tacrolimus and Colitis--Ulcerative

Patients with ulcerative proctitis have favorable long-term outcomes but are typically excluded from ulcerative colitis clinical trials. Refractory proctitis presents a management conundrum for gastroenterologists, and there remains a lack of clarity as to the best therapeutic strategy. This study aimed to undertake a systematic review of studies assessing the clinical efficacy and safety of therapies for refractory proctitis. PubMed, Embase, Cochrane Library, and MEDLINE databases were searched without restriction from inception to October 27, 2022. Both interventional and noninterventional studies examining efficacy of therapeutic modalities for the induction and/or maintenance of remission in refractory proctitis were included. Included studies were grouped by therapeutic modalities as follows: (i) immunomodulators, (ii) monoclonal antibodies, (iii) topical calcineurin inhibitors, (iv) other topical therapies, and (v) appendicectomy. The search strategy identified 3301 studies, of which 13 met eligibility criteria for inclusion. Clinical remission rates for systemic therapies ranged from 20-26% for azathioprine to 50-69% for tumor necrosis factor-α inhibitor therapies. The use of systemic therapies for proctitis raised safety concerns, with 22-37% of patients discontinuing therapies due to adverse effects across four retrospective cohort studies. Prospective clinical trials of topically applied tacrolimus demonstrated clinical remission rates of 42-46%, with a favorable safety profile. Substantial heterogeneity in study design precluded meta-analysis. Refractory ulcerative proctitis remains a neglected entity, with a dearth of prospective clinical trials to guide therapeutic decision-making. Current evidence supports a role for topically administered tacrolimus.

Topics: Colitis, Ulcerative; Humans; Proctitis; Prospective Studies; Remission Induction; Retrospective Studies; Tacrolimus

There are limited treatment options for children with steroid-refractory or dependent ulcerative colitis (UC). A few observational studies suggest efficacy of oral tacrolimus. We performed a systematic review and meta-analysis to assess the efficacy of tacrolimus in pediatric UC.. PubMed and Scopus were searched for publications related to the use of oral tacrolimus in pediatric UC. Data regarding the clinical response and colectomy-free survival were extracted from studies that met the selection criteria.. The search strategy yielded 492 articles of which 7 studies were included in the final review. They included 166 children (111 steroid-refractory, 52 steroid-dependent, 3 no steroids). Majority of cases (150/166 [90%]) were naïve to biologics. An initial response to tacrolimus therapy was seen in 84% (95% CI: 73%-93%) (n = 7 studies). No difference was observed between children with high (>10 ng/mL) or low tacrolimus levels (127/150 [85%] vs 12/16 [75%], P = 0.3). No difference in initial response between the children who were steroid refractory or dependent (92/111 [83%] vs 46/52 [88%], P = 0.36). The response in the biologic-exposed group (n = 10) was 70%. At 1-year follow-up, 15.2% (95% CI: 7%-21%) (n = 2 studies, 85 patients) had a sustained response on only tacrolimus. The pooled frequency of 1-year colectomy-free survival in children treated with initial oral tacrolimus was 64% (95% CI: 53%-75%). Twelve (7.2%) patients required cessation of therapy because of side effects.. Tacrolimus has a high initial response in biologic naïve UC children. It can be effectively used as a bridge to other therapies with a 1-year colectomy-free survival of 64%.

Topics: Child; Colitis, Ulcerative; Humans; Immunosuppressive Agents; Steroids; Tacrolimus; Treatment Outcome

Ulcerative proctitis (UP) is a common highly symptomatic form of ulcerative colitis that can be difficult to treat.. To assess the efficacy of medical treatments for UP.. We searched MEDLINE, EMBASE, and CENTRAL on 23 November 2022 for randomised controlled trials (RCTs) of medical therapy for adults with UP. Primary outcomes included induction and maintenance of clinical remission. Pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated for each outcome.. We included 53 RCTs (n = 4096) including 46 induction studies (n = 3731) and seven maintenance studies (n = 365). First-line therapies included topical 5-aminosalicylic acid (5-ASA), conventional corticosteroids, budesonide, and oral 5-ASA. Therapy for refractory UP included topical tacrolimus and small molecules. Topical 5-ASA was superior to placebo for induction (RR 2.72, 95% CI 1.94-3.82) and maintenance of remission (RR 2.09, 95% CI 1.26-3.46). Topical corticosteroids were superior to placebo for induction of remission (RR 2.83, 95% CI 1.62-4.92). Topical budesonide was superior to placebo for induction of remission (RR 2.34, 95% CI 1.44-3.81). Combination therapy with topical 5-ASA and topical corticosteroids was superior to topical monotherapy with either agent. Topical tacrolimus was superior to placebo. Etrasimod was superior to placebo for induction (RR 4.71, 95% CI 1.2-18.49) and maintenance of remission (RR 2.08, 95% CI 1.31-3.32).. Topical 5-ASA and corticosteroids are effective for active UP. Topical 5-ASA may be effective for maintenance of remission. Tacrolimus may be effective for induction of remission. Etrasimod may be effective for induction and for maintenance of remission. Trials should include UP to expand the evidence base for this under-represented population.

Topics: Administration, Oral; Adult; Anti-Inflammatory Agents, Non-Steroidal; Budesonide; Colitis, Ulcerative; Humans; Mesalamine; Proctitis; Remission Induction; Tacrolimus

There are a limited number of treatment options for people with corticosteroid-refractory ulcerative colitis. Animal models of inflammatory bowel disease and uncontrolled studies in humans suggest that tacrolimus may be an effective treatment for ulcerative colitis.. To evaluate the efficacy and safety of tacrolimus for induction of remission in people with corticosteroid-refractory ulcerative colitis.. We searched the Cochrane Gut group specialised register, CENTRAL, MEDLINE (PubMed), Embase, Clinicaltrials.gov and WHO ICTRP from inception to October 2021 to identify relevant randomised controlled trials (RCT).. Two review authors independently selected potentially relevant studies to determine eligibility based on the prespecified criteria.. Two review authors independently extracted data and analysed them using Review Manager Web. The primary outcomes were induction of remission and clinical improvement, as defined by the studies and expressed as a percentage of the participants randomised (intention-to-treat analysis).. This review included five RCTs with 347 participants who had active ulcerative colitis or ulcerative proctitis. The duration of intervention varied between two weeks and eight weeks. Tacrolimus versus placebo Tacrolimus (oral and rectal) may be superior in achieving clinical remission compared to placebo (oral and rectal) (14/87 participants with tacrolimus versus 1/61 participants with placebo; risk ratio (RR) 3.76, 95% confidence interval (CI) 1.03 to 13.73; 3 studies). These results are of low certainty due to imprecision and risk of bias. Tacrolimus (oral and rectal) may be superior for clinical improvement compared to placebo (oral and rectal) (45/87 participants with tacrolimus versus 7/61 participants with placebo; RR 4.47, 95% CI 2.15 to 9.29; 3 studies). These results are of low certainty due to imprecision and risk of bias. The evidence is very uncertain about the effects of tacrolimus (oral and rectal) on serious adverse events compared to placebo (oral and rectal) (2/87 participants with tacrolimus versus 0/61 participants with placebo; RR 2.44, 95% CI 0.12 to 48.77; 3 studies). These results are of very low certainty due to high imprecision and risk of bias. Tacrolimus versus ciclosporin One study compared oral tacrolimus to intravenous ciclosporin, with an intervention lasting two weeks and 113 randomised participants. The evidence is very uncertain about the effect of tacrolimus on achievement of clinical remission compared to ciclosporin (15/33 participants with tacrolimus versus 24/80 participants with ciclosporin; RR 1.52, 95% CI 0.92 to 2.50). The results are of very low certainty due to risk of bias and high imprecision. The evidence is very uncertain about the effect of tacrolimus on clinical improvement compared to intravenous ciclosporin (23/33 participants with tacrolimus versus 62/80 participants with ciclosporin; RR 0.90, 95% CI 0.70 to 1.16). The results are of very low certainty due to risk of bias and imprecision. Tacrolimus versus beclometasone One study compared tacrolimus suppositories with beclometasone suppositories in an intervention lasting four weeks with 88 randomised participants. There may be little to no difference in achievement of clinical remission (16/44 participants with tacrolimus versus 15/44 participants with beclometasone; RR 1.07, 95% CI 0.60 to 1.88). The results are of low certainty due to high imprecision. There may be little to no difference in clinical improvement when comparing tacrolimus suppositor. There is low-certainty evidence that tacrolimus may be superior to placebo for achievement of clinical remission and clinical improvement in corticosteroid-refractory colitis or corticosteroid-refractory proctitis. The evidence is very uncertain about the effect of tacrolimus compared to ciclosporin for achievement of clinical remission or clinical improvement. There may be no difference between tacrolimus and beclometasone for inducing clinical remission or clinical improvement. The cohorts studied to date were small, with missing data sets, offered short follow-up and the clinical endpoints used were not in line with those suggested by regulatory bodies. Therefore, no clinical practice conclusions can be made. This review highlights the need for further research that targets the relevant clinical questions, uses appropriate trial methodology and reports key findings in a systematic manner that facilitates future integration of findings with current evidence to better inform clinicians and patients. Future studies need to be adequately powered and of pertinent duration so as to capture the efficacy and effectiveness of tacrolimus in the medium to long term. Well-structured efficacy studies need to be followed up by long-term phase 4 extensions to provide key outputs and inform in a real-world setting.

Topics: Adrenal Cortex Hormones; Beclomethasone; Colitis, Ulcerative; Cyclosporine; Humans; Proctitis; Remission Induction; Suppositories; Tacrolimus

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.

Topics: Colitis, Ulcerative; Cost-Benefit Analysis; Cost-Effectiveness Analysis; Cyclosporine; Humans; Infliximab; Network Meta-Analysis; Quality-Adjusted Life Years; Tacrolimus; Treatment Outcome

Topics: Administration, Oral; Administration, Rectal; Adrenal Cortex Hormones; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Colitis, Ulcerative; Drug Development; Endpoint Determination; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Mesalamine; Proctitis; Randomized Controlled Trials as Topic; Sigmoidoscopy; Tacrolimus; Treatment Outcome

Nowadays, non-biological treatments remain valuable approaches among the therapeutic armamentarium of inflammatory bowel disease (IBD). Mesalamine is the core treatment of mild‑to‑moderate ulcerative colitis (UC) and corticosteroids are crucial for the induction of remission of moderate‑to‑severe flares in both UC and Crohn's disease (CD). Even approaches as cyclosporine, tacrolimus, azathioprine, methotrexate, and surgery still have a nuclear position as strategies to induce and/or maintain remission in IBD. Due to their particularities and to the accumulated evidence, each of these strategies conquered peculiar roles in the overall IBD strategy, all of them contributing to better outcomes. This review emphasizes the particular roles that non-biological treatments gained over time: recent mesalamine formulations to increase adhesion rates, higher doses of 5-ASA for high-risk patients, MMX technology to improve drug release and attain higher bowel concentrations, cyclosporine as a bridge to vedolizumab, tacrolimus as a potential alternative to thiopurines or infliximab, azathioprine in combination therapy with infliximab and dubious in monotherapy, and surgery as a mean to a "better end".

Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents; Colitis, Ulcerative; Crohn Disease; Cyclosporine; Digestive System Surgical Procedures; Gastrointestinal Agents; Humans; Mesalamine; Methotrexate; Tacrolimus; Treatment Outcome

Positioning infliximab (IFX), cyclosporine and tacrolimus (TAC) for treating ulcerative colitis (UC) is in great debate.. A literature search identified studies that investigated IFX vs. cyclosporine or IFX vs TAC in UC patients. Short-term remission, short-term, 1-year and 3-year colectomy rate were employed as primary end-points to assess efficacy. Odds ratios (ORs) with 95% confidence intervals (CIs) were analyzed.. Overall, 15 studies comprised 596 patients in IFX group and 866 in calcineurin inhibitors group (644 received cyclosporine and 222 received TAC). No significant difference was seen between IFX and calcineurin inhibitors with regard to short-term remission. IFX led to a lower short-term (OR: 0.59, 95% CI: 0.43-0.82, P:.001), 1-year (OR: 0.53, 95% CI: 0.38-0.73, P < .001), 3-year colectomy (OR: 0.41, 95% CI: 0.20-0.84, P:.02) than calcineurin inhibitors. IFX led to a lower short-term (OR: 0.51, 95% CI: 0.36-0.71, P < .001), 1-year (OR: 0.53, 95% CI: 0.37-0.74, P:.003) colectomy and a trend of lower 3-year colectomy (OR: 0.49, 95% CI: 0.22-1.06, P:.07) than cyclosporine while no significant difference was seen between IFX and TAC. Results of network meta-analysis showed that the order was cyclosporine, TAC and IFX from high rate to low with regard to short-term and 1-year colectomy.. IFX treatment leads to a lower short-term, 1-year colectomy rate and a trend of lower 3-year colectomy rate in UC patients than cyclosporine while no significant difference is seen between IFX and TAC. TAC may be superior than cyclosporine with regard to efficacy based on indirect comparisons. Randomized trials with fixed protocol are warranted to identify the optimal medical strategy in patients with UC.

Topics: Colectomy; Colitis, Ulcerative; Cyclosporine; Humans; Immunosuppressive Agents; Infliximab; Remission Induction; Tacrolimus; Treatment Outcome

Inflammatory bowel diseases are known for a chronic inflammatory process of the gastrointestinal tract and include Crohn's disease and ulcerative colitis (UC). Patients who are dependent on or resistant to corticosteroids account for about 20% of severe UC patients. Tacrolimus is a calcineurin inhibitor that has recently been used in the treatment of steroid-refractory ulcerative colitis. Tacrolimus has been demonstrated to have remarkable therapeutic efficacy in UC patients, without increased risk of severe adverse effects such as induction of remission and maintenance therapy. This article reviews the mechanism of action, pharmacogenetics, efficacy, and safety of tacrolimus for patients with steroid-refractory ulcerative colitis.

Topics: Calcineurin Inhibitors; Colitis, Ulcerative; Humans; Induction Chemotherapy; Maintenance Chemotherapy; Steroids; Tacrolimus; Treatment Outcome

This narrative review was to determine which medication, tacrolimus (TAC) or infliximab (IFX), is safer and more effective in the management of active UC. Our literature search identified 5 studies directly comparing the outcomes of TAC versus IFX for active UC. A review of the 5 studies was undertaken.. The incidence of serious adverse events was not significantly different between the TAC and IFX groups. The short-term clinical remission and response rates and the colectomy-free rates were similar between the groups. TAC was usually withdrawn at week 12 and, therefore, the long-term efficacy of TAC could not be properly evaluated. The majority of patients in the IFX group maintained clinical remission in the long-term. The efficacy of IFX as second-line salvage therapy after failure of TAC appeared to be favourable, but the efficacy of TAC after failure of IFX was questionable. Key Messages: Both TAC and IFX appeared to be equally safe and effective in the short-term for patients with active UC. For the moment, treatment choice, TAC or IFX, should be guided by physician and centre experience. Randomised controlled trials are urgently warranted to rigorously compare the efficacy of TAC versus IFX for active UC.

Topics: Calcineurin Inhibitors; Colectomy; Colitis, Ulcerative; Female; Humans; Infliximab; Middle Aged; Tacrolimus; Treatment Outcome

Acute moderate-to-severe steroid-refractory ulcerative colitis (UC) has a poor prognosis and requires optimal rescue therapy. A pooled analysis was conducted to assess tacrolimus and infliximab (IFX) as rescue agents in patients with moderate-to-severe and steroid-refractory UC.. A literature search identified studies that investigated tacrolimus and IFX in moderate-to-severe steroid-refractory patients with UC. The primary outcome was short-term clinical response to treatment, including the remission and response rates. Secondary outcomes included the rates of colectomy at 3 months and adverse events rate.. A total of 6 studies comprising 438 cases were eligible for inclusion. The pooled analysis showed that the short-term clinical response rate, clinical remission rate, and 3-month colectomy rate were 72.1%, 52.4%, and 10.1%, respectively, for those receiving tacrolimus, and 76.9%, 48.8%, and 12.4%, respectively, for those receiving IFX. No significant difference was, however, seen for tacrolimus compared with IFX with regard to clinical remission rate (odds ratio [OR] =1.08, 95% confidence interval [CI] = 0.77-1.49, P = .67), clinical response rate (OR = 0.92, 95% CI = 0.63-1.34, P = .66), and 3-month colectomy rate (OR = 0.86, 95% CI = 0.39-1.93, P = .72). More adverse events were, however, observed in the Tac group (OR = 2.16, 95% CI = 1.25-3.76, P = .006).. Our meta-analysis suggested that both tacrolimus and IFX appeared to be effective and safe for the rescue therapy of moderate-to-severe active UC and steroid-refractory UC. Therefore, tacrolimus is another choice for these patients.

Topics: Adult; Colitis, Ulcerative; Female; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Induction Chemotherapy; Infliximab; Male; Tacrolimus; Treatment Outcome

A limited option of therapies is available for hospitalized patients with severe steroid refractory ulcerative colitis (UC). Furthermore, there exists a paucity of direct comparisons between them. To provide a comparative evaluation of the efficacy and safety of pharmacologic therapies, we conducted a network meta-analysis combined with a benefit-risk analysis of randomized controlled trials (RCTs) performed in hospitalized patients with severe steroid refractory UC.. Electronic databases were searched through November 2015 for RCTs evaluating the efficacy of therapies for severe steroid refractory hospitalized UC. The outcomes were clinical response, colectomy free rate, and severe adverse events leading to discontinuation of therapy. The primary endpoints were the rank of therapies based on network meta-analysis combined with benefit-risk analysis between clinical response and severe adverse events as well as colectomy free rate and severe adverse events.. Eight RCTs of 421 patients were identified. Cyclosporine, infliximab, and tacrolimus as well as placebo were included in our analysis. Network meta-analysis with benefit-risk analysis simultaneously assessing clinical response and severe adverse events demonstrated the rank order of efficacy as infliximab, cyclosporine, tacrolimus, and placebo. Similar analysis for colectomy-free rate and severe adverse events demonstrated the same rank order of efficacy. The differences among infliximab, cyclosporine, and tacrolimus were small in all analyses.. The results of the present comprehensive benefit-risk assessment using network meta-analysis provide RCT-based evidence on efficacy and safety of infliximab, cyclosporine, and tacrolimus for hospitalized patients with severe steroid refractory UC.

Topics: Colitis, Ulcerative; Cyclosporine; Databases, Bibliographic; Hospitalization; Humans; Infliximab; Randomized Controlled Trials as Topic; Severity of Illness Index; Tacrolimus; Treatment Outcome

Restorative proctocolectomy with ileal pouch anal anastomosis (IPAA) is considered the procedure of choice in patients with ulcerative colitis (UC) refractory to medical therapy. The incidence of pouchitis is 40% at 5 years. Ten to 15% of patients with pouchitis experience chronic pouchitis.. To determine the efficacy of medical therapies for the treatment of chronic refractory pouchitis in patients undergoing IPAA for UC.. A systematic computer-assisted search of the on-line bibliographic database MEDLINE and EMBASE was performed between 1966 and February 2016. All original studies reporting remission rates following medical treatment for chronic pouchitis were included. All study designs were considered. Remission was defined according to the individual study. Remission endpoints ranged from 15 days to 10 weeks. Chronic pouchitis was defined by each study.. Twenty-one papers were considered eligible. Results from all studies combined suggested that overall remission was obtained in 59% of patients (95% CI: 44-73%). Antibiotics significantly induced remission in patients with chronic pouchitis with 74% remission rate (95% CI:56-93%), (P < 0.001). Biologics significantly induced remission in patients with chronic pouchitis with 53% remission rate (95% CI:30-76%), (P < 0.001). Steroids, bismuth, elemental diet and tacrolimus all can induce remission but failed to achieve significance. Faecal microbiota transplantation in a single study was not found to achieve remission.. Treatment of chronic refractory pouchitis remains difficult and is largely empirical. Larger randomised controlled trials will help aid the management of chronic pouchitis.

Topics: Algorithms; Anal Canal; Colitis, Ulcerative; Colonic Pouches; Humans; Pouchitis; Proctocolectomy, Restorative; Remission Induction; Tacrolimus

Approximately 25% of patients with ulcerative colitis [UC] experience a severe flare requiring steroid therapy to avoid colectomy. We performed a systematic review and meta-analysis to assess the efficacy of tacrolimus as a rescue therapy for active UC.. Electronic databases were searched for relevant studies assessing the efficacy of tacrolimus for active UC. Outcomes included short- and long-term clinical response, colectomy free rates, and rate of adverse events in randomised controlled trials [RCTs] and observational studies.. Two RCTs comparing high trough concentration [10-15ng/ml] versus placebo [n = 103] and 23 observational studies [n = 831] were identified. Clinical response at 2 weeks was significantly higher with tacrolimus compared with placebo (risk ratio [RR] = 4.61, 95% confidence interval [CI] = 2.09-10.17, p = 0.15 x 10(-3)] among RCTs. Rates of clinical response at 1 and 3 months were 0.73 [95% CI = 0.64-0.81] and 0.76 [95% CI = 0.59-0.87], and colectomy-free rates remained high at 1, 3, 6, and 12 months [0.86, 0.84, 0.78, and 0.69, respectively] among observational studies. Among RCTs, adverse events were more frequent compared with placebo [RR = 2.01, 95% CI = 1.20-3.37, p = 0.83 x 10(-2)], but there was no difference in severe adverse events [RR = 3.15, 95% CI = 0.14-72.9, p = 0.47]. Severe adverse events were rare among observational studies [0.11, 95% CI = 0.06-0.20].. In the present meta-analysis, tacrolimus was associated with high clinical response and colectomy-free rates without increased risk of severe adverse events for active UC.

Topics: Colitis, Ulcerative; Humans; Immunosuppressive Agents; Tacrolimus; Treatment Outcome

Approximately one-third of children with ulcerative colitis will experience at least 1 attack of acute severe colitis (ASC) before 15 years of age. Severe disease can be defined in children when Pediatric Ulcerative Colitis Activity Index is >65 and/or ≥6 bloody stools per day, and/or 1 of the following: tachycardia, fever, anemia, and elevated erythrocyte sedimentation rate with or without systemic toxicity. Our aim was to provide practical suggestions on the management of ASC in children. The goal of medical therapy is to avoid colectomy while preventing complications of disease, side effects of medications, and mortality.. A systematic search was carried out through Medline via PubMed to identify all articles published in English to date, based on the following keywords "ulcerative colitis," "pediatric ulcerative colitis," "biological therapy," and "acute severe colitis." Multidisciplinary clinical evaluation is recommended to identify early nonresponders to conventional treatment with intravenous corticosteroids, and to start, if indicated, second-line therapy or "rescue therapy," such as calcineurin inhibitors (cyclosporine, tacrolimus) and anti-tumor necrosis factor molecules (infliximab).. Pediatric Ulcerative Colitis Activity Index is a valid predictive tool that can guide clinicians in evaluating response to therapy. Surgery should be considered in the case of complications or rapid clinical deterioration during medical treatment.. Several pitfalls may be present in the management of ASC, and a correct clinical and therapeutic approach is recommended to reduce surgical risk.

Topics: Adrenal Cortex Hormones; Biological Products; Calcineurin Inhibitors; Child; Colitis, Ulcerative; Cyclosporine; Drug Therapy, Combination; Gastrointestinal Agents; Hospitalization; Humans; Immunosuppressive Agents; Infliximab; Severity of Illness Index; Tacrolimus

Topics: Adalimumab; Adolescent; Adrenal Cortex Hormones; Anti-Bacterial Agents; Antibodies, Monoclonal, Humanized; Azathioprine; Colitis, Ulcerative; Crohn Disease; Enteral Nutrition; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infliximab; Mesalamine; Methotrexate; Sulfasalazine; Tacrolimus

To date, corticosteroids have been the primary therapies for acute, severe ulcerative colitis (UC). Patients not responding to intravenous steroids assessed at 3-5 days of the treatment are candidates for second-line rescue therapy. Cyclosporine (CsA), tacrolimus and infliximab (IFX) are also effective therapeutic options in acute, severe UC. In this review we summarized the results of the published studies examining and comparing the efficacy of CsA, tacrolimus and IFX as rescue therapies, and assessing the outcome of switching the drugs in case of therapeutic failure.

