Steroid-refractory Ulcerative Colitis Research Articles

Long-term Efficacy and Safety of Tacrolimus Plus Ustekinumab Combination Therapy in Children With Steroid-refractory Ulcerative Colitis.

Long-term Efficacy and Safety of Tacrolimus Plus Ustekinumab Combination Therapy in Children With Steroid-refractory Ulcerative Colitis.

P1218 Non-invasive point-of-care stool sample for detection of Cytomegalovirus infection in patients with Active or Refractory Ulcerative Colitis using multiplex polymerase chain reaction (mPCR): a pilot feasibility study

Abstract Background Cytomegalovirus (CMV) infection is associated with more flare-ups and deteriorates the prognosis of active inflammatory bowel disease (IBD). Patients with refractory IBD should be tested for CMV colitis, especially if they are not responding to immunosuppressive therapy. The prevalence of CMV co-infection ranges from 10% to 30% in steroid-refractory acute colitis. Concurrent CMV-colitis is associated with an increased risk of worse therapeutic outcomes, resistance to corticosteroids, and need for salvage therapy. One of the two gold standards of diagnosis of CMV colitis in IBD patients with active disease requires the analysis of tissue biopsies using PCR. The aim of our pilot study was to evaluate the diagnostic accuracy of non-invasive point-of-care faecal samples using mPCR for detecting CMV in patients with ulcerative colitis compared to standard practice biopsies PCR. Methods We performed a prospective, observational, feasibility study including 62 consecutive patients with active ulcerative colitis (UC) requiring intravenous steroids or steroid-refractory UC in the Department of Gastroenterology of University Hospital „Tsaritsa Yoanna – ISUL", from April 2022 to October 2023. In all UC patients, colonic tissue biopsies were performed and analyzed by qualitative CMV PCR. Faecal sample mPCR CMV was performed on the positive patient cohort to compare the feasibility of (ME) Panel IVD using FilmArray mPCR (Biofire, bioMerieux, France). All the tested patients had undergone immunosuppressive therapy and initial stool specimen cultures were obtained to exclude infection with C. difficile and other pathogen flora. Results Out of 62 active UC patients with colonic tissue samples qualitative CMV PCR, n=5 (8%) were positive. Of these n=5 UC patients, n=4 (80%) were positive from the Fecal sample mPCR CMV, resulting in a compatibility of 80% for diagnosing CMV in these patients by the two DNA extraction methods. Calculated Sensitivity and diagnostic accuracy was 80% (95% CI) for the mPCR CMV. The patient cohort predominantly comprised males (75%) with a median age of 45 years (range: 30–72 years). Three patients (75%) out of this cohort group were treated with peroral antiviral agent Valganciclovir, one (25%) of them went into clinical and endoscopic remission after the treatment and two patients (50%) received colectomy. The median time performing the Faecal sample mPCR CMV was approx. 1 hour. Conclusion This novel faecal mPCR point-of-care test is a promising, fast and easy non-invasive tool for detection CMV in active or refractory UC patients, comparable with the colonic tissue CMV-DNA PCR.

S3184 Tofacitinib-Induced Remission in a Case of Infliximab and Steroid Refractory Acute Severe Ulcerative Colitis

S3184 Tofacitinib-Induced Remission in a Case of Infliximab and Steroid Refractory Acute Severe Ulcerative Colitis

Protective effect of the novel calcineurin inhibitor voclosporin in experimental colitis.

Acute severe steroid-refractory ulcerative colitis remains a medically challenging condition with frequent need of surgery. It can be treated with the calcineurin inhibitor cyclosporine A with the need for therapeutic drug monitoring and significant toxicity. Recently, a novel calcineurin inhibitor, voclosporin, has been approved for the treatment of lupus nephritis with no need for therapeutic drug monitoring and an improved long-term safety profile. However, the therapeutic effect of voclosporin in acute severe steroid-refractory ulcerative colitis is still uncertain. We aimed to assess the therapeutic potential of voclosporin to ameliorate inflammation in an experimental model of colitis. We used the dextran sodium sulfate-induced model of colitis in C57BL/6 J wildtype mice treated with either cyclosporine A, voclosporin or solvent control. We employed endoscopy, histochemistry, immunofluorescence, bead-based multiplex immunoassays and flow cytometry to study the therapeutic effect of calcineurin inhibitors in a preventive setting. Acute colitis was induced by dextran sodium sulfate characterized by weight loss, diarrhea, mucosal erosions and rectal bleeding. Both cyclosporine A and voclosporin strongly ameliorated the course of disease and reduced colitis severity in a similar manner. Voclosporin was identified as biologically effective in a preclinical model of colitis and may be a potential therapeutic option in treating acute severe steroid-refractory ulcerative colitis.

