Predicting outcomes in acute severe ulcerative colitis

Response to corticosteroid treatment in acute severe ulcerative colitis (ASUC) has changed very little in the past 50 years. Predicting those at risk at an early stage helps stratify patients into those who may require second line therapy or early surgical treatment. Traditionally, risk scores have used a combination of clinical, radiological and biochemical parameters; established indices include the ‘Travis’ and ‘Ho’ scores. Recently, inflammatory bowel disease genetic risk alleles have been built into models to predict outcome in ASUC. Given the multifactorial nature of inflammatory bowel disease pathogenesis, in the future, composite scores integrating clinical, biochemical, serological, genetic and other ‘-omic’ data will be increasingly investigated. Although these new genetic prediction models are promising, they have yet to supplant traditional scores, which remain the best practice. In this modern era of rescue therapies in ASUC, robust scoring systems to predict failure of ciclosporine and infliximab must be devised.     

Management of acute severe ulcerative colitis

Ulcerative colitis is a chronic relapsing and remitting inflammatory disorder that can generally be managed successfully with maintenance oral medications. However, approximately 15% of patients with ulcerative colitis will develop a severe exacerbation and require hospitalization. While many patients with acute severe ulcerative colitis will respond to a short course of intravenous corticosteroids, up to a third will fail to improve. In these patients with steroid-refractory colitis, the choice is between rescue medical therapy with ciclosporin or infliximab, or surgery. Well-timed rescue medical therapy is generally safe when administered by experienced physicians, and is effective in the majority of cases. Surgery is unavoidable in some cases, but is the treatment of choice in others. While ileal pouch–anal anastomosis offers the prospect of life without a permanent ileostomy, there are issues with its long-term functional outcome.     

Examining maintenance care following infliximab salvage therapy for acute severe ulcerative colitis

Background and Aim

Data supporting the optimal maintenance drug therapy and strategy to monitor ongoing response following successful infliximab (IFX) induction, for acute severe ulcerative colitis (ASUC), are limited. We aimed to evaluate maintenance and monitoring strategies employed in patients post‐IFX induction therapy.

Methods

Patients in six Australian tertiary centers treated with IFX for steroid‐refractory ASUC between April 2014 and May 2015 were identified via hospital IBD and pharmacy databases. Patients were followed up for 1 year with clinical data over 12 months recorded. Analysis was limited to patient outcomes beyond 3 months.

Results

Forty one patients were identified. Five of the 41 (12%) patients underwent colectomy within 3 months, and one patient was lost to follow‐up. Six of 35 (17%) of the remaining patients progressed to colectomy by 12 months. Maintenance therapy: Patients maintained on thiopurine monotherapy (14/35) versus IFX/thiopurine therapy (15/35) were followed up. Two of 15 (13%) patients who received combination maintenance therapy underwent a colectomy at 12 months, compared with 1/14 (7%) patients receiving thiopurine monotherapy (P = 0.610). Monitoring during maintenance: Post‐discharge, thiopurine metabolites were monitored in 15/27 (56%); fecal calprotectin in 11/32 (34%); and serum IFX levels in 4/20 (20%). Twenty of 32 (63%) patients had an endoscopic evaluation after IFX salvage with median time to first endoscopy of 109 days (interquartile range 113–230).

Conclusion

Following IFX induction therapy for ASUC, the uptake of maintenance therapy in this cohort and strategies to monitor ongoing response were variable. These data suggest that the optimal maintenance and monitoring strategy post‐IFX salvage therapy remains to be defined.     

Management of acute, severe ulcerative colitis

When a patient is hospitalized with acute, severe ulcerative colitis, the primary decision is whether or not to proceed directly to surgery. Absolute indications for an immediate colectomy include exsanguinating hemorrhage, perforation and cancer. If medical therapy is undertaken, however, the decision for urgent surgery or non-operative salvage therapy will still be required in 15-50% of the patients in which there is a failure to respond within 3-5 days to a standard regimen of i.v. steroids, antibiotics, decompressive maneuvers, fluid and electrolyte replacement and other supportive measures. The options for medical salvage therapy are usually cyclosporine or infliximab. There are theoretical and practical arguments on each side; the current GETAID and CONSTRUCT trials will probably provide support for either. The choice between colectomy or medical salvage therapy, however, must not be delayed under any circumstances. Before choosing salvage therapy, one must first be certain that there is the luxury of time, that there is a post-hospital strategy for the maintenance of remission and that the colon is worth saving. The priority is not so much saving colons as it is saving lives.     