Topics: Acute Disease; Adrenal Cortex Hormones; Antibodies, Monoclonal; Colitis, Ulcerative; Cyclosporine; Drug Resistance; Drug Substitution; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infliximab; Salvage Therapy; Severity of Illness Index; Tacrolimus; Treatment Failure

Inflammatory bowel diseases are chronic conditions that frequently affect patients during their childbearing years. Considering the characteristics of disease and the medications used to treat it, several issues arise in the care of these patients when they attempt or achieve conception. We review the most current evidence concerning fertility and pregnancy outcomes in patients with inflammatory bowel diseases. With the exception of those women who undergo pelvic surgery, patients with inflammatory bowel diseases have no decreased fertility. Sulfasalazine decreases fertility in men. When looking at obstetrical outcomes, active disease at conception is associated with an increased risk of preterm delivery and low birth weight. While most medications used to treat inflammatory bowel diseases are low risk, some precautions need to be taken and the risk-to-benefit ratio needs to be considered on an individualized basis. In general, aminosalicylates and thiopurines should be continued, but methotrexate is contraindicated. Anti-tumour necrosis factor agents are considered safe to continue but full monoclonal antibodies do cross the placenta. As a general rule, the it is important to counsel women that conception is optimal when disease is in remission, as adverse obstetrical outcomes are directly associated with disease activity. Clinicians need to educate patients before, during and after conception, emphasizing treatment compliance.

Topics: Adalimumab; Adrenal Cortex Hormones; Aminosalicylic Acids; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azathioprine; Breast Feeding; Certolizumab Pegol; Colitis, Ulcerative; Contraindications; Crohn Disease; Cyclosporine; Female; Fertility; Humans; Immunoglobulin Fab Fragments; Immunosuppressive Agents; Infliximab; Mercaptopurine; Methotrexate; Natalizumab; Polyethylene Glycols; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Tacrolimus

Chronic active ulcerative colitis (UC) is associated with significant morbidity, loss of productivity, increased colorectal cancer risk and cost. Up to 18% of patients suffer chronic active disease, with 30% requiring colectomy at 10 years. The management remains challenging given the relatively few clinical trials in this area.. To summarise the evidence regarding optimal management strategies for patients with chronic active UC of differing disease extents and degrees of treatment refractoriness.. A literature search using the PubMed and Medline databases was performed. No time limit was set on article publication for inclusion.. The principles of management should focus on confirming disease activity, exclusion of alternative diagnoses, adherence and treatment escalation. Infliximab and topical tacrolimus are options in refractory proctitis, although the evidence for these therapies is limited. Both infliximab and adalimumab are effective in corticosteroid-refractory disease, although the proportions of patients achieving corticosteroid-free remission remain modest (24% at 30 weeks and 16.9% at 8 weeks respectively). Alternatives include ciclosporin and tacrolimus, and possibly methotrexate. Colectomy often leads to an improved quality of life; medical strategies unlikely to provide durable corticosteroid-free remission should not be pursued.. No current pharmacological treatment delivers mucosal healing in the majority of patients. Newer treatments such as vedolizumab and tofacitinib may represent valuable future therapies. Available medical options should be discussed with patients at every step of their management, with an honest appraisal of the evidence. Surgery should always be considered in patients with chronic refractory disease of any extent.

Topics: Adalimumab; Adrenal Cortex Hormones; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Clinical Trials as Topic; Colectomy; Colitis, Ulcerative; Cyclosporine; Humans; Immunosuppressive Agents; Infliximab; Remission Induction; Tacrolimus; Treatment Outcome

Topics: Colitis, Ulcerative; Humans; Immunosuppressive Agents; Remission Induction; Tacrolimus

Intravenous cyclosporine A (CsA) is an effective treatment for patients with severe, steroid-refractory ulcerative colitis (UC). Like the response to CsA, clinical trials have shown that two-thirds of patients with refractory UC respond to tacrolimus therapy. However, it is unclear how/when this agent should be used for patients with active UC.. We reviewed the results of previous studies regarding calcineurin inhibitors in UC patients. We examined the best way to use tacrolimus to obtain maximum efficacy by comparing the results from clinical trials with those from a recent survey in Japan.. Calcineurin inhibitors are useful to induce remission in patients with refractory UC; however, the long-term prognosis has not been shown to be improved by CsA. Early intervention with CsA/tacrolimus may improve the long-term prognosis of UC patients just as infliximab does for Crohn's disease patients. Recent studies have indicated that a fasting state and administration of a higher dosage of tacrolimus at the beginning of therapy are critical in ensuring that the target trough concentration of the agent is reached.. The use of higher initial doses of tacrolimus ensured that patients achieved their target levels. Further studies will be needed to elucidate the efficacy of top-down therapy with tacrolimus in patients with UC. Physicians must know how to use calcineurin inhibitors to obtain maximum efficacy.

Topics: Anti-Inflammatory Agents; Antibodies, Monoclonal; Calcineurin Inhibitors; Colitis, Ulcerative; Crohn Disease; Cyclosporine; Humans; Immunosuppressive Agents; Infliximab; Tacrolimus

Inflammatory bowel disease (IBD) is a non-curable disease. Although we seem to have a definitive surgical solution for ulcerative colitis, patients are at risk of suffering from acute and chronic pouchitis as well as peri- and postoperative complications. In Crohn's disease medical treatment is able to prolong surgery-free survival, but no definitive healing strategy is as yet at hand. Moreover, effective medication exposes patients to potentially life-threatening complications. The severely compromised patient in particular needs careful surveillance and requires a balanced treatment strategy endorsed by gastroenterologists and surgeons. Treatment is still aimed at suppressing immune mechanisms and is far from being causal. Nevertheless, this approach has resulted in a reduction in surgical procedures and hospitalizations. The following overview covers special issues related to strategies for severe and fulminant flares of inflammatory bowel disease.

Topics: Algorithms; Anti-Inflammatory Agents; Antibodies, Monoclonal; Colitis, Ulcerative; Critical Care; Crohn Disease; Cyclosporine; Humans; Immunosuppressive Agents; Infliximab; Interdisciplinary Communication; Patient Care Team; Tacrolimus; Tumor Necrosis Factor-alpha

Ulcerative colitis (UC) is a chronic disease featuring recurrent inflammation of the colonic mucosa. The goal of medical treatment is to rapidly induce a steroid-free remission while at the same time preventing complications of the disease itself and its treatment. The choice of treatment depends on severity, localization and the course of the disease. For proctitis, topical therapy with 5-aminosalicylic acid (5-ASA) compounds is used. More extensive or severe disease should be treated with oral and local 5-ASA compounds and corticosteroids to induce remission. Patients who do not respond to this treatment require hospitalization. Intravenous steroids or, when refractory, calcineurin inhibitors (cyclosporine, tacrolimus), tumor necrosis factor-α antibodies (infliximab) or immunomodulators (azathioprine, 6-mercaptopurine) are then called for. Indications for emergency surgery include refractory toxic megacolon, perforation, and continuous severe colorectal bleeding. Close collaboration between gastroenterologist and surgeon is mandatory in order not to delay surgical therapy when needed. This article is intended to give a general, practice-orientated overview of the key issues in ulcerative colitis treatment. Recommendations are based on published consensus guidelines derived from national and international guidelines on the treatment of ulcerative colitis.

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Azathioprine; Colitis, Ulcerative; Cyclosporine; Endoscopy; Gastroenterology; Humans; Infliximab; Mercaptopurine; Mesalamine; Remission Induction; Steroids; Tacrolimus; Treatment Outcome; Tumor Necrosis Factor-alpha

Inflammatory Bowel Disease (IBD) is thought to be the result of an overly aggressive immune response to ubiquitous antigens. Immuno -modulation and -suppression is therefore currently the treatment of choice. It was long anticipated that the course of pre-existing IBD should improve after orthotopic liver transplantation (OLT) due to increased immunosuppression. We report the case of a patient who developed acute fulminant colitis despite triple immunosuppression and mesalazine and review the relevant literature.

Topics: Cholangitis, Sclerosing; Colectomy; Colitis, Ulcerative; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Mesalamine; Middle Aged; Mycophenolic Acid; Prednisone; Recurrence; Tacrolimus

Topics: Antibodies, Monoclonal; Colitis, Ulcerative; Cyclosporine; Drug Resistance; Humans; Infliximab; Steroids; Tacrolimus

Topics: Adalimumab; Antibodies, Monoclonal, Humanized; Colitis, Ulcerative; Colorectal Neoplasms; Humans; Probiotics; Remission Induction; Salicylates; Tacrolimus; Thiazolidines

Approximately 15% of patients with ulcerative colitis will experience a severe episode requiring hospitalization. Although intravenous corticosteroids are the current first-line therapy for these patients, about 30% of patients do not respond to corticosteroids and require either an alternative anti-inflammatory agent or surgery. Ciclosporin has proven its efficacy in a number of controlled trials in this setting and is characterized by high early response rates. Patients who respond to ciclosporin and avoid colectomy are more likely to retain their colon if they bridge to immunomodulators in the medium term. Infliximab has also demonstrated efficacy in reducing early colectomy rates and longer term data are awaited. Other agents, such as tacrolimus and basiliximab, and leukocytapheresis, have been studied in small trials and may be alternative options. Key issues remain as to what should be first- and second-line therapies, when surgery should be undertaken, and the risk of switching between immunosuppressants in these critical patients.

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Basiliximab; Colectomy; Colitis, Ulcerative; Cyclosporine; Drug Resistance; Humans; Immunosuppressive Agents; Infliximab; Leukapheresis; Recombinant Fusion Proteins; Tacrolimus

There are a limited number of treatment options for patients with refractory ulcerative colitis. Animal models of inflammatory bowel disease and uncontrolled studies in humans suggest that tacrolimus may be effective treatment for ulcerative colitis.. This review aims to evaluate the efficacy of tacrolimus for induction of remission in patients with corticosteroid refractory ulcerative colitis.. MEDLINE (PubMed), The Cochrane Central Register of Controlled Trials, the IBD/FBD review group specialized register and the ISI-Research Institute were searched (January 1997 to November 2007) to identify relevant studies all randomized trials.. Each author independently reviewed potentially relevant studies to determine eligibility based on the pre-specified criteria.. A data extraction form was developed and used to extract data from included studies. Two authors independently extracted data. Data were analyzed using Review Manager (RevMan 4.2.9). The primary outcomes were induction of remission and clinical improvement, as defined by the studies and expressed as a percentage of the patients randomized (intention to treat analysis).. One randomized controlled trial comparing high target serum concentration and low target serum concentration tacrolimus versus placebo was identified and included in the review. Clinical remission was observed in 19% (4/21) of patients in the high target serum concentration group, in 9% (2/22) in the low target serum concentration group and in 5% (1/20) in the placebo group (OR 2.27; 95% CI 0.35 to 14.75). A statistically significant benefit for clinical improvement at two weeks was observed. Clinical improvement was observed in 62% (13/21) of patients in the high target serum concentration group, in 36% (8/22) in the low target serum concentration group and in 10% (2/20) in the placebo group (OR 8.66; 95% CI 1.79 to 42.00; RD 0.39; 95% CI 0.20 to 0.59; NNT = 3). Patients in the high serum target concentration group were significantly more likely than placebo patients to experience adverse events related to treatment (P = 0.043). Finger tremor (n = 6) was the most common adverse event in the tacrolimus group. Other adverse events included: gastroenteritis, sepsis, sleepiness, hot flush, headache, queasiness and stomach discomfort.. Tacrolimus may be effective for short-term clinical improvement in patients with refractory ulcerative colitis. However, these results should be interpreted with caution due to the small number of patients enrolled in the trial and other study limitations. Insufficient treatment and follow-up intervals prevent any conclusions with regard to long term safety and efficacy. The use of tacrolimus in the clinical setting requires careful consideration of risks versus benefits as well as close monitoring for adverse events. More data from well designed and controlled studies are needed to determine the long-term efficacy and safety of tacrolimus.

Topics: Colitis, Ulcerative; Humans; Immunosuppressive Agents; Randomized Controlled Trials as Topic; Remission Induction; Tacrolimus

Topics: Anti-Allergic Agents; Anti-Inflammatory Agents; Colitis, Ulcerative; Drugs, Chinese Herbal; Humans; Immunosuppressive Agents; Mercaptopurine; Prednisolone; Sulfasalazine; Tacrolimus; Time Factors

Ulcerative colitis (UC) has been known as inflammatory bowel disease. Progress in UC management strategies has led to optimized approaches for achieving the two primary clinical goals of therapy: induction and maintenance of remission. We here review about immunosuppressants in management of UC; Cyclosporine A (CsA) has been used for the induction therapy in steroid resistant refractory UC. Although it has been reported that CsA has high response rate in severe UC, long-term efficacy (maintenance of remission) has not been proven. To improve maintenance therapy, immunosuppressant has been re-considered in management of UC. In recent years, it has been reported that efficacy of 6-mercaptopurine/azathioprine in maintenance of remission of UC is superior to 5-aminosalicylate (5-ASA). Pharmacological studies have indicated thiopurine methyltransferase (TPMT) activity is essential for maintenance of blood concentration of 6-thioguanine nucleotide (6-TG).

Topics: Azathioprine; Colitis, Ulcerative; Cyclosporine; Drug Therapy, Combination; Guanine Nucleotides; Humans; Immunosuppressive Agents; Mercaptopurine; Methyltransferases; Mycophenolic Acid; Tacrolimus; Thionucleotides

Topics: Adalimumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azathioprine; Colitis, Ulcerative; Crohn Disease; Cyclosporine; Cytapheresis; Female; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infliximab; Male; Tacrolimus

Topics: Adrenal Cortex Hormones; Adult; Aminosalicylic Acids; Anti-Bacterial Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Azathioprine; Budesonide; Colitis, Ulcerative; Colonoscopy; Controlled Clinical Trials as Topic; Crohn Disease; Diagnosis, Differential; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Magnetic Resonance Imaging; Mercaptopurine; Methotrexate; Metronidazole; Pouchitis; Remission Induction; Tacrolimus; Time Factors; Tomography, X-Ray Computed; Ultrasonography

This review concentrates on the clinical evaluation, imaging, therapy, and prognostic factors in acute severe colitis of idiopathic as well as infectious origin. Older concepts as well as more recent are critically scrutinized.

Topics: Acute Disease; Adrenal Cortex Hormones; Anti-Bacterial Agents; Colitis, Ulcerative; Cyclosporine; Diagnosis, Differential; Humans; Ileostomy; Immunosuppressive Agents; Life Style; Prognosis; Severity of Illness Index; Tacrolimus

5-aminosalicylic compounds and corticosteroids are standard drugs, which have been used for treatment of ulcerative colitis (UC). Although unusually we experience severe active UC, such as refractory cases to these drugs. Immunosuppressive agents are introduced and effective for these cases. In the treatment for UC, 6-mercaptopurine and azathioprine are effective, but it takes a few months until their optimum effect. So these drugs are not suitable for severe active UC which needs rapid treatment. On the other hand, newer immunosuppressive agents such as cyclosporin, tacrolimus have a rapid onset of action. These drugs are very effective, but have side effects. We will review immunosuppressive treatment strategy of UC.

Topics: Azathioprine; Colitis, Ulcerative; Cyclosporine; Cytokines; Depression, Chemical; Humans; Immunosuppressive Agents; Mercaptopurine; Tacrolimus

The course of inflammatory bowel disease after liver transplantation has been reported as variable with usually no change or improvement, but there may be an increased risk of early colorectal neoplasms. In many centres steroids are often withdrawn early after transplantation and this may affect inflammatory bowel disease activity.. To evaluate the course of inflammatory bowel disease in primary sclerosing cholangitis transplant patients who were treated without long term steroids.. Between 1989 and 1996, there were 30 patients transplanted for primary sclerosing cholangitis who survived more than 12 months. Ulcerative colitis was diagnosed in 18 (60%) patients before transplantation; two had previous colectomy. All patients underwent colonoscopy before and after transplantation and were followed for 38 (12-92) months. All received cyclosporin or tacrolimus with or without azathioprine as maintenance immunosuppression.. Ulcerative colitis course after transplantation compared with that up to five years before transplantation was the same in eight (50%) and worse in eight (50%) patients. It remained quiescent in eight and worsened in four of the 12 patients with pretransplant quiescent course, whereas it worsened in all four patients with pretransplant active course (p=0.08). New onset ulcerative colitis developed in three (25%) of the 12 patients without inflammatory bowel disease before transplantation. No colorectal cancer has been diagnosed to date.. Preexisting ulcerative colitis often has an aggressive course, while de novo ulcerative colitis may develop in patients transplanted for primary sclerosing cholangitis and treated without long term steroids.

Topics: Adolescent; Adult; Cholangitis, Sclerosing; Colitis, Ulcerative; Cyclosporine; Female; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Precancerous Conditions; Risk Factors; Tacrolimus

Ulcerative proctitis (UP) refractory to 5-aminosalicylic acid (5-ASA) suppositories is a challenge to treat, often requiring step up to immunomodulator or biological therapy. Topical tacrolimus is effective and safe in patients with refractory UP. However, it is not clear how tacrolimus suppositories fit into in the treatment algorithm of UP.. We performed a randomized controlled, double-blind study at 8 hospitals in the Netherlands and Belgium from 2014 through 2017. Eighty-five patients with refractory UP (65% women) were randomly assigned to groups given once daily tacrolimus suppositories (2 mg; n = 43) or beclomethasone (3 mg; n = 42) for 4 weeks. The primary outcome was clinical response (decrease in Mayo score of 3 or more). Secondary outcomes included clinical remission, endoscopic response and remission, adverse events and quality of life. Outcomes were compared using Fisher's exact test and Mann-Whitney U test.. Proportions of patients with clinical responses were 63% in the tacrolimus group and 59% in the beclomethasone group (P = .812); proportions of patients in clinical remission were 46% and 38%, respectively (P = .638). Proportions of patients with an endoscopic response were 68% and 60% in the tacrolimus group and in the beclomethasone group (P = .636); proportions in endoscopic remission rates were 30% and 13%, respectively (P = .092) Median increases in the inflammatory bowel disease questionnaire score were 18.0 in the tacrolimus group and 20.5 in the beclomethasone group (P = .395). Adverse event rates did not differ significantly between groups.. In a 4-week randomized controlled trial, tacrolimus and beclomethasone suppositories induce comparable clinical and endoscopic responses in patients with UP refractory to 5-ASA. There were no significant differences in adverse events rates. Tacrolimus and beclomethasone suppositories are therefore each safe and effective treatment options for 5-ASA refractory disease. EUDRACT 2013-001259-11; Netherlands Trial Register NL4205/NTR4416.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Beclomethasone; Colitis, Ulcerative; Female; Humans; Male; Mesalamine; Proctitis; Quality of Life; Suppositories; Tacrolimus

Although tacrolimus is useful as an induction therapy in patients with ulcerative colitis (UC), information regarding the long-term outcome after tacrolimus therapy is insufficient. The aim of this study was to evaluate the clinical significance of the pretreatment neutrophil-to-lymphocyte ratio (NLR) as a prognostic factor in patients with UC receiving tacrolimus, to aid treatment selection.. Patients with moderate-to-severe active UC who received oral tacrolimus induction therapy and subsequent immunomodulatory maintenance therapy at our hospital between 2009 and 2017 and who showed clinical response at week 12, were retrospectively enrolled. Cox regression analysis was conducted to study the prognostic role of the pretreatment NLR. The combined impact of the NLR and other known prognostic factors was investigated with multivariate regression.. Among 45 patients included in this study, 21 patients experienced relapse during a median follow-up period of 16.6 months. Multivariate Cox regression analysis identified the pretreatment NLR (hazard ratio [HR]: 0.82, 95% confidence interval [CI]: 0.72-0.94, P < 0.01) and the use of immunomodulators at the start of tacrolimus treatment (HR: 0.18, 95% CI: 0.05-0.66, P = 0.01) as independent predictors of clinical relapse.. The pretreatment NLR is an independent prognostic factor in patients with UC treated with tacrolimus.

Topics: Adult; Colitis, Ulcerative; Female; Follow-Up Studies; Humans; Leukocyte Count; Lymphocytes; Male; Middle Aged; Neutrophils; Predictive Value of Tests; Recurrence; Tacrolimus

Resistant ulcerative proctitis can be extremely difficult to manage. Topically administered tacrolimus, however, may be effective in difficult-to-treat proctitis. This was a randomized, double-blind, placebo-controlled induction trial of rectal tacrolimus in patients with active ulcerative colitis.. Eleven patients received rectal tacrolimus (0.5 mg/mL), and 10 placebo, for 8 weeks. The primary endpoint was clinical response by using the Mayo Clinic score.. A planned interim analysis after 20 patients had completed the study demonstrated highly significant differences between the groups and the study was closed because of ethical considerations with patients already recruited allowed to complete the study. The primary endpoint was met in 8 of 11 patients receiving rectal tacrolimus and 1 of 10 patients receiving placebo (73% vs 10%; P = .004). Of the secondary endpoints, 5 patients with rectal tacrolimus achieved clinical remission compared with none receiving placebo (45% vs 0%; P = .015). Mucosal healing at Week 8 was achieved in 8 patients receiving rectal tacrolimus compared with 1 (73% vs 10%) receiving placebo (P = .004). The Inflammatory Bowel Disease Questionnaire increased ≥16 points over baseline in 5 of the tacrolimus and 2 (45% vs 20%) of the placebo patients (P = .36). Finally, the average partial Mayo score was numerically lower in the tacrolimus-treated group compared with placebo at Week 2 (4.3 ± 0.74 vs 5.8 ± 0.64; P = .15) and Week 4 (3.7 ± 0.96 vs 5.8 ± 0.6; P = .08) but was significantly lower at Week 8 (3.3 ± 1.2 vs 6.7 ± 0.62; P = .01). There were no safety issues identified with rectal tacrolimus use.. Rectal tacrolimus was more effective than placebo for induction of a clinical response, clinical remission, and mucosal healing in resistant ulcerative proctitis (Clinicaltrials.gov registration: NCT01418131).

Topics: Administration, Rectal; Adolescent; Adult; Colitis, Ulcerative; Double-Blind Method; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Placebos; Proctitis; Tacrolimus; Young Adult

Treatment of patients with steroid-refractory ulcerative colitis is still a challenge for physicians. A recent study has evaluated the effectiveness and safety of sequential rescue therapies in this subgroup of patients.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Colectomy; Colitis, Ulcerative; Cyclosporine; Drug Resistance; Humans; Immunosuppressive Agents; Infliximab; Steroids; Tacrolimus

Patients with inflammatory bowel disease who are refractory to standard therapies frequently require surgery. The long-term efficacy of tacrolimus in patients who fail standard immunosuppressive and antitumor necrosis factor α therapy is unknown.. Thirty-five patients (11 Crohn's disease and 24 ulcerative colitis) with medication-resistant disease were treated with oral tacrolimus and reviewed retrospectively. Patients were commenced on tacrolimus 0.1 mg/kg/day, with a trough level targeted between 8 and 12 ng/mL. Clinical response or remission at 30 days, 90 days, and 1 year was assessed. The overall risk of requiring surgery and predictive factors were also assessed.. All patients had failed a thiopurine, 5 (14%) had also failed methotrexate, while 90% had a primary or secondary nonresponse, or an incomplete response, to an antitumor necrosis factor α agent. The proportions that achieved a clinical response at 30 days, 90 days, and 1 year was 65.7%, 60%, and 31.4%, respectively, whereas the corresponding proportions in remission were 40%, 37.1%, and 22.9%. The cumulative risk of requiring surgery was 40.4% at 1 year and 59.3% at 2 years with a median time to surgery of 22 months (range, 0.5-84 months). Patients who were steroid refractory, or dependent, before starting tacrolimus were more likely to have surgery (P = 0.006), whereas patients who were able to achieve or maintain a clinical response with tacrolimus by 90 days were less likely (P = 0.004).. Tacrolimus is able to induce a clinical response in a third and remission in a fifth of medically refractory patients with inflammatory bowel disease at 1 year. A 90-day therapeutic trial is worthwhile in difficult to treat patients.

