Volume 1 - Issue 1, June 2017

2017 Update in IBD Treatment Algorithm Back

Introduction

Inflammatory bowel disease (IBD) primarily includes ulcerative colitis (UC) and Crohn’s disease (CD). Despite relatively low incidence in Taiwan when compared with other countries, the prevalence of UC and CD has raised 10 fold in the past decade1. Considering the climbing of the prevalence and special factors for Taiwanese population, Taiwan Society of Inflammatory Bowel Disease (TSIBD) completed the clinical guidelines of UC and CD at the end of 2016.

Besides steroid, tumor necrosis factor (TNF) inhibitors, and immunosuppressants, vedolizumab (Entyvio) has been made available in Taiwan by 2016, offering another treatment option for patients with IBD. Vedolizumab is a novel agent. Working as an antibody of integrin, vedolizumab can block the interaction of α4β7 integrin on T cells with MAdCAM-1 expressed on endothelium of the intestinal vasculature with increased concentrations at sites of inflammation. By affecting the gut-specific homing process, it can inhibit T cells going into inflamed gastrointestinal tissue, leading to reduction of chronic inflammation in patients with IBD. Now let’s take a look at the updates of TSIBD guidelines and clinical trials and real-life experience of vedolizumab, and to discuss the role of vedolizumab in treating patients with IBD.

TSIBD臨床治療指引之更新

成大醫院胃腸肝膽科的莊喬雄醫師以及台大 醫院內科部的魏淑鉁副教授說明了TSIBD臨 床治療指引的內容。早於2010年TSIBD就提 議應訂定台灣本土對於UC與CD的臨床治療 指引,國際上雖已有各國所出的指引,但由 於台灣的疾病分佈與狀態、地方性疾病(特 別是B型肝炎與結核病)以及健保所給付的範 圍等可能都與他國不同。為了幫助年輕醫師 更正確及有效率地診斷IBD,且能因應健保 規定照顧IBD患者,因此特別邀請包括腸胃 科、直腸外科、小兒腸胃科、病理科與放射 科等27位專家,根據目前有關IBD的文獻證 據,並考慮到與台灣相關的各個因子,在經 過6次會議討論與投票後,於2016年年底完成 了TSIBD分別對於UC與CD的臨床治療指引。

TSIBD臨床治療指引之內容簡介

TSIBD臨床指引內容包括流行病學、診斷、藥物與手術治療、監測追蹤、使用免疫抑制劑之前的特殊考量與特殊族群(懷孕婦女與 小兒科病患等。診斷部份描述了病人的臨床病史與理學檢查、UC與CD的臨床指標、內 視鏡檢查、影像檢查以及病理檢查等內容。治療部份不論是UC或CD,都先將病患以病 情活性程度分類,再依建議的流程選擇適合 病患的治療方式。由於使用的藥物大部份都 是免疫抑制劑,因此在用藥前對於感染風險 的考量特別重要。

台灣使用免疫抑制劑前之特殊考量

台灣B型肝炎帶原者的比例與他國相比甚高,因此TSIBD的指引建議在開始給予IBD患者免疫抑制劑,像是類固醇或生物製劑治療之前,應先抽血檢查B型肝炎表面抗原(HBsAg)、B型肝炎表面抗體(HBsAb)與B型肝炎核心抗體(HBcAb)。若病患的HBsAg及/或HBcAb是陽性的,在開始使用免疫抑制劑之前應進行B型肝炎病毒量檢測(HBV DNA quantification)。若病患的B型肝炎病毒量偵測得到,則建議應給予抗病毒藥物以預防B型肝炎的活化(健保並未給付),或至少密集監測HBV DNA,並在病毒量增加時開始抗病毒藥物。若病患的HBsAg、HBsAb與HBcAb皆為陰性,則建議施打B型肝炎疫苗。