Infliximab or cyclosporine for acute severe ulcerative colitis: a retrospective analysis

Background and Aim: Medical treatment of steroid‐refractory ulcerative colitis (UC) is limited to either cyclosporine or infliximab. Studies comparing cyclosporine with either placebo or intravenous methylprednisone showed promise for cyclosporine, but associated it with significant toxicity. There is conflicting, but increasingly positive evidence for using infliximab. There are no studies directly comparing these two treatments. Our aim was to compare the outcomes of patients with steroid‐refractory UC treated with either intravenous cyclosporine or infliximab. Methods: We carried out a retrospective review of inpatients with steroid‐refractory UC, treated with either intravenous cyclosporine or infliximab, at Waitemata District Health Board, between January 2001 and February 2010. The primary end‐points were time to colectomy, and colectomy rates at 3 and 12 months. Secondary end‐points were time to discharge from initiation of treatment, steroid dependence at 12 months, and reported adverse events. Results: The total study population was 38, with 19 in the infliximab group. Follow up to 12 months was complete in all patients. At 3 months, the colectomy rate was 63% for cyclosporine, compared to 21% (P = 0.0094). By 12 months the rate was 68% and 37% for cyclosporine and infliximab, respectively (P = 0.06). Patients in the cyclosporine group required an additional 5 days in hospital (P = 0.0086). Steroid dependence at 12 months was 50% for cyclosporine versus 25% for infliximab (P = 0.36). Cyclosporine caused more adverse events (P = 0.17). Conclusions: Infliximab improved clinical outcomes compared to the previous use of intravenous cyclosporine in patients admitted with steroid‐refractory acute severe UC.     

Diffuse gastroduodenitis associated with ulcerative colitis: Treatment by infliximab

Diffuse gastroduodenitis resembling ulcerative colitis in respect to macro‐ and microscopic findings occurs in ulcerative colitis, although it is rare. Reports of gastroduodenitis associated with ulcerative colitis treated with infliximab are rare. A 58‐year‐old man had tarry stool in March 2011. He had a history of ulcerative colitis that was diagnosed in 1984. He underwent subtotal colectomy in 1991. Endoscopy and radiography revealed diffuse friable mucosa throughout the duodenum and an ulcer in the middle of the descending portion, resulting in a narrow portion.In the stomach, numerous small aphthae were observed in the antrum. Biopsy specimens of the duodenum and antrum showed marked inflammatory cell infiltration in both areas and cryptitis in the duodenum. Standard induction therapy of infliximab was started in April. The ulcer in the descending portion became a scar without diffuse mucosal friability in September 2011.     

