piperidines and Colitis--Ulcerative

Recent real-world effectiveness studies investigating tofacitinib have been encouraging. Questions remain regarding the long-term effectiveness and safety of tofacitinib, effect on endoscopic remission rates, histologic changes, and alterations in fecal calprotectin levels.. This retrospective study includes consecutive patients with inflammatory bowel disease (IBD) who initiated tofacitinib therapy. We reviewed electronic medical records for demographic and clinical data, as well as all adverse events and hospitalizations. All patients receiving tofacitinib were included in the safety analysis and only patients with ulcerative colitis (UC) were included in the effectiveness analysis.. 119 patients with IBD (97 UC, 12 CD, and 10 pouchitis) seen at our center between 2014 and 2020 were included in this study. Median follow-up was 32 weeks (interquartile range (IQR) 3-252). Clinical response and remission were observed in 70% and 21%, 59% and 33%, and 49%, and 37% at weeks 8, 24, and 52, respectively. Endo-histologic healing was achieved by 11%, 25%, and 37.5% of patients at weeks 8, 24, and 52, respectively. Histologic normalization occurred as early as 24 weeks in this cohort and was achieved by 26% of patients in endoscopic remission. Overall, there were 27 (25%) adverse events with 6 (5%) resulting in treatment discontinuation. There were 11 (10%) infections, none required treatment discontinuation. Ten (10.3%) patients underwent colectomy during the follow-up period. There were no cardiovascular adverse events in the cohort during follow-up.. This study demonstrates the effectiveness and long-term safety of tofacitinib in patients with UC. Importantly, we show that the endpoint of endo-histologic healing is achievable with tofacitinib and can occur as early as week 8 of therapy.

Topics: Colitis, Ulcerative; Humans; Inflammatory Bowel Diseases; Piperidines; Retrospective Studies

Tofacitinib has emerged as a new potential treatment for acute severe ulcerative colitis [ASUC]. We conducted a systematic review to assess efficacy, safety and integration in ASUC algorithms.. Systematic searching was done in MEDLINE, EMBASE, Cochrane Library and Clinicaltrials.gov until August 17, 2022, including all studies reporting original observations on tofacitinib for ASUC, preferably defined according to Truelove and Witts criteria. The primary outcome was colectomy-free survival.. Of 1072 publications identified, 21 studies were included of which three were ongoing clinical trials. The remaining comprised a pooled cohort originating from 15 case publications [n = 42], a GETAID cohort study [n = 55], a case-control study [n = 40 cases] and a paediatric cohort [n = 11]. Of these 148 reported cases, tofacitinib was used as second-line treatment after steroid failure in previous infliximab failures or third-line after sequential steroid and infliximab or cyclosporine failure, 69 [47%] were female, median age range was 17-34 years and disease duration was 0.7-10 years. Overall, 30-day colectomy-free survival was 85% [n = 123 of 145; n = 3 without colectomy had follow-up <30 days], 90-day 86% [n = 113 of 132; n = 16 follow-up <90 days] and 180-day 69% [n = 77 of 112; n = 36 follow-up <180 days]. Tofacitinib persistence at follow-up was 68-91%, clinical remission 35-69% and endoscopic remission 55%. Adverse events occurred in 22 patients, predominantly being infectious complications other than herpes zoster [n = 13], and resulted in tofacitinib discontinuation in seven patients.. Tofacitinib appears promising for treatment of ASUC with high short-term colectomy-free survival among refractory patients who are otherwise deemed to require colectomy. However, large high-quality studies are needed.

Topics: Colitis, Ulcerative; Humans; Janus Kinase Inhibitors; Piperidines; Pyrimidines; Treatment Outcome

Despite rescue therapy, acute severe ulcerative colitis (ASUC) is associated with a high risk of colectomy, while treatment options remain limited. Tofacitinib, a rapidly acting Janus Kinase (JAK) inhibitor, is gaining ground as an effective alternative treatment option for the management of acute severe ulcerative colitis, which may prevent emergency colectomy.. A systematic literature search of PubMed and Embase was undertaken for studies of adult patients with ASUC treated with tofacitinib.. In total, two observational studies, seven case series and five case reports incorporating 134 patients who received tofacitinib in ASUC were identified with a follow-up period ranging from 30 days to 14 months. Overall, the pooled colectomy rate was 23.9% (95% CI 16.6-31.2). The pooled 90-day and 6-month colectomy free rate were 79.9% (95% CI 73.1-86.7) and 71.6% (95% CI 64-79.2) respectively. The most frequent adverse event was C. Difficile infection.. Tofacitinib appears to be a promising option for the treatment of ASUC. Randomized clinical trials are required to further access the efficacy, safety and optimal dose of tofacitinib in cases of ASUC.

Topics: Adult; Clostridioides difficile; Colectomy; Colitis, Ulcerative; Humans; Janus Kinase Inhibitors; Piperidines; Pyrimidines; Treatment Outcome

Extraintestinal manifestations (EIMs) are commonly seen in patients with inflammatory bowel disease (IBD); management of EIMs is difficult and increases the primary disease burden. Recently, tofacitinib (TOF) was reported to be a promising option for treatment of EIMs. We aimed to review published articles and report experience to date.. The PubMed, Cochrane Library, and Web of Science databases were searched to identify eligible studies. The inclusion criteria were as follows: confirmed diagnosis of IBD; definitive EIMs; treatment with TOF; human study and published in English. The Newcastle-Ottawa Scale score and Cochrane Collaboration's tool for assessing risk of bias were used to determine the quality of the selected studies.. Twenty-three studies met the inclusion criteria and were included. For nonrandomized studies, 16 were low quality, 5 were moderate quality, and 1 was high quality. For the one randomized controlled trial, the overall bias risk was low. The most concerning EIMs were dermatological manifestations, rheumatologic manifestations, and others, such as primary sclerosing cholangitis, autoimmune hepatitis, uveitis, and Takayasu arteritis. After administering doses of 5-20 mg/d TOF, the included studies reported varying degrees of clinical remission for both the primary disease and EIMs, except for musculoskeletal EIMs.. TOF might benefit EIMs in IBD, especially ulcerative colitis, and elevated dosages and longer treatment times may increase its effectiveness. Manifestation-specific results and large prospective studies are highly warranted.

Topics: Colitis, Ulcerative; Humans; Inflammatory Bowel Diseases; Piperidines; Prospective Studies; Pyrimidines; Uveitis

Tofacitinib has emerged as a useful drug for the treatment of ulcerative colitis (UC).. There is an unmet need for cost-effective, non-immunogenic drugs with a safe adverse effect profile to treat patients with ulcerative colitis. In the present review, we evaluate the available literature to inform the appropriate positioning of tofacitinib in the current drug landscape and identify subsets where its use should be done with caution.. Tofacitinib is helpful in the treatment of patients where the standard conventional or biological therapies have failed or were not tolerated. With lower costs of the generic drug than the biologicals (or biosimilars), it could be an important therapy in low- to middle-income countries. The risk of infections, especially Herpes Zoster and tuberculosis, needs to be addressed before initiation. Tofacitinib should be avoided in patients with venous thromboembolism and cardiovascular disease risk factors. Due to limited evidence, the use is not recommended in pregnancy, while it should be used with caution in elderly citizens. Future trials should look into the head-to-head comparison of tofacitinib with biologicals. The role of tofacitinib in acute severe colitis needs evaluation with comparative trials with current standards of care.

Topics: Aged; Biosimilar Pharmaceuticals; Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Pyrroles

Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). The induction dose is 10 mg twice daily (b.d.), whilst for maintenance therapy, the lowest effective dose should be used.. To examine published evidence on the two tofacitinib dosing strategies used in UC treatment, including expert interpretation of the data and how they could inform clinical practice.. The use of tofacitinib 5 or 10 mg b.d. was assessed using data from the tofacitinib UC clinical programme in the context of different clinical scenarios. We include experts' opinions on the clinical implications of dose adjustment to inform the benefit/risk of using tofacitinib 5 or 10 mg b.d., based on clinical scenarios and real-world data.. Factors to consider when adjusting the tofacitinib dose include disease severity, comorbidities and previous biological exposure. The endoscopic subscore can determine whether a patient is a good candidate for dose reduction. Following disease relapse, the response can be recaptured in a substantial number of patients with a dose increase. Furthermore, data are now published showing real-world use of tofacitinib and, so far, these are consistent with data from the clinical trials.. Clinicians must consider the benefit/risk balance of tofacitinib 10 versus 5 mg b.d. in terms of dose-related side effects, as well as the safety implications of undertreating active disease. All patients should be closely monitored for disease relapse following dose reduction or interruption for early recapture of response.

Topics: Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Pyrroles; Recurrence

Knowledge of the real-world effectiveness and safety of tofacitinib for ulcerative colitis (UC) is relevant to confirm the benefit observed in clinical trials.. This systematic review and meta-analysis evaluated the real-world effectiveness of tofacitinib for moderate to severely active UC. The primary outcome was clinical remission evaluated at week 8, weeks 12 to 16, and month 6. Secondary outcomes were response, corticosteroid-free remission, mucosal healing, colectomy, and safety.. Seventeen studies with a total of 1162 patients with UC were included. Remission (11 studies) was achieved in 34.7% of patients at week 8 (95% confidence interval [CI], 24.4%-45.1%), 47% at weeks 12 to 16 (95% CI, 40.3%-53.6%), and 38.3% at month 6 (95% CI, 29.2%-47.5%) at month 6 duplicated. Response was achieved in 62.1%, 64.2%, 50.8%, and 41.8% of patients at week 8, weeks 12 to 16, month 6, and month 12, respectively. Corticosteroid-free remission (5 studies) was achieved in 38.4%, 44.3%, 33.6%, and 31% of patients at week 8, weeks 12 to 16, month 6, and month 12, respectively. Mucosal healing was achieved in 48.3% and 45.3% of patients at week 8 and weeks 12 to 16, respectively. Patients who were biologic-naïve (11.6%) had a significantly higher rate of response at week 8 (1.38; 95% CI, 1.03-1.84). The incidence rates of serious adverse events and herpes zoster was 8.9 and 6.9 per 100 patient-years, respectively.. This meta-analysis of real-world studies confirms the effectiveness of tofacitinib in a highly refractory population of patients with moderate to severely active UC. Tofacitinib showed an acceptable safety profile. These findings were consistent with clinical trials and further support the use of tofacitinib in UC.

Topics: Colectomy; Colitis, Ulcerative; Humans; Piperidines; Pyrimidines

Several observational studies on Tofacitinib (TOFA) in ulcerative colitis (UC) have been published over the last 2 years.. To estimate effectiveness and safety of TOFA arising from real-world experience.. PubMed Central/Medline and Embase were systematically searched for real-world observational studies on TOFA for the treatment of UC through November 2020.. Seven studies comprising 759 patients met the inclusion criteria. The pooled estimate rates were 49% for clinical response, 40% for clinical remission, and 34% for corticosteroid-free clinical remission at induction, while the rates of endoscopic response and endoscopic remission were 37% and 19%, respectively. At maintenance, the pooled estimate rates of clinical response, clinical remission, and corticosteroid-free clinical remission were 36%, 35%, and 24%, respectively. The pooled estimate of incidence rate of adverse events was 53.0 per 100 person-years (PY), while the pooled estimate of incidence rate of withdrawal of TOFA due to adverse events was 9.3 per 100 PY, with a pooled rate of infections of 17.6 per 100 PY.. Cumulative analysis of data from real-world studies confirmed the good efficacy of TOFA in UC shown by randomized controlled trials for both induction and maintenance, while the safety profile was consistent with previous reports.

Topics: Adult; Colitis, Ulcerative; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Incidence; Induction Chemotherapy; Janus Kinase Inhibitors; Maintenance Chemotherapy; Male; Middle Aged; Observational Studies as Topic; Piperidines; Pyrimidines; Treatment Outcome

BACKGROUND Ulcerative colitis (UC) is a chronic autoimmune inflammatory disease of the colon that infrequently affects children. The disease requires immunosuppressive therapy to achieve remission and keep the disease in remission. Currently, many therapies are approved for use in pediatric patients with UC, including steroid, 5-aminosalicylic acid (5-ASA), azathioprine, and biologic therapy with anti-tumor necrosis factor (TNF) inhibitors. Despite their efficacy, many patients have refractory severe disease that fails therapy and may require surgical interventions. Recently, the small molecule Janus Kinase (JAK) inhibitor tofacitinib has been approved for moderate to severe UC that fails biologic therapy in adults. However, the safety and efficacy of this drug has not been tested in pediatric UC patients. CASE REPORT We describe a case of a 13-year-old girl with 2-year history of severe UC who had secondary loss response to both infliximab and adalimumab over 2 years, despite adequate trough serum drug levels and the concomitant use of azathioprine. She was also dependent on steroid to control her disease. Infectious work-ups were always negative for infectious organisms. She was then successfully treated with tofacitinib 5 mg orally twice daily. She went into complete clinical, endoscopic, and steroid-free remission. CONCLUSIONS This case report highlights the safety and efficacy of tofacitinib in pediatric patients with severe refractory UC, potentially avoiding proctocolectomy in this young patient population. Future research should study the role of tofacitinib in patients with moderate to severe UC in children.

Topics: Adolescent; Adult; Child; Colitis, Ulcerative; Female; Humans; Piperidines; Pyrimidines; Steroids

For a significant proportion of patients with inflammatory bowel disease (IBD), primary non-response and secondary loss of response to treatment remain significant issues. Anti-tumor necrosis factor therapies have been licensed for use in IBD. Other disease-related pathways have been targeted as well, including the interleukin 12/23 axis and lymphocyte tracking. However, the need for parenteral administration and the associated costs of dispensing and monitoring all biologics remain a burden on healthcare systems and patients. Janus kinase inhibitors are small-molecule drugs that can be administered orally and are relatively inexpensive, thus offering an additional option for treating IBD. They have been shown to be effective in patients with ulcerative colitis (UC), but they are less effective in those with Crohn's disease (CD). Nonetheless, given the immune-system-based mechanism of these drugs, their safety profile remains a cause for concern. This article provides an overview of Janus kinase (JAK) inhibitors and new trends in the treatment of IBD.

Topics: Adamantane; Colitis; Colitis, Ulcerative; Crohn Disease; Heterocyclic Compounds, 3-Ring; Humans; Inflammatory Bowel Diseases; Janus Kinase Inhibitors; Janus Kinases; Niacinamide; Piperidines; Pyridines; Pyrimidines; Pyrroles; Triazoles

Tofacitinib citrate is an oral Janus kinase 1/3 inhibitor approved for rheumatoid arthritis, ulcerative colitis, and active psoriatic arthritis. Tofacitinib is being increasingly used off-label for dermatological conditions, with varying efficacy across recent studies. A review of these studies will be a helpful resource for dermatologists considering the use of tofacitinib for conditions refractory to first-line therapies.. MEDLINE, Embase, CINAHL Plus, Cochrane Library, Scopus, Web of Science, Clinicaltrials.gov, and the WHO International Clinical Trials Registry Platform were all searched for articles and trials mentioning the term 'tofacitinib', then manually reviewed to identify published data on off-label uses of tofacitinib. The article was structured according to the quality of the evidence available.. Tofacitinib appears to show strong efficacy for numerous dermatologic conditions. Randomized controlled trial data is available for atopic dermatitis, alopecia areata, and plaque psoriasis. Case report and case series data is available for numerous other dermatologic conditions.. While tofacitinib has a wide array of immunoregulatory properties, making it a possible candidate for treating many dermatologic conditions refractory to other treatments, further testing is needed to better characterize its efficacy and utility moving forward, as well as its safety and adverse effect profile.

Topics: Alopecia Areata; Arthritis, Psoriatic; Colitis, Ulcerative; Dermatitis, Atopic; Dermatology; Humans; Off-Label Use; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Randomized Controlled Trials as Topic

Biological agents are commonly used for the treatment of ulcerative colitis (UC). As new treatments, tofacitinib, and fecal microbiota transplantation (FMT) have demonstrated efficacy in treating UC. This network meta-analysis aims to determine the efficacy and safety of biological agents, tofacitinib, and FMT.. A network meta-analysis was conducted by systematically searching the PubMed, Embase, and Cochrane Libraries. According to strict inclusion and exclusion criteria, we included randomized controlled trials (RCTs) of biological agents, tofacitinib, and FMT in UC. A random-effect model was chosen by the network meta-analysis and sensitivity analysis. Heterogeneity test and publication bias test were performed to determine the efficacy of treatments.. Data were extracted from 16 RCTs and we found that all treatments were more effective than the placebos. A total of 21 comparisons were made to determine efficiency. We found that infliximab, vedolizumab, and FMT performed better curative effect in terms of absolute effects and relative ranks. Furthermore, there was no statistical difference in the efficacy of biological agents, tofacitinib, and FMT. Moreover, no treatments were found to increase the occurrence of adverse events when compared with placebos, except infliximab. However, vedolizumab seemed to reduce the occurrence of adverse events compared with infliximab.. Of the biological agents, vedolizumab and infliximab were the most effective, suggesting that biological agents are still a better choice. Nevertheless, tofacitinib and FMT may be promising alternatives with high efficacies. However, more safety and maintenance studies need to be conducted in future for the acquisition of more accurate results.

Topics: Antibodies, Monoclonal; Biological Factors; Colitis, Ulcerative; Fecal Microbiota Transplantation; Humans; Janus Kinase Inhibitors; Network Meta-Analysis; Piperidines; Pyrimidines; Randomized Controlled Trials as Topic; Treatment Outcome

The use of Janus kinase (JAK) inhibitors is a new approach in the therapy of inflammatory diseases with immune base. Tofacitinib is one of these inhibitors targeting JAK1 and JAK3, and its efficacy has been demonstrated in the treatment of moderate to severe ulcerative colitis (UC). It is a small synthetic molecule administered orally, with a fast bioavailability and elimination rate, predictable pharmacokinetics and lack of immunogenicity, which are convenient characteristics for both efficacy and safety. This article reviews the pharmacological characteristics of tofacitinib and its safety profile.

Topics: Arthritis, Rheumatoid; Colitis, Ulcerative; Drug Interactions; Herpes Zoster; Herpes Zoster Vaccine; Humans; Janus Kinase 1; Janus Kinase 3; Janus Kinase Inhibitors; Neoplasms; Piperidines; Pyrimidines; Venous Thromboembolism

To evaluate the cost-effectiveness of tofacitinib versus other treatment options currently available for the management of adult patients with moderate-to-severe ulcerative colitis, who have had an inadequate response, loss of response, or were intolerant to conventional therapy or a biologic agent, in Greece.. A Markov model was adapted for projecting lifetime costs and outcomes, for a cohort of patients with moderate-to-severe ulcerative colitis from a Greek payer perspective. Patients entered the model in the active ulcerative colitis state and transitioned to a remission or response state or they underwent colectomy. Following an initial 8-week induction treatment period, patients received maintenance therapy until loss of response. Nonresponders could switch to up to two subsequent biologic lines. Clinical efficacy, adverse event rates and utilities derived from OCTAVE trials and a network-meta-analysis (NMA), while adverse event-related disutilities were obtained from the literature. Information on treatment pathways and resource use was provided by an advisory board due to a lack of local data. Unit costs derived from official national sources (€, 2018).. Over a life-time horizon, treating moderate-to-severe active ulcerative colitis with tofacitinib resulted in additional quality-adjusted life-years (QALYs) and lower total costs compared to vedolizumab (0.018; €6408), infliximab (biosimilar) (0.009; €3031), golimumab (0.042; €1988) and infliximab (originator) (0.009; €6724). Hence, tofacitinib was estimated to be dominant over all comparators.. The results of the analysis suggest that in the Greek setting, tofacitinib could be considered a cost-effective (dominant) treatment option for the treatment of patients with moderate-to-severe active ulcerative colitis.

Topics: Adult; Colitis, Ulcerative; Cost-Benefit Analysis; Greece; Humans; Piperidines; Pyrimidines

Janus kinase [JAK] inhibitors are a completely novel therapy for the treatment of patients with immune-mediated inflammatory disorders. The oral formulation of tofacitinib has recently been approved for the treatment of moderate-to-severe ulcerative colitis. In the placebo-controlled OCTAVE programme, tofacitinib proved to be efficacious for both inducing and maintaining clinical remission, and this both in anti-tumour necrosis factor-naïve and exposed patients. Several other anti-JAK inhibitors are currently explored. This review summarises the available efficacy data from all anti-JAK inhibitors in ulcerative colitis.

Topics: Adamantane; Colitis, Ulcerative; Heterocyclic Compounds, 3-Ring; Humans; Janus Kinase Inhibitors; Niacinamide; Piperidines; Pyrimidines; Treatment Outcome

This review provides guidance in the decision-making process regarding when to choose a janus kinase [JAK] inhibitor as medical treatment strategy. The focus will be on ulcerative colitis, because the only yet available JAK inhibitor, tofacitinib, has approval for use in ulcerative colitis. The guidance path will include consideration of disease activity, previous treatment, comorbidities, family planning, patient preferences, pharmacology as well as concurrent chronic inflammatory diseases or extraintestinal manifestations. The suggested guidance path illustrates our daily difficulties in the decision-making process regarding best choice for the individual patient. However if predictive biomarkers are lacking, the named criteria can be applied to any other strategy and hence provide support in daily practice.

