炎癥性腸病治療中生物制劑的個(gè)體化選擇

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、沒有復(fù)雜并發(fā)癥、且沒有使用過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):過敏是英夫利昔單抗相對(duì)常見的不良反應(yīng),急性過敏反應(yīng)可出現(xiàn)呼吸短促和蕁麻疹,嚴(yán)重可能會(huì)導(dǎo)致過敏性休克.遲發(fā)型過敏反應(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,常見的嚴(yán)重不良事件如疾病惡化、腹痛.

烏司奴單抗常見的藥物不良反應(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,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)師帶來了希望的同時(shí),也對(duì)IBD治療模式提出了挑戰(zhàn).未來的研究方向,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IBD個(gè)體化精準(zhǔn)治療和新型治療模式的開展.

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