Corticosteroid-refractory Colitis Research Articles

Tacrolimus (FK506) for induction of remission in corticosteroid-refractory ulcerative colitis.

Tacrolimus (FK506) for induction of remission in corticosteroid-refractory ulcerative colitis.

Efficacy of Infliximab Dose Escalation in Patients with Refractory Immunotherapy-Related Colitis: A Case Series.

Immune checkpoint inhibitor-related colitis is a common complication of immunotherapy use in patients with cancer. Current guidelines recommend treatment with standard dose infliximab (IFX) for corticosteroid-refractory colitis; however, this case series suggests IFX dose escalation may be a viable treatment option for refractory cases.

Immune checkpoint inhibition-related colitis: Correlation between ulcers and need for infliximab.

e21062 Background: Immune checkpoint inhibition has improved survival of patients with several types of advanced cancer. With these new treatments previously unseen adverse events (AE) have become relevant. Considering the fact that most of these immune related AEs can be reversed when identified early and treated adequately, the need for updated algorithms is crucial. Colitis is one of the most severe AEs upon anti-CTLA-4 (e.g. ipilimumab) monotherapy or combination therapies. Severe colitis with deep ulcerations is associated with life-threatening complications such as perforation. Therefore, early recognition and treatment is warranted. Anti-TNF therapy (infliximab) can resolve colitis fast. We sought to identify endoscopic features that indicate the need for early treatment with infliximab. Methods: We retrospectively analyzed all patients who developed diarrhea upon checkpoint inhibition. Only patients undergoing endoscopy were included. All patients were treated at the NKI between August 2010 and March 2016 for either metastatic melanoma or non-small cell lung cancer. Results: A total of 89 patients underwent an endoscopy due to immune related diarrhea (irDiarrhea). Patients were treated with either monotherapy anti-CTLA-4, anti-PD-(L)1, a combination of both, or the combination of anti-CTLA-4 and radiofrequency ablation. Median age was 58 years (range 30-88) and 54% of patients were female. A colonoscopy was performed in 64 (72%) patients and a sigmoidoscopy in 25 (28%) patients. Ulcers were seen during 29 endoscopies (32%). In 18 endoscopies (20%) there were ≤ 10 ulcers and in 11 endoscopies (12%) > 10. Of all patients that had ulcers at endoscopy 23 (79%) required additional infliximab treatment for corticosteroid refractory colitis, while only 25 (42%) of patients without ulcers required additional infliximab ( p= 0.001). Conclusions: Patients with ulcerative irColitis require twice as often infliximab in addition to corticosteroids. Early treatment with infliximab may be indicated in ulcerative irColitis. Treatment based on endoscopic features makes colonoscopy an important diagnostic tool in irDiarrhea. Prospective analysis of endoscopy-driven management of irColitis is warranted.

Ipilimumab-induced toxicities and the gastroenterologist.

Ipilimumab has been shown to improve overall survival in patients with advanced melanoma. Ipilimumab acts through immune-modulation, and is recognized to cause potentially severe immune-related adverse events (irAEs) including dermatitis, colitis, thyroiditis, hypophysitis, and hepatitis. The acceptance of ipilimumab as a treatment for metastatic melanoma means patients will continue to be treated with this agent and gastroenterologists will be increasingly called upon to assist in managing severe autoimmune-related hepatitis and colitis. To date, the recommendations for managing irAEs secondary to ipilimumab have been steroids at a moderate dose of prednisolone (1 mg/kg) as well as immunosuppressive agents such as mycophenolate mofetil (MMF) for steroid-refractory hepatitis and infliximab in the management of corticosteroid-refractory colitis. However, the dosing and the duration of immunosuppressive therapy have not been systematically studied in the setting of treating ipilimumab-induced irAEs. Therefore, additional immune-modifying agents and/or a change in dosing may be required to manage severe irAEs unresponsive to existing treatment recommendations. We describe a treatment paradigm illustrated by a series of five patients who experienced irAEs. In three cases of metastatic melanoma, ipilimumab-induced hepatitis was successfully treated with high-dose parenteral pulsed methylprednisolone. In two other melanoma patients with ipilimumab-induced colitis, one patient had satisfactory resolution of his colitis with high-dose corticosteroid therapy alone and the other patient required infliximab infusion. We have reviewed the current literature and management algorithms for ipilimumab-induced irAEs. Treatment options and the rationale for their use are discussed, including the use of pulsed high-dose steroids, MMF, azathioprine and calcineurin inhibitors.