Topics: Administration, Oral; Adolescent; Adult; Biological Products; Colitis, Ulcerative; Crohn Disease; Drug Resistance; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Prognosis; Remission Induction; Retrospective Studies; Salvage Therapy; Survival Rate; Tacrolimus; Young Adult

Pouchitis is the most common complication after restorative proctocolectomy for ulcerative colitis, and it leads to pouch failure. The administration of oral antibiotics is the main treatment for pouchitis; however, in some cases, antibiotic-refractory pouchitis may develop, which requires further medical therapy.. We investigated the applicability of topical tacrolimus for refractory pouchitis.. We performed a prospective pilot study. The study protocols were registered with the University Hospital Medical Information Network Clinical Trials Registry, 000006658.. This study was conducted in the Surgical Department of Hyogo College of Medicine.. Patients with antibiotic-refractory pouchitis were treated for 8 weeks with a tacrolimus enema.. The efficacy was assessed by comparing Pouchitis Disease Activity Index scores. Safety was assessed by measuring whole blood tacrolimus trough levels.. Ten patients with refractory pouchitis were enrolled. No severe adverse events occurred. The mean scores decreased from 15.9 ± 0.8 to 7.8 ± 0.8 during 8 weeks of treatment (p < 0.01). Specifically, the clinical symptom, endoscopic finding, and histological finding subscores decreased to 0.8 ± 0.6, 3.9 ± 0.2, and 2.9 ± 0.4. Nine patients recovered from their clinical symptoms, and 3 patients recovered from pouchitis.. This small study was neither blinded nor randomized.. This study demonstrates that the use of topical tacrolimus for the treatment of refractory pouchitis is safe and effective in the short term for clinical symptoms. Although complete endoscopic healing was not achieved, this treatment may have early rescue efficacy in the treatment of antibiotic-refractory pouchitis.

Topics: Administration, Topical; Adult; Anti-Bacterial Agents; C-Reactive Protein; Colitis, Ulcerative; Enema; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Pilot Projects; Pouchitis; Proctocolectomy, Restorative; Severity of Illness Index; Tacrolimus; Treatment Failure

We report a multicenter study of oral tacrolimus (FK506) therapy in steroid-refractory ulcerative colitis (UC).. In a placebo-controlled, double-blind study, 62 patients with steroid-refractory, moderate-to-severe UC were randomized into either a tacrolimus group or a placebo for 2 weeks. Patients were evaluated using the Disease Activity Index (DAI). As an entry criterion, patients had to have a total DAI score of 6 or more as well as a mucosal appearance subscore of 2 or 3. Clinical response was defined as improvement in all DAI subscores. Mucosal healing was defined as mucosal appearance subscore of 0 or 1. Clinical remission was defined as a total DAI score ≤ 2 with an individual subscore of 0 or 1.. The mean total DAI score at study entry was 9.8 ± 1.61 in the tacrolimus group and 9.1 ± 1.05 in the placebo group. At week 2 the clinical response rate was 50.0% (16/32) in the tacrolimus group and 13.3% (4/30) in the placebo group (P = 0.003). The rate of mucosal healing observed was 43.8% (14/32) in the tacrolimus group and 13.3% (4/30) in the placebo group (P = 0.012) and the rate of clinical remission observed was 9.4% (3/32) in the tacrolimus group and 0.0% (0/30) in the placebo group (P = 0.238). The therapies in this study were well tolerated, with only minor side effects.. Oral tacrolimus therapy in patients with steroid-refractory UC shortened the acute phase and induced rapid mucosal healing. These results suggest that tacrolimus therapy is useful as an alternative therapy for steroid-refractory UC.

Topics: Administration, Oral; Colitis, Ulcerative; Disease Management; Double-Blind Method; Drug Resistance; Follow-Up Studies; Hospitalization; Humans; Immunosuppressive Agents; Patient Compliance; Remission Induction; Steroids; Tacrolimus; Treatment Outcome

Although the efficacy of tacrolimus for inducing remission of refractory ulcerative colitis (UC) is established, its efficacy for maintaining remission of UC has not been evaluated.. The aim of this study was to evaluate the efficacy of tacrolimus compared with thiopurines for maintaining remission in patients with refractory UC.. Twenty-four UC patients treated with tacrolimus and 34 treated with thiopurines to maintain remission were enrolled as the tacrolimus group and the thiopurine group, respectively. In the tacrolimus group, 82.8% of the patients were treated with tacrolimus for induction of the remission, whereas 70% of the patients in the thiopurine group were induced remission with either corticosteroid or cytapheresis. Proportions of patients who kept steroid-free remission between the tacrolimus and the thiopurine groups were compared. Maintenance of remission using tacrolimus or thiopurines was defined as no need for other therapies other than aminosalicylates without relapse for at least 3 months. Secondarily, to determine whether the response to thiopurines affects the long-term efficacy of tacrolimus maintenance therapy, the overall cumulative relapse-free survival based on the Kaplan-Meier method was estimated in thiopurine-naive or thiopurine-intolerant patients and thiopurine-refractory ones in the tacrolimus group.. Remission was successfully maintained in 17 patients (70.8%) of the tacrolimus group, and 28 patients (82.4%) of the thiopurine group. The overall cumulative relapse-free survival of thiopurine-naive or thiopurine-intolerant patients in the tacrolimus group was similar to that in the thiopurine group, and significantly higher than that of thiopurine-refractory patients in the tacrolimus group.. Maintenance therapy with tacrolimus for patients with UC could be considered an alternative to thiopurine therapy.

Topics: Adolescent; Adult; Aged; Azathioprine; Colitis, Ulcerative; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Remission Induction; Secondary Prevention; Tacrolimus; Treatment Outcome; Young Adult

Little is known about long-term outcome of tacrolimus therapy for ulcerative colitis. Aim To evaluate long-term efficacy and safety of tacrolimus in Japanese patients with refractory ulcerative colitis.. Twenty-seven patients with UC refractory to conventional therapy were administered tacrolimus with trough whole-blood levels of 10-15 ng/mL to induce remission and 5-10 ng/mL to maintain remission. Median treatment duration was 11 months (1-39 months) and median follow-up duration was 17 months (2-65 months). Evaluation of the clinical response was based on a modified Truelove-Witts severity index (MTWSI).. Tacrolimus produced a clinical response in 21 patients (77.8%), and remission was achieved in 19 of these 21 (70.4%) within 30 days. Overall cumulative colectomy-free survival was estimated as 62.3% at 65 months. In 18 of 19 patients treated with corticosteroids at the initiation of tacrolimus therapy, corticosteroids were discontinued or tapered. Adverse events were tremor (25.9%), renal function impairment (18.5%), infectious disease (14.8%), hot flashes (11.1%), hyperkalaemia (7.4%), headache (7.4%), epigastralgia (7.4%) and nausea (3.7%). No mortality occurred.. Long-term administration of tacrolimus appears to be an effective and well-tolerated treatment for Japanese patients with refractory ulcerative colitis.

Topics: Adolescent; Adult; Aged; Colitis, Ulcerative; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Long-Term Care; Male; Middle Aged; Remission Induction; Tacrolimus; Treatment Outcome

Immunosuppressive therapy with intravenous ciclosporin is an alternative treatment option to total colectomy for patients with ulcerative colitis (UC), while the benefits of oral administration of tacrolimus are not well defined and are based on reports of several uncontrolled studies.. Patients with refractory active UC were randomly assigned to a high trough concentration (10-15 ng/ml) group (HT group) (n = 21), low trough concentration (5-10 ng/ml) group (LT group) (n = 22), or placebo group (n = 20). Patients received an initial oral dose of 0.025 [DOSAGE ERROR CORRECTED] mg/kg tacrolimus or placebo twice daily. Efficacy was evaluated in 60 patients based on a disease activity index (DAI) score. Fifty eight patients had additional treatment with tacrolimus and were evaluated for efficacy in a 10 week open label extension.. An improvement in DAI score (>or=4 points, all categories improved) was observed for 68.4% of cases in the HT group compared with 10.0% in the placebo group (p<0.001). In the HT group, 20.0% of patients had clinical remission and 78.9% had mucosal healing. In the open label extension, 55.2% of all patients had an improved DAI score at week 10. Mean dose of prednisolone was reduced from 19.7 mg/day at study entry to 7.8 mg/day at week 10. The incidence of side effects in the HT group was significantly higher than that of the placebo group (p = 0.043). The most common event was mild finger tremor.. Our findings demonstrate dose dependent efficacy and safety of oral tacrolimus for remission-induction therapy of refractory UC. The optimal target range appears to be 10-15 ng/ml in terms of efficacy with two week therapy.

Topics: Administration, Oral; Adult; Colitis, Ulcerative; Dose-Response Relationship, Drug; Double-Blind Method; Drug Monitoring; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Severity of Illness Index; Tacrolimus; Treatment Outcome

Intravenous cyclosporine has proven to be an alternative to emergency colectomy in steroid-refractory ulcerative colitis, whereas the experience with FK506 is limited. In this report we compare intravenous to oral FK506 treatment in 38 patients with refractory ulcerative (n = 33) or indeterminate (n = 5) colitis. FK506 was started intravenously in the first group (n = 18) at a dose of 0.01 to 0.02 mg/kg up to 14 days, followed by 0.1 to 0.2 mg/kg orally, or was started orally at this dose in a second group (n = 20). Additional azathioprine/6-mercaptopurine was given and steroids were tapered in responding patients, followed by a dose reduction of FK506. Clinical disease activity and laboratory parameters were assessed to evaluate efficacy and safety. Primary objectives were the induction of remission (Truelove index of mild) and colectomy-free survival. Treatment lasted for a mean of 7.6 months, and the mean observation period was 16.2 months. Eighteen of 38 patients improved within 14 days, and a complete remission was achieved in 13 patients after 1 month. A colectomy within 1 month was performed in 3 of 38 patients. The overall colectomy rate was 34%. One-half of the patients with a minimum follow-up of 2 years required a colectomy. Intravenous and per oral administration were equally safe and effective. The most frequent adverse events included tremor, hyperglycemia, hypertension, and infection, but none were severe. Renal impairment was rare and subsided upon drug withdrawal. In conclusion. FK506 is effective in the treatment of refractory colitis with per oral dosing being equivalent to intravenous administration.

Topics: Administration, Oral; Adolescent; Adult; Colectomy; Colitis, Ulcerative; Dose-Response Relationship, Drug; Female; Humans; Immunosuppressive Agents; Infusions, Intravenous; Male; Middle Aged; Remission Induction; Retrospective Studies; Tacrolimus; Time Factors; Treatment Outcome

To evaluate the efficacy of oral tacrolimus as an induction agent in steroid-refractory severe colitis.. Open-label, multicenter trial of oral tacrolimus in patients with severe colitis. Patients not responding to conventional therapy received tacrolimus, 0.1 mg/kg/dose given twice a day, and the dosage was adjusted to achieve blood levels between 10 and 15 ng/mL. Response was defined as improvement in a number of clinical parameters (including abdominal pain, diarrhea, rectal bleeding, and cessation of transfusions). Patients who responded by 14 days continued to receive tacrolimus, and 6-mercaptopurine or azathioprine was added as a steroid-sparing agent 4 to 6 weeks after the tacrolimus was instituted.. Fourteen patients were enrolled in the study. One patient elected to withdraw after 48 hours. Of the 13 remaining, 9 (69%) responded and were discharged. Tacrolimus was continued for 2 to 3 months in the responders, except for 1 patient who was given tacrolimus for 11 months. After 1 year of follow-up, only 5 (38%) patients were receiving maintenance therapy; the other 4 responders had undergone colectomy.. Although tacrolimus is effective induction therapy for severe ulcerative or Crohn's colitis, fewer than 50% of patients treated will successfully achieve a long-term remission.

Topics: Adolescent; Adult; Azathioprine; Child; Child, Preschool; Colitis, Ulcerative; Crohn Disease; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Infant; Male; Mercaptopurine; Prospective Studies; Remission Induction; Severity of Illness Index; Tacrolimus

Topics: Colitis, Ulcerative; Humans; Immunosuppressive Agents; Remission Induction; Tacrolimus; Treatment Outcome; Ustekinumab

The short-term efficacy of tacrolimus (Tac) for steroid-dependent and steroid-resistant refractory ulcerative colitis (UC) has been demonstrated; however, its long-term outcomes have not been well documented. Thus, this study aimed to clarify the long-term outcomes of patients who achieved Tac-induced remission and identify its predictors.. This study included patients with moderate-to-severe active UC who started receiving Tac at our hospital between July 2004 and December 2016. Short-term treatment response was assessed using the Lichtiger index 3 months after starting Tac, and responding patients were further followed up to assess long-term outcomes. The primary endpoint was the relapse-free survival after Tac-induced remission, and the secondary endpoint was the identification of factors associated with relapse after Tac-induced remission.. The cumulative relapse-free survival rate at 10 years after Tac-induced remission was 33.2%. Multivariate analysis revealed that being thiopurine naïve at Tac induction was associated with the absence of relapse (hazard ratio: 0.45; 95% confidence interval: 0.22-0.92).. Approximately one-third of patients who achieved Tac-induced remission maintained long-term remission. Being thiopurine naïve at Tac induction was a predictor of the absence of relapse.

Topics: Colitis, Ulcerative; Humans; Immunologic Factors; Immunosuppressive Agents; Recurrence; Remission Induction; Steroids; Tacrolimus; Treatment Outcome

One-third of children and young adults admitted for management of acute severe colitis (ASC) fail intravenous corticosteroids. Infliximab (IFX) or tacrolimus (TAC) is often used to prevent urgent colectomy in these patients. However, no prior studies have reviewed the outcome of pediatric patients with ASC who were treated with either IFX or TAC.. We retrospectively identified 170 pediatric patients with ASC admitted to our institution who did not respond to intravenous corticosteroids and were subsequently treated with either IFX or TAC. We compared 6-month colectomy rates, time to colectomy, improvement in disease activity indices, and adverse effects.. The mean age of patients in the IFX (n = 84) and TAC (n = 86) groups were 14 and 13.8 years, respectively. The median study follow-up time was 23 months. The rate of colectomy 6 months from rescue therapy was similar whether patients received IFX or TAC (22.6% vs 26.7%, respectively, P = 0.53). The mean decline in Pediatric Ulcerative Colitis Activity Index scores from admission to discharge in those treated with IFX (31.9) or TAC (29.8) was similar (P = 0.63). Three patients treated with IFX experienced infusion reactions. Six patients treated with TAC experienced changes in renal function or electrolytes, and 4 patients reported neurologic symptoms.. There were no significant differences in the likelihood of colectomy 6 months after initiating IFX or TAC rescue therapy. Efficacy of both agents was comparable. The types of adverse effects differed by therapy. These data support the use of either TAC or IFX in children with ASC refractory to intravenous corticosteroids.

Topics: Child; Colectomy; Colitis, Ulcerative; Gastrointestinal Agents; Humans; Infliximab; Retrospective Studies; Tacrolimus; Treatment Outcome; Young Adult

This multicenter observational cohort study aimed to evaluate the utilization and short-term efficacy of advanced therapy (AT) in hospitalized patients with acute severe ulcerative colitis (ASUC).. In total, 221 patients with ASUC were enrolled between August 2020 and July 2021. The primary endpoint was clinical remission (CR, defined as a patient-reported outcome score < 2 with no blood in the stool) rate on Day 7 and 14 in hospitalized patients who received corticosteroids (CS) and AT.. Among patients with ASUC, 120 and 101 patients received CS or any AT as first-line treatment, respectively. The CR rates on Day 7 and 14 were 22.5% and 35.0%, respectively, in hospitalized patients who received CS as first-line treatment. Most patients who used ATs had CS-dependent or frequent recurrences. Eight different ATs (apheresis, tacrolimus, infliximab, golimumab, tofacitinib, vedolizumab, ustekinumab, and cyclosporine) were used as first-line treatment in patients with ASUC, and the CR rates on Day 7 and 14 were 16.8% and 29.7%, respectively. Twenty-five patients received the second ATs after hospitalizations, and the CR rates on Day 7 and 14 were 0% and 12%, respectively. The CR rates on Day 14 were significantly higher in patients who changed to AT than in those whose dose of CS increased (34.0% vs 10.7%, p = 0.020) among patients who had already used CS before hospitalization.. Most first-use ATs were effective for patients with ASUC, while second-use ATs might have had limited benefits in inducing CR. These findings may contribute to considerations for the management of hospitalized patients.

Topics: Adrenal Cortex Hormones; Colitis, Ulcerative; Humans; Infliximab; Tacrolimus; Treatment Outcome

Therapy regimens used in patients with inflammatory Bowel Disease (IBD) have been associated with enhanced risk of viral infections or viral reactivation. Moreover, it is uncertain whether IBD patients have increased risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or infected patients may have an increased risk for severe coronavirus disease 2019 (Covid-19). Managing severe acute flare in ulcerative colitis during the Covid-19 pandemic is a challenge for clinicians and their patients. The results of the published studies mainly report on the role of the prior medication, but not how to treat severe acute flare of IBD patients with severe Covid-19 pneumonia.. We report the case of a 68-year-old patient with a long history of ulcerative colitis. He was initially admitted to an external hospital because of severe acute flare. The initiation of a high-dose oral cortisone therapy did not improve the clinical symptoms. During the inpatient treatment, he was tested positive for SARS-CoV-2. At admission to our hospital the patient showed severe flare of his ulcerative colitis and increased Covid-19 symptoms. A cortisone-refractory course was noticed. After detailed multidisciplinary risk-benefit assessment, we initiated an intravenous tacrolimus therapy and dose of prednisolone was tapered gradually. After clinical response, the therapy was adjusted to infliximab. Additionally, the Covid-19 pneumonia was kept under control despite immunosuppression and the patient could be discharged in clinical remission.. This case suggest the use of tacrolimus as a bridging therapeutic option for severe acute, cortisone refractory ulcerative colitis in Covid-19 patients. Nevertheless, the best treatment strategy for IBD patients presenting a flare during the outbreak has yet to be defined. Further data for IBD patients under calcineurin inhibitor therapy are urgently needed.

Topics: Aged; Colitis, Ulcerative; Cortisone; COVID-19; Humans; Male; Pandemics; Remission Induction; SARS-CoV-2; Tacrolimus

Topics: Colitis, Ulcerative; Humans; Immunosuppressive Agents; Remission Induction; Tacrolimus; Treatment Outcome; Ustekinumab

The calcineurin inhibitor tacrolimus is reportedly effective for moderate/severe ulcerative colitis (UC); however, it is also reportedly associated with nephrotoxicity. We investigated the risk factors for tacrolimus-induced nephrotoxicity and whether renal impairment adversely affected the outcomes of tacrolimus treatment in patients with UC.. We conducted a retrospective study of 93 patients with UC who were administered tacrolimus leading to high trough levels (10-15 ng/mL) for 2 weeks and low trough levels (5-10 ng/mL) for 3 months.. Acute kidney injury (AKI) occurred in 44 patients (47.3%) during tacrolimus treatment. Of these patients, 34 (36.6%) developed AKI during the high trough phase and 17 (18.3%) developed AKI when the trough value exceeded the original target value of 15 ng/mL. Multivariate logistic regression analysis revealed that the male sex was significantly associated with AKI (p = 0.002, AOR = 4.38, 95% CI [1.69-11.3]). Clinical remission rate after 4, 8, 12, and 24 weeks of tacrolimus treatment in patients with AKI was lower than that in patients without AKI. Six patients (6.5%) had chronic kidney disease (CKD) after tacrolimus treatment completion, and all patients with CKD developed AKI during treatment. The median duration of treatment with no improvement in AKI was significantly longer in patients with CKD than in those without CKD (p = 0.016).. We revealed the risk factors for tacrolimus-induced nephrotoxicity. Renal impairment occurrence adversely affected the tacrolimus treatment outcome; therefore, it is important to carefully administer tacrolimus to prevent renal impairment.

Topics: Acute Kidney Injury; Colitis, Ulcerative; Humans; Immunosuppressive Agents; Male; Renal Insufficiency, Chronic; Retrospective Studies; Risk Factors; Tacrolimus; Treatment Outcome

Tacrolimus therapy for ulcerative colitis is ineffective in certain patients; these patients require biologics or colectomy. We examined the ability of serum albumin levels and leukocyte subtypes to predict the therapeutic efficacy of tacrolimus. Patients with ulcerative colitis treated with tacrolimus were divided into non-failure and failure (required colectomy or switch to biologics or systemic steroids) groups. Serum albumin levels and leukocyte subtypes at induction, week 1, and week 2 after reaching high trough levels were retrospectively examined. Tacrolimus therapy failed in 18/45 patients within 3 months. The week 2/week 1 albumin ratio was significantly different between the failure and non-failure groups (P < 0.001). The receiver operating characteristic curve analysis revealed optimal cut-off value of the week 2/week 1 albumin ratio was 1.06, and area under the curve was 0.815. Analysis of leukocyte subtypes revealed significant between-group difference in the week 1 lymphocyte to monocyte ratio (P < 0.001). Multivariate analysis showed week 2/week 1 albumin ratio ≤ 1.06 and week 1 lymphocyte to monocyte ratio ≤ 3.86. Therefore, a low week 2/week 1 albumin and low week 1 lymphocyte to monocyte ratio predicted failure within 3 months of tacrolimus induction; a combination of these markers could accurately predict failure.

Topics: Biological Products; Colitis, Ulcerative; Humans; Immunosuppressive Agents; Lymphocytes; Monocytes; Retrospective Studies; Serum Albumin; Severity of Illness Index; Tacrolimus; Treatment Outcome

Topics: BNT162 Vaccine; Colitis, Ulcerative; COVID-19; Humans; Immunosuppressive Agents; Male; Middle Aged; Tacrolimus; Vitiligo

Intravenous corticosteroid is the mainstay for managing acute severe ulcerative colitis, but one-third of patients do not respond to intravenous corticosteroid. Tacrolimus, a salvage therapy before colectomy, is usually orally administered, though its bioavailability is low compared intravenous administration. The efficacy of intravenous tacrolimus has not been widely studied.. To determine the efficacy and safety of intravenous tacrolimus for the treatment of acute severe ulcerative colitis.. Eighty-seven hospitalized acute severe ulcerative colitis patients were enrolled for a prospective cohort study between 2009 and 2017. Sixty-five patients received intravenous tacrolimus and 22 received oral tacrolimus. The primary outcome was the achievement of clinical remission within 2 weeks. Relapse and colectomy incidence and adverse events were assessed at 24 weeks.. Response rates of both treatments exceeded 50% but were not significantly different. The remission rate was higher in intravenous tacrolimus compared with oral tacrolimus. At 24 weeks, oral and intravenous tacrolimus showed similar relapse-free survival rates; however, colectomy-free survival rates were higher in intravenous tacrolimus compared with oral tacrolimus.. Patients receiving intravenous tacrolimus achieved superior remission and colectomy-free survival rates compared with patients receiving oral tacrolimus. Safety was similar between the two treatments.

