Anti-MADCAM therapy for ulcerative colitis

ABSTRACT

Introduction: The mucosal addressin cell adhesion molecule-1 (MAdCAM-1) plays a key role in the endothelial adhesion and migration of lymphocytes to sites of inflammation in inflammatory bowel disease. Therapies that target this pathway appear to be a promising therapeutic approach in the management of ulcerative colitis (UC).

Areas covered: This review provides a summary of the preclinical and available clinical data on the safety and efficacy of ontamalimab (SHP647), a fully human monoclonal antibody that binds and inhibits the action of MAdCAM-1.

Expert opinion: Intestinal immune cell trafficking is emerging as an important component in the pathogenesis of UC. Ontamalimab (SHP647) inhibits this process by preventing the binding of integrins found on the surface of lymphocytes and the endothelial ligand adhesion molecule MAdCAM-1. This monoclonal antibody has already demonstrated safety and efficacy in phase II clinical trials. Its targeted mechanism of action suggests a superior safety profile as compared with the current systemic immunosuppressive therapies. Results from the phase III trials are awaited to establish ontamalimab (SHP647) as a therapeutic option in the management of UC.     

Fecal transplantation for ulcerative colitis: current evidence and future applications

ABSTRACT

Introduction: Established evidence suggests that gut microbiota plays a role in ulcerative colitis (UC). Fecal microbiota transplantation (FMT) is clearly recognized as a highly effective treatment for patients with recurrent Clostridium difficile infection and has been investigated also in patients with UC, with promising results.

Areas covered: Literature review was performed to select publications concerning current evidence on the role of gut microbiota in the pathogenesis of UC, and on the effectiveness of FMT in this disorder.

Expert opinion: The randomized controlled trials published investigating the use of FMT suggested a potential role for FMT in the treatment of mild to moderate UC. However, given several unanswered questions regarding donor selection, dose, route of administration and duration of therapy, this is not yet recommended as a viable therapy option. FMT has allowed for more in depth investigation with regards to the role the gut microbiota may be playing in UC. This knowledge is critical to identifying where FMT may appropriately fit in the UC treatment paradigm. As our understanding of the role the microbiome plays in this chronic disease, FMT, and then eventually defined microbes, will hopefully serve in a complementary role to conventional IBD therapies.     

E-钙粘附蛋白在溃疡性结肠炎发病中的作用

通过研究Ｅ－钙粘附蛋白（Ｅ－ＣＤ）在溃疡性结肠炎（ＵＣ）中的表达,探讨Ｅ－ＣＤ在ＵＣ发病中的作用。方法应用免疫组织化学方法,研究正常结肠和ＵＣ标本中的Ｅ－ＣＤ表达。结果正常组和ＵＣ组中Ｅ－ＣＤ水平无显著性差异（Ｐ＞０．０５）：ＵＣ组中Ｅ－ＣＤ表达与病情程度不相关（Ｐ＞０．０５）。结论Ｅ－ＣＤ在ＵＣ进展阶段不起主要作用,Ｅ－ＣＤ在ＵＣ触发阶段的作用尚须进一步研究。     

Gallium-67-citrate scintigraphy in ulcerative colitis

Gallium-67-citrate scanning was performed in 9 patients with ulcerative colitis. In all patients there was good correlation between the regional uptake of gallium and the extent and activity of disease. In 2 patients the scans were positive during an acute exacerbation and reverted to normal or near normal during clinical remission. In one patient in whom the colon was resected because of toxic dilatation, good correlation was found between pathologic and scintigraphic examinations. During the acute attack of ulcerative colitis, when colonoscopy or barium enema may be contraindicated, gallium scanning may be a noninvasive means of assessing the extent of colonic involvement. It may also be an alternative means of following the clinical course of the disease.     

Anti-interleukin-23 agents for the treatment of ulcerative colitis

ABSTRACT

Introduction: Treatment of ulcerative colitis (UC) aims to control symptoms and to suppress intestinal inflammation. Despite considerable advances, a proportion of patients do not respond to currently available drugs. The interleukin (IL)-23 axis plays a significant role in the pathogenesis of UC and has thus become an important target for drug development.

Areas covered: The review briefly summarizes the pathophysiology of the IL-12/23 axis and provides a synopsis of the available evidence for efficacy and safety of ustekinumab, mirikizumab (LY3074828), risankizumab (BI655066/ABBV066), brazikumab (MEDI2070; formerly AMG139) and guselkumab (CNTO1959) in UC. We also provide an overview of ongoing and anticipated trials in this field.

