Management of Severe Ulcerative Colitis with Ambulatory Intravenous Corticosteroids (MOSAIC): A Treatment Approach to Avoid Hospitalization in Immunocompromised Patients

Infliximab for Ulcerative Colitis: Finally Some Answers

A Phase I Study of Visilizumab, a Humanized Anti-CD3 Monoclonal Antibody, in Severe Steroid-Refractory Ulcerative Colitis

Approximately 15% of patients with ulcerative colitis develop an acute attack of severe colitis, and 30% of these patients require colectomy. Severe ulcerative colitis is therefore considered a medical emergency, the management of which requires close collaboration between gastroenterologists and surgeons. The mortality rate for patients with severe ulcerative colitis is now <1% in specialist centers, but it was high before intravenous steroid therapy and early surgery were introduced; indeed, mortality is still high in nonspecialized centers. As colectomy severely affects quality of life, therapy with intravenous ciclosporin and, more recently, infliximab has been introduced to try to avoid the need for surgery. Ciclosporin induces short-term remission, but the long-term benefit remains unsatisfactory as colectomy is often only delayed. A significant short-term reduction in the colectomy rate has, however, been observed after infliximab treatment. The use of infliximab versus ciclosporin in patients with severe ulcerative colitis remains to be defined. The timing of surgery remains a cardinal decision in the management of severe ulcerative colitis; increased morbidity resulting from prolonged ineffective medical treatment and, therefore, a delay in surgical treatment should be avoided.

AIMTo investigate the current state of research output from Chinese studies into severe ulcerative colitis (SUC) using a bibliometric analysis of publications.METHODSThe contents of the Chinese periodical databases WANFANG, VIP, and China National Knowledge Infrastructure were searched for all papers regarding UC or SUC published in last the 15 years (from 2001 to 2015). The number of publications in each year was recorded to assess the temporal trends of research output. All SUC related publications were downloaded and the complexity of this research was evaluated with methods described previously. The number of patients with SUC reported each year was recorded and their clinical characteristics were analyzed using information available in the relevant papers.RESULTSThere were 13499 publications regarding UC published in Chinese medical journals between 2001 and 2015, of which 201 focused on SUC. The number of publications increased rapidly with more than half of all papers being published in the most recent 5-year period. There was a significant increase in analytical studies and clinical trials over the study period (P < 0.01), with research into the management of SUC, included pharmacotherapy, nutrition support as well as surgery, predominating. Almost half (46.2%) of the observational analytical studies and clinical trials focused on Traditional Chinese Medicine, with little research on the efficacy of cyclosporin and infliximab in disease management. About 6222 patients with SUC were reported in the 201 SUC relevant papers, with a ratio of male/female of 1.38. The number of patients reported in each 5-year period significantly increased. The colectomy rate and short-term mortality rate were 7.7% and 0.8% respectively. The most commonly employed operation was total proctocolectomy with ileal pouch-anal anastomosis.CONCLUSIONThe output and complexity of research related to SUC in China increased significantly over the previous 15 years, however few of these studies focused on salvage therapy.

Our aim was to determine if transabdominal intestinal ultrasound changes after 48 ± 24 h of intravenous corticosteroids can predict treatment outcomes in hospitalised patients with severe ulcerative colitis. We performed a blinded observational multicentre study. Ultrasound parameters were assessed before treatment initiation, after 48 ± 24 h, and 6 ± 1 days. Treatment response was determined within 7 days by two outcome measures: 1] partial Mayo score reduction; 2] no administration of rescue therapy. Out of 69 recruited patients, 56 were included in the final analysis, with 37 responders. The colon segment with the highest baseline bowel wall thickness was analysed, being the sigmoid in all patients. There was no difference in baseline bowel wall thickness between responders and non-responders in the partial Mayo score outcome. At 48 ± 24 h, a significant difference between responders and non-responders was identified in both absolute bowel wall thickness [median 3.1 mm vs 4.9 mm; p <0.0001], absolute reduction [-1.9 mm vs -0.2 mm; p <0.001], and relative reduction [-35.9% vs -4.1%; p <0.0001]. A ≤20% reduction had a sensitivity of 84.2% (95% confidence interval [CI] 60.4, 96.6%) and a specificity of 78.4% [61.8, 90.2%] for determining non-response [area under the curve 0.85]. In the multivariable analysis, a >20% reduction had the highest odds ratio (22.6 [4.2, 201.2]; p = 0.001) for determining response. Similar results were seen for the rescue therapy outcome. Changes in bowel wall thickness, after 48 ± 24 h following intravenous corticosteroid treatment in hospitalised patients with severe ulcerative colitis, identify responders with high accuracy and might be used as an early marker to guide accelerated rescue therapy.