Topics: Colitis, Ulcerative; Humans; Inflammatory Bowel Diseases; Janus Kinase Inhibitors; Piperidines; Pyrimidines

Tofacitinib is an oral Janus kinase (JAK) inhibitor which blocks cytokine signaling involved in the pathogenesis of autoimmune diseases including ulcerative colitis (UC). The etiology of UC is poorly understood, however research suggests the development and progression of the disease is due to a dysregulated immune response leading to inflammation of the colonic mucosa in genetically predisposed individuals. Additional medications are currently required since some patients do not respond to the available medications and some medications are associated with serious adverse events (SAEs). JAK inhibitors have been widely studied in diseases including rheumatoid arthritis and Crohn's disease and may represent a promising and novel therapeutic option for the treatment of UC.. The primary objective was to assess the efficacy and safety of oral JAK inhibitors for the maintenance of remission in participants with quiescent UC.. We searched the following databases from inception to 20 September 2019: MEDLINE, Embase, CENTRAL, and the Cochrane IBD Group Specialized Register, WHO trials registry and clinicaltrials.gov. References and conference abstracts were searched to identify additional studies.. Randomized control trial (RCTs) in which an oral JAK inhibitor was compared with placebo or active comparator in the treatment of quiescent UC were eligible for inclusion.. Two review authors independently screened studies for inclusion and extraction. Bias was assessed using the Cochrane 'Risk of bias' tool. The primary outcome was the proportion of participants who failed to maintain remission as defined by any included studies. Secondary outcomes included failure to maintain clinical response, failure to maintain endoscopic remission, failure to maintain endoscopic response, disease-specific quality of life, adverse events (AEs), withdrawal due to AEs and SAEs. We calculated the risk ratio (RR) and 95% confidence intervals (95% CI) for each dichotomous outcome. Data were analyzed on an intention-to-treat basis. The overall certainty of the evidence supporting the outcomes was evaluated using the GRADE criteria.. One RCT (593 participants) including patients with moderately to severely active UC met the inclusion criteria. Patients were randomly assigned in a 1:1:1 ratio to receive maintenance therapy with tofacitinib at 5 mg twice daily, 10 mg twice daily or placebo for 52 weeks. The primary endpoint was remission at 52 weeks and the secondary endpoints included mucosal healing at 52 weeks, sustained remission at 24 and 52 weeks and glucocorticosteroid-free remission. This study was rated as low risk of bias. The study reported on most of the pre-specified primary and secondary outcomes for this review including clinical remission, clinical response, endoscopic remission, AEs, SAEs and withdrawal due to AEs. However, the included study did not report on endoscopic response or disease-specific quality of life. Sixty-three per cent (247/395) of tofacitinib participants failed to maintain clinical remission at 52 weeks compared to 89% (176/198) of placebo participants (RR 0.70, 95% CI 0.64 to 0.77; high-certainty evidence). Forty-three per cent (171/395) of tofacitinib participants failed to maintain clinical response at 52 weeks compared to 80% (158/198) of placebo participants (RR 0.54, 95% CI 0.48 to 0.62; high-certainty evidence). Eighty-four per cent (333/395) of tofacitinib participants failed to maintain endoscopic remission at 52 weeks compared to 96% (190/198) of placebo participants (RR 0.88, 95% CI 0.83 to 0.92; high-certainty evidence). AEs were reported in 76% (299/394) of tofacitinib participants compared with 75% (149/198) of placebo participants (RR 1.01, 95% CI 0.92 to 1.11; high-certainty evidence). Commonly reported AEs included worsening UC, nasopharyngitis, arthralgia (joint pain)and headache. SAEs were reported in 5% (21/394) of tofacitinib participants compared with 7% (13/198) of placebo participants (RR 0.81, 95% CI 0.42 to 1.59; low-certainty evidence). SAEs included non-melanoma skin cancers, cardiovascular events, cancer other than non-melanoma skin cancer, Bowen's disease, skin papilloma and uterine leiomyoma (a tumour in the uterus). There was a higher proportion of participants who withdrew due to an AE in the placebo group compared to the tofacitinib group. Nine per cent (37/394) of participants taking tofacitinib withdrew due to an AE compared to 19% (37/198) of participants taking placebo (RR 0.50, 95% CI 0.33 to 0.77; moderate-certainty evidence). The most common reason for withdrawal due to an AE was worsening UC. The included stu. High-certainty evidence suggests that tofacitinib is superior to placebo for maintenance of clinical and endoscopic remission at 52 weeks in participants with moderate-to-severe UC in remission. The optimal dose of tofacitinib for maintenance therapy is unknown. High-certainty evidence suggests that there is no increased risk of AEs with tofacitinib compared to placebo. However, we are uncertain about the effect of tofacitinib on SAEs due to the low number of events. Further studies are required to look at the long-term effectiveness and safety of using tofacitinib and other oral JAK inhibitors as maintenance therapy in participants with moderate-to-severe UC in remission.

Topics: Colitis, Ulcerative; Humans; Janus Kinase Inhibitors; Maintenance Chemotherapy; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Quality of Life; Randomized Controlled Trials as Topic

Topics: Adalimumab; Antibodies, Monoclonal, Humanized; Colitis, Ulcerative; Crohn Disease; Gastrointestinal Agents; Humans; Infliximab; Patient Selection; Piperidines; Prognosis; Pyrimidines; Risk Factors; Ustekinumab

Janus kinases inhibitors (JAKi) are new small molecules recently introduced in the armamentarium of treatments for Inflammatory Bowel Disease (IBD). Janus Kinases (JAK) are tyrosine kinases that act by linkage with different intracellular receptors, regulating cytokines gene transcription implicated in the inflammatory burden seen in IBD patients.. A comprehensive literature search was performed to retrieve studies on JAKi and IBD to discuss the latest developments and how the selectivity of these drugs is changing the natural course of IBD.. Available data on efficacy and safety of JAKi in IBD are highly encouraging and because of their selectivity, these drugs might become among the foremost options in the treatment algorithm.

Topics: Colitis, Ulcerative; Crohn Disease; Heterocyclic Compounds, 3-Ring; Humans; Janus Kinase 1; Janus Kinase 2; Janus Kinase 3; Janus Kinase Inhibitors; Naphthyridines; Nitriles; Piperidines; Pyridines; Pyrimidines; Signal Transduction; Triazoles; TYK2 Kinase

The increasing knowledge on ulcerative colitis' pathophysiology has contributed to the expansion of the therapeutic arsenal for this condition. However, to date, 25-40% of patients with ulcerative colitis remain primary or secondary non-responders to therapy, and up to 10% need to eventually undergo a colectomy. Janus kinase inhibitors block cytokine signalling involved in the pathogenesis of several inflammatory conditions. Tofacitinib is the first drug of this class approved for moderate-to-severely active ulcerative colitis in patients for whom disease worsened and those who did not improve with conventional therapy (aminosalicylates, corticosteroids and immunosuppressants) or monoclonal antibodies. We aimed to review the main aspects and concerns related to the current use of tofacitinib and to explore its future application.

Topics: Adult; Antibodies, Monoclonal, Humanized; C-Reactive Protein; Colitis, Ulcerative; Colon; Colonoscopy; Cytokines; Drug Approval; Drug Resistance; Female; Humans; Infliximab; Intestinal Mucosa; Janus Kinase Inhibitors; Janus Kinases; Maintenance Chemotherapy; Piperidines; Pyrimidines; Remission Induction; Severity of Illness Index; Signal Transduction; Treatment Outcome

Inflammatory bowel diseases (IBDs) are immune-mediated chronic inflammatory disorders of the gastrointestinal tract whose pathogenesis is not yet fully understood. Despite the advent of biological agents, there are still unmet needs for IBD patients, due to suboptimal rate of sustained remission achieved. Small molecule drugs (SMDs), the next generation of selective drugs in IBD, show promising results in ongoing trials.. We describe the pharmacodynamics and pharmacokinetic features of novel SMDs and their main differences with biologic agents.. Small molecule drugs are a promising class of drugs for the treatment of ulcerative colitis and Crohn's disease with good results in inducing and maintaining remission. Hence, over the next few years physicians will have numerous options of small molecule drugs for the treatment of patients with IBD. This group of drugs are potentially easier to use over biological agents due to pharmacokinetic features such as oral administration, short half-life, high volume of distribution, and lack of immunogenicity. On the other hand, drug-drug interactions can happen with small-molecule drugs, principally due to competitive metabolic and clearance mechanisms.

Topics: Acetates; Animals; Clinical Trials as Topic; Colitis, Ulcerative; Crohn Disease; Heterocyclic Compounds, 3-Ring; Humans; Indans; Indoles; Janus Kinase Inhibitors; Oxadiazoles; Piperidines; Pyridines; Pyrimidines; Quinolones; Sphingosine-1-Phosphate Receptors; Triazoles

This article reviews nonbiologic immunosuppressive agents in the induction and maintenance of remission of ulcerative colitis. Based on meta-analyses and North American guidelines, azathioprine, mercaptopurine, and methotrexate monotherapy are not recommended for induction therapy. Thiopurines are recommended in combination with infliximab. Tofacitinib has been shown to be an effective induction agent. Cyclosporine or tacrolimus are calcineurin inhibitors that can be used as induction therapy. Thiopurine monotherapy is suggested or recommended as maintenance therapy for patients who have achieved steroid-induced remission. Methotrexate monotherapy is not recommended. Tofacitinib has been shown to be an effective maintenance agent in moderate to severe disease.

Topics: Azathioprine; Colitis, Ulcerative; Contraindications, Drug; Glucocorticoids; Humans; Immunosuppressive Agents; Maintenance Chemotherapy; Mercaptopurine; Meta-Analysis as Topic; Methotrexate; Piperidines; Pyrimidines; Remission Induction

Tofacitinib is an oral, small-molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We analyzed inflammation, lipid concentrations, and incidence rates of major adverse cardiovascular (CV) events (MACEs) in patients who received tofacitinib in worldwide studies.. We collected data from 1157 patients who participated in 3 8-week induction studies (1 phase-2 study and 2 phase-3 studies; patients received tofacitinib 10 mg twice daily or placebo), a 52-week phase-3 maintenance study of responders (patients received tofacitinib 5 or 10 mg twice daily or placebo), and an ongoing long-term extension study of patients who did and did not respond to induction or maintenance therapy (patients received tofacitinib 5 or 10 mg twice daily). Lipid concentrations were assessed from induction baseline to week 61 (week 52 of maintenance therapy). We calculated MACE incidence rates (patients with ≥1 event per 100 patient-years of exposure) and Reynolds risk score (RRS; a composite score used to determine CV risk) for patients given tofacitinib vs placebo.. The mean RRS was <5% at baseline and week 8 of treatment with tofacitinib. At week 8, there were greater increases from baseline in total cholesterol, high-density lipoprotein cholesterol (HDL-c), and low-density lipoprotein cholesterol in patients given tofacitinib compared with placebo. There were correlations between reduced levels of high-sensitivity C-reactive protein and increased serum concentrations of lipid in patients given tofacitinib or placebo (P < .001). Lipid concentrations were increased in patients given tofacitinib vs patients given placebo through week 61. Overall, ratios of low-density lipoprotein cholesterol to HDL-c and total cholesterol to HDL-c did not change significantly over the 61-week period. Four MACEs were reported; the incidence rate was 0.24 (95% CI, 0.07-0.62) and 3 of these patients had 4 or more CV risk factors.. In an analysis of data from 5 trials of patients with UC who received tofacitinib, we found reversible increases in lipids with treatment and inverse correlations with reduced levels of high-sensitivity C-reactive protein. We did not find clinically meaningful changes in lipid ratios or RRS. MACEs were infrequent and not dose-related. Clinicaltrials.gov: A3921063 (NCT00787202); OCTAVE Induction 1 (NCT01465763); OCTAVE Induction 2 (NCT01458951); OCTAVE Sustain (NCT01458574); OCTAVE Open (NCT01470612).

Topics: Adult; Aged; C-Reactive Protein; Cardiovascular Diseases; Cholesterol; Colitis, Ulcerative; Female; Humans; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Risk Factors

Recent years have brought about several advances in the treatment of patients with ulcerative colitis (UC). Here, we discuss salient recommendations of recent treatment guidelines; review the efficacy, safety, and real-world data of vedolizumab and tofacitinib; appraise their place vis-à-vis established agents; and consider the newly proposed approaches of risk-stratified and treat-to-target therapy.. Once daily oral mesalamine dosing is equivalent to split dosing in mild-moderate UC. Real-world data are accumulating on the effectiveness and safety of vedolizumab for moderate to severe UC, while there are few such data on the most recently approved agent, tofacitinib. High-dose infliximab is being investigated for severe UC. New approaches are challenging the established paradigm of selecting therapy based on current disease activity. The risk-stratified approach incorporates long-term risk as well as the current burden of inflammation. The treat-to-target approach aims at improved long-term outcomes by adjusting therapy to resolve intestinal inflammation. The therapeutic options for UC are continually expanding. Risk-stratified therapy and the treat-to-target approach represent paradigm shifts in UC management. Optimal disease control requires an individualized approach that takes into consideration current inflammatory burden, long-term risk, patient preferences, and ongoing assessment of response to treatment.

Topics: Antibodies, Monoclonal, Humanized; Colitis, Ulcerative; Critical Pathways; Gastrointestinal Agents; Humans; Piperidines; Practice Guidelines as Topic; Prognosis; Pyrimidines; Pyrroles; Risk Assessment; Treatment Outcome

Recent advances in the understanding of the pathophysiology of ulcerative colitis (UC) have led to the expansion of our therapeutic arsenal. Conventional treatment options, including aminosalicylates, corticosteroids, thiopurines, and calcineurin inhibitors, fail to control the disease in a significant proportion of patients. Approximately 25-50% of the patients treated with tumor necrosis factor antibodies (anti-TNFα) are primary and secondary non-responders to therapy. Tofacitinib is a novel orally administered small synthetic molecule that inhibits a homologous family of enzymes, termed Janus kinases that modulate multiple key cytokines involved in the pathogenesis of UC. Phase II and III trials showed promising results in UC, leading the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) to approve its administration for the induction and maintenance of remission in moderate-to-severe UC. Herein, we review tofacitinib for the management of UC, its mechanism of action pharmacokinetic properties, efficacy, and safety.

Topics: Administration, Oral; Colitis, Ulcerative; Humans; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles

Ulcerative colitis (UC) is an inflammatory disease of the colon and rectum. Treatment options include biologics and tofacitinib.. We aim to summarize the evidence on efficacy and safety of biologics and tofacitinib in moderate-to-severe UC.. PubMed, Embase, Scopus, and the Cochrane Library were systematically searched to identify meta-analyses of randomized controlled trials assessing adalimumab, golimumab, infliximab, vedolizumab, and tofacitinib in UC. Efficacy outcomes included induction and maintenance of clinical response, clinical remission and mucosal healing. Safety outcomes included adverse events and serious adverse events.. The overview involved 31 meta-analyses. All four biologics and tofacitinib were superior to placebo regarding efficacy. Indirect comparisons suggested that infliximab may be better than adalimumab and golimumab to induce clinical response and mucosal healing. Safety analyses indicated no increased rates of adverse events, except for infliximab.. Biologics and tofacitinib are efficacious and safe for treating UC. These findings can support clinical decision-making.

Topics: Biological Factors; Biomarkers; Clinical Trials as Topic; Colitis, Ulcerative; Drug Therapy, Combination; Humans; Molecular Targeted Therapy; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Severity of Illness Index; Treatment Outcome

The treatment of ulcerative colitis (UC) is based on conventional therapies (aminosalicylates, corticosteroids, and immunosuppressants) and when these are ineffective, biologic drugs. However, in a substantial portion of patients undergoing treatment with biologic agents there is primary or secondary loss of response. Thus, new therapeutic options are been actively explored; among these, there is interest in the Janus kinase (JAK) inhibitors, small molecules that can be administered orally.. We carried out an extensive literature search concerning the effects of JAK inhibitors for the treatment of patients with UC.. Tofacitinib is the drug more extensively studied in this setting, and it was recently approved in Europe for the treatment of moderate to severe UC. The available data suggest that this drug can be effective in obtaining clinical and endoscopic remission in UC patients unresponsive to other treatments, even in those previously treated with biologic drugs. In addition, the drug was able to improve significantly the quality of life of these patients. There are still few data available for the treatment of UC with other JAK inhibitors.. The JAK inhibitors, in particular tofacitinib, are a new class of orally administered drugs effective for the treatment of UC. However, more studies are needed to ascertain the safety of tofacitinib in the long term and whether other compounds of this class may be equally effective.

Topics: Administration, Oral; Colitis, Ulcerative; Humans; Janus Kinase Inhibitors; Piperidines; Pyrimidines; Pyrroles; Quality of Life

There are limited data to inform positioning of agents for treating moderate-severe ulcerative colitis (UC).. To assess comparative efficacy and safety of different therapies as first-line (biologic-naïve) and second-line (prior exposure to anti-tumour necrosis factor(TNF)-α) agents for moderate-severe UC, through a systematic review and network meta-analysis, and appraise quality of evidence (QoE) using grading of recommendations, assessment, development and evaluation (GRADE) approach.. We identified randomised controlled trials (RCTs) in adults with moderate-severe UC treated with anti-TNF agents, anti-integrin agents and janus kinase (JAK) inhibitors, as first-line or second-line agents, and compared with placebo or another active agent. Efficacy outcomes were induction/maintenance of remission and mucosal healing; and safety outcomes were serious adverse events and infections. Network meta-analyses were performed, and ranking was assessed using surface under the cumulative ranking (SUCRA) probabilities.. In biologic-naïve patients (12 trials, no head-to-head comparisons), infliximab and vedolizumab were ranked highest for induction of clinical remission (infliximab: odds ratio [OR], 4.10 [95% confidence intervals [CI], 2.58-6.52]; SUCRA,0.85; vedolizumab:SUCRA,0.82) and mucosal healing (infliximab:SUCRA,0.91; vedolizumab:SUCRA,0.81) (moderate QoE). In patients with prior anti-TNF exposure (4 trials, no head-to-head comparisons), tofacitinib was ranked highest for induction of clinical remission (OR, 11.88 [2.32-60.89]; SUCRA, 0.96) and mucosal healing (moderate QoE). Differences in trial design limited comparability of trials of maintenance therapy for efficacy. Vedolizumab was ranked safest in terms of serious adverse events (SUCRA, 0.91), and infection (SUCRA, 0.75) in maintenance trials.. Infliximab and vedolizumab are ranked highest as first-line agents, and tofacitinib is ranked highest as second-line agent, for induction of remission and mucosal healing in patients with moderate-severe UC, based on indirect comparisons. Head-to-head trials are warranted to inform clinical decision-making with greater confidence.

Topics: Adult; Antibodies, Monoclonal, Humanized; Biological Factors; Biological Products; Colitis, Ulcerative; Drug Therapy; Humans; Infliximab; Network Meta-Analysis; Piperidines; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Severity of Illness Index; Tumor Necrosis Factor-alpha

Biological therapies have improved the care of patients with ulcerative colitis (UC). Tofacitinib, an oral small-molecule Janus kinase inhibitor, is potentially a new treatment option.. To comparatively assess efficacy and harm of tofacitinib and biologics (infliximab, adalimumab, golimumab and vedolizumab) in adult patients not previously exposed to TNF antagonists.. We performed a comprehensive search of PubMed, Embase, Scopus, clinical trial registries, regulatory authorities' websites and major conference proceedings, through August 2017, to identify randomised, placebo-controlled or head-to-head trials assessing tofacitinib or biologics as induction and/or maintenance therapy in moderate-to-severe UC. Two reviewers independently extracted study data and outcomes, and investigated each trial's risk-of-bias. We used conventional meta-analysis to synthesise direct evidence, and network meta-analysis for adjusted indirect treatment comparisons.. Fifteen randomised, double-blind, placebo-controlled trials (n = 3130) contributed data for induction: All treatments are superior to placebo. Indirect treatment comparisons showed that infliximab is better than adalimumab (OR: 2.01, 95% CI: 1.36-2.98) and golimumab (1.67, 1.08-2.59) in clinical response, better than adalimumab (2.10, 1.21-3.64) in clinical remission, and better than adalimumab (1.87, 1.26-2.79) and golimumab (1.75, 1.13-2.73) in mucosal healing. No indirect comparisons between tofacitinib and biologics reached statistical significance. Nine studies (n = 1776) contributed maintenance data showing that all treatments have higher clinical efficacy than placebo. Safety analyses indicated no increased rates of adverse events for the treatments under evaluation (except for infliximab), while vedolizumab may have an advantage regarding the occurrence of serious adverse events.. Tofacitinib and biologics are efficacious and safe for UC. Further high-quality research is warranted to establish the best therapeutic option.

Topics: Adult; Biological Products; Biological Therapy; Colitis, Ulcerative; Double-Blind Method; Humans; Network Meta-Analysis; Piperidines; Pyrimidines; Pyrroles; Severity of Illness Index

The treatment of inflammatory bowel disease has evolved with the development of anti-TNF agents. In spite of long-term effectiveness, many patients do not respond or no longer responds to these drugs. Therefore, the development of new drugs that act on different inflammatory pathways has become necessary. Vedolizumab, a gut-specific biological agent, inhibits interaction α4β7 integrin with mucosal addressin cell adhesion molecule-1 without inhibiting systemic immune responses. Long-term vedolizumab therapy in patients with Crohn's disease and ulcerative colitis was safe and effective. Additionally, vedolizumab can be used in patients already failed an anti-TNF therapy. Ustekinumab is a fully human immunoglobulin G1 kappa monoclonal antibody that blocks the p40 subunit of IL-12 and IL-23. Ustekinumab will be a clinically effective agent to use in medically-refractory Crohn's disease especially as a second line drug. Tofacitinib is an oral, small molecule that inhibits JAK1, JAK3 and in a lesser extent, JAK2. Perhaps the most attractive things of these JAK inhibitors is that they are given orally instead of parenterally. Early results showed that patients with moderately to severely active ulcerative colitis receiving tofacitinib were more likely to achieve remission at 8 weeks than those receiving placebo. However, these results have not been as robust in Crohn's disease. Much of the positioning will depend on the safety profile such as opportunistic infection and atherogenic risk. The challenges for the future are to determine the therapeutic drug monitoring-guided dose optimization, optimal timing and drug combinations to produce the most effective, and safest outcomes for IBD patients.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Colitis, Ulcerative; Crohn Disease; Gastrointestinal Agents; Humans; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Tumor Necrosis Factor-alpha; Ustekinumab

Treatment options for ulcerative colitis (UC) remain limited because conventional therapies do not succeed at controlling the disease in a considerable percentage of patients, while up to 30% of those receiving biologics are primary nonresponders and 10%-20% lose response per year, requiring an increase in the treatment dose or the use of a different drug. Recently, tofacitinib, an orally administered small molecule that inhibits the Janus kinases, was proven efficacious for inducing and maintaining remission in adult patients with moderate to severe UC. Tofacitinib may represent a therapeutic alternative for the management of UC, pending approval by the US Food and Drug Administration, the European Medicines Agency, and other international regulatory authorities. Herein, we review tofacitinib's efficacy and safety data reported from randomized controlled trials in UC populations, with the aim to define how this new molecule could be inserted into the therapeutic algorithm of patients with UC.