Expert opinion: A Phase 2 trial with mirikizumab and a Phase 3 trial with ustekinumab have demonstrated the efficacy of anti-IL-23 agents in achieving clinical and endoscopic outcomes in UC with a favorable safety profile. Trials of other anti-IL-23 agents in UC are under way and designed to explore head-to-head efficacy with existing biologics, as well as the prospect of combination biological therapy. Apart from data on longer term efficacy and safety, future trials should also explore strategies to inform the positioning of IL-23 antagonists in therapeutic algorithms.     

Biological agents for ulcerative colitis: hypes and hopes

Ulcerative colitis (UC) is an idiopathic chronic inflammatory disease of the colonic mucosa. Over the last decade, the increasing knowledge on the pathogenic mechanisms underlying intestinal inflammation has led to the development of a number of biological agents, mainly addressed to molecules and/or pathways demonstrated to have a pathogenic role in UC. In UC, clinical course and therapeutic decisions mainly depend on disease activity and extent. While therapeutic approach to mild-to-moderate UC by using aminosalicylates and corticosteroids has been well established, treatment of severe UC is far from being satisfactory. A severe attack of UC remains a challenge to be managed jointly by gastroenterology, surgery, and intensive care units. However, the recent introduction of biological therapies has led to promising changes in the management of UC patients. Aim of this paper is to review the recent advances and future perspectives for the use of biological agents in UC.     

The 17-year single-center experience with the use of azathioprine to maintain remission in ulcerative colitis

Despite the accumulation of positive data, the role of azathioprine (AZA) in the maintenance of remission of ulcerative colitis is still controversial. We looked at the follow-up of the ulcerative colitis patients who, after responding to either steroids or cyclosporin (CsA), received AZA at our referral center for over a decade. The 39 patients (29 m/10f) were treated between 1991 and 2007. Twenty-five of them had responded to CsA, the remaining 14 to corticosteroids. AZA was usually overlapped with either of the two agents at the initial dose of 2 mg/kg/day. The definitions of remission, relapse, and AZA toxicity followed commonly agreed criteria. The median duration of the AZA treatment was 14 months (<1–201). Fifty-two percent and 14%, respectively, of the CsA and the steroid responders needed surgery (overall rate = 38%). The figures were 32 and 15 at the first year. The majority of the patients had 1–2 relapses often in connection with withdrawal of AZA; only 3 of these relapsers needed hospitalization. AZA caused toxicity in 16/39 (41%) patients, requiring withdrawal in 23% of the cases; leukopenia (17%) and hepatitis/cholestasis (10%) ranked first and second for frequency. All of the patients in whom AZA was stopped (or reduced) relapsed. In conclusion, the 1-year colectomy rates compare favorably with the figures reported by the literature. By contrast, the toxicity rates were higher than expected. Failure to genotype or to use escalating AZA doses can only be hypothesized as causes.     

Tofacitinib for the treatment of ulcerative colitis: A review of the literature

Ulcerative colitis (UC) is a chronic immune-mediated inflammatory condition affecting the colon. Recently, tofacitinib, an oral small molecule that is an inhibitor of the Janus kinase signal transduction pathway, was proven efficacious for inducing and maintaining remission in adult patients with moderate to severe UC in three global Phase III studies. The purpose of this review is to summarize existing data on the efficacy, safety, and quality of life issues related to use tofacitinib as well as highlight recent real-world experience with this drug among patients with UC.     

Type 2 autoimmune pancreatitis associated with severe ulcerative colitis: Three case reports

BACKGROUNDType two autoimmune pancreatitis is a rare and difficult to diagnose, steroid responsive non-IgG4 inflammatory pancreatopathy that can be associated with inflammatory bowel disease. CASE SUMMARYThis case series describes three cases with varied clinical presentations and re-presentations of autoimmune pancreatitis, and all associated with an aggressive course of ulcerative colitis. The pancreatopathy was independent of bowel disease activity and developed in one case following colectomy. CONCLUSIONClinician awareness about this condition is important to allow early diagnosis, treatment and avoid unnecessary pancreatic surgery.     

Zingiber officinale and oxidative stress in patients with ulcerative colitis: A randomized,placebo-controlled,clinical trial

ObjectivesOxidative stress plays an essential role in ulcerative colitis (UC) initiation and severity. We aimed to investigate the effect of ginger as a well-known antioxidant agent on the quality of life, disease activity index and oxidative stress in patients with UC.MethodsForty six patients with active mild to moderate UC randomly assigned to consume 2000 mg/day dried ginger powder in 4 capsules or similar placebo capsules for 12 weeks. Disease activity index, quality of life and some oxidative stress factors were measured before, at the middle and at the end of the intervention through valid and reliable questionnaires and blood sampling.ResultsGinger reduced Malondialdehyde (MDA) significantly after 6 weeks (p = 0.003) and 12 weeks (p < 0.001) of intervention, whereas it did not affect serum total anti-oxidant capacity (TAC). The scores of severity of disease activity at 12th week was significantly improved in ginger group in comparison to placebo (p = 0.017). Moreover, ginger increased patients quality of life significantly at 12^th week (p = 0.039).ConclusionOur data indicate that ginger supplementation can improve treatment of patients with UC. Further clinical trials with different dosages and duration of ginger or its standard extract supplementation are needed to obtain firm conclusion.     