Topics: Administration, Intravenous; Colitis, Ulcerative; Humans; Immunosuppressive Agents; Induction Chemotherapy; Prospective Studies; Remission Induction; Severity of Illness Index; Tacrolimus; Treatment Outcome

Between 20% and 40% of patients with severe ulcerative colitis (UC) are either steroid-refractory UC (SRUC) or steroid-dependent UC (SDUC). Tacrolimus is an oral and relatively inexpensive drug, which has been extensively used in Japan for steroid-refractory and steroid-dependent disease.. Patients diagnosed with SDUC/SRUC were treated with tacrolimus 0.05-0.1 mg/kg in this prospective study. Clinical Mayo score (CMS) and UC Endoscopic Index of Severity (UCEIS) were evaluated prior to starting the drug and subsequently after 8 weeks. 5-Aminosalicylic acid agents (5-ASA) and immunomodulators were continued if the patients were previously on these drugs. Clinical response at 8 weeks was defined as decrease in CMS by at least 3 points. Clinical remission was defined as CMS ≤2 and combined remission as CMS≤2 with UCEIS <3.. Fifty-two patients (29 males) with a mean age of 35.1± 12.8 years with predominantly E3 disease (71%) were prospectively evaluated in this study. SDUC and SRUC were diagnosed in 31 and 21 patients, respectively. Seven failed treatment within 8 weeks, four were subjected to surgery, and 3 were switched to infliximab. Forty-two patients continued tacrolimus for 8 weeks. Mean CMS and UCEIS prior to starting tacrolimus were 6 ± 1.1 and 4.8 ± 1.1, respectively. At 8 weeks, median CMS and UCEIS decreased to 2.6 ± 1.7 and 2.7 ± 1.3, respectively. Clinical response was documented in 29 patients (56%) at week 8 whereas clinical remission was seen in 25 patients (48%). Combined clinical and endoscopic remissions were seen in 18 patients (35%). Except for a single  patient who developed reversible renal dysfunction, no other adverse event was  observed.. Our results show that tacrolimus is effective in inducing a clinical response in 56% of patients with SDUC and SRUC. In view of its low cost and safety profile, it may be considered first-line therapy for SDUC/SRUC.

Topics: Adult; Colitis, Ulcerative; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Prospective Studies; Severity of Illness Index; Steroids; Tacrolimus; Tertiary Care Centers; Treatment Outcome; Young Adult

Vedolizumab is a widely used and safe therapy in inflammatory bowel disease, particularly in ulcerative colitis (UC), making it a promising candidate for enhanced efficacy by combining it with additional immunomodulatory medications. In this study, we studied the impact of vedolizumab monotreatment vs vedolizumab coadministration with other immunomodulatory drugs on intestinal inflammation and intestinal immune cells in vivo.. Colon tissue from human patients with UC with active disease or in remission with or without vedolizumab treatment was stained by immunohistochemistry. We reconstituted NOD-SCID-SGM3 mice with human CD34+ cells and treated them with dextran sodium sulfate to induce acute colitis. Mice were treated with vedolizumab alone, or in combination with tacrolimus, ozanimid, or tofacitinib.. Vedolizumab reduced the number of CD3+ T cells and CD68+ monocytes/macrophages in the colon of patients with UC with active disease. Vedolizumab moderately decreased immune cell numbers in acute dextran sodium sulfate-induced colitis. The combination of vedolizumab with tacrolimus further reduced the number of infiltrating CD3+ T cells and CD68+ monocytes/macrophages and was superior in ameliorating intestinal inflammation when compared to vedolizumab monotreatment. In contrast, cotreatment using vedolizumab with ozanimod or tofacitinib had no additive effect.. Our data show that vedolizumab reduces the number of innate and adaptive immune cells in the mucosa of patients with UC. Further, the combination of vedolizumab with tacrolimus was more efficient to reduce immune cell numbers and to increase therapeutic efficacy than vedolizumab monotreatment. This finding indicates that combination treatment using these two drugs may be beneficial for patients who do not respond to vedolizumab monotherapy.

Topics: Animals; Antibodies, Monoclonal, Humanized; Colitis, Ulcerative; Dextrans; Gastrointestinal Agents; Humans; Immunomodulating Agents; Inflammation; Mice; Mice, Inbred NOD; Mice, SCID; Tacrolimus; Treatment Outcome

Tacrolimus (Tac) is an effective remission inducer of refractory ulcerative colitis (UC). Gene polymorphisms result in interindividual variability in Tac pharmacokinetics. In this study, we aimed to examine the relationships between gene polymorphisms and the metabolism, pharmacokinetics, and therapeutic effects of Tac in patients with UC. Forty-five patients with moderate-to-severe refractory UC treated with Tac were retrospectively enrolled. Genotyping for cytochrome P450 (CYP) 3A4*1G, CYP3A5*3, CYP2C19*2, CYP2C19*3, nuclear receptor subfamily 1 group I member 2 (NR1I2)-25385C>T, ATP-binding cassette subfamily C member 2 (ABCC2)-24C>T, ABCC2 1249G>A, and ABCC2 3972C>T was performed. Concentration/dose (C/D) ratio, clinical therapeutic effects, and adverse events were evaluated. The C/D ratio of Tac in UC patients with the CYP3A4*1G allele was statistically lower than in those with the CYP3A4*1/*1 allele (P = 0.005) and significantly lower in patients with CYP3A5*3/*3 than in those with CYP3A5*1 (P < 0.001). Among patients with the CYP3A4*1G allele, the C/D ratio was significantly lower in patients with CYP3A5*1 than in those with CYP3A5*3/*3 (P = 0.001). Patients with the NR1I2-25385C/C genotype presented significantly more overall adverse events than those with the C/T or T/T genotype (P = 0.03). Although CYP3A4*1G and CYP3A5*3 polymorphisms were related to Tac pharmacokinetics, CYP3A5 presented a stronger effect than CYP3A4. The NR1I2-25385C/C genotype was related to the overall adverse events. The evaluation of these polymorphisms could be useful in the treatment of UC with Tac.

Topics: Adult; Colitis, Ulcerative; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP3A; Drug-Related Side Effects and Adverse Reactions; Female; Genotype; Humans; Inactivation, Metabolic; Male; Middle Aged; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Polymorphism, Single Nucleotide; Tacrolimus

Oral tacrolimus is a therapeutic agent for moderate to severe steroid-dependent or resistant ulcerative colitis (UC), but remission induction is difficult, and it is necessary to treat the patient while considering the next treatment.. To examine serum albumin (Alb) level as a prognostic factor for the therapeutic effect of tacrolimus in clinical practice.. Forty-seven patients with UC treated with tacrolimus at our institution were divided into remission and failure groups (colectomy or switch to biologics), and the biological data at the start of observation and at weeks 1 and 2 were retrospectively examined. Kaplan-Meier and multivariate analyses were performed using Alb as a prognostic factor in UC treatment.. During the three months observed, 17 (36.2%) patients failed treatment with tacrolimus. A comparison between the failure and remission groups showed a significant difference only in Alb in week 2, and in the week 2/week 0 Alb ratio, which showed the rate of change in Alb. The cut-off value of the week 2/week 0 Alb ratio that predicted failure was 1, and its area under the curve was 0.751 (95%CI: 0.604-0.898). In the Kaplan-Meier analysis, a week 2/week 0 Alb ratio ≤ 1 had a significantly higher failure rate than that of > 1; Cox proportional hazard regression analysis also showed that a week 2/week 0 Alb ratio ≤ 1 was an independent prognostic factor for failure within 3 mo after the start of tacrolimus treatment.. A week 2/week 0 Alb ratio ≤ 1 predicts failure within 3 mo of tacrolimus administration for UC. High failure risk exists with week 2 Alb values ≤ 1 on admission.

Topics: Colitis, Ulcerative; Humans; Immunosuppressive Agents; Retrospective Studies; Serum Albumin; Severity of Illness Index; Tacrolimus; Treatment Outcome

Tacrolimus is a calcineurin inhibitor commonly used for prophylaxis of rejection in renal and liver transplantation. There are limited but favourable data regarding its possible use in patients with inflammatory bowel disease (IBD).. To evaluate the efficacy and safety of tacrolimus in patients with IBD in clinical practice.. We performed a retrospective, multicentre study in 22 centres in Spain. All adult patients who received oral tacrolimus for luminal or perianal IBD were included. Clinical response was assessed by Harvey-Bradshaw index and partial Mayo score after 3 months. Perianal disease was evaluated by fistula drainage assessment.. One hundred and forty-three patients were included (mean age 38 years; 51% male; median disease duration 110 months). In ulcerative colitis (UC) (n = 58), the partial Mayo score decreased after 3 months from median 6 to 3 (P = 0.0001), whereas in Crohn's disease (CD) (n = 85), the Harvey-Bradshaw index decreased after 3 months from median 9 to 7 (P = 0.011). In CD patients, blood tacrolimus concentrations during induction (>10 ng/mL vs <10 ng/mL; odds ratio 0.23, 95% CI 0.05-0.87) and the concomitant use of thiopurines (odds ratio 0.18, 95% CI 0.04-0.81) were associated with lower clinical disease activity at 3 months. Of 62 patients with perianal disease, complete closure was observed in 8% (n = 5) of patients with perianal fistulas, with 34% (n = 21) showing partial response. Treatment was maintained for a median of 6 months (IQR, 2-16). After a median clinical follow-up of 24 months (IQR, 15-57), the rate of treatment-related adverse events was 34%, correlating with blood drug concentrations (P = 0.021). Finally, 120 patients (84%) discontinued tacrolimus, usually due to absence or loss of response. Three patients (2%) were subsequently diagnosed with cancer. The overall rate of surgery was 39%, with a 33% colectomy rate in UC.. Tacrolimus shows a clinical benefit in both CD and UC after 3 months of treatment, but its long-term effectiveness and frequent adverse events remain relevant issues in clinical practice.

Topics: Adult; Colectomy; Colitis, Ulcerative; Crohn Disease; Female; Humans; Inflammatory Bowel Diseases; Male; Middle Aged; Recurrence; Retrospective Studies; Spain; Tacrolimus; Time Factors; Treatment Outcome

Tacrolimus (TAC) is a powerful remission-inducing drug for refractory ulcerative colitis (UC). However, it is unclear whether mucosal healing (MH) influences relapse after completion of TAC.We investigated whether MH is related to relapse after TAC.. Among 109 patients treated with TAC, 86 patients achieved clinical remission and 55 of them underwent colonoscopy at the end of TAC. These 55 patients were investigated.. Patients with MH at the end of TAC were classified into the MH group (n = 41), while patients without MH were classified into the non-MH group (n = 14). These groups were compared with respect to 1) clinical characteristics before treatment, 2) clinical characteristics on completion of treatment, and 3) the relapse rate and adverse events rates. This is a retrospective study conducted at a single institution.. 1) There was a significant difference in baseline age between the two groups before TAC therapy, but there were no significant differences in other clinical characteristics. The NMH group was younger (MH group: 48.1 (23-79) years, NMH group: 36.3 (18-58) years, P = 0.007). Endoscopic scores showed significant differences between the 2 groups at the end of TAC. There were also significant differences in the steroid-free rate after 24 weeks (MH group: 85.3%, NMH group 50%, P = 0.012). There was no significant difference in the relapse rate between the 2 groups at 100 days after remission, but a significant difference was noted at 300 days (17% vs. 43%), 500 days (17% vs. 75%), and 1000 days (17% vs. 81%) (all P < 0.05).. TAC is effective for refractory ulcerative colitis. However, even if clinical remission is achieved, relapse is frequent when colonoscopy shows that MH has not been achieved. It is important to evaluate the mucosal response by colonoscopy on completion of TAC.

Topics: Colitis, Ulcerative; Colonoscopy; Humans; Intestinal Mucosa; Recurrence; Remission Induction; Retrospective Studies; Tacrolimus; Treatment Outcome

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.

Topics: Adalimumab; Adult; C-Reactive Protein; Colitis, Ulcerative; Female; Humans; Infliximab; Logistic Models; Male; Middle Aged; Proportional Hazards Models; Steroids; Tacrolimus; Treatment Outcome; Tumor Necrosis Factor-alpha

BACKGROUND In recent years, a plethora of therapeutic agents for ulcerative colitis (UC), especially novel biologics (Bio), have become available. Although it is now possible to use biological drugs, there should be no need for frequently changing medications. To avoid first-pass metabolism in the liver, thus reducing systemic bioavailability, budesonide foam has been applied as a topical steroid. We therefore evaluated whether budesonide foam has therapeutic value in UC patients who responded inadequately to Bio or to tacrolimus. MATERIAL AND METHODS We enrolled 10 patients who were experiencing an inadequate response to Bio (n=7) or to tacrolimus (n=3) at Juntendo University. We used Lichtiger's index to assess UC activity and clinical response. RESULTS Of the study patients, 4 were receiving adalimumab, 3 golimumab, and 3 tacrolimus. The average Lichtiger's index before budesonide administration was 7.1 (range 13-3), which improved to 3.4 (range 7-0) after budesonide therapy (p=0.01). Notably, 4 of the 6 cases with a Lichtiger's index >4 before budesonide administration achieved improvement of ≥3 points or remission. CONCLUSIONS Although the number of patients was small, budesonide foam had significant efficacy when added to the treatment of patients having an inadequate response to Bio or to tacrolimus. These results suggest that in cases responding poorly to Bio, adding budesonide foam as combination therapy can achieve a clinical remission.

Topics: Adalimumab; Adult; Antibodies, Monoclonal; Biological Therapy; Budesonide; Colitis, Ulcerative; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Male; Middle Aged; Remission Induction; Retrospective Studies; Severity of Illness Index; Tacrolimus; Treatment Outcome

Although evidence for the short- to medium-term efficacy of adalimumab in ulcerative colitis (UC) patients is emerging, there are a limited number of reports on the long-term efficacy of adalimumab. This study was to understand baseline demographic features, which potentially could be risk factors for relapse or colectomy following induction of remission by adalimumab in UC patients. Additionally, factors affecting long-term outcomes were to be identified.. Twenty-one patients with UC who had been treated with adalimumab were reviewed retrospectively. Comparative analyses were undertaken by factoring steroid withdrawal versus non-withdrawal, long-term remission versus relapse following remission, and requiring surgical intervention for UC versus surgery-free.. Adalimumab treatment was associated with steroid tapering in steroid-dependent cases in the long term. Of the 14 patients in whom clinical remission was achieved, the cumulative nonrelapse survival rate at 350 weeks was 43.8% and the cumulative nonoperative survival rate was 85.7%. Risk factors for surgery included intolerance to salicylates (p = 0.005) and past treatment with tacrolimus (p = 0.023).. Adalimumab treatment was associated with long-term efficacy in patients with mild UC - patients achieved a high cumulative nonoperative survival rate over a long period of time, beyond 6 years.

Topics: Adalimumab; Adolescent; Adult; Aged; C-Reactive Protein; Colectomy; Colitis, Ulcerative; Female; Humans; Infliximab; Kaplan-Meier Estimate; Male; Middle Aged; Practice Patterns, Physicians'; Retrospective Studies; Risk Factors; Serum Albumin; Steroids; Tacrolimus; Time Factors; Treatment Outcome; Young Adult

The patient was diagnosed with ulcerative colitis and received remission induction therapy with prednisolone. While they developed muscle pain in the lower extremities after starting prednisolone, they ultimately achieved clinical remission. After discharge, hematemesis and gastric discomfort developed. Esophagogastroduodenoscopy showed mucosal edema, redness, and oozing bleeding in the gastric body. In addition, the patient had bloody stool and was considered to have a relapse of ulcerative colitis. They therefore received remission induction therapy with tacrolimus. The patient achieved clinical remission again; however, gastric discomfort and muscle pain remained. A drug lymphocyte stimulation test revealed positivity for prednisolone; therefore, the patient was diagnosed with an allergy to prednisolone.

Topics: Administration, Oral; Adult; Anti-Inflammatory Agents; Colitis, Ulcerative; Drug Hypersensitivity; Hematemesis; Humans; Male; Mesalamine; Prednisolone; Remission Induction; Tacrolimus; Treatment Outcome

The target trough concentration of tacrolimus for ulcerative colitis is recommended to be 10-15 ng/mL in the initial two weeks and 5-10 ng/mL in the later phase. However, the effectiveness of rapid attainment of these target trough concentrations of tacrolimus in patients with ulcerative colitis is still unclear. In the present study, we evaluated the clinical efficacy and safety of rapid attainment of target trough concentrations of tacrolimus in patients with ulcerative colitis.. A prospective cohort was conducted at Gifu University Hospital in Gifu, Japan. Hospitalized patients who received tacrolimus for the treatment of ulcerative colitis between April 2009 and March 2017 were enrolled. Since June 2011, the initial loading dose of tacrolimus increased from 0.05 to 0.1-0.2 mg/kg/d, and the maintenance dose to achieve the target trough concentration was determined to be 12.5 ng/mL by proportional calculation with measured blood concentration. The period required to attain target trough concentration and the clinical efficacy before and after dosage modification was compared.. The initial dose after dosage modification was significantly increased compared to that before dosage modification (0.10 [0.04-0.22], median [range] mg/kg/d vs 0.05 [0.03-0.05] mg/kg/d, P < 0.001). The period required to attain a target trough concentration over 10 ng/mL was significantly shortened by dosage modification (6 [4-14] days before dosage modification vs 4.5 [2-8] days after modification, P = 0.048). Further, stool frequency score was significantly improved after dosage modification, without affecting the incidence of adverse events.. Our findings suggest that rapid attainment of the target trough concentration of tacrolimus improves clinical symptoms in patients with ulcerative colitis.

Topics: Adolescent; Adult; Aged; Colitis, Ulcerative; Female; Humans; Immunosuppressive Agents; Japan; Male; Middle Aged; Prospective Studies; Tacrolimus; Treatment Outcome; Young Adult

Topics: Adolescent; Amputation, Surgical; Colitis, Ulcerative; Diagnosis, Differential; Fingers; Humans; Immunosuppressive Agents; Male; Pyoderma Gangrenosum; Staphylococcal Infections; Staphylococcus aureus; Tacrolimus

Acute severe ulcerative colitis unresponsive to systemic steroid treatment is a life-threatening medical condition requiring hospitalization and often colectomy. Despite the increasing choice of medical therapy options for ulcerative colitis, the condition remains a great challenge in the field of inflammatory bowel diseases (IBD). The performance of the calcineurin inhibitor tacrolimus in this clinical setting is insufficiently elucidated.. To evaluate the short and long-term outcomes of tacrolimus therapy in adult inpatients with steroid-refractory acute severe ulcerative colitis.. We conducted a retrospective monocentric study enrolling 22 patients at a tertiary care center for the treatment of IBD. All patients who were admitted to one of the wards of the Department of Gastroenterology and Hepatology of the Heidelberg University Hospital with acute severe ulcerative colitis between 2007 and 2018, and who received oral or intravenous tacrolimus for steroid-refractory disease were included. Baseline characteristics and data on the disease courses were retrieved from entirely computerized patient charts. The primary study endpoint was clinical response to tacrolimus therapy, resulting in discharge from the hospital. Secondary study endpoints were colectomy rate and time to colectomy, achievement of clinical remission under tacrolimus therapy, and the occurrence of side effects.. In the majority of the 22 included patients (68.2%), tacrolimus therapy was initiated intravenously and subsequently converted to oral administration. The treatment duration was 128 ± 28.5 d (mean ± SEM), and the patients were followed up for 705 ± 110 d after treatment initiation. Among all patients, 86.4% were discharged from the hospital under continued oral tacrolimus therapy. In 36.4% of the patients, the administration of tacrolimus resulted in clinical remission at some point during the treatment. Thirty-two percent of the patients underwent colectomy between 5 and 194 d after the initiation of tacrolimus treatment (mean: 97.4 ± 20.8 d). Colectomy-free survival rates at 1, 3, 6 and 12 mo after the initiation of tacrolimus therapy were 90.9%, 86.4%, 77.3% and 68.2%, respectively. The safety profile of tacrolimus was overall favorable. Only two patients discontinued the treatment due to side effects.. The short-term outcome of tacrolimus in steroid-refractory acute severe ulcerative colitis was beneficial, and side effects were rare. In all, tacrolimus therapy appears to be a viable option for short-term treatment of steroid-refractory acute severe ulcerative colitis besides ciclosporin and anti-tumor necrosis factor α treatment.

Topics: Adult; Aged; Colitis, Ulcerative; Drug Resistance; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Male; Middle Aged; Remission Induction; Retrospective Studies; Severity of Illness Index; Tacrolimus; Time Factors; Treatment Outcome; Young Adult

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 > 3 months 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 ≥ 3 months 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 6 months, 1 year, and 2 years 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.

Topics: Adolescent; Adult; Colitis, Ulcerative; Female; Humans; Immunosuppressive Agents; Japan; Male; Middle Aged; Recurrence; Remission Induction; Severity of Illness Index; Tacrolimus; Treatment Outcome; Young Adult

Objective The need for and efficacy of immunomodulators for maintaining remission after tacrolimus therapy have not been sufficiently defined. This study evaluated the efficacy of immunomodulators for maintaining remission in patients with ulcerative colitis after tacrolimus therapy. Methods Patients with active ulcerative colitis who started oral tacrolimus between January 2009 and September 2017 and were responsive were retrospectively evaluated. Long-term outcomes were compared using Cox proportional hazard regression with inverse probability of treatment weighting. Results Among the 63 patients in the study, 45 received immunomodulators. During the follow-up, 30 patients (47.6%) experienced a relapse. The relapse-free survival rate was significantly worse in the group that did not receive immunomodulators than in those that did (p=0.01, log-rank test); the 2-year relapse-free rates were 22.5% and 63.6% in the non-immunomodulator and immunomodulator groups, respectively. A multivariate analysis showed immunomodulator treatment to be an independent protective factor for clinical relapse (adjusted hazard ratio: 0.35, 95% confidence interval: 0.16-0.78, p=0.01). A Cox regression analysis using inverse probability of treatment weighting also showed that immunomodulator maintenance therapy was correlated with a longer relapse-free survival (hazard ratio: 0.31, 95% confidence interval: 0.15-0.64, p<0.01), A similar response was also observed in non-steroid-dependent patients (hazard ratio: 0.36, 95% confidence interval: 0.14-0.99, p=0.047). No serious adverse events occurred due to tacrolimus or immunomodulator, and immunomodulator use did not increase the incidence of adverse events caused by tacrolimus. Conclusion Our data suggest that the use of immunomodulators to maintain remission after tacrolimus therapy is beneficial for patients with ulcerative colitis.

Topics: Adult; Azathioprine; Colitis, Ulcerative; Female; Follow-Up Studies; Humans; Immunologic Factors; Immunosuppressive Agents; Male; Middle Aged; Proportional Hazards Models; Remission Induction; Retrospective Studies; Tacrolimus; Treatment Outcome; Young Adult

Topics: Colitis, Ulcerative; Computed Tomography Angiography; Coronary Angiography; Coronary Vasospasm; Electrocardiography; Humans; Immunosuppressive Agents; Male; Middle Aged; Recurrence; Tacrolimus; Treatment Outcome; Vasodilator Agents

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.. 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.

Topics: Adult; Colitis, Ulcerative; Cytochrome P-450 CYP3A; Dose-Response Relationship, Drug; Drug Resistance; Female; Genotyping Techniques; Humans; Immunosuppressive Agents; Male; Middle Aged; Polymorphism, Genetic; Precision Medicine; Remission Induction; Retrospective Studies; ROC Curve; Tacrolimus; Time Factors; Treatment Outcome

Pyoderma gangrenosum (PG) is a rare, neutrophil-predominant dermatosis that usually presents as a papule or pustule and progresses into a painful ulcer. Clinical and histopathological features are nonspecific, making PG a challenging condition to diagnose. Lesions may occur anywhere on the body; however, the lower extremity is the most common location. Solitary lesions in atypical locations such as the scalp are uncommon, making this clinical variant especially difficult to recognize and diagnose. Although the clinical features and subsequent management of scalp PG might be different from other anatomic sites, the typical presentation and treatment of scalp PG is still unclear. The authors present a recent case of a 34-year-old woman with scalp PG and summarize 16 other cases documented in the literature. This case report and literature review illustrate several similarities and differences between scalp PG and classic PG: (1) scalp PG occurs in a wider age demographic of patients; (2) as with classic PG, inflammatory bowel disease and pregnancy are associated conditions, but head injury and preexisting inflammatory skin conditions of the scalp may be additional predisposing factors for scalp PG; and (3) as with classic PG, scalp PG generally responds well to corticosteroids and immunosuppressive therapy. Scarring occurs in all conditions, though disfigurement and psychosomatic effects may be disproportionately higher in scalp PG.