Topics: Algorithms; Colitis, Ulcerative; Humans; Piperidines; Prognosis; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Severity of Illness Index

Increased risk of herpes zoster (HZ) has been observed in patients with immune-mediated diseases, including rheumatoid arthritis (RA), psoriasis (PsO), and inflammatory bowel disease; this risk can be further increased by the use of immunosuppressive therapy. One advancing modality of therapy for these diseases is Janus kinase (JAK) inhibition. Tofacitinib is an oral JAK inhibitor for the treatment of RA and psoriatic arthritis, which is currently under investigation for the treatment of ulcerative colitis (UC) and was previously investigated for psoriasis. JAK inhibitors have been associated with HZ events in patients across a number of indications. The pathogenesis underlying this risk of HZ is currently unknown. An increased risk of HZ has been noted in patients receiving immunosuppressive therapies for UC, including tofacitinib. In clinical trials, there was a dose-dependent risk of HZ (higher dose linked with increased risk). However, the majority of HZ cases are nonserious and noncomplicated, mild to moderate in severity, and manageable without permanent discontinuation of treatment. This review will discuss HZ risk in patients receiving JAK inhibitors, focusing on tofacitinib with respect to the potential mechanisms and epidemiology of HZ. Current guidelines for the prevention of HZ will be highlighted, and proposed management reviewed.

Topics: Antiviral Agents; Colitis, Ulcerative; Disease Management; Herpes Zoster; Herpesvirus 3, Human; Humans; Janus Kinase Inhibitors; Janus Kinases; Piperidines; Prognosis; Pyrimidines; Pyrroles

New generations of small molecules are being developed for the treatment of ulcerative colitis. Among them, tofatinib (a Janus kinase (JAK) inhibitor) has demonstrated efficacy for inducing and maintaining remission and achieving mucosal healing with a reasonable safety profile. Oral administration is attractive for patients and lack of immunogenicity represents an advantage over biologic drugs. Areas covered: This review discusses the molecular aspects of the JAK-STAT pathway; the mechanism of action of tofacitinib pertinent to ulcerative colitis and the evidence on the efficacy of tofacitinib for achieving clinically relevant outcomes, including clinical remission, mucosal healing, and normalization of quality of life, as well as safety aspects with special attention to adverse events related to the mode of action of the drug. Expert commentary: Tofacitinib will be the first drug on the class of JAK inhibitors to be available for treatment of ulcerative colitis. The efficacy of the drug, with a rapid onset of action even in cases of severe colitis, oral administration, and possibility to use the drug intermittently without generating immunogenicity, will bring about a redesign of current treatment paradigms for ulcerative colitis.

Topics: Animals; Colitis, Ulcerative; Drug-Related Side Effects and Adverse Reactions; Expert Testimony; Humans; Janus Kinases; Piperidines; Pyrimidines; Pyrroles; Quality of Life; Signal Transduction; STAT Transcription Factors; Treatment Outcome

Patient-reported outcomes are important in the assessment of efficacy of intervention for ulcerative colitis (UC).. To compare the impact of interventions for moderate-to-severe UC on health-related quality of life (HRQL).. We searched Medline, Embase, CENTRAL and grey literature sources through October 2017. We included randomised controlled trials (RCTs) that compared infliximab, adalimumab, golimumab, vedolizumab or tofacitinib to each other or placebo. Outcomes included the change in quality of life scores and the proportion of patients with improvement in quality of life. We performed random-effect pairwise and network meta-analysis. We assessed confidence in estimates using the CINeMA (Confidence in Network Meta-Analysis) framework.. Fourteen RCTs assessed HRQL using the Inflammatory Bowel Disease Questionnaire (IBDQ) (14 trials), the Short Form questionnaire-36 (SF-36) (seven trials) or the European Quality of Life-5 Dimensions questionnaire (EQ-5D) (three trials). At induction (13 trials), low to very low confidence evidence suggested that all agents significantly improved both generic and disease-specific HRQL scores compared to placebo. However, only infliximab (MD 18.58; 95% CI 13.19-23.97) and vedolizumab (MD 18.00; 95% CI 11.08-24.92) showed clinically meaningful improvement in IBDQ score. Differences among individual interventions were imprecise. For maintenance (four trials), very low confidence evidence suggested that vedolizumab, tofacitinib and adalimumab maintained improvement in HRQL.. Induction treatment with infliximab, adalimumab, golimumab, vedolizumab or tofacitinib improves quality of life compared to placebo. Evidence on maintenance therapy is sparse and uncertain. Head-to-head comparisons could enhance confidence in conclusions about differences between drugs in terms of HRQL.

Topics: Adalimumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Biological Products; Colitis, Ulcerative; Gastrointestinal Agents; Humans; Infliximab; Network Meta-Analysis; Piperidines; Pyrimidines; Pyrroles; Quality of Life; Severity of Illness Index

Various investigational medicinal products have been developed for ulcerative colitis (UC). Our aim was to systematically evaluate novel pharmacological therapeutic agents for the treatment of UC.. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations were followed. A search of the medical literature was conducted in the MEDLINE database for original research papers published between 01 January 2010 and 31 October 2014.. Twenty one studies, including 11,524 adults were analyzed. Thirteen different novel therapeutic drug options were identified. Vedolizumab and golimumab were superior to placebo as induction and maintenance therapy. Tofacitinib showed dose related efficacy for induction therapy. Etrolizumab showed higher clinical remission rates compared to placebo. Phosphatidylcholine led to an improved clinical activity index. HMPL-004 may become a mesalamine alternative for mild to moderate UC. PF00547,659 was well tolerated. Statins were not beneficial for acute exacerbations of UC. Abatacept, rituximab and visilizumab did not lead to improved outcomes compared to placebo. Higher concentration of BMS 936557 was associated with improved efficacy compared to placebo. Basiliximab did not enhance corticosteroid efficacy.. Patients with UC might achieve clinical response or remission by utilizing some of these agents with a favorable side effect profile. Further studies are needed to evaluate their short- and long-term efficacy and safety.

Topics: Andrographis paniculata; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Colitis, Ulcerative; Gastrointestinal Agents; Humans; Induction Chemotherapy; Mesalamine; Piperidines; Plant Extracts; Pyrimidines; Pyrroles; Remission Induction

There is an ongoing, unmet need for effective therapies for Crohn's disease. Treatments for Crohn's disease continue to evolve from the traditional biologics to novel small molecules, with targeted mechanisms directed toward pathways that are dysregulated in Crohn's disease. There are multiple emerging mechanisms of action, including Janus kinase inhibition, Smad7 inhibition, and sphingosine-1-phosphate receptor modulators, that are administered as oral medications, and small molecules represent the next generation of therapies for Crohn's disease.

Topics: B-Lymphocytes; Colitis, Ulcerative; Crohn Disease; Humans; Indans; Janus Kinase 1; Janus Kinase Inhibitors; Oligonucleotides; Oxadiazoles; Piperidines; Pyridines; Pyrimidines; Pyrroles; Receptors, Lysosphingolipid; Smad7 Protein; T-Lymphocytes; Triazoles

Cytokines orchestrate immune and inflammatory responses involved in the pathogenesis of ulcerative colitis (UC). Protein kinases are essential for signal transduction in eukaryotic cells. Janus kinases (JAKs) are a family of protein tyrosine kinases that play a pivotal role in cytokine receptor signaling. Indeed, a major subgroup of cytokines use Type I and II cytokine receptors which signal via the activation of JAKs. Tofacitinib is an oral JAK inhibitor that has been studied in autoimmune pathologies, including UC and rheumatoid arthritis with good overall efficacy and acceptable safety profile. This literature review was performed with the goal of summarizing the knowledge on JAK inhibitors in UC treatment.

Topics: Animals; Arthritis, Rheumatoid; Autoimmunity; Colitis, Ulcerative; Cytokines; Humans; Janus Kinases; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Signal Transduction

Management of patients with active ulcerative colitis (UC), one of the most frequent inflammatory bowel diseases in human beings, is mainly based on the use of mesalamine and corticosteroids. Since in the long-term, these two drugs may be ineffective in nearly one third of the patients, immunosuppressants and/or biologics are needed to control disease activity.. The marked activation of JAK/STAT molecules in inflamed mucosa of UC patients and the demonstration that UC-associated mucosal injury is driven by soluble factors that signal through JAK/STAT pathways led to investigation of JAK inhibitors for the treatment of active UC. Tofacitinib, an oral inhibitor of the cytokine-driven JAK-STAT signalling cascade, has recently been proposed for the treatment of moderate-to-severe UC. Phase 2 study showed the efficacy of tofacitinib to induce clinical and endoscopic improvement/remission and the safety profile of the drug. Herein the authors review this compound.. The results obtained from clinical trials with tofacitinib suggest that this drug could be a new treatment option for patients with moderate to severe UC. However, further experimentation is needed to assess the efficacy of this drug in selected subgroups of patients as well as to maintain remission and to determine the long-term safety profile of the drug.

Topics: Administration, Oral; Animals; Colitis, Ulcerative; Humans; Intestinal Mucosa; Janus Kinases; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Severity of Illness Index; Signal Transduction; STAT Transcription Factors

Recently, several medical treatments for ulcerative colitis (UC) have been developed, including 5-aminosalicylic acids (5-ASAs), corticosteroids, thiopurine, calcineurin inhibitors, and anti-tumor necrosis factor (TNF) α treatments. Treatment options including calcineurin inhibitors and anti-TNF treatment for refractory UC are discussed in this article. Furthermore, upcoming treatments are introduced, such as golimumab, vedolizumab, AJM300, tofacitinib. Budesonide foamwill be used as one treatment option in patients with distal colitis. Herbal medicine, such as Qing-Dai is also effective for active UC and may be useful for patients who are refractory to anti-TNFα treatments. In the near future, physicians will able to use many different treatments for UC patients. However, we should not forget 5-ASA and corticosteroids as the fundamental treatments for UC patients.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Budesonide; Calcineurin Inhibitors; Colitis, Ulcerative; Drug Therapy, Combination; Drugs, Chinese Herbal; Forecasting; Gastrointestinal Agents; Glucocorticoids; Humans; Phenylalanine; Piperidines; Pyrimidines; Pyrroles; Quinazolinones; Tumor Necrosis Factor-alpha

Conventional medical treatment for ulcerative colitis can have limited efficacy or severe adverse reactions requiring additional treatment or colectomy. Hence, different biological agents that target specific immunological pathways are be-ing investigated for treating ulcerative colitis. Anti-tumor necrosis factor (TNF) agents were the first biologics to be used for treating inflammatory bowel disease. For example, infliximab and adalimumab, which are anti-TNF agents, are be-ing used for treating ulcerative colitis. Recently, golimumab, another anti-TNF agent, and vedolizumab, an anti-adhesion therapy, have been approved for ulcerative colitis by the U.S. Food and Drug Administration. In addition, new medications such as tofacitinib, a Janus kinase inhibitor, and etrolizumab, another anti-adhesion therapy, are emerging as therapeutic agents. Therefore, there is a need for further studies to select appropriate patient groups for these biologics and to improve the outcomes of ulcerative colitis treatment through appropriate medical usage.

Topics: Adalimumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Biological Factors; Cell Adhesion Molecules; Colitis, Ulcerative; Humans; Infliximab; Janus Kinases; Piperidines; Pyrimidines; Pyrroles

The constitutional isomers and tautomers of oxadiazolones, as well as their mono- and disulfur analogues, were calculated at the B3LYP/aug-cc-pVDZ level. Four groups of 30 molecules each were considered: oxadiazolone, oxadiazolthione, thiadiazolone, and thiadiazolthione isomers. The compounds were categorized into six groups according to permutations of three heteroatoms in the five-membered ring. Additionally, each of the constitutional isomer was considered to have five tautomers conserving stable five-membered ring: two NH tautomers, two rotameric OH (or SH) forms and one CH. La trombocitosis es un hallazgo casual frecuente en pediatría. En niños, predominan las formas secundarias, siendo las infecciones su causa más prevalente. Se distinguen 4 grados de trombocitosis en función del número de plaquetas; en la forma extrema, se supera el 1.000.000/mm. Endoscopic thrombin injection was similar to glue injection in achieving successful hemostasis of AGVH. However, a higher incidence of complications may be associated with glue injection.

Topics: Acetaminophen; Administration, Oral; Adolescent; Adsorption; Adult; Allyl Compounds; Amylopectin; Amylose; Anaerobiosis; Animals; Anti-Bacterial Agents; Anura; Arginase; Arthritis, Rheumatoid; Asthma; Atmosphere; B-Lymphocytes; Basic Helix-Loop-Helix Transcription Factors; Bioelectric Energy Sources; Biofilms; Biofuels; Biomarkers; Biopolymers; Bioreactors; Brain; Brain Injuries, Traumatic; Breast Neoplasms; Calibration; Carbon Tetrachloride; Caspase 3; Catalysis; Catechin; Cations; Cattle; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Body; Cell Line, Tumor; Cell Plasticity; Chemical and Drug Induced Liver Injury; Chemistry Techniques, Synthetic; China; Chitosan; Chloride Channels; Chromatography, High Pressure Liquid; Chromosome Mapping; Cognition; Cognitive Dysfunction; Cohort Studies; Colitis, Ulcerative; Colloids; Coloring Agents; Congresses as Topic; Correlation of Data; Crystallization; Cyanoacrylates; Cyclohexane Monoterpenes; Cyprinidae; Cytochrome P-450 CYP1A1; Death, Sudden; Dent Disease; Dietary Supplements; Diffusion Magnetic Resonance Imaging; Disease Models, Animal; Disease Progression; Disease Resistance; Disulfides; Drug Monitoring; Drug Stability; Ecotoxicology; Electricity; Electrodes; Endocytosis; Environmental Exposure; Environmental Monitoring; Enzyme Inhibitors; Epithelial-Mesenchymal Transition; Esophageal and Gastric Varices; Esters; Fagopyrum; Female; Ferrosoferric Oxide; Flame Retardants; Flavobacteriaceae; Flow Cytometry; Follow-Up Studies; Formoterol Fumarate; Fusarium; Garlic; Gastrointestinal Hemorrhage; Gene Expression; Genes, Plant; Genetic Markers; Glial Fibrillary Acidic Protein; Gliosis; Global Health; Glutathione Transferase; Glycine max; Gum Arabic; Hemostasis, Endoscopic; Hepatocytes; Hippocampus; Humans; Hydrogen-Ion Concentration; Illinois; Immunoglobulin G; Indoleamine-Pyrrole 2,3,-Dioxygenase; Infant, Newborn; Infant, Small for Gestational Age; Injections, Intraperitoneal; Interleukin-4; Iowa; Iron; Ki-67 Antigen; Kidney; Kinetics; Kynurenine; Lakes; Levofloxacin; Lipid Peroxidation; Lipids; Liver; Liver Cirrhosis, Experimental; Magnetic Fields; Magnetic Iron Oxide Nanoparticles; Male; Manure; Maze Learning; Memory, Short-Term; Metal Nanoparticles; Metals, Heavy; Methane; Mice; Mice, Inbred C57BL; Mice, Knockout; Michigan; Microalgae; Microbial Consortia; Mitochondria; Models, Animal; Models, Chemical; Models, Neurological; Molecular Structure; Molecular Weight; Mutation; Myeloid-Derived Suppressor Cells; NADPH Oxidase 2; Neoplasm Recurrence, Local; Neurites; Neurons; Neuroprotective Agents; NF-kappa B; NIH 3T3 Cells; Nitric Oxide Synthase Type II; Nitrogen; Ohio; Ointments; Ontario; Organelle Biogenesis; Organophosphates; Organophosphorus Compounds; Oxidative Stress; Palladium; Particle Size; Pectins; Phenotype; Phytotherapy; Piperidines; Placenta; Plant Diseases; Plant Extracts; Polymers; Polymorphism, Genetic; Polyphenols; Powders; Pregnancy; Pregnancy Trimester, First; Prospective Studies; Protein Kinase Inhibitors; Protein Structure, Secondary; Proteins; Pyridines; Pyrimidines; Rats, Wistar; Real-Time Polymerase Chain Reaction; Receptors, Aryl Hydrocarbon; Receptors, Chemokine; Receptors, Formyl Peptide; Receptors, Lipoxin; Recovery of Function; Recurrence; Reference Standards; Reference Values; Reproducibility of Results; Respiratory Function Tests; Retrospective Studies; Risk; Sensitivity and Specificity; Sewage; Signal Transduction; Sodium Glutamate; Soil; Solanum tuberosum; Solubility; Solutions; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis; Spermatozoa; STAT3 Transcription Factor; Sulfamethoxazole; Tea; Temperature; Thermodynamics; Thrombin; Treatment Outcome; Triazoles; United States; Viscosity; Waste Disposal, Fluid; Wastewater; Water; Water Pollutants, Chemical; Water Purification; White Matter; Wisconsin; X-Ray Diffraction; Zea mays

The advent of anti-Tumor Necrosis Factor (TNF) therapy has changed the way of treating inflammatory bowel disease (IBD). However, primary and secondary failure are relatively frequent with all anti-TNF agents, which are available only as parenteral agents. Tofacitinib is an oral janus kinase (JAK) inhibitor that inhibits JAK family kinase members, in particular JAK1 and JAK3, achieving a broad limitation of inflammation by interfering with several cytokine receptors. It first proved its efficacy as an immunosuppressive regimen after renal transplantation, and was recently approved by the FDA for rheumatoid arthritis. First data in IBD are promising, especially in ulcerative colitis. Ongoing clinical trials in both UC and Crohn's disease (CD) are needed to further explore its efficacy in CD and to better assess its safety profile.

Topics: Arthritis, Rheumatoid; Clinical Trials as Topic; Colitis, Ulcerative; Crohn Disease; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Inflammatory Bowel Diseases; Janus Kinases; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; United States; United States Food and Drug Administration

In recent years, many new agents have been evaluated for the treatment of inflammatory bowel disease. In this paper, we critically review recently published literature about these novel therapies, which have been the result of extensive research identifying molecular targets. Of the various biologicals and small molecules that have recently been tested in clinical trials, several demonstrated clinical efficacy with a tolerable safety profile. We discuss a number of them with specific focus on vedolizumab, a monoclonal antibody directed against the alpha4beta7 integrin on lymphocytes, ustekinumab, a monoclonal antibody against the p40 subunit of interleukin-12 and interleukin-23, and tofacitinib, a small molecule targeting Janus-activated kinase. Most likely, these three agents will find their way to the market and offer significant therapeutic alternatives for the management of Crohn's disease and/or ulcerative colitis.

Topics: Adalimumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cell Adhesion Molecules; Certolizumab Pegol; Colitis, Ulcerative; Crohn Disease; Humans; Immunoglobulin Fab Fragments; Infliximab; Natalizumab; Piperidines; Polyethylene Glycols; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Quinolones; Tumor Necrosis Factor-alpha; Ustekinumab

Topics: Arthritis, Rheumatoid; Colitis, Ulcerative; Enzyme Inhibitors; Humans; Janus Kinases; Nitriles; Piperidines; Primary Myelofibrosis; Pyrazoles; Pyrimidines; Pyrroles; Signal Transduction

Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We report herpes zoster (HZ) incidence and risk factors in the tofacitinib UC clinical program (up to 7.8 years).. Proportions and incidence rates (IRs; unique patients with events/100 patient-years) of HZ were evaluated in 4 cohorts: Induction (phase 2 and 3 induction study data), Maintenance (phase 3 maintenance study data), Overall (data from all phase 2, 3, and open-label, long-term extension studies), and Overall plus interim 6-month phase 3b and 4 data. Herpes zoster risk factors were assessed by Cox regression analysis.. In the Induction and Maintenance Cohorts, IRs for HZ (nonserious and serious) were numerically higher with tofacitinib 10 mg twice daily (BID) vs placebo and tofacitinib 10 vs 5 mg BID, respectively. With all tofacitinib doses (5 or 10 mg BID), IRs (95% confidence intervals) for HZ in the Overall and Overall plus phase 3b/4 Cohorts (total exposure, 2814.4 and 2999.7 patient-years, respectively) were 3.38 (2.73-4.15) and 3.30 (2.67-4.04), respectively. In the Overall plus phase 3b/4 Cohort, >90% of HZ were nonserious; >90% were mild/moderate; >90% resolved without discontinuing tofacitinib; 0.6% of patients had multiple HZ events. Herpes zoster IRs were stable when analyzed by 6-month intervals up to >30 months. Herpes zoster risk factors included older age, lower weight, geographic region, and prior tumor necrosis factor inhibitor (TNFi) failure.. Most HZ events were mild/moderate. Herpes zoster IRs remained stable over 7.8 years of exposure. Older age, lower weight, geographic region, and prior TNFi failure were associated with increased HZ risk.. NCT00787202;NCT01465763;NCT01458951;NCT01458574;NCT01470612;NCT03281304.. Incidence rates for herpes zoster in patients with ulcerative colitis have remained stable over 7.8 years of tofacitinib exposure. Older age, lower weight, geographic region, and prior tumor necrosis factor inhibitor failure were identified as significant herpes zoster risk factors.

