Active Refractory Ulcerative Colitis Research Articles

P728 Comparative assessment of faecal microbiota transplantation and current therapies as induction treatment for active refractory ulcerative colitis: A systematic review and network meta-analysis

Abstract Background Emerging evidence suggests that faecal microbiota transplantation (FMT) can induce remission in patients with refractory to standard treatment ulcerative colitis (UC). Methods We performed a systematic review and network meta-analysis to assess the comparative efficacy and safety of FMT and current therapies as induction treatments in UC. We searched Medline, Embase, CENTRAL and grey literature sources up to October 2019. We included randomised controlled trials of patients with active UC that compared FMT, infliximab, adalimumab, golimumab, vedolizumab and tofacitinib to each other or placebo. Efficacy outcomes were clinical remission and response. Safety outcomes were incidence of any adverse event (AE), serious AEs and infections. We conducted random-effects network meta-analysis and ranked treatments based on the surface under the cumulative ranking (SUCRA) probabilities. Results Twenty trials (5177 patients) were included in the analysis. There was only one head to head RCT (vedolizumab vs. adalimumab). FMT was superior to placebo for induction of clinical remission (OR 2.80; 95% CI 1.50–5.23) and response (OR 2.53; 95% CI 1.53–4.20). No indirect comparisons between FMT and licensed treatments reached statistical significance for efficacy outcomes. On SUCRA analysis, FMT (SUCRA 0.57, 0.58) had comparable SUCRA values with golimumab (SUCRA 0.53, 0.39) and vedolizumab (SUCRA 0.58, 0.61) in terms of clinical remission and response respectively. Infliximab (SUCRA 0.71, 0.93) and tofacitinib (SUCRA 0.85, 0.75) were ranked highest while adalimumab (SUCRA 0.23, 0.21) was ranked lowest. There was no increase in the rates of any AEs for FMT and licensed therapies and no differences in indirect comparisons. Vedolizumab (SUCRA 0.81) was the safest option, followed by tofacitinib (SUCRA 0.55). FMT (SUCRA 0.38) had comparable SUCRA values with adalimumab (SUCRA 0.37) and golimumab (SUCRA 0.47). Only tofacitinib increased the incidence of infections compared with placebo (OR 1.51; 95%CI 1.05–2.19). Based on SUCRAs, FMT (SUCRA 0.83) was the safest in terms of infections. Vedolizumab had lower incidence of serious AEs compared with FMT and placebo, while FMT was ranked as the least safe treatment. In subgroup analysis, FMT through the lower gastrointestinal (GI) tract was superior to placebo (OR 3.92; 95%CI 1.94–7.92) and performed numerically better than FMT through the upper GI tract (OR 0.29; 95%CI 0.08–1.13). Conclusion Evidence suggests that FMT could be an efficacious and safe alternative induction therapy for refractory UC. Lower GI delivery of FMT might be more effective. Due to the absence of head-to-head trials and the limited size of FMT trials, conclusions must be interpreted with caution.

A Multicentre, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy, Safety, and Tolerability of the S1P Receptor Agonist KRP203 in Patients with Moderately Active Refractory Ulcerative Colitis

Background and Aims: KRP203 is a potent oral agonist of the sphingosine-1-phosphate receptor subtype 1 that induces the sequestration of peripheral lymphocytes, thereby potentially reducing the number of activated lymphocytes circulating to the gastrointestinal tract. Methods: We conducted a multicentre, double-blind, placebo-controlled, parallel-group, proof-of-concept study to evaluate the efficacy, safety, and tolerability of KRP203 in patients with moderately active 5-aminosalicylate-refractory ulcerative colitis (UC). Patients were randomly assigned to receive 1.2 mg KRP203 or placebo daily for 8 weeks. Primary efficacy variable was clinical remission, defined as partial Mayo Score 0–1 and modified Baron Score 0–1 with rectal bleeding subscore 0. Results: KRP203 was safe and well tolerated overall. The most common adverse events (AEs) were gastrointestinal disorders and headache. Importantly, no KRP203-related cardiac AEs were reported. Total peripheral lymphocytes and selectively affected lymphocyte subtypes decreased, causing marked decreases in naive and central memory CD4+ and CD8+ T cells, and also in B cells. Clinical remission occurred in 2/14 (14%) patients under KRP203, compared with 0/8 (0%) under placebo. Conclusions: Overall, KRP203 was safe and well tolerated by patients with UC. Importantly, no cardiac AEs were reported. Although KRP203 did not meet the minimum clinically relevant threshold for efficacy, the results may suggest that KRP203 treatment is superior to placebo. However, in this small study population, the difference was insignificant. Based on these data, studies with an improved design and a larger population should be considered.

Appropriate Timing of Discontinuation of Tacrolimus Therapy for Refractory Ulcerative Colitis.