Colitis Associated With Active Systemic Lupus Erythematosus Successfully Treated With Rituximab

Intestinal vasculitis is a serious and often underrecognized complication of systemic lupus erythematosus (SLE) usually managed with high-dose corticosteroids. We report a case of corticosteroid refractory colitis (likely due to intestinal vasculitis) that achieved remission with a single cycle of high-dose rituximab. This has not previously been described to our knowledge. A 46-year-old woman with SLE presented with 1-week history of bloody diarrhea, abdominal pain, worsening joint pains, fatigue, and mouth ulcers. There was evidence of increased SLE activity with low C4, raised anti-double-stranded DNA antibody, leukopenia, and anemia. Colonoscopy showed active pancolitis (confirmed histologically). A diagnosis of acute colitis associated with active SLE was made, and she received intravenous methylprednisolone 1 g daily for 3 days followed by 60 mg oral prednisolone daily. She continued to have symptomatic colitis with worsening anemia requiring frequent blood transfusions. She then received 2 doses of rituximab 1 g (750 mg/m(2)) 2 weeks apart that led to improvement in colitis symptoms and SLE disease activity over the next 4 weeks. A repeat colonoscopy (and histology) confirmed good resolution of colitis. Six months later, she continued to be in remission with low-dose prednisolone. Intestinal vasculitis should be considered as a possible cause of acute abdominal pain in SLE as early recognition and treatment can improve long-term survival. Rituximab can be an effective alternative for patients refractory to conventional treatment.

Outcomes and adverse events in children and young adults undergoing tacrolimus therapy for steroid-refractory colitis

Children with severe corticosteroid-resistant ulcerative colitis either need to undergo surgery or be treated with more intensive immunosuppression. Our aim was to characterize the short- and long-term outcomes and adverse events associated with the use of tacrolimus in a steroid-refractory pediatric population. We retrospectively reviewed the medical records of 46 children with steroid-refractory colitis treated with tacrolimus at Children's Hospital Boston between 1994 and 2008. Oral tacrolimus was initiated at a dose of 0.1 mg/kg twice a day and titrated to yield trough levels of 10-15 ng/mL for induction, and 5-10 ng/mL once in remission. The Pediatric Ulcerative Colitis Activity Index (PUCAI) and other measures of disease activity, adverse events, and long-term outcomes were assessed. Statistical analysis of outcomes was performed using SAS statistical software. Ninety-three percent of patients were discharged without undergoing surgery. The median length of stay after starting tacrolimus was 10 days (range 4-37 days). The mean PUCAI score was 68 ± 13 prior to initiating tacrolimus, and 27 ± 18 at the time of hospital discharge. The probability of avoiding colectomy after starting tacrolimus was 40% at 26 months. The most common adverse events included hypertension (52%) and tremor (44%). There was one seizure and no deaths. Tacrolimus is useful as induction therapy in pediatric patients with corticosteroid-refractory colitis and side effects are generally mild and reversible. Despite these findings, many patients develop exacerbations of colitis upon transition to maintenance therapies. The long-term colectomy rate in this challenging population remains ≈60% over time.

W1187 Outcome Following Infliximab Therapy in Pediatric Patients with Ulcerative Colitis: Results from a Multicenter Study

Background: Children with severe ulcerative colitis resistant to corticosteroids either need to undergo surgery or be treated with more intensive immunosuppression (e.g. cyclosporine, tacrolimus, infliximab). The short and long term efficacy of such therapies is not well described in children. Methods: From 1994 to 2008, 52 children (26M; mean age 13y, range 4-21 y) with steroid-refractory colitis were treated with tacrolimus at our institution. Medical record reviewwas performed on these patients. Data extracted allowed the calculation of the Pediatric Ulcerative Colitis Activity Index (PUCAI). In addition, other measures of disease activity, adverse events, and long-term outcomes were assessed. Statistical analysis of outcomes was performed using SAS statistical software. Results: Out of 52 patients, 46 were treated with tacrolimus with the intent to transition to maintenance medical therapy, while 6 were treated to allow corticosteroid weaning prior to elective colectomy. The median dose of tacrolimus utilized was 0.2 mg/kg/day (range 0.1-0.5 mg/kg/day) in two divided doses; the median trough level during induction therapy was 11 ng/ml. The median length of stay after the institution of tacrolimus was 10 days (range 3-37 days). The mean PUCAI score was 66.8 (±14.3 SD) prior to the initiation of tacrolimus therapy, and 21.9 (±14.8 SD) at time of hospital discharge. Of the 46 patients that were treated with the aim of postponing surgery, 43/46 (94%) were discharged without surgery. Patients were maintained on tacrolimus for 3 to 6 months (median 114 days), and transitioned to maintenance therapy (6MP, AZA, or infliximab). The probability of colectomy in this patient cohort was 7% at 1 month, 14% at 3 months, 30% at 12 months, and 57% at 25 months. No colectomies were performed in patients followed for longer than 25 months (longest follow-up 13 years). The most common adverse events noted in the first three months included tremor (32%), hypertension (21%), infections (9%), creatinine >1.5 x baseline (9%), and hyperglycemia (8%). These adverse effects resolved with weaning of steroids or transition to maintenance therapy. Conclusion: Tacrolimus is effective induction therapy in corticosteroid refractory colitis, and is generally well tolerated. However, many patients will develop exacerbations of colitis upon transition to maintenance therapies. The long term colectomy rate in this challenging population remains approximately 60% over time.