P621 Combination treatment of biologics with immunomodulator increases risk of infection after discharge in biologics naive steroid refractory acute severe ulcerative colitis patient: A KASID multicenter study

Abstract Background Biologics such as infliximab is the main treatment for steroid refractory acute severe ulcerative colitis (ASUC), However, there are only a few studies on the effectiveness and safety of biologics in steroid refractory ASUC. In this study, we evaluated the effectiveness and safety of biologics as a rescue therapy for biologics naïve steroid refractory ASUC patient in Korea. Methods We retrospectively included patients who were hospitalized at seven tertiary medical centers for ASUC management between January 2015 to December 2020, and data on the demographic and clinical variables, disease activity, treatment method, treatment response, adverse event, readmission due to any reasons were checked Results A total of 230 ASUC patients were included, of which 220 were biologic naïve patient. The response rate of steroid in these patients was 74%, and infliximab was administered as rescue therapy to 53 patients who failed initial steroid treatment. The response rate to infliximab as rescue therapy was 96%, and 2 patients who did not respond received colectomy. One of the two patients who underwent colectomy died of sepsis. There was no infliximab-related adverse event during hospitalization. Although infliximab itself was not a factor associated with infection after discharge (10% vs. 16%, p=0.355), combination therapy with thiopurine was a risk factor for infection after discharge. (Odd ratio 7.302, 95% CI 2.101-25.372, p=0.002). A total of 12 infections occurred in patients treated with infliximab after discharge (3 pneumonia, 1 skin infection, 3 cytomegalovirus colitis, 4 Clostridium difficile infection) and were associated with readmission. (40.1% vs. 75%, p=0.031) Conclusion As a rescue therapy in biologics naive steroid refractory ASUC, infliximab showed a 96% therapeutic response. Although infliximab itself did not increase the risk of infection after discharge, the combination with thiopurine increased the risk of infection after discharge

P472 Cyclosporine versus infliximab in patients with Acute Severe Ulcerative Colitis: A single-centre retrospective study

Abstract Background In steroid refractory acute severe ulcerative colitis (ASUC), cyclosporine or infliximab are potential rescue treatments to avoid colectomy. Our objective is to assess the short-term and long-term efficacy and safety of cyclosporine versus infliximab as rescue agents. Methods We performed a retrospective analysis of 121 patients admitted with ASUC to a single gastroenterology centre during 2010-2020. ASUC was defined by the Truelove & Witts criteria. Primary outcome was short-term colectomy-free rate, secondary outcomes were severe adverse events, re-hospitalization or need of treatment with steroids within 2 years due to flare ups and colectomy rate at 2-year follow-up. Results 119 patients initially received intravenous corticosteroids, while 2 patients underwent emergency colectomy on the first day. Sixty-four (53%) were females, median age of all patients was 33 (IQR 27-49) years. 66 (55%) patients responded to intravenous corticosteroids (IVS), while 53 (45%) failed to respond to steroid therapy: 45 (37%) patients received second-line rescue therapy (29 with cyclosporine, 16 with infliximab). Evaluating the short-term efficacy of treatment there was no significant difference between cyclosporine and infliximab: during admission colectomy was performed in 10.3% vs. 12.5% of patients, respectively (p=0.826). In terms of long-term outcomes, the colectomy rate was higher in the infliximab group at 2-year follow-up, although the difference did not reach statistical significance (10.3% vs. 31.2%, p=0.079). The need for oral steroids during follow-up was comparable in both groups (38,5% vs. 50%, p=0.481). Comparing patients who did not undergo colectomy, patients in the infliximab group were more often re-hospitalized due to the need for IVS at 2-year follow-up (7.7% vs. 50%, p=0.002). No severe side effects due to infliximab and cyclosporine were observed. Conclusion In the treatment of steroid refractory ASUC infliximab and cyclosporine were equally effective in short-term period and there was no difference in safety, however cyclosporine treated patients trended to have better long-term outcomes, with significantly rarer re-hospitalization. Additional analysis is needed for other factors that may have contributed to differences in long-term outcomes between the cyclosporine and infliximab groups.