Topics: Adrenal Cortex Hormones; Adult; Anti-Bacterial Agents; Colitis, Ulcerative; Combined Modality Therapy; Comorbidity; Dermatologic Agents; Female; Humans; Immunosuppressive Agents; Interdisciplinary Communication; Pyoderma Gangrenosum; Recurrence; Scalp; Skin Transplantation; Tacrolimus; Treatment Outcome

Oral drug delivery with nanoparticles has demonstrated great potential for drugs with poor bioavailability. Efficient delivery is possible by overcoming both the mucus and epithelial barrier of the gastrointestinal tract (GIT). Cationic lipid-assisted nanoparticles (CLANs), which are composed of amphiphilic block copolymers and cationic lipids, have been well studied and have been proved beneficial for drug delivery. In this study, CLANs prepared by poly(ethylene glycol)-block-poly(lactic acid) (PEG-b-PLA) and 1,2-dioleoyl-3-trimethylammonium-propanechloride (DOTAP) or N,N-bis(2-hydroxyethyl)-N-methyl-N-(2-cholesteryloxycarbonyl aminoethyl)ammoniumbromide (BHEM-Chol) were used for oral delivery of tacrolimus (FK506) for ulcerative colitis treatment. The average size of these nanoparticles is around 110 nm and the zeta-potential is 35 mV. These nanoparticles maintained their size in buffer solutions of pH 1.2 and 6.8, and slowly release the encapsulated drug. CLANs can be accumulated in the colon and transported through the epithelium in the colitis model by dextran sulfate sodium salt (DSS), leading to attenuation of DSS-induced colitis.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Cholesterol Esters; Colitis, Ulcerative; Disease Models, Animal; Drug Carriers; Drug Compounding; Drug Liberation; Fatty Acids, Monounsaturated; Female; Hydrogen-Ion Concentration; Kinetics; Lactates; Mice; Mice, Inbred C57BL; Nanoparticles; Particle Size; Polyethylene Glycols; Quaternary Ammonium Compounds; Sodium Dodecyl Sulfate; Tacrolimus

Tacrolimus (TAC) is an important drug for inflammatory diseases. However, TAC has several limitations, such as variable trough concentrations among individuals and a high medication frequency. In this study, we created NK61060, a novel micellar TAC formulation, to circumvent these disadvantages.. Immunosuppressive activity of NK61060 was determined in the collagen-induced arthritis rat model, mannan-induced arthritis mouse model and dextran sodium sulfate-induced colitis mouse model. The pharmacokinetics and toxicology of NK61060 were evaluated in those models.. In arthritis and colitis models, NK61060 exhibited superior immunosuppressive activity compared with that of TAC. Pharmacokinetic and toxicological analyses indicated that NK61060 had a wider safety margin and could be administered at a reduced medication frequency.. NK61060 mitigates the trough concentration variability and the medication frequency and it may be a safer and more effective option for use in clinical settings. Further studies are needed to determine its clinical usefulness.

Topics: Animals; Area Under Curve; Arthritis, Experimental; Arthritis, Rheumatoid; Colitis, Ulcerative; Collagen; Dextran Sulfate; Drug Administration Schedule; Drug Carriers; Drug Evaluation, Preclinical; Female; Humans; Immunosuppressive Agents; Mannans; Mice; Mice, Inbred ICR; Micelles; Polyethylene Glycols; Rats; Rats, Sprague-Dawley; Tacrolimus

While some studies have shown that IFX and TAC exhibit similar efficacy against UC in the short-term, it is unclear which drug produces better long-term outcomes. In this study, we compared the long-term efficacy of IFX and TAC in patients with moderate to severe UC.. This retrospective study was conducted from 2009 to 2017. It included patients with no history of IFX or TAC treatment. We analyzed the clinical response and remission rates at 12 and 52 weeks, and colectomy-free and relapse-free survival were evaluated until the end of the study.. At 12 weeks, 94.4% and 77.8% of the patients in the IFX group (n = 18) had demonstrated clinical responses and clinical remission, respectively, whereas 72.7% of the patients in the TAC group (n = 11) exhibited clinical responses and clinical remission. The clinical response, clinical remission, and colectomy-free rates did not differ significantly between the groups. At 52 weeks, clinical responses and clinical remission had been achieved in 76.5% and 70.6% of the patients both in the IFX group, respectively. In the TAC group, clinical responses and clinical remission were achieved in 50.0% of patients. Relapse-free and colectomy-free survival were estimated significantly better in IFX group evaluated by Kaplan-Meier curves.. This study indicates that IFX and TAC produce similar short-term outcomes in UC patients, but IFX produces better long-term outcomes than TAC especially with avoidance of colectomy. Our data suggest that IFX therapy may be prioritized over TAC for the treatment of moderate to severe UC.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Calcineurin Inhibitors; Child; Colitis, Ulcerative; Female; Gastrointestinal Agents; Humans; Infliximab; Male; Middle Aged; Retrospective Studies; Tacrolimus; Young Adult

BACKGROUND Tacrolimus is reportedly effective for the treatment of refractory ulcerative colitis (UC). At our hospital, there has been an increase in the number of patients, including elderly patients, with refractory UC treated with tacrolimus. Here, we review the data from 5 patients with elderly-onset UC treated with tacrolimus as remission induction therapy. CASE REPORT The subjects were 5 patients ≥65 years of age with refractory UC who had received oral tacrolimus as remission induction therapy between 2009 and 2014 (3 men and 2 women; median age at onset, 75 years). At the start of the tacrolimus treatment, the median duration of disease was 3 months, and the type of UC was total colitis in 4 cases, and left-sided colitis in 1 case. The drugs used concomitantly at the start of tacrolimus treatment were mesalazine (5 cases) and an immunomodulator drug (1 case). Standard induction therapy (0.05 mg/kg/day) was used in 2 patients and rapid induction therapy (0.1 mg/kg/day) was used in the remaining 3 patients. One week after the start of treatment, the blood trough concentrations of tacrolimus were over the target level of 15 mg/mL in 4 patients. The clinical activity index values on day 0 and day 14 were 10.6±2.1 and 7.6±3.4, respectively. The ulcerative colitis endoscopic index of severity in the remaining 3 patients, after excluding the 2 patients who required colectomy within 14 days after the start of tacrolimus therapy, was 7.3±1.0 before the start of the tacrolimus treatment, improving to 4.5±0.5 on day 14. Subsequently, 1 of these 3 patients was also judged to need surgery due to symptom exacerbation, while complete remission was maintained in the other 2 patients. CONCLUSIONS In elderly-onset refractory UC patients, tacrolimus appears to be effective as remission induction therapy. However, since tacrolimus concentrations in the blood can rise easily in elderly patients, frequent monitoring of the drug concentrations and dosage adjustments are necessary.

Topics: Administration, Oral; Aged; Colitis, Ulcerative; Female; Humans; Immunosuppressive Agents; Male; Remission Induction; Severity of Illness Index; Tacrolimus

Oral tacrolimus is an effective drug that induces clinical remission in patients with moderate to severe ulcerative colitis refractory to steroids. However, there is little data with regard to its medium to long-term efficacy and safety. The aim of this study was to assess the medium to long-term efficacy and safety of oral tacrolimus in this challenging clinical situation.. This was a retrospective observational review of the clinical charts of 34 patients with moderate to severe ulcerative colitis refractory to steroids treated with oral tacrolimus at our hospital (July 2001-July 2016). Remission was defined as a Lichtiger index score < 3 and response was defined as a score < 10 with a reduction of at least three points compared to the baseline score.. Seven patients (20.58%) required colectomy during the follow-up period (mean 65 months). Nine patients required rescue with infliximab (four patients during the first six months of follow-up and the other five after the first six months). The short to medium clinical efficacy combining both remission and clinical response was 82% at six months. Kaplan-Meier analysis showed that the percentage of patients free from colectomy and additional sequential rescue therapy was 75% at 54 months (median follow-up). The early introduction of thiopurines (< 2 months from start of tacrolimus) showed no significant improvement in prognosis (p = 0.72). Fifty-three per cent of patients experienced adverse effects, none of whom required treatment withdrawal. No severe infections were noted during the follow-up.

Topics: Adult; Colitis, Ulcerative; Drug Resistance; Female; Humans; Immunosuppressive Agents; Male; Prospective Studies; Steroids; Tacrolimus; Treatment Outcome; Young Adult

Tacrolimus is an immunosuppressive agent, used in the remission induction therapy of ulcerative colitis (UC).. We investigated the correlation between CYP3A5 genetic polymorphisms and the adverse events in patients with UC. The pharmacokinetics of tacrolimus after oral administration were also analyzed.. CYP3A5 expressers and non-expressers were 16 and 13, respectively. C/D ratios of CYP3A5 expressers were significantly lower compared to non-expressers. The response rate in CYP3A5 non-expressers was relatively higher in the early phase of treatment compared to expressers, but not statistically significant. The incidence of overall adverse events was significantly higher in CYP3A5 expressers than in non-expressers (P=0.034, chi-squared test). In particular, the incidence of nephrotoxicity was significantly higher in CYP3A5 expressers compared to non-expressers (P=0.027, chi-squared test). All of the nephrotoxicity were reversible and resolved by discontinuation or dose reduction of tacrolimus.. The adverse events especially nephrotoxicity were frequently observed in CYP3A5 expressers. CYP3A5 expressers should be paid attention to the onset of nephrotoxicity.

Topics: Acute Kidney Injury; Colitis, Ulcerative; Cytochrome P-450 CYP3A; Female; Genotype; Humans; Immunosuppressive Agents; Male; Polymorphism, Single Nucleotide; Tacrolimus; Treatment Outcome

Tacrolimus is now considered to be one of the main therapeutic options for refractory ulcerative colitis. Both cytochrome P-450 3A5 (CYP3A5) and ATP-binding cassette subfamily B member 1 (ABCB1) associated with tacrolimus metabolism are known to have several genetic polymorphisms. However, it remains controversial whether these polymorphisms affect the therapeutic efficacy for ulcerative colitis. We aimed to investigate the influence of both CYP3A5 and ABCB1 polymorphisms on the efficacy of tacrolimus in ulcerative colitis treatment under the tight dose-adjusting strategy.. Sixty-one Japanese patients with ulcerative colitis treated with tacrolimus were enrolled retrospectively. Tacrolimus treatment was performed using the tight dose-adjusting strategy. Genotyping for CYP3A5*3, ABCB1 1236C>T, 2677G>A,T, and 3435C>T were performed, and the clinical outcomes at 12 weeks after the initiation of tacrolimus were compared among the genotypes.. There was no association between the CYP3A5 genotypes and therapeutic efficacy. In contrast, a significant association was observed with the ABCB1 1236C > T polymorphism and therapeutic efficacy. The ABCB1 1236CC+CT groups (n = 41) had a significantly higher response rate (73% vs 35%; P = 0.004) and remission rate (61% vs 20%; P = 0.002) than the TT group (n = 20). The multivariate logistic regression analysis also revealed that ABCB1 1236C>T was identified as an independent factor associated with remission.. ABCB1 1236C>T polymorphism significantly affects the therapeutic efficacy of tarcolimus at 12 weeks under the tight dose-adjusting treatment for ulcerative colitis.

Topics: Adult; ATP Binding Cassette Transporter, Subfamily B; Colitis, Ulcerative; Cytochrome P-450 CYP3A; Female; Genetic Association Studies; Humans; Logistic Models; Male; Middle Aged; Polymorphism, Genetic; Retrospective Studies; Tacrolimus; Treatment Outcome; Young Adult

Both infliximab (IFX) and tacrolimus (Tac) are effective for inducing clinical remission in patients with ulcerative colitis (UC). However, no randomized study has addressed the relative efficacies of IFX and Tac for patients with moderate to severe UC. This study aimed to conduct a retrospective study on the relative efficacy of IFX and Tac in patients with moderate to severe UC, using an inverse probability of treatment weighting (IPTW) technique to adjust background factors statistically.. Between July 2009 and March 2016, data obtained from 122 patients with moderate to severe UC who were treated with either IFX (n = 58) or Tac (n = 64) were analyzed retrospectively. We compared the short-term therapeutic efficacy between the IFX group and Tac group using IPTW technique.. The clinical remission rate at 14 weeks after treatment was 37.9% (22/58) in the IFX group and 50% (32/64) in the Tac group, respectively. The efficacy of IFX and Tac for clinical remission rate was not different according to univariate (Odds ratio [OR] 1.64, 95% confidence interval [CI] 0.80-3.37 P = 0.18) and multivariate analyses (OR 2.19, 95% CI 0.85-5.61, P = 0.10). After the background and confounders factors were adjusted by using IPTW based on propensity score, the efficacy of IFX and Tac for clinical remission rate was not differed statistically (OR, 1.483; 95% CI, 0.581-3.785; P = 0.409) Conclusion. IFX and Tac have equivalent short-term efficacies for induction in patients with moderate to severe UC.

Topics: Adult; Aged; Colitis, Ulcerative; Female; Gastrointestinal Agents; Humans; Infliximab; Male; Middle Aged; Remission Induction; Retrospective Studies; Tacrolimus; Treatment Outcome

A 20-year-old woman presented with acute exacerbation of ulcerative colitis. After treatment with infliximab, she developed a fulminant liver failure. Under supportive therapy and steroid medication, recovery of symptoms and transaminases occurred. A few case reports about hepatic side effects of anti-TNF-α antibodies in patients with inflammatory bowel disease have been published. These side effects ranged from asymptomatic increase of transaminases to fulminant liver failure necessitating transplantation. The pathomechanism is not fully understood; in some case reports autoimmune phenomena have been described.

Topics: Colitis, Ulcerative; Diagnosis, Differential; Disease Progression; Drug Therapy, Combination; Female; Humans; Hydrocortisone; Infliximab; Infusions, Intravenous; Liver Failure, Acute; Liver Function Tests; Prednisolone; Sigmoidoscopy; Tacrolimus; Tomography, X-Ray Computed; Young Adult

Tacrolimus is recommended for the treatment of steroid-refractory ulcerative colitis (UC). Concomitantly started purine analogues (PAs) are used for the maintenance of remission, though their therapeutic relevance remains uncertain. Here we studied the role of PAs in the long-term outcome of steroid-refractory UC after tacrolimus treatment.. In five centres, charts of tacrolimus-treated UC patients with a steroid-refractory moderate to severe course were reviewed. Long-term efficacy was determined by colectomy rates and clinical remission in cases of colectomy-free survival for 3 months.. We identified 156 patients (median age 34 years) with a median Lichtiger score of 12 (4-17) and pancolitis (E3) in 65% (101). The Kaplan-Meier curve for colectomy-free survival after month 3 showed a benefit in the PA group (p = 0.02). In patients treated with PA clinical remission was achieved in 82% (65/79) vs 67% (39/58) in those not treated with PA (p = 0.02). Time to colectomy was 2 years (median, 0.7-5.8) in the PA group and 0.8 years (0.3-4.7) in the group not treated with PAs (p = 0.02). Time to relapse was 1.2 years (median, 0.3-6.2) in patients with PA treatment and 0.5 years (0.3-3.9) in those without PA treatment (p = 0.05). Overall, clinical remission was achieved in 67% (104/156) of patients. Colectomy was performed in 29% (45/156) 0.5 years (median, 0.04-5.79) after initiation of tacrolimus. Ten (6%) patients had to stop tacrolimus due to adverse events and two (without PA treatment) died.. Our study supports the efficacy of tacrolimus in steroid-refractory UC. Purine analogues appear to be beneficial for the long-term outcome of these patients.

Topics: Adult; Aged; Cohort Studies; Colectomy; Colitis, Ulcerative; Colonoscopy; Databases, Factual; Drug Therapy, Combination; Female; Follow-Up Studies; Germany; Humans; Immunosuppressive Agents; Intestinal Mucosa; Kaplan-Meier Estimate; Male; Mercaptopurine; Middle Aged; Proportional Hazards Models; Retrospective Studies; Risk Assessment; Severity of Illness Index; Statistics, Nonparametric; Steroids; Survival Rate; Tacrolimus; Time Factors; Treatment Outcome; Wound Healing; Young Adult

The aim of the study is to assess the relationship between the introduction of biologic and immunosuppressant therapy and the number of patients undergoing surgery for ulcerative colitis (UC).. A questionnaire survey about patients undergoing surgery for UC was sent to 26 teaching hospitals throughout Japan. The questionnaire period spanned from 2008 to 2013, to account for the introduction of tacrolimus (2009) and infliximab (2010).. The total number of patients who underwent surgery was 297, 291, 273, 255, 300, and 305 in 2008, 2009, 2010, 2011 2012, and 2013, respectively. The emergency surgery rate remained stable at 32-34 % each year. The proportion of patients who underwent surgery for cancer increased from 13.8 % in 2008 to 20 % in 2013. In 2013, 41, 38, and 6 % of patients who underwent surgery had received treatment with a biologic, tacrolimus, and cyclosporine, respectively. No institution reported an increase in postoperative complications among patients treated with immunosuppressive drugs.. The number of patients undergoing surgery decreased temporarily soon after infliximab and tacrolimus first became widely available, but subsequently increased again. The emergency surgery rate remained unchanged throughout the study period. These data show that immunosuppressive drugs have had little effect on the risk of postoperative complications.

Topics: Biological Factors; Colitis, Ulcerative; Cyclosporine; Digestive System Surgical Procedures; Hospitals, Teaching; Humans; Immunosuppressive Agents; Infliximab; Japan; Postoperative Complications; Risk; Surgery Department, Hospital; Surveys and Questionnaires; Tacrolimus; Time Factors

Adrenomedullin (AM) is a multifunctional biologically active peptide that has an ameliorative effect against inflammatory bowel disease in several experimental models. We reported the first case where AM infusion dramatically improved symptoms and colonoscopy findings in patients with refractory ulcerative colitis (UC). To confirm the reproducibility of the efficacy and safety of AM infusion, this pilot study evaluated the clinical feasibility of intravenous administration of AM in patients with refractory UC.. Seven patients with active refractory UC participated and received intravenous infusion of AM (1.5 pmol/kg/min) for 8 h daily for 14 days, and their Disease Activity Index (DAI) were evaluated before and 2 and 12 weeks after beginning AM administration.. DAI were improved in all patients after AM administration. Within 2 weeks, marked declines in DAI (≥ 3 points and ≥ 30%) were observed in six patients (85.7%), while a more modest decline was observed in one patient (14.3%). Overall mean DAI improved from 9.3 ± 0.6 at baseline to 4.6 ± 0.8 at 2 weeks, and then to 1.2 ± 0.5 at 12 weeks. Endoscopic examination revealed substantial amelioration of ulcers, with mucosal healing and scarring. Four patients remained in clinical remission 12 months after AM treatment. AM administration produced significant increases in plasma AM concentrations (approximately 2.5-fold) that had a mild effect on blood pressure and heart rate, but with no serious adverse effects.. AM is a potentially useful agent that acts via a novel mechanism to safely induce mucosal healing and clinical remission in patients with refractory UC.

Topics: Adrenomedullin; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Colitis, Ulcerative; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Male; Mesalamine; Middle Aged; Pilot Projects; Prednisolone; Prospective Studies; Tacrolimus; Treatment Outcome; Vasodilator Agents

The Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and the Mayo endoscopic score (Mayo ES) are used to evaluate ulcerative colitis (UC) severity. This study compared UCEIS and the Mayo ES for evaluating UC severity and outcomes in patients undergoing remission induction during routine clinical practice with the aim of predicting medium- to long-term prognosis.. Forty-one UC patients who received colonoscopy before and after tacrolimus remission induction therapy were included. An index of clinical activity and endoscopic findings scored by both the UCEIS and the Mayo ES were determined. Changes in UCEIS and Mayo ES before and after induction therapy were compared.. The mean UCEIS improved from 6.2±0.9 to 3.4±2.1 (p < 0.001). Based on the UCEIS, a significant reduction was reached in both the response and the remission groups. In contrast, the Mayo ES did not reflect a significant change in the response group. The discrepancy appeared to be due to ulcers becoming smaller and shallower during the early stages of mucosal healing; the Mayo ES seems to miss these early changes. In other words, whereas the UCEIS indicates improvements when ulcers shrink, the Mayo ES does not distinguish deep ulcers from shallow ulcers and is 3 (severe UC) for both deep and shallow ulcers. Additionally, better UCEIS strata after induction therapy were associated with lower incidences of colectomy (p = 0.0001) or relapse (p = 0.0008).. The UCEIS accurately reflects clinical outcomes and predicts the medium- to long-term prognosis in UC patients undergoing induction therapy. These findings should support decision-making in clinical practice settings.

Topics: Administration, Oral; Adolescent; Adult; Aged; Colitis, Ulcerative; Colonoscopy; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Induction Chemotherapy; Male; Middle Aged; Prognosis; Retrospective Studies; Severity of Illness Index; Tacrolimus; Young Adult

To report of a case successful use of infliximab (IFX) and tacrolimus (TAC) in a patient with ulcerative colitis (UC).. A 22-year-old woman diagnosed with UC started treatment with azathioprine 2.5 mg/kg. After 3 years of therapy, she developed a severe relapse. A colonoscopy was performed showing diffuse continuous mucosal disease and multiple erosions (< 5 mm) with no signs of spontaneous bleeding. Treatment with IFX 5 mg/kg at weeks 0, 2, and 6 was started. After IFX induction, she remained with symptoms: six stools per day, as well as presenting bloody diarrhea, tenesmus, and no abdominal pain. An IFX dose intensification of 5 mg/kg every 6 weeks was prescribed. After 6 months of azathioprine plus IFX therapy, patient's clinical condition was improved: 3 - 4 stools per day, 20% of bloody diarrhea, tenesmus, and no abdominal pain. Her Mayo endoscopic subscore was 6.3 months later, and a severe relapse of ulcerative colitis was presented. The patient refused a surgical treatment. Azathioprine 2.5 mg/kg/day was suspended and TAC 0.2 mg/kg/day (12 mg/day) as a compassionate use was added to IFX dose intensification of 10 mg/kg every 8 weeks and mesalamine 800 mg 3 times daily. After the first month of combined therapy, the patient's clinical condition improved with no bloody stools and abdominal pain. After 6 months of combination therapy, the patient was in remission, with two stools per day, no tenesmus and no abdominal pain. Due to the patient's clinical remission, IFX was suspended. Tacrolimus was continued on 10 mg/day. After 6 months of TAC monotherapy, the patient continued without symptoms (1 - 2 normal stools per day).. Based on our case, the combination therapy of IFX and TAC could be selected as an effective approach for the patients with UC refractory to IFX dose intensification plus AZA. However, further studies need to be performed to evaluate the efficacy of this combination therapy.

Topics: Adult; Azathioprine; Colitis, Ulcerative; Drug Therapy, Combination; Female; Humans; Infliximab; Tacrolimus

There have been no comparative studies of tacrolimus vs. anti-tumour necrosis factor (anti-TNF) agents to determine which treatment is safer or more effective in refractory ulcerative colitis (UC).. To compare short-term safety and efficacy of tacrolimus vs. anti-TNF agents for active UC.. One hundred patients with moderate-to-severe active UC were studied. Fifty patients were treated with oral tacrolimus (TAC group). The other 50 patients were treated with anti-TNF agents (anti-TNF group): 40 with infliximab and 10 with adalimumab. Primary endpoints were clinical response and remission rates, colectomy rate, and the incidence of adverse events during 12 weeks.. The incidence of adverse events was 12% in the TAC vs. 18% in the anti-TNF groups (P = 0.58). At week 12, clinical remission rate was 40% in the TAC vs. 28% in the anti-TNF groups (P = 0.29). Clinical response (including remission) rate was 62% in the TAC vs. 64% in the anti-TNF groups (P > 0.99). Five patients (10%) in the TAC and 8 (16%) in the anti-TNF groups required colectomy (P = 0.55). In a subgroup analysis restricted to severely active UC, the response rate was 50% in the TAC vs. 25% in the anti-TNF groups (P = 0.24). In severely active UC, the response rate tended to be higher in patients treated with tacrolimus, albeit not statistically significant.. Both tacrolimus and anti-TNF agents appeared to be safe and effective in the management of moderate-to-severe active UC. However, randomised controlled trials are warranted to confirm the results obtained in this study.

