Treatment of fulminant ulcerative colitis with cyclosporine A

Abstract

Objective. Fulminant ulcerative colitis not responding to high doses of corticosteroids remains a clinical challenge. Intravenous infusion of cyclosporine A (CyA) has shown an excellent short-term response, but its use has been restricted by potential serious adverse events and reports of high short- and long-term colectomy rates. The purpose of this study was to report on the Oslo experience with CyA in fulminant ulcerative colitis. Material and methods. Between 1993 and 2006, intravenous CyA (5 mg/kg) was administered to 18 patients with fulminant ulcerative colitis. Responders were discharged under a 6 months' course of oral CyA. Patients were prospectively followed at 2, 6, 12 and 24 months after discharge. Results. Fifteen patients (83%) responded to intravenous CyA treatment. On follow-up at 2, 6, 12 and 24 months, the colectomy-free rates were 72%, 67%, 61% and 56%, respectively. After a median follow-up of 60.3 months (range 1.7–146), 8 patients (44%) still had avoided having to undergo a colectomy. All patients had at least one relapse during follow-up. Only one patient had to discontinue CyA owing to adverse events. Conclusion. At our institution, CyA treatment of fulminant ulcerative colitis is an effective and safe treatment.     

Pyoderma gangrenosum complicating ulcerative colitis: Successful treatment with methylprednisolone pulse therapy and cyclosporine

A 32-year-old woman with ulcerative colitis had a relapsed of pyoderma gangrenosum during puerperium. Both the pyoderma gangrenosum and ulcerative colitis had been well controlled with oral prednisolone, but ulcerative colitis relapsed in pregnancy, and pyoderma gangrenosum relapsed in the puerperium. The pyoderma gangrenosum responded to methylprednisolone pulse therapy initially, but relapsed when prednisolone was tapered. A second trial of pulse therapy combined with cyclosporine resulted in complete remission of the pyoderma gangrenosum, and no recurrence was recognized after prednisolone was tapered. This is a very rare case of successful treatment with methylprednisolone pulse therapy combined with cyclosporine for pyoderma gangrenosum complicating ulcerative colitis. (Received May 6, 1997; accepted Sept. 26, 1997)     

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.     

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.     

Predictors of a response to cyclosporine or leukocyte removal therapy in patients with refractory ulcerative colitis

Introduction: Despite decades of clinical experience in optimizing the induction and maintenance of remission in patients with ulcerative colitis (UC), some patients remain refractory to conventional medical treatment while, in others, the effectiveness of drugs is limited by side‐effects. We investigated factors predictive of the efficacy of cyclosporine and leukocyte removal therapy in patients with intractable UC. Methods: Forty‐five patients with moderate to severe UC who were refractory to corticosteroid therapy were enrolled. Twenty‐six patients were treated with cyclosporine and 19 by leukocyte removal therapy. Disease activity index (DAI) score assessment, and colonoscopic and histological examinations were done before and at 10, 20 and 40 days after the initiation of treatment. A clinical response to treatment was defined as a decrease in DAI score of 3 points or more at 40 days. Results: Responder ratio did not significantly differ between the cyclosporine (65.6%) and leukocyte removal therapy (63.2%) groups. Factors predictive of a response to cyclosporine therapy were fever (≥ 38.0°C), anemia and large mucosal ulceration. In contrast, mucosal bleeding and poor extensibility of the intestinal lumen were predictive of a poor response to cyclosporine. No significant differences in any clinical or endoscopic parameter predictive of a response to leukocyte removal therapy were identified. Conclusions: Intravenous cyclosporine may be effective in patients who have severe steroid‐refractory UC, and leukocyte removal therapy may be useful in patients with moderate active UC predicted to be refractive to cyclosporine.     

Tacrolimus in corticosteroid-resistant ulcerative colitis

We report a case of refractory ulcerative colitis treated with tacrolimus. The patient was a 73-year-old woman with a 45-year history of ulcerative colitis. An attack unresponsive to intravenous corticosteroid therapy occurred when she was age 73. Leukocytapheresis therapy was attempted, but was discontinued because of the patient's poor general condition. Cyclosporine A therapy brought about fair control of the disease. A liver injury that was suspected to be associated with this agent, however, occurred within 5 weeks of its initiation. At that time, the cyclosporine A was discontinued and azathioprine treatment was started. Within 6 weeks, signs of exacerbation of the ulcerative colitis became apparent. Tacrolimus administered at that time brought about remission of the disease, and the corticosteroid dose was then reduced. Tacrolimus, like cyclosporine A, appears to be effective for the treatment of attacks of ulcerative colitis. Received: August 23, 1999 / Accepted: January 28, 2000     

The beneficial effect of azathioprine on maintenance of remission in severe ulcerative colitis