結核病同樣也是需要特別注意的另一個感染疾病。雖然新診斷的結核病例在過去十年內已逐漸減少,但是與其他國家相比發生率仍屬較高。類固醇與TNF抑制劑都是會使得潛伏結核病再活化的危險因子,因此 TSIBD的指引建議在開始給予IBD患者生物製劑療法之前,應以胸部X光(及丙型干擾素血液測驗 [interferon-γ release assays,IGRA ])或結核菌素皮膚測試(tuberculin skin test,TST)篩檢潛伏結核感染。TST並不是最建議的篩檢方式,因為曾接受過疫苗的患者也有可能導致檢測結果偽陽性。在接受生物製劑療法期間,患者應至少每年做一次胸部X光檢查,以監測結核病的狀況。若病患經診斷患有潛伏性結核病,在開始生物製劑療法的至少前4週應開始接受預防性療法。根據TSIBD的研究,大部份有潛伏性結核病且接受TNF抑制劑治療的台灣IBD患者,都在開始生物製劑之前接受了isoniazid的預防性療法,且都有效地抑制結核病的活化。

TSIBD臨床治療指引關於治療之建議

目前台灣健保對於UC所給付的生物製劑包括adalimumab(40週)與golimumab(38週),病患須有Mayo score大於9分。而對於CD所給付的生物製劑僅有adalimumab,病患須有CDAI大於250分,且一個療程最多給付52週。若停藥後症狀再度復發,可再次申請。

TSIBD臨床指引建議輕、中度的UC病患應從局部的藥物開始治療,並視疾病部位加上口服藥物(見圖一)。重度病患則從靜脈給藥的類固醇開始治療,有最高劑量的建議是因為即使劑量高於此建議量,也不會造成較好的病患結果。臨床上根據病患的徵兆與症狀適時判定以藥物或手術治療是非常重要的,若使用類固醇與免疫抑制劑治療過久而無反應,將會增加術後併發症與死亡的風險。在靜脈輸注類固醇後若無反應,接下來考慮使用的藥物為cyclosporine或生物製劑,如infliximab。在cyclosporine與infliximab一對一比較的試驗中,已證實兩個藥物不論在開始後三個月或三年,其結果都是不相上下的2, 3。Cyclosporine有許多可能的不良反應與狹窄的治療濃度區間,但相較於infliximab有較短的半衰期,對於病患需要緊急結腸切除術時可能會是重要的。

除了infliximab之外,adalimumab與golimumab都已在臨床試驗中證實其對UC的 的療效。在ULTRA試驗中不論是誘導期或維持期,不管病患是否曾接受過生物製劑療法,adalimumab都證實了能提供比安慰劑顯著較多的病患達到臨床反應(clinical response)與臨床緩解(clinical remission)4。而golimumab則在PURSUIT試驗中,證實了它在誘導期與維持期比安慰劑都能提供顯著較多病患達到臨床反應與臨床緩解5, 6

圖一、UC的建議治療流程。Source: Page 24 of http://www.tsibd.org.tw/news.php?index=25&c1=5

圖一、UC的建議治療流程。Source: Page 24 of http://www.tsibd.org.tw/news.php?index=25&c1=5

圖二、CD的建議治療流程。Source: Page 20 of http://www.tsibd.org.tw/news.php?index=27&c1=5

圖二、CD的建議治療流程。Source: Page 20 of http://www.tsibd.org.tw/news.php?index=27&c1=5

TSIBD臨床指引對於CD的治療也一樣分病情活性程度來決定(見圖二)。健保目前有給付的生物製劑為adalimumab,在CLASSIC-1試驗中呈現了在誘導期的療效7,CHARM試驗則證實了在維持期的療效8。雖然adalimumab比安慰劑有顯著療效,但在一項TSIBD的試驗中發現,台灣67位接受adalimumab治療的中度到重度CD病患中,在停藥後有37位病患復發(55%),且復發的時間約為15.3個月(中位數),在三年後只有25%的病患能維持不復發8。使用adalimumab再次治療的病患中,臨床反應的比例較第一次治療時少(60.4% vs. 79.8%)9,這有可能是抗藥抗體的產生。因此依照目前健保規定的52週療法,對CD患者並不是最理想的方式。

以生物製劑療法治療IBD仍存有的問題

雖然adalimumab與golimumab與安慰劑相比都能提供顯著較多病患達到療效,但仍約有30-50%左右的病患無法對這兩個藥物產生反應5-7, 10。同時在長期使用生物製劑治療之下,有些病患會產生抗藥抗體,導致漸漸失去療效。而有許多病患在停藥之後,就會發生復發的問題。

