Tacrolimus In Ulcerative Colitis Research Articles

Network meta-analysis and cost-effectiveness analysis of infliximab, cyclosporine and tacrolimus for ulcerative colitis.

Assess the efficiency and cost-effectiveness of infliximab, cyclosporine and tacrolimus for the treatment of ulcerative colitis (UC). A literature search identified studies that investigated infliximab, cyclosporine or tacrolimus compared with placebo in UC patients. Short-term, long-term remission rates and response rates were employed to assess efficacy. Odds ratios with 95% confidence intervals were analyzed. A Markov model was constructed to simulate the progression in a cohort of patients with UC, with an over 10 years of time horizon, with a discount rate of 3%, and established threshold of €30,000/quality-adjusted life-year (QALY) or ¥82442/QALY. Results of network meta-analysis showed that the order was cyclosporine, tacrolimus, infliximab and placebo from high rate to low with regard to short-term clinical response. The comparison between infliximab versus cyclosporine achieved an incremental cost effectiveness ratio (ICER) of €184435/QALY and ¥531607/QALY, with a 0.34893 QALYs difference of efficacy, and an incremental cost of €64355 and ¥185494. Tacrolimus versus cyclosporine reached an ICER of €44236/QALY and ¥57494/QALY, with a difference of 0.40963 QALYs in efficacy, and a raising cost to €18120 and ¥23551. The probabilistic sensitivity analysis shows that cyclosporine would be cost-effective in the 75.8% of the simulations, tacrolimus in the 24.2%, and infliximab for the 0%. Infliximab, cyclosporine and tacrolimus as salvage therapies are efficacious. For long-term of clinical remission, the order of pharmacological agents was tacrolimus, infliximab and cyclosporine from high efficacy to low while no significant difference is seen. In cost-effectiveness analysis, the cyclosporine versus infliximab or tacrolimus is expected to be at best.

P466 Is it possible avoid colectomy with rescue dual therapy with vedolizumab plus tacrolimus in ulcerative colitis that losing response to anti-tumour necrosis factor?

Abstract Background There is an increasing number of ulcerative colitis (UC) patients that losing response to anti-tumour necrosis factor (TNF) drugs. There is low evidence about combining Tacrolimus (TAC) with vedolizumab (VED) for UC patients, who have failed treatment with anti-TNF therapy. The aim of the present study was to assess the efficacy and safety of TAC with VED in UC patient refractory to anti-TNF therapies. Methods Inclusion criteria: patients with moderately to severely active UC and who failed or showed intolerance to at least one TNF antagonists that received dual therapy with VED and oral TAC (Envarsus®). TAC blood levels were monitored at weeks 2,4,8 and then every 2 months. Rates of clinical response and remission were evaluated in November 2019 using the Mayo score. Clinical response was considered when PCR and calprotectin were decreased ³50% and biological remission was considered when PCR and calprotectin achieved normal values. Results Seven UC patients (1 proctitis, 3 left colon disease, 2 Pancolitis and 1 pouchitis) had sufficient dTNF for analysis. Demographic dTNF: age 51 ± years and 10.4 ± years since UC was diagnosed. All patients received thiopurine therapy and 86% received corticosteroids. 43% of patients were corticodependent and 43% were corticosteroid-refractory. 29% of patients failed to one TNF antagonists and 71% of patients failed to two TNF antagonists. Previous to started dual therapy; 29% of patients with moderate endoscopic activity and 71% of patients with severe endoscopic activity. Thiopurine treatment was suspended and 3 corticosteroid-refractory patients received IV cyclosporine therapy. The median dual therapy follow-up was 12.8 months (range 6–30 months). At the end of the study period; all patients presented clinical response, 86% of patients were corticosteroids free and biological remission was achieved in 71% of patients and any patient required colectomy. Fifty-seven per cent of patients needed VED dose intensification. Side effects were mild; abdominal pain (1), tremor (4), hypertension (1), moderate decrease creatinine clearance (1), insomnia (1) and arthralgías (1). Any patient discontinued dual therapy by adverse drug effect. At the end of the study, 4 patients continued with the dual therapy and 3 patients TAC was discontinued due to maintained clinical remission Conclusion In UC patients that losing response to anti-tumour necrosis factor (TNF) drugs and corticosteroid-refractory, the dual therapy with VED plus TAC could be an alternative, effective and safe therapy.

Tacrolimus for ulcerative colitis in children: a multicenter survey in Japan.