Reviewing treatments and outcomes in the evolving landscape of ulcerative colitis

Ulcerative colitis (UC) is a chronic inflammatory disease extending proximally from the rectum to varying lengths of the colon that is characterized by alternating cycles of relapse and remission. Therapeutic goals for patients with active UC include induction and maintenance of remission and improvement in quality of life, as well as mucosal healing, a clinical outcome recently recognized in treatment guidance as being equally important. Mucosal healing is associated with favorable long-term patient outcomes related to remission, surgery, hospitalization, and quality of life. Given the increasing number of newer therapies available, it is important to properly position the use of each agent within the landscape of established UC therapies, evolving therapeutic goals, and established guidelines. Extent of disease is important to consider when selecting a treatment, as is an understanding of the short- and long-term outcomes (e.g. corticosteroid-free remission, mucosal healing) associated with each treatment. The purpose of this narrative review is to provide an overview of newer therapies for the treatment of UC and how they may best fit in the evolving landscape of UC.     

Efficacy of oral colon-specific delivery capsule of low-molecular-weight heparin on ulcerative colitis

Low-molecular-weight heparin has the potential for the treatment of ulcerative colitis, and targeted drug delivery to the colon is important for topical treatment of this disease, so low-molecular-weight heparin oral colon-specific delivery capsule was prepared, and the in vitro and in vivo drug release behavior was investigated. The macroscopical and histological scoring systems, wet colon mass index and myeloperoxidase activity were assessed to evaluate the efficacy of the capsule after administered orally to experimental colitis mice. Serum levels, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and a link factor of blood coagulation and inflammation factor Xa (FXa) were assayed by enzyme-linked immunosorbent assay. The expression of Musashi-1 (as an intestinal stem cell marker) in the colons was assessed by immunohistochemical analysis. The in vitro and in vivo drug release studies clearly indicated that the specific coated capsules were capable of protecting low-molecular-weight heparin from releasing in stomach and small intestine, while specifically delivering at colon. The oral colon-specific delivery capsule of low-molecular-weight heparin could attenuate macroscopic and histological features of colitis. The results showed that low-molecular-weight heparin oral colon-specific delivery capsule significantly decreased the serum levels of TNF-α, IL-6 as well as FXa, while increased the expression of Musashi-1 in colon compared with acetic acid-induced ulcerative colitis model group. The results showed that low-molecular-weight heparin oral colon-specific delivery capsule had the potential for treatment of inflammatory bowel disease.     

Concurrent monoclonal gammopathy and systemic lupus erythematosus in a known case of ulcerative colitis: A case report

Our patient had previously been diagnosed with Ulcerative colitis. The clinical manifestations of the patient along with laboratory tests such as anti‐dsDNA and proteinuria were also positive. Therefore, the clinical manifestation was consistent with SLE. In the following work up, monoclonal gammopathy in serum electrophoresis was also detected.     

Topical butyrate improves efficacy of 5-ASA in refractory distal ulcerative colitis: results of a multicentre trial

BACKGROUND: The treatment of distal ulcerative colitis, refractory to conventional 5-ASA/steroid treatment, is still a matter of debate. The present study aimed at confirming, with adequate statistical power, previous data indicating the usefulness of topical butyrate and 5-ASA in the treatment of this condition. DESIGN: Double-blind, placebo-controlled, multicentre study. A total of 51 patients with distal (< 65 cm) ulcerative colitis, refractory to topical 5-ASA/cortisone, were randomly allocated to receive topical 5-ASA 2 g and 80 mM L-1 sodium-butyrate bid (Group A; 24 patients) or 5-ASA 2 g and 80 mL saline bid (Group B; 27 patients) for 6 weeks. Sigmoidoscopy with biopsies, as well as clinical and laboratory evaluations, were carried out at enrollment and at the end of the trial. Primary endpoints: remission or marked improvement in endoscopic, histologic and clinical findings. RESULTS: Most parameters showed a significant improvement vs. baseline in both groups. Remission in six patients and improvement in 12 patients in Group A vs. one remission and 13 with improvement in Group B (P < 0.05). A significant difference in favour of Group A was recorded regarding the number of bowel movements (P < 0.01), urgency (P < 0.05) and the patients' self evaluation (P < 0.01). DISCUSSION: The combined treatment with topical butyrate and 5-ASA is significantly more effective than 5-ASA alone in the management of refractory distal colitis. Further improvements in the treatment of refractory distal ulcerative colitis may be feasible based on the identification of patient subgroups and the association of two or more active drugs. Butyrate may well be one of them.     