另一個在台灣的問題則是老化,醫師在治療許多年老病患時,因為剛開始症狀較輕,且顧及易有感染與淋巴瘤的風險,因而使用較低劑量或較少的免疫抑制劑治療,反而造成更多的手術與更高的死亡率11。若能有安全性較高的生物製劑,便能較安心地治療老年IBD病患。

因此在IBD的治療上,仍有許多未滿足的需求。目前有許多試驗正在尋找發炎反應中的不同路徑作為治療IBD的標的,希望能在不久的將來提供病患更多更有效的療法。

腸道專一導向過程在IBD的重要性

台大醫院風濕免疫科的許秉寧教授解釋了腸道特定的導向過程導致IBD的發炎反應,因而可藉由此途徑尋找治療IBD的方式。

IBD的發病原理為一複雜之發炎過程

IBD是腸道內慢性發炎的疾病,以腸道發炎的深度與範圍分類,UC是非全壁式(non-transmural)的發炎,疾病只影響大腸部份;而CD則是全壁式的發炎,疾病可能影響腸胃道從口腔至肛門的任一部位。一般常見的症狀包括腹痛、嘔吐、腹瀉、血便與體重減輕等12。IBD的發病原理為一複雜的發炎過程。腸道中存有許多微生物,當他們突破上皮層的障礙後會先與先天性淋巴球(innate lymphoid cell,簡稱ILC)結合,經由一連串路徑活化T cell與B cell,最後放大成為發炎反應,導致IBD的發生。因此與IBD相關有感受性的基因座(loci)非常多。

ILC分為三類,ILC1經interleukin-12 (IL-12)刺激後會產生interferon gamma (IFN-γ);ILC2主要位在呼吸道產生IL-4、IL-5,與過敏反應有關;ILC3則主要位在腸道,上皮層細胞在與細菌接觸後刺激IL-23,活化ILC3產生IL-17與IL-22,最後導致發炎反應。因此IL-23在慢性腸道發炎中扮演關鍵的驅動角色。要把活化的T cell聚集到發炎腸道中則是一個錯綜複雜的導向過程(homing)。

IBD是由腸道專一的導向過程所導致而成
淋巴球在血液中滾動,是靠著淋巴球與內皮細胞多次碰撞而減慢滾動速度。接著因為細胞上黏著分子的親和力,像是未活化T cell上的LFA-1與上皮細胞的ICAM-1,或是已活化T cell上的VLA-4與上皮細胞的VCAM-1等,互相識別並結合,加上selectin的有效黏合,使得淋巴球能夠固定在內皮層上而停止滾動。接著淋巴球轉變形狀成為如變形蟲般穿過內皮細胞的間隙,因而進入受傷的組織中(見圖三)。

圖三、淋巴球自血液中進入組織的步驟

在腸胃道中則有特定的黏著分子。Integrin是連結細胞與細胞外基質的一種受體,由α與β兩種分子所組成的雙聚體,可經由細胞內的訊息刺激產生構造上的轉變,因而開始其黏著的功能。與腸道最相關的intergrins就是α4β7與αEβ7。已活化T cell上的α4β7 integrin會被腸道內皮細胞上所呈現的MAdCAM-1所吸引,固定在上皮組織並穿過上皮細胞而來到固有層(lamina propria)。接著αEβ7 integrin會被發炎部位的CCL25所吸引並結合,因而停在此處引起一連串放大的發炎反應(見圖四)。為了要控制IBD的發炎反應,這些與導向過程相關的分子便成為發展治療藥物的潛在標的。

圖四、淋巴球在腸道中特定的導向過程

從腸道特定的導向過程可尋找IBD療法
過去曾有許多嘗試從integrins上找尋IBD的治療目標卻失敗了,例如α4β1抑制劑natalizumab可阻擋α4β1與VCAM-1及其他上皮細胞分子的結合,原本經臨床試驗證實可治療CD,但在上市後發現有引起進行性多灶性白質腦病變(progressive multifocal leukoencephalopathy,簡稱PML)的問題。