Background/AimsTacrolimus is effective for refractory ulcerative colitis in adults, while data for children is sparse. We aimed to evaluate the effectiveness and safety of tacrolimus for induction and maintenance therapy in Japanese children with ulcerative colitis. MethodsWe retrospectively reviewed the multicenter survey data of 67 patients with ulcerative colitis aged < 17 years treated with tacrolimus between 2000 and 2012. Patients’ characteristics, disease activity, Pediatric Ulcerative Colitis Activity Index (PUCAI) score, initial oral tacrolimus dose, short-term (2-week) and long-term (1-year) outcomes, steroid-sparing effects, and adverse events were evaluated. Clinical remission was defined as a PUCAI score < 10; treatment response was defined as a PUCAI score reduction of ≥ 20 points compared with baseline. ResultsPatients included 35 boys and 32 girls (median [interquartile range] at admission: 13 [11–15] years). Thirty-nine patients were steroid-dependent and 26 were steroidrefractory; 20 had severe colitis and 43 had moderate colitis. The initial tacrolimus dose was 0.09 mg/kg/day (range, 0.05–0.12 mg/kg/day). The short-term clinical remission rate was 47.8%, and the clinical response rate was 37.3%. The mean prednisolone dose was reduced from 19.2 mg/day at tacrolimus initiation to 5.7 mg/day at week 8 (P< 0.001). The adverse event rate was 53.7%; 6 patients required discontinuation of tacrolimus therapy. ConclusionsTacrolimus was a safe and effective second-line induction therapy for steroid-dependent and steroid-refractory ulcerative colitis in Japanese children.

The efficacy of maintenance therapy after remission induction with tacrolimus in ulcerative colitis with and without previous tumor necrosis factor-α inhibitor.

Background and AimTacrolimus (TAC) is an important therapeutic option for remission induction in patients with refractory ulcerative colitis (UC). However, there is little evidence available on long‐term outcomes and maintenance treatments after TAC therapy, especially in cases with previous tumor necrosis factor‐α (TNF‐α) inhibitor therapy.MethodsLong‐term outcomes and remission induction after TAC treatment were retrospectively examined in refractory UC patients with and without previous TNF‐α inhibitor therapy.ResultsThe mean disease activity index and the endoscopic activity index scores decreased significantly during the 12‐week treatment after TAC therapy in both groups, showing a significantly greater decrease in the group without TNF‐α inhibitor therapy than in the group with previous TNF‐α inhibitor therapy. One year or more after TAC therapy, TNF‐α inhibitor and/or azathioprine was used as maintenance therapy in most cases in the group without previous TNF‐α inhibitor treatment, while azathioprine was primarily used in the group with previous TNF‐α inhibitor treatment. Colectomy was performed in 45.5% (5/11) and 15.6% (7/45) of the groups with and without previous TNF‐α inhibitor therapy, respectively, and the group without previous TNF‐α inhibitor treatment had a better colectomy‐free rate than the group with previous TNF‐α inhibitor treatment after TAC therapy on Kaplan–Meier analysis.ConclusionsTAC is effective for remission induction in refractory UC patients with and without previous TNF‐α inhibitor treatment. Maintenance medication after TAC therapy is an issue for the future, especially in UC cases with previous TNF‐α inhibitor treatment failure.

Individualized treatment based on CYP3A5 single-nucleotide polymorphisms with tacrolimus in ulcerative colitis.

Background/AimsThe pharmacokinetics of tacrolimus (TAC) is known to be largely influenced by single-nucleotide polymorphisms (SNPs) in CYP3A5. Patients starting TAC require careful dose adjustment, owing to the wide range of optimal dosages, depending on their CYP3A5 expression status. Here, we evaluated whether individualization of TAC dosages based on CYP3A5 SNPs would improve its therapeutic efficacy in ulcerative colitis. MethodsTwenty-one patients were prospectively treated, with their initial dosage adjusted according to their CYP3A5 status (0.1, 0.15, and 0.2 mg/kg/day for CYP3A5*3/*3, CYP3A5*1/*3, and CYP3A5*1/*1, respectively). Their clinical outcomes were compared with those of patients treated with a fixed dose (0.1 mg/kg/day).ResultsThe first blood trough level of CYP3A5 expressors, CYP3A5*1/*3 or CYP3A5*1/*1, and the overall rate in achieving the target blood trough level within a week in the individualized-dose group were significantly higher than those in the fixed-dose group (5.15±2.33 ng/mL vs. 9.63±0.79 ng/mL, P=0.035 and 12.5% vs. 66.7%, P=0.01). The remission rate at 2 weeks in the expressors was as high as that in the nonexpressors, CYP3A5*3/*3, in the individualized-dose group.ConclusionsIndividualized TAC treatment is effective against ulcerative colitis regardless of the CYP3A5 genotype.