Topics: Colitis, Ulcerative; Herpes Zoster; Herpesvirus 3, Human; Humans; Piperidines; Pyrimidines

Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis [UC]. We evaluated the relationship between Mayo/Inflammatory Bowel Disease Questionnaire [IBDQ] scores and Work Productivity and Activity Impairment-UC [WPAI-UC] components in patients with UC.. All available pooled data from three Phase 3 tofacitinib studies [OCTAVE Induction 1 and 2 and OCTAVE Sustain] were included. Relationships were estimated using repeated measures regression models with Mayo score/subscores or IBDQ total/domain scores as a separate anchor predictor and WPAI-UC components as the outcome.. Evidence for linear relationships was confirmed between Mayo/IBDQ scores and WPAI-UC components. Robust relationships between total Mayo score/IBDQ total score and WPAI-UC presenteeism, work productivity loss, and activity impairment were observed; relationships with absenteeism were weak. Total Mayo scores of 0 and 12 corresponded, on average, to WPAI-UC component scores of < 15% and ≥ 60%, respectively, and IBDQ total scores of 224 and 32 corresponded, on average, to WPAI-UC component scores of < 6% and ≥ 90%, respectively. Presenteeism, work productivity loss, and activity impairment [all 0-100%], respectively, improved on average by 14.7, 13.6, and 16.4 percentage points for every 3-point improvement in total Mayo score, and by 8.1, 7.9, and 8.8 percentage points for every 16-point improvement in IBDQ total score.. Robust relationships between Mayo/IBDQ scores with WPAI-UC presenteeism, work productivity loss, and activity impairment suggest that patient productivity and non-work activities are strongly associated with disease activity and HRQoL. The weak relationships with absenteeism suggest that patients attend work regardless of their disease activity/poor HRQoL. ClinicalTrials.gov: NCT01465763;NCT01458951;NCT01458574.

Topics: Colitis, Ulcerative; Humans; Janus Kinase Inhibitors; Piperidines; Quality of Life; Surveys and Questionnaires

Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). The tofacitinib OCTAVE clinical program included phase III induction (OCTAVE Induction 1 and 2) and maintenance (OCTAVE Sustain) studies, and an open-label, long-term extension study (OCTAVE Open).. This post hoc analysis assessed selected long-term, disease-specific patient-reported outcome (PRO) and health-related quality-of-life (HRQoL) measurements in patients with UC receiving tofacitinib in the OCTAVE clinical program.. Analyses included patients from OCTAVE Open assigned to tofacitinib 5 mg twice daily (subpopulation in remission at Week 52 of OCTAVE Sustain). OCTAVE Open data from the final analyses are shown to Month 48. Endpoints included rectal bleeding subscore (RBS) = 0, stool frequency subscore (SFS) ≤ 1, and HRQoL measure, Inflammatory Bowel Disease Questionnaire (IBDQ) remission (IBDQ total score ≥ 170); with non-responder imputation for missing data at all visits, and last observation carried forward for visits after a patient advanced to the next study (NRI-LOCF). Observed cases were also assessed.. At Month 48, of 175 patients, 95 (54.3%) and 96 (54.9%) achieved/maintained RBS = 0 and SFS ≤ 1, respectively (NRI-LOCF). Additionally, 93 (53.1%) patients achieved/maintained IBDQ remission at Month 48 (NRI-LOCF).. Among patients who entered OCTAVE Open in remission, most maintained normalization of rectal bleeding and improvement in stool frequency for ≤ 4 years of follow-up in OCTAVE Open. IBDQ remission was also generally maintained in OCTAVE Open. These data show robust maintenance of key UC PROs and durability of response with tofacitinib 5 mg twice daily.. http://www.. gov (NCT01465763 [21/10/2011]; NCT01458951 [21/10/2011]; NCT01458574 [21/10/2011]; NCT01470612 [21/10/2011]).

Topics: Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Quality of Life; Remission Induction; Treatment Outcome

Patients with ulcerative colitis (UC) often report impaired health-related quality of life (HRQoL). Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of UC. In addition to previous demonstrations of improved clinical measures (e.g., Mayo score), tofacitinib has been shown to improve HRQoL in patients with UC. This analysis explored the interrelationships among tofacitinib treatment, HRQoL, and disease activity (measured using Mayo subscores) using mediation modeling.. Data were collected from two 8-week induction studies (OCTAVE Induction 1 and 2) in patients with moderate to severe UC treated with tofacitinib or placebo. Two mediation models were specified. First, Mayo subscores were mediators between the binary treatment variable (tofacitinib vs. placebo) and the eight Short Form-36 Health Survey (SF-36) domain scores as outcomes. Second, the four Inflammatory Bowel Disease Questionnaire (IBDQ) domain scores served as outcomes. Both models used data collected at week 8.. Overall, 1,073 and 1,079 patients were included in the SF-36- and IBDQ-based models, respectively. For all SF-36 domains, improvements in Mayo subscores were estimated to explain 65.6% (bodily pain) to 92.9% (mental health) of the total treatment effect on SF-36 domain scores (all p < 0.05). For all IBDQ domains, improvements in Mayo subscores explained 71.6% (systemic symptoms) to 84.7% (emotional function) of the total treatment effect (all p < 0.05).. Mayo scores and Mayo subscores are significant but incomplete contributors to tofacitinib's effect on HRQoL in patients with moderate to severe UC.. gov: NCT01465763; NCT01458951.

Topics: Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Quality of Life; Treatment Outcome

Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis. We evaluated tofacitinib efficacy and safety in the 52-week maintenance study, OCTAVE Sustain, by baseline Mayo endoscopic subscore (MES) following 8-week induction.. The proportion of patients achieving efficacy endpoints at Week 24 or 52 of OCTAVE Sustain was evaluated by baseline MES following 8-week induction. Using logistic regression, the difference in treatment effect (tofacitinib vs. placebo) between baseline MES (0 vs. 1) for each endpoint was assessed. Adverse events were evaluated.. At Week 52 of OCTAVE Sustain, a numerically higher proportion of tofacitinib-treated patients achieved remission with OCTAVE Sustain baseline MES of 0 versus 1 (61.9% vs. 36.5% for tofacitinib 5 mg twice daily [BID] and 75.0% vs. 54.2% for tofacitinib 10 mg BID). Similar trends were observed for endoscopic remission and endoscopic improvement. Logistic regression analyses showed a larger treatment effect at Week 52 in patients with baseline MES of 0 versus 1 for clinical response (p = 0.0306) in the tofacitinib 5 mg BID group (other endpoints all p > 0.05); differences were not significant for any endpoint in the 10 mg BID group (all p > 0.05). Infection adverse events were less frequent among patients with baseline MES 0 versus 1.. MES may be important in predicting long-term efficacy outcomes for tofacitinib maintenance treatment. Aiming for endoscopic remission during induction with tofacitinib 10 mg BID may allow successful maintenance with tofacitinib 5 mg BID. Safety was consistent with the known tofacitinib safety profile. Trial registration NCT01458574.

Topics: Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Pyrroles; Treatment Outcome

Although the clinical efficacy of tofacitinib in patients with ulcerative colitis (UC) has been assessed in the OCTAVE trial, there is a lack of adequate data on its efficacy in real-world clinical settings.. To analyze the efficacy of tofacitinib and the predictors of its continuation.. Changes in clinical activity index (CAI), blood test results (C-reactive protein [CRP], albumin [Alb], and hemoglobin), and endoscopic scores (Mayo endoscopic subscore [MES], ulcerative colitis endoscopic index of severity [UCEIS]) were evaluated, and we investigated the factors that affect the rate and continuity of tofacitinib.. Twenty-two patients with UC who were treated with tofacitinib were enrolled. Tofacitinib was continued in 16/22 (72.7%) patients. CAI significantly improved 4 weeks after tofacitinib induction (P < 0.01). In the blood tests, only Alb level improved significantly at week 2 compared with baseline (P = 0.03). In the non-failure group, serum Alb and CRP levels improved significantly from week 0 to week 24; however, similar changes were not observed in the failure group. After 6 months, the overall MES and UCEIS had significantly improved (P = 0.03 and P = 0.02, respectively). Kaplan-Meier analysis demonstrated that those with baseline UCEIS ≥ 5 had significantly lower tofacitinib continuation rate than those with baseline UCEIS ≤ 4, suggesting that baseline UCEIS may be a predictor of tofacitinib continuation (log-rank test: P < 0.01).. Tofacitinib is a promising therapeutic agent for the induction and maintenance therapy in UC. Baseline UCEIS may predict its therapeutic effects.

Topics: Colitis, Ulcerative; Colonoscopy; Humans; Piperidines; Pyrimidines; Severity of Illness Index

Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis. We evaluate baseline characteristics as predictors of sustained response and remission in patients with ulcerative colitis receiving tofacitinib maintenance therapy.. Patients with clinical response following OCTAVE Induction 1 and 2 entered OCTAVE Sustain and were rerandomized to receive tofacitinib 5 or 10 mg twice daily or placebo. Baseline characteristics were stratified by week 52 efficacy endpoints (remission, sustained remission, clinical response, sustained clinical response). Associations between baseline characteristics and efficacy endpoints were evaluated using logistic regression analyses.. Overall, 170 of 487 (34.9%) patients were in remission at week 52. In multivariable modeling, endoscopic subscore at baseline of OCTAVE Induction 1 and 2 (2 vs 3; odds ratio [OR], 1.60; 95% confidence interval [CI], 1.06-2.44]), partial Mayo score (<2 vs ≥2; OR, 1.92; 95% CI, 1.27-2.90), and age (per 10-years; OR, 1.19; 95% CI, 1.02-1.39) at baseline of OCTAVE Sustain (following 8 weeks' tofacitinib induction therapy) were associated with higher odds of remission at week 52. Oral corticosteroid use (OR, 0.63; 95% CI, 0.42-0.96) and C-reactive protein (per unit; OR, 0.94; 95% CI, 0.89-0.99) at baseline of OCTAVE Sustain were associated with reduced likelihood of remission at week 52. In general, opposite associations were observed for time to loss of response.. Patients with greater clinical improvement after 8 weeks of tofacitinib induction therapy are more likely to maintain response or remission with tofacitinib regardless of dose received during maintenance, highlighting the importance of a robust response to induction therapy.

Topics: Child; Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Pyrroles; Remission Induction

Tofacitinib is an oral small molecule JAK inhibitor for the treatment of ulcerative colitis. Relationships between plasma tofacitinib concentration and efficacy were characterized using exposure-response (E-R) models, with demographic and disease covariates evaluated as potential predictors of efficacy. Data were from phase II and III (OCTAVE Induction 1 and 2) induction studies, and a phase III maintenance study (OCTAVE Sustain). Induction studies included 1,355 patients (tofacitinib 0.5, 3, 10, or 15 mg b.i.d. or placebo). The maintenance study included 592 patients (tofacitinib 5 or 10 mg b.i.d. or placebo). E-R models, including induction patients predicted placebo-adjusted remission rates of 6.4% and 12.7% at week 8 for tofacitinib 5 and 10 mg b.i.d., respectively; corresponding rates in patients without prior tumor necrosis factor inhibitor (TNFi) failure were 12.8% and 20.4%. Estimates to achieve/maintain remission at week 52 of maintenance were 29% and 18% (tofacitinib 5 mg b.i.d.), and 41% and 26% (tofacitinib 10 mg b.i.d.), for patients in remission or not following induction, respectively. During maintenance, patients with prior TNFi failure had lower probability of remission on 5 mg b.i.d. (24.9%) than 10 mg b.i.d. (35.0%). Results indicated tofacitinib 10 mg b.i.d. was an appropriate induction dose but suggested efficacy with 5 mg b.i.d. in patients without prior TNFi failure. Tofacitinib 5 mg b.i.d. was efficacious for maintenance, although patients with prior TNFi failure might see additional benefit on 10 mg b.i.d. Per product labeling, recommended tofacitinib induction dose is 10 mg b.i.d., then maintenance at 5 mg b.i.d. For patients who lose response during maintenance, 10 mg b.i.d. may be considered, limited to the shortest duration. Clinicaltrials.gov: NCT00787202; NCT01465763; NCT01458951; and NCT01458574.

Topics: Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Pyrroles; Remission Induction

Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). The efficacy and safety of tofacitinib in patients with moderate to severe UC, up to 1 year, have been reported. We investigated maintenance of efficacy in patients in remission after 52 weeks of maintenance treatment in the pivotal phase 3 study (OCTAVE Sustain); these patients received open-label, long-term treatment with tofacitinib 5 mg twice daily.. Patients with moderate to severe UC who completed a 52-week, phase 3 maintenance study (OCTAVE Sustain) were eligible to enroll into the ongoing, phase 3, multicenter, open-label, long-term extension (OCTAVE Open). We analyzed data from 142 patients who were in remission following tofacitinib treatment in OCTAVE Sustain who received tofacitinib 5 mg twice daily during OCTAVE Open. We assessed efficacy (including remission [based on total Mayo score], endoscopic improvement, clinical response, and partial Mayo score up to month 36 of OCTAVE Open) and safety data.. After 12 months of tofacitinib 5 mg twice daily in OCTAVE Open, 68.3% of patients were in remission, 73.9% had endoscopic improvement, and 77.5% had a clinical response. At month 36, 50.4%, of the patients were in remission, 55.3% had endoscopic improvement, and 56.0% had a clinical response. The safety profile of tofacitinib 5 mg twice daily revealed no new safety risks associated with long-term exposure up to 36 months.. Efficacy endpoints were maintained for up to 36 months, regardless of prior tofacitinib dose, including patients who reduced from tofacitinib 10 mg to 5 mg twice daily upon OCTAVE Open entry. No new safety risks were identified. ClinicalTrials.gov: OCTAVE Sustain (NCT01458574); OCTAVE Open (NCT01470612).

Topics: Colitis, Ulcerative; Humans; Janus Kinase Inhibitors; Piperidines; Pyrimidines; Remission Induction; Treatment Outcome

Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). The efficacy and safety of tofacitinib were demonstrated in a dose-ranging phase 2 induction trial, 3 phase 3 randomized, placebo-controlled trials (OCTAVE Induction 1 and 2; and OCTAVE Sustain), and an ongoing, open-label, long-term extension trial (OCTAVE Open) in patients with moderately to severely active UC. Here, we assessed short- and long-term efficacy and safety of extended induction (16 weeks) with tofacitinib 10 mg twice daily (BID) in patients who failed to respond to initial induction (8 weeks) treatment.. In patients who achieved a clinical response following extended induction (delayed responders), the efficacy and safety of tofacitinib were evaluated up to Month 36 of OCTAVE Open.. 52.2% of patients who did not achieve clinical response to 8 weeks' treatment with tofacitinib 10 mg BID in the induction studies achieved a clinical response following extended induction (delayed responders). At Month 12 of OCTAVE Open, 70.3%, 56.8%, and 44.6% of delayed responders maintained clinical response and achieved endoscopic improvement and remission, respectively. Corresponding values at Month 36 were 56.1%, 52.0%, and 44.6%. The safety profile of the subsequent 8 weeks was similar to the initial 8 weeks.. Overall, the majority of patients achieved a clinical response after 8 or 16 weeks' induction therapy with tofacitinib 10 mg BID. Tofacitinib 10 mg BID, administered as induction therapy for up to 16 weeks, had a comparable safety profile to 8 weeks' induction therapy. Most delayed responders at Month 36 were in remission.. gov: NCT00787202; NCT01465763; NCT01458951; and NCT01470612.

Topics: Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Pyrroles; Remission Induction; Treatment Outcome

Tofacitinib is an oral, small-molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We summarize the efficacy and safety data of tofacitinib 5 or 10 mg twice daily in the UC clinical program, stratified by prior tumor necrosis factor inhibitor (TNFi) failure status.. Efficacy was assessed in the pooled phase 3 OCTAVE Induction 1 and 2 studies (N = 1139), the phase 3 OCTAVE Sustain maintenance study (N = 593), and the dose-escalation subpopulation of the open-label, long-term extension OCTAVE Open study (N = 59). Safety was assessed in OCTAVE Sustain, the dose-escalation subpopulation, and the Overall Cohort, which included patients from OCTAVE Induction 1 and 2, OCTAVE Sustain, and OCTAVE Open (N = 1124; no prior TNFi failure N = 541; prior TNFi failure N = 583; phase 2 data were excluded when stratified by prior TNFi failure status). The dose-escalation subpopulation received tofacitinib 10 mg twice daily in OCTAVE Induction 1 and 2, tofacitinib 5 mg twice daily in OCTAVE Sustain, and tofacitinib 10 mg twice daily in OCTAVE Open.. Tofacitinib had greater efficacy than placebo, regardless of prior TNFi failure status. In OCTAVE Sustain and the Overall Cohort, herpes zoster [HZ] (nonserious and serious) rates were numerically higher in tofacitinib-treated patients with vs without prior TNFi failure. Dose escalation to tofacitinib 10 mg twice daily generally recaptured clinical response for most patients. HZ (nonserious and serious) rates were numerically higher in the dose-escalation subpopulation vs the Overall Cohort.. Tofacitinib was efficacious in patients with UC regardless of prior TNFi failure status. HZ (nonserious and serious) rates were numerically higher in patients who had previously failed TNFi. ClinicalTrials.gov: A3921063 (NCT00787202); OCTAVE Induction 1 (NCT01465763); OCTAVE Induction 2 (NCT01458951); OCTAVE Sustain (NCT01458574); and OCTAVE Open (NCT01470612).

Topics: Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Pyrroles; Treatment Outcome; Tumor Necrosis Factor Inhibitors

Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We present integrated analyses of nonmelanoma skin cancer (NMSC) incidence in the tofacitinib UC clinical program.. Nonmelanoma skin cancer events were evaluated from 3 randomized, placebo-controlled studies: 2 identical, 8-week induction studies (NCT01465763, NCT01458951), a 52-week maintenance study (NCT01458574), and an open-label, long-term extension study (NCT01470612). Cohorts analyzed were: Induction, Maintenance, and Overall (patients receiving ≥1 dose of tofacitinib 5 mg or 10 mg twice daily [BID]). An independent adjudication committee reviewed potential NMSC. Proportions and incidence rates (IRs; unique patients with events per 100 patient-years of exposure) for NMSC were evaluated. A Cox proportional hazards model was used for risk factor analysis.. Nonmelanoma skin cancer was evaluated for 1124 patients (2576.4 patient-years of tofacitinib exposure; ≤6.8 years' treatment). In the Induction Cohort, NMSC IR was 0.00 for placebo and 1.26 for 10 mg BID. Nonmelanoma skin cancer IR was 0.97 for placebo, 0.00 for 5 mg BID and 1.91 for 10 mg BID in the Maintenance Cohort, and 0.73 (n = 19) in the Overall Cohort. No NMSC was metastatic or led to discontinuation. In the Overall Cohort, Cox regression identified prior NMSC (hazard ratio [HR], 9.09; P = 0.0001), tumor necrosis factor inhibitor (TNFi) failure (3.32; P = 0.0363), and age (HR per 10-year increase, 2.03; P = 0.0004) as significant independent NMSC risk factors.. For patients receiving tofacitinib, NMSC occurred infrequently. Older age, prior NMSC, and TNFi failure, which are previously reported NMSC risk factors in patients with UC, were associated with increased NMSC risk.

Topics: Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Skin Neoplasms

Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We examined the effect of tofacitinib induction treatment on Inflammatory Bowel Disease Questionnaire (IBDQ) items in adults with moderate to severe UC.. Data were pooled from the randomized, 8‑week, double-blind, phase 3 OCTAVE Induction 1 and 2 studies. The IBDQ was self-administered by patients at baseline, week 4, and week 8, with higher scores indicating better health-related quality of life (HRQoL). Change from baseline in IBDQ items was analyzed for 10 mg of tofacitinib twice daily (BID) vs placebo using a linear mixed-effects model, with no multiplicity adjustment performed. Effect sizes were calculated. Subgroup analyses by tumor necrosis factor inhibitor (TNFi) experience were performed.. Significant improvements (nominal P < 0.05) were observed in all IBDQ items with 10 mg of tofacitinib BID vs placebo at weeks 4 and 8. For the overall population, the largest treatment differences across all items were reported for "bowel movements been loose" at weeks 4 and 8, and "problem with rectal bleeding" at week 8 (mean treatment differences all 1.1; both in bowel symptoms domain). These items also showed the largest effect sizes. Treatment benefits were generally slightly numerically higher in TNFi-experienced vs TNFi-naïve patients.. Tofacitinib induction therapy improved all IBDQ items vs placebo in patients with UC, reflecting improvements in HRQoL, with greatest benefits reported in bowel symptoms domain items (Funded by Pfizer Inc; OCTAVE Induction 1 and OCTAVE Induction 2; ClinicalTrials.gov, NCT01465763 and NCT01458951, respectively).

