克罗恩病治疗以深度缓解和高谷浓度为目标
Aim for deep remission, high troughs in Crohn’s
3月刊《临床胃肠与肝病学》发表的2项最新分析显示，克罗恩病的“深度缓解”与更佳的生活质量、躯体功能及费用节省相关。不仅如此，或许能通过监测肿瘤坏死因子拮抗剂的血浆浓度最有效地达到这一复合临床和内镜终点。这意味着，这些治疗的药代动力学决定着最佳治疗时机。
在第一项研究中，纽约医学院西奈山医院的Jean-Frédéric Colombel医生及其同事对参与EXTEND试验的135例成年中至重度回肠结肠克罗恩病患者进行了分析。EXTEND是一项为期52周的随机、双盲、安慰剂对照的阿达木单抗试验(doi:10.1016/j.cgh.2013.06.019)。
EXTEND试验旨在评估诱导加维持剂量阿达木单抗的疗效，并与仅用诱导剂量相比较。所有患者均在4周诱导期内接受了开放标记的阿达木单抗治疗(0周和2周时分别给予160 mg和80 mg)，继而被随机分组，接受隔周40 mg阿达木单抗或安慰剂治疗。
总体而言，接受阿达木单抗诱导加维持治疗的患者19%达到了所谓的深度缓解，后者定义为无黏膜溃疡且临床缓解(克罗恩病活动指数[CDAI]＜150)。在其余的应答者中，8例无黏膜溃疡但未获得临床缓解，19例获得了临床缓解但有持续性黏膜溃疡。
第二项分析同样由Colombel医生及其同事开展，探讨了TNF拮抗剂在克罗恩病中的最佳用法(doi:10.1016/j.cgh.2013.10.025)。
在这项事后分析中，Colombel医生等人对参加MUSIC试验的患者进行了分析。MUSIC是一项为期54周的多中心、单组、开放标记的临床试验，评估了中至重度克罗恩病患者的内镜改善。
所有患者在0、2和4周时接受负荷量赛妥珠单抗400 mg治疗，之后每4周接受维持量400 mg。
作者们发现，10周时达到临床和内镜应答的患者在8周时具有“正常较高”的血浆赛妥珠单抗谷浓度：有临床应答的患者为16.5 mcg/ml，有内镜应答的患者为19.8 mcg/ml，无临床应答的患者为13.7 mcg/ml，无内镜应答的患者为11.5 mcg/ml。
相似的，10周时达到临床和内镜缓解的患者在8周时也具有“正常较高”的血浆赛妥珠单抗谷浓度：获得临床缓解的患者为17.6 mcg/ml，未临床缓解的患者为11.1 mcg/ml，获得内镜缓解的患者为19.2 mcg/ml，未内镜缓解的患者为12.6 mcg/ml。
“尚需开展更多研究，探讨临床应答、体重和血浆TNF拮抗剂之间的关联。”
Colombel医生及其同事报告称与药企存在多种关联，包括阿达木单抗与赛妥珠单抗的生产商；EXTEND试验由阿达木单抗的生产商AbbieVie资助，MUSIC试验由赛妥珠单抗的生产商UCB制药公司资助。
随刊述评：不同的治疗途径
这两篇文章探讨了克罗恩病治疗的重要新理念——将黏膜愈合列为一项潜在治疗终点，以及肿瘤坏死因子拮抗剂治疗期间的监测。
由于当前采用的克罗恩病活动度指数评分＜150这一终点并不能很好地追踪内镜下愈合情况，后者似乎与良好远期结局(例如对皮质激素、住院和腹部大手术的需求减少)相关。
对EXTEND试验的分析表明，12周内达到“深度缓解”(即临床缓解且内镜未发现溃疡)的患者，比未达到深度缓解的患者更少住院和接受手术。
有趣的是，获得深度缓解的患者的结局优于获得内镜缓解但未获得临床缓解的患者，而与仅获得临床缓解相比，获得深度缓解并无额外获益。
我们应当将这项分析视为将深度缓解作为终点的概念验证研究，并且需要等待前瞻性试验来确定是否能将深度缓解作为所有患者的一项终点。
第二篇文章是对MUSIC试验的二次分析，试图确定赛妥珠单抗浓度与内镜应答或缓解的关联。作者们发现，8周时浓度与10周时内镜应答率和缓解率显著相关。他们还发现，体重较大、血清C反应蛋白水平较高与赛妥珠单抗水平较低相关。
这项研究印证了既往研究的结果，即英夫利昔和阿达木单抗的浓度与临床结局有关。而且，赛妥珠单抗血浆浓度及体重、C反应蛋白水平等其他因素的相互关系，凸显了这些生物制剂的复杂药代动力学特性，强调了对治疗药物监测的潜在需求。
述评作者Edward V. Loftus Jr.医生是罗切斯特梅奥医院炎症性肠病门诊部主任。他是AbbVie、UCB、杨森、武田-千禧年和Immune制药公司的顾问，接受了上述公司及辉瑞、安进、Santarus、Robarts临床试验公司、百时美施贵宝、葛兰素时刻、基因泰克、Shire和Braintree实验室提供的研究支持。
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By: DENISE NAPOLI, Internal Medicine News Digital Network
"Deep remission" of Crohn’s disease is associated with better quality of life, physical function, and cost savings.
Moreover, this composite clinical and endoscopic endpoint may be best accomplished through monitoring of the tumor necrosis factor antagonists’ plasma concentration, meaning that the pharmacokinetics of these therapies must be accounted for when optimizing drug treatment.
Those are the findings from two new analyses in the March issue of Clinical Gastroenterology and Hepatology, both by Dr. Jean-Frédéric Colombel of the Mount Sinai Hospital School of Medicine in New York.