Colectomy rate in acute severe ulcerative colitis in the infliximab era

BACKGROUND: Severe ulcerative colitis is a potentially life-threatening condition. Due to advances in medical therapy, the mortality rate has dropped to <2% over the past 30 years, but the colectomy rate reaches 30%. Recently, infliximab has been shown to be effective as rescue therapy but little is known about long-term benefits. AIM: To evaluate short-and long-term colectomy rates for severe ulcerative colitis in the era of biological treatment and to identify predictive factors of long-term colectomy. PATIENTS AND METHODS: From 2001 to 2006 all in-patients with severe ulcerative colitis, according to Truelove and Witts criteria, were retrospectively reviewed. All patients had received intravenous steroid treatment; infliximab (5 mg/kg at 0, 2 and 6 weeks) was used as rescue therapy in steroid-refractory patients; colectomy was performed in patients who deteriorated whilst on steroid treatment or failed to respond to infliximab. RESULTS: Of the 314 ulcerative colitis patients hospitalized during the study period, 52 (16.5%) met the criteria of severe ulcerative colitis. After median 7 days (range 4-15) on intravenous steroids, 37/52 (71%) patients showed a clinical response, while 15/52 (29%) were steroid-refractory. Of these, four underwent urgent colectomy and 11 received infliximab. A clinical response was observed in all infliximab-treated patients. In the long-term, another six patients underwent elective colectomy. The overall colectomy rate, following the acute attack, was 19%; the cumulative probability of a course without colectomy was 90%, 86%, 84%, 81%, after 6, 12, 18 and 24 months, respectively. No deaths occurred. The long-term colectomy risk was comparable in patients treated with infliximab and in steroid-responsive patients (18% vs. 11% respectively; OR 1.9; 95% CI 0.26-14.5). No predictive factors of colectomy, in the long-term, were identified. CONCLUSIONS: Surgery continues to play an important role in acute severe ulcerative colitis. Infliximab can avoid urgent colectomy in steroid-refractory patients but the risk of elective colectomy, in the long-term, is not modified.     

Efficacy and safety of infliximab as rescue therapy for ulcerative colitis refractory to tacrolimus

Background and Aim: Little is known about the efficacy and safety of infliximab for ulcerative colitis refractory to tacrolimus. The aim of this study was to evaluate the efficacy and safety of infliximab in the induction of remission in ulcerative colitis patients with persistent symptoms despite tacrolimus therapy. Methods: We report a retrospective, observational, single‐center case series of 12 consecutively enrolled patients with ulcerative colitis refractory to tacrolimus that received infliximab therapy for the induction of remission. Eight patients received a single infusion of infliximab, and four received two or more infusions. Median follow‐up duration was 16.0 months (range, 1.6–41.4 months). The clinical response was evaluated based on a modified Truelove‐Witts severity index. Results: Six patients (50.0%) achieved clinical remission within 30 days. Overall cumulative colectomy‐free survival was estimated to be 58.3% at 41.4 months. Adverse events included an elevation of liver enzymes (1/12; 8.3%) and a mild infusion reaction (1/12; 8.3%). No mortality occurred. Conclusions: Infliximab can induce remission in patients with ulcerative colitis who do not tolerate or respond to tacrolimus therapy.     

Therapeutic options in acute severe ulcerative colitis

Ulcerative colitis is a relapsing–remitting inflammatory disease affecting the colon and is associated with considerable morbidity. In acute severe attacks, there continues to be an associated mortality rate of 1–2%, even in specialist units. During an acute severe exacerbation, approximately two-thirds of patients will respond to intravenous corticosteroid therapy, the accepted first-line therapy in such cases. For steroid-refractory patients, options are limited to surgery (colectomy) or second-line agents, such as ciclosporin or infliximab, used in an attempt to salvage the colon. Considerable debate exists over the optimal management of such patients. During the last decade, an increased understanding of the pathogenesis of inflammatory bowel disease has led to the rapid development of other biological agents, such as basiliximab and visilizumab. Novel methods, such as leucopheresis, have been studied and other established immunomodulatory agents, such as tacrolimus, have also been suggested. The purpose of this review is to highlight some of the areas of recent development in the treatment of acute severe ulcerative colitis and review important safety data, with a particular emphasis on biological agents.     

Irreversible optic neuritis after infliximab treatment in a patient with ulcerative colitis

Abstract

This article reports the first known case of permanent blindness due to irreversible unilateral optic neuritis (ON) related to infliximab (Remicade) treatment of a patient with ulcerative colitis. A young male, with a family history of inflammatory bowel disease, was diagnosed with ulcerative colitis at the age of 20. He was treated with steroids and a 5-aminosalicylic acid drug without considerable effect, and later admitted to our hospital due to a relapse during reduction of the prednisolone dosage. A new colonoscopy showed moderate ulcerative colitis activity and the patient was declared as a steroid nonresponder. A treatment of 400 mg intravenous infliximab was initiated along with 150 mg/day of azathioprine (Imurel). Three days after the second infliximab treatment the patient woke up with no vision on the left eye and with pain during ocular movement. Brain and orbitae magnetic resonance imaging showed ON on the left optical nerve without any abscess or thrombosis. The patient was treated with 1000 mg methylprednisolone (Solu-Medrol) intravenous for 3 days and afterward with 75 mg prednisolone orally without any effect. At the 3-month follow up, the patient’s vision had not improved, and he was declared permanently blind on the left eye. A neurologist also examined the patient, but no abnormality or cause of the ON was found.     