Background. The search is on to find more effective drug regimens for patients with severe ulcerative colitis, as conventional drugs such as sulfasalazine and its congeners fail to prevent relapse in a significant number of patients. Azathioprine has also been reported to be useful as a steroid-sparing drug in patients who suffer from frequent relapses. As these drugs when used individually fail to sustain remission in a significant number of patients, we evaluated the combination of these two drugs. Methods. Thirty-five newly diagnosed patients with severe ulcerative colitis were randomized into two groups; group A (combination therapy) received sulfasalazine and azathioprine, while group B (sulfasalazine monotherapy) received sulfasalazine and placebo. In addition, all the patients received steroids initially to achieve clinical remission. The patients were followed-up for a period of 1 year. The therapeutic outcome was measured by the number of patients who suffered relapse in each group. Results. All the patients completed the 1-year study period. While 4 patients (23.5%) in group A suffered relapse of disease, 10 (55.6%) in group B suffered relapse, the difference being statistically significant. The relapse-free period was also significantly longer in group A. Conclusions. Combination therapy (sulfasalazine and azathioprine) is more effective than sulfasalazine and placebo in the maintenance of remission in patients with severe ulcerative colitis. Received: November 20, 2000 / Accepted: September 14, 2001     

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.     

Randomized, double-blind comparison of 4 mg/kg versus 2 mg/kg intravenous cyclosporine in severe ulcerative colitis

BACKGROUND AND AIMS: Cyclosporine A is highly effective in severe attacks of ulcerative colitis (UC) but is associated with important adverse effects that are mainly dose dependent. Our single center, randomized, double-blind, controlled trial aimed to evaluate the additional clinical benefit of 4 mg/kg over 2 mg/kg IV cyclosporine in the acute treatment of severe UC. METHODS: Primary end point was the proportion of patients with a clinical response. Secondary end points included time to response, colectomy rate, and adverse effects. RESULTS: Seventy-three patients were included. Day-8 response rates were 84.2% (32 of 38, 4 mg/kg) and 85.7% (32 of 35, 2 mg/kg) after a median of 4 days in both groups. Short-term colectomy rates were 13.1% (4 mg/kg) and 8.6% (2 mg/kg). Mean cyclosporine blood levels were 237 +/- 33 in the 2-mg/kg group and 332 +/- 43 ng/mL in the 4-mg/kg group. Active smoking was inversely correlated with clinical response (odds ratio, 0.06), but concomitant azathioprine or steroids were not predictive. A trend toward a higher incidence of hypertension was observed in the 4-mg/kg group (23.7% vs. 8.6%, 2 mg/kg, P < 0.08). CONCLUSIONS: High-dose IV cyclosporine has no additional clinical benefit over low dose in the treatment of severe UC. Although we did not observe differences in adverse effects on the short term, the use of 2 mg/kg IV cyclosporine should provide an improved toxicity profile for medical treatment of severe UC.     

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.     

Anti-tumour necrosis factor alpha (Infliximab) in the treatment of severe ulcerative colitis: result of an open study on 13 patients

BACKGROUND: Conventional treatment options for patients with severe steroid-refractory ulcerative colitis include intravenous cyclosporine, which is frequently burdened by toxicity, or colectomy. Preliminary data suggest a benefit from anti-tumour necrosis factor alpha (Infliximab) therapy in patients with steroid refractory ulcerative colitis. AIM: To evaluate the efficacy of Infliximab in the treatment of severe ulcerative colitis refractory to conventional therapy PATIENTS AND METHODS: A series of 13 patients with severe ulcerative colitis, refractory to therapy with methyl-prednisolone, 60 mg daily for seven or more days, were treated with a single intravenous infusion of Infliximab 5 mg/kg. RESULTS AND CONCLUSIONS: Of these 13 patients, 10 (77%) had a clinical response to therapy defined by a clinical activity index 10 on two consecutive days. In 2 patients (15%) total colectomy was necessary on account of clinical worsening whilst one patient refused surgery and was lost to follow-up. All patients who responded showed very rapid clinical improvement, within 2 to 3 days of infusion. Infusion with Infliximab produced no significant adverse events. The mean time of follow-up was 10.1 months (range 5-12; during this time, 9 out of 10 patients (90%) maintained clinical remission and were able to discontinue corticosteroid therapy. Infliximab appears to be an effective agent for inducing long-standing remission in refractory patients with severe ulcerative colitis.     