Currently, how to provide a timely and accurate therapeutic regiment comprised of internal medicine or surgical treatment for sever ulcerative colitis (UC) patient has posed a great challenge to both physicians and surgeons. Thus, with the aim of improving medical condition in diagnose and treatment of severe UC, this article reviews the characteristics of severe UC, as well as illustrates the respective superiorities and disadvantages of internal and surgical treatment strategies to severe UC from a landscape of the physician and the surgeon. Key words: Severe ulcerative colitis; Medical treatment; Surgery

Cyclosporine and infliximab (IFX) are effective medical therapies for inducing remission in patients with steroid-refractory ulcerative colitis (UC). Patients with acute severe disease who do not respond to these therapies require colectomy, however, the risk of postoperative complications in such patients is not known. Analyzing patients with acute severe UC, we compared the incidence of postoperative complications in patients who failed rescue therapy with cyclosporine or IFX with that in patients who received intravenous (IV) corticosteroids alone. We performed a retrospective cohort study of UC patients who underwent colectomy after inpatient treatment with cyclosporine plus IV corticosteroids (CsA+IVS), infliximab plus IV corticosteroids (IFX+IVS), or IV corticosteroids alone (IVS) at the University of Chicago Hospitals from October 1, 2006 to October 1, 2012. Primary endpoints were infectious, noninfectious, and total complications occurring within 30 days of colectomy. Of 78 patients, 19 were treated with CsA+IVS, 24 with IFX+IVS, 4 with both CsA and IFX+IVS, and 31 with IVS alone. Patients treated with rescue therapy plus IVS had no difference in total postoperative complications compared with those receiving IVS alone (CsA+IVS: relative risk (RR) = 0.63, 95% confidence interval (CI), 0.33-1.23; IFX+IVS: RR = 0.65, 95% CI, 0.36-1.17). There remained no difference in postoperative complications between the rescue therapy and IVS alone groups when subcategorizing overall complications into infectious (CsA+IVS: RR = 0.54, 95% CI, 0.17-1.76; IFX+IVS: RR = 0.86, 95% CI, 0.36-2.09) and noninfectious (CsA+IVS: RR = 0.88, 95% CI, 0.43-1.80; IFX+IVS: RR = 0.40, 95% CI, 0.15-1.07) causes. Cyclosporine and IFX are not associated with an increased risk for postoperative complications in patients hospitalized for severe UC refractory to corticosteroids.

Background and AimsMicroarray analysis of RNA expression allows gross examination of pathways operative in inflammation. We aimed to determine whether genes expressed in whole blood early following initiation of intravenous corticosteroid treatment can be associated with response.MethodsFrom a prospectively accrued cohort of 128 pediatric patients hospitalized for intravenous corticosteroid treatment of severe UC, we selected for analysis 20 corticosteroid responsive (hospital discharge or PUCAI ≤45 by day 5) and 20 corticosteroid resistant patients (need for second line medical therapy or colectomy, or PUCAI >45 by day 5). Total RNA was extracted from blood samples collected on day 3 of intravenous corticosteroid therapy. The eluted transcriptomes were quantified on Affymetrix Human Gene 1.0 ST arrays. The data was analysed by the local-pooled error method for discovery of differential gene expression and false discovery rate correction was applied to adjust for multiple comparisons.ResultsA total of 41 genes differentially expressed between responders and non-responders were detected with statistical significance. Two of these genes, CEACAM1 and MMP8, possibly inhibited by methylprednisolone through IL8, were both found to be over-expressed in non-responsive patients. ABCC4 (MRP4) as a member of the multi-drug resistance superfamily was a novel candidate gene for corticosteroid resistance. The expression pattern of a cluster of 10 genes selected from the 41 significant hits were able to classify the patients with 80% sensitivity and 80% specificity.ConclusionsElevated expression of several genes involved in inflammatory pathways was associated with resistance to intravenous corticosteroid therapy early in the course of treatment. Gene expression profiles may be useful to classify resistance to intravenous corticosteroids in children with severe UC and assist with clinical management decisions.

