致殘性的腸道炎性疾病[1,2],可累及回腸、結(jié)腸、直腸甚至全消化道,主要包括潰瘍性結(jié)腸炎(ulcerative colitis,UC)和克羅恩病(Crohn’s disease,CD).傳統(tǒng)治療藥物包括氨基水楊酸類、糖皮質(zhì)激素、免疫抑制劑等,但可能出現(xiàn)療效不佳,復(fù)發(fā)率高,藥物不良反應(yīng)嚴(yán)重等情況[3].2020年美國(guó)胃腸病協(xié)會(huì)(AGA)發(fā)表的中-重度UC臨床實(shí)踐指南建議,對(duì)于門診的中-重度成人UC患者,應(yīng)盡早使用生物制劑,而不是在5-氨基水楊酸(5-ASA)治療不佳后再使用[4].因此臨床實(shí)踐中如何優(yōu)化使用生物制劑,獲得更好的治療結(jié)果,是當(dāng)前關(guān)注的熱點(diǎn).面對(duì)當(dāng)前眾多的生物制劑,我們應(yīng)把患者疾病特點(diǎn)與藥物特征相結(jié)合,充分權(quán)衡風(fēng)險(xiǎn)利弊,為患者制定個(gè)體化的治療方案.本文將對(duì)不同生物制劑的特點(diǎn)及其風(fēng)險(xiǎn)權(quán)衡做一綜述,旨在更好地為患者提供個(gè)體化治療方案.

1 不同生物制劑的作用機(jī)制及臨床應(yīng)用

1.1 抗腫瘤壞死因子-α 抗腫瘤壞死因子-α(tumor necrosis factor-alpha,TNF-α)是參與IBD發(fā)病中異常免疫反應(yīng)的一個(gè)關(guān)鍵中介因素,IBD的病情與腸黏膜中TNF-α的表達(dá)水平有關(guān),抗TNF-α藥物可促進(jìn)IBD的臨床緩解及黏膜愈合,已被臨床廣泛應(yīng)用.目前上市的抗TNF-α藥物有以下四種.

1.1.1 英夫利西單抗:英夫利西單抗(Infliximab,IFX)是一種人-鼠嵌合的(含25%鼠蛋白和75%人蛋白)單克隆抗體,與TNF-α高親和力結(jié)合后可中和其生物活性,從根源上抑制TNF-α引起的免疫損傷和炎性反應(yīng),促進(jìn)腸道黏膜修復(fù)[5].誘導(dǎo)和維持治療階段均以5 mg/kg劑量靜脈注射.作為第一種獲得美國(guó)FDA批準(zhǔn)上市的抗TNF-α制劑,英夫利西單抗被批準(zhǔn)用于治療中重度活動(dòng)性CD、瘺管型CD 和中重度活動(dòng)性UC.一項(xiàng)Meta分析統(tǒng)計(jì)結(jié)果顯示[6],單獨(dú)使用英夫利昔單抗治療組的臨床緩解率(60.91%)、黏膜愈合率(38.10%)均明顯高于對(duì)照組(分別為45.68%和25.54%).2020年AGA指南推薦英夫利西單抗作為急性重癥UC挽救治療的一線藥物,且英夫利昔單抗是唯一適應(yīng)癥覆蓋瘺管型CD的生物制劑[4].

IBD目前被認(rèn)為是一種全身性疾病,其病變不僅累及消化道,而且可影響全身各個(gè)器官和組織,高達(dá)50%的IBD患者至少有一種腸外表現(xiàn)[7].腸外表現(xiàn)會(huì)嚴(yán)重影響患者的生活質(zhì)量甚至威脅生命.臨床已證實(shí)英夫利西單抗對(duì)持續(xù)性外周型關(guān)節(jié)炎、耐藥的葡萄膜炎、復(fù)發(fā)和難治類型皮膚結(jié)節(jié)性紅斑、壞疽性膿皮病有較好的療效,且目前該藥對(duì)于IBD合并腸外表現(xiàn)中應(yīng)用最多且療效確切[8].國(guó)外有多種生物制劑用于兒童CD,如英夫利西單抗、阿達(dá)木單抗等,但目前國(guó)內(nèi)獲批在臨床應(yīng)用的僅有英夫利西單抗[9].

1.1.2 阿達(dá)木單抗:阿達(dá)木單抗(Adalimumab,ADA)是一種皮下注射、重組、全人免疫球蛋白G1單克隆抗體,與人TNF具有較高的親和力和特異性,與可溶性人TNF-α結(jié)合并阻斷其與細(xì)胞表面TNF受體p55和p75的相互作用,從而有效地阻斷TNF-α的致炎作用[10].

作為皮下注射使用的阿達(dá)木單抗,具有高生物利用度和使用方便的優(yōu)點(diǎn),且療效持久穩(wěn)定.對(duì)于既往未接受過(guò)生物制劑的成人中重度UC門診患者,如果患者很重視自行注射的便利性,阿達(dá)木單抗可能是一線生物療法的合理替代方案[4].阿達(dá)木單抗較英夫利西單抗相比藥物起效慢,因此,目前阿達(dá)木單抗并不作為急性重癥UC患者首選生物制劑,多用于對(duì)英夫利西單抗不耐受者或常規(guī)治療效果差的患者.在非頭對(duì)頭研究中,在第8周阿達(dá)木單抗治療UC患者黏膜愈合率高于安慰劑組,使用阿達(dá)木單抗的UC患者有41%達(dá)到黏膜愈合,而安慰劑組僅為31%[11].

CD患者接受阿達(dá)木單抗治療1周后即可出現(xiàn)CRP改善,4周時(shí)近一半患者(46.3%)達(dá)到臨床緩解[12,13].有一項(xiàng)隨訪4年的研究結(jié)果表明,大多數(shù)(56.5%)CD患者可長(zhǎng)期維持臨床緩解[14].其他分析結(jié)果也顯示,阿達(dá)木單抗長(zhǎng)期使用可提高CD患者生活質(zhì)量,降低住院率和手術(shù)風(fēng)險(xiǎn).同樣IBD合并腸外表現(xiàn)(例如關(guān)節(jié)炎、葡萄膜炎、壞疽性膿皮病)且傳統(tǒng)治療藥物無(wú)效也可以作為首選[8].1.1.3 戈利木單抗:戈利木單抗(Golimumab,GOL)作為TNF-α抑制劑的新成員,為一種高親和力、可特異性結(jié)合TNF-α的全人源單抗,靶向并中和可溶性的和跨膜活性形式的TNF-α,阻止其與細(xì)胞表面的TNF-α受體結(jié)合,從而拮抗TNF-α的生物學(xué)活性[15].雖然到目前為止戈利木單抗已開展過(guò)許多經(jīng)典的誘導(dǎo)緩解研究試驗(yàn)和維持緩解研究試驗(yàn)[16-18],均證明能夠誘導(dǎo)和維持傳統(tǒng)治療無(wú)效的中重度難治性UC的臨床緩解和黏膜愈合,也已被 FDA 批準(zhǔn)用于中重度UC的治療,但目前在國(guó)內(nèi)的應(yīng)用還比較少,缺乏長(zhǎng)期安全性數(shù)據(jù).