Topics: Adalimumab; Adult; Colitis, Ulcerative; Female; Humans; Infliximab; Male; Middle Aged; Retrospective Studies; Tacrolimus; Treatment Outcome; Tumor Necrosis Factor-alpha

Both tacrolimus (Tac) and infliximab (IFX) are effective for moderate-to-severe ulcerative colitis (UC). The aim of this study was to compare the therapeutic efficacy and safety of both drugs.. We performed a retrospective analysis of 46 patients with moderate-to-severe UC who were treated either by Tac (n = 21) or IFX (n = 25). We compared the remission and response rates for 10 weeks between the two groups. In patients who achieved a clinical response, the subsequent relapse rate was compared. The overall adverse events were also compared between the two groups.. The remission and response rates at week 10 did not differ between patients treated with Tac (67% and 86%, respectively) and patients treated with IFX (76% and 92%, respectively). Among 41 patients showing a clinical response, eight of 23 patients treated with IFX and eight of 18 patients treated with Tac showed a subsequent relapse. The risk of relapse was not different between the two groups. While no serious adverse events were observed, the incidence of adverse events was higher in patients treated with Tac than in those treated with IFX.. Tac and IFX may be equally efficacious for the induction and maintenance of remission in patients with UC while minor adverse events are more frequent with the former treatment.

Topics: Adult; Colitis, Ulcerative; Comparative Effectiveness Research; Drug Administration Schedule; Female; Humans; Immunosuppressive Agents; Induction Chemotherapy; Infliximab; Kaplan-Meier Estimate; Maintenance Chemotherapy; Male; Middle Aged; Proportional Hazards Models; Recurrence; Retrospective Studies; Severity of Illness Index; Tacrolimus; Treatment Outcome

Topics: Colitis, Ulcerative; DNA Mutational Analysis; Genetic Predisposition to Disease; Humans; Immunosuppressive Agents; Infant; Male; Mutation; Phenotype; Receptors, Interleukin-10; Tacrolimus; Treatment Failure

Topics: Colitis, Ulcerative; Humans; Molecular Targeted Therapy; Tacrolimus; Tumor Necrosis Factor-alpha

Topics: Anti-Inflammatory Agents; Colitis, Ulcerative; Humans; Immunosuppressive Agents; Tacrolimus; Tumor Necrosis Factor-alpha

Topics: Anti-Inflammatory Agents; Colitis, Ulcerative; Humans; Immunosuppressive Agents; Tacrolimus; Tumor Necrosis Factor-alpha

Topics: Colitis, Ulcerative; Humans; Immunosuppressive Agents; Tacrolimus

Topics: Colitis, Ulcerative; Humans; Immunosuppressive Agents; Tacrolimus

Tacrolimus has shown efficacy in patients with ulcerative colitis.. To evaluate the efficacy of tacrolimus as remission induction therapy and assess medium to long-term outcomes in patients who achieve remission.. Forty-four ulcerative colitis patients who were treated with tacrolimus in three institutes during 2009-2013 were retrospectively reviewed. Short-term efficacy was based on the clinical activity index and the Mayo endoscopic subscores. Clinical activity index≤4 meant clinical remission, while Mayo endoscopic subscore 0 or 1 meant mucosal healing. Medium to long-term prognosis was based on relapse free survival in relation to the Mayo endoscopic subscore and duration of tacrolimus therapy in patients who achieved remission.. At 12 weeks, clinical remission was achieved in 29 of 44 patients (65.9%). Thirty-two patients received endoscopic evaluations, and mucosal healing rate was 43.8%. Among patients with clinical remission, mucosal healing rate was 60.9%. Relapse-free survival at 6, 12, and 24 months were 66%, 56%, and 50%, respectively, and was higher in patients on long-term tacrolimus (over 4 months, P=0.03), and patients with better endoscopic subscore (P=0.009).. Mucosal healing observed within 12 weeks or after a longer duration of tacrolimus therapy was associated with significantly better remission maintenance time.

Topics: Adult; Colitis, Ulcerative; Colonoscopy; Female; Humans; Immunosuppressive Agents; Intestinal Mucosa; Male; Middle Aged; Remission Induction; Retrospective Studies; Severity of Illness Index; Tacrolimus; Time Factors; Treatment Outcome

To determine the efficacy and safety of rapid induction therapy with oral tacrolimus without a meal in steroid-refractory ulcerative colitis (UC) patients.. This was a prospective, multicenter, observational study. Between May 2010 and August 2012, 49 steroid-refractory UC patients (55 flare-ups) were consecutively enrolled. All patients were treated with oral tacrolimus without a meal at an initial dose of 0.1 mg/kg per day. The dose was adjusted to maintain trough whole-blood levels of 10-15 ng/mL for the first 2 wk. Induction of remission at 2 and 4 wk after tacrolimus treatment initiation was evaluated using Lichtiger's clinical activity index (CAI).. The mean CAI was 12.6 ± 3.6 at onset. Within the first 7 d, 93.5% of patients maintained high trough levels (10-15 ng/mL). The CAI significantly decreased beginning 2 d after treatment initiation. At 2 wk, 73.1% of patients experienced clinical responses. After tacrolimus initiation, 31.4% and 75.6% of patients achieved clinical remission at 2 and 4 wk, respectively. Treatment was well tolerated.. Rapid induction therapy with oral tacrolimus shortened the time to achievement of appropriate trough levels and demonstrated a high remission rate 28 d after treatment initiation. Rapid induction therapy with oral tacrolimus appears to be a useful therapy for the treatment of refractory UC.

Topics: Administration, Oral; Adult; Colitis, Ulcerative; Drug Monitoring; Female; Humans; Immunosuppressive Agents; Induction Chemotherapy; Japan; Male; Middle Aged; Prospective Studies; Remission Induction; Tacrolimus; Time Factors; Treatment Outcome

Oral tacrolimus therapy is effective for refractory ulcerative colitis (UC), but dose adjustment according to the trough concentrations which varies largely among individuals, is required. This study aimed to identify factors to predict the tacrolimus dose required for achieving the target trough level for remission induction of UC.. Forty-seven consecutive UC patients who were treated with tacrolimus were retrospectively analyzed. Tacrolimus doses were adjusted every 2 or 3 days to achieve trough concentrations of 10-15 ng/mL. The dose required for reaching the target trough level was analyzed based on disease characteristics, course of trough concentrations, and gene polymorphism related to tacrolimus metabolism.. Median daily dose of tacrolimus required for achieving the target trough level was 0.19 (0.07-0.42) mg/kg, and patients were divided into high or low dose group (< 0.2 mg/kg or > 0.2 mg/kg). The value of initial trough concentration/starting dose was higher in the low dose group than in the high dose group (1.35 ng/mL/mg vs. 0.78 ng/mL/mg, p < 0.0001). Although presence of CYP3A5 *1 was more frequently observed in the high dose group, initial trough concentration was the only significant factor for determining requirement of high dose of tacrolimus (OR = 28.0, 95% confidence interval 3.20 - 631).. The most practical predictor of the dose required for achieving the target trough concentration was the trough concentration measured 2 or 3 days after starting tacrolimus therapy. Our findings would make tarcolimus administration for UC safer, easier and more effective.

Topics: Administration, Oral; Adolescent; Adult; Aged; Child; Colitis, Ulcerative; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Immunosuppressive Agents; Induction Chemotherapy; Male; Middle Aged; Retrospective Studies; Tacrolimus; Treatment Outcome; Young Adult

Currently, limited data of the outcome of inflammatory bowel disease (IBD) in patients after solid organ transplantation (SOT) are available. We aimed to analyze effects of SOT on the IBD course in a large IBD patient cohort.. Clinical data from 1537 IBD patients were analyzed for patients who underwent SOT (n = 31) between July 2002 and May 2014. Sub-analyses included SOT outcome parameters, IBD activity before and after SOT, and efficacy of IBD treatment.. 4.74% of patients with ulcerative colitis (UC) and 0.84% of patients with Crohn's disease (CD) underwent SOT (p = 2.69 x 10(-6), UC vs. CD). 77.4% of patients with SOT underwent liver transplantation (LTx) with tacrolimus-based immunosuppressive therapy after SOT. All LTx were due to primary sclerosing cholangitis (PSC) or PSC overlap syndromes. Six patients (19.4%) required renal transplantation and one patient (3.2%) heart transplantation. A survival rate of 83.9% after a median follow-up period of 103 months was observed. Before SOT, 65.0% of patients were in clinical remission and 5 patients received immunosuppressive therapy (16.1%). After SOT, 61.0% of patients were in remission (p = 1.00 vs. before SOT) and 29.0% required IBD-specific immunosuppressive or anti-TNF therapy (p = 0.54 vs. before SOT). 42.9% of patients with worsening of IBD after SOT were at higher risk of needing steroid therapy for increased IBD activity (p = 0.03; relative risk (RR): 10.29; 95% CI 1.26-84.06). Four patients (13.0%) needed anti-TNF therapy after SOT (response rate 75%).. SOT was more common in UC patients due to the higher prevalence of PSC-related liver cirrhosis in UC. Despite mainly tacrolimus-based immunosuppressive regimens, outcome of SOT and IBD was excellent in this cohort. In this SOT cohort, concomitant immunosuppressive therapy due to IBD was well tolerated.

Topics: Adult; Aged; Colitis, Ulcerative; Crohn Disease; Female; Heart Transplantation; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Liver Transplantation; Male; Middle Aged; Survival Rate; Tacrolimus; Treatment Outcome; Tumor Necrosis Factor-alpha

The management of patients with ulcerative colitis who are dependent on corticosteroid for control of symptoms, or refractory to corticosteroids or standard immunosuppressive therapy, is challenging. The development of newer medical therapies has increased the options for managing patients in this situation, but access and funding remain limited. This guideline summarises the literature regarding this situation and provides guidance as to the management of refractory colitis in the New Zealand setting.

Topics: Adalimumab; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Appendectomy; Azathioprine; Colitis, Ulcerative; Cyclosporine; Drug Resistance; Drug Therapy, Combination; Fecal Microbiota Transplantation; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infliximab; Leukapheresis; Mercaptopurine; Mesalamine; Methotrexate; New Zealand; Pediatrics; Piperidines; Proctocolectomy, Restorative; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Recurrence; Severity of Illness Index; Tacrolimus; Tumor Necrosis Factor-alpha

Ulcerative colitis (UC) occurring during childhood is generally extensive and is associated with severe flares that may require intravenous steroid treatment. In cases of corticosteroid resistance is necessary to introduce a second-line treatment to avoid or delay surgery.. To describe the efficacy and safety of oral tacrolimus for the treatment of severe steroid-resistant UC.. We performed a retrospective study that included all patients under age 18 suffering from severe steroid-resistant UC treated with oral tacrolimus during the period January 1998 to October 2012 and with a follow-up period after treatment of 24 months or more.. A total of ten patients were included. The age at baseline was 9.4±4.9 years, and the time from diagnosis was 1.3 months (IQR, 1-5.7). Seven of the patients were in their first flare of disease. All of them received an oral dose of 0.12 mg/kg/day of tacrolimus divided in two doses. Trough plasma levels of tacrolimus were maintained between 4 and 13 ng/ml. Response was seen in 5/10 patients at 12 months, colectomy was eventually performed in 60% of patients during the follow-up period.. Tacrolimus is useful in inducing remission in patients with severe steroid-resistant UC, preventing or delaying colectomy, and allowing the patient and family to prepare for a probable surgery. Tacrolimus may also be used as a treatment bridge for corticosteroid-dependent patients until the new maintenance therapy takes effect.

Topics: Administration, Oral; Adolescent; Child; Child, Preschool; Colectomy; Colitis, Ulcerative; Drug Resistance; Female; Humans; Immunosuppressive Agents; Male; Remission Induction; Retrospective Studies; Severity of Illness Index; Steroids; Tacrolimus

Appropriate influenza vaccination is important for patients with inflammatory bowel disease under immunosuppressive therapy. The purpose of this study was to evaluate the influence of immunosuppressive therapy on the immune response to the trivalent influenza vaccine in adult patients with inflammatory bowel disease.. In this cohort study, 91 participants received a single dose of influenza vaccine for the 2010/2011 season. Serum samples were collected at 3 different times (pre-vaccination, 3 weeks post-vaccination, and after flu season) to measure hemagglutination inhibition antibody titers. Immune responses were compared based on immunosuppressive therapy.. Among the 88 subjects who completed the study, the influenza vaccine induced a more than 4-fold increase in the mean antibody level for all flu strains. The overall seroprotection proportion (post-vaccination titer ≥ 1:40) was 81% for H1N1, 61% for H3N2, and 86% for B. Treatment with an immunomodulator reduced the immune response to the H1N1 strain (OR=0.20, p=0.01), and treatment with infliximab reduced the immune response to the other strains (H3N2 strain: OR=0.37, p=0.02; B strain: OR=0.18, p=0.03). Combination therapy with azathioprine/6-mercaptopurine and infliximab significantly inhibited the immune response to H1N1 (OR=0.056, p=0.02).. Infliximab and/or immunomodulators inhibit immune responses to some strains of trivalent influenza vaccination in adults with inflammatory bowel disease. For optimization of the trivalent influenza vaccination for patients with adult inflammatory bowel disease treated with immunosuppressive agents, establishing an effective vaccination method is crucial.

Topics: Adrenal Cortex Hormones; Adult; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antibodies, Viral; Azathioprine; Colitis, Ulcerative; Crohn Disease; Drug Therapy, Combination; Female; Humans; Immunity, Active; Immunosuppressive Agents; Infliximab; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza B virus; Influenza Vaccines; Male; Mercaptopurine; Methotrexate; Middle Aged; Prospective Studies; Tacrolimus

The pharmacokinetics of tacrolimus (Tac) differ among individuals, and genetic polymorphisms of cytochrome P-450 (CYP) 3A4, CYP3A5, and ABCB1 are thought to be involved. The aim of this study was to clarify whether these genetic polymorphisms affect the pharmacokinetics of Tac in patients with ulcerative colitis.. The subjects in this study were 45 patients with moderate-to-severe ulcerative colitis who were resistant to other therapies and were treated with Tac. The subjects were tested for genetic polymorphisms of CYP3A4, CYP3A5, and ABCB1, and the relationship between Tac pharmacokinetics and the remission rate was investigated.. Of the 45 subjects, 24 (53.3%) were CYP3A5 expressers (Exp), and 21 (46.7%) were non-expressers (Non-Exp). The trough level and the dose-adjusted trough level on days 2-5 were significantly higher in the Non-Exp group than in the Exp group (10.16 ± 5.84 vs 4.47 ± 2.50 ng/mL, P < 0.0001, 139.36 ± 77.43 vs 61.37 ± 41.55 ng/mL per mg/kg/day, P < 0.0001). The percentage of patients achieving the optimal trough level on days 2-5 was significantly higher in the Non-Exp group than in the Exp group (40.0% vs 4.3%, P = 0.01). This trend was also observed on days 7-10. On multivariate analysis, factors associated with achievement of the optimal trough level were food non-intake and Non-Exp of CYP3A5. The remission rate was significantly higher in the Non-Exp group than in the Exp group (47.6% vs 16.7%, P = 0.046).. CYP3A5 genetic polymorphisms affected the pharmacokinetics of Tac, so that the short-term clinical remission rate was different between Exp and Non-Exp of CYP3A5.

Topics: Adult; Asian People; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Colitis, Ulcerative; Cytochrome P-450 CYP3A; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Polymorphism, Genetic; Remission Induction; Tacrolimus

To evaluate the efficacy and safety of salvage therapy, and to identify risk factors of operative complications among hospitalized ulcerative colitis (UC) patients.. We evaluated 88 UC patients hospitalized at our center between April 2010 and November 2012. We compared characteristics of corticosteroid-refractory patients treated with calcineurin inhibitor and those with infliximab as second-line therapy. Furthermore, we compared the characteristics of operative and nonoperative patients. The association between perioperative treatments and complications was also investigated.. Calcineurin inhibitor and infliximab were used in 42 and 22 patients, respectively. We found no difference in the clinical background between them. Efficacy rates were 67 and 50%, respectively. Eight out of 10 nonresponders of each treatment were treated with the other drug as third-line therapy. The efficacy rates of calcineurin inhibitor and infliximab as the third-line therapy were 75 and 50%, respectively. Operative patients had more severe disease (87.5 vs. 31%, p < 0.01), higher Lichtiger score (14.1 vs. 11.5, p < 0.01), higher Rachmilewitz endoscopic index (10.5 vs. 8.4, p < 0.01), higher C-reactive protein (7.6 vs. 4.0, p = 0.015) and lower serum albumin (3.1 vs. 3.6, p = 0.014) than nonoperative patients. Complications were observed in 7 out of 16 (44 %) operative patients. Postoperative complications were not increased even when patients were treated with second- or third-line therapy. However, the complication rate in corticosteroid users was 54.5 (6/11) and 20% (1/5) in nonusers.. Third-line salvage therapy is effective and tolerable in carefully selected UC patients. Perioperative use of corticosteroids may lead to more adverse outcomes.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Calcineurin Inhibitors; Colitis, Ulcerative; Cyclosporins; Female; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infliximab; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Salvage Therapy; Tacrolimus; Treatment Outcome; Young Adult

We investigated the safety, clinical efficacy, and significance of tacrolimus trough levels in 20 outpatients with active ulcerative colitis. Adverse effects were observed in 16 (80%) patients, and most events were reversible and showed improvement or complete recovery. Three patients required hospitalization because of disease aggravation. The rate of efficacious tacrolimus trough levels was 60% within 1 week and 95% within 2 weeks. At 12 weeks, the clinical remission rate was 25% and the improvement rate was 55%. The clinical remission rate was significantly higher in patients with the relapse-remission type than in those with the chronic inflammation type. These results indicate that the use of tacrolimus in outpatients with ulcerative colitis is safe and that efficacious trough levels can be rapidly achieved in these patients.

Topics: Adult; Aged; Colitis, Ulcerative; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Outpatients; Prospective Studies; Remission Induction; Tacrolimus; Time Factors; Treatment Outcome

Among patients with steroid-refractory ulcerative colitis (UC) in whom a first rescue therapy has failed, a second line salvage treatment can be considered to avoid colectomy.. To evaluate the efficacy and safety of second or third line rescue therapy over a one-year period.. Response to single or sequential rescue treatments with infliximab (5mg/kg intravenously (iv) at week 0, 2, 6 and then every 8weeks), ciclosporin (iv 2mg/kg/daily and then oral 5mg/kg/daily) or tacrolimus (0.05mg/kg divided in 2 doses) in steroid-refractory moderate to severe UC patients from 7 Swiss and 1 Serbian tertiary IBD centers was retrospectively studied. The primary endpoint was the one year colectomy rate.. 60% of patients responded to the first rescue therapy, 10% went to colectomy and 30% non-responders were switched to a 2(nd) line rescue treatment. 66% of patients responded to the 2(nd) line treatment whereas 34% failed, of which 15% went to colectomy and 19% received a 3(rd) line rescue treatment. Among those, 50% patients went to colectomy. Overall colectomy rate of the whole cohort was 18%. Steroid-free remission rate was 39%. The adverse event rates were 33%, 37.5% and 30% for the first, second and third line treatment respectively.. Our data show that medical intervention even with 2(nd) and 3(rd) rescue treatments decreased colectomy frequency within one year of follow up. A longer follow-up will be necessary to investigate whether sequential therapy will only postpone colectomy and what percentage of patients will remain in long-term remission.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Colectomy; Colitis, Ulcerative; Cyclosporine; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Infliximab; Male; Middle Aged; Retreatment; Retrospective Studies; Salvage Therapy; Severity of Illness Index; Steroids; Tacrolimus; Treatment Failure; Young Adult

Tacrolimus 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.. Charts 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.. Twelve (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.. Oral monotherapy with tacrolimus may be a valuable long-term therapeutic option in selected patients with moderate-to-severe active refractory ulcerative colitis.

Topics: Administration, Oral; Adult; Colitis, Ulcerative; Drug Administration Schedule; Female; Humans; Immunosuppressive Agents; Induction Chemotherapy; Maintenance Chemotherapy; Male; Middle Aged; Patient Selection; Retrospective Studies; Severity of Illness Index; Tacrolimus; Treatment Outcome

Toxic megacolon is an infrequent but life-threatening complication that occurs most commonly in patients with severe ulcerative colitis. Intravenous steroids are often recommended for patients with toxic megacolon secondary to ulcerative colitis. However, steroid dependency may mask the presence of intra-abdominal sepsis and is associated with refractoriness, during which cytomegalovirus reactivation may occur. In this report, we present two rare cases of megacolon accompanying pancolonic severe ulcerative colitis that were successfully treated with oral tacrolimus, including one steroid-naïve patient. In cases of ulcerative colitis with megacolon, treatment with oral tacrolimus is recommended, thereby avoiding steroid dependency and improving the long-term prognosis.

Topics: Administration, Oral; Colitis, Ulcerative; Female; Humans; Immunosuppressive Agents; Male; Megacolon, Toxic; Middle Aged; Prognosis; Tacrolimus; Treatment Outcome

We encountered a rare case of severe diffuse duodenitis associated with ulcerative colitis (UC). A 23-year-old man underwent total proctocolectomy with ileal J-pouch anal anastomosis for UC. He suffered from severe abdominal pain, fever and bloody diarrhea for six months after the surgery. Upper double-balloon enteroscopy disclosed severe diffuse duodenitis, of which the findings were endoscopically and histologically similar to those of colonic lesions of UC. Although the administration of prednisolone was ineffective, treatment with intravenous tacrolimus markedly improved the clinical findings. This is the first report of the successful treatment of severe UC-associated diffuse duodenitis with intravenous tacrolimus.

Topics: Colitis, Ulcerative; Colonic Pouches; Double-Balloon Enteroscopy; Duodenitis; Humans; Immunosuppressive Agents; Male; Proctocolectomy, Restorative; Tacrolimus; Young Adult

Acute severe ulcerative colitis as defined by Truelove Witt's criteria is a medical emergency which requires hospitalization. Patient requires close clinical monitoring with assessment of daily vital parameters, stool frequency, serum electrolytes and daily abdominal examination Intravenous corticosteroids are the mainstay of therapy. Approximately two thirds of patients will respond to steroids. Response to steroids should be assessed at day 3 of admission and partial/non-responders should be considered for alternative medical therapy/surgery. Medical rescue therapies include intravenous cyclosporin and infliximab. This article provides an time bound step up algorithm for management of acute severe ulcerative colitis.

Topics: Acute Disease; Adrenal Cortex Hormones; Algorithms; Antibodies, Monoclonal; Colectomy; Colitis, Ulcerative; Counseling; Cyclosporine; Emergencies; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infliximab; Infusions, Intravenous; Monitoring, Physiologic; Nutritional Support; Remission Induction; Tacrolimus

Ulcerative colitis (UC) is defined as a chronic inflammatory condition causing continuous mucosal inflammation of the colon without granulomas on biopsy. It affects the rectum, and, to a variable extent, the colon in continuity and is characterized by a relapsing and remitting course. Oral 5-aminosalicylic acid (5-ASA) regimens are recommended as first-line induction therapy for mild to moderately active pediatric UC and for maintenance of remission regardless of other initial treatments. In large clinical trials in adults, mesalamine intolerance was found in 2-5 % of the patients. We present a case of an 8-year-old female patient with intolerance to mesalamine and proctitis resistant to conventional therapy who responded to rectal tacrolimus treatment. The patient started with a dose of 2 mg/day at night with an excellent response. She reported feeling better than any of the previously prescribed treatments and without feeling the discomfort of previously administered enemas. After four weeks of treatment, the dose was reduced to 2 mg/week with no relapses. Tacrolimus suppositories were very well tolerated, and no adverse effects have been reported. Although only very little data has been published, rectal tacrolimus seems to be safe and of efficacy in ulcerative proctitis resistant to standard therapy.