Analysis of the Clinical Efficacy of Infliximab in the Treatment of Steroid-Refractory Ulcerative Colitis in Children

Background: Incidence of ulcerative colitis (UC) in children has increased worldwide. Objectives: In the current study, we summarized our clinical experience using infliximab (IFX) in the treatment of children with steroid-refractory UC. Methods: The clinical data of 9 steroid-refractory UC patients with average age of 8 years who were treated with IFX in our hospital were analyzed. Results: At the end of the induction period, 6 achieved a clinically significant response. Of the 6 children, 4 had mucosal healing and 2 had endoscopic remission. At week 30, among the 6 children who achieved a clinically significant response, 3 had persistent clinical remission and mucosal healing, 1 achieved mucosal healing from endoscopic remission, 1 had mild disease, and the other child had not reached 30 weeks of treatment as of this writing. At week 54, 6 of 9 children achieved clinical remission and 5 had mucosal healing. The hemoglobin concentration in the children who achieved a clinically significant response was higher than pre-treatment and the inflammation markers were lower than pre-treatment. During IFX treatment, five children had a loss of response, three had a primary non-response, and two had a secondary non-response. The latter children achieved clinical remission with optimized treatment. Conclusions: IFX is a salvage treatment option for children with moderate-to-severe steroid-refractory UC. The course of treatment and the timing of drug withdrawal warrants further study.

Cyclosporine Therapy as a Rescue Treatment in Steroid Refractory Acute Severe Ulcerative Colitis: A Real Life Data From a Tertiary Center.

Cyclosporine is a rescue treatment alternative to avoid colectomy in corticosteroid refractory acute severe ulcerative colitis. In this study, we aimed to evaluate the long-term efficacy and safety of cyclosporine therapy in acute severe ulcerative colitis patients. Acute severe ulcerative colitis (basal Lichtiger score > 10) patients who did not respond to 40 mg intravenous methylpredniso- lone therapy after 3-5 days were included in the study. The presence of clinical response and remission was assessed at 1st week, 1st, 6th, and 12th month according to the Lichtiger index. In this study, 40 patients, whose steroid refractory acute severe ulcerative colitis and basal Lichtiger score > 10 points were enrolled. The median disease duration was 49.3 months (2-204). All patients received cyclosporine for 132 ± 78 days (7-270). Clinical response was obtained on seventh day in 82.5%. The clinical response rates of the first and sixth months were 72.5% and 62.5%, respectively. A total of 17/40 (42.5%) patients underwent colectomy within 1 year. In the patients who underwent colectomy, the basal LS (14.2 ± 1.9 vs 12.3 ± 1.7) (P = .002) was higher and the basal hemoglobin value (11.8 ± 2.3 vs 10.1 ± 1.5) (P = .037) was lower than those who did not undergo colectomy. Our findings suggest that cyclosporine treatment may be successfully and safely used in steroid refractory acute severe ulcerative colitis patients. Cyclosporine is a drug that has recently started to come up again with the introduction of new maintenance treatments. Especially in patients who develop a loss of response to infliximab therapy, or where infliximab therapy is contraindicated, or who have azathioprine intolerance, or are unresponsive.

P304 Intensified versus conventional infliximab induction in acute severe steroid-refractory Ulcerative Colitis