W1188 Growth in Pediatric Patients with IBD Treated with Infliximab or 6-Mercaptopurine/Azathioprine

Background: Children with severe ulcerative colitis resistant to corticosteroids either need to undergo surgery or be treated with more intensive immunosuppression (e.g. cyclosporine, tacrolimus, infliximab). The short and long term efficacy of such therapies is not well described in children. Methods: From 1994 to 2008, 52 children (26M; mean age 13y, range 4-21 y) with steroid-refractory colitis were treated with tacrolimus at our institution. Medical record reviewwas performed on these patients. Data extracted allowed the calculation of the Pediatric Ulcerative Colitis Activity Index (PUCAI). In addition, other measures of disease activity, adverse events, and long-term outcomes were assessed. Statistical analysis of outcomes was performed using SAS statistical software. Results: Out of 52 patients, 46 were treated with tacrolimus with the intent to transition to maintenance medical therapy, while 6 were treated to allow corticosteroid weaning prior to elective colectomy. The median dose of tacrolimus utilized was 0.2 mg/kg/day (range 0.1-0.5 mg/kg/day) in two divided doses; the median trough level during induction therapy was 11 ng/ml. The median length of stay after the institution of tacrolimus was 10 days (range 3-37 days). The mean PUCAI score was 66.8 (±14.3 SD) prior to the initiation of tacrolimus therapy, and 21.9 (±14.8 SD) at time of hospital discharge. Of the 46 patients that were treated with the aim of postponing surgery, 43/46 (94%) were discharged without surgery. Patients were maintained on tacrolimus for 3 to 6 months (median 114 days), and transitioned to maintenance therapy (6MP, AZA, or infliximab). The probability of colectomy in this patient cohort was 7% at 1 month, 14% at 3 months, 30% at 12 months, and 57% at 25 months. No colectomies were performed in patients followed for longer than 25 months (longest follow-up 13 years). The most common adverse events noted in the first three months included tremor (32%), hypertension (21%), infections (9%), creatinine >1.5 x baseline (9%), and hyperglycemia (8%). These adverse effects resolved with weaning of steroids or transition to maintenance therapy. Conclusion: Tacrolimus is effective induction therapy in corticosteroid refractory colitis, and is generally well tolerated. However, many patients will develop exacerbations of colitis upon transition to maintenance therapies. The long term colectomy rate in this challenging population remains approximately 60% over time.

W1189 Indeterminate Colitis (IC) in Children: A Two-Year Follow-Up

Background: Children with severe ulcerative colitis resistant to corticosteroids either need to undergo surgery or be treated with more intensive immunosuppression (e.g. cyclosporine, tacrolimus, infliximab). The short and long term efficacy of such therapies is not well described in children. Methods: From 1994 to 2008, 52 children (26M; mean age 13y, range 4-21 y) with steroid-refractory colitis were treated with tacrolimus at our institution. Medical record reviewwas performed on these patients. Data extracted allowed the calculation of the Pediatric Ulcerative Colitis Activity Index (PUCAI). In addition, other measures of disease activity, adverse events, and long-term outcomes were assessed. Statistical analysis of outcomes was performed using SAS statistical software. Results: Out of 52 patients, 46 were treated with tacrolimus with the intent to transition to maintenance medical therapy, while 6 were treated to allow corticosteroid weaning prior to elective colectomy. The median dose of tacrolimus utilized was 0.2 mg/kg/day (range 0.1-0.5 mg/kg/day) in two divided doses; the median trough level during induction therapy was 11 ng/ml. The median length of stay after the institution of tacrolimus was 10 days (range 3-37 days). The mean PUCAI score was 66.8 (±14.3 SD) prior to the initiation of tacrolimus therapy, and 21.9 (±14.8 SD) at time of hospital discharge. Of the 46 patients that were treated with the aim of postponing surgery, 43/46 (94%) were discharged without surgery. Patients were maintained on tacrolimus for 3 to 6 months (median 114 days), and transitioned to maintenance therapy (6MP, AZA, or infliximab). The probability of colectomy in this patient cohort was 7% at 1 month, 14% at 3 months, 30% at 12 months, and 57% at 25 months. No colectomies were performed in patients followed for longer than 25 months (longest follow-up 13 years). The most common adverse events noted in the first three months included tremor (32%), hypertension (21%), infections (9%), creatinine >1.5 x baseline (9%), and hyperglycemia (8%). These adverse effects resolved with weaning of steroids or transition to maintenance therapy. Conclusion: Tacrolimus is effective induction therapy in corticosteroid refractory colitis, and is generally well tolerated. However, many patients will develop exacerbations of colitis upon transition to maintenance therapies. The long term colectomy rate in this challenging population remains approximately 60% over time.