In the first study, Dr. Colombel and his colleagues looked at 135 adults with moderate to severe ileocolonic Crohn’s enrolled in the EXTEND trial, a 52-week, randomized, double-blind placebo-controlled trial of adalimumab (doi:10.1016/j.cgh.2013.06.019).
The goal of EXTEND was to assess the effect of induction plus maintenance dosing of adalimumab, versus induction only. All patients received open-label adalimumab (160 mg and 80 mg at weeks 0 and 2, respectively) during the 4-week induction phase and were randomized at week 4 to receive adalimumab 40 mg every other week or placebo.
Overall, 19% of patients who received both adalimumab induction and maintenance therapy achieved so-called deep remission, defined as the absence of mucosal ulceration plus clinical remission (Crohn’s Disease Activity Index [CDAI], less than 150). Of the remaining responders, 8 had an absence of mucosal ulceration without clinical remission, and 19 had clinical remission with persistent mucosal ulceration.
Dr. Colombel and his coinvestigators found that patients in deep remission registered significantly fewer days absent from work, less work productivity impairment, greater work productivity, and less daily nonwork activity impairment, compared with patients who did not achieve deep remission (P less than .05 for all).
Moreover, at 1 year after therapy induction, significantly more patients in the deep remission group achieved remission according to the Inflammatory Bowel Disease Questionnaire (64% vs. 26%; Pless than .05) and normal Short Form–36 Health Survey status (55% vs. 19%; P less than .05), compared with patients who were not in deep remission.
Finally, during the 40 weeks after early deep remission achievement, estimated savings among deep remission patients were $6,117 for direct medical costs and $4,243 for indirect costs related to productivity, compared with the costs for patients not in deep remission.
"This treatment target in CD [of deep remission], which combines symptom control with an objective indicator of inflammatory disease activity, still is evolving," wrote the investigators.
However, "current analysis provides preliminary evidence that early [deep remission] is achievable and may be a useful treatment target," they added.
The second analysis, also by Dr. Colombel, looked at the optimization of TNF antagonists in Crohn’s disease – specifically, at certolizumab pegol (doi:10.1016/j.cgh.2013.10.025).
In this post hoc analysis, Dr. Colombel looked at patients enrolled in the MUSIC trial, a 54-week, multicenter, single-arm open-label study assessing endoscopic improvement in patients with moderate to severe Crohn’s disease.