Abstract Background Infliximab is effective as salvage therapy in severe steroid-refractory Ulcerate Colitis. However, up to one third of patients do not respond to this treatment and require surgery. There is still insufficient evidence regarding the benefits of intensified infliximab induction regimens in this setting. Methods Retrospective study including, 51 patients meeting the Truelove and Witts criteria for severe acute Ulcerative Colitis with refractoriness to intravenous steroids requiring infliximab rescue therapy. We compared patients under conventional infliximab induction therapy (n=29) with patients performing an intensified infliximab induction regimen (n=22), defined as a higher dose/shorter interval of treatment during induction. Results There was no difference in respect to median age [IQR] (32.0 [27.0–43.0] vs, 42.0 [29.0–58.0], p=0.116), and male gender (69.0 % vs, 63.6%, p=, 0.458) between patients with conventional or intensified infliximab. Compared to patients with conventional induction, patients under optimized infliximab presented reduced admission to intermediary/intensive care unit (4.5% vs, 31.0%, p=, 0.019), and surgery (13.6% vs, 41.4%, p=, 0.031). There were no differences in deaths (3.4% vs, 9.1%, p=0.396), readmission rates (17.2% vs, 28.6%, p=, 0.270), and median duration [IQR] of hospitalization (19.0 [10.5–31.0] vs, 12.0 [8.0–15.5], p=0.094) between patients with conventional or intensified regimens. In a multivariate analysis, the use of an intensified infliximab induction regimen was associated with a lower risk of surgery (OR, 0.224, 95%CI [0.054–0.929], p=, 0.039). Conclusion In this small cohort, there was some suggestions that intensified infliximab induction may improve treatment outcomes in acute severe steroid refractory Ulcerative Colitis.

German S3-Guideline on the treatment of Psoriasis vulgaris, adapted from EuroGuiDerm - Part 2: Treatment monitoring and specific clinical or comorbid situations.

German S3-Guideline on the treatment of Psoriasis vulgaris, adapted from EuroGuiDerm - Part 2: Treatment monitoring and specific clinical or comorbid situations.

P452 Oral ciclosporin is a convenient, effective and safe rescue therapy in steroid refractory Acute Severe Ulcerative Colitis: A single tertiary centre experience

Abstract Background Parenteral ciclosporin (CsA) is an effective rescue therapy for acute severe ulcerative colitis (ASUC) and has similar efficacy to infliximab (IFX). Although CsA is cheaper and can facilitate bridging to any IBD therapy, including newer biologics, its use is limited by variable pharmacokinetics and possibility of significant systemic toxicity particularly associated with the intravenous preparation. Despite favourable pharmacokinetics and bioavailability, the use of lipid-emulsified oral CsA in steroid-refractory ASUC is undefined. Methods All patients who received oral CsA (Neoral®) rescue therapy for ASUC at Addenbrooke’s Hospital, Cambridge, UK from Nov 2014 to May 2020 were identified from electronic healthcare records. Baseline data and outcomes were extracted and compared to patients who received IFX rescue therapy. Statistical significance was assessed using non-parametric tests. Survival estimates were computed using the Kaplan-Meier method. Results A total of 37 patients received oral CsA for refractory ASUC. Median time from admission to CsA initiation was 5 days (IQR 4–6 d) and median initial dose was 8 mg/kg/d (IQR 7–8 mg/kg/d). At admission, the median CRP was 26 (IQR 14–95) and Truelove and Witt’s severity criteria met in 21/37 (57%). 70% of patients (26/37) avoided colectomy during the index admission. No parameters were demonstrated to predict need for acute colectomy. Median follow-up after hospital discharge was 3 years (IQR 2-5years). For those who avoided acute colectomy, median duration of therapy was 4 months (IQR 2.5-5months) with bridging to azathioprine (24/26, 92%), vedolizumab (1/26, 4%), or 5-ASA (1/26, 4%). Estimated colectomy-free survival in responders were 84%, 84% and 78% at 12, 24, and 60 months. No parameters were shown to predict colectomy-free survival. Comparable colectomy-free outcomes were obtained for contemporaneous IFX-treated ASUC patients in our hospital. 9 of 26 patients remained biologic-naïve and colectomy-free after a median of 3 years. Estimated colectomy and biologic-free survival were 51%, 47% and 18% at 12, 24, and 60 months. 15 patients experienced adverse events, which were all mild and self-limiting. There were 3 infective complications. No patients required drug cessation and no serious adverse events associated with parenteral CsA occurred. Conclusion In this cohort, oral CsA was a safe, well tolerated and effective rescue therapy for steroid-refractory ASUC. A proportion of patients remain biologic and colectomy-free for up to 5 years. Given the feasibility to bridge to effective maintenance therapies, including newer biologics, oral CsA should be considered as a rescue therapy in ASUC and avoids many of the side effects associated with intravenous CsA.

Cytapheresis re-induces high-rate steroid-free remission in patients with steroid-dependent and steroid-refractory ulcerative colitis.