1.1.4 賽妥珠單抗:賽妥珠單抗(Certolizumab pegol,CZP)是一種聚乙二醇人源化 Fab片段的抗TNF-α單克隆抗體.其給藥途徑為皮下注射,故無(wú)靜脈輸液反應(yīng),給藥方便.賽妥珠單抗對(duì)于中重度活動(dòng)性CD有顯著的誘導(dǎo)緩解和維持緩解的作用,診斷后盡早使用能夠提高療效.賽妥珠單抗對(duì)英夫利昔單抗失去應(yīng)答或不耐受的CD患者同樣有效[19].但目前應(yīng)用賽妥珠單抗治療IBD及腸外表現(xiàn)的臨床研究還比較少,尚需要更多的研究來(lái)證明其有效性及安全性.

1.2 抗整合素抗體 淋巴細(xì)胞表面會(huì)表達(dá)一種信號(hào)蛋白,稱為“整合素”,不同的整合素,指引著不同的淋巴細(xì)胞前往不同的部位、器官.由于α4β7整合素能特異性介導(dǎo)淋巴細(xì)胞向腸道聚集,故開發(fā)了針對(duì)此整合素的藥物.目前臨床應(yīng)用于治療IBD的抗整合素主要為維得利珠單抗(Vedolizumab,VDZ),它是一種人源化IgG1單克隆抗體,特異性結(jié)合α4β7整合素,通過(guò)與MAdCAM-1相互作用,從而精準(zhǔn)選擇性抑制腸道炎癥,不影響全身的正常免疫功能[20].誘導(dǎo)和維持治療階段均以300 mg劑量靜脈滴注.

目前的臨床指南推薦,維得利珠單抗可作為治療IBD的一線生物制劑,也可用于治療抗-TNF藥物難治的患者[21,22].有研究表明,使用維得利珠單抗治療中重度UC,在第52周臨床緩解率可高達(dá)46.9%,無(wú)激素臨床緩解率高達(dá)44.6%[23].英夫利昔單抗治療不佳的UC患者應(yīng)用維得利珠單抗可以獲得更好的治療效果和更高的生存率[24],因此,維得利珠單抗可以作為英夫利昔單抗的替代方案.一項(xiàng)探索維得利珠單抗治療UC有效性和安全性的大型真實(shí)臨床實(shí)踐研究發(fā)現(xiàn)[25]:維得利珠單抗可以有效達(dá)到UC的臨床緩解和內(nèi)鏡緩解,但之前使用過(guò)抗-TNF藥物會(huì)顯著影響維得利珠單抗的治療效果.2019年ACG指南[26]推薦維得利珠單抗可用于重癥UC患者經(jīng)誘導(dǎo)緩解后的維持治療.

關(guān)于維得利珠單抗III期臨床試驗(yàn)和7年長(zhǎng)期隨訪的事后分析結(jié)果顯示[27],CD患者早期接受維得利珠單抗治療獲益更大,長(zhǎng)期手術(shù)風(fēng)險(xiǎn)更低.維得利珠單抗療效最好的對(duì)象是疾病早期、沒(méi)有復(fù)雜并發(fā)癥、且沒(méi)有使用過(guò)其它生物制劑治療的初治CD患者.維得利珠單抗作為腸道選擇性的生物制劑,似乎對(duì)腸外表現(xiàn)的作用較少,對(duì)于腸外表現(xiàn)的改善可能與其抑制了IBD疾病本身的活動(dòng)性有關(guān),但缺少相關(guān)數(shù)據(jù)[28].目前還沒(méi)有足夠的證據(jù)推薦使用維得利珠單抗促進(jìn)瘺管愈合.

1.3 抗白細(xì)胞介素 白細(xì)胞介素(interleukin,IL)作為一種細(xì)胞因子,在調(diào)節(jié)組織炎癥中發(fā)揮重要作用.研究表明IL-12和IL-23在腸道急性炎癥和慢性炎癥中均發(fā)揮重要作用[29],抑制二者的異常上調(diào)可改善腸道炎癥狀態(tài).為此目前針對(duì)此靶點(diǎn)研究了烏司奴單抗,是首個(gè)全人源“雙靶向”的IL-12和IL-23抑制劑.

烏司奴單抗(Ustekinumab,UST)是全球唯一獲批治療CD的抗IL-12/23的生物制劑.2019年ECCO指南更新也推薦烏司奴單抗可作為CD患者傳統(tǒng)治療或抗TNF-α治療不佳的生物制劑選擇[30].近期發(fā)表的一項(xiàng)多中心回顧性研究表明,烏司奴單抗可作為合并肛周病變的難治性CD的一種治療方案,但缺乏更多證據(jù)[31].也有研究表明,烏司奴單抗可用于中-重度UC患者的誘導(dǎo)和維持緩解治療[32].

目前對(duì)于生物制劑頭對(duì)頭的研究較少,無(wú)法對(duì)各種生物制劑的療效進(jìn)行全面評(píng)價(jià),已有的諸多臨床隨機(jī)對(duì)照試驗(yàn)以安慰劑的療效作為標(biāo)準(zhǔn),去間接比較不同藥物對(duì)中-重度UC的療效并進(jìn)行排序.RCT結(jié)果[33]顯示所有生物制劑在IBD治療臨床緩解和黏膜愈合率方面均優(yōu)于安慰劑組或?qū)φ战M.但是由于缺乏頭對(duì)頭有效研究,且各項(xiàng)研究的入選標(biāo)準(zhǔn)、設(shè)計(jì)及隨訪時(shí)間方面均存在差異,所以不能直接對(duì)比各項(xiàng)生物制劑在IBD治療中的療效差異.2019年發(fā)表在《新英格蘭醫(yī)學(xué)雜志》的臨床Ⅲb期VARSITY研究,是目前IBD生物制劑領(lǐng)域唯一的頭對(duì)頭有效研究,比較了維得利珠單抗及阿達(dá)木單抗治療中重度活動(dòng)性UC患者的療效,結(jié)果顯示維得利珠單抗的療效顯著優(yōu)于阿達(dá)木單抗,治療1年的臨床緩解率和黏膜愈合率均更高,尤其是在之前未使用過(guò)任何生物制劑的患者中,維得利珠單抗的療效優(yōu)勢(shì)更加顯著;而在之前生物制劑治療失敗的患者中,兩種藥物的應(yīng)答率沒(méi)有差異[34].