Background Intestinal ultrasound (IUS) is an objective marker for inflammation in ulcerative colitis (UC). Few studies have examined if repeated IUS can predict treatment outcomes in UC. Our aim was to determine if IUS changes after 48±24h of intravenous corticosteroids can predict treatment outcomes in hospitalized patients with severe UC. Methods We performed a blinded observational multicenter study at three university hospitals in Denmark. Bowel wall thickness (BWT), colour doppler signals (CDS), inflammatory mesenteric fat (I-fat), haustration, and bowel wall stratification (BWS) were assessed before treatment initiation and after 48±24h. Treatment response was assessed with a partial Mayo score (pMayo) at day 6±1, defined as a ≥30% and ≥3 point reduction with either a rectal bleeding subscore of 0 or 1 OR a decrease in rectal subscore ≥1 point. If infliximab was administered earlier (≥3 days), pMayo was evaluated at administration. The treating physician was blinded to the IUS findings, and the IUS examiner was blinded to all non-IUS disease parameters. Results Fifty-six patients were recruited between February 2019 and March 2021 (Table 1). Thirty-seven (66%) responded to intravenous corticosteroid therapy within seven days of treatment, while 19 (34%) did not. There was no difference in baseline BWT between groups. However, at follow-up, significant differences between responders and non-responders were identified in both absolute BWT (median 3.1mm vs 4.9mm), absolute reduction ΔBWT (median -1.9mm vs -0.2mm), and percentage reduction (median -35.9% vs -4.1%) all p&amp;lt;0.005, (Figure 1). Receiver operating characteristic curve analysis for BWT at 48±24h to predict non-response showed an area under the curve of 0.85. BWT ≥4mm had a sensitivity of 84.2 (95% CI 60.4–96.6), specificity of 75.7 (95% CI 58.8–88.2), a negative predictive value of 90.3 (95% CI 74.2–98.0), and a positive predictive value of 64 (95% CI 42.5–82.0) for determining non-response. The absence of I-fat, and the presence of BWS and haustration all had significant odds ratio (OR) for detecting response at follow-up. However, BWT was the only significant parameter in the multivariable analysis and, thereby, the most important parameter for response assessment (BWT &amp;gt;20% reduction adjusted OR 10.8 (95% CI 2.5 - 56.6) and BWT ≤4mm adjusted OR 8.8 (95% CI 1.9 - 51.3), both p&amp;lt;0.01). Conclusion Changes in IUS BWT after 48±24h following intravenous corticosteroid treatment in hospitalized severe ulcerative colitis patients, identify responders with high accuracy. IUS might be utilized as an early corticosteroid non-response marker to guide accelerated rescue infliximab regimes.

A prospective double blind controlled trial was undertaken to examine the role of metronidazole as an adjunct to corticosteroids in the management of severe ulcerative colitis. Thirty nine patients with severe ulcerative colitis were randomised on admission to hospital to receive either intravenous metronidazole 500 mg eight hourly (19 patients) or an identical intravenous placebo (20 patients). The two groups were similar with respect to age, sex, and the extent of colitis. In addition all patients received a standard intravenous regimen consisting of methyl prednisolone 16 mg six hourly and parenteral nutrition together with a twice daily hydrocortisone 100 mg enema. Treatment was continued for five days when the patients were formally assessed. Fourteen of 19 patients (74%) receiving metronidazole and 14/20 (70%) receiving placebo were substantially improved, or in remission at the end of five days. Five patients treated with metronidazole and six with placebo had no improvement and all proceeded to urgent colectomy with no operative mortality. There were three late deaths, one in the metronidazole and two in the placebo group. These results do not support the routine use of intravenous metronidazole in the treatment of severe ulcerative colitis.