Topics: Adult; Colitis, Ulcerative; Double-Blind Method; Humans; Piperidines; Pyrimidines; Quality of Life; Surveys and Questionnaires

Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Creatine kinase (CK) levels and CK-related adverse events (AEs) in tofacitinib-treated patients with UC were evaluated.. Data were analyzed for three UC cohorts: Induction (phase 2 and 3 induction studies); Maintenance (phase 3 maintenance study); Overall [patients who received tofacitinib 5 or 10 mg twice daily (b.d.) in phase 2, phase 3, or open-label, long-term extension studies; data at November 2017]. Clinical trial data for tofacitinib-treated patients with rheumatoid arthritis, psoriasis, and psoriatic arthritis are presented for contextualization.. Week 8 mean change from baseline CK with tofacitinib 10 mg b.d. induction therapy was 91.1 U/L (95% CI, 48.1-134.1) versus 19.2 U/L (8.5-29.9) with placebo. Among patients completing induction with 10 mg b.d. and re-randomized to 52 weeks of maintenance therapy, mean increases from induction baseline to the end of maintenance were 35.9 (8.1-63.7), 90.3 (51.9-128.7), and 115.6 U/L (91.6-139.7), with placebo, 5 and 10 mg b.d., respectively. The incidence rate (unique patients with events per 100 patient-years) for AEs of CK elevation in the tofacitinib-treated UC Overall cohort was 6.6 versus 2.2, 6.5, and 3.7 for tofacitinib-treated patients with rheumatoid arthritis, psoriasis, and psoriatic arthritis, respectively. No serious AEs of CK elevation or AEs of myopathy occurred in UC studies.. In patients with UC, CK elevations with tofacitinib appeared reversible and not associated with clinically significant AEs. UC findings were consistent with tofacitinib use in other inflammatory diseases.. NCT00787202; NCT01465763; NCT01458951; NCT01458574; NCT01470612; NCT01262118; NCT01484561; NCT00147498; NCT00413660; NCT00550446; NCT00603512; NCT00687193; NCT01059864; NCT01164579; NCT00976599; NCT01359150; NCT02147587; NCT00960440; NCT00847613; NCT00814307; NCT00856544; NCT00853385; NCT01039688; NCT02187055; NCT00413699; NCT00661661; NCT01710046; NCT00678210; NCT01276639; NCT01309737; NCT01241591; NCT01186744; NCT01163253; NCT01877668; NCT01882439; NCT01976364.

Topics: Adult; Arthritis, Psoriatic; Arthritis, Rheumatoid; Cohort Studies; Colitis, Ulcerative; Creatine Kinase; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Risk Factors

Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis. We report integrated analyses of infections in the Phase [P]2 and P3 OCTAVE programmes.. Three cohorts were analysed: Induction [P2/3 induction studies]; Maintenance [P3 maintenance study]; and Overall [all tofacitinib-treated patients in induction, maintenance, or ongoing, open-label, long-term extension studies; as of May 2019]. Proportions and incidence rates [IRs; unique patients with events/100 patient-years] of serious infections [SIs], herpes zoster [HZ] [non-serious and serious], and opportunistic infections [OIs] are reported [censored at time of event].. In the Induction Cohort [N = 1220], no patients receiving placebo and eight [0.9%] receiving tofacitinib 10 mg twice daily [BID] developed SIs. Maintenance Cohort [N = 592] SI IRs (95% confidence interval [CI]) were 1.94 [0.23-7.00] for placebo and 1.35 [0.16-4.87] and 0.64 [0.02-3.54] for tofacitinib 5 and 10 mg BID, respectively; HZ IRs were 0.97 [0.02-5.42], 2.05 [0.42-6.00], and 6.64 [3.19-12.22], respectively. In the Overall Cohort [N = 1157; 82.9% predominantly received tofacitinib 10 mg BID], SI, HZ, and non-HZ OI IRs were 1.70 [1.24-2.27], 3.48 [2.79-4.30], and 0.15 [0.04-0.38], respectively. No SIs resulted in death.. During induction, SIs were more frequent with tofacitinib versus placebo. SIs were generally infrequent in the Maintenance and Overall Cohorts, with rates comparable between treatment groups. Maintenance Cohort HZ IR was numerically higher with tofacitinib 10 mg BID versus 5 mg BID. Overall Cohort HZ IRs remained stable over time. Non-HZ OIs and viral infections were rare.

Topics: Adult; Colitis, Ulcerative; Dose-Response Relationship, Drug; Female; Herpes Zoster; Humans; Immunocompromised Host; Incidence; Infections; Janus Kinase Inhibitors; Male; Medication Therapy Management; Opportunistic Infections; Piperidines; Pyrimidines; Risk Assessment; Severity of Illness Index

Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis. We present primary completion analysis from RIVETING, an ongoing, double-blind, randomised, parallel-group trial evaluating efficacy and safety of tofacitinib dose reduction to 5 mg twice daily [BID] versus remaining on 10 mg BID in patients in stable remission on tofacitinib 10 mg BID maintenance therapy.. Patients had received tofacitinib 10 mg BID for ≥ 2 consecutive years and been in stable remission for ≥ 6 months before enrolment. The primary endpoint was modified Mayo score remission at Month 6. Safety was assessed up to February 20, 2020 [data cut-off].. In all, 140 patients were randomised [1:1] to tofacitinib 5 or 10 mg BID; 77.1% and 90.0% of patients in the 5 and 10 mg BID groups, respectively, were in modified Mayo score remission at Month 6 (adjusted difference 12.9%; 95% confidence interval [CI] 0.5-25.0). Smaller differences between treatment groups were seen in patients with baseline endoscopic subscore of 0 versus 1 [9.8%; -3.0-22.6, and 21.1%; -6.1-48.2, respectively], and in patients without versus with prior tumour necrosis factor inhibitor [TNFi] failure [9.5%; -6.6-25.6, and 17.4%; -1.6-36.3, respectively]. Adverse events [AE] and serious AE rates were similar across treatment groups; no deaths were reported.. Most patients in stable remission on 10 mg BID maintenance therapy maintained remission following dose de-escalation. For patients who dose de-escalated, those in deep endoscopic remission and those without prior TNFi failure were more likely to maintain remission. Efficacy data were limited to the first 6 months; a longer duration of follow-up during RIVETING will further characterise the impact of dose reduction on maintenance of remission. Safety findings were consistent with the established safety profile of tofacitinib.

Topics: Administration, Oral; Colitis, Ulcerative; Double-Blind Method; Drug Tapering; Female; Humans; Maintenance Chemotherapy; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Remission Induction

Topics: Administration, Oral; Adult; Biological Variation, Population; Colitis, Ulcerative; Ethnicity; Female; Half-Life; Humans; Janus Kinase Inhibitors; Male; Middle Aged; Models, Biological; Observer Variation; Piperidines; Placebos; Pyrimidines; Severity of Illness Index; Treatment Outcome

Tofacitinib, a selective inhibitor of JAK/STAT pathway, has recently become available in our region. Here, we examined the safety and efficacy of tofacitinib in active ulcerative colitis (UC).. In a prospective, non-randomized, placebo-free, 52-week clinical trial defined in two phases of induction and maintenance, adult patients with active UC and no response or loss of response to previous conventional treatments, or anti-TNF were recruited (IRCT20181217042020N2). Patients received 10 mg/BID of tofacitinib for 8 weeks. Clinically responding patients were entered into the maintenance phase and received tofacitinib 5 mg/BID for 44 weeks. Clinical evaluation, biochemical tests and endoscopy at time points of baseline, 8, 24 and 52 weeks were performed. The primary outcome was clinical remission at 8 and 52 weeks.. Fifty out of 53 enrolled patients completed the induction phase. Clinical response and clinical remission at 8 weeks occurred in 84% and 9.5%, respectively. Forty-two patients who had clinical response entered the maintenance phase. Clinical remission based on the total Mayo score and the partial Mayo score occurred in 38.9% and 55.3% at 24 weeks and in 61.1% and 72.2% at 52 weeks, respectively. There was significant correlation between the total and partial Mayo score with regard to clinical remission in both 24 and 52 weeks. No serious adverse events, no case of herpes zoster, but two cases of deep vein thrombosis were seen.. Our study showed acceptable efficacy and safety for tofacitinib and suggested a correlation between the total Mayo score with partial Mayo score with regard to clinical remission.

Topics: Adult; Colitis, Ulcerative; Humans; Iran; Piperidines; Prospective Studies; Pyrimidines; Remission Induction; Tumor Necrosis Factor Inhibitors

For patients with UC, flexible maintenance dosing therapy may confer advantages for safety, efficacy, costs and patient preference. Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of UC.. To assess the efficacy and safety of tofacitinib dose de-escalation and escalation in patients with UC.. We evaluated data (November 2017 data cut-off) from OCTAVE Open, an ongoing, open-label, long-term extension study. The dose de-escalation group comprised 66 tofacitinib induction responders in remission following 52 weeks' tofacitinib 10 mg b.d. maintenance therapy, subsequently de-escalated to 5 mg b.d. in OCTAVE Open. The dose escalation group comprised 57 tofacitinib induction responders who experienced treatment failure while receiving 5 mg b.d. maintenance therapy, subsequently escalated to 10 mg b.d. in OCTAVE Open.. After tofacitinib de-escalation, 92.4% (61/66) and 84.1% (53/63) of patients maintained clinical response and 80.3% (53/66) and 74.6% (47/63) maintained remission, at months 2 and 12, respectively. After dose escalation, 57.9% (33/57) and 64.9% (37/57) of patients recaptured clinical response and 35.1% (20/57) and 49.1% (28/57) were in remission, at months 2 and 12, respectively. The incidence rate of herpes zoster with dose escalation (7.6 patients with events/100 patient-years) was numerically higher than in the overall tofacitinib UC programme.. Following tofacitinib de-escalation in patients already in remission on 10 mg b.d., most maintained remission, although 25.4% lost remission, at month 12. For induction responders who dose-escalated following treatment failure on 5 mg b.d. maintenance therapy, 49.1% achieved remission by month 12. (ClinicalTrials.gov number: NCT01470612).

Topics: Adult; Colitis, Ulcerative; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Maintenance Chemotherapy; Male; Middle Aged; Piperidines; Pyrimidines; Pyrroles; Remission Induction; Treatment Outcome

Tofacitinib is an oral, small-molecule inhibitor of JAK approved in several countries for the treatment of ulcerative colitis (UC). We report integrated safety analyses of tofacitinib-treated patients with moderate to severe UC.. Patients receiving placebo or tofacitinib (5 or 10 mg) twice daily were analyzed as 3 cohorts: induction (phase 2 and 3 induction studies, n = 1220), maintenance (phase 3 maintenance study, n = 592), and overall (patients receiving tofacitinib 5 or 10 mg twice daily in phase 2, phase 3, or open-label, long-term extension studies, n = 1157; 1613 patient-years' exposure). Incidence rates (IRs; patients with events per 100 patient-years of exposure) were evaluated for select adverse events.. In the maintenance cohort, IRs for select adverse events were similar among treatment groups, except for a numerically higher IR of herpes zoster infection among patients who received tofacitinib 5 mg twice daily (2.1; 95% CI, 0.4-6.0) and statistically higher IR among patients who received tofacitinib 10 mg twice daily (IR, 6.6; 95% CI, 3.2-12.2) vs placebo (IR, 1.0, 95% CI, 0.0-5.4). For the overall cohort (84% received average dose of tofacitinib 10 mg twice daily), IRs were: death, 0.2 (95% CI, 0.1-0.6); serious infections, 2.0 (95% CI, 1.4-2.8); opportunistic infections, 1.3 (95% CI, 0.8-2.0); herpes zoster infection, 4.1 (95% CI, 3.1-5.2); malignancy (excluding non-melanoma skin cancer), 0.7 (95% CI, 0.3-1.2); non-melanoma skin cancer, 0.7 (95% CI, 0.3-1.2); major adverse cardiovascular events, 0.2 (95% CI, 0.1-0.6); and gastrointestinal perforations, 0.2 (95% CI, 0.0-0.5).. In safety analyses of patients with moderate to severe UC treated with tofacitinib, we observed a dose relationship with herpes zoster infection. Although follow-up time was relatively short, the safety profile of tofacitinib for patients with UC appeared similar to that reported for patients with rheumatoid arthritis and for patients with UC treated with biologic agents, except for the higher IR of herpes zoster infection. ClinicalTrials.gov, no: NCT00787202, NCT01465763, NCT01458951, NCT01458574, and NCT01470612.

Topics: Adult; Aged; Colitis, Ulcerative; Colonoscopy; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Janus Kinase 3; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Severity of Illness Index; Time Factors; Treatment Outcome

Tofacitinib is an oral, small molecule Janus kinase [JAK] inhibitor that is being investigated for ulcerative colitis [UC]. We evaluated health-related quality of life [HRQoL] in tofacitinib UC Phase 3 studies.. Patients ≥ 18 years old in OCTAVE Induction 1 [N = 598] and 2 [N = 541] with moderately to severely active UC were randomised [1:4] to placebo or tofacitinib 10 mg twice daily [BID] for 8 weeks. Subsequently, OCTAVE Sustain re-randomised [1:1:1] clinical responders [N = 593] from induction studies to placebo, tofacitinib 5 mg BID, or 10 mg BID, for 52 weeks. Inflammatory Bowel Disease Questionnaire [IBDQ] and SF-36v2® Health Survey [SF-36v2] assessed HRQoL.. In OCTAVE Induction 1 and 2, mean changes from baseline IBDQ were greater with tofacitinib 10 mg BID at Week 8 [28.9 and 31.5] versus placebo [15.4 and 17.2; p < 0.0001]; mean changes from baseline SF-36v2 Physical and Mental Component Summaries [PCS/MCS] were also greater with 10 mg BID [PCS: 6.8 and 6.8; MCS: 6.8 and 7.6] versus placebo [PCS: 2.5 and 4.6; MCS: 3.5 and 4.4; p < 0.01]. In OCTAVE Sustain atWeek 52, changes in IBDQ were maintained with tofacitinib 5 mg [-1.3] and 10 mg BID [0.6], and larger with placebo [-20.2; p < 0.0001]. Changes in SF-36v2 PCS/MCS were also maintained with 5 mg [PCS: 0.0; MCS: -1.0] and 10 mg BID [PCS: 0.3; MCS: 0.1] versus placebo [PCS: -5.2; MCS: -6.7; p < 0.0001] at Week 52 in OCTAVE Sustain.. Tofacitinib 10 mg BID induction therapy significantly improved HRQoL versus placebo at Week 8. Improvements were maintained through 52 weeks' maintenance therapy with tofacitinib 5 mg and 10 mg BID.. NCT01465763, NCT01458951 and NCT01458574.

Topics: Adult; Colitis, Ulcerative; Double-Blind Method; Female; Humans; Induction Chemotherapy; Janus Kinase Inhibitors; Maintenance Chemotherapy; Male; Middle Aged; Piperidines; Pyrimidines; Pyrroles; Quality of Life; Surveys and Questionnaires; Time Factors

Tofacitinib is an oral, small molecule JAK inhibitor being investigated for ulcerative colitis (UC). In a phase 2 dose-ranging study, tofacitinib demonstrated efficacy vs. placebo as UC induction therapy. In this posthoc analysis, we aimed to compare tofacitinib dose and plasma concentration as predictors of efficacy and identify covariates that determined efficacy in patients with UC.. One- and two-compartment pharmacokinetic models, with first-order absorption and elimination, were evaluated to describe plasma tofacitinib concentration-time data at baseline and week 8. Relationships between tofacitinib exposure (dose, average plasma drug concentration during a dosing interval at steady state [C. Plasma tofacitinib concentrations increased proportionately with dose and estimated oral clearance, and C. Exposure-response characterization demonstrated the potential of tofacitinib 10 and 15 mg twice daily as induction therapy for UC without monitoring of plasma drug concentrations for dose optimization.

Topics: Adult; Aged; Anti-Inflammatory Agents; Colitis, Ulcerative; Dose-Response Relationship, Drug; Double-Blind Method; Female; Gastrointestinal Agents; Humans; Janus Kinase Inhibitors; Male; Middle Aged; Models, Biological; Piperidines; Pyrimidines; Pyrroles; Remission Induction; Severity of Illness Index; Treatment Outcome; Young Adult

Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for ulcerative colitis (UC). Tofacitinib is approved for rheumatoid arthritis and psoriatic arthritis, where it has been shown to increase herpes zoster (HZ) risk. We evaluated HZ risk among UC patients using tofacitinib.. HZ cases were identified in tofacitinib phase II/III/ongoing, open-label, long-term extension (OLE) UC trials. We calculated HZ incidence rates (IRs) per 100 patient-years of tofacitinib exposure within phase III maintenance (Maintenance Cohort) and phase II/III/OLE (Overall Cohort) studies, stratified by baseline demographics and other factors. HZ risk factors were evaluated in the Overall Cohort using Cox proportional hazard models.. Overall, 65 (5.6%) patients developed HZ. Eleven patients had multidermatomal involvement (2 nonadjacent or 3-6 adjacent dermatomes), and 1 developed encephalitis (resolved upon standard treatment). Five (7.7%) events led to treatment discontinuation. HZ IR (95% confidence interval [CI]) in the Overall Cohort was 4.07 (3.14-5.19) over a mean (range) of 509.1 (1-1606) days, with no increased risk observed with increasing tofacitinib exposure. IRs (95% CI) were highest in patients age ≥65 years, 9.55 (4.77-17.08); Asian patients, 6.49 (3.55-10.89); patients with prior tumor necrosis factor inhibitor (TNFi) failure, 5.38 (3.86-7.29); and patients using tofacitinib 10 mg twice daily, 4.25 (3.18-5.56). Multivariate analysis identified older age and prior TNFi failure as independent risk factors.. In tofacitinib-treated UC patients, there was an elevated risk of HZ, although complicated HZ was infrequent. Increased HZ rates occurred in patients who were older, Asian, or had prior TNFi failure (NCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612).

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Colitis, Ulcerative; Female; Herpes Zoster; Herpesvirus 3, Human; Humans; Incidence; Male; Middle Aged; Piperidines; Prognosis; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; United States; Young Adult

Tofacitinib, an oral, small-molecule Janus kinase inhibitor, was shown to have potential efficacy as induction therapy for ulcerative colitis in a phase 2 trial. We further evaluated the efficacy of tofacitinib as induction and maintenance therapy.. We conducted three phase 3, randomized, double-blind, placebo-controlled trials of tofacitinib therapy in adults with ulcerative colitis. In the OCTAVE Induction 1 and 2 trials, 598 and 541 patients, respectively, who had moderately to severely active ulcerative colitis despite previous conventional therapy or therapy with a tumor necrosis factor antagonist were randomly assigned to receive induction therapy with tofacitinib (10 mg twice daily) or placebo for 8 weeks. The primary end point was remission at 8 weeks. In the OCTAVE Sustain trial, 593 patients who had a clinical response to induction therapy were randomly assigned to receive maintenance therapy with tofacitinib (either 5 mg or 10 mg twice daily) or placebo for 52 weeks. The primary end point was remission at 52 weeks.. In the OCTAVE Induction 1 trial, remission at 8 weeks occurred in 18.5% of the patients in the tofacitinib group versus 8.2% in the placebo group (P=0.007); in the OCTAVE Induction 2 trial, remission occurred in 16.6% versus 3.6% (P<0.001). In the OCTAVE Sustain trial, remission at 52 weeks occurred in 34.3% of the patients in the 5-mg tofacitinib group and 40.6% in the 10-mg tofacitinib group versus 11.1% in the placebo group (P<0.001 for both comparisons with placebo). In the OCTAVE Induction 1 and 2 trials, the rates of overall infection and serious infection were higher with tofacitinib than with placebo. In the OCTAVE Sustain trial, the rate of serious infection was similar across the three treatment groups, and the rates of overall infection and herpes zoster infection were higher with tofacitinib than with placebo. Across all three trials, adjudicated nonmelanoma skin cancer occurred in five patients who received tofacitinib and in one who received placebo, and adjudicated cardiovascular events occurred in five who received tofacitinib and in none who received placebo; as compared with placebo, tofacitinib was associated with increased lipid levels.. In patients with moderately to severely active ulcerative colitis, tofacitinib was more effective as induction and maintenance therapy than placebo. (Funded by Pfizer; OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain ClinicalTrials.gov numbers, NCT01465763 , NCT01458951 , and NCT01458574 , respectively.).

Topics: Adult; Chi-Square Distribution; Colitis, Ulcerative; Double-Blind Method; Female; Humans; Induction Chemotherapy; Janus Kinases; Maintenance Chemotherapy; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Remission Induction

Accurate biomarkers of disease activity and therapeutic response can be valuable for clinical trials. We performed a post hoc analysis of data from a phase 2 trial to assess the relationship between the concentration of fecal calprotectin (FCP) and clinical and endoscopic outcomes of patients with moderate to severe ulcerative colitis receiving tofacitinib.. In a double-blind, placebo-controlled, phase 2 trial, 194 patients were assigned randomly to groups given tofacitinib (0.5, 3, 10, or 15 mg twice daily) or placebo. Clinical and endoscopic outcomes were assessed at week 8 using the Mayo scoring system. Receiver operating characteristics were used to evaluate the relationships between FCP concentration and clinical and endoscopic outcomes, and to determine the FCP cut-off concentration that correlated with patient outcome.. Week 8 median concentrations of FCP were significantly lower in responders than in nonresponders (P < .001): clinical response, 156 vs 725 mg/kg; clinical remission, 64 vs 617 mg/kg; endoscopic remission, 44 vs 489 mg/kg; and mucosal healing, 127 vs 753 mg/kg. Area-under-the-curve values for FCP receiver operating characteristic models were 0.80 for clinical remission, 0.81 for endoscopic remission, and 0.78 for mucosal healing. An FCP cut-off value of 150 mg/kg achieved the highest summation of sensitivity and specificity for clinical remission (0.68 and 0.79, respectively; κ coefficient, 0.44) and endoscopic remission (0.79 and 0.75, respectively; κ coefficient, 0.38).. Concentrations of FCP correlate with clinical and endoscopic outcomes of patients with moderate to severe ulcerative colitis receiving tofacitinib, although at an individual level the agreement was moderate. FCP concentration with a cut-off value of 150 mg/kg had only fair to good accuracy in classifying clinical and endoscopic outcomes in a clinical trial. ClinicalTrials.gov no: NCT00787202.