2 不同生物制劑的風(fēng)險(xiǎn)權(quán)衡

2.1 不良反應(yīng)

2.1.1 病毒性肝炎和結(jié)核:在活動(dòng)性乙型肝炎患者中,使用抗TNF-α藥物可增加病毒復(fù)制,導(dǎo)致肝功能損害甚至肝功能衰竭[35].專家建議IBD患者在接受抗TNF-α藥物治療前應(yīng)進(jìn)行乙肝病毒篩選,如果檢測(cè)到HBV復(fù)制,應(yīng)在生物制劑治療前予以抗病毒治療.在英夫利昔單抗治療的患者中,結(jié)核病發(fā)生率較普通人群明顯升高,這與隱性結(jié)核感染被激活密切相關(guān)[36].因此 對(duì)潛伏性結(jié)核感染進(jìn)行篩查對(duì)英夫利西治療IBD具有重要意義.國(guó)外多項(xiàng)報(bào)道不斷強(qiáng)調(diào)英夫利西使用前需要進(jìn)行結(jié)核篩查[37,38].目前對(duì)臨床試驗(yàn)和上市后安全性監(jiān)測(cè)數(shù)據(jù)表明,使用維得利珠單抗并沒(méi)有增加IBD患者結(jié)核感染的風(fēng)險(xiǎn)[39].

2.1.2 機(jī)會(huì)性感染:由于生物制劑的免疫抑制作用,導(dǎo)致其在治療IBD患者時(shí),機(jī)體抵御外界病原菌入侵的能力減弱,患者在治療期間感染發(fā)生率增加.在一項(xiàng)全國(guó)范圍的隊(duì)列研究中,報(bào)告了使用TNF-α抑制劑的嚴(yán)重感染風(fēng)險(xiǎn)增加,盡管僅對(duì)皮膚和軟組織感染具有統(tǒng)計(jì)學(xué)意義[40].

一項(xiàng)基于隊(duì)列研究的系統(tǒng)評(píng)價(jià)和薈萃分析顯示[41],在不同抗-TNF藥物之間相比,英夫利西單抗治療UC患者的嚴(yán)重感染風(fēng)險(xiǎn)低于阿達(dá)木單抗(相對(duì)風(fēng)險(xiǎn)RR=0.57,95%CI:0.33-0.97),但兩種TNF-α抑制劑治療CD的嚴(yán)重感染風(fēng)險(xiǎn)相似(相對(duì)風(fēng)險(xiǎn)RR=0.57,95%CI:0.33-0.97).這項(xiàng)研究還觀察到,與免疫抑制劑相比,TNF-α抑制劑單藥治療的嚴(yán)重感染數(shù)據(jù)更高,且TNF-α抑制劑+免疫抑制劑聯(lián)合治療的感染風(fēng)險(xiǎn)比TNF-α抑制劑單藥治療增加19%.維得利珠單抗作為腸道選擇性生物制劑,作用于消化道,基本不影響其它組織和器官,不增加IBD患者感染或嚴(yán)重感染風(fēng)險(xiǎn)[42]

2.1.3 腫瘤:研究表明[43],無(wú)論用抗TNF-α單藥,還是聯(lián)合治療,患者發(fā)生淋巴瘤的風(fēng)險(xiǎn)均高于未使用生物制劑者,且聯(lián)合治療較單用抗TNF-α治療患淋巴瘤風(fēng)險(xiǎn)更高.同時(shí)抗TNF-α藥物被發(fā)現(xiàn)會(huì)增加黑色素瘤的發(fā)生率[44],也有非黑色素皮膚癌增加的一些證據(jù),有待進(jìn)一步研究確認(rèn).維得利珠單抗惡性腫瘤的發(fā)生率與總IBD群體中的發(fā)生率相似[45].對(duì)伴實(shí)體腫瘤、淋巴瘤、非黑色素瘤及黑色素瘤的IBD患者,若既往使用的生物制劑為維得利珠單抗,可繼續(xù)使用,無(wú)需停藥[46].GEMINI研究統(tǒng)計(jì)了維得利珠單抗長(zhǎng)期安全性的情況,結(jié)果顯示全部病例沒(méi)有出現(xiàn)感染、惡性腫瘤、輸液相關(guān)反應(yīng)等不良事件[47].但由于缺乏大型研究的證據(jù),未能充分評(píng)估維得利珠單抗的癌癥風(fēng)險(xiǎn),但是2019年的美國(guó)克利夫蘭診所發(fā)表IBD的實(shí)用指南分析了現(xiàn)有主要治療藥物的安全性數(shù)據(jù),指出維得利珠單抗單抗安全性居于首位[48].

2020年9月,《炎癥性腸病雜志》發(fā)表了烏司奴單抗治療炎癥性腸病的安全性分析結(jié)果,6項(xiàng)Ⅱ/Ⅲ期臨床研究顯示烏司奴單抗治療IBD1年的安全性與安慰劑相當(dāng)[49].由于上市時(shí)間不長(zhǎng)或缺乏大型研究的證據(jù),目前烏司奴單抗的癌癥風(fēng)險(xiǎn)尚不清楚.

2.1.4 其他不良反應(yīng):過(guò)敏是英夫利昔單抗相對(duì)常見(jiàn)的不良反應(yīng),急性過(guò)敏反應(yīng)可出現(xiàn)呼吸短促和蕁麻疹,嚴(yán)重可能會(huì)導(dǎo)致過(guò)敏性休克.遲發(fā)型過(guò)敏反應(yīng)可出現(xiàn)肌痛、關(guān)節(jié)痛、發(fā)熱、皮疹或類似的血清病樣反應(yīng)癥狀.其他還可能出現(xiàn)輸液反應(yīng)、肝損傷、充血性心力衰竭、心悸等[50,51].

GEMINI研究中[47],894名UC患者和1349名CD患者使用維得利珠單抗8年后,分別有93%和96%的患者發(fā)生不良事件,常見(jiàn)不良反應(yīng)有關(guān)節(jié)痛、鼻咽炎、頭痛.有31%的UC和41%的CD患者報(bào)告了嚴(yán)重的不良事件,常見(jiàn)的嚴(yán)重不良事件如疾病惡化、腹痛.

烏司奴單抗常見(jiàn)的藥物不良反應(yīng)包括感染、注射部位反應(yīng)、CD惡化、腹痛、惡心、關(guān)節(jié)痛和頭痛.阿達(dá)木單抗導(dǎo)致的不良反應(yīng)大多較輕微,最常見(jiàn)的不良反應(yīng)包括感染、注射部位反應(yīng)、頭痛和皮疹.最嚴(yán)重的不良反應(yīng)包括嚴(yán)重感染、神經(jīng)系統(tǒng)反應(yīng)和惡性腫瘤[52].