DOP44 Efficacy and safety of tacrolimus in ulcerative colitis: a nationwide, multi-centre study from GETECCU

DOP44 Efficacy and safety of tacrolimus in ulcerative colitis: a nationwide, multi-centre study from GETECCU

Tacrolimus Dose Optimization Strategy for Refractory Ulcerative Colitis Based on the Cytochrome P450 3A5 Polymorphism Prediction Using Trough Concentration after 24 Hours

Background: In the tacrolimus treatment for refractory ulcerative colitis (UC), dose adjustment is necessary because the required doses to keep appropriate drug concentrations are significantly different among individuals. Cytochrome P450 (CYP) 3A5 polymorphism affects tacrolimus blood concentrations. However, it is difficult to obtain genetic information in real clinical practice. In the present study, we investigated possible factors that may predict CYP3A5 polymorphism and proposed a dose optimization strategy based on the obtained predicting factors. Summary: We retrospectively analyzed 41 patients who underwent remission induction therapy with tacrolimus for UC in our hospital. First, we performed a correlation analysis of CYP3A5 polymorphism and pharmacokinetics. In the CYP3A5 non-expressers, the dose of tacrolimus (mg/kg) was lower and dose-adjusted trough levels (ng/mL per mg/kg) were higher compared with those in expressers. Next, we investigated factors that could predict CYP3A5 polymorphism. Trough concentration 24 h following tacrolimus administration was extracted as a significant factor. When the trough cutoff value at 24 h was set to 2.6 ng/mL, sensitivity and specificity for estimation of CYP3A5 polymorphism were 63 and 96% respectively. Therefore, when the trough concentration 24 h after administration is ≤2.6 ng/mL, the patient can be estimated as a CYP3A5 expresser and an increase in dose should be proposed. Key Message: The trough concentration 24 h after the first tacrolimus administration appears to be a useful predictor of ­CYP3A5 polymorphism. Performing dose optimization strategy based on the prediction of CYP3A5 polymorphism can lead to earlier and safer remission induction.

Letter: which patient profile for tacrolimus in ulcerative colitis?

Letter: which patient profile for tacrolimus in ulcerative colitis?

Effects of CYP3A5 Genotype on Efficacy and Safety of Tacrolimus in Refractory Ulcerative Colitis: An Experience From a Tertiary Referral Center in Japan

Introduction: A calcineurin inhibitor, tacrolimus (TAC), is widely used as an induction therapy for steroid-refractory ulcerative colitis (UC) patients in Japan. Although its efficacy in inducing remission is comparable with other treatment options such as anti-tumor necrosis factor antibodies, its longterm efficacy is not well studied. Its long-term use may lead to an increased incidence of side effects including renal dysfunction. Furthermore, its efficacy as well as toxicity depends on the blood trough level, which requires the frequent monitoring of blood concentration. Both patients and physicians may want to avoid using Tac due to these factors. Here we retrospectively tried to examine the association of genotyping the single nucleotide polymorphism of CYP3A5, the metabolizing enzyme of tacrolimus, with the dosing, long-term efficacy, and incidence of renal dysfunction by TAC for UC in our institution. Methods: Medical records of 21 patients with UC who were treated with TAC for more than 2 weeks were retrospectively reviewed (M:F=13:8). Mean duration of TAC treatment was 308 +/- 284 days. CYP3A5*3(A6986G) was genotyped using the TaqMan real-time polymerase chain reaction assays. 1) Dose of TAC required to reach the therapeutic level (10 ug/ml) 2) incidence of renal dysfunction 3) short- and long-term clinical efficacy outcome was examined in combination of CYP3A5 genotypes. Renal dysfunction was defined by the 25% increase of serum creatinine (Cr). All analyses were conducted under the approval of institutional review board of Kitasato Institute Hospital. Results: CYP3A5*3 genotypes were *3/*3 in 10, *1/*3 in 9, and *1/*1 in 2 patients. 1) The dose required to reach the therapeutic trough level was significantly lower in non-expressor (*3/*3) compared with expressor (*1/*3 and *1/*1). 2) 13 out of 21patients (62%) suffered from renal dysfunction, which was not associated with CYP3A5 genotype but with the trough concentration during the treatment. Most cases recovered after discontinuing or switching Tac to thiopurines. 3) Short- and long-term efficacy outcome was not affected by the genotype. Conclusion: CYP3A5 genotype seemed useful for determining the initial dose of TAC, but was not associated with the incidence of side effects and efficacy. There was a significant proportion of patients who were maintained for longer than 3 months by TAC in combination with thiopurines, however, the incidence of gradual decrease of renal function was frequent.