Topics: Administration, Oral; Adult; Area Under Curve; Biomarkers; Colitis, Ulcerative; Colonoscopy; Confidence Intervals; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Feces; Female; Follow-Up Studies; Humans; Leukocyte L1 Antigen Complex; Male; Middle Aged; Piperidines; Pyrimidines; Pyrroles; ROC Curve; Severity of Illness Index; Treatment Outcome; Young Adult

This mediation modelling analysis evaluated direct and indirect effects of tofacitinib, an oral, small molecule Janus kinase inhibitor under investigation for ulcerative colitis, on patient treatment satisfaction.. Data from an 8-week randomized Phase 2 trial [NCT00787202] in adults with moderate-to-severe, active ulcerative colitis receiving twice-daily tofacitinib 0.5-15mg [n=146] or placebo [n=48] were analysed in patient-reported [n=149] and clinician-reported [n=170] outcomes-based mediation models. Binary predictor variable: Treatment [pooled active treatment vs placebo]. Eventual dependent variable: Week 8 patient treatment satisfaction [measured on a five-point Likert scale]. Mediators of treatment effect on satisfaction: Week 8 Inflammatory Bowel Disease Questionnaire domains [Bowel Symptoms, Emotional Health, Social Function and Systemic Symptoms] and Mayo scale domains [Stool Frequency, Rectal Bleeding, Physician's Global Assessment and Endoscopic Disease Activity] for patient-reported and clinician-reported models, respectively.. Overall tofacitinib indirect effect on satisfaction via Inflammatory Bowel Disease Questionnaire domains was 40.5% [p<0.05] and via Mayo scale domains was 84.0% [p<0.01] for patient-reported and clinician-reported models, respectively. Bowel function had the most important indirect effect: of the total tofacitinib effect on satisfaction, 32.4% [p=0.05] was indirectly mediated via Bowel Symptoms; and 30.0% [p=0.04] via Stool Frequency. In total, 59.5% [p<0.01] and only 16.0% [p=0.56] of tofacitinib's effect on satisfaction was unrelated to Inflammatory Bowel Disease Questionnaire and Mayo scale domains in the patient-reported and clinician-reported models, respectively.. Bowel function is an important factor for patient treatment satisfaction with tofacitinib. Treatment effect on patient satisfaction was almost completely mediated via improvement in Mayo scale domains.

Topics: Adult; Anti-Inflammatory Agents; Colitis, Ulcerative; Double-Blind Method; Female; Humans; Male; Patient Satisfaction; Piperidines; Pyrimidines; Pyrroles; Remission Induction; Surveys and Questionnaires; Treatment Outcome

Tofacitinib, a novel, oral Janus kinase inhibitor, demonstrated a dose-dependent efficacy for induction of clinical response and remission in patients with active ulcerative colitis (UC). The objective of the current study was to determine the effect of tofacitinib on patient-reported outcomes (PROs).. Eligible patients (≥18 years of age) with a diagnosis of active UC (total Mayo score of 6-12 points and moderately-to-severely active disease on sigmoidoscopy) were randomized in a 2:2:2:3:3 ratio to receive oral tofacitinib 0.5 mg, 3 mg, 10 mg, or 15 mg, or placebo twice daily (BID) for 8 weeks. PROs were assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ) and the Inflammatory Bowel Disease Patient-Reported Treatment Impact (IBD PRTI) survey.. At Week 8, mean IBDQ total scores had improved relative to baseline across all five treatment groups (baseline range 123.2-134.5; Week 8 range 149.6-175.4). Improvement from baseline was significantly greater (P = 0.001) for tofacitinib 15 mg BID versus placebo. For tofacitinib 15 mg BID, most patients reported satisfaction or extreme satisfaction, definite preference for tofacitinib, and definite willingness to use tofacitinib again on the IBD PRTI at week 8. Patients achieving endoscopic remission (Mayo endoscopy score of 0) had significantly higher IBDQ scores and favorable PRTI scores than those not achieving endoscopic remission.. Short-term treatment with tofacitinib BID was associated with dose-dependent improvement in health-related quality of life and patient preferences for tofacitinib. The results complement previously reported efficacy and safety data for the Phase II study. (NCT 00787202, November 6, 2008).

Topics: Colitis, Ulcerative; Colonoscopy; Humans; Patient Preference; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Quality of Life; Remission Induction; Self Report; Severity of Illness Index

The constitutional isomers and tautomers of oxadiazolones, as well as their mono- and disulfur analogues, were calculated at the B3LYP/aug-cc-pVDZ level. Four groups of 30 molecules each were considered: oxadiazolone, oxadiazolthione, thiadiazolone, and thiadiazolthione isomers. The compounds were categorized into six groups according to permutations of three heteroatoms in the five-membered ring. Additionally, each of the constitutional isomer was considered to have five tautomers conserving stable five-membered ring: two NH tautomers, two rotameric OH (or SH) forms and one CH. La trombocitosis es un hallazgo casual frecuente en pediatría. En niños, predominan las formas secundarias, siendo las infecciones su causa más prevalente. Se distinguen 4 grados de trombocitosis en función del número de plaquetas; en la forma extrema, se supera el 1.000.000/mm. Endoscopic thrombin injection was similar to glue injection in achieving successful hemostasis of AGVH. However, a higher incidence of complications may be associated with glue injection.

Topics: Acetaminophen; Administration, Oral; Adolescent; Adsorption; Adult; Allyl Compounds; Amylopectin; Amylose; Anaerobiosis; Animals; Anti-Bacterial Agents; Anura; Arginase; Arthritis, Rheumatoid; Asthma; Atmosphere; B-Lymphocytes; Basic Helix-Loop-Helix Transcription Factors; Bioelectric Energy Sources; Biofilms; Biofuels; Biomarkers; Biopolymers; Bioreactors; Brain; Brain Injuries, Traumatic; Breast Neoplasms; Calibration; Carbon Tetrachloride; Caspase 3; Catalysis; Catechin; Cations; Cattle; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Body; Cell Line, Tumor; Cell Plasticity; Chemical and Drug Induced Liver Injury; Chemistry Techniques, Synthetic; China; Chitosan; Chloride Channels; Chromatography, High Pressure Liquid; Chromosome Mapping; Cognition; Cognitive Dysfunction; Cohort Studies; Colitis, Ulcerative; Colloids; Coloring Agents; Congresses as Topic; Correlation of Data; Crystallization; Cyanoacrylates; Cyclohexane Monoterpenes; Cyprinidae; Cytochrome P-450 CYP1A1; Death, Sudden; Dent Disease; Dietary Supplements; Diffusion Magnetic Resonance Imaging; Disease Models, Animal; Disease Progression; Disease Resistance; Disulfides; Drug Monitoring; Drug Stability; Ecotoxicology; Electricity; Electrodes; Endocytosis; Environmental Exposure; Environmental Monitoring; Enzyme Inhibitors; Epithelial-Mesenchymal Transition; Esophageal and Gastric Varices; Esters; Fagopyrum; Female; Ferrosoferric Oxide; Flame Retardants; Flavobacteriaceae; Flow Cytometry; Follow-Up Studies; Formoterol Fumarate; Fusarium; Garlic; Gastrointestinal Hemorrhage; Gene Expression; Genes, Plant; Genetic Markers; Glial Fibrillary Acidic Protein; Gliosis; Global Health; Glutathione Transferase; Glycine max; Gum Arabic; Hemostasis, Endoscopic; Hepatocytes; Hippocampus; Humans; Hydrogen-Ion Concentration; Illinois; Immunoglobulin G; Indoleamine-Pyrrole 2,3,-Dioxygenase; Infant, Newborn; Infant, Small for Gestational Age; Injections, Intraperitoneal; Interleukin-4; Iowa; Iron; Ki-67 Antigen; Kidney; Kinetics; Kynurenine; Lakes; Levofloxacin; Lipid Peroxidation; Lipids; Liver; Liver Cirrhosis, Experimental; Magnetic Fields; Magnetic Iron Oxide Nanoparticles; Male; Manure; Maze Learning; Memory, Short-Term; Metal Nanoparticles; Metals, Heavy; Methane; Mice; Mice, Inbred C57BL; Mice, Knockout; Michigan; Microalgae; Microbial Consortia; Mitochondria; Models, Animal; Models, Chemical; Models, Neurological; Molecular Structure; Molecular Weight; Mutation; Myeloid-Derived Suppressor Cells; NADPH Oxidase 2; Neoplasm Recurrence, Local; Neurites; Neurons; Neuroprotective Agents; NF-kappa B; NIH 3T3 Cells; Nitric Oxide Synthase Type II; Nitrogen; Ohio; Ointments; Ontario; Organelle Biogenesis; Organophosphates; Organophosphorus Compounds; Oxidative Stress; Palladium; Particle Size; Pectins; Phenotype; Phytotherapy; Piperidines; Placenta; Plant Diseases; Plant Extracts; Polymers; Polymorphism, Genetic; Polyphenols; Powders; Pregnancy; Pregnancy Trimester, First; Prospective Studies; Protein Kinase Inhibitors; Protein Structure, Secondary; Proteins; Pyridines; Pyrimidines; Rats, Wistar; Real-Time Polymerase Chain Reaction; Receptors, Aryl Hydrocarbon; Receptors, Chemokine; Receptors, Formyl Peptide; Receptors, Lipoxin; Recovery of Function; Recurrence; Reference Standards; Reference Values; Reproducibility of Results; Respiratory Function Tests; Retrospective Studies; Risk; Sensitivity and Specificity; Sewage; Signal Transduction; Sodium Glutamate; Soil; Solanum tuberosum; Solubility; Solutions; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis; Spermatozoa; STAT3 Transcription Factor; Sulfamethoxazole; Tea; Temperature; Thermodynamics; Thrombin; Treatment Outcome; Triazoles; United States; Viscosity; Waste Disposal, Fluid; Wastewater; Water; Water Pollutants, Chemical; Water Purification; White Matter; Wisconsin; X-Ray Diffraction; Zea mays

Ulcerative colitis is a chronic inflammatory disease of the colon for which current treatments are not universally effective. One additional treatment may be tofacitinib (CP-690,550), an oral inhibitor of Janus kinases 1, 2, and 3 with in vitro functional specificity for kinases 1 and 3 over kinase 2, which is expected to block signaling involving gamma chain-containing cytokines including interleukins 2, 4, 7, 9, 15, and 21. These cytokines are integral to lymphocyte activation, function, and proliferation.. In a double-blind, placebo-controlled, phase 2 trial, we evaluated the efficacy of tofacitinib in 194 adults with moderately to severely active ulcerative colitis. Patients were randomly assigned to receive tofacitinib at a dose of 0.5 mg, 3 mg, 10 mg, or 15 mg or placebo twice daily for 8 weeks. The primary outcome was a clinical response at 8 weeks, defined as an absolute decrease from baseline in the score on the Mayo scoring system for assessment of ulcerative colitis activity (possible score, 0 to 12, with higher scores indicating more severe disease) of 3 or more and a relative decrease from baseline of 30% or more with an accompanying decrease in the rectal bleeding subscore of 1 point or more or an absolute rectal bleeding subscore of 0 or 1.. The primary outcome, clinical response at 8 weeks, occurred in 32%, 48%, 61%, and 78% of patients receiving tofacitinib at a dose of 0.5 mg (P=0.39), 3 mg (P=0.55), 10 mg (P=0.10), and 15 mg (P<0.001), respectively, as compared with 42% of patients receiving placebo. Clinical remission (defined as a Mayo score ≤2, with no subscore >1) at 8 weeks occurred in 13%, 33%, 48%, and 41% of patients receiving tofacitinib at a dose of 0.5 mg (P=0.76), 3 mg (P=0.01), 10 mg (P<0.001), and 15 mg (P<0.001), respectively, as compared with 10% of patients receiving placebo. There was a dose-dependent increase in both low-density and high-density lipoprotein cholesterol. Three patients treated with tofacitinib had an absolute neutrophil count of less than 1500.. Patients with moderately to severely active ulcerative colitis treated with tofacitinib were more likely to have clinical response and remission than those receiving placebo. (Funded by Pfizer; ClinicalTrials.gov number, NCT00787202.).

Topics: Administration, Oral; Adult; Colitis, Ulcerative; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Janus Kinases; Lipoproteins, HDL; Lipoproteins, LDL; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Remission Induction

Fifteen patients (20 to 66 years) with long-standing chronic diarrhea of varying etiology were selected for an open trial of loperamide 2 mg capsules. The optimal daily dose for substantial reduction of the diarrhea ranged from two to seven capsules. Eleven patients showed a significant improvement in stool consistency and stool frequency, and a decrease of abdominal cramps. Loperamide appeared to be ineffective in two patients with cholerrheic diarrhea, and in one patient with laxative-induced diarrhea, and in one patient with diarrhea of unknown etiology. The eleven successfully treated patients then entered a double-blind placebo-controlled trial for ten days or until relapse, the daily dose being identical to the optimal one previously determined in the open phase. The investigator was able to guess the code correctly in ten out of eleven cases. Twenty ileostomy patients (ages 25 to 73 years) volunteered for the evaluation of the inhibitory activity on small intestinal peristalsis by loperamide in a double-blind placebo-controlled cross-over study. Mean daily ileostomy output decreased by 22% in the loperamide period, as compared with the drug-free study phase (P less than 0.001). Of the 20 patients, 16 were able to guess their code correctly, whereas four were uncertain, although their fecal weights were lower with loperamide. Many patients noticed an increased urinary production and experienced an improvement in their ileostomy care during loperamide treatment. Because of its effectiveness, its low side-effect liability and its lack of toxicity, loperamide is considered a promising drug in the symptomatic treatment of chronic diarrhea, and as a reliable agent in the treatment of ileostomy patients.

Topics: Adult; Aged; Chronic Disease; Clinical Trials as Topic; Colitis, Ulcerative; Colonic Diseases, Functional; Diarrhea; Female; Humans; Ileostomy; Loperamide; Male; Middle Aged; Piperidines

Topics: Adolescent; Adult; Aged; Chronic Disease; Clinical Trials as Topic; Colitis, Ulcerative; Diarrhea; Dimethylamines; Female; Gastrointestinal Agents; Humans; Male; Middle Aged; Pain; Piperidines; Placebos

Topics: Adult; Aged; Amides; Antidiarrheals; Chlorobenzenes; Chronic Disease; Clinical Trials as Topic; Colitis, Ulcerative; Colonic Diseases, Functional; Crohn Disease; Diarrhea; Drug Evaluation; Female; Gastrointestinal Agents; Humans; Isonipecotic Acids; Male; Middle Aged; Naloxone; Nitriles; Piperidines; Placebos; Reflex, Pupillary

Topics: Colitis, Ulcerative; Colonic Pouches; Humans; Infliximab; Piperidines; Postoperative Complications; Proctocolectomy, Restorative

In patients with ulcerative colitis (UC), risks of infection and malignancies increase with age. Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of UC. This analysis assessed age as a risk factor for adverse events of special interest (AESI) in the tofacitinib UC clinical program.. Data were from phase 2 and 3 induction studies, a phase 3 maintenance study, and an open-label, long-term extension study. Efficacy and/or safety outcomes were analyzed in the Induction, Maintenance, and Overall Cohorts (patients who received ≥ 1 dose of tofacitinib), stratified by age. The effects of baseline demographic and disease-related factors on AESI incidence were assessed by Cox proportional-hazards regression analysis.. In the Overall Cohort (1157 patients with ≤ 6.8 years' tofacitinib treatment), age was a statistically significant predictor of herpes zoster (HZ), malignancies excluding nonmelanoma skin cancer (NMSC), and NMSC. Other statistically significant predictors included prior tumor necrosis factor inhibitor failure for HZ, NMSC, and opportunistic infection events, and prior duration of UC for malignancies excluding NMSC. In the Induction and Maintenance Cohorts, a higher proportion of tofacitinib-treated than placebo-treated patients (numerical difference) achieved the efficacy endpoints (endoscopic improvement, clinical remission, clinical response) across all age groups.. Older individuals receiving tofacitinib as induction and maintenance therapy to treat UC may have an increased risk of HZ, malignancies (excluding NMSC), and NMSC versus similarly treated younger patients, consistent with findings from the general population. Across all age groups, tofacitinib demonstrated greater efficacy than placebo as an induction and maintenance therapy.. NCT00787202; NCT01465763; NCT01458951; NCT01458574; NCT01470612.. Age was assessed as a risk factor for adverse events of special interest in the tofacitinib ulcerative colitis clinical program. Older individuals receiving tofacitinib may have an increased risk of herpes zoster, malignancies (excluding nonmelanoma skin cancer), and nonmelanoma skin cancer versus similarly treated younger patients.

Topics: Colitis, Ulcerative; Herpes Zoster; Herpesvirus 3, Human; Humans; Janus Kinase Inhibitors; Piperidines; Skin Neoplasms

We aimed to evaluate the real-world effectiveness and safety of tofacitinib for the treatment of ulcerative colitis (UC).. REMIT-UC is a Canadian multicenter cohort study. Standardized data collection was performed on 334 consecutive adult outpatients with UC treated with tofacitinib. The primary outcomes were achievement of clinical and endoscopic remission. Safety outcomes were reported using incidence rates (events/100 patient-years of exposure). A multivariable Cox proportional hazards model was used to evaluate predictors of loss of response after tofacitinib dose de-escalation to 5 mg twice daily (BID).. Clinical remission was achieved by 35.3% (106/300), 36.0% (104/289), and 35.2% (93/264) of patients at weeks 12, 24, and 52, respectively. Endoscopic remission was achieved by 18.5% (15/81), 23.0% (28/122), and 25.7% (35/136) of patients at weeks 12, 24, and 52, respectively. Incidence of serious infections, herpes zoster, and venous thromboembolism were 2.1 [0.9-4.2], 0.5 [0.1-1.9], and 1.1 [0.3-2.7], respectively. Among responders, 44.5% (109/245) lost response during follow-up, which was recaptured in 54.9% (39/71) of patients who re-escalated to 10 mg BID. Patients with a baseline Mayo endoscopic score of 3 (adjusted hazard ratio 3.60 [95% confidence interval: 1.70-7.62]) and prior biologic failure (adjusted hazard ratio 3.89 [95% confidence interval: 1.28-11.86]) were at a higher risk for losing response after dose reduction.. One-third of patients with UC treated with tofacitinib achieved clinical remission with few serious adverse events. However, half of patients lost response with de-escalation, which was only partially recaptured with increasing the maintenance dose. Those with negative prognostic factors should be counselled about the risks and benefits of continuing high doses of tofacitinib.

Topics: Adult; Canada; Cohort Studies; Colitis, Ulcerative; Humans; Piperidines

Topics: Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Pyrroles

Topics: Colitis, Ulcerative; Colonic Pouches; Crohn Disease; Humans; Piperidines; Pouchitis; Proctocolectomy, Restorative; Pyrimidines; United States

Tofactinib is a JAK inhibitor approved for ulcerative colitis in humans. Despite of its' proven effectiveness in humans, mechanistic data are scarce on the effectiveness of Tofactinib in experimental colitis in mice. We induced experimental colitis by transfer of CD4+CD25- isolated T cells into RAG2-/- (T and B cell deficient) mice and treated these mice with tofacitinib for 5-6 weeks either with a dosage of 10 or 40 mg/kg body weight immediately after CD4+ transfer or started treatment after first symptoms of disease for several weeks. While treatment with tofacitinib immediately after transfer resulted in an enhanced expansion of CD4+ T cells and did not prevent occurrence of colitis, treatment after start of symptoms of colitis ameliorated disease activity on a clinical basis and in histological analyses. Tofacitinib is effective in the treatment of murine experimental T cell transfer colitis, however does not prevent occurrence of disease.

Topics: Animals; CD4-Positive T-Lymphocytes; Colitis; Colitis, Ulcerative; Humans; Mice; Piperidines

Topics: Colitis, Ulcerative; Humans; Janus Kinase Inhibitors; Janus Kinases; Piperidines; Protein Kinase Inhibitors

Topics: Colitis, Ulcerative; Humans; Piperidines; Pyrimidines

In the absence of head-to-head clinical trials, indirect comparative studies are needed to help position therapies in ulcerative colitis (UC). We aimed to compare the efficacy of infliximab vs. tofacitinib for moderate-severe UC among biologic-naïve participants at post-induction.. This was a post-hoc analysis of patient-level data from four clinical trials including 659 biologic-naïve UC participants. We compared proportions of patients achieving week 8 clinical remission (CR), endoscopic improvement, and endoscopic remission. Clinical response at week 2 was also assessed. Multiple logistic regression models were adjusted for potential confounders identified as having an association with the outcome of interest on univariate analysis. Propensity scores were calculated to create a cohort of participants with similar distribution of baseline co-variates.. Patients treated with infliximab had significantly greater odds of CR at week 8 compared to tofacitinib [88/242 (36.4%) vs. 100/417 (24.0%), aOR: 1.65 (95% CI 1.11-2.44), p = 0.013]. Endoscopic improvement at week 8 was also significantly greater among infliximab-treated patients [149/242 (61.6%) vs. 159/417 (38.1%), aOR: 2.12 (95% CI 1.45-3.10), p < 0.001]. Similar findings were observed with week 8 endoscopic remission [61/242 (25.2%) vs. 43/417 (10.3%); aOR: 2.72 (95% CI 1.66-4.46), p < 0.001]. A similar proportion of participants attained clinical response at week 2 [205/242 (84.7%) vs. 334/417 (80.1%), aOR: 1.48 (95% CI 0.93-2.37), p = 0.101]. Similar results were observed among the propensity score matched cohort.. Based on the efficacy observed in this post-hoc analysis, consideration should be given to use of infliximab over tofacitinib for treatment of moderate to severe biologic-naïve UC. However, baseline characteristic mismatches persisted despite propensity score matching, and further studies are needed to confirm our findings.