2.2 生殖

2.2.1 女性妊娠:IBD的發(fā)病高峰年齡在20-40歲,與人類生育年齡有重合,因此,妊娠是IBD育齡期患者不可避免的一個(gè)重要問(wèn)題.IBD女性妊娠不良結(jié)局往往與受孕時(shí)疾病活動(dòng)度有關(guān),因此IBD女性患者應(yīng)盡可能選擇在緩解期受孕,以盡量保證整個(gè)妊娠期疾病處于靜止?fàn)顟B(tài).有Meta分析表明,妊娠期間抗TNF-α藥物不會(huì)增加不良妊娠結(jié)局、先天性異常、早產(chǎn)和低出生體重的風(fēng)險(xiǎn)[53].但ECCO共識(shí)建議在妊娠第22-24 wk停止TNF-α抑制劑治療,以盡量減少經(jīng)胎盤轉(zhuǎn)移的風(fēng)險(xiǎn)和其他未知的風(fēng)險(xiǎn)[54].妊娠晚期阿達(dá)木單抗胎盤通過(guò)率明顯低于英夫利昔單抗,因此妊娠期阿達(dá)木單抗治療時(shí)間可適當(dāng)延長(zhǎng),以維持病情穩(wěn)定[55].賽妥珠單抗在妊娠期間和哺乳期使用被認(rèn)為是安全的[55].關(guān)于妊娠期間使用戈利木單抗的報(bào)道甚少.

一個(gè)關(guān)于IBD患者妊娠期間使用維得利珠單抗或?yàn)跛九珕慰沟亩嘀行年?duì)列研究結(jié)果顯示[56],與懷孕期間使用抗-TNF藥物的患者相比,使用維得利珠單抗或?yàn)跛九珕慰拱l(fā)生不良妊娠結(jié)局或新生兒結(jié)局的風(fēng)險(xiǎn)相似,但仍需更多的證據(jù)支持.因此,妊娠期使用維得利珠單抗或?yàn)跛九珕慰箖H在充分權(quán)衡妊娠患者的獲益高于風(fēng)險(xiǎn)的前提下使用,由于目前證據(jù)有限,建議在妊娠期、哺乳期慎用.

2.2.2 男性生殖:在對(duì)男性性功能、生殖激素和生育能力影響方面,抗-TNF藥物和維得利珠單抗未提示副作用.值得一提的是,TNF-a在精子發(fā)生和睪丸穩(wěn)態(tài)中起著重要作用,至少對(duì)于被診斷為類風(fēng)濕性關(guān)節(jié)炎的患者,抗-TNF藥物似乎對(duì)精子質(zhì)量有積極的影響,但仍需要進(jìn)一步研究[57].

2.3 疫苗接種 由于缺乏疫苗接種知識(shí)、擔(dān)心疫苗安全性等原因,IBD患者的疫苗接種率低于一般人群.接受抗-TNF藥物治療的患者對(duì)滅活疫苗的起始和維持免疫反應(yīng)均可能會(huì)減弱.而與健康對(duì)照人群相比,維得利珠單抗無(wú)論是單藥治療或與免疫抑制劑聯(lián)合應(yīng)用,均不影響IBD患者對(duì)流感疫苗的反應(yīng)[58].一項(xiàng)英國(guó)多中心隊(duì)列研究證實(shí)[59],使用英夫利西單抗治療與SARS-CoV-2感染相關(guān)血清學(xué)免疫反應(yīng)減弱存在相關(guān)性.盡管SARS-CoV-2疑似和確診感染率與維得利珠單抗相似,但接受英夫利西單抗治療的患者中觀察抗體免疫反應(yīng)較低.

3 抗TNF-α治療失敗的挽救治療

目前的一項(xiàng)研究表明[60],在第一種抗TNF-α不耐受、原發(fā)無(wú)效或繼發(fā)失效后,IBD患者可以選擇第二種抗TNF-α藥物治療.基于綜合的考慮,在臨床實(shí)踐中如果第二種抗TNF-α治療失敗,通常不建議采用第三種抗TNF-α治療的策略.

一項(xiàng)多中心回顧性隊(duì)列研究顯示[61],維得利珠單抗和抗TNF-α藥物在IBD二線生物制劑治療時(shí)的持續(xù)治療率和安全性方面沒(méi)有明顯差異.因此對(duì)于第一種抗TNF-α藥物失敗的IBD患者,治療選擇需要考慮其他因素,例如價(jià)格、給藥途徑、個(gè)人特征等.法國(guó)的一篇多中心回顧性研究比較了烏司奴單抗和維得利珠單抗在抗TNF-α治療失敗后的CD患者中的療效,結(jié)果顯示,第48周烏司奴單抗治療的臨床緩解率、無(wú)激素緩解率和藥物留存率(54.4%、44.7%和71.5%)均顯著高于維得利珠單抗(38.3%、34.0%和49.7%)[62].越來(lái)越多新證據(jù)提示,抗TNF-α治療失敗后,二線使用烏司奴單抗的臨床療效優(yōu)于另一種抗-TNF藥物和維得利珠單抗.

4 生物制劑治療藥物監(jiān)測(cè)

治療藥物監(jiān)測(cè)已成為個(gè)性化給藥的重要工具,尤其是基于觀察到的血清藥物濃度與治療效果之間的關(guān)聯(lián)治療[63].在目前新的生物制劑的使用中,治療藥物檢測(cè)還處于起步階段,與抗TNF-α藥物相比,免疫抑制劑的使用不會(huì)影響維得利株的清除率、促使機(jī)體產(chǎn)生抗體或提高維得利株的療效[64].基于目前所有維得利株單抗免疫原性的證據(jù)可知,除非出現(xiàn)了應(yīng)答喪失的情況,常規(guī)測(cè)定抗維得利株抗體對(duì)于指導(dǎo)治療無(wú)價(jià)值.與維得利珠單抗相似,在UNITI和UNIFI試驗(yàn)中,抗烏司奴單抗的抗體非常罕見(jiàn),總發(fā)生率分別為2.3%和5.7%.臨床上烏司奴單抗劑量強(qiáng)化治療在失去應(yīng)答的患者中是否有用尚有爭(zhēng)議[65].

5 總結(jié)與展望

隨著生物制劑日新月異的發(fā)展,IBD患者有了更多的選擇,個(gè)體化治療、達(dá)標(biāo)治療的呼聲越來(lái)越高,面對(duì)百花齊放的生物制劑,需根據(jù)不同IBD個(gè)體權(quán)衡好風(fēng)險(xiǎn)和獲益,結(jié)合患者意愿選擇最佳的生物制劑.生物制劑中起效速度較快的英夫利昔單抗,被推薦作為急性重癥UC挽救治療的一線藥物.對(duì)于CD并發(fā)肛瘺或合并腸外表現(xiàn),抗TNF-α藥物臨床療效確切,同時(shí)妊娠早期使用的安全性已得到肯定.作為唯一的腸道選擇性生物制劑,療效持久且安全等級(jí)居于IBD藥物首位的維得利珠單抗是腫瘤患者和感染患者首先考慮的,且被推薦作為中重度UC的一線治療藥物.皮下給藥的阿達(dá)木單抗和烏司奴單抗,其便捷性會(huì)是許多患者的首選考慮.目前隨著更多治療靶點(diǎn)被發(fā)現(xiàn),越來(lái)越多的生物制劑被研究,患者和臨床醫(yī)生的選擇性在增加.但新型生物制劑的出現(xiàn)給患者和醫(yī)師帶來(lái)了希望的同時(shí),也對(duì)IBD治療模式提出了挑戰(zhàn).未來(lái)的研究方向,是預(yù)測(cè)不同患者使用不同藥物的療效,以獲得更好的治療結(jié)果.加強(qiáng)對(duì)IBD發(fā)病機(jī)制和臨床熱點(diǎn)的研究,將有助于未來(lái)IBD個(gè)體化精準(zhǔn)治療和新型治療模式的開展.