Corticosteroids are still the first-line treatment for active ulcerative colitis more than 50 years after the publication of trials assessing their beneficial effect, with about a 50% remission rate in cases of severe disease. The mortality related to severe attacks of ulcerative colitis has decreased dramatically, to less than 1%, in experienced centers, due to the appropriate use of intensive therapeutic measures (intravenous steroids, fluids and electrolytes, artificial nutritional support, antibiotics, etc), along with timely decision-making about second-line medical therapy and early identification of patients requiring colectomy. One of the most difficult decisions in the management of severe ulcerative colitis is knowing for how long corticosteroids should be administered before deciding that a patient is a non-responder. Studies assessing the outcome of acute attacks after steroid initiation have demonstrated that, in steroid-sensitive patients, the response generally occurs early on, in the first days of treatment. Different indexes to predict treatment failure, when applied on the third day of treatment, have demonstrated a high positive predictive value for colectomy. In contrast to this resolute approach, which is the most widely accepted, other authors have suggested that in some patients a complete and prolonged response to steroids may take longer. Either way, physicians taking care of these patients need to recognize that severe ulcerative colitis may be life-threatening, and they need to be careful with excessively prolonged medical treatment and delayed surgery.

Cyclosporin is advocated in the treatment of acute severe ulcerative colitis that has failed to respond to high-dose corticosteroid therapy. This approach is controversial, with critics highlighting the temporary nature of remissions and the potential for adverse effects. There have been few reports of the long-term outcome of those patients who do respond. The purpose of this study was to investigate the clinical outcome of all patients treated with cyclosporin at our institution over the past five years. We conducted a retrospective study of 46 patients who presented to a tertiary referral center. Initial responders were those who avoided colectomy; a sustained response was defined as a remission that lasted while the patient was taking oral cyclosporin and for three months after this therapy was discontinued. Thirty-two (69 percent) of 46 patients had an initial response to therapy, and 50 percent met criteria for a sustained response. Eleven of 23 sustained responders subsequently relapsed. At a mean of 22 months' follow-up, 26 percent of patients remain well and have never relapsed. Serious infective complications occurred in two patients, possibly attributable to therapy. No factors predictive of a likely response were identifiable on retrospective analysis. This study confirms the efficacy of cyclosporin in the management of severe ulcerative colitis. Although many initial responders subsequently relapse, such patients may benefit from having even a short time to adjust to the need for surgery. A substantial minority (26 percent) of all patients treated remain in long-term remission.

Medical management of severe ulcerative colitis

Severe ulcerative colitis is a potentially life-threatening condition but the mortality has fallen dramatically over the past 30-40 years. It is now less than 2%, including surgical mortality, and should only be seen in patients with significant co-existing disease. Early recognition of the severity of the colitis, intensive medical therapy, close liaison between physician and surgeon, and prompt surgery when necessary have all contributed to this improved outcome. Despite the use of high-dose intravenous corticosteroids, 20-30% of patients will make a poor response and will require urgent surgery. The use of intravenous cyclosporin has proved effective at reducing the immediate surgical rate in this group of unresponsive patients and appears safe. Whether cyclosporin reduces the need for surgery in the longer term is much less certain. Clinical, radiological, endoscopic and laboratory parameters can now be used to predict the course of a severe attack. These help in the timing of urgent surgery and are potentially helpful in determining when to begin other therapies such as cyclosporin.

Acute severe steroid-refractory ulcerative colitis (ASUC) provides challenges for physicians and surgeons who manage these patients. When a patient is diagnosed with ASUC, they should be admitted for inpatient management including intravenous corticosteroids, venous thromboembolism prophylaxis, oral or enteral feeding if tolerated, and exclusion of infection including Clostridium difficile. Failure to improve by day 3 of corticosteroids requires escalation to medical rescue therapies such as infliximab or cyclosporine, or surgical management with colectomy. This chapter will review management of ASUC with a focus on the medical rescue options available.