Topics: Biological Products; Colitis, Ulcerative; Humans; Infliximab; Piperidines; Treatment Outcome

Tofacitinib is associated with sustained steroid-free remission in patients with ulcerative colitis (UC), with the lowest effective dose recommended for maintenance therapy. However, there are limited real-world data to guide decisions on the optimal maintenance regimen. We aimed to evaluate predictors and outcomes of disease activity after tofacitinib dose de-escalation in this population.. Included were adults with moderate-severe UC treated with tofacitinib between June 2012 and January 2022. The primary outcome was evidence of UC disease activity-related events: hospitalization/surgery, corticosteroid initiation, tofacitinib dose increase, or therapy switch.. Among 162 patients, 52% continued 10 mg twice daily while 48% underwent dose de-escalation to 5 mg twice daily. Cumulative incidence rates of UC events at 12 months were similar in patients with and without dose de-escalation (56% vs 58%; P = .81). In univariable Cox regression among patients with dose de-escalation, an induction course with 10 mg twice daily for more than 16 weeks was protective of UC events (hazard ratio [HR], 0.37; 95% CI, 0.16-0.85) while ongoing severe disease (Mayo 3) was associated with UC events (HR, 6.41; 95% 95% CI, 2.23-18.44), which remained significant after adjusting for age, sex, duration of induction course, and corticosteroid use at dose de-escalation (HR, 6.05; 95% CI, 2.00-18.35). Twenty-nine percent of patients with UC events had their dose re-escalated to 10 mg twice daily, with only 63% able to recapture clinical response at 12 months.. In this real-world cohort, we observed a 56% cumulative incidence of UC events at 12 months in patients with tofacitinib dose de-escalation. Observed factors associated with UC events after dose de-escalation included induction course for fewer than 16 weeks and active endoscopic disease 6 months after initiation.

Topics: Adrenal Cortex Hormones; Adult; Colitis, Ulcerative; Humans; Janus Kinase Inhibitors; Piperidines; Treatment Outcome

Topics: Colitis, Ulcerative; Female; Humans; Lactation; Milk, Human; Piperidines

Topics: Colitis, Ulcerative; Humans; Piperidines; Pleural Effusion; Pyrimidines

Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Post-marketing surveillance (PMS) is an important part of monitoring adverse events (AEs).. To report an analysis of PMS case safety reports for tofacitinib in patients with UC METHODS: Worldwide tofacitinib PMS reports received in the Pfizer safety database from 30 May 2018 (first regulatory approval) to 25 August 2020 were analysed. The type and estimated reporting rate (RR) of serious AEs of interest, including infection, gastrointestinal, vascular, respiratory, neoplasm and cardiac events, were reviewed. Patient-years of exposure (PY) was estimated based on worldwide sales data and the calculated daily regimens of tofacitinib 5 or 10 mg twice daily, immediate- or extended-release formulations.. During the 27-month reporting period, worldwide post-marketing exposure to tofacitinib was 8916 PY. Overall, 4226 case reports were received and included 12 103 AEs, of which 1839 were serious AEs (SAEs). Among the cases reported, 1141 (27.0%) included an SAE and 18 (0.4%) were fatal. The RR (per 100 PY) for SAEs of interest by Medical Dictionary for Regulatory Activities System Organ Class were 3.28 for infections, 1.26 for vascular disorders, 0.74 for respiratory disorders, 0.55 for neoplasms and 0.50 for cardiac disorders.. The types of AEs were consistent with those reported in tofacitinib clinical trials. Most reported AEs were non-serious. Limitations of PMS reports and reliance on estimated RRs due to lack of precise values for exposure, required for incidence rate calculation, should be considered when interpreting these results.

Topics: Colitis, Ulcerative; Humans; Marketing; Piperidines; Pyrimidines; Pyrroles

Topics: Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Pyrroles; Tuberculosis

Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis. We present final data from OCTAVE Open, an open-label, long-term extension study.. The primary objective of OCTAVE Open was to assess the safety and tolerability of long-term tofacitinib in patients with ulcerative colitis; evaluating efficacy was a secondary objective.. Eligible patients included OCTAVE Induction 1&2 non-responders and OCTAVE Sustain completers/treatment failures. Patients in remission at OCTAVE Open baseline received tofacitinib 5 mg b.d.; all others received 10 mg b.d. Incidence rates (unique patients with events/100 patient-years) for adverse events of special interest were calculated; ≤7.0 years of observation. Efficacy endpoints derived from Mayo score were reported ≤36 months (last scheduled endoscopy visit).. In OCTAVE Open, 769 of 944 patients (81.5%) initially received tofacitinib 10 mg b.d. Among all patients (2440.8 patient-years of exposure), incidence rates (IRs; 95% confidence intervals) for deaths and adverse events of special interest were: deaths, 0.25 (0.09-0.54); serious infections, 1.61 (1.14-2.20); herpes zoster (non-serious and serious), 3.16 (2.47-3.97); opportunistic infections, 0.87 (0.54-1.33); major adverse cardiovascular events, 0.16 (0.04-0.42); malignancies (excluding non-melanoma skin cancer), 1.03 (0.67-1.52); non-melanoma skin cancer, 0.75 (0.45-1.19); deep vein thrombosis, 0.04 (0.00-0.23); pulmonary embolism, 0.21 (0.07-0.48). At Month 36, 66.9% and 40.3% showed clinical response, 64.6% and 37.1% had endoscopic improvement, and 58.9% and 33.7% maintained or achieved remission, with tofacitinib 5 and 10 mg b.d. respectively.. Tofacitinib demonstrated consistent safety up to 7.0  years. Data collected up to Month 36 support long-term efficacy beyond the 52-week maintenance study.

Topics: Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Pyrroles; Treatment Outcome

We sought to define the effectiveness and safety of tofacitinib in a real-world (RW) cohort of Israeli patients with moderate to severe ulcerative colitis (UC).. This was a multi-center retrospective observational cohort study (2019-2020) to assess the effectiveness and safety of tofacitinib induction and maintenance therapy up to 26 weeks. Clinical response and remission were defined as a reduction in Simple Clinical Colitis Activity Index (SCCAI) or partial Mayo score (PMS) of ≥3 points, and SCCAI ≤2 or a PMS ≤1, respectively.. We included 73 patients, 47% male; median age 26 years [IQR: 19.5-39.5], disease duration 7 years [IQR: 2.5-14.5], follow-up 7.1 months [IQR: 3-12], 91% biologics-experienced, and 74% ≥ 2-biologics. Half of patients used concomitant corticosteroids (CS). Overall, 56.1% discontinued therapy due to either lack of response and/or adverse events (AEs), median time to discontinuation - 9.7 months [IQR 3.4-16]. Overall, response, remission, and CS-free-remission were achieved in 47.6%, 20.6%, and 17.5% of patients, respectively. At early maintenance (week 26), response, remission, and CS-free-remission were achieved in 65%, 22.5%, and 20% of patients, respectively. At week 26, tofacitinib 10 mg BID was still used in 43%. Seventeen patients (23.2%) had an adverse event including herpes zoster- 2.7%, hospitalization- 12.3%, and colectomy- 2.7%.. Tofacitinib was effective in achieving CS-free-remission in about 1/5 of highly biologics -experienced patients with UC. Despite a considerable proportion of patients maintained on tofacitinib 10 mg bid, it was well tolerated and safe. Earlier positioning of tofacitinib in the therapeutic algorithm may result in improved outcomes.

Topics: Adrenal Cortex Hormones; Adult; Colectomy; Colitis, Ulcerative; Drug Therapy, Combination; Female; Follow-Up Studies; Hospitalization; Humans; Induction Chemotherapy; Israel; Janus Kinase Inhibitors; Male; Piperidines; Pyrimidines; Retrospective Studies; Tertiary Care Centers; Time Factors; Treatment Outcome

Topics: Colitis, Ulcerative; Humans; Marketing; Piperidines; Pyrimidines

Topics: Colitis, Ulcerative; Humans; Piperidines; Pyrimidines

tofacitinib is a Janus kinase inhibitor approved for the treatment of moderate-severe ulcerative colitis (UC). This study aimed to evaluate its efficacy in a real-life setting.. a retrospective and multicenter observational study was performed with UC patients treated with tofacitinib. Short and long-term treatment effectiveness, treatment survival, need for dose escalation and safety were analyzed. Clinical response and remission were defined in accordance with the partial Mayo score.. seventy-four patients were included, 98.3 % had received prior biological treatment, 55.4 % with three or more biologicals and up to 64.9% with two or three different mechanisms of action. Clinical remission and response rates were 37.8 % and 77 % at eight weeks, and 41.8 % and 70.1 % at 16 weeks. With regard to non-responders at eight weeks, 37.5 % achieved a delayed clinical response at 16 weeks. Mean treatment duration was 19 months (95 % CI: 16-22), with a treatment survival of 56 % at 28 months, and remission and response rates at 24 months of 53.8 % and 61.5 %. Twenty-three treatments were withdrawn, most of them (18) during the induction period. There were adverse events in a quarter of the patients; only four were severe and led to treatment discontinuation.. tofacitinib has a demonstrated efficacy in clinical practice to induce and maintain clinical response in treatment-refractory UC patients, with an acceptable safety profile.

Topics: Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Retrospective Studies

The JAK/STAT inhibitor tofacitinib, recently approved for the treatment of ulcerative colitis, is found to modulate the intestinal endothelial barrier functions in directing the leukocyte adhesion and transmigration in ulcerative colitis patients displaying high levels of endothelial STAT3/STAT6 phosphorylation.

Topics: Colitis, Ulcerative; Humans; Leukocytes; Piperidines; Pyrimidines

Topics: Colitis, Ulcerative; Humans; Piperidines; Pyrimidines

Topics: Calcineurin Inhibitors; Colitis, Ulcerative; Humans; Piperidines; Pyrimidines

Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis (UC).. This post hoc analysis evaluated tofacitinib persistence in patients with UC in OCTAVE Open, an open-label, long-term extension study of patients receiving tofacitinib 5 or 10 mg twice daily.. Kaplan-Meier estimates for tofacitinib drug survival and reasons for discontinuations were evaluated. Baseline factors were analysed as predictors of persistence.. This analysis included 603 patients: 280 entered OCTAVE Open with a clinical response (164 in remission and 116 not in remission), 220 were delayed responders, 75 were retreatment responders and 35 were dose escalation responders, treated for up to 7 years in OCTAVE Open. Of these, 118 (42.1%) responders, 121 (55.0%) delayed responders, 40 (53.3%) retreatment responders and 17 (48.6%) dose escalation responders discontinued tofacitinib with a median time to discontinuation of 5.6, 4.5, 4.0 and 4.4 years, respectively. The estimated 2- and 5-year drug survival rates in the responders (including patients in remission and not in remission) were 73.9% and 54.5%, respectively. Corresponding persistence values for delayed responders were 69.5% and 45.2%, for retreatment responders, 70.7% and 40.0%, and for dose escalation responders, 74.3% and 32.8%.. In OCTAVE Open, a high proportion of patients maintained tofacitinib treatment, with the median survival by group ranging from 4.0 to 5.6 years although these analyses are post hoc and limited by sample size. Further research should focus on factors to enhance persistence with tofacitinib treatment in patients with UC.

Topics: Colitis, Ulcerative; Humans; Longitudinal Studies; Piperidines; Pyrimidines; Pyrroles

Extraintestinal manifestations are common in patients with chronic inflammatory bowel disease (IBD). Peripheral arthritis occurs in ∼10% of patients with IBD. Treatment of both arthritis and the IBD disease is challenging, and involvement of both the rheumatologist and the gastroenterologist is essential. We present a case with concomitant polyarthritis and ulcerative colitis successfully treated with tofacitinib. A 32-year-old woman with ulcerative colitis currently treated with azathioprine and adalimumab was referred to our rheumatology clinic due to pain and swelling in her knees and finger joints. The patient was diagnosed with IBD-related arthritis. Intra-articular injection with steroid was initially effective, but the arthritis was persistent. Treatment attempts with salazopyrine and golimumab were discontinued due to drug-induced pancreatitis and urticaria, respectively. Subsequently treatment with tofacitinib 10 mg twice daily was effective within weeks, and apart from a mild folliculitis, there were no side effects. With this case report, we would like to draw attention to the fact that treatment with tofacitinib may constitute a good treatment option in refractory cases of IBD-related arthritis.

Topics: Adult; Arthritis; Colitis, Ulcerative; Female; Humans; Inflammatory Bowel Diseases; Piperidines; Pyrimidines

Ulcerative colitis (UC) is an incurable, chronic inflammatory disease of the large bowel whose etiology and pathogenesis have not yet been comprehensively explained. Tofacitinib is a small molecule Janus kinase inhibitor that was introduced for treating refractory UC. We aimed to examine the efficacy and safety of tofacitinib for the treatment of 18 patients with UC. Continuous treatment rates were 50, 38, and 33% at 8, 24, and 52 weeks, respectively. Overall, 83.3% of these patients showed tumor necrosis factor (TNF) antibody failure status. When the effective status was defined as a Lichtiger index (LI) that decreased by 3 points or more or was less than 4 points and remission status was defined as an LI less than 4 points, the effective and remission rates (%) at 2, 8, and 16 weeks were 55.5 (10/18) and 22.2 (4/18), 38.8 (7/18) and 33.3 (6/18), and 38.8 (7/18) and 38.8 (7/18), respectively. Background characteristics of 2-week responders and non-responders were compared. C-reactive protein level in responders was significantly lower than that in non-responders, and the hemoglobin level in responders was significantly higher than that in non-responders. This study provides preliminary results of the effectiveness of tofacitinib even for TNF antibody and tacrolimus failure patients.

Topics: Colitis, Ulcerative; Humans; Janus Kinase Inhibitors; Piperidines; Pyrimidines; Treatment Outcome

Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of UC. We aimed to describe the real-world treatment experience and corticosteroid utilisation of patients treated with tofacitinib in a US claims database.. Patients with a UC diagnosis who initiated tofacitinib, vedolizumab or tumour necrosis factor inhibitor (TNFi) treatment between May 2018 and July 2019 were identified from the Optum Research Database. Demographic and clinical characteristics of patients who initiated tofacitinib, vedolizumab or TNFi were described. Oral corticosteroid use prior to and following tofacitinib initiation was evaluated. Tofacitinib adherence (proportion of days covered) and continuation was assessed for 6 months following initiation. Analyses were descriptive and stratified by prior biologic use (naïve, 1 or ≥ 2; minimum of 12 months prior to tofacitinib initiation).. Among patients initiating tofacitinib (N = 225), mean age was 45.6 (SD 16.5) years and 50.2% were female. Of these, 43 (19.1%) patients were biologic-naïve and 182 (80.9%) had prior biologic use (92 [40.9%], 1 prior biologic; 90 [40.0%], ≥ 2 prior biologics). Among patients with 1 prior biologic, 82.6% were previously treated with a TNFi. Among patients with ≥ 2 prior biologics, 54.4% were previously treated with vedolizumab and a TNFi, 16.7% with two TNFi and 28.9% with ≥ 3 prior biologics. In the 6 months prior to tofacitinib initiation, 65.8% of patients had received oral corticosteroids (74.4%, 60.9% and 66.7% for biologic-naïve, 1 and ≥ 2 prior biologics, respectively). The proportion of patients with ongoing oral corticosteroid use 3-6 months after tofacitinib initiation decreased to 13.3% (9.3%, 18.5% and 10.0% for biologic-naïve, 1 and ≥ 2 prior biologics, respectively), and 19.6% of patients discontinued oral corticosteroid use during the 6 months after tofacitinib initiation. Overall, tofacitinib adherence, as determined by the mean proportion of days covered during the 6-month follow-up, was 0.7 (median 0.8). During the 6-month follow-up, 84.9% of patients continued tofacitinib.. Among patients with UC initiating tofacitinib, the majority had prior biologic use. Tofacitinib adherence was high, discontinuation was low and oral corticosteroid utilisation decreased irrespective of prior biologic use. Further research with longer follow-up and a larger sample size is required.

Topics: Adrenal Cortex Hormones; Biological Products; Colitis, Ulcerative; Female; Humans; Middle Aged; Piperidines; Pyrimidines

Tofacitinib is an oral, small-molecule Janus kinase inhibitor approved in South Korea for the treatment of moderate to severe ulcerative colitis (UC) on May 1, 2019. However, safety data are lacking. We investigated the incidence of serious adverse events (SAEs) in patients with UC using tofacitinib from the National Health Insurance Service database. In all, 1,026 UC patients were enrolled in this study. The overall incidences (100 person-years; 95% confidence interval) of SAEs were 4.06 (1.63-8.36) and 6.30 (4.59-8.43) in the tofacitinib and anti-TNFi groups, respectively. No thromboembolic event occurred and major cardiovascular events occurred in only three patients (two unstable angina and one congestive heart failure) in the tofacitinib group. The incidence of herpes zoster and tuberculosis did not differ between the two groups. There was no difference in the overall incidence of SAEs, including thromboembolic events, between tofacitinib- and TNFi-treated UC patients.

Topics: Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Tumor Necrosis Factor Inhibitors

Tofacitinib is the first in class, pan-JAK inhibitor approved for ulcerative colitis (UC). Clinical efficacy has been shown, but long-term real-life endoscopic and histologic data are lacking.. To investigate the effects of tofacitinib in patients with refractory UC focussing on endoscopic, histologic and molecular outcomes, including STAT3 phosphorylation (pSTAT3) detection in the spatial context of mucosal inflammation METHODS: We prospectively monitored 59 highly refractory patients (96.7% anti-TNF exposure, 91.7% vedolizumab exposure) initiating tofacitinib at two IBD referral centres and assessed outcome at the end of induction and after 48 weeks of therapy. Endoscopic improvement was defined as a Mayo endoscopic subscore ≤1, endoscopic and histologic remission as Mayo endoscopic subscore 0 and Nancy histologic score 0. Multiplex immunohistochemistry with multispectral imaging was used to assess pSTAT3.. Endoscopic improvement was achieved by 24.4% and 30.5% of patients at weeks 8 and 48, respectively. Endoscopic and histologic remission rates were 11.1%, 23.7 and 16.7%, 21.4%, respectively. Endoscopic improvement at week 8 was significantly associated with treatment continuation in the long-term (72.7% vs 20.6%, p = 0.003). Although we observed a gradual decrease of mucosal pSTAT3 levels in both remitters and non-remitters (p < 0.05), no association with treatment outcome could be demonstrated. However, lamina propria pSTAT3 was significantly associated with the Nancy Histologic index (p = 0.004).. Tofacitinib can induce and maintain endoscopic and histologic remission in up to one-quarter of highly refractory UC patients. Longitudinal monitoring of nuclear pSTAT3 in mucosal tissue compartments reflects distinctive on-target effects, independently of long-term treatment outcomes.

Topics: Colitis, Ulcerative; Humans; Janus Kinase Inhibitors; Phosphorylation; Piperidines; Pyrimidines; Remission Induction; STAT3 Transcription Factor; Treatment Outcome

Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We report a model-informed drug development approach for bridging efficacy from immediate-release (IR) to extended-release (XR) tofacitinib formulations in patients with UC. IR-XR efficacy bridging was supported by exposure-response analysis of phase 3 induction/maintenance studies of the IR formulation in UC to identify exposure metrics relevant for efficacy. Pharmacokinetic studies in healthy subjects were used to confirm similarity of relevant exposure metrics of tofacitinib IR 5 mg twice daily to XR 11 mg once daily, and tofacitinib IR 10 mg twice daily to XR 22 mg once daily, thereby bridging efficacy between IR and XR formulations. Food effect was evaluated at both XR formulation dose levels. Exposure-response analysis demonstrated that area under the plasma concentration-time curve (average plasma concentration) was a relevant predictor of efficacy. Pharmacokinetic studies demonstrated that area under the plasma concentration-time curve was equivalent between formulations under single-dose and steady-state conditions, and other exposure metrics were also similar. These results also supported bridging of safety data for IR-XR formulations. Food had no impact on tofacitinib XR exposure. These data support efficacy/safety bridging of IR-XR formulations in patients with UC.

Topics: Colitis, Ulcerative; Delayed-Action Preparations; Drug Development; Humans; Piperidines; Pyrimidines

Topics: Colitis, Ulcerative; Humans; Keratoderma, Palmoplantar; Piperidines; Pyrimidines

Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We present safety and efficacy data from patients from East Asia (Japan, Korea, and Taiwan) in OCTAVE Open, an open-label, long-term extension study.. Patients in remission at OCTAVE Open baseline received tofacitinib 5 mg twice daily (BID); all others received tofacitinib 10 mg BID. Proportions and IRs (unique patients with events/100 patient-years) were calculated for adverse events (AEs) of special interest. Efficacy endpoints were evaluated up to 36 months.. In OCTAVE Open, 105/944 patients were from East Asia (tofacitinib 5 mg BID, n = 22; tofacitinib 10 mg BID, n = 83). Overall, 87.6% and 24.8% of patients had AEs and serious AEs, respectively; IRs (95% CI) for AEs of special interest were herpes zoster (HZ; non-serious and serious), 6.07 (3.40-10.02); serious infections, 1.47 (0.40-3.76); opportunistic infections, 1.91 (0.62-4.45); major cardiovascular adverse events, 0.37 (0.01-2.04); malignancies (excluding non-melanoma skin cancer [NMSC]), 0.37 (0.01-2.04); and NMSC, 0.00 (0.00-1.35). No deaths, venous thromboembolic events, or gastrointestinal perforations occurred. At month 36, 68.2% and 54.2% of patients had a clinical response, 68.2% and 53.0% had endoscopic improvement, and 63.6% and 49.4% were in remission with tofacitinib 5 and 10 mg BID, respectively.. The HZ IR in East Asian patients was numerically higher versus the global study population; excluding HZ, tofacitinib safety and efficacy were consistent with the global study population.