Long-term maintenance treatment in ulcerative colitis: a 10-year follow-up

BACKGROUND: With the extensive use of mesalamine, the natural history of ulcerative colitis is probably changed. AIM: To evaluate the relapse rate and the duration of remission in patients with ulcerative colitis on maintenance treatment with mesalamine. PATIENTS AND METHODS: Enrolled in the study were 95 patients divided into 4 groups according to macroscopic location of the disease and treated with the same therapy starting from the date of enrolment. Patients in all 4 groups were followed-up until relapse occurred. The disease activity was evaluated by the Clinical Activity Index and Endoscopic Index. Patients suitable for recruitment showed a Clinical Activity Index and Endoscopic Index lower than 6 and 4, respectively. The patients with ulcerative pancolitis or left-sided colitis were treated with 1.6 g/day while the cases with proctosigmoiditis or proctitis were treated with 5-acetylsalicylic acid enemas 4 g/day Each patient was evaluated with clinical and endoscopic assessment at a 6-month interval. Relapse was defined as an increase in Clinical Activity Index and Endoscopic Index, of more than 6 and 4, respectively. RESULTS: Five patients dropped-out. All enrolled patients showed a clinical and/or endoscopic relapse within 10 years, the majority 2 or 3 years after diagnosis: pancolitis and left-sided colitis within 2-3 years and patients with distal colitis within 9-10 years. CONCLUSIONS: A relapse was observed in most cases within 3 years, and in all recruited patients within a space of ten years. The extent of the disease in the colon is an important prognostic factor, as patients with distal colitis showed a lesser tendency to relapse.     

Factors affecting the efficacy of cyclosporin A therapy for refractory ulcerative colitis

Background and Aims: Cyclosporin A (CSA), an immunosuppressive agent, is highly efficacious in patients with refractory ulcerative colitis (UC). We retrospectively investigated patients with refractory UC treated with CSA therapy to elucidate the efficacy and the prognostic factors. Methods: Forty‐one patients (26 men and 15 women) were enrolled. The efficacy of CSA was assessed at three time points: short‐ and mid‐term assessments took place 2 weeks and 1 year after CSA administration, respectively, and long‐term assessments at the end of the observation period. Results: The short‐term response rate was 71%. Background analysis revealed risk factors for CSA unresponsiveness: (i) more than 10 000 mg of prednisolone used before CSA treatment; (ii) the presence of circulating (C7‐HRP); and (iii) disease duration more than 4 years. The mid‐term relapse‐free survival rate was 51.0%. The addition of azathioprine (AZA) after CSA treatment significantly suppressed the incidence of relapse at 1 year (72.5% vs 26.7%, P = 0.0237). The overall colectomy‐free survival rate was 46.4%, and the induction of AZA after CSA treatment significantly reduced the colectomy rate (66.7% vs 30.5%, P = 0.0419). Among CSA responders, AZA naïve patients had significant lower‐probabilities for colectomies compared to patients with prior AZA treatment (22.5% vs 56.7%, P = 0.0309). The administration of CSA was discontinued in five cases. Conclusion: Our results revealed factors affecting the efficacy of CSA therapy for patients with refractory UC. AZA is an important agent that maintains disease quiescence once one responds to CSA. However, refractory patients despite AZA treatment are more likely to have consequent colectomies.     

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.     

Golimumab for moderate to severe ulcerative colitis

Introduction: Golimumab (GLM) is a subcutaneously administered human anti-tumor necrosis factor (TNF) agent that has been approved by the regulatory authorities for the treatment of moderate to severe ulcerative colitis (UC) in 2013.

Areas covered: Maintained clinical remission rates up to 50% have been shown in UC patients receiving GLM, and higher GLM serum concentrations have been associated with improved clinical outcomes. Approximately 50% of UC patients do not respond to induction therapy with GLM, and up to 40% of GLM responders will lose response over time. In most patients, loss of response is associated with low serum GLM concentrations, which suggests insufficient exposure to GLM. Low GLM serum concentrations may be avoided by therapeutic drug monitoring.

Expert commentary: So far, the therapeutic window for GLM has not yet been defined, but options to dose increase GLM based on therapeutic drug monitoring might result in improved clinical outcome and higher success rates.     

Right-sided ulcerative colitis

This report describes a case of right-sided ulcerative colitis in which multiple shallow ulcers and erosion with symmetric luminal stenosis were distributed segmentally from the ascending colon to the cecum, with a skip lesion composed of superficial erosions in the right half of the transverse colon. Both the rectum and the left colon were spared at the time of onset. Biopsies taken from the lesions showed non-specific inflammation, while those from the rectum and sigmoid colon showed no abnormal findings. A 5-year follow-up study was made based on radiography and endoscopy. Other inflammatory bowel diseases, such as Crohn's disease, tuberculosis, Yersinosis, Behçet's disease, and ischemic colitis were all ruled out, based on the macroscopic and microscopic findings as well as the clinical course. To our knowledge, this is the first report of right-sided ulcerative colitis that has been followed for a long period.     

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.