Tacrolimus is very effective at inducing remission in patients with refractory ulcerative colitis. However, the optimal time-point for the discontinuation of tacrolimus is controversial because administration of tacrolimus for > 3months is currently not approved for insurance reimbursement in Japan. We conducted this study to determine the optimal time of discontinuation of tacrolimus in patients with ulcerative colitis. Of 38 patients who received tacrolimus as remission induction therapy for refractory active ulcerative colitis between 2009 and 2018, this study included 21 patients who received tacrolimus for ≥ 3months before being switched to thiopurines. These patients were divided into two groups for analysis: the confirmed switch (CS) group (n = 13), in which tacrolimus was switched to azathioprine after endoscopic confirmation of mucosal improvement, and the mandatory switch (MS) group (n = 8), in which tacrolimus was switched to a thiopurine agent without endoscopic confirmation of improvement. The relapse rates after the switch to azathioprine were 23% and 88% in the CS and MS groups, respectively (p = 0.0075). No patient of the CS group underwent surgery, while 50% of patients of the MS group underwent surgery (p = 0.0117). The cumulative event-free rates at 6months, 1year, and 2years were 92%, 92%, and 65%, respectively, in the CS group and 15%, 15%, and 0%, respectively, in the MS group (p < 0.0001). The incidence rate of adverse reactions was 31% in the CS group and 13% in the MS group, but there were no serious adverse reactions. It seems preferable to discontinue tacrolimus after endoscopic confirmation of mucosal healing. However, attention should be paid to the potential occurrence of adverse reactions associated with long-term tacrolimus therapy.

Mo1786 A Multi-Center, Double-Blind, Placebo Controlled, Parallel Group, Proof of Concept Study to Evaluate the Efficacy, Safety and Tolerability of the S1P Receptor Modulator Krp203 in Subjects With Moderately Active Refractory Ulcerative Colitis

Mo1786 A Multi-Center, Double-Blind, Placebo Controlled, Parallel Group, Proof of Concept Study to Evaluate the Efficacy, Safety and Tolerability of the S1P Receptor Modulator Krp203 in Subjects With Moderately Active Refractory Ulcerative Colitis

P372. A multicentre, double-blind, placebo-controlled, parallel group, proof of concept study to evaluate the efficacy, safety and tolerability of the S1P receptor modulator KRP203 in subjects with moderately active refractory ulcerative colitis*

P372. A multicentre, double-blind, placebo-controlled, parallel group, proof of concept study to evaluate the efficacy, safety and tolerability of the S1P receptor modulator KRP203 in subjects with moderately active refractory ulcerative colitis*

Attempted Salvage Therapy Through Inpatient Initiation of Vedolizumab in Two Patients With Refractory Active Ulcerative Colitis

Attempted Salvage Therapy Through Inpatient Initiation of Vedolizumab in Two Patients With Refractory Active Ulcerative Colitis

Tacrolimus induction followed by maintenance monotherapy is useful in selected patients with moderate-to-severe ulcerative colitis refractory to prior treatment

BackgroundTacrolimus in refractory ulcerative colitis often serves as a bridge to long-term maintenance therapy with thiopurines. Our aim was to review efficacy and safety of tacrolimus in active ulcerative colitis resistant to conventional therapies, including anti-tumour necrosis factor. MethodsCharts of consecutive outpatients with refractory ulcerative colitis, in whom tacrolimus was orally administered as a 12 week-induction (target trough levels 10–15ng/mL) followed by a maintenance therapy (target trough levels 5–10ng/mL), were retrospectively reviewed. Clinical remission and response at weeks 4, 12 and 52 as well as adverse events within 1-year therapy were reported. ResultsTwelve (40%) and six (20%) of the 30 patients included (14 males, mean age 37.1±1.4 years) achieved a clinical remission and response, respectively, at week 12. Three responders to tacrolimus initiation experienced drug-related adverse events requiring discontinuation. Among the 18 remaining initial responders who tolerated tacrolimus, 8 (27%) were in clinical remission at week 52, whereas the remainder either experienced adverse events requiring drug withdrawal (n=4) or relapsed (n=6). Overall adverse events were recorded in 14 patients (46%), mainly finger tremor and urinary infections. ConclusionOral monotherapy with tacrolimus may be a valuable long-term therapeutic option in selected patients with moderate-to-severe active refractory ulcerative colitis.

Rescue therapy: ciclosporin or infliximab?

Evaluation of: Laharie D, Bourreille A, Branche J et al.; Groupe d’Etudes Thérapeutiques des Affections Inflammatoires Digestives. Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial. Lancet 380(9857), 1909–1915 (2012).Severe active refractory ulcerative colitis is a potentially life-threatening disease. The introduction of intensive steroid treatment and early surgery has reduced mortality in recent years. Ciclosporin and infliximab are effective rescue therapies in steroid refractory colitis. A head-to-head study proposed by Laharie et al. failed to demonstrate the superiority of ciclosporin but confirmed the efficacy and safety of infliximab to control active disease and to maintain remission.