6 參考文獻(xiàn)

1 Torres J,Mehandru S,Colombel JF,Peyrin-Biroulet L.Crohn’s disease.Lancet2017;389:1741-1755 [PMID:27914655 DOI:10.1016/S0140-6736(16)31711-1]

2 Ungaro R,Mehandru S,Allen PB,Peyrin-Biroulet L,Colombel JF.Ulcerative colitis.Lancet2017;389:1756-1770 [PMID:27914657 DOI:10.1016/S0140-6736(16)32126-2]

3 Rencz F,Péntek M,Bortlik M,Zagorowicz E,Hlavaty T,?liwczyński A,Diculescu MM,Kupcinskas L,Gecse KB,Gulácsi L,Lakatos PL.Biological therapy in inflammatory bowel diseases:access in Central and Eastern Europe.World J Gastroenterol2015;21:1728-1737 [PMID:25684937 DOI:10.3748/wjg.v21.i6.1728]

4 Feuerstein JD,Isaacs KL,Schneider Y,Siddique SM,Falck-Ytter Y,Singh S;AGA Institute Clinical Guidelines Committee.AGA Clinical Practice Guidelines on the Management of Moderate to Severe Ulcerative Colitis.Gastroenterology2020;158:1450-1461[PMID:31945371 DOI:10.1053/j.gastro.2020.01.006]

5 Danese S.Mechanisms of action of infliximab in inflammatory bowel disease:an anti-inflammatory multitasker.Dig Liver Dis2008;40 Suppl 2:S225-S228 [PMID:18598993 DOI:10.1016/S1590-8658(08)60530-7]

6 張巧,曾健,周金秋,蒙張敏,黃曉麗,甘華田.中國(guó)炎癥性腸病生物制劑使用現(xiàn)狀的系統(tǒng)回顧和Meta分析.臨床內(nèi)科雜志 2020;37:281-286 [DOI:10.3969/j.issn.1001-9057.2020.04.012]

7 Vavricka SR,Rogler G,Gantenbein C,Spoerri M,Prinz Vavricka M,Navarini AA,French LE,Safroneeva E,Fournier N,Straumann A,Froehlich F,Fried M,Michetti P,Seibold F,Lakatos PL,Peyrin-Biroulet L,Schoepfer AM.Chronological Order of Appearance of Extraintestinal Manifestations Relative to the Time of IBD Diagnosis in the Swiss Inflammatory Bowel Disease Cohort.Inflamm Bowel Dis2015;21:1794-1800 [PMID:26020601 DOI:10.1097/MIB.0000000000000429]

8 Harbord M,Annese V,Vavricka SR,Allez M,Barreiro-de Acosta M,Boberg KM,Burisch J,De Vos M,De Vries AM,Dick AD,Juillerat P,Karlsen TH,Koutroubakis I,Lakatos PL,Orchard T,Papay P,Raine T,Reinshagen M,Thaci D,Tilg H,Carbonnel F;European Crohn’s and Colitis Organisation.The First European Evidence-based Consensus on Extra-intestinal Manifestations in Inflammatory Bowel Disease.J Crohns Colitis2016;10:239-254[PMID:26614685 DOI:10.1093/ecco-jcc/jjv213]

9 Ruemmele FM,Veres G,Kolho KL,Griffiths A,Levine A,Escher JC,Amil Dias J,Barabino A,Braegger CP,Bronsky J,Buderus S,Martín-de-Carpi J,De Ridder L,Fagerberg UL,Hugot JP,Kierkus J,Kolacek S,Koletzko S,Lionetti P,Miele E,Navas López VM,Paerregaard A,Russell RK,Serban DE,Shaoul R,Van Rheenen P,Veereman G,Weiss B,Wilson D,Dignass A,Eliakim A,Winter H,Turner D;European Crohn’s and Colitis Organisation;European Society of Pediatric Gastroenterology,Hepatology and Nutrition.Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn’s disease.J Crohns Colitis2014;8:1179-1207 [PMID:24909831 DOI:10.1016/j.crohns.2014.04.005]

10 Colombel JF,Sandborn WJ,Rutgeerts P,Enns R,Hanauer SB,Panaccione R,Schreiber S,Byczkowski D,Li J,Kent JD,Pollack PF.Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease:the CHARM trial.Gastroenterology2007;132:52-65 [PMID:17241859 DOI:10.1053/j.gastro.2006.11.041]

11 Sandborn WJ,van Assche G,Reinisch W,Colombel JF,D’Haens G,Wolf DC,Kron M,Tighe MB,Lazar A,Thakkar RB.Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis.Gastroenterology2012;142:257-65.e1-3 [PMID:22062358 DOI:10.1053/j.gastro.2011.10.032]

12 Hanauer SB,Sandborn WJ,Rutgeerts P,Fedorak RN,Lukas M,MacIntosh D,Panaccione R,Wolf D,Pollack P.Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease:the CLASSIC-I trial.Gastroenterology2006;130:323-33;quiz 591 [PMID:16472588 DOI:10.1053/j.gastro.2005.11.030]

13 Sandborn WJ,Colombel JF,Panés J,Castillo M,Robinson AM,Zhou Q,Yang M,Thakkar R.Exploring the use of adalimumab for patients with moderate Crohn’s disease:subanalyses from induction and maintenance trials.J Crohns Colitis2013;7:958-967[PMID:23517933 DOI:10.1016/j.crohns.2013.02.016]

14 Panaccione R,Colombel JF,Sandborn WJ,D’Haens G,Zhou Q,Pollack PF,Thakkar RB,Robinson AM.Adalimumab maintains remission of Crohn’s disease after up to 4 years of treatment:data from CHARM and ADHERE.Aliment Pharmacol Ther2013;38:1236-1247 [PMID:24134498 DOI:10.1111/apt.12499]

15 Tracey D,Klareskog L,Sasso EH,Salfeld JG,Tak PP.Tumor necrosis factor antagonist mechanisms of action:a comprehensive review.Pharmacol Ther2008;117:244-279 [PMID:18155297 DOI:10.1016/j.pharmthera.2007.10.001]

16 Rutgeerts P,Feagan BG,Marano CW,Padgett L,Strauss R,Johanns J,Adedokun OJ,Guzzo C,Zhang H,Colombel JF,Reinisch W,Gibson PR,Sandborn WJ;PURSUIT-IV study group.Randomised clinical trial:a placebo-controlled study of intravenous golimumab induction therapy for ulcerative colitis.Aliment Pharmacol Ther2015;42:504-514 [PMID:26119226 DOI:10.1111/apt.13291]