目前最成功能治療IBD的integrin抑制劑是vedolizumab,它是一種會結合α4β7 integrin的單株抗體,能阻斷α4β7和MAdCAM-1的結合,抑制T cell進入發炎的腸道組織。除了可安全且有效地治療UC與CD之外,可能對治療原發性硬化膽道炎(primary sclerosing cholangitis)與難治型結腸袋炎(refractory pouchitis)也有療效。

治療案例:使用vedolizumab治療潰瘍性結腸炎
高雄醫學大學附設中和紀念醫院胃腸內科的許文鴻醫師分享了他以vedolizumab治療一位UC病患的經驗。

病患的病程與治療介紹
病患為45歲男性,2009年3月已在他院診斷為UC,並開始服用Asacol 800 mg TID與prednisolone BID的治療。然而,2009年12月來求診時,每天仍有4-5次的排便,偶爾有夜間腹瀉,且伴有出血、黏膜,裡急後重與輕微腹痛,病患無其它病史,也無抽菸、飲酒的習慣,從事室內設計的工作。

病患除了體重較輕(身高178公分,體重63公斤,BMI=19.9),CRP高達26.25 ug/ml以外,其他檢查並無異常。內視鏡檢查發現直腸、乙狀結腸、降結腸與脾彎處都有發炎反應,潰瘍性結腸炎內視鏡嚴重程度指數(UCEIS)為5分,Mayo subgroup score為2分。綜合評估為Mayo score 8分的中度嚴重度UC,將治療改成了Basazyde 750 mg TID、prednisolone 2顆TID與Asacol enema QD。

2010年年初病患獲得加入vedolizumab第三期臨床試驗(C13006)3的機會,在第0週與第2週接受誘導期(induction)治療,接著在第6到52週期間,每接受一次維持期(maintenance)治療。雖然試驗為雙盲且與安慰劑對照的設計,但依病患的反應(見圖五)猜測病患獲得的應是vedolizumab 300 mg。病患在第6週臨床症狀就大幅改善,Mayo score從9降到2。由於試驗設計要求若臨床狀況許可,應將類固醇療法逐漸減量至停藥,病患約於第6至8週後就可逐漸將類固醇減量最後停用,而口服Asacol雖持續但劑量也可從4.8 gm降到2.4 gm。第52週的內視鏡檢查結果顯示了黏膜癒合,UCEIS與Mayo subgroup score都為0分。由於病患反應良好,因此接著也參與了長期試驗(C13008),於2011年至2015年期間都持續接受vedolizumab療法。最後因為病情控制非常好,病患不想要繼續治療才退出了長期試驗。

圖五、病患Mayo score與藥物治療的變化。資料 來源:高雄醫學大學附設醫院許文鴻醫師。

圖五、病患Mayo score與藥物治療的變化。資料 來源:高雄醫學大學附設醫院許文鴻醫師。

 

病患對於自身病情的期待是要能夠正常地工作與生活,因此希望治療不但要有效且能有方便性。Vedolizumab只需病患每個月回診一次接受治療,順從性可簡單地達到。病患在第六週即達到黏膜癒合,全程五年間不必服用類固醇,沒有住院、手術或嚴重感染,也沒有其他不良反應的產生。Vedolizumab不論對於病患或醫師而言,都是理想的療法。

然而,病患在停藥後的今年初(2017年)又開始伴有黏膜與出血的腹瀉狀況,每天約有3-4次的排便且偶有夜間腹瀉,內視鏡檢查結果UCEIS為3分,Mayo subgroup score為2分。由於Mayo score總分為8分,尚未達到健保規定可使用生物製劑的9分,因此目前使用Asacol口服與浣腸劑治療。

Vedolizumab臨床試驗的結果
根據一項追蹤病患長達10年的UC試驗,發現約有50%病患不會有良好的病程,只有50%的病患會慢慢趨於穩定13。Vedolizumab為近年新的一項生物製劑藥品,在收入中度到重度UC病患的第三期臨床試驗中,證實了與安慰劑相比可讓較高比例的病患達到臨床反應、臨床緩解與黏膜癒合14。不但在第六週即可觀察到不同,且效果可持續一年。接受vedolizumab期間病患可不必使用類固醇(見圖六),可減少許多類固醇可能帶來的不良反應14。此外,觀察接受vedolizumab長達5年的試驗也發現,只要在六週誘導期內對vedolizumab有療效的病患,有近96%的病患都能持續維持此療效15, 16。這些臨床試驗的結果都與前述病患使用經驗相符。