All patients received loading doses of certolizumab pegol 400 mg at 0, 2, and 4 weeks, followed by a maintenance dose of 400 mg every 4 weeks.
The authors found that at week 10, patients who achieved a clinical and an endoscopic response had "nominally higher" trough plasma certolizumab pegol concentrations at week 8 than those with no response or remission (16.5 mcg/mL for patients with a clinical response and 19.8 mcg/mL for patients with an endoscopic response, vs. 13.7 mcg/mL and 11.5 mcg/mL in the clinical and endoscopic nonresponders).
Similarly, patients who achieved clinical and endoscopic remission at week 10 also had nominally higher trough plasma concentrations at week 8, with clinical remission patients registering 17.6 mcg/mL (vs. 11.1 mcg/mL in patients without clinical remission) and endoscopic remission patients measuring 19.2 mcg/mL (vs. 12.6 mcg/m L in patients who did not achieve that endpoint).
"Plasma certolizumab pegol concentration is not readily measured in standard clinical practice at this time," wrote the authors.
However, "additional studies are needed to understand the relationships among clinical response, body weight, and plasma concentration of the TNF antagonist," they added.
Dr. Colombel and his colleagues disclosed numerous financial relationships with pharmaceutical companies, including the makers of adalimumab and certolizumab pegol; the EXTEND trial was funded by AbbieVie, the maker of adalimumab, and the MUSIC trial was funded by UCB Pharma, maker of certolizumab pegol.
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Different approaches to management
This month's issue of Clinical Gastroenterology and Hepatology contains two articles that explore important, novel concepts in the management of patients with Crohn's disease - that of mucosal healing as a potential therapeutic endpoint and that of therapeutic drug monitoring of tumor necrosis factor antagonists.
New endpoints are required because the currently accepted endpoint of a Crohn's Disease Activity Index score of less than 150 points does not optimally track with endoscopic healing, which appears to correlate with favorable longer-term outcomes such as reduced need for corticosteroids, hospitalizations, and major abdominal surgeries.
In a secondary analysis of the EXTEND trial (a study of endoscopic healing of Crohn's disease with adalimumab), the authors were able to show that patients who had achieved the endpoint of "deep remission" (that is, clinical remission and absence of ulcerations on endoscopy) by week 12 had fewer hospitalizations and surgeries than those who had not achieved deep remission.
Interestingly, those patients achieving deep remission had better outcomes than those who achieved endoscopic but not clinical remission, whereas there didn't appear to be an incremental benefit of achieving deep remission over clinical remission alone.
One should consider this a proof of concept study of the potential utility of deep remission as an endpoint, and we need to see prospective trials before concluding that deep remission is an endpoint to strive for in all of our patients.
The second article was a secondary analysis of the MUSIC trial (a study of endoscopic improvement of Crohn's disease with certolizumab pegol) and attempted to correlate certolizumab pegol concentrations with endoscopic response or remission.
The authors found that levels at week 8 were significantly associated with rates of endoscopic response and remission at week 10. They also found that higher body weight and serum C-reactive protein levels were associated with lower certolizumab levels.
This study corroborates evidence from other studies that concentrations of infliximab and adalimumab can be correlated to clinical outcomes.
Furthermore, the relationship between certolizumab plasma levels and other factors such as body weight and C-reactive protein levels highlights the complex pharmacokinetics of these biologic agents and underscores the potential need for therapeutic drug monitoring.
Dr. Edward V. Loftus Jr., AGAF, is professor of medicine and director, inflammatory bowel disease clinic, division of gastroenterology and hepatology, Mayo Clinic, Rochester, Minn. He is a consultant for AbbVie, UCB, Janssen, Takeda-Millennium, and Immune Pharmaceuticals and receives research support from AbbVie, UCB, Janssen, Takeda-Millennium, Pfizer, Amgen, Santarus, Robarts Clinical Trials, Bristol-Myers Squibb, GlaxoSmithKline, Genentech, Shire, and Braintree Labs.
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