BACKGROUNDIt is a crucial issue for patients with refractory ulcerative colitis (UC), including steroid-dependent and steroid-refractory patients, to achieve and maintain steroid-free remission. However, clinical studies focused on the achievement of steroid-free remission in refractory UC patients are insufficient. Cytapheresis (CAP) is a non-pharmacological extracorporeal therapy that is effective for active UC with fewer adverse effects. This study comprised UC patients treated with CAP and suggested the efficacy of CAP for refractory UC patients.AIMTo clarify the efficacy of CAP in achieving steroid-free remission in refractory UC patients.METHODSWe retrospectively reviewed the collected data from 55 patients with refractory UC treated with CAP. We analyzed the following points: (1) Efficacy of the first course of CAP; (2) Efficacy of the second, third, and fourth courses of CAP in patients who experienced relapses during the observation period; (3) Efficacy of CAP in colonic mucosa; and (4) Long-term efficacy of CAP. Clinical efficacy was evaluated using Lichtiger’s clinical activity index or Sutherland index (disease activity index). Mucosal healing was evaluated using Mayo endoscopic subscore. The primary and secondary endpoints were the rate of achievement of steroid-free remission and the rate of sustained steroid-free remission, respectively. Statistical analysis was performed using the paired t-test and chi-squared test.RESULTSThe rates of clinical remission, steroid-free remission, and poor effectiveness after CAP were 69.1%, 45.5%, and 30.9%, respectively. There were no significant differences in rate of steroid-free remission between patients with steroid-dependent and steroid-refractory UC. The mean disease activity index and Lichtiger’s clinical activity index scores were significantly decreased after CAP (P < 0.0001). The rates of steroid-free remission after the second, third, and fourth courses of CAP in patients who achieved steroid-free remission after the first course of CAP were 83.3%, 83.3%, and 60%, respectively. Mucosal healing was observed in all patients who achieved steroid-free remission after the first course of CAP. The rates of sustained steroid-free remission were 68.0%, 60.0%, and 56.0% at 12, 24, and 36 mo after the CAP. Nine patients (36%) had maintained steroid-free remission throughout the observation period.CONCLUSIONOur results suggest that CAP effectively induces and maintains steroid-free remission in refractory UC and re-induces steroid-free remission in patients achieving steroid-free remission after the first course of CAP.

Maintaining infliximab induced clinical remission with azathioprine and 5-aminosalicylates in acute severe steroid-refractory ulcerative colitis has lower cost and high efficacy (MIRACLE): a multicenter study.

Background/AimsInfliximab (IFX) has been used to induce and maintain remission in patients with severe steroid-refractory ulcerative colitis (UC). Long-term use of biologics in developing countries is limited by high cost and frequent side effects. An optimal maintenance strategy in these patients needs to be established.MethodsA retrospective analysis of maintenance of clinical remission with combination of azathioprine (AZA) and 5-aminosalicylates (5-ASA) in patients with severe steroid-refractory UC where IFX (5 mg/kg intravenously at weeks 0, 2, 6) had been used only as an induction therapy was done at 2 centers in India. Primary outcome was the proportion of patients maintaining corticosteroid-free sustained clinical remission (SCR) at the end of study period. Rates of relapse and cost of therapy were also analyzed.ResultsOf the 137 patients who received rescue IFX induction therapy, 77 (56.2%) achieved clinical remission (mean age 34.81 ± 13.32 years, 68.83% males, median follow-up 4 years, range 3 months to 6 years) and were included. Cumulative corticosteroid-free SCR was maintained in 68%, 59%, 42%, and 35% patients at 1, 2, 4, and 6 years respectively. Sixty-seven relapses were observed in 33 patients. Majority of the relapses (45/67, 67.16%) occurred within first 2 years of follow-up. Two relapses were managed with re-induction with IFX, one required colectomy, whereas all other responded to repeat course(s) of corticosteroids. Annual per capita maintenance therapy with 5-ASA and AZA was cheaper by US$ 4,526 compared to maintaining remission with IFX.ConclusionsClinical remission achieved with IFX induction therapy in severe steroid-refractory UC can be sustained over long time with a combination of AZA and 5-ASA.

The efficacy and safety of infliximab and calcineurin inhibitors in steroid-refractory UC patients: A meta-analysis.