圖六、Vedolizumab第三期臨床試驗中病患類固醇用量的變化

結論
UC病患對於自己病情控制希望能有操之在我的感覺,vedolizumab能提供有效、安全、簡單好用的療法,且能長期維持療效,提供病患與醫師一個理想的治療。

Novel biologics in treating IBD

Dr. Stefan Schreiber from Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein introduced novel biologic agents in treating IBD.

Induction and maintenance effects have been established for anti-TNF, vedolizumab and ustekinumab

No head-to-head comparison was conducted for all biologic agents in treating CD and UC. However, infliximab, certolizumab pegol, adalimumab, and vedolizumab have all been proven to be effective in treating UC when compared to placebo. All of them and ustekinumab have also been proven to treat CD effectively when compared to placebo. Patients

Figure 7. Indirect comparisons of biologics as induction therapy in IBD

Figure 7. Indirect comparisons of biologics as induction therapy in IBD

Figure 8. Indirect comparisons of biologics in maintenance therapy of IBD (observed from the induction phase)

Using biologic agents early in the disease brings more benefit

Certolizumab, adalimumab and vedolizumab have all proved to have better outcomes when treating patients with shorter duration of disease or those who were anti-TNF naïve21-23.  

The emerging role of vedolizumab in IBD
Dr. Stefan Schreiber continued to share the abundant clinical data of vedolizumab in IBD treatment.

Large unmet needs in IBD treatment

Current available therapies for treating IBD include 5-aminosalicylic acid (5-ASA), oral immunosuppressants, glucocorticoids, biologics and operation. The choice depends on the severity/acuity and the complexity of patients’ diseases. Without treatments, patients with CD would have lots of complications within two years. However, if anti-TNF therapy could be initiated a few weeks after diagnosis, risk of complications would be attenuated dramatically24
Clinical trials had demonstrated remission rate of 18.2%-48.2% at week 4 for infliximab, certolizumab or adalimumab induction therapy25-27. If patients have success in induction therapy, there are only around 50% patients maintaining the effect after 1 year even with dose escalation12, 28, 29. Therefore, unmet need remains in treating IBD.
Another risk to consider when treating patients with IBD is infection. Not only IBD itself is a risk factor30, but anti-TNF therapy would also increase the risk of infection, especially in elderly patients31.

Unlike anti-TNF drug, vedolizumab is targeted on blocking the interaction of α4β7 integrin with MAdCAM-1, therefore inhibiting the migration of memory T-lymphocytes across the endothelium into inflamed gastrointestinal parenchymal tissue17. Its effects were demonstrated without the need for dose escalation.  

Proven effects of vedolizumab in treating UC
GEMINI I is a randomized, double-blind, placebo-controlled phase 3 study investigating vedolizumab as the induction and maintenance therapy in patients with moderate to severe UC3. Patients included were diagnosed as UC for 6.1-7.1 years with mean Mayo Clinic score of 8.5-8.63. At week 6 of the induction phase, significantly more patients receiving vedolizumab had clinical response, clinical remission and mucosal healing when compared to patients receiving placebo (see Fig.9; 47.1% vs. 25.5%, 16.9% vs. 5.4% and 40.9% vs. 24.8%, respectively)3. Although the outcomes from vedolizumab were significantly better regardless of receiving prior anti-TNF therapy, patients who were anti-TNF naïve responded better than those who were previously exposed to anti-TNF therapy (clinical response rate of 53.1% vs. 39.0% and clinical remission rate of 23.1% vs. 9.8%)32.