W1186 Outcomes and Adverse Events in Children and Young Adults with Steroid-Refractory Colitis Treated with Tacrolimus

Background: Children with severe ulcerative colitis resistant to corticosteroids either need to undergo surgery or be treated with more intensive immunosuppression (e.g. cyclosporine, tacrolimus, infliximab). The short and long term efficacy of such therapies is not well described in children. Methods: From 1994 to 2008, 52 children (26M; mean age 13y, range 4-21 y) with steroid-refractory colitis were treated with tacrolimus at our institution. Medical record reviewwas performed on these patients. Data extracted allowed the calculation of the Pediatric Ulcerative Colitis Activity Index (PUCAI). In addition, other measures of disease activity, adverse events, and long-term outcomes were assessed. Statistical analysis of outcomes was performed using SAS statistical software. Results: Out of 52 patients, 46 were treated with tacrolimus with the intent to transition to maintenance medical therapy, while 6 were treated to allow corticosteroid weaning prior to elective colectomy. The median dose of tacrolimus utilized was 0.2 mg/kg/day (range 0.1-0.5 mg/kg/day) in two divided doses; the median trough level during induction therapy was 11 ng/ml. The median length of stay after the institution of tacrolimus was 10 days (range 3-37 days). The mean PUCAI score was 66.8 (±14.3 SD) prior to the initiation of tacrolimus therapy, and 21.9 (±14.8 SD) at time of hospital discharge. Of the 46 patients that were treated with the aim of postponing surgery, 43/46 (94%) were discharged without surgery. Patients were maintained on tacrolimus for 3 to 6 months (median 114 days), and transitioned to maintenance therapy (6MP, AZA, or infliximab). The probability of colectomy in this patient cohort was 7% at 1 month, 14% at 3 months, 30% at 12 months, and 57% at 25 months. No colectomies were performed in patients followed for longer than 25 months (longest follow-up 13 years). The most common adverse events noted in the first three months included tremor (32%), hypertension (21%), infections (9%), creatinine >1.5 x baseline (9%), and hyperglycemia (8%). These adverse effects resolved with weaning of steroids or transition to maintenance therapy. Conclusion: Tacrolimus is effective induction therapy in corticosteroid refractory colitis, and is generally well tolerated. However, many patients will develop exacerbations of colitis upon transition to maintenance therapies. The long term colectomy rate in this challenging population remains approximately 60% over time.

Review article: how and when to use ciclosporin in ulcerative colitis

Although colectomy for ulcerative colitis is curative, long-term quality of life is reduced. Intravenous ciclosporin 4 mg/kg/day has significant toxicity. There is now evidence that low-dose ciclosporin (2 mg/kg daily by intravenous infusion, or 5-6 mg/kg daily in a twice daily oral dosage) has an acceptable safety profile, even when used in combination with corticosteroids. Drug dosage should be adjusted to the levels of 150-250 ng/mL initially (random levels during intravenous infusion, or trough levels for oral use). Ciclosporin should be considered not only in those who have failed 7 days of corticosteroids, but also in fulminant colitis at day 3, if not responding to corticosteroids. The drug should be avoided in frail or elderly patients with significant comorbidity, and also where colectomy is likely to be necessary in the short to medium term. Ciclosporin should not be continued for more than 7 days, unless there is a definite response. A 70-80% initial response is likely, and responders are discharged on oral ciclosporin, adding thiopurines and tailing prednisolone rapidly. The drug should be continued for 3 months. The likelihood of avoiding colectomy over 2-3 years is 40-50%. More studies are needed to evaluate the use of oral ciclosporin in corticosteroid-refractory colitis in out-patients, and to assess whether monotherapy (without corticosteroids) is significantly safer, without loss of efficacy.