Background:Infliximab (IFX) and calcineurin inhibitors (cyclosporine [CYS] and tacrolimus [TAC]) were considered as rescue therapy in steroid-refractory ulcerative colitis (UC). The objective of our study was to perform a meta-analysis evaluating the short-term and long-term efficacy and safety of IFX and calcineurin inhibitors in steroid-refractory UC.Methods:We systematically searched the databases from inception to September 2020 that evaluated IFX, CYS, and TAC in steroid-refractory UC. The primary outcome was the response rates, remission rates, mucosal healing rates, and colectomy rates after therapy initiation. The secondary outcomes were the rates of adverse events (AE), serious adverse events (SAE), and mortality. Odds ratios (OR) with 95% confidence intervals (CIs) were calculated.Results:Nineteen studies comprising 1323 Acute severe ulcerative colitis (ASUC) patients were included in the meta-analysis. Among the non-randomized studies, a significantly higher therapeutic response rate was seen with IFX treatment, with a pooled OR of 3.15 (95% CI 2.26–4.40). Among non-randomized studies, IFX was associated with a significantly lower first-year OR (0.46 [95% CI 0.27–0.79]), second-year (OR 0.53 [95% CI 0.28–0.97]), third-year (OR 0.43 [95% CI 0.24–0.75]) colectomy rate. But the randomized controlled trials (RCTs) did not suggest any difference between IFX and CYS as rescue therapies for steroid-refractory UC. There were no significant differences among IFX, CYS, and TAC in the rates of AE, SAE, or mortality.Conclusion:Our meta-analysis suggested a better treatment response rate and lower risk of colectomy in the first, second and third year, with IFX, compared with CYS in steroid-refractory UC patients. There was no significant difference among IFX and calcineurin inhibitors in AE, SAE, and mortality.

Transcriptomic Profiling of Collagenous Colitis Identifies Hallmarks of Nondestructive Inflammatory Bowel Disease.

Background and AimsThe pathophysiology of the inflammatory bowel disease collagenous colitis (CC) is poorly described. Our aim was to use RNA sequencing of mucosal samples from patients with active CC, CC in remission, refractory CC, ulcerative colitis (UC), and control subjects to gain insight into CC pathophysiology, identify genetic signatures linked to CC, and uncover potentially druggable disease pathways.MethodsWe performed whole transcriptome sequencing of CC samples from patients before and during treatment with the corticosteroid drug budesonide, CC steroid-refractory patients, UC patients, and healthy control subjects (n = 9–13). Bulk mucosa and laser-captured microdissected intestinal epithelial cell (IEC) gene expression were analyzed by gene set enrichment and gene set variation analyses to identify significant pathways and cells, respectively, altered in CC. Leading genes and cells were validated using reverse-transcription quantitative polymerase chain reaction or immunohistochemistry.ResultsWe identified an activation of the adaptive immune response to bacteria and viruses in active CC that could be mediated by dendritic cells. Moreover, IECs display hyperproliferation and increased antigen presentation in active CC. Further analysis revealed that genes related to the immune response (DUOX2, PLA2G2A, CXCL9), DNA transcription (CTR9), protein processing (JOSD1, URI1), and ion transport (SLC9A3) remained dysregulated even after budesonide-induced remission. Budesonide-refractory CC patients fail to restore normal gene expression, and displayed a transcriptomic profile close to UC.ConclusionsOur study confirmed the implication of innate and adaptive immune responses in CC, governed by IECs and dendritic cells, respectively, and identified ongoing epithelial damage. Refractory CC could share pathomechanisms with UC.

Comparative efficacy of antitumor necrosis factor agents and tacrolimus in na\xefve steroid-refractory ulcerative colitis patients

While retrospective studies have compared the efficacy of anti–tumour necrosis factor (TNF) agents and tacrolimus (TAC) in ulcerative colitis (UC), information regarding first-time use of these agents is limited. The aim of our study was to investigate the short- and long-term efficacy of anti-TNF agents [adalimumab (ADA) and infliximab (IFX)] and TAC in anti-TNF agent- and TAC-naïve steroid-refractory UC patients. We evaluated 150 steroid-refractory UC patients receiving anti-TNF agents (IFX: n = 30, ADA: n = 41) or TAC (n = 79) at eight institutions in Japan. Clinical response rates at 8 weeks were 73.2% and 75.9% while remission rates were 30.1% and 25.3% in the anti-TNF and TAC groups, respectively. Logistic regression analysis showed the male sex and higher C-reactive protein to be independent factors for response to anti-TNF agents and TAC, respectively. Use of TAC was an independent factor for relapse. No differences in response to the treatment or relapse were observed between IFX and ADA. In conclusion, TAC and anti-TNF agents promoted similar short-term effects, but anti-TNF agents ensured better long-term outcomes at first-time treatment of steroid-refractory UC patients.