Surgical and medical treatment in patients with acute severe ulcerative colitis

Ulcerative colitis (UC) is a chronic inflammatory disease of the mucosa of the colorectum. The treatment of UC depends on the severity of symptoms and the extent of the disease. Acute severe colitis (ASC) occurs in 12–25% of patients with UC. Patients with ASC must be managed by a multidisciplinary team. Medically or surgically aggressive treatment is carried out with the final aim of reducing mortality. Intravenous administration of corticosteroids is the mainstay of the therapy. Medical rescue therapy based on cyclosporine or infliximab should be considered if there is no response to corticosteroids for 3 days. If there has been no response to medical rescue therapy after 4–7 days, the patient must undergo colectomy in emergency surgery. Prolonged observation is counterproductive, as over time it increases the risk of toxic megacolon and perforation, with a very high mortality rate. The best potential treatment is subtotal colectomy with ileostomy and preservation of the rectum. Emergency surgery in UC should not be seen as a last chance, but can be considered as a life‐saving procedure. Colectomies in emergency setting are characterized by high morbidity rates but the mortality is low.     

Severe attack of ulcerative colitis in children: retrospective clinical survey

AIM: To obtain clinical data concerning severe attacks of ulcerative colitis in children. PATIENTS AND METHODS: A retrospective chart review of 37 children with ulcerative colitis was carried out in order to assess the prevalence, risk factors, timing of presentation, and outcome of severe attacks of ulcerative colitis. RESULTS: A total of 20 severe attacks occurred in 15 out of the 37 patients. No difference in the occurrence of severe attacks was detected in relation to age or disease extent at diagnosis. The mean interval between disease diagnosis and a severe attack was 9.1 months (range 0-30). Of the 20 severe attacks, 11 were resolved with medical treatment in a mean time of 1 1 +/- 4.6 days while 9 out of 20 needed urgent surgery in a mean time of 7.4 +/- 4.8 days. Of 10 out of the 15 patients who recovered from the first attack 4 required colectomy after a mean time of 6.7 months, another 4 are still in remission at a mean period of 40.7 months, one needed elective surgery after 25 months and one was lost to follow-up. CONCLUSIONS: Severe attacks of ulcerative colitis had a high prevalence rate [40%); age and disease extent at presentation were not predictors of their occurrence. Approximately half the attacks resolved with medical treatment alone, while the other half required emergency surgery. After successful medical treatment of the first attack, 40% of children maintained long-term remission, while 40% required early colectomy     

Infliximab in ulcerative colitis: real-life analysis of factors predicting treatment discontinuation due to lack of response or colectomy: ECIA (ACAD Colitis and Infliximab Study)