17 Sandborn WJ,Feagan BG,Marano C,Zhang H,Strauss R,Johanns J,Adedokun OJ,Guzzo C,Colombel JF,Reinisch W,Gibson PR,Collins J,J?rnerot G,Hibi T,Rutgeerts P;PURSUITSC Study Group.Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis.Gastroenterology2014;146:85-95;quiz e14-5[PMID:23735746 DOI:10.1053/j.gastro.2013.05.048]

18 Sandborn WJ,Feagan BG,Marano C,Zhang H,Strauss R,Johanns J,Adedokun OJ,Guzzo C,Colombel JF,Reinisch W,Gibson PR,Collins J,J?rnerot G,Rutgeerts P;PURSUITMaintenance Study Group.Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis.Gastroenterology2014;146:96-109.e1 [PMID:23770005 DOI:10.1053/j.gastro.2013.06.010]

19 Da W,Zhu J,Wang L,Lu Y.Efficacy and safety of certolizumab pegol for Crohn’s disease:a systematic review and meta-analysis.Adv Ther2013;30:541-553 [PMID:23681504 DOI:10.1007/s12325-013-0026-3]

20 Novak G,Hindryckx P,Khanna R,Jairath V,Feagan BG.The safety of vedolizumab for the treatment of ulcerative colitis.Expert Opin Drug Saf2017;16:501-507 [PMID:28276855 DOI:10.1080/14740338.2017.1300251]

21 Bressler B,Marshall JK,Bernstein CN,Bitton A,Jones J,Leontiadis GI,Panaccione R,Steinhart AH,Tse F,Feagan B;Toronto Ulcerative Colitis Consensus Group.Clinical practice guidelines for the medical management of nonhospitalized ulcerative colitis:the Toronto consensus.Gastroenterology2015;148:1035-1058.e3 [PMID:25747596 DOI:10.1053/j.gastro.2015.03.001]

22 Dassopoulos T,Cohen RD,Scherl EJ,Schwartz RM,Kosinski L,Regueiro MD.Ulcerative Colitis Care Pathway.Gastroenterology2015;149:238-245 [PMID:26025078 DOI:10.1053/j.gastro.2015.05.036]

23 Feagan BG,Rutgeerts P,Sands BE,Hanauer S,Colombel JF,Sandborn WJ,Van Assche G,Axler J,Kim HJ,Danese S,Fox I,Milch C,Sankoh S,Wyant T,Xu J,Parikh A;GEMINI 1 Study Group.Vedolizumab as induction and maintenance therapy for ulcerative colitis.N Engl J Med2013;369:699-710 [PMID:23964932 DOI:10.1056/NEJMoa1215734]

24 Favale A,Onali S,Caprioli F,Pugliese D,Armuzzi A,Macaluso FS,Orlando A,Viola A,Fries W,Rispo A,Castiglione F,Mocci G,Chicco F,Usai P,Calabrese E,Biancone L,Monteleone G,Fantini MC;Italian Group for the study of Inflammatory Bowel Disease (IG-IBD).Comparative Efficacy of Vedolizumab and Adalimumab in Ulcerative Colitis Patients Previously Treated With Infliximab.Inflamm Bowel Dis2019;25:1805-1812 [PMID:30931477 DOI:10.1093/ibd/izz057]

25 Narula N,Peerani F,Meserve J,Kochhar G,Chaudrey K,Hartke J,Chilukuri P,Koliani-Pace J,Winters A,Katta L,Shmidt E,Hirten R,Faleck D,Parikh MP,Whitehead D,Boland BS,Singh S,Sagi SV,Fischer M,Chang S,Barocas M,Luo M,Lasch K,Bohm M,Lukin D,Sultan K,Swaminath A,Hudesman D,Gupta N,Shen B,Kane S,Loftus EV,Siegel CA,Sands BE,Colombel JF,Sandborn WJ,Dulai PS.Vedolizumab for Ulcerative Colitis:Treatment Outcomes from the VICTORY Consortium.Am J Gastroenterol2018;113:1345[PMID:29946178 DOI:10.1038/s41395-018-0162-0]

26 Rubin DT,Ananthakrishnan AN,Siegel CA,Sauer BG,Long MD.ACG Clinical Guideline:Ulcerative Colitis in Adults.Am J Gastroenterol2019;114:384-413 [PMID:30840605 DOI:10.14309/ajg.0000000000000152]

27 Dulai PS,Peyrin-Biroulet L,Demuth D,Lasch K,Hahn KA,Lindner D,Patel H,Jairath V.Early Intervention With Vedolizumab on Longer Term Surgery Rates in Crohn’s Disease:Post Hoc Analysis of the GEMINI Phase 3 and Long-term Safety Programs.J Crohns Colitis2020 [PMID:32691844 DOI:10.1093/ecco-jcc/jjaa153]

28 Shahidi N,Bressler B,Panaccione R.The role of vedolizumab in patients with moderate-to-severe Crohn’s disease and ulcerative colitis.Therap Adv Gastroenterol2016;9:330-338 [PMID:27134663 DOI:10.1177/1756283X16635081]

29 Moschen AR,Tilg H,Raine T.IL-12,IL-23 and IL-17 in IBD:immunobiology and therapeutic targeting.Nat Rev Gastroenterol Hepatol2019;16:185-196 [PMID:30478416 DOI:10.1038/s41575-018-0084-8]

30 Torres J,Bonovas S,Doherty G,Kucharzik T,Gisbert JP,Raine T,Adamina M,Armuzzi A,Bachmann O,Bager P,Biancone L,Bokemeyer B,Bossuyt P,Burisch J,Collins P,El-Hussuna A,Ellul P,Frei-Lanter C,Furfaro F,Gingert C,Gionchetti P,Gomollon F,González-Lorenzo M,Gordon H,Hlavaty T,Juillerat P,Katsanos K,Kopylov U,Krustins E,Lytras T,Maaser C,Magro F,Marshall JK,Myrelid P,Pellino G,Rosa I,Sabino J,Savarino E,Spinelli A,Stassen L,Uzzan M,Vavricka S,Verstockt B,Warusavitarne J,Zmora O,Fiorino G.ECCO Guidelines on Therapeutics in Crohn’s Disease:Medical Treatment.J Crohns Colitis2020;14:4-22 [PMID:31711158 DOI:10.1093/ecco-jcc/jjz180]

31 Chapuis-Biron C,Kirchgesner J,Pariente B,Bouhnik Y,Amiot A,Viennot S,Serrero M,Fumery M,Allez M,Siproudhis L,Buisson A,Pineton de Chambrun G,Abitbol V,Nancey S,Caillo L,Plastaras L,Savoye G,Chanteloup E,Simon M,Dib N,Rajca S,Amil M,Parmentier AL,Peyrin-Biroulet L,Vuitton L;GETAID BioLAP Study Group.Ustekinumab for Perianal Crohn’s Disease:The BioLAP Multicenter Study From the GETAID.Am J Gastroenterol2020;115:1812-1820 [PMID:33156100 DOI:10.14309/ajg.0000000000000810]