Topics: Administration, Rectal; Anti-Inflammatory Agents, Non-Steroidal; Child; Colitis, Ulcerative; Female; Humans; Immunosuppressive Agents; Mesalamine; Proctitis; Remission Induction; Tacrolimus

Infliximab and tacrolimus are effective for the treatment of patients with moderate or severe corticosteroid-dependent/refractory ulcerative colitis. However, regarding treatment for these patients, whether tacrolimus therapy should precede infliximab as a second-line therapy remains controversial. To address this issue, we retrospectively investigated the efficacy of infliximab salvage therapy for patients with severe or moderate ulcerative colitis who failed to respond to tacrolimus.. We assessed clinical backgrounds and therapeutic outcomes at baseline, 8, and 30 weeks for 13 patients receiving infliximab for severe or moderate ulcerative colitis who showed refractoriness or loss of response to tacrolimus, or no tolerance.. Mean partial Mayo score was significantly decreased (P<0.05) to 5.69, 3.07, and 2.77 at baseline, 8, and 30 weeks, respectively. Six of 13 patients (46.2%) showed clinical remission at 8 weeks and four (30.8%) showed clinical remission at 30 weeks. Two patients who did not respond to infliximab finally underwent colectomy. Rates of clinical remission at 8 and 30 weeks were 60.0 and 40.0% in tacrolimus responders, and good remission rates of 37.5 and 25.0%, respectively, were also obtained in tacrolimus nonresponders. No serious adverse events were encountered.. Infliximab salvage therapy following tacrolimus tended to appear more efficacious in tacrolimus responders (loss of response or no tolerance) than in nonresponders (refractoriness), although nonresponders also achieved satisfactory results. Sequential therapy may thus prove useful and well tolerated. In addition, we should avoid missing the proper timing of colectomy, and care is warranted regarding adverse events.

Topics: Adolescent; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Colitis, Ulcerative; Drug Administration Schedule; Drug Evaluation; Female; Gastrointestinal Agents; Glucocorticoids; Humans; Immunosuppressive Agents; Infliximab; Male; Middle Aged; Prednisolone; Retrospective Studies; Salvage Therapy; Severity of Illness Index; Tacrolimus; Treatment Failure; Young Adult

Topics: Colitis, Ulcerative; Drug Resistance; Humans; Immunosuppressive Agents; Steroids; Tacrolimus

A 30-year-old woman was referred to our hospital with recurrent refractory ulcerative colitis. She also suffered from avascular necrosis of the left femoral head caused by steroid use. We had expected that tacrolimus would contribute to remission, but effects remained insufficient even after 16 days of treatment. Intensive leukocytapheresis (LCAP) therapy was added to tacrolimus therapy, and this combination achieved remission. Tacrolimus plus intensive LCAP combination therapy appears useful in treating refractory ulcerative colitis.

Topics: Adult; Colitis, Ulcerative; Female; Humans; Immunosuppressive Agents; Leukapheresis; Tacrolimus

The medical management of refractory ulcerative colitis (UC) remains a significant challenge. Two randomised controlled studies have demonstrated tacrolimus therapy is effective for the induction of remission of moderate to severe UC. However, the long term outcomes of UC patients treated with tacrolimus as maintenance therapy are not certain.. This study aims to assess the efficacy of tacrolimus maintenance therapy for refractory UC.. A retrospective review of patients with UC treated with tacrolimus at two London tertiary centres was performed. Clinical outcomes were assessed at six months, at the end of tacrolimus treatment, or at the last follow-up for patients continuing tacrolimus treatment. Modified Truelove-Witts score (mTW) and Mayo endoscopy subscores were calculated.. 25 patients with UC, treated with oral tacrolimus between 2005 and 2011, were identified. The median duration of tacrolimus treatment was 9 months (IQR 3.7-18.2 months). The median duration of follow-up was 27 months (range 3-66 months). At six months thirteen (52%) patients had achieved and maintained clinical response and eleven (44%) were in clinical remission. The mean mTW score decreased from 10+/-0.5 before therapy, to 5.8+/-0.8 (p≤0.001 95% CI 2.7-5.8) at cessation of treatment or last follow-up. Mayo endoscopy subscore decreased from 2.6+/-0.1 to 1.2+/-0.2 (p≤0.001 mean reduction 1.4, 95% CI 0.8-1.9). Eight patients (32%) subsequently underwent a colectomy within a mean time of 17 months (range 2-45 months).. Tacrolimus is effective for the maintenance of refractory UC and can deliver sustained improvement in mucosal inflammation.

Topics: Adolescent; Adult; Aged; Cohort Studies; Colectomy; Colitis, Ulcerative; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; London; Male; Middle Aged; Recurrence; Retrospective Studies; Risk Assessment; Severity of Illness Index; Tacrolimus; Tertiary Care Centers; Time Factors; Treatment Outcome; United Kingdom; Young Adult

Oral administration of tacrolimus is an effective remission induction therapy for steroid-refractory/dependent ulcerative colitis (UC).. This study aimed to evaluate the short- as well as medium- and long-term effectiveness of tacrolimus therapy.. The 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.. The clinical effectiveness combining clinical remission and improvement was observed in 62.7% of the patients at 3 months. Thirty-six patients underwent colonoscopy at 3 months, 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 6 months, 49.9% at 1 year, and 37.8% at 2 years. Patients with a Mayo endoscopic score of 0-1 at 3 months 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.. Tacrolimus 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.

Topics: Administration, Oral; Adolescent; Adult; Aged; Anti-Inflammatory Agents; Colitis, Ulcerative; Colonoscopy; Disease-Free Survival; Drug Resistance; Female; Humans; Immunosuppressive Agents; Intestinal Mucosa; Male; Middle Aged; Remission Induction; Retrospective Studies; Severity of Illness Index; Steroids; Tacrolimus; Time Factors; Wound Healing; Young Adult

The primary purpose of this study was to investigate the relationship between Pediatric Ulcerative Colitis Activity Index (PUCAI) and operative management. We also specifically evaluated those patients receiving tacrolimus for their disease.. A retrospective review (1/06-1/11) identified ulcerative colitis patients (≤21 years old) undergoing restorative proctocolectomy with rectal mucosectomy and ileal pouch-anal anastomosis. Main outcomes included pre-operative PUCAI, combined versus staged procedure, and postoperative complications. Patients receiving tacrolimus within 3 months of surgical intervention were identified. PUCAI at tacrolimus induction and medication side effects were also noted.. Sixty patients were identified. Forty-two (70%) underwent combined and 18 (30%) had staged procedures. Pre-operative PUCAI was lower for combined versus staged patients (p = < 0.001). Furthermore, a higher pre-operative PUCAI strongly correlated with the likelihood of undergoing a staged procedure (p < 0.001). Forty-four patients (73%) received tacrolimus. Significant improvement in their PUCAI was noted from induction to pre-operative evaluation (p < 0.001). Minor and reversible side effects occurred in 46% of patients receiving tacrolimus, but complication rates were not significantly different.. There is a very strong correlation between the PUCAI and the likelihood of undergoing a staged procedure. A significant improvement in PUCAI occurs following preoperative tacrolimus therapy.

Topics: Adolescent; Child; Child, Preschool; Colitis, Ulcerative; Female; Humans; Immunosuppressive Agents; Male; Predictive Value of Tests; Retrospective Studies; Tacrolimus; Young Adult

A 23-year-old woman was admitted with a relapse of ulcerative colitis. Tacrolimus therapy was initiated following inadequate response to corticosteroid therapy. Although the symptoms partially improved, she suddenly developed severe pain localized to the lower limbs on day 16 of tacrolimus therapy. By day 17, she was unable to move. Magnetic resonance imaging revealed born marrow edema in the lower limbs. We suspected calcineurin-inhibitor induced pain syndrome (CIPS) due to tacrolimus therapy. The pain improved within approximately four weeks of tacrolimus cessation. CIPS that is not associated with organ transplantation is a rare occurrence. Here we report a rare case of CIPS that was caused by tacrolimus therapy in a patient with ulcerative colitis.

Topics: Calcineurin Inhibitors; Colitis, Ulcerative; Female; Humans; Pain; Syndrome; Tacrolimus; Young Adult

Steroid-refractory ulcerative colitis (UC) remains a challenging condition warranting surgery upon failure of pharmacological treatment. Calcineurin inhibitors or infliximab are alternatives in this situation. Data on the efficacy and safety of tacrolimus in this setting are limited.. To study the short-term efficacy and safety of tacrolimus in moderate-to-severe steroid-refractory UC. The role of thiopurines in this situation and predictors of colectomy were evaluated.. In three centers, all charts from tacrolimus-treated patients with steroid-refractory UC were reviewed. Efficacy was assessed by colectomy-free survival and clinical remission at 3 months.. We identified 130 patients with pancolitis in 75 (59%), left-sided disease in 35 (27%) and proctitis in 18 patients (14%) (disease localisation not obtainable in two patients). The median age was 40 (range: 18-81). Clinical activity according to the median Lichtiger score decreased from 13 (range: 4-17) at baseline to 3 (0-14) at week 12. Eighteen patients underwent colectomy within the first 3 months of treatment with tacrolimus (14%). Clinical remission was achieved in 94 patients (72%) in this period. Thiopurines given in parallel to tacrolimus tended to limit colectomy and significantly increased remission (P = 0.002) in the short-term. No other predictors of colectomy or remission were identified. Side effects were noticed in 53% of patients and no severe events occurred.. This large survey confirms the efficacy and safety of tacrolimus in patients with steroid-refractory ulcerative colitis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Colectomy; Colitis, Ulcerative; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Randomized Controlled Trials as Topic; Remission Induction; Severity of Illness Index; Tacrolimus; Time Factors; Treatment Outcome; Young Adult

The calcineurin inhibitor tacrolimus has been shown to be safe and effective as salvage therapy for steroid-refractory ulcerative colitis (UC). Since differences in the onset of action between various agents are thought to influence the achievement and maintenance of disease remission, top-down or accelerated step-up therapy with tacrolimus may be useful. However, the efficacy of tacrolimus in moderate to severe UC patients not receiving concomitant steroids remains unknown.. Ten patients (11 attacks) with active, moderate to severe UC were treated with oral tacrolimus at a dose of 0.1 mg/kg body weight daily. The dosages were adapted to maintain trough whole-blood levels of 10 to 15 ng/mL to induce remission and 5 to 10 ng/mL to maintain remission. Lichtiger scores, the incidence of adverse effects (serum creatinine and glucose) and long-term outcomes were assessed.. At four weeks after the initiation of tacrolimus therapy, clinical remissions were observed for eight attacks (72.7%) and clinical responses were demonstrated for three attacks. At 12 weeks after the initiation of tacrolimus treatment, clinical remissions were achieved for nine attacks (90%). After a mean follow-up of 10.4 months, clinical remissions were maintained for eight of 11 attacks. During the tacrolimus treatment, the serum creatinine and glucose levels were not significantly elevated.. Oral tacrolimus is a safe and effective therapy for the treatment of moderate to severe UC in patients not receiving concomitant treatment with systemic steroids. Although further studies are required to establish the efficacy and safety of oral tacrolimus therapy in patients with UC, oral tacrolimus may represent a top-down or accelerated step-up treatment option for patients with moderate to severe UC.

Topics: Administration, Oral; Adrenal Cortex Hormones; Adult; Cohort Studies; Colitis, Ulcerative; Dose-Response Relationship, Drug; Drug Administration Schedule; Endoscopy, Gastrointestinal; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Intestinal Mucosa; Male; Middle Aged; Patient Safety; Retrospective Studies; Severity of Illness Index; Tacrolimus; Time Factors; Treatment Outcome; Young Adult

Topics: Colitis, Ulcerative; Drug Resistance; Humans; Immunosuppressive Agents; Steroids; Tacrolimus

Topics: Colitis, Ulcerative; Female; Humans; Immunosuppressive Agents; Male; Tacrolimus

Topics: Colitis, Ulcerative; Female; Humans; Immunosuppressive Agents; Male; Tacrolimus

Topics: Colitis, Ulcerative; Female; Humans; Immunosuppressive Agents; Male; Tacrolimus

Topics: Colitis, Ulcerative; Drug Resistance; Humans; Immunosuppressive Agents; Steroids; Tacrolimus

Pyoderma gangrenosum (PG) is often associated with inflammatory bowel disease even after bowel surgery, but it remains an extremely rare pathology. The purpose of this study was to investigate the clinical features and treatment of PG and to consider proper management for peristomal PG.. Demographic data for patients who underwent colorectal surgery with ostomy creation at Hyogo College of Medicine between July 2007 and July 2011 were prospectively collected. The main outcome measures were postoperative occurrence of peristomal PG by type: explosive and rapidly spreading type (type R) and indolent and gradually spreading type (type G).. Overall prevalence was 11/738 (1.5%), with type R in 5 patients and type G in 6. Type R and type G were significantly more common in ulcerative colitis and Crohn's disease, respectively (p = 0.01). Type R developed within 6 days after surgery. Type G developed a mean of 52 days after surgery. Complete healing required a long time in both types, with means of 69 days for type R and 48 days for type G.. Although peristomal PG was a rare complication after surgery, differences in the development of PG were observed between ulcerative colitis and Crohn's disease. Careful observation and knowledge of PG are needed.

Topics: Adolescent; Adult; Aged; Anti-Inflammatory Agents; Colitis, Ulcerative; Crohn Disease; Enterostomy; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Postoperative Complications; Prednisolone; Pyoderma Gangrenosum; Risk Factors; Surgical Stomas; Surgical Wound Infection; Tacrolimus

Few clinical predictors are associated with definitive proctocolectomy in children with ulcerative colitis (UC). The purpose of the present study was to identify clinical predictors associated with surgery in children with UC using a disease-specific database.. Children diagnosed with UC at age <18 years were identified using the Pediatric Inflammatory Bowel Disease Consortium (PediIBDC) database. Demographic and clinical variables from January 1999 to November 2003 were extracted alongside incidence and surgical staging.. Review of the PediIBDC database identified 406 children with UC. Approximately half were girls (51%) with an average age at diagnosis of 10.6 ± 4.4 years in both boys and girls. Average follow-up was 6.8 (±4.0) years. Of the 57 (14%) who underwent surgery, median time to surgery was 3.8 (interquartile range 4.9) years after initial diagnosis. Children presenting with weight loss (hazard ratio [HR] 2.55, 99% confidence interval [CI] 1.21-5.35) or serum albumin <3.5 g/dL (HR 6.05, 99% CI 2.15-17.04) at time of diagnosis and children with a first-degree relative with UC (HR 1.81, 99% CI 1.25-2.61) required earlier surgical intervention. Furthermore, children treated with cyclosporine (HR 6.11, 99% CI 3.90-9.57) or tacrolimus (HR 3.66, 99% CI 1.60-8.39) also required earlier surgical management. Other symptoms, laboratory tests, and medical therapies were not predictive for need of surgery.. Children with UC presenting with hypoalbuminemia, weight loss, a family history of UC, and those treated with calcineurin inhibitors frequently require restorative proctocolectomy for definitive treatment. Early identification and recognition of these factors should be used to shape treatment goals and initiate multidisciplinary care at the time of diagnosis.

Topics: Calcineurin Inhibitors; Child; Colitis, Ulcerative; Cyclosporine; Family; Female; Genetic Predisposition to Disease; Humans; Hypoalbuminemia; Immunosuppressive Agents; Incidence; Male; Proctocolectomy, Restorative; Risk Assessment; Serum Albumin; Tacrolimus; Time Factors; Weight Loss

Calcineurin inhibitors (CNIs) such as cyclosporine and tacrolimus have been shown to be effective for treatment of patients with steroid-dependent or steroid-refractory ulcerative colitis (UC) with moderate to severe activity. However, it has not been determined whether readministration of CNIs is effective in patients who experience relapse after remission induced by CNIs.. To determine the effect of readministration of CNIs in patients who had initially responded to CNIs.. A review of the medical records of 46 patients with moderate to severe UC who were treated with a CNI at a single tertiary teaching hospital with 840 beds was conducted. Remission was defined as a clinical activity index (CAI) score of 3 or less within 2 months of starting CNI therapy. Response was defined as a CAI score of 4 or higher but had decreased by half from the start of CNI therapy. Relapse was defined as flare-up of symptoms that required an additional treatment or colectomy.. Of the 46 patients, 37 (80%) achieved clinical remission or response with the initial CNI treatment. Among those 37 patients, 19 experienced relapse (median duration to relapse, 6.4 months), 12 of whom were readministered a CNI. Of the 12 patients, 2 achieved clinical remission, 2 had a response, and the remaining 8 had no response to the CNI. In addition, all patients who responded to CNI readministration experienced relapse within 6 months. CNI readministration was significantly less effective than the initial administration for treatment of UC (80% vs 33%; p = 0.0014).. Readministration of CNIs for relapse after remission with CNI treatment does not seem to be successful. Alternative therapies such as anti-tumor necrosis factor antibody should be used or colectomy should be considered.

Topics: Adolescent; Adult; Aged; Calcineurin Inhibitors; Child; Colitis, Ulcerative; Cyclosporine; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Recurrence; Tacrolimus; Treatment Outcome; Young Adult

Topics: Adult; Colectomy; Colitis, Ulcerative; Endoscopy, Gastrointestinal; Enteritis; Female; Humans; Immunosuppressive Agents; Jejunum; Postoperative Complications; Tacrolimus; Tomography, X-Ray Computed

Topics: Antibodies, Monoclonal; Colitis, Ulcerative; Cyclosporine; Humans; Inflammatory Bowel Diseases; Infliximab; Polymorphism, Single Nucleotide; Tacrolimus; Treatment Failure

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.

Topics: Acute-Phase Proteins; Adolescent; Adrenal Cortex Hormones; Adult; Child; Child, Preschool; Cohort Studies; Colitis, Ulcerative; Drug Resistance; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Retrospective Studies; Tacrolimus; Treatment Outcome; Young Adult

Topics: Adult; Colitis, Ulcerative; Drugs, Investigational; Female; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Male; Retreatment; Tacrolimus; Treatment Outcome

Tacrolimus (Tac) is effective in the treatment of steroid-refractory ulcerative colitis (UC); however, nonresponse and unpredictable side effects are major limitations. Because Tac response in patients who have undergone solid-organ transplantation has been associated with the presence of variants in CYP3A and ABCB1, we elucidated the contributions of CYP3A4*1B and CYP3A5*3 and of ABCB1 1236C>T, 2677G>T,A, and 3435C>T polymorphisms to Tac response in 89 patients with UC. Short-term remission and response were achieved in 61 and 14% of the patients, respectively, and were associated with colectomy-free survival. In a linear logistic regression model, patients with homozygous variants for one of the three ABCB1 alleles showed significantly higher short-term remission rates as compared with those of other genotypes. The effects held true after multivariate analysis including multiple comparisons and were more pronounced after correction for dose-adjusted Tac blood trough levels. We suggest that ABCB1, but not CYP3A5, may predict short-term remission of Tac in steroid-refractory UC.

Topics: Adolescent; Adult; Aged; Alleles; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Colitis, Ulcerative; Cytochrome P-450 CYP3A; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Logistic Models; Male; Middle Aged; Multivariate Analysis; Polymorphism, Single Nucleotide; Remission Induction; Tacrolimus; Treatment Outcome; Young Adult

Topics: Adult; Colitis, Ulcerative; Humans; Immunosuppressive Agents; Male; Ointments; Pyoderma; Pyoderma Gangrenosum; Tacrolimus

Topics: Azathioprine; Colitis, Ulcerative; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Tacrolimus

The introduction of immunosuppressants and biologic agents has led to active debate and research about optimal therapeutic strategies considering risk factors and predictors of clinical outcome in inflammatory bowel disease (IBD). Data about gender-specific treatment differences and risk factors is lacking for IBD. The aim of the present study was to evaluate gender-related differences in the treatment of a distinct IBD patient population treated in the Rhein-Main region, Germany.. Data about past medical history, disease status and medical treatment of 986 outpatients treated in ten gastroenterological practices and three hospitals were collected from November 1st 2005-July 31st 2007 and analyzed with regard to gender-related differences in therapy and disease management.. With the exception of an extended disease duration in women, no significant gender-related differences in demographic and clinical characteristics were observed. Men showed a significantly higher remission rate than women (p=0.025), while women received significantly less immunosuppressive medication compared to men (p=0.011). In addition, treatment with immunosuppressants was not different in women with child-bearing potential compared to menopausal women.. Our investigation demonstrates for the first time gender-specific differences in the therapeutic management in a large cohort of IBD patients.

Topics: Adrenal Cortex Hormones; Adult; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Azathioprine; Budesonide; Colitis, Ulcerative; Crohn Disease; Cross-Sectional Studies; Cyclosporine; Female; Germany; Humans; Immunosuppressive Agents; Infliximab; Male; Mercaptopurine; Mesalamine; Methotrexate; Middle Aged; Practice Patterns, Physicians'; Prospective Studies; Remission Induction; Severity of Illness Index; Sex Factors; Tacrolimus

Topics: Administration, Oral; Adult; Behcet Syndrome; Colitis, Ulcerative; Female; Humans; Immunosuppressive Agents; Tacrolimus

Topics: Administration, Oral; Adolescent; Child; Colitis, Ulcerative; Dose-Response Relationship, Drug; Female; Humans; Immunosuppressive Agents; Male; Pediatrics; Remission Induction; Tacrolimus; Treatment Outcome

The calcineurin inhibitor tacrolimus and the anti-TNF-antibody infliximab are established options in steroid-refractory ulcerative colitis (UC).. To evaluate the efficacy of infliximab-salvage therapy in patients with refractory UC failing to respond to tacrolimus.. Twenty-four patients were enrolled in this evaluation. Reasons for tacrolimus therapy were steroid-refractory disease in 19 patients and steroid-dependency in five patients. All patients receiving infliximab had tacrolimus-refractory active disease (Lichtiger score >10) and were treated with 5 mg/kg at weeks 0, 2 and 6 and every 8 weeks thereafter, if tolerated.. Six of 24 patients (25%) achieved remission following infliximab infusion and four of 24 (17%) had an initial response only, but underwent proctocolectomy later because of loss of response (3) or development of a delayed hypersensitivity reaction (1). Fourteen patients (58%) completely failed to respond with 10 undergoing colectomy. Eight patients experienced side effects under infliximab, including two infectious complications (herpes zoster and herpes pneumonia).. Infliximab offers a therapeutic option as rescue therapy in about a quarter of patients with active UC after failing to respond to tacrolimus. This benefit has to be weighed against the risks of infectious complications.