P378 High restarting rate among patients with Crohn's disease after cessation of one-year treatment period with biologicals: Result of national RASH study

Background: Infliximab has been shown to be effective for moderate-to-severe ulcerative colitis (UC). We evaluated the long-term outcome after Infliximab treatment in patients with distal steroids-dependent refractory UC. Methods: From January 2007 to October 2011 109 consecutive patients (median age 32 years, range 15 65) with distal active refractory UC (mean Mayo score 6, range 4 9) were treated with Infliximab (induction with 5mg/kg at week 0, 2, 6 and maintenance at the same dose every 8 weeks) and prospectively followed. Primary end-point was colectomy free survival. Secondary end-points were sustained clinical response and mucosal healing. Results: Thirty-one patients (28.5%) underwent colectomy during a median follow-up of 40 months (range 6 56). Mean time to colectomy was 24 months (range 12 45) after first infliximab infusion. Indipendent predictors of colectomy were absence of short-term endoscopic response and steroidsdependency. Short-term clinical response (defined as a decrease in the partial Mayo score of at least 3 points at week 12) was obtained in 73 patients (67%) and short-term mucosal healing (endoscopic portion of Mayo score 1 or less) in 62 patients (57%). Sustained clinical response was observed in 78 patients (71.5%). No serious adverse events were observed during the follow-up. Conclusions: Our single-center experience shows that 67% of patients have a clinical improvement after 6 weeks-treatment and 71.5% have colectomy-free survival during follow up. Infliximab is an effective treatment in moderate to severe distal ulcerative colitis in patients refractory to standard treatments.

P377 Long-term outcome after infliximab treatment for distal refractory ulcerative colitis. A single tertiary center experience

Background: Infliximab has been shown to be effective for moderate-to-severe ulcerative colitis (UC). We evaluated the long-term outcome after Infliximab treatment in patients with distal steroids-dependent refractory UC. Methods: From January 2007 to October 2011 109 consecutive patients (median age 32 years, range 15 65) with distal active refractory UC (mean Mayo score 6, range 4 9) were treated with Infliximab (induction with 5mg/kg at week 0, 2, 6 and maintenance at the same dose every 8 weeks) and prospectively followed. Primary end-point was colectomy free survival. Secondary end-points were sustained clinical response and mucosal healing. Results: Thirty-one patients (28.5%) underwent colectomy during a median follow-up of 40 months (range 6 56). Mean time to colectomy was 24 months (range 12 45) after first infliximab infusion. Indipendent predictors of colectomy were absence of short-term endoscopic response and steroidsdependency. Short-term clinical response (defined as a decrease in the partial Mayo score of at least 3 points at week 12) was obtained in 73 patients (67%) and short-term mucosal healing (endoscopic portion of Mayo score 1 or less) in 62 patients (57%). Sustained clinical response was observed in 78 patients (71.5%). No serious adverse events were observed during the follow-up. Conclusions: Our single-center experience shows that 67% of patients have a clinical improvement after 6 weeks-treatment and 71.5% have colectomy-free survival during follow up. Infliximab is an effective treatment in moderate to severe distal ulcerative colitis in patients refractory to standard treatments.

W1302 Long-Term Results of Infliximab in Refractory Active Ulcerative Colitis: Analysis of Predictors of Response

W1302 Long-Term Results of Infliximab in Refractory Active Ulcerative Colitis: Analysis of Predictors of Response

P135 - Efficacy of infliximab in active refractory ulcerative colitis

P135 - Efficacy of infliximab in active refractory ulcerative colitis

Successful Treatment of Steroid Refractory Active Ulcerative Colitis with Natural Interferon-β - an Open Long-Term Trial