32 Rowan CR,Boland K,Harewood GC.Ustekinumab as Induction and Maintenance Therapy for Ulcerative Colitis.N Engl J Med2020;382:91 [PMID:31875504 DOI:10.1056/NEJMc1915042]

33 Singh S,Fumery M,Sandborn WJ,Murad MH.Systematic review with network meta-analysis:first-and second-line pharmacotherapy for moderate-severe ulcerative colitis.Aliment Pharmacol Ther2018;47:162-175 [PMID:29205406 DOI:10.1111/apt.14422]

34 Sands BE,Peyrin-Biroulet L,Loftus EV Jr,Danese S,Colombel JF,T?rüner M,Jonaitis L,Abhyankar B,Chen J,Rogers R,Lirio RA,Bornstein JD,Schreiber S;VARSITY Study Group.Vedolizumab versus Adalimumab for Moderate-to-Severe Ulcerative Colitis.N Engl J Med2019;381:1215-1226 [PMID:31553834 DOI:10.105/NEJMoa1905725]

35 戴張晗,王天蓉,鄭青,冉志華.英夫利西單抗在HBV感染炎癥性腸病患者中使用的安全性.胃腸病學(xué) 2017;22:582-587 [DOI:10.3969/j.issn.1008-7125.2017.10.002]

36 Andersen NN,Jess T.Risk of infections associated with biological treatment in inflammatory bowel disease.World J Gastroenterol2014;20:16014-16019 [PMID:25473153 DOI:10.3748/wjg.v20.i43.16014]

37 Cruz AT,Starke JR,Lobato MN.Old and new approaches to diagnosing and treating latent tuberculosis in children in lowincidence countries.Curr Opin Pediatr2014;26:106-113 [PMID:24299911 DOI:10.1097/MOP.0000000000000049]

38 Heilig CM,Feng PJ,Joloba ML,Johnson JL,Morgan K,Gitta P,Boom WH,Mayanja-Kizza H,Eisenach KD,Bozeman L,Goldberg SV.How we determined the most reliable solid medium for studying treatment of tuberculosis.Tuberculosis (Edinb)2014;94:317-322 [PMID:24661816 DOI:10.1016/j.tube.2014.02.006]

39 Ng SC,Hilmi IN,Blake A,Bhayat F,Adsul S,Khan QR,Wu DC.Low Frequency of Opportunistic Infections in Patients Receiving Vedolizumab in Clinical Trials and Post-Marketing Setting.Inflamm Bowel Dis2018;24:2431-2441 [PMID:30312414 DOI:10.1093/ibd/izy153]

40 Nyboe Andersen N,Pasternak B,Friis-M?ller N,Andersson M,Jess T.Association between tumour necrosis factor-α inhibitors and risk of serious infections in people with inflammatory bowel disease:nationwide Danish cohort study.BMJ2015;350:h2809[PMID:26048617 DOI:10.1136/bmj.h2809]

41 Singh S,Facciorusso A,Dulai PS,Jairath V,Sandborn WJ.Comparative Risk of Serious Infections With Biologic and/or Immunosuppressive Therapy in Patients With Inflammatory Bowel Diseases:A Systematic Review and Meta-Analysis.Clin Gastroenterol Hepatol2020;18:69-81.e3 [PMID:30876964 DOI:10.1016/j.cgh.2019.02.044]

42 Colombel JF,Sands BE,Rutgeerts P,Sandborn W,Danese S,D’Haens G,Panaccione R,Loftus EV Jr,Sankoh S,Fox I,Parikh A,Milch C,Abhyankar B,Feagan BG.The safety of vedolizumab for ulcerative colitis and Crohn’s disease.Gut2017;66:839-851[PMID:26893500 DOI:10.1136/gutjnl-2015-311079]

43 Lemaitre M,Kirchgesner J,Rudnichi A,Carrat F,Zureik M,Carbonnel F,Dray-Spira R.Association Between Use of Thiopurines or Tumor Necrosis Factor Antagonists Alone or in Combination and Risk of Lymphoma in Patients With Inflammatory Bowel Disease.JAMA2017;318:1679-1686 [PMID:29114832 DOI:10.1001/jama.2017.16071]

44 Annese V,Beaugerie L,Egan L,Biancone L,Bolling C,Brandts C,Dierickx D,Dummer R,Fiorino G,Gornet JM,Higgins P,Katsanos KH,Nissen L,Pellino G,Rogler G,Scaldaferri F,Szymanska E,Eliakim R;ECCO.European Evidence-based Consensus:Inflammatory Bowel Disease and Malignancies.J Crohns Colitis2015;9:945-965 [PMID:26294789 DOI:10.1093/ecco-jcc/jjv141]

45 Colombel JF,Sands BE,Rutgeerts P,Sandborn W,Danese S,D’Haens G,Panaccione R,Loftus EV Jr,Sankoh S,Fox I,Parikh A,Milch C,Abhyankar B,Feagan BG.The safety of vedolizumab for ulcerative colitis and Crohn’s disease.Gut2017;66:839-851[PMID:26893500 DOI:10.1136/gutjnl-2015-311079]

46 Click B,Regueiro M.A Practical Guide to the Safety and Monitoring of New IBD Therapies.Inflamm Bowel Dis2019;25:831-842 [PMID:30312391 DOI:10.1093/ibd/izy313]

47 Loftus EV Jr,Feagan BG,Panaccione R,Colombel JF,Sandborn WJ,Sands BE,Danese S,D’Haens G,Rubin DT,Shafran I,Parfionovas A,Rogers R,Lirio RA,Vermeire S.Long-term safety of vedolizumab for inflammatory bowel disease.Aliment Pharmacol Ther2020;52:1353-1365 [PMID:32876349 DOI:10.1111/apt.16060]

48 Click B,Regueiro M.A Practical Guide to the Safety and Monitoring of New IBD Therapies.Inflamm Bowel Dis2019;25:831-842 [PMID:30312391 DOI:10.1093/ibd/izy313]

49 Sandborn WJ,Feagan BG,Danese S,O’Brien CD,Ott E,Marano C,Baker T,Zhou Y,Volger S,Tikhonov I,Gasink C,Sands BE,Ghosh S.Safety of Ustekinumab in Inflammatory Bowel Disease:Pooled Safety Analysis of Results from Phase 2/3 Studies.Inflamm Bowel Dis2020 [PMID:32964215 DOI:10.1093/ibd/izaa236]

50 Kwon HJ,Coté TR,Cuffe MS,Kramer JM,Braun MM.Case reports of heart failure after therapy with a tumor necrosis factor antagonist.Ann Intern Med2003;138:807-811 [PMID:12755552 DOI:10.7326/0003-4819-138-10-200305200-00008]

51 Cheifetz A,Smedley M,Martin S,Reiter M,Leone G,Mayer L,Plevy S.The incidence and management of infusion reactions to infliximab:a large center experience.Am J Gastroenterol2003;98:1315-1324 [PMID:12818276 DOI:10.1111/j.1572-0241.2003.07457.x]