P-107: Effect of exclusive enteral nutrition on the course of CD and intestinal microbiota

P-107: Effect of exclusive enteral nutrition on the course of CD and intestinal microbiota

P-106: The clinical relevance of tacrolimus for ulcerative colitis in children: a national survey of the treatments for pediatric inflammatory bowel disease in Japan

P-106: The clinical relevance of tacrolimus for ulcerative colitis in children: a national survey of the treatments for pediatric inflammatory bowel disease in Japan

Mucosal healing with oral tacrolimus is associated with favorable medium- and long-term prognosis in steroid-refractory/dependent ulcerative colitis patients

BackgroundOral administration of tacrolimus is an effective remission induction therapy for steroid-refractory/dependent ulcerative colitis (UC). AimThis study aimed to evaluate the short- as well as medium- and long-term effectiveness of tacrolimus therapy. MethodsThe medical records of 51 patients treated with tacrolimus for UC at our hospital between July 2009 and December 2011 were reviewed retrospectively. Clinical remission and improvement were defined as a Lichtiger score of 4 or less and as a Lichtiger score of ≤10 and a reduction in the score of ≥3 compared with the baseline score, respectively. Endoscopic findings were evaluated based on the endoscopic activity index and Mayo endoscopic score. ResultsThe clinical effectiveness combining clinical remission and improvement was observed in 62.7% of the patients at 3months. Thirty-six patients underwent colonoscopy at 3months, and 12 (33.3%) and 10 patients (27.8%) showed Mayo endoscopic scores of 0 and 1, respectively. On Kaplan–Meier analysis, the overall percentage of event-free survivors, who did not require colectomy nor switching to other induction therapy such as infliximab, was 73.0% at 6months, 49.9% at 1year, and 37.8% at 2years. Patients with a Mayo endoscopic score of 0–1 at 3months showed significantly better medium- and long-term prognosis than those with a score of 2–3 (p<0.01). All adverse events, including infections in 2 patients, were reversible. ConclusionsTacrolimus therapy was effective for inducing clinical and endoscopic remission of steroid-refractory/dependent UC. Endoscopic improvement was associated with favorable medium- and long-term prognosis.

Commentary: short‐term efficacy of tacrolimus in steroid‐refractory ulcerative colitis

The medical management of patients with refractory ulcerative colitis (UC) remains a significant challenge. Up to one-third of patients with UC require surgery. Immunomodulators are fundamental in the management of refractory UC. However, a proportion of patients are unresponsive to, or intolerant of, thiopurines. Data for other medical options are limited, with serious potential adverse effects. Further data for other pharmacological agents are needed for these patients. Two randomised studies 4 demonstrate the efficacy of tacrolimus in the induction of remission of moderate to severe UC in hospitalised patients at 2 weeks. Only small retrospective analyses have assessed longer term outcomes following tacrolimus treatment for this group. 6 Additional evidence is necessary regarding the efficacy of tacrolimus for steroid-refractory UC beyond the first few weeks of treatment. Schmidt et al. report a large retrospective study conducted across three centres of 130 patients with moderate to severe UC treated with tacrolimus. Clinical remission was achieved in 72% of patients after 3 months. Remission was achieved significantly more frequently in patients concomitantly treated with a thiopurine. Fourteen per cent of patients underwent colectomy within 3 months of initiating tacrolimus treatment. Adverse effects were observed in over half of the patients, but only in two cases was tacrolimus discontinued with no opportunistic infections or deaths occurring. This study is subject to the limitations of retrospective data. One-third of patients were treated de novo with a thiopurine concomitantly, data regarding patients’ tacrolimus levels are limited and other biological and endoscopic data are not presented. However, it provides an evaluation of a large group of patients with steroidrefractory UC treated with tacrolimus, with promising short-term outcomes, although longer term outcomes with tacrolimus in UC remain unclear.