Topics: Adolescent; Adult; Aged; Antibodies, Monoclonal; Colitis, Ulcerative; Drug Resistance; Female; Gastrointestinal Agents; Humans; Infliximab; Male; Middle Aged; Tacrolimus; Treatment Outcome; Young Adult

Little is known about the efficacy and safety of infliximab for ulcerative colitis refractory to tacrolimus. The aim of this study was to evaluate the efficacy and safety of infliximab in the induction of remission in ulcerative colitis patients with persistent symptoms despite tacrolimus therapy.. We report a retrospective, observational, single-center case series of 12 consecutively enrolled patients with ulcerative colitis refractory to tacrolimus that received infliximab therapy for the induction of remission. Eight patients received a single infusion of infliximab, and four received two or more infusions. Median follow-up duration was 16.0 months (range, 1.6-41.4 months). The clinical response was evaluated based on a modified Truelove-Witts severity index.. Six patients (50.0%) achieved clinical remission within 30 days. Overall cumulative colectomy-free survival was estimated to be 58.3% at 41.4 months. Adverse events included an elevation of liver enzymes (1/12; 8.3%) and a mild infusion reaction (1/12; 8.3%). No mortality occurred.. Infliximab can induce remission in patients with ulcerative colitis who do not tolerate or respond to tacrolimus therapy.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Anti-Inflammatory Agents; Antibodies, Monoclonal; Colectomy; Colitis, Ulcerative; Drug Resistance; Female; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infliximab; Infusions, Intravenous; Japan; Kaplan-Meier Estimate; Male; Middle Aged; Remission Induction; Retrospective Studies; Severity of Illness Index; Tacrolimus; Time Factors; Treatment Outcome; Young Adult

Topics: Anti-Inflammatory Agents; Antibodies, Monoclonal; Colitis, Ulcerative; Cytomegalovirus; Humans; Infliximab; Tacrolimus; Treatment Outcome

Here we report 2 cases of fatal Pneumocystis jirovecii pneumonia in patients with severe ulcerative colitis receiving combination immunosuppression including tacrolimus. We discuss the necessity of a P. jirovecii prophylaxis especially in elderly patients according to the European evidence-based consensus on the prevention and management of opportunistic infections in inflammatory bowel disease.

Topics: Aged; Colitis, Ulcerative; Fatal Outcome; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Male; Opportunistic Infections; Pneumocystis carinii; Pneumonia, Pneumocystis; Risk Factors; Tacrolimus

The improvement of pre-existing inflammatory bowel disease after orthotopic liver transplant might be anticipated. However, both the exacerbation of inflammatory bowel disease and de novo inflammatory bowel disease after orthotopic liver transplant (despite sufficient allograft immunosuppressive therapy) have been described.. We present a case of ulcerative colitis in a pediatric liver transplant recipient.. A 13-year-old boy with cryptogenic liver cirrhosis received an orthotopic liver transplant from a deceased donor. Five months later, he presented with watery diarrhea and abdominal distention. He was treated with the immunosuppressive agents tacrolimus (0.15 mg/kg/d) and mycophenolate mofetil (20 mg/kg/d). A general physical examination revealed a boy with stable vital signs and without fever. The only positive finding was enlargement of the abdomen without tenderness. Many pus cells and a few red blood cells were detected in the patient's stool, but the results of a stool culture for bacteria were negative. Because of his chronic diarrhea, this patient underwent colonoscopy, which revealed diffuse erythematous mucosa, multiple ulcers, exudate, and pseudopolyps with a diffuse loss of vascularity. Those findings are indicators of colitis. The results of histopathologic examination of the colonic mucosa suggested ulcerative colitis. The patient was treated with mesalamine and prednisolone, and a repeat colonoscopy revealed an improvement in his bowel disease.. De novo inflammatory bowel disease should be considered in patients in whom chronic diarrhea develops after an orthotopic liver transplant. We suggest that colonoscopy and biopsy should always be performed if other causes of diarrhea have been excluded.

Topics: Adolescent; Anti-Inflammatory Agents; Biopsy; Chronic Disease; Colitis, Ulcerative; Colon; Colonoscopy; Diarrhea; Drug Therapy, Combination; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Intestinal Mucosa; Liver Cirrhosis; Liver Transplantation; Male; Mesalamine; Mycophenolic Acid; Prednisolone; Tacrolimus; Transplantation, Homologous; Treatment Outcome

Topics: Administration, Topical; Adult; Colectomy; Colitis, Ulcerative; Colonic Neoplasms; Fatal Outcome; Humans; Male; Pyoderma; Risk Assessment; Severity of Illness Index; Stomatitis; Tacrolimus; Treatment Outcome

Resistant ulcerative proctitis can be extremely difficult to manage. Oral tacrolimus can be effective, but may have numerous adverse effects. Topically administered tacrolimus, however, may also be effective in proctitis. Aim To undertake a pilot study to assess a potential role for topical tacrolimus in the management of resistant ulcerative proctitis.. Patients with resistant ulcerative proctitis were assessed prospectively by the colitis activity index (CAI) and Modified Mayo score. Topical rectal tacrolimus ointment was commenced at 0.3 mg/mL 3 mL b.d. and increased depending on clinical response. CAI and modified Mayo scores were assessed at 0 and 8 weeks, as were steroid usage and adverse effects.. Eight patients (five male/three female) with inflammation to a maximum of 30 cm from the anus were included. All patients had failed disease control with 5-aminosalicylic acids, steroids, immunosuppressants and infliximab therapy. The mean initial CAI was 12.1 (range 9-16) and the mean modified Mayo score was 8.0 (range 6-9). After 8 weeks, six of eight patients achieved remission with steroids reduced or ceased in five of six. There were no significant adverse effects.. This prospective pilot study demonstrated that topical rectal tacrolimus ointment can be effective in ulcerative proctitis. The preparation was well tolerated with no significant adverse effects. Further controlled studies are required.

Topics: Adult; Colitis, Ulcerative; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Ointments; Pilot Projects; Proctitis; Prospective Studies; Rectum; Severity of Illness Index; Tacrolimus; Treatment Outcome; Western Australia; Young Adult

Topics: Adult; Colitis, Ulcerative; Humans; Immunosuppressive Agents; Intestinal Mucosa; Male; Remission Induction; Tacrolimus

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.

Topics: Cohort Studies; Colitis, Ulcerative; Crohn Disease; Female; Humans; Male; North America; Retrospective Studies; Tacrolimus; Treatment Outcome

This study aimed to evaluate the efficacy of oral tacrolimus in patients with inflammatory bowel disease (IBD) refractory to conventional therapy, including azathioprine, 6-mercaptopurine, and infliximab.. Retrospective review of all patients with IBD treated with oral tacrolimus was undertaken. Tacrolimus was administered t an initial dose of 0.05 mg/kg twice daily, aiming for serum trough levels of 5-10 ng/mL. We evaluated clinical response, a retrospective estimated Crohn's disease activity index (CDAI) for Crohn's disease (CD), modified Truelove-Witts index for ulcerative colitis (UC), and modified pouch disease activity index (mPDAI) for pouchitis. Patients had been monitored clinically for benefit and side effects and by whole blood tacrolimus level approximately every 4 weeks for the duration of treatment. Clinical remission was defined as an estimated CDAI <150 (CD), an inactive disease score on the Truelove-Witts index (UC), and mPDAI <5 (pouchitis).. Twelve patients with CD, six with UC, and one with pouchitis, all resistant to previous therapies, were treated for a median of 5 months. After 4 weeks 10 CD (83%), four UC (67%) patients, and one pouchitis patient had a clinical response. There was a median reduction of the estimated CDAI of 108 points (range 35-203; P = 0.002) and stool frequency of three per day at week 4. Remission was achieved in 42% (5/12) of CD and 50% (3/6) of UC patients at the end of follow-up. Side effects included temporary elevated creatinine (n = 1), tremor (n = 3), arthralgia (n = 1), insomnia (n = 1), and malaise (n = 1). Four patients discontinued treatment due to side effects. CONCLUSION-: Oral tacrolimus is well tolerated and effective in patients with refractory IBD in the short- to medium-term. Further controlled, long-term evaluation is warranted.

Topics: Administration, Oral; Adolescent; Adult; Aged; Colitis, Ulcerative; Crohn Disease; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Intestinal Fistula; Male; Middle Aged; Pouchitis; Tacrolimus; Treatment Outcome

The purpose of this article is to describe the outcomes of the pouches of 14 children with ulcerative colitis (UC) who were pretreated with calcineurin inhibitors before they underwent their ileal pouch anal anastomosis (IPAA) surgery.. An institutional review board-approved retrospective review of the charts of consecutive patients with UC treated with calcineurin inhibitors before undergoing IPAA surgery at a tertiary pediatric center between 1998 and 2003 was performed. The primary endpoint was pouch outcome after at least 2 years of follow-up (healthy pouch, acute pouchitis, chronic refractory pouchitis, or pouch failure); the secondary endpoints were early postoperative complications, number of stages, and time between stages.. Fourteen of 53 consecutive patients who underwent IPAA for UC were treated with calcineurin inhibitors before their surgery (26%; 6 with cyclosporine and 8 with tacrolimus). All 14 patients were concomitantly treated with systemic steroids. Ten patients (71%) were also taking 6-mercaptopurine or azathioprine, and 9 (64%) were also taking mesalamine. Three patients (21%) had healthy pouches with no clinical evidence of pouchitis, 6 (43%) had at least one episode of acute pouchitis (average of 2 episodes per year), 3 (21%) had chronic relapsing pouchitis, and 2 (14%) were later determined to have Crohn's disease. There was no pouch failure. Two patients (14%) had an early postoperative complication (intraabdominal abscess, anastomotic stricture). Five patients (36%) had a 2-staged procedure, and 8 (64%) had a 3-staged procedure. For the 2-staged procedures, the mean time between the first and second stages was 3.14 months (range, 3-4 months). For the 3-staged procedures, the mean time between the first and second stages was 4.25 months (range, 2-6 months) and that between the second and third stages was 4 months (range, 2.5-6 months).. In this series, chronic pouchitis was an infrequent complication among children who were pretreated with calcineurin inhibitors. Calcineurin inhibitor use did not lead to or portend increased early postoperative complications or affect the number or duration of surgical stages. Further studies are required to determine if preoperative calcineurin inhibitors improve pouch outcomes or facilitate the performance of 2-staged procedures.

Topics: Adolescent; Calcineurin Inhibitors; Child; Child, Preschool; Colitis, Ulcerative; Colonic Pouches; Cyclosporine; Female; Humans; Immunosuppressive Agents; Male; Proctocolectomy, Restorative; Retrospective Studies; Tacrolimus; Treatment Outcome

A19-year-old man complaining of severe diarrhea and hematochezia was admitted to our hospital. Endoscopic findings and laboratory data revealed that he had ulcerative colitis (UC). Despite combination therapy with high-dose corticosteroids and intensive granulocytapheresis, his condition did not improve. Therefore, we initiated tacrolimus therapy. Intravenous administration of tacrolimus with a trough level of 10 to 15 ng/ml relieved his abdominal symptoms within 1 week. The patient experienced no UC relapse 1 year after treatment with oral tacrolimus. Tacrolimus is a promising therapy for patients with UC refractory to the combination of high-dose corticosteroids and leukocytapheresis.

Topics: Administration, Oral; Adrenal Cortex Hormones; Adult; Colitis, Ulcerative; Combined Modality Therapy; Dose-Response Relationship, Drug; Humans; Immunosuppressive Agents; Leukapheresis; Male; Salvage Therapy; Tacrolimus

To alert clinicians to a potential novel adverse drug effect of interferon beta 1a, we herein report a patient with relapsing-remitting multiple sclerosis who developed ulcerative colitis following treatment with interferon beta 1a. Ulcerative colitis persisted despite discontinuation of interferon beta 1a treatment and switching the patient to glatiramer acetate. Tacrolimus (FK506), 6-mercaptopurine, and prednisolone were required to induce remission. Both ulcerative colitis and multiple sclerosis were eventually well controlled using this regimen. Our report underscores that caution should be exercised when prescribing immunostimulatory agents in patients with inflammatory bowel disease (IBD) and challenges current efforts to stimulate innate immunity as a novel therapeutic concept for IBD.

Topics: Adjuvants, Immunologic; Adult; Colitis, Ulcerative; Female; Glatiramer Acetate; Humans; Immunity, Innate; Immunosuppressive Agents; Interferon beta-1a; Interferon-beta; Mercaptopurine; Multiple Sclerosis; Peptides; Prednisolone; Recurrence; Tacrolimus

To evaluate tacrolimus in 3 situations: for the induction of remission in children with severe steroid-resistant ulcerative colitis (UC); for steroid sparing in children with steroid-dependent UC in whom treatment with other immunosuppressants fails; and for the maintenance of remission in children with steroid-dependent and steroid-resistant UC.. We retrospectively evaluated 18 consecutive patients (13 with pancolitis) who were treated with oral tacrolimus at our institution from May 1999 to October 2005. Nine patients had steroid-resistant UC and 9 patients were steroid-dependent. We started patients initially on tacrolimus 0.2 mg/kg divided twice daily, with a goal plasma trough level of 10 to 15 ng/mL for the first 2 weeks, and then titrated doses to achieve plasma levels between 7 and 12 ng/mL after induction.. Of the 18 patients in this study, 17 showed a positive response to tacrolimus therapy (ie, cessation of diarrhea and other symptoms) and 5 showed a prolonged response to tacrolimus. The mean time from initiation of tacrolimus therapy until response was 8.5 days. The mean duration of response was 260 days. Eleven of 18 patients required colectomy, including all of the patients with steroid-resistant UC, but only 2 of 9 who were steroid-dependent. The mean time from initiation of tacrolimus until colectomy was 392 days.. It is possible that tacrolimus may benefit selected patients with steroid-dependent UC, including those who are intolerant of 6-mercaptopurine or azathioprine. Conversely, patients with steroid-resistant UC are unlikely to sustain a prolonged clinical response to tacrolimus and seem to require colectomy eventually. Careful considerations of risk versus benefit, as well as close monitoring for adverse effects, are essential in all patients.

Topics: Administration, Oral; Adolescent; Child; Child, Preschool; Colitis, Ulcerative; Dose-Response Relationship, Drug; Drug Resistance; Female; Humans; Immunosuppressive Agents; Infant; Male; Remission Induction; Retrospective Studies; Steroids; Tacrolimus; Time Factors; Treatment Outcome

We and others have reported the use of tacrolimus in refractory inflammatory bowel disease (IBD). Little is known about its long-term efficacy and safety.. In this retrospective, observational single center study the charts of 53 adult patients with steroid-dependent (n = 18) or steroid-refractory (n = 35) IBD, Crohn's disease (CD) (n = 11), ulcerative colitis (UC) (n = 40), or pouchitis (PC) (n = 2) were reviewed. Tacrolimus (0.1 mg/kg body weight per day) was administered orally in all and initially intravenously in 2 patients (0.01 mg/kg body weight per day), aiming for serum trough levels of 4-8 ng/mL. Forty-one of 53 (77.1%) patients were receiving concomitant azathioprine. The mean treatment duration was 25.2 +/- 4.6 SD months (0.43-164 months). Patients were followed for a mean of 39 +/- 4.1 SD months (5-164 months). Response was evaluated using a modified clinical activity index (M-CAI).. Thirty-one UC (78%), 10 CD (90.1%), and both PC (100%) patients experienced an immediate clinical response or went into remission at 30 days. A statistically significant drop on the M-CAI was documented for UC and CD patients. Nine UC patients (22.5%) underwent colectomy between 1.6 and 41.3 months following initiation. Mean colectomy-free survival was 104.8 +/- 15.5 (95% CI 74.4-135.2) months (limited to 164.4 months). Cumulative colectomy-free survival was estimated 56.5% at 43.8 months. Steroids were reduced or discontinued in 40 of 45 UC and CD patients (90%) taking steroids. Side effects included a temporary rise of creatinine (n = 4, 7.6%), tremor or paresthesias (n = 5, 9.4%), hyperkalemia (n = 1, 1.9%), hypertension (n = 1, 1.9%), and opportunistic infections (n = 2, 3.8%).. Long-term tacrolimus therapy appears safe and effective in refractory IBD.

Topics: Adult; Aged; Azathioprine; Colectomy; Colitis, Ulcerative; Crohn Disease; Drug Resistance; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Pouchitis; Remission Induction; Retrospective Studies; Steroids; Tacrolimus; Treatment Outcome

Topics: Administration, Oral; Colitis, Ulcerative; Humans; Immunosuppressive Agents; Tacrolimus; Treatment Outcome

We report a case of severe ulcerative colitis complicated with primary diabetes mellitus that was effectively treated with oral tacrolimus. A 36-year-old man suffered his first attack of ulcerative colitis. Because it was difficult to control the patient's diabetes, we instituted tacrolimus and azathioprine without a corticosteroid regimen as the initial treatment. Within two weeks, the ulcerative colitis activity went into remission and the patient's diabetes did not worsen.

Topics: Administration, Oral; Adult; Colitis, Ulcerative; Diabetes Mellitus, Type 1; Humans; Immunosuppressive Agents; Male; Tacrolimus

Topics: Adult; Colitis, Ulcerative; Female; Humans; Immunosuppressive Agents; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Tacrolimus

Topics: Azepines; Cholinergic Agents; Colitis, Ulcerative; Crohn Disease; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Isoquinolines; Pyridazines; Tacrolimus; Thiazoles

We describe two male patients with ulcerative colitis and refractory pyoderma gangrenosum including periorbital phlegmona in one case. Both patients were successfully managed with low dose oral tacrolimus (0.1 mg/kg bodyweight per day). Serum trough levels were closely monitored and maintained between 4 and 6 ng/mL. A rapid response was noted in both cases. Complete non-scarring skin restitution without side effects was accomplished in both cases. Low dose oral tacrolimus provides a valuable alternative treatment option for IBD patients with refractory pyoderma gangrenosum.

Topics: Adult; Cellulitis; Colitis, Ulcerative; Humans; Immunosuppressive Agents; Male; Orbital Diseases; Pyoderma Gangrenosum; Tacrolimus; Treatment Outcome

Steroid refractory ulcerative colitis is most commonly treated with intravenous ciclosporin to avoid colectomy. In search for an alternative drug that can be administered orally we investigated oral tacrolimus (FK 506) for this indication.. Nine patients with active, moderate/severe steroid refractory UC were treated with oral tacrolimus with a daily dose of 0.15 mg/kg body weight. After patients had responded azathioprine was added for long-term immunosuppression.. All patients responded within 1-2 weeks. After 12 weeks of tacrolimus therapy six patients (67%) were in complete remission, two patients (22%) had mild to moderate disease activity, and one patient (11%) underwent colectomy. After a mean follow up of 21 months six of the nine patients (67%) had their colon in situ. Two patients developed severe side-effects, one thrombopenia with intestinal bleeding, and one bicytopenia. Mild side-effects were common.. Oral tacrolimus may be an effective alternative to intravenous ciclosporin for the therapy of steroid-refractory ulcerative colitis. Patients receiving tacrolimus need to be watched carefully for side-effects.

Topics: Administration, Oral; Adolescent; Adult; Colitis, Ulcerative; Female; Follow-Up Studies; Humans; Immunity, Innate; Immunosuppressive Agents; Male; Middle Aged; Recurrence; Steroids; Tacrolimus; Treatment Outcome

Topics: Administration, Topical; Adolescent; Colitis, Ulcerative; Humans; Immunosuppressive Agents; Male; Pyoderma Gangrenosum; Tacrolimus; Treatment Outcome

Pyoderma gangrenosum is a distinct clinical entity characterized by chronic, recurring, destructive ulcerations. Although the pathogenesis of pyoderma gangrenosum is unknown, immunologic aberrations of neutrophil granulocytes seem to be important. Systemic steroids and macrolide lactones such as cyclosporin A and tacrolimus have been reported to be useful in the clinical management of disease. Pyoderma gangrenosum has been found to be associated with several systemic diseases. The association with chronic ulcerative colitis is well known, but the diagnosis may be complicated by early administration of systemic steroids. Therefore, local immunosuppression with topically applied agents could be an efficient therapeutic alternative especially for mild or early cutaneous lesions.We describe the successful topical treatment of a patient with multiple lesions of pyoderma gangrenosum with 0,1% tacrolimus (FK506) ointment which is known to have better dermal penetration and higher immunosuppressive potency than topical cyclosporin A. In addition, other indications for topical tacrolimus are discussed.

Topics: Abdomen; Adult; Colitis, Ulcerative; Humans; Immunosuppressive Agents; Male; Ointments; Pyoderma Gangrenosum; Tacrolimus; Time Factors; Ultrasonography

Inflammatory bowel disease is accompanied by cutaneous manifestations in about 10% of cases. Erythema nodosum and pyoderma gangraenosum are most frequently observed, which often subside on treatment of the underlying disease.. A 30-year-old male with a history of long-standing ulcerative colitis experienced an acute attack despite treatment with azathioprine. Further he noticed dull red, elevated and tender maculae on the forelegs. A disseminated and papulosquamous exanthema arose on the back of the trunk and the upper extremities without pruritus. Well-being was compromised and blood sampling revealed an inflammatory response. High-dose steroids with antibiotics were without benefit until they were combined with tacrolimus, an immunosuppressive agent acting similar to ciclosporin. Remission occurred rapidly and the skin lesions resolved. Six months later the patient is currently still in remission and developed no signs of recurrent exanthema.. The cutaneous lesions are thought to be related to ulcerative colitis and were classified as erythema nodosum and Sweet syndrome. This is the first report on the successful use of tacrolimus in steroid-refractory ulcerative colitis with extraintestinal cutaneous involvement.

Topics: Adult; Anti-Inflammatory Agents; Colitis, Ulcerative; Drug Therapy, Combination; Drug Tolerance; Erythema Nodosum; Humans; Immunosuppressive Agents; Male; Steroids; Sweet Syndrome; Tacrolimus; Treatment Outcome

We report a case of refractory ulcerative colitis treated with tacrolimus. The patient was a 73-year-old woman with a 45-year history of ulcerative colitis. An attack unresponsive to intravenous corticosteroid therapy occurred when she was age 73. Leukocytapheresis therapy was attempted, but was discontinued because of the patient's poor general condition. Cyclosporine A therapy brought about fair control of the disease. A liver injury that was suspected to be associated with this agent, however, occurred within 5 weeks of its initiation. At that time, the cyclosporine A was discontinued and azathioprine treatment was started. Within 6 weeks, signs of exacerbation of the ulcerative colitis became apparent. Tacrolimus administered at that time brought about remission of the disease, and the corticosteroid dose was then reduced. Tacrolimus, like cyclosporine A, appears to be effective for the treatment of attacks of ulcerative colitis.

Topics: Aged; Azathioprine; Colitis, Ulcerative; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Leukapheresis; Methylprednisolone; Prednisolone; Remission Induction; Sulfasalazine; Tacrolimus; Treatment Failure

Steroid treatment failure in acute Crohn's disease and ulcerative colitis frequently necessitates surgical intervention. Several alternative therapeutic strategies have been raised. The most promising so far has been intravenous cyclosporine, but the results in the long term have been discouraging. We assessed the efficacy and safety of the new macrolide immunomodulator tacrolimus as an alternative to cyclosporine A.. Eleven patients with steroid-refractory disease (six ulcerative colitis, two indeterminate colitis, two Crohn's disease, one pouchitis) and severe activity according to the Truelove and Witts criteria or Crohn's disease activity index > 150, respectively, were eligible for the study. All patients were treated with intravenous tacrolimus for 7-10 days followed by oral treatment over a median period of 7 months (range 0.25-16). Azathioprine and mesalamine were given concomitantly. Steroids were tapered according to clinical activity.. Seven of 11 patients achieved remission rapidly, whereas a modest improvement was noted in two. Only two patients required an early and one a delayed colectomy. Moreover, a rectovaginal fistula closure in a case of Crohn's disease and an improvement of pouchitis was observed. A tapering to low dose steroids was possible during oral tacrolimus therapy in all nine responders and remission was maintained in five of them (mean follow-up 9.2 months). The drug was well tolerated and side effects were managed conservatively.. Tacrolimus induced rapid remission in steroid resistant inflammatory bowel disease in the majority of cases. It appears to be an effective treatment modality that may be superior to cyclosporine with respect to maintenance of remission.

Topics: Adolescent; Adult; Aged; Anti-Inflammatory Agents; Colitis, Ulcerative; Crohn Disease; Cyclosporine; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Pilot Projects; Prospective Studies; Remission Induction; Steroids; Tacrolimus; Time Factors; Treatment Failure

Topics: Azathioprine; Cholangitis, Sclerosing; Colitis, Ulcerative; Crohn Disease; Cyclophosphamide; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Liver Transplantation; Male; Middle Aged; Muromonab-CD3; Retrospective Studies; Steroids; Tacrolimus