52 Davies SC,Nguyen TM,Parker CE,MacDonald JK,Jairath V,Khanna R.Anti-IL-12/23p40 antibodies for maintenance of remission in Crohn’s disease.Cochrane Database Syst Rev2019;12:CD012804 [PMID:31828765 DOI:10.1002/14651858.CD012804.pub2]

53 Shihab Z,Yeomans ND,De Cruz P.Anti-Tumour Necrosis Factor α Therapies and Inflammatory Bowel Disease Pregnancy Outcomes:A Meta-analysis.J Crohns Colitis2016;10:979-988[PMID:26755733 DOI:10.1093/ecco-jcc/jjv234]

54 van der Woude CJ,Ardizzone S,Bengtson MB,Fiorino G,Fraser G,Katsanos K,Kolacek S,Juillerat P,Mulders AG,Pedersen N,Selinger C,Sebastian S,Sturm A,Zelinkova Z,Magro F;European Crohn’s and Colitis Organization.The second European evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease.J Crohns Colitis2015;9:107-124 [PMID:25602023 DOI:10.1093/ecco-jcc/jju006]

55 Puchner A,Gr?chenig HP,Sautner J,Helmy-Bader Y,Juch H,Reinisch S,H?genauer C,Koch R,Hermann J,Studnicka-Benke A,Weger W,Puchner R,Dejaco C.Immunosuppressives and biologics during pregnancy and lactation :A consensus report issued by the Austrian Societies of Gastroenterology and Hepatology and Rheumatology and Rehabilitation.Wien Klin Wochenschr2019;131:29-44 [PMID:30643992 DOI:10.1007/s00508-019-1448-y]

56 Wils P,Seksik P,Stefanescu C,Nancey S,Allez M,Pineton de Chambrun G,Altwegg R,Gilletta C,Vuitton L,Viennot S,Serrero M,Fumery M,Savoye G,Collins M,Goutorbe F,Brixi H,Bouguen G,Tavernier N,Boualit M,Amiot A,Abitbol V,Laharie D,Pariente B;PREGNANCY-GETAID study group.Safety of ustekinumab or vedolizumab in pregnant inflammatory bowel disease patients:a multicentre cohort study.Aliment Pharmacol Ther2021;53:460-470 [PMID:33345331 DOI:10.1111/apt.16192]

57 Perez-Garcia LF,Dolhain RJEM,Vorstenbosch S,Bramer W,van Puijenbroek E,Hazes JMW,Te Winkel B.The effect of paternal exposure to immunosuppressive drugs on sexual function,reproductive hormones,fertility,pregnancy and offspring outcomes:a systematic review.Hum Reprod Update2020;26:961-1001 [PMID:32743663 DOI:10.1093/humupd/dmaa022]

58 Caldera F,Ley D,Hayney MS,Farraye FA.Optimizing Immunization Strategies in Patients with IBD.Inflamm Bowel Dis2021;27:123-133 [PMID:32232388 DOI:10.1093/ibd/izaa055]

59 Kennedy NA,Goodhand JR,Bewshea C,Nice R,Chee D,Lin S,Chanchlani N,Butterworth J,Cooney R,Croft NM,Hart AL,Irving PM,Kok KB,Lamb CA,Limdi JK,Macdonald J,McGovern DP,Mehta SJ,Murray CD,Patel KV,Pollok RC,Raine T,Russell RK,Selinger CP,Smith PJ,Bowden J,McDonald TJ,Lees CW,Sebastian S,Powell N,Ahmad T;Contributors to the CLARITY IBD study.Anti-SARS-CoV-2 antibody responses are attenuated in patients with IBD treated with infliximab.Gut2021;70:865-875 [PMID:33753421 DOI:10.1136/gutjnl-2021-324388]

60 Casanova MJ,Chaparro M,Mínguez M,Ricart E,Taxonera C,García-López S,Guardiola J,López-San Román A,Iglesias E,Beltrán B,Sicilia B,Vera MI,Hinojosa J,Riestra S,Domènech E,Calvet X,Pérez-Calle JL,Martín-Arranz MD,Aldeguer X,Rivero M,Monfort D,Barrio J,Esteve M,Márquez L,Lorente R,García-Planella E,de Castro L,Bermejo F,Merino O,Rodríguez-Pérez A,Martínez-Montiel P,Van Domselaar M,Alcaín G,Domínguez-Cajal M,Mu?oz C,Gomollón F,Fernández-Salazar L,García-Sepulcre MF,Rodríguez-Lago I,Gutiérrez A,Argüelles-Arias F,Rodriguez C,Rodríguez GE,Bujanda L,Llaó J,Varela P,Ramos L,Huguet JM,Almela P,Romero P,Navarro-Llavat M,Abad á,Ramírez-de la Piscina P,Lucendo AJ,Sesé E,Madrigal RE,Charro M,García-Herola A,Pajares R,Khorrami S,Gisbert JP.Effectiveness and Safety of the Sequential Use of a Second and Third Anti-TNF Agent in Patients With Inflammatory Bowel Disease:Results From the Eneida Registry.Inflamm Bowel Dis2020;26:606-616 [PMID:31504569 DOI:10.1093/ibd/izz192]

61 Rundquist S,Sachs MC,Eriksson C,Olén O,Montgomery S,Halfvarson J;SWIBREG Study Group.Drug survival of anti-TNF agents compared with vedolizumab as a second-line biological treatment in inflammatory bowel disease:results from nationwide Swedish registers.Aliment Pharmacol Ther2021;53:471-483 [PMID:33340426 DOI:10.1111/apt.16193]

62 Alric H,Amiot A,Kirchgesner J,Tréton X,Allez M,Bouhnik Y,Beaugerie L,Carbonnel F,Meyer A.The effectiveness of either ustekinumab or vedolizumab in 239 patients with Crohn’s disease refractory to anti-tumour necrosis factor.Aliment Pharmacol Ther2020;51:948-957 [PMID:32249966 DOI:10.1111/apt.15706]

63 Papamichael K,Vogelzang EH,Lambert J,Wolbink G,Cheifetz AS.Therapeutic drug monitoring with biologic agents in immune mediated inflammatory diseases.Expert Rev Clin Immunol2019;15:837-848 [PMID:31180729 DOI:10.1080/1744666X.2019.1630273]

64 Hedin C,Halfvarson J.Should we use vedolizumab as mono or combo therapy in ulcerative colitis?Best Pract Res Clin Gastroenterol2018;32-33:27-34 [PMID:30060935 DOI:10.1016/j.bpg.2018.05.002]

65 Alsoud D,Vermeire S,Verstockt B.Monitoring vedolizumab and ustekinumab drug levels in patients with inflammatory bowel disease:hype or hope?Curr Opin Pharmacol2020;55:17-30[PMID:33039940 DOI:10.1016/j.coph.2020.09.002]