Objective. To describe clinical practice with infliximab (IFX) in ulcerative colitis (UC); identification of predictive factors for IFX treatment discontinuation due to insufficient response and for colectomy. Material and methods. Retrospective, multicentric and observational study including every UC IFX-treated patient in 10 Spanish hospitals. Variables analyzed: epidemiological data; variables for poor prognosis; IFX prior treatments; characteristics of the IFX treatment; time from the UC diagnosis to induction with IFX; time from induction to colectomy or until data collection. Predictive and protective factors for IFX discontinuation due to lack of response and for colectomy were analyzed with binary logistic regression and Cox analysis. Results. Follow-up time from induction with IFX to the collection of data or colectomy: 36.7 ± 25.7 months. Prior treatment with immunomodulator medications (IMM): 79%; IFX + immunosuppressant therapy: 77%; discontinuation of IFX: 26%, colectomy 16%. Independent predictive or protective factors for IFX discontinuation: IMM resistance (OR: 2.9, p = 0.022, 95%CI: 1.2–7.2), prior use of leukocytapheresis (OR: 3.3, p = 0.024, 95%CI: 1.1–9.4), IFX + IMM therapy (OR: 0.3, p = 0.022, 95%CI: 0.1–0.9, and HR: 0.4, p = 0.006, 95%CI: 0.2–0.8) and corticosteroid use in induction (HR: 1.9, p = 0.049, 95%CI: 1.0–3.8). Independent predictive or protective factors for colectomy: Use of leukocytapheresis (OR: 3.0, p = 0.036, 95%CI: 1.1–8.4), IFX + IMM therapy (OR: 0.3, p = 0.022, 95%CI: 0.1–0.8, and HR: 0.3, p = 0.011, 95%CI: 0.1–0.8) and severe cortico-resistant flare-up (HR: 2.5, p = 0.032, 95%CI: 1.1–5.9). Conclusions. Prior use of IMM and leukocytapheresis, the use of corticosteroids in induction and a severe cortico-resistant flare predict a worse response to IFX and the need for colectomy. Combination therapy is a protective factor for both.     

Long-term effects and colectomy rates in ulcerative colitis patients treated with infliximab: A Danish single center experience

Abstract

Objective. Infliximab (IFX) is a well-established treatment for both acute, severe ulcerative colitis (UC) and chronic, refractory UC. However, data on the long-term clinical outcome and colectomy rates after IFX treatment in a routine clinical setting are sparse. The aim of this study was to provide further data on the long-term effect of IFX for acute, severe and chronic, refractory UC in unselected patients treated at a single center. Material and Methods. A retrospective analysis of all patients (n = 52) treated with IFX for UC before February 2009 was performed. The material comprised 19 patients (37%) with acute, severe UC and 33 patients (63%) with chronic, refractory UC. The primary outcome was colectomy rate; the secondary outcome clinical response. Results. The overall colectomy rate was 27% (14/52 patients) after a median follow-up of 22 months (range 4–57 months). The colectomy rate was 37% (7/19 patients) in the group with acute, severe UC and 21% (7/33 patients) among those with chronic, refractory UC. In all, 77% of the patients had clinical response to IFX treatment with no difference between the two subgroups. Among those with an initial clinical response, 50% (20/40 patients) had sustained clinical response. Conclusion. IFX is of long-term benefit as rescue treatment in selected patients with acute, severe UC with about two-thirds of the patients avoiding colectomy. The beneficial effect on colectomy rate in chronic, refractory UC seems less convincing although these patients may still achieve a sustained clinical response.     

Ability of different rescue therapies to save the bowel in acute,severe, steroid-refractory ulcerative colitis

To date, corticosteroids have been the primary therapies for acute, severe ulcerative colitis (UC). Patients not responding to intravenous steroids assessed at 3–5 days of the treatment are candidates for second-line rescue therapy. Cyclosporine (CsA), tacrolimus and infliximab (IFX) are also effective therapeutic options in acute, severe UC. In this review we summarized the results of the published studies examining and comparing the efficacy of CsA, tacrolimus and IFX as rescue therapies, and assessing the outcome of switching the drugs in case of therapeutic failure.     

Education in practice: How to manage: acute severe colitis

Acute severe ulcerative colitis (ASUC) is a medical emergency which is associated with significant morbidity and a mortality rate of 1%. ASUC requires prompt recognition and treatment. Optimal management includes admission to a specialist gastrointestinal unit and joint management with colorectal surgeons. Patients need to be screened for concomitant infections and thromboprophylaxis should be administered to mitigate against the elevated risk of thromboembolism. Corticosteroids are still the preferred initial medical therapy but approximately 30%–40% of patients fail steroid therapy and require rescue medical therapy with either infliximab or cyclosporine. Emergency colectomy is required in a timely manner for patients who fail rescue medical therapy to minimise the risk of adverse post-operative outcomes. We discuss current and emerging evidence in the management of ASUC and outline management approaches for clinicians involved in managing ASUC.