粪便钙卫蛋白及血清C反应蛋白检测在溃疡性结肠炎活动性判定中的应用

目的探讨粪便钙卫蛋白(CP)及血清C反应蛋白(CRP)检测在溃疡性结肠炎(UC)活动性判定中的应用价值。方法 100例UC患者根据病理检查结果分为缓解期组(n=24)、活动期Ⅰ级(n=25)、Ⅱ级(n=33)和Ⅲ级组(n=18),另选取30例健康体检者设为对照组,检测各组粪便CP及血清CRP的含量,并分析其与病理分级的相关性。结果粪便CP及血清CRP在对照组中含量最低,在活动期Ⅲ级患者中最高,活动期各组显著高于对照组及缓解期组(P0.01),且活动期3组之间两两比较差异显著(P0.01);UC活动期患者粪便CP及血清CRP含量均与病理分级呈显著正相关(r=0.733,0.527,P0.01)。结论粪便CP及血清CRP在活动期UC患者中显著高表达,且与病理分级具有较好的相关性,能客观反映UC炎症的活动性,可作为内镜检查的辅助指标。     

Treatment of acute severe ulcerative colitis using accelerated infliximab regimen based on infliximab trough level: A case report

BACKGROUNDAcute severe ulcerative colitis (ASUC) is a complication of ulcerative colitis associated with high levels of circulating tumor necrosis factor alpha, due to the intense inflammation and faster stool clearance of anti-tumor necrosis factor drugs. Dose-intensified infliximab treatment can be beneficial and is associated with lower rates of colectomy. The aim of the study was to present a case of a patient with ASUC and megacolon, treated with hydrocortisone and accelerated scheme of infliximab that was monitored by drug trough level.CASE SUMMARYA 22-year-old female patient diagnosed with ulcerative colitis, presented with diarrhea, rectal bleeding, abdominal pain, vomiting, and distended abdomen. During investigation, a positive toxin for Clostridium difficile and colonic dilatation of 7 cm consistent with megacolon were observed. She was treated with oral vancomycin for pseudomembranous colitis and intravenous hydrocortisone for severe colitis, which led to the resolution of megacolon. Due to the persistent severe colitis symptoms, infliximab 5 mg/kg was prescribed, monitored by drug trough level (8.8 μg/mL) and fecal calprotectin of 921 μg/g (< 30 μg/g). Based on the low infliximab trough level after one week from the first infliximab dose, the patient received a second infusion at week 1, consistent with the accelerated regimen (infusions at weeks 0, 1, 2 and 6). We achieved a positive clinical and endoscopic response after 6 mo of therapy, without the need for a colectomy.CONCLUSIONInfliximab accelerated infusions can be beneficial in ASUC unresponsive to the treatment with intravenous corticosteroids. Longitudinal studies are necessary to define the best therapeutic drug monitoring and treatment regimen for these patients.     

溃疡性结肠炎合并结肠多发性锯齿状息肉的临床病理分析

目的 探讨溃疡性结肠炎(UC)合并结肠多发性锯齿状息肉的临床病理特点及免疫组化表型. 方法报告2例分别有10年和8年溃疡性结肠炎病史、合并多发性结肠锯齿状息肉病的临床、内窥镜及病理组织学改变.行AE1/AE3、CK7、CK20、CEA、CD34、SMA、p53和Ki-67免疫组化染色,并结合文献进行复习讨论. 结果 2名患者均为中年女性,间断腹泻10年和8年,分别多次行内窥镜检查发现结直肠黏膜多处糜烂、浅表溃疡.例1,降、乙状结肠可见密集分布、大小不等的息肉,最大直径3cm;例2,全结肠可见10余枚息肉.镜检:结直肠溃疡糜烂处符合溃疡性结肠炎病变;息肉处腺体大部分呈锯齿状扩张增生,部分细胞核增生呈复层,可见异型增生.免疫组化:息肉部腺体CEA(+),Ki-67阳性细胞位于锯齿状隐窝基底及中1/3;例2局部p53(+).结论 UC相关锯齿状息肉/腺瘤病具有肿瘤性病变特征,UC合并锯齿状息肉或腺瘤可能更易癌变.