Figure 9. Patients’ outcomes at week 6 of GEMINI I

At week 52 in the maintenance phase, almost 50% of the patients who received vedolizumab either every 4 weeks or every 8 weeks had reached clinical remission compared to 15% of the patients who received placebo (see Fig.10)3. Meanwhile, the effects of vedolizumab on clinical response, mucosal healing or clinical remission sustained throughout 52 weeks (see Fig.10)3. Vedolizumab given every 4 weeks and every 8 weeks resulted in 45.2% and 31.4% of patients at glucocorticoid-free remission during the study3. Therefore, physicians in Europe can increase the dosing frequency of vedolizumab from every 8 weeks to every 4 weeks if necessary.

Figure 10. Patients’ outcomes at week 52 of GEMINI I

In the long-term open-label study, 88% of the patients who responded to vedolizumab induction were still in remission after 104 weeks of exposure. Clinical response and remission rates were similar in patients with prior anti-TNF failure and those who were anti-TNF naïve5.

Proven effects of vedolizumab in treating CD

GEMINI II studied vedolizumab as the induction and maintenance therapy in patients with moderate to severe CD33. The patients included were diagnosed as CD for 8.2-9.2 years with mean Crohn’s Disease Activity Index (CDAI) score of 325-327 and CRP level of 13.7-15.3 mg/dL33. At week 6 of the induction phase, significantly more patients who received vedolizumab had reached clinical remission (14.5% vs. 6.8%, p=0.02); however, the percentage of patients who had CDAI-100 response was not significantly different (31.4% vs. 25.7%, p=0.23)33. This indicated that 6 weeks were not long enough to completely turn down inflammation reaction in CD patients.

GEMENI III investigated the effect of vedolizumab in patients with or without prior anti-TNF failure34. At week 10, the difference of clinical remission rate between vedolizumab group and placebo group was statistically significant regardless of previous anti-TNF failure (see Fig. 11)34.

Figure 11. Patients’ outcomes at week 10 of GEMINI III

At week 52 in the maintenance phase of GEMINI II, vedolizumab resulted in significantly more patients with clinical remission, CDAI-100 response and glucocorticoid-free remission (see Fig. 12)33. Patients who received vedolizumab also had significantly lower mean CRP levels at week 52, corresponding to mucosal healing33. The patients without any prior anti-TNF failure had better results from vedolizumab when compared to those with anti-TNF failure35, suggesting that patients would have better outcomes if being treated with vedolizumab earlier.

Figure 12. Patients’ outcomes at week 52 of GEMINI II

In the long-term study, efficacy with continuous vedolizumab treatment beyond 52 weeks was observed. Increased dosing frequency from every 8 weeks to every 4 weeks was beneficial in a subset of patients who had loss of response to 8-week dosing. Even those patients who were retreated with vedolizumab after up to 1 year of interrupted therapy experienced clinical benefits36.

Pooled data from GEMINI studies demonstrated the safety of vedolizumab
Total of 2,884 patients were exposed to vedolizumab in GEMINI I, II, III and long-term studies37. All patients were pre-screened for tuberculosis and only 4 tuberculosis infections were reported during treatment38.

Nasopharyngitis and upper respiratory tract infection were the most common adverse events37. The infection risk actually went down under vedolizumab treatment, possibly because those patients did not receive steroid therapy after reaching remission. Predictors of serious infection included prior anti-TNF failure, on-study narcotic use and on-study corticosteroid use37.

Real world experience with vedolizumab was consistent with what was found in clinical trials
Various real-life cohort studies from German, France, United States, Sweden and Spain regarding using vedolizumab treating over 1,300 patients with UC and CD have been published20, 39-46. US data indicated that about 16 to 32.8% CD patients were receiving vedolizumab as their first biologic treatment. Vedolizumab was shown to effectively improve disease activity, decrease steroid usage and reduce inflammation markers in both patients with UC and those with CD. Vedolizumab also appeared to be particularly effective in patients who were anti-TNF naïve. The safety profiles from real-world cohorts were consistent with what was found in the clinical trials.

Conclusion

Vedolizumab was proven to improve outcomes in patients with UC and CD from clinical trials and real-world experience. Patients who receive vedolizumab early have a higher chance for clinical improvements and lower risk for adverse events. Physicians shall review patients as early as week 4 to 6 after initiation of vedolizumab. The patients who respond to vedolizumab in the induction therapy usually will maintain the therapeutic effects continuously.  

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