Topics: Colitis, Ulcerative; Humans; Janus Kinase Inhibitors; Piperidines; Pyrimidines; Pyrroles; Treatment Outcome

Topics: Colitis, Ulcerative; Humans; Phosphorylation; Piperidines; Precision Medicine; Pyrimidines; STAT3 Transcription Factor

In this case series, 6 patients with chronic pouchitis (n = 3), cuffitis (n = 2), or Crohn’s-like disease of the pouch (n = 1) were treated with tofacitinib. One patient achieved clinical response; however, all patients ultimately discontinued therapy due to nonresponse or adverse events.

Topics: Colitis, Ulcerative; Colonic Pouches; Humans; Piperidines; Pouchitis; Proctocolectomy, Restorative; Pyrimidines

Topics: Colitis, Ulcerative; Erythema Nodosum; Humans; Piperidines; Pyrimidines

Topics: Colitis, Ulcerative; Humans; Janus Kinase Inhibitors; Piperidines; Pyrimidines; Takayasu Arteritis

Topics: Colitis, Ulcerative; Humans; Janus Kinase Inhibitors; Piperidines; Pyrimidines; Takayasu Arteritis

Topics: Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Takayasu Arteritis

Topics: Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Takayasu Arteritis

Topics: Colitis, Ulcerative; Gastrointestinal Agents; Humans; Infliximab; Piperidines; Pyrimidines; Treatment Outcome

Preliminary data regarding the effectiveness of tofacitinib in acute severe ulcerative colitis [ASUC] have been presented in two previous case series. We aimed to describe the novel use of high-dose tofacitinib immediately following non-response to infliximab in the setting of steroid-refractory ASUC.. Five patients who received high-dose tofacitinib 10 mg three times a day immediately following non-response to infliximab for steroid-refractory ASUC were identified at an Australian tertiary inflammatory bowel disease centre.. Four of the five patients demonstrated clinical response to high-dose tofacitinib induction during their inpatient admission, with one patient requiring colectomy owing to a lack of clinical response. At 90 days, all four initial responders remained colectomy-free, with two patients achieving combined clinical and endoscopic remission. No adverse events directly attributable to high-dose tofacitinib were identified.. High-dose tofacitinib may have a role as salvage therapy in the setting of steroid-refractory ASUC. Prospective studies are required to determine the safety and efficacy of high-dose tofacitinib to determine whether it can be routinely recommended as primary or sequential salvage therapy in the setting of steroid-refractory ASUC.

Topics: Adolescent; Adult; Australia; Colitis, Ulcerative; Gastrointestinal Agents; Humans; Infliximab; Janus Kinase Inhibitors; Male; Piperidines; Pyrimidines; Salvage Therapy; Severity of Illness Index

Topics: Colitis, Ulcerative; Cytokines; HLA-B52 Antigen; Humans; Piperidines; Positron Emission Tomography Computed Tomography; Pyrimidines; Takayasu Arteritis

Endoscopy is routine in trials of ulcerative colitis therapies.. To investigate agreement between central and local Mayo endoscopic subscore (MES) reads in the OCTAVE programme METHODS: Flexible sigmoidoscopy was performed in tofacitinib induction (OCTAVE Induction 1&2, NCT01465763 and NCT01458951), maintenance (OCTAVE Sustain, NCT01458574) and open-label, long-term extension (OCTAVE Open, NCT01470612) studies. Kappa statistics and Bowker's tests evaluated agreement/disagreement between centrally and locally read MES, with potential determinants of differences analysed by logistic regression.. Moderate-to-substantial agreement was observed between central and local reads at screening (77.1% agreement; kappa 0.62 [95% confidence interval 0.59-0.66]), OCTAVE Induction 1&2 week (Wk) 8 (63.8%; 0.62 [0.59-0.66]), OCTAVE Sustain Wk 52 (55.6%; 0.56 [0.50-0.62]) and for induction non-responders at OCTAVE Open month 2 (59.9%; 0.54 [0.48-0.60]). Where disagreements occurred, local reads were systematically lower than central reads at OCTAVE Induction 1&2 Wk 8, OCTAVE Sustain Wk 52 and OCTAVE Open month 2 (Bowker's P < 0.0001); this difference was not observed at screening (P = 0.0852). Using multivariable logistic regression, geographical region, C-reactive protein (Wk 8), partial Mayo score (Wk 8) and prior tumour necrosis factor antagonist failure were associated with disparity at OCTAVE Induction 1&2 Wk 8 (P < 0.05). In OCTAVE Induction 1&2 and OCTAVE Sustain, significantly higher proportions of patients endoscopic improvement, remission and endoscopic remission with tofacitinib vs placebo, using either central or local reads.. Moderate-to-substantial agreement was observed between central and local endoscopic reads. Where disagreements occurred, local reads were systematically lower than central reads at most timepoints, suggesting potential bias. ClinicalTrials.gov identifier: NCT01465763, NCT01458951, NCT01458574, NCT01470612.

Topics: Colitis, Ulcerative; Endoscopy; Humans; Piperidines; Pyrimidines; Reading

Topics: Colitis, Ulcerative; Humans; Liver Transplantation; Male; Middle Aged; Piperidines; Postoperative Complications; Protein Kinase Inhibitors; Pyrimidines

Adverse events (AEs) including reactivation of herpes zoster (HZ) and venous thromboembolism (VTE) have been reported from clinical trials of tofacitinib in ulcerative colitis (UC). We investigated the incidence rates of AEs in a real-world study of UC patients given tofacitinib.. We collected data from 260 patients with UC in the Tofacitinib Real-world Outcomes in Patients with ulceratIve colitis and Crohn's disease consortium study, performed at 6 medical centers in the United States. Patients were followed up for a median of 6 months (interquartile range, 2.7-11.5 mo). AEs were captured using a standardized data collection instrument before study initiation and at weeks 8, 16, 26, 39, and 52. Serious AEs were defined as life-threatening or resulting in a hospitalization, disability, or discontinuation of therapy. Logistic regression was performed to examine risk factors for AEs.. AEs occurred in 41 patients (15.7%); most were infections (N = 13; 5.0%). The incidence rate of any AE was 27.2 (95% CI, 24.4-30.7 per 100 patient-years of follow-up evaluation). Fifteen were serious AEs (36.6% of AEs), and tofacitinib was discontinued for 12 patients (4.6% of cohort). The incidence rates of serious AEs was 10.0 (95% CI, 8.9-11.2 per 100 patient-years of follow-up evaluation). Five patients developed HZ infection and 2 developed VTE (all receiving 10 mg tofacitinib, twice per day).. Real-world safety signals for tofacitinib are similar to those for clinical trials, with AEs reported from almost 16% of patients. HZ infection and VTE occurred in patients receiving 10 mg tofacitinib twice per day. These results support dose de-escalation after induction therapy, to reduce the risk of AEs.

Topics: Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Pyrroles

Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Here, we performed an integrated analysis of malignancy events from the tofacitinib phase 3 UC clinical development program (excluding nonmelanoma skin cancer [NMSC]).. Data (up to May 2019) were pooled from two phase 3 induction studies, a phase 3 maintenance study, and an ongoing, open-label, long-term extension (OLE) study, and analyzed as 3 cohorts: induction (N = 1139), maintenance (N = 592), and overall (induction, maintenance, and ongoing OLE study; N = 1124). Proportions and incidence rates (IRs; unique patients with events per 100 patient-years [PY] of exposure) for malignancies confirmed by adjudication were calculated.. The overall cohort consisted of patients who received at least 1 dose of tofacitinib at 5 or 10 mg twice daily, for up to 6.8 years, with an exposure of 2576.4 PY. Of the 1124 overall cohort tofacitinib-treated patients, 20 developed a malignancy (excluding NMSC; IR, 0.75; 95% confidence interval, 0.46-1.16), of which 17 occurred in patients treated with tofacitinib 10 mg twice daily; importantly, more than 80% of patients predominantly received this dose. Furthermore, there was no apparent clustering of malignancy types, and IRs were stable over time.. In the tofacitinib UC clinical development program, malignancy events were infrequent, and rates were comparable with those in the tofacitinib rheumatoid arthritis and psoriatic arthritis clinical development programs, and for biologic UC treatments. ClinicalTrials.gov: NCT01465763, NCT01458951, NCT01458574, and NCT01470612.

Topics: Clinical Trials, Phase III as Topic; Colitis, Ulcerative; Humans; Janus Kinase Inhibitors; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Skin Neoplasms; Treatment Outcome

Patients with ulcerative colitis (UC) are at elevated risk of cardiovascular disease vs the general population, despite a lower prevalence of traditional risk factors, including hyperlipidemia. Mechanistic studies in patients with rheumatoid arthritis and psoriasis suggest that tofacitinib restores serum lipids to preinflammation levels by reversing inflammation-induced cholesterol metabolism changes. We reviewed data on lipid levels and cardiovascular events, alongside recommendations for managing lipid levels during tofacitinib treatment in patients with UC, based on up-to-date expert guidelines.. Data were identified from a phase 3/open-label, long-term extension (OLE) tofacitinib UC clinical program (cutoff May 27, 2019). Literature was identified from PubMed (search terms "lipid," "cholesterol," "lipoprotein," "cardiovascular," "inflammation," "atherosclerosis," "tofacitinib," "rheumatoid arthritis," "psoriasis," "inflammatory bowel disease," "ulcerative colitis," "hyperlipidemia," and "guidelines") and author knowledge. Data were available from 4 phase 3 clinical trials of 1124 patients with moderately to severely active UC who received ≥1 dose of tofacitinib 5 or 10 mg twice daily in induction (two identical trials), maintenance, and OLE studies (treatment duration ≤6.8 years; 2576.4 patient-years of drug exposure).. In the OLE study, tofacitinib treatment was not associated with major changes from baseline in total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, total cholesterol/high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol/high-density lipoprotein cholesterol, with lipid levels and ratios generally remaining stable over time. The major adverse cardiovascular events incidence rate was 0.26/100 patient-years (95% confidence interval, 0.11-0.54).. Lipid levels and ratios remained generally unchanged from baseline in the OLE study after tofacitinib treatment, and major adverse cardiovascular events were infrequent. Long-term studies are ongoing.. NCT01465763, NCT01458951, NCT01458574, NCT01470612.

Topics: Arthritis, Rheumatoid; Cardiovascular Diseases; Cholesterol; Clinical Trials, Phase III as Topic; Colitis, Ulcerative; Heart Disease Risk Factors; Humans; Inflammation; Lipids; Lipoproteins, HDL; Lipoproteins, LDL; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Risk Factors; Treatment Outcome

Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD) characterized by chronic gastrointestinal inflammation. In most patients, the disease cycles through periods of remission and exacerbations. The complex etiology involves multiple factors including environmental, genetic, and immune causal elements. Janus Kinase (JAK) family is an essential component of a cytokine-signaling cascade partially responsible for the pathogenesis of UC. Treating UC presents difficulties despite various therapeutic options. Medications that block the JAK-signaling pathway can interfere with the inflammatory pathway of UC and possibly reduce symptoms and frequency of exacerbations. Tofacitinib is an oral pan-JAK inhibitor, primarily of JAK1 and JAK3, that was recently approved by the Food and Drug Administration (FDA) for the chronic treatment of UC in 2018. The following review describes the newly approved Janus kinase inhibitor,

Topics: Adult; Colitis, Ulcerative; Humans; Janus Kinase Inhibitors; Piperidines; Pyrimidines; Pyrroles

Topics: Alopecia; Colitis, Ulcerative; Dermatitis, Atopic; Humans; Piperidines; Pyrimidines

Medications are major cost drivers in the treatment of patients with inflammatory bowel disease. Recent analyses suggest that there is no added efficacy in continuing nor harm in stopping 5-aminosalicylate (ASA) therapy in patients with inflammatory bowel disease escalated to biological therapies or tofacitinib. We assessed the cost-effectiveness of discontinuing 5-ASA therapy in patients with ulcerative colitis on biological therapies or tofacitinib, compared with continuing 5-ASA therapy.. We performed a cost-effectiveness analysis of 5-ASA with biologic therapy and tofacitinib compared with the same treatment without 5-ASA. Our primary outcome was to determine whether biologic/tofacitinib monotherapy was cost-effective compared with biologic/tofacitinib and 5-ASA combination therapy using the incremental cost-effectiveness ratio at a willingness to pay of $50,000/quality-adjusted life year. Owing to the uncertainty surrounding outcome probabilities, probabilistic sensitivity analyses with 10,000 simulations were also performed. We conducted a sensitivity analysis comparing biologic/tofacitinib and 5-ASA therapy compared with biologic/tofacitinib monotherapy, whereby vedolizumab was the first biologic used, followed by infliximab and finally tofacitinib.. Our model shows that biologic/tofacitinib monotherapy dominates (cheaper and more effective) combination therapy of biologics/tofacitinib with 5-ASA. Probabilistic sensitivity analyses simulations resulted in biologic/tofacitinib monotherapy dominating 100% of the scenarios, with mean cost savings of $24,483.01 over 2 years. When vedolizumab was the first-line therapy in the sensitivity analysis, biologic/tofacitinib monotherapy continued to dominate the combination of 5-ASA and biologic/tofacitinib therapy.. This analysis in patients with ulcerative colitis who require treatment with biologics or tofacitinib demonstrates that continuing 5-ASA therapy is not a cost-effective strategy. Discontinuation of 5-ASA therapy in these patients is safe and less expensive and should be recommended.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal, Humanized; Biological Products; Colitis, Ulcerative; Cost-Benefit Analysis; Deprescriptions; Drug Therapy, Combination; Gastrointestinal Agents; Humans; Infliximab; Markov Chains; Mesalamine; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Quality-Adjusted Life Years

To evaluate the effectiveness and safety of tofacitinib in ulcerative colitis [UC] in real life.. Patients from the prospectively maintained ENEIDA registry and treated with tofacitinib due to active UC were included. Clinical activity and effectiveness were defined based on Partial Mayo Score [PMS]. Short-term response/remission was assessed at Weeks 4, 8, and 16.. A total of 113 patients were included. They were exposed to tofacitinib for a median time of 44 weeks. Response and remission at Week 8 were 60% and 31%, respectively. In multivariate analysis, higher PMS at Week 4 (odds ratio [OR] = 0].2; 95% confidence interval [CI] = 0].1-0.4) was the only variable associated with lower likelihood of achieving remission at Week 8. Higher PMS at Week 4 [OR = 0.5; 95% CI = 0.3-0.7] and higher PMS at Week 8 [OR = 0.2; 95% CI = 0.1-0.5] were associated with lower probability of achieving remission at Week 16. A total of 45 patients [40%] discontinued tofacitinib over time. Higher PMS at Week 8 was the only factor associated with higher tofacitinib discontinuation [hazard ratio = 1.5; 95% CI = 1.3-1.6]. A total of 34 patients had remission at Week 8; of these, 65% had relapsed 52 weeks after achieving remission; the dose was increased to 10 mg/12 h in nine patients, and five of them reached remission again. Seventeen patients had adverse events.. Tofacitinib is effective and safe in UC patients in real practice, even in a highly refractory cohort. A relevant proportion of patients discontinue the drug over time, mainly due to primary failure.

Topics: Colitis, Ulcerative; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Male; Middle Aged; Patient Acuity; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Recurrence; Registries; Remission Induction; Spain; Treatment Outcome

Topics: Acute Disease; Anti-Inflammatory Agents; Colitis, Ulcerative; Drug Therapy, Combination; Humans; Induction Chemotherapy; Maintenance Chemotherapy; Methylprednisolone; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Recurrence; Severity of Illness Index

Topics: Adult; Aged; Colitis, Ulcerative; Female; Humans; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies

Topics: Aged; Colitis, Ulcerative; Female; Humans; Piperidines; Pneumonia; Protein Kinase Inhibitors; Pyrimidines

Nontraditional combination of existing therapies is often the only option to avoid surgery in refractory inflammatory bowel disease (IBD) patients. We aim to assess the efficacy and safety of concomitant use of 2 biologic therapies or combination of biologic and tofacitinib in a refractory pediatric IBD cohort.. As part of an ongoing single-center observational cohort study of therapeutic outcomes in pediatric IBD patients (younger than 18 years), data were collected for patients receiving dual therapy. Primary outcome was 6 months of steroid-free remission. Secondary outcomes included time to steroid-free remission, change in serum biomarkers (C-reactive protein and erythrocyte sedimentation rate) and albumin between baseline and 6 months, and adverse events.. Sixteen children (9 ulcerative colitis/IBD-unspecified, 7 Crohn's disease), with a disease duration of 3 (2.1-5.0) years, initiated dual therapy at an age of 15.9 (13.5-16.8) years after failing ≥2 biologic therapies. Nine (56%) were treated with vedolizumab/tofacitinib, 4 (25%) with ustekinumab/vedolizumab, and 3 (19%) with ustekinumab/tofacitinib. Twelve (75%; 7 ulcerative colitis/IBD-unspecified, 5 Crohn's disease ) achieved steroid-free remission at 6 months. Erythrocyte sedimentation rate and C-reactive protein decreased (P = 0.021 and P = 0.015, respectively) and albumin increased (P = 0.003) between baseline and 6 months. One patient on 30 mg of vedolizumab/tofacitinib and prednisone daily developed septic arthritis and a deep vein thrombosis.. Our data suggest that dual therapy may be an option for patients with limited therapeutic options remaining. Safety concerns should always be at the forefront of decision-making, and larger studies are needed to help confirm the preliminary safety data observed.

Topics: Antibodies, Monoclonal, Humanized; Biological Products; C-Reactive Protein; Child; Colitis, Ulcerative; Crohn Disease; Humans; Inflammatory Bowel Diseases; Piperidines; Pyrimidines; Treatment Outcome; Ustekinumab

Anti-tumour necrosis factor alpha [anti-TNF] treatment accounts for 31% of health care expenditures associated with ulcerative colitis [UC]. Withdrawal of anti-TNF in patients with UC in remission may decrease side effects and infections, while promoting cost containment. Approximately 36% of patients relapse within 12-24 months of anti-TNF withdrawal, but reintroduction of treatment is successful in 80% of patients. We aimed to evaluate the cost-effectiveness of continuation versus withdrawal of anti-TNF in patients with UC in remission.. We developed a Markov model comparing cost-effectiveness of anti-TNF continuation versus withdrawal, from a health care provider perspective. Transition probabilities were calculated from literature, or estimated by an expert panel of 11 gastroenterologists. Deterministic and probabilistic sensitivity analyses were performed to account for assumptions and uncertainty. The cost-effectiveness threshold was set at an incremental cost-effectiveness ratio of €80,000 per quality-adjusted life-year [QALY].. At 5 years, anti-TNF withdrawal was less costly [-€10,781 per patient], but also slightly less effective [-0.04 QALY per patient] than continued treatment. Continuation of anti-TNF compared with withdrawal costs €300,390/QALY, exceeding the cost-effectiveness threshold. Continued therapy would become cost-effective if the relapse rate following anti-TNF withdrawal was ≥43% higher, or if adalimumab or infliximab [biosimilar] prices fell below €87/40 mg and €66/100 mg, respectively.. Continuation of anti-TNF in UC patients in remission is not cost-effective compared with withdrawal. A stop-and-reintroduction strategy is cost-saving but is slightly less effective than continued therapy. This strategy could be improved by identifying patients at increased risk of relapse.

Topics: Adalimumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Biosimilar Pharmaceuticals; Colitis, Ulcerative; Cost-Benefit Analysis; Gastrointestinal Agents; Humans; Infliximab; Markov Chains; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Quality-Adjusted Life Years; Recurrence; Remission Induction; Ustekinumab

Topics: Cardiovascular Diseases; Colitis, Ulcerative; Heart Disease Risk Factors; Humans; Lipids; Piperidines; Pyrimidines; Risk Factors

The Janus kinase/signal transducer and activator of transcription (JAK/STAT) inhibitor tofacitinib has been recently approved for the treatment of ulcerative colitis (UC) but not Crohn's disease (CD). Systematic analysis of the JAK/STAT pathway in inflammatory bowel disease is still missing. The aim of this study was to investigate JAK/STAT activation and adjacent signaling in monocytes of patients with inflammatory bowel diseases, which are key players in inflammatory responses.. Blood samples of active UC (n = 28) and CD patients (n = 28) and healthy controls (n = 22) were collected for primary monocyte investigation. STAT phosphorylation (pSTAT), cytokine secretion, and surface marker expression ± prior tofacitinib blockade in addition to Th-17 and regulatory T cell induction in cocultures were analyzed upon interferon (IFN)-γ timulation.. Baseline frequencies of pSTAT1+ and pSTAT3+ monocytes were significantly higher in UC, whereas IFN-γ-associated crosstalk induction of pSTAT3+ monocytes was missing in UC-derived monocytes compared with controls and CD. This coincided with decreased interleukin (IL)-10 and cluster of differentiation (CD)39 levels, diminished regulatory T cell (Treg) induction, and increased IL-12 and IL-23 secretion compared with controls, which was not observed in CD monocytes. Tofacitinib induced stronger inhibition of inflammatory cytokine release (IL-6, TNFα, IL-12, IL-23) in UC compared with CD monocytes.. In UC monocytes, IFN-γ-associated activation of the JAK/STAT pathway is impaired with an imbalance between STAT1 and STAT3, coinciding with stronger induction of inflammatory monocytes by IFN-γ compared with controls or CD. The fact that tofacitinib had stronger regulatory impact on UC than on CD monocytes further underlines a stronger inflammatory involvement of the JAK/STAT pathway in UC pathogenesis, which might result from missing STAT3 activation to counteract STAT1-induced inflammation.

Topics: Colitis, Ulcerative; Crohn Disease; Cytokines; Humans; Interferon-gamma; Janus Kinase Inhibitors; Monocytes; Piperidines; Pyrimidines; STAT3 Transcription Factor

Topics: Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Remission Induction

Topics: Colitis, Ulcerative; Humans; