Steroid-resistant Ulcerative Colitis Research Articles

Basiliximab for the treatment of steroid‐resistant ulcerative colitis: further experience in moderate and severe disease

Preliminary data have suggested that interleukin-2 receptor blockade with basiliximab may increase steroid sensitivity. We have previously reported a small case series demonstrating the potential of basiliximab as a novel agent for the treatment of steroid-resistant ulcerative colitis. To report further experience of the efficacy and safety of treatment with the interleukin-2 receptor blocking monoclonal antibody basiliximab, in addition to steroids, for the treatment of severe and moderate steroid-resistant ulcerative colitis. Twenty patients were enrolled - 13 patients with moderate steroid-resistant ulcerative colitis (Ulcerative Colitis Symptom Score: >or=6) and seven patients with severe steroid-resistant ulcerative colitis. All were given a single dose of 40 mg basiliximab plus standard steroid therapy in an open-label, uncontrolled trial. Primary end point was clinical remission within 8 weeks (Ulcerative Colitis Symptom Score: <or=2). Within 8 weeks, 10 of 20 (50%) patients achieved clinical remission (seven of 13 moderate, and three of seven severe). At 24 weeks, 13 of 20 (65%) patients were in clinical remission. Five patients required colectomy (four severe, one moderate ulcerative colitis) and one required rescue ciclosporin (moderate ulcerative colitis). Two patients developed herpes zoster, but treatment was generally well tolerated. Basiliximab appears to promote prolonged remission after a single treatment. Taken in combination with previously reported data, basiliximab shows particular promise in moderate steroid-resistant ulcerative colitis.

Long-term results of intravenous cyclosporine in steroid-resistant ulcerative colitis.

Depts. of Gastroenterology1 Clinical Pharmacology2, Isala klinieken, Zwolle, The Netherlands Abstracts of the Netherlands Societies of Gastroenterology and the Netherlands Society of Hepatology

Natural History of Patients Hospitalized with Fulminant Ulcerative Colitis

Purpose: To study the immune-status of patients with fulminant ulcerative colitis (UC) who have been hospitalized for treatment with intravenous glucocorticoids. To study the long-term clinical outcome of this patient population. Methods: A cohort of oral steroid resistant UC patients (N = 201) were evaluated for Epstein Barr Virus (EBV) and cytomegalovirus (CMV) viral load and lymphocyte subsets during and subsequent to receiving IV steroids. EBV viral load data were also obtained for a cohort of patients (N = 64) with mild to moderate UC. Retrospectively, the clinical outcome data from the Kaiser Permanente IBD Registry were analyzed for a third cohort of patients (N = 663) who had received intravenous steroids during their initial hospitalization for fulminant UC. Results: Of the first cohort evaluated, 40% had measurable copies of EBV genome in their blood as compared to 0% of less severe UC patients, and 31% had CD4 counts below 200/mcL. Furthermore, 9% had both low CD4 counts and detectable EBV. Of a subset of patients screened for CMV (N = 73), only 5% were positive for CMV genome. Of the 663 patients reviewed from the Kaiser Permanente IBD Registry, 133 underwent colectomy during the index hospitalization. 497 patients left the hospital without colectomy, 82% of which tapered off steroids within 6 months of discharge, while 18% did not. However, 41% had re-started steroids by the first anniversary of their discharge date, 21% were re-hospitalized, and 10% underwent colectomy within 12 months of the initial discharge date. Conclusions: UC Patients receiving IV steroids experience significant immunosuppression, as evidenced by increases in EBV viral load and decreased CD4 counts. This contrasts with the EBV status and CD4 counts5 of patients with mild to moderate UC, both of which are within normal range. UC patients from a community-based practice who were hospitalized for severe UC and treated with IV steroids were at significant risk for immediate colectomy before release (20%), while those who were released without colectomy were at significant risk for relapse of disease (72%) and for colectomy (10%) in the ensuing 12 months. 5 Gut 1991 32(7):779–83

Low‐dose oral microemulsion ciclosporin for severe, refractory ulcerative colitis

The optimal modalities of treatment with oral microemulsion ciclosporin in patients with severe, steroid-refractory ulcerative colitis are uncertain. To assess the applicability, in terms of efficacy and tolerability, of a standard oral microemulsion ciclosporin treatment protocol targeting relatively low blood ciclosporin concentrations, in patients with severe, steroid-resistant ulcerative colitis. Patients with a severe attack of ulcerative colitis and no satisfactory response to intravenous corticosteroids were started on oral microemulsion ciclosporin. Dosages were adapted according to a standard protocol, targeting a blood predose ciclosporin concentration (C0) of 100-200 ng/mL. Patients without a clinical response on day 8 were scheduled for colectomy. Sixteen patients were enrolled. A clinical response was observed in 14/16 (88%). The mean clinical activity index scores and concentrations of C-reactive protein on days 0, 4 and 8 were 11.8, 6.7 and 4.1, and 50.3, 19.3 and 9.7 mg/L respectively. The mean C0 (days 0-8) was 149 pg/mL. The mean creatinine clearance rates on days 0 and 8 were 88 and 96 mL/min. One patient had an acute elevation of transaminases that resulted in discontinuing ciclosporin. Even when dosed for a target C0 of 100-200 ng/mL, oral microemulsion ciclosporin for severe, steroid-refractory ulcerative colitis achieves an efficacy similar to that attained with higher, potentially more toxic levels. The oral route should replace intravenous treatment in this clinical setting.

Efficacy of intravenous cyclosporin in moderately severe ulcerative colitis refractory to steroids

The efficacy of intravenous cyclosporin (CSA) in acute severe ulcerative colitis (UC) is well established. The aim of this study was to evaluate its efficacy in moderately severe colitis refractory to steroids. Twenty-six patients (17 men, mean age 41 +/- 14 yr) with UC refractory to steroids treated with CSA were included in this study. Severity was defined according to Truelove criteria. A clinical activity score below 10 during 2 consecutive days defined clinical response. According to Truelove criteria, all patients had moderate UC. CSA was administered IV at a mean daily dose of 3.7 +/- 0,5 mg/kg until response and then orally for 3.5 +/- 2.6 months. A clinical response was achieved in 20/26 patients (76,9%) within 5.7 +/- 2.8 days (5/6 failures were treated by proctocolectomy). During a follow-up of 27.8 +/- 20.8 months, relapse rate was 60% (12/20): 7 patients underwent proctocolectomy and 5 had clinical remission with CSA retreatment (N=4) and steroids (N=1). At the end of follow-up, 12 patients (46%) were in clinical remission, 12 (46%) required colectomy, 1 had chronic active UC and 1 was lost of follow-up. The probability to avoid surgery was 52% at 78 months. The only factor associated with avoidance of surgery was concomitant treatment with azathioprine (P=0.007). Ten reversible adverse events occurred in 9 patients. This study shows that CSA is safe and effective in moderately severe steroid resistant UC. Concomitant treatment with azathioprine significantly decreases the rate of subsequent surgery. CSA may act as a "bridge" until the therapeutic action of azathioprine is achieved for maintenance treatment. These results should be further confirmed by a prospective controlled study.

Stool decay‐accelerating factor as a marker for monitoring the disease activity during leukocyte apheresis therapy in patients with refractory ulcerative colitis

We have shown previously that concentrations of stool decay-accelerating factor (DAF; CD55), a complement regulatory protein, in patients with ulcerative colitis (UC) are increased in relation to the severity of the colonic mucosal inflammation. In the present study, we evaluated the usefulness of stool DAF as a marker for monitoring disease activity in patients with steroid-resistant active UC being treated with leukocyte apheresis performed with a centrifugal cell separator. Twenty-one patients with active and steroid-resistant UC were treated with leukocyte apheresis once a week for 4 weeks, and stool DAF concentrations were determined weekly by immunoassay. After treatment, 11 (52%) of the 21 UC patients went into remission. Stool DAF concentrations decreased promptly and steadily in the responsive group. The difference reached statistical significance as soon as after the second apheresis session (P < 0.003), compared with values before the therapy and corresponding values in the non-responsive group (P = 0.024). The reduction in stool DAF concentrations after the second apheresis session was significantly greater in the responsive group (median 90%, range 22-90%) than in the non-responsive group (median -13%, range -307-94%) (P = 0.008). Hematological tests, that is, white blood cell (WBC) count and C-reactive protein, declined significantly during the apheresis therapy, but not in relation to therapeutic response. Stool DAF concentration is a useful marker in the clinical response of UC patients to treatment with leukocyte apheresis.

P0704 LEUKOCYTAPHERESIS TREATMENT FOR 5 JAPANESE ADOLESCENT WITH ULCERATIVE COLITIS

Introduction: Leukocytapheresis (LCAP) and granulocytapheresis (GCAP) have come to be conducted for the treatment of steroid-resistant ulcerative colitis (UC) in adults. LCAP and GCAP are believed to be effective alternative strategies for the treatment of this condition, aimed at reducing the total dose of steroids and side effects. However, there are only a few reports on the treatment of UC occurring in childhood. Methods: Six Japanese adolescents were diagnosed as having UC at our hospital after 1994, who had repeated remissions and exacerbations of the disease despite therapy with mesalazine and steroids. The effectiveness of GCAP and LCAP was investigated in these patients in relation to the age at the time of diagnosis of the disease, total dose of steroids required, course of clinical symptoms before and after these treatment procedures, complications and prognosis. Results: The age of the patients at the time of diagnosis of the condition ranged from 9 to 13 years. UC affected the whole colon in all of the patient. LCAP was performed in five of the patients and GCAP in the remaining one patient. The age of the patients at the time of treatment by LCAP or GCAP ranged from 13 to 21 years. Four of the six patients had recurrent UC, but the remaining one patient, in whom single LCAP was conducted, had the first attack of UC. The frequency of diarrhea and bloody stools decreased in 4 of the 5 patients after the start of treatment. In the remaining one patient, the symptoms scarcely resolved, and the treatment had to be interrupted after 6 sessions, because the patient complained of discomfort during the treatment. At the end of the treatment, 2 patients entered into remission, and the daily dose of prednisolone could be reduced. However, both the patients developed disease exacerbation again one month after the end of treatment. The one patient who never entered remission and another in whom the treatment was interrupted, underwent total excision of the large intestine thereafter. The patient with the first attack of UC entered into remission after combined cytapheresis and steroid pulse therapy, and the dose of prednisolone is being gradually tapered. Conclusion: Repeated recurrences, requirements of high dose of steroids, and the attendant side effects, including failure to thrive, have been issues among childhood UC patients. In our report, LCAP and GCAP seem to be effective for resolution of the morbid condition in the acute stage. However, treatment by cytapheresis was partially effective in a patient who eventually required surgical treatment, and some of the patients showing early recurrence. Thus, assessment of the optimum timing of performance of GCAP and LCAP and initiation of remission-maintenance therapy in future studies is necessary.

Infliximab in ulcerative colitis: is there a placebo (effect) in the house?

Infliximab in ulcerative colitis: is there a placebo (effect) in the house?

Basiliximab (IL-2 receptor antagonist) as a steroid sensistising agent in steroid resistant ulcerative colitis

Basiliximab (IL-2 receptor antagonist) as a steroid sensistising agent in steroid resistant ulcerative colitis

A humanized anti-CD3 monoclonal antibody, visilizumab, for treatment of severe steroid-refractory ulcerative colitis: Preliminary results of a phase I study

Purpose: In severe, steroid-resistant ulcerative colitis (UC), therapeutic approaches have involved targeting T-cells to control excess inflammation. We hypothesize that the humanized anti-CD3 monoclonal antibody, visiliaumab (Protein Design Labs, Inc., Fremont, CA), may provide therapeutic benefit in UC Methods: We report preliminary results from multicenter, phase I dose-escalation study of visilianmab in patients with severe UC whose disease has not responded to a minimum of 5 days of intravenous (IV) corticosteroids. Seven patients have been enrolled to date; five patients (reported here) have passed the day 30 evaluation. All patients received an IV infusion of visilizumab at 15 p,/kg on study days 1 and 2. Results: At enrollment, the first 5 patients had a median modified Truelove and Witts (MTWS]) score of 13 (range 11-16); all had an endoscopy score of 3 (scale 0-3, 3 = severe disease), with >60 cm of colon involvement by endoscopy. At day 30, these 5 patients all achieved clinical and endoscopic remLssion (defined as an MTWSI of <3) and an endoscopy score of 0 or 1. Patients have continued to maintain clinical improvement for several months following treatment. The first 3 patients are now beyond 90 days and have been tapered off steroids onto 5-ASA's or are receiving no additional therapy. Transient (1-4 week) decreases in T-lymphocyte counts from peripheral blood were observed. Moderate cytokine release symptoms (nausea, vomiting, chifis, arthmlgias) were observed in four patients, and one patient had severe dehydration that required fluid support. These symptoms were transient, resolving within 1-2 hours and occurred predominantly on day 1. Two patients had transienL low-level Epstein-Barr titers (3640, 5153 copies/m1) in whole-blood detected by PCR that were not associated with clinical symptoms. There have been no documented infectious complications. Conclusions: This preliminary analysis of an open-label phase [ study of visilizumab in patients with severe UC has demonstrated potential tolerahility and clinical activity at a very low dose. Enrollment into this study continues and the data will be updated at the meeting.

Leukocyte apheresis using a centrifugal cell separator in refractory ulcerative colitis: a multicenter open label trial.

Recently, successful results of ulcerative colitis (UC) treatments with leukocyte apheresis have been reported by several institutes. To certify the efficacy of leukocyte apheresis in refractory UC patients, a multicenter open label trial was conducted, and results were analyzed. Fifty patients diagnosed with active steroid-resistant UC were enrolled in this study from 14 medical centers. Using a centrifugal cell separator (Component Collection System, Haemonetics), leukocyte apheresis was performed once a week for 5 weeks. General conditions and abdominal symptoms were recorded daily, and laboratory tests were followed weekly. Changes of colonoscopic and histological manifestations of luminal activity through the study period were evaluated. At the end of the study period, stool frequency was decreased to less than 4 times a day in 68.4% (26 of 38) and serum C-reactive protein (CRP) concentration was normalized in 56.7% (17 of 30) of the patients. Colonoscopic remission was achieved in 57.7% (26 of 45), and histological improvement was noted in 54.1% (20 of 37) of the patients tested. Improved disease activity was demonstrated in 74% (37 of 50) of the patients by general assessment criteria. Analysis of the trial data confirmed the valid clinical efficacy of leukocyte apheresis by centrifugal cell separator in refractory UC patients.

Cytomegalovirus Infection in a Patient With Steroid-Resistant Ulcerative Colitis

A 56-year-old Japanese man with ulcerative colitis was admitted because of being judged as resistance to treatment with intravenous prednisolone (60-100 mg/day) and oral sulfasalazine (3 g/day) over 1.5 months at another hospital. Colonoscopy at our hospital showed multiple punched-out ulcers from the cecum to the descending colon without active inflammation in the rectum. Although cytomegalovirus superinfection after long-term steroid administration was highly suspected and the treatment for it was planned, he developed massive bleeding and progressive clinical deterioration that necessitated emergency total colectomy in several days after the colonoscopic examination. Histopathologically, cytomegalic inclusion bodies were identified on the ulcer rim and base, while the activity of ulcerative colitis was kept under control with steroid. Because the antigenemia of cytomegalovirus continued positive even after colectomy, ganciclovir was administered until the antigenemia was turned into negative. The present case showed that cytomegalovirus superinfection should be considered in patients with inflammatory bowel disease having long-term steroid administration and immediate serological and histological investigation should be performed when the clinical course is unusual.

Effective maintenance leukocytapheresis for patients with steroid dependent or resistant ulcerative colitis.

We prospectively examined the effect of leukocytapheresis (LA) on the maintenance of remission in 7 patients with ulcerative colitis (UC) who were initially refractory to corticosteroid therapy (steroid resistant or steroid dependent). The patients with refractory UC had been in remission due to LA (induction LA) in combination with the steroid therapy. They were then treated with LA once or twice a month for the purpose of maintaining remission (maintenance LA). The maintenance LA was performed by either a centrifuge method in 5 patients or a polyester adsorbent column method in 2 patients. Steroid dosage was gradually tapered as little as possible without recurrence based on clinical and/or colonoscopical judgments. Four patients were maintained in remission without steroids over 12 months. Recurrence was observed in 3 patients at 3, 3, and 6 months after the beginning of the maintenance LA, respectively. Two of the 3 patients were again conducted to remission by the second induction LA and maintained in remission by the second maintenance LA. Two patients finally underwent total colectomy because of recurrence of UC in a severe form. It is concluded that the maintenance LA therapy might be effective in some patients with steroid dependent or resistant UC for the maintenance of remission without steroids.

Nocardia asteroides lung abscess in acute ulcerative colitis treated with cyclosporine

Cyclosporine is a potent suppresser of cell-mediated immunity that is mainly used in organ transplantation to prevent rejection. It is also being used increasingly outside of transplantation and probably is the only new treatment to have made an impact in acute ulcerative colitis (UC) resistant to steroid therapy. We describe a case of Nocardia asteroides lung abscess in a patient treated with cyclosporine for acute steroid resistant UC that was successfully managed with antibiotics and by discontinuing cyclosporine. With increasing use of cyclosporine for acute UC it is to be anticipated that opportunistic infections such as Nocardia will be more frequently encountered in the future.

Factors predictive of response to cyclosporin treatment for severe, steroid-resistant ulcerative colitis

OBJECTIVE: Cyclosporin-A (CSA) has been demonstrated to be effective for treatment of severe, steroid-resistant ulcerative colitis (UC). Use of CSA has been limited, however, because of low 1-yr response rates and the potential for complications. The aim of this study is to define clinical and laboratory factors predictive of response in severe, steroid-resistant UC. METHODS: A retrospective review of 36 cases of severe, steroid-resistant UC treated with CSA was performed. Intravenous ( i.v.) CSA was administered at an initial dose of 2.5 mg/kg, and oral ( p.o.) CSA was given as twice the i.v. dose. Clinical response was recorded and logistic regression analysis was performed on clinical and laboratory factors for prediction of response to CSA. RESULTS: Of 36 patients, 25 responded to i.v. CSA and were switched to p.o. CSA. Of the 25, 13 required colectomy by 9 months. The other 12 patients had a sustained response to CSA and avoided colectomy at 9 months. Overall, 24 of 36 patients treated with CSA required colectomy by 9 months. A high percentage of band neutrophils (bands) on admission was found to be a significant predictor of response to CSA. CONCLUSIONS: Bands on admission are predictive of response to CSA and ultimately, the requirement for surgery in steroid-resistant UC.

Prospective analysis on efficacy of cyclosporin in steroid-resistant ulcerative colitis

Prospective analysis on efficacy of cyclosporin in steroid-resistant ulcerative colitis

Intravenous cyclosporin in ulcerative colitis: a five-year experience

OBJECTIVE: Cyclosporin (CSA) is a promising alternative for patients with severe steroid-refractory ulcerative colitis (UC) previously facing only surgical options. Concerns over the long term efficacy and side effects resulted in this investigation of the University of Chicago’s 5-yr CSA experience in these patients. METHODS: All steroid-refractory severe ulcerative colitis (UC) patients treated with IV CSA from 1991 to 1995 were identified by using the university’s IBD database, with additional information from patient charts and physician files. RESULTS: A total of 42 patients with severe UC unresponsive to IV steroids were treated with IV CSA (4 mg/kg/day). Of 42 patients, 36 (86%) responded; 31 were continued on oral CSA (8 mg/kg/day) for an overall mean of 20 wk. Ten initial CSA responders had colectomies after a mean of 6 months. Of the 36 initial responders, 25 (69%) also received 6-mercaptopurine (6-MP) or azathioprine (aza), and CSA and steroids were tapered. A total of 20% required colectomy, vs 45% of those not receiving 6MP/aza. In all, 62% of all patients, 72% of initial CSA responders, and 80% of initial CSA responders receiving 6MP/aza have avoided colectomy, with a life table analysis of “noncolectomy survival” of 58%, 70%, and 71%, respectively, at 5.5 yr. All colectomies occurred within 18 months of CSA initiation. Complications, resulting in CSA discontinuation in six patients, were all reversible, with complete recovery. CONCLUSIONS: CSA successfully allows most severe steroid resistant UC patients to retain their colons, and provides time for “elective” colectomy in others, especially if 6MP/aza are also given. Careful monitoring for side effects, including PCP prophylaxis, should be part of the treatment protocol.

Intravenous cyclosporin in ulcerative colitis: a five-year experience.

Cyclosporin (CSA) is a promising alternative for patients with severe steroid-refractory ulcerative colitis (UC) previously facing only surgical options. Concerns over the long term efficacy and side effects resulted in this investigation of the University of Chicago's 5-yr CSA experience in these patients. All steroid-refractory severe ulcerative colitis (UC) patients treated with IV CSA from 1991 to 1995 were identified by using the university's IBD database, with additional information from patient charts and physician files. A total of 42 patients with severe UC unresponsive to IV steroids were treated with IV CSA (4 mg/kg/day). Of 42 patients, 36 (86%) responded; 31 were continued on oral CSA (8 mg/kg/day) for an overall mean of 20 wk. Ten initial CSA responders had colectomies after a mean of 6 months. Of the 36 initial responders, 25 (69%) also received 6-mercaptopurine (6-MP) or azathioprine (aza), and CSA and steroids were tapered. A total of 20% required colectomy, vs 45% of those not receiving 6MP/aza. In all, 62% of all patients, 72% of initial CSA responders, and 80% of initial CSA responders receiving 6MP/aza have avoided colectomy, with a life table analysis of "noncolectomy survival" of 58%, 70%, and 71%, respectively, at 5.5 yr. All colectomies occurred within 18 months of CSA initiation. Complications, resulting in CSA discontinuation in six patients, were all reversible, with complete recovery. CSA successfully allows most severe steroid resistant UC patients to retain their colons, and provides time for "elective" colectomy in others, especially if 6MP/aza are also given. Careful monitoring for side effects, including PCP prophylaxis, should be part of the treatment protocol.

Continuously infused cyclosporine at low dose is sufficient to avoid emergency colectomy in acute attacks of ulcerative colitis without the need for high-dose steroids.

A dosage of 4 mg/kg/day intravenous cyclosporine as an adjunct to high-dosage hydrocortisone has been recommended to avoid colectomy in acute steroid-resistant ulcerative colitis. In treating eight such patients, four of whom presented with toxic megacolon, we immediately tapered the steroid dosage and infused a lower dosage of only 2 mg/kg cyclosporine for 15 days to fit a therapeutic range of 60-240 ng/ml, as previously designed for a kidney transplant program. Seven of the eight (87.5%), including three with megacolon, went into remission and started the chronic phase of treatment; the eighth patient underwent colectomy. Of the seven, one died on day 3 of the chronic phase because of pulmonary embolism while in clinical remission, and another discontinued treatment. The other five (62.5%) remain in remission on 6 mg/kg oral cyclosporine, or have already switched from cyclosporine to azathioprine. Two episodes of reversible nephrotoxicity appeared in the chronic phase only. These results emphasize the efficacy and safety of cyclosporine in acute ulcerative colitis, but there is still a need for further dose-response and drug association relationship studies.