In some steroid refractory patients with active ulcerative colitis (UC), treatment with immunosuppressive agents, such as cyclosporin, azathioprine or 6-mercaptopurin is effective. However, there are patients who fail to respond to these treatment options or who cannot tolerate them. Application of natural interferon-beta (nIFN-beta) may offer an alternative. Following our positive results with nIFN-beta in a previously published open-labeled study, the present study was designed as an extension with the hypothesis that administration of higher dosage of nIFN-beta (1.0 vs. 0.5 MIU) could result in fewer relapse events. 46 steroid refractory patients with active UC and a mean clinical activity index (CAI) of 13.2 +/- 3.7 (range 9-23) were treated with nIFN-beta in addition to existing basic medication (5-ASA/SASP plus corticosteroids). During an induction period of eight weeks, 18 patients (group A) received 0.5 MIU nIFN-beta daily and 28 patients (group B), 1.0 MIU nIFN-beta daily intravenously as a bolus injection. Patients who achieved complete remission (decrease of CAI to < or = 4) during the induction period received maintenance therapy with nIFN-beta at the same dose level three times a week and corticosteroids were withdrawn. Remissions and maintenance of remissions were evaluated. In both groups, a comparable number of complete remissions occurred during the induction period: in 16 / 18 patients (89 %) in group A and in 24 / 28 patients (86 %) in group B. Duration of maintenance treatment was 60.0 +/- 90.0 weeks in group A and 52.7 +/- 9.6 weeks in group B. Under this treatment, relapses (increase of CAI to > or = 6) occurred in 5 / 16 patients (31 %) vs. 1 / 24 patients (4 %) (p < or = 0.05). Hence, regarding maintaining remissions, the 1.0 MIU group outscored the 0.5 MIU group. Apart from known flu-like side effects, the therapy was well tolerated by all patients in both groups. nIFN-beta may be a safe and effective alternative to induce and maintain remissions in patients with steroid refractory active UC. To validate the presented results, its effect has to be investigated in a randomized, placebo-controlled dose-finding trial.

Infliximab-induced retrobulbar optic neuritis

A 51-year-old woman underwent four cycles of intravenous infliximab for refractory active ulcerative colitis diagnosed 15 years earlier. She had a 1-month history of fever, abdominal pain and bloody diarrhoea, findings consistent with a relapse of her disease. She was also taking oral mesalazine, prednisone and azathioprine. Three weeks later, during the last cycle of infliximab, she developed pain, blurred vision and a loss in the visual field of the right eye. The results of a neurological examination were unremarkable. Laboratory evaluation revealed a white-cell count of 17 200/mm 3 , and initial ocular examination revealed visual acuities of 20/60 in the right eye and 20/20 in the left eye. Fundus fluorescein angiography was normal; findings from automated perimetry were normal in the left eye but showed an ‘arcuate’ scotoma in the right eye (A). Gadolinium-enhanced T1-weighted coronal magnetic resonance imaging of the brain and orbits (B) revealed enhancement of the orbital portion of her right optic nerve (arrow), findings compatible with retrobulbar optic neuritis. There were no other lesions consistent with demyelination within the brain. Retrobulbar optic neuritis associated with infusion of infliximab is rare, but has occasionally been reported in recent years (Arch Ophthalmol 2002; 120:985–7; Ann Intern Med 2004; 140:W34). Within four weeks of treatment with initial intravenous methylprednisolone, followed by a tapering dose of oral prednisone, the symptoms resolved (visual acuity was 20/20).

Efficacy and Effective Endoscopic Findings of Granulocyte and Monocyte Absorption Apheresis (GCAP) and Leukocytapheresis (LCAP) Therapy in Patients with Refractory Active Ulcerative Colitis (UC)

Background: UC is a chronic inflammatory bowel disease of unknown etiology. Frequent relapse often results in long-term medication and impaired quality of life of the patients. Recently it has been proved that GCAP and LCAP are effective and safe for patients with moderate to severe UC. Aim: The aim of the present study is to prove efficacy and endoscopic findings of GCAP and LCAP in active UC patients, especially in refractory and steroid-dependent cases. Subjects and methods: Active UC patients (Mean age 39.8; Duration of the disease 5.6 years; 19 male, 9 female; 24 total colitis, 4 left-sided colitis; 18 refractory to conventional therapy and 7 steroid dependent) were treated with GCAP (n=18) or LCAP (n=10). The patients received one or two GCAP/LCAP session per week for 5 consecutive weeks. And the patients received colonoscopy before and after GCAP/LCAP session. Results: About 68 % of the patients achieved clinical response, and no severe adverse-effects were observed. Most of steroid-dependent patients or patients who had side-effect due to steroid (6 osteoporosis, 3 diabetes, 1 compression fracture of lumbar vertebra, 1 femoral bone necrosis, 1 schizophrenia, 1 erythema nodosum) were successfully controlled. Seven patients underwent scheduled colectomy for future exacerbation of the disease in remission stage and one patient with semi-emergent operation. Endoscopically, 12/14 cases with shallow ulcers and erosion throughout the colon and 7/12 with deep ulcerations responded to the treatment, however, 2 with massive ulceration of whole mucosa did not respond. Conclusion: GCAP/LCAP were valuable therapies for refractory or steroid-dependent patients, and endoscopic findings are helpful in expecting clinical effectiveness.

Effectiveness of cyclosporine a (CsA) in the treatment of active refractory ulcerative colitis (UC)

Effectiveness of cyclosporine a (CsA) in the treatment of active refractory ulcerative colitis (UC)

Effectiveness of cyclosporine a (CsA) in the treatment of active refractory ulcerative colitis(UC)

Effectiveness of cyclosporine a (CsA) in the treatment of active refractory ulcerative colitis(UC)