CYP3A5 Genotype as a Potential Pharmacodynamic Biomarker for Tacrolimus Therapy in Ulcerative Colitis in Japanese Patients.

Tacrolimus has been used to induce remission in patients with steroid-refractory ulcerative colitis. It poses a problem of large individual differences in dosage necessary to attain target blood concentration and, often, this leads to drug inefficacy. We examined the difference in mRNA expression levels of ATP binding cassette transporter B1 (ABCB1) between inflamed and non-inflamed tissues, and the influence of CYP3A5 genotype on tacrolimus therapy. The mRNA expression of CYP3A4 in colonic mucosa and that of cytochrome p450 3A5 (CYP3A5) and ABCB1 in inflamed and non-inflamed areas were examined in 14 subjects. The mRNA expression levels of CYP3A5 were higher than that of CYP3A4. The mRNA expression of ABCB1 was lower in the inflamed than in the non-inflamed mucosa, despite that of CYP3A5 mRNA level being not significantly changed. Hence, the deterioration of the disease is related to the reduction of the barrier in the inflamed mucosa. The relationship between CYP3A5 genotype and blood concentration, dose, and concentration/dose (C/D) ratio of tacrolimus in 15 subjects was studied. The tacrolimus dose to maintain equivalent blood concentrations was lower in CYP3A5*3/*3 than in CYP3A5*1 carriers, and the C/D ratio was significantly higher in the latter. Thus, CYP3A5 polymorphism information played a role in determining the initial dose of tacrolimus. Furthermore, since the effect of tacrolimus appears earlier in CYP3A5*3/*3 than in CYP3A5*1/*1 and *1/*3, it seems necessary to change the evaluation time of therapeutic effect by CYP3A5 genotype. Additionally, the relationship between CYP3A5 genotype and C/D ratio of tacrolimus in colonic mucosa was investigated in 10 subjects. Tacrolimus concentration in the mucosa was two-fold higher in CYP3A5*3/*3 than in CYP3A5*1 carriers, although no significant difference in tacrolimus-blood levels was observed. Therefore, the local concentration of tacrolimus affected by CYP3A5 polymorphism might be related to its therapeutic effect.

Encapsulated cyclosporine does not change the composition of the human microbiota when assessed ex vivo and in vivo.

Introduction. Management of steroid-refractory ulcerative colitis has predominantly involved treatment with systemic cyclosporine A (CyA) and infliximab.Aim. The purpose of this study was to assess the effect of using a colon-targeted delivery system CyA formulation on the composition and functionality of the gut microbiota.Methodology. Ex vivo faecal fermentations from six healthy control subjects were treated with coated minispheres (SmPill) with (+) or without (-) CyA and compared with a non-treated control in a model colon system. In addition, the in vivo effect of the SmPill+CyA formulation was investigated by analysing the gut microbiota in faecal samples collected before the administration of SmPill+CyA and after 7 consecutive days of administration from eight healthy subjects who participated in a pilot study.Results. Analysis of faecal samples by 16S rRNA gene sequencing indicated little variation in the diversity or relative abundance of the microbiota composition before or after treatment with SmPill minispheres with or without CyA ex vivo or with CyA in vivo. Short-chain fatty acid profiles were evaluated using gas chromatography, showing an increase in the concentration of n-butyrate (P=0.02) and acetate (P=0.32) in the faecal fermented samples incubated in the presence of SmPill minispheres with or without CyA. This indicated that increased acetate and butyrate production was attributed to a component of the coated minispheres rather than an effect of CyA on the microbiota. Butyrate and acetate levels also increased significantly (P=0.05 for both) in the faecal samples of healthy individuals following 7 days' treatment with SmPill+CyA in the pilot study.Conclusion. SmPill minispheres with or without CyA at the clinically relevant doses tested here have negligible direct effects on the gut microbiota composition. Butyrate and acetate production increased, however, in the presence of the beads in an ex vivo model system as well as in vivo in healthy subjects. Importantly, this study also demonstrates the relevance and value of using ex vivo colon models to predict the in vivo impact of colon-targeted drugs directly on the gut microbiota.