Tacrolimus in ulcerative colitis – extended three center experience

Aims: In steroid-refractory or dependent attacks of ulcerative colitis (UC) tacrolimus has been shown to be beneficial although its long term efficacy remains unclear. Furthermore, the need of concomitant immunosuppression is ill defined. Objectives: Aim of this three center retrospective analysis was to evaluate efficacy and safety of tacrolimus in moderately to severely active UC for induction and maintenance of remission. Primary endpoints were short term response and colectomy free survival. Secondary outcome data were safety and tolerability. Methods: Charts of 161 patiens with steroid-dependent or -refractory UC were reviewed. Tacrolimus was administered po at 0.1mg/kg/d, in some instances iv at 0.01mg/kg. 104 out of 161 patients received triple immunosuppression with purine analogues or methotrexate. Response to treatment at weeks 0, 4 and 12 was evaluated using the Truelove-Witt's index, patients were visited on a regular outpatient basis. Results: Tacrolimus treatment was started in median 4 years after disease onset (range 0–33). Distribution of disease localisation was E3 in 90 (57%), E2 in 44 (27%), E1 in 23 patients (14%). Median tacrolimus dose was 8mg/d (range 0.56–21). At baseline 118 patients (74%) experienced severe and 31 (19%) moderate activitiy. Early proctocolectomy was nessessary in 7 patients after 4 and additional 12 after 12 weeks. Disease activity dropped to mild activity in 83 and 78 patients at weeks 4 and 12, respectively. Overall colectomy was performed in 36, 11 and 4 patients within the first, second and third year. Kaplan Meier analysis revealed a colectomy free survival in the complete cohort of 65% and 28% at one and two years, respectively. Purine analogues delayed the necessarity of proctocolectomy although the overall colectomy rate did not differ beyond 3 years. Adverse events were recorded and will be presented. Conclusions: Experience with tacrolimus in UC on this three center basis confirms previous findings. It may serve as treatment choice to achieve an operable state or as a bridge to immunosuppressants with a time lag of action. The role of concomitant immunosuppression additionally to tacrolimus seems to be advantageous in the midterm although the long term role remains doubtful.

656 Efficacy of Tacrolimus in Ulcerative Colitis is Associated With Polymorphisms in the ABCB1 Gene

656 Efficacy of Tacrolimus in Ulcerative Colitis is Associated With Polymorphisms in the ABCB1 Gene

Efficacy and safety of tacrolimus in refractory ulcerative colitis and Crohnʼs disease: A single-center experience

The published experience regarding the use of tacrolimus in Crohn's disease (CD) and ulcerative colitis (UC) refractory to more commonly used medical therapy has been fairly limited. Our objective was to describe our experience with its use in a cohort of patients which, to our knowledge, represents the largest North American cohort described to date. This was a retrospective, single-center chart analysis. Patients were identified by compiling all hospital discharges with principle diagnoses of ICD-9 codes for 555.0-555.9 (regional enteritis) and 556.0-556.9 (ulcerative colitis) from January 1, 2000, to October 31, 2005, and then cross-referencing the electronic charts for tacrolimus serum concentrations ordered during this time period. Additional patients were identified through verbal communication with participating clinicians. Information abstracted included proportion with clinical response and remission (using a modified disease activity index), ability to wean from steroids, need for surgery / time to surgery, and side-effect profile. In all, 32 UC patients and 15 CD patients were identified. The mean disease duration was: UC 81 months (range, 1 month to 37 years), CD 100 months (range, 1 month to 35 years). The disease distribution for UC was: pancolitis 12 (37.5%), extensive colitis 6 (18.8%), left-sided 11 (34.4%), and proctitis 3(9.4%). For CD this was: TI 2 (13.3%), small bowel 2 (13.3%), colonic 3 (20.7%), ileocolonic 7(46.7%), and perianal 1 (6.7%). The duration of tacrolimus treatment for UC was mean, 29 weeks. For CD it was mean, 9.9 weeks. In all, 30/32 UC and 7/15 CD patients were on steroids; 4/30 UC and 0/7 CD patients were able to subsequently wean off steroids. In all, 12/32 UC patients proceeded to colectomy. Mean time to colectomy was 28 weeks and 6/15 CD patients proceeded to a resective surgery. The mean time to surgery was 22 weeks. In all, 22/32 UC patients achieved a clinical response; 3/32 achieved remission and 8/15 CD patients achieved a clinical response; 1/15 achieved remission. Adverse reactions were generally mild. In 6 patients the drug had to be discontinued because of an adverse reaction. There were no opportunistic infections identified, no cases of renal insufficiency related to drug administration, and no deaths while on the medicine. Our experience with tacrolimus in UC and CD indicates that it is safe and relatively well tolerated, although its clinical efficacy is quite variable. More prospective studies assessing its use are necessary.