P445 Efficacy and safety of induction therapy with calcineurin inhibitors followed by maintenance therapy with vedolizumab in severe ulcerative colitis: a large patient cohort with long-term follow-up

Abstract Background The options for the medical management of patients with severe ulcerative colitis failing IV steroids are limited and include the calcineurin inhibitors cyclosporin or tacrolimus, especially in patients who had previously failed anti-TNF agents. Following induction therapy with a calcineurin inhibitor, transitioning to vedolizumab as maintenance therapy could be an option. We report on the largest cohort of patients successfully induced with calcineurin inhibitors who were then transitioned to vedolizumab maintenance therapy. Methods We performed a retrospective observational study of adult ulcerative colitis patients followed at the University of Chicago Inflammatory Bowel Disease Center. Patients with severe steroid-refractory ulcerative colitis were included if they received a calcineurin inhibitor (ciclosporin or tacrolimus) as induction therapy followed by maintenance therapy with vedolizumab between January 2014 and December 2018. Patients who had a follow-up of fewer than three months were excluded. The primary endpoint was colectomy-free survival. Secondary endpoints included survival without vedolizumab discontinuation as well as clinical, steroid-free and biochemical remission at week 14. Results A total of 71 patients (59% male) were treated with vedolizumab after induction therapy with calcineurin inhibitors for severe steroid-refractory colitis. Truelove and Witts criteria for Acute Severe Ulcerative Colitis were fulfilled in 77% of patients, and 97% of patients had moderate to severe endoscopic disease. Patients were followed for a median time of 25 months (IQR 16–36). Colectomy free survival rates from vedolizumab initiation were 67% at one year and 55% at two years (Figure 1, Panel A). At the end of induction with vedolizumab at week 14, 50% of patients were in clinical remission, and 62% of patients had a normal CRP. At one and two years following vedolizumab initiation, 43% and 28% of patients were still on vedolizumab, respectively (Figure 1, Panel B). Vedolizumab was dose escalated to infusions every four weeks in 44% of patients. The median time to dose escalation was 5.6 months (IQR 4.1–8.2). No serious adverse events were recorded in our patient cohort. Conclusion Transitioning to vedolizumab following induction of remission with calcineurin inhibitors is effective and safe. Such a treatment strategy should be considered in patients with severe steroid-refractory ulcerative colitis, especially in cases of previous anti-TNF failure.

Efficacy and safety of induction therapy with calcineurin inhibitors followed by vedolizumab maintenance in 71 patients with severe steroid-refractory ulcerative colitis.

Following induction therapy with a calcineurin inhibitor (CNI) in severe ulcerative colitis, transitioning to vedolizumab as maintenance therapy could be an option. To report on the largest cohort of patients successfully induced with CNIs who were transitioned to vedolizumab maintenance therapy. This is a retrospective observational study of adult patients with severe steroid-refractory ulcerative colitis. Patients were included if they were induced with a CNI followed by maintenance therapy with vedolizumab between January 2014 and December 2018. The primary endpoint was colectomy-free survival. Secondary endpoints included survival without vedolizumab discontinuation as well as clinical, steroid-free and biochemical remission at week 14. A total of 71 patients (59% male) were treated with vedolizumab after induction therapy with CNIs for severe steroid-refractory colitis. Patients were followed for a median time of 25months (IQR 16-36). Colectomy-free survival rates from vedolizumab initiation were 93% at 3months, 67% at 1year and 55% at 2years. At the end of induction with vedolizumab at week 14, 50% of patients were in clinical remission, and 62% of patients had a normal CRP. At 1 and 2years following vedolizumab initiation, 43% and 28% of patients were still on vedolizumab respectively. Vedolizumab was dose escalated to infusions every 4weeks in 44% of patients. The median time to dose escalation was 5.6months (IQR 4.1-8.2). No serious adverse events were recorded in our patient cohort. Transitioning to vedolizumab following induction of remission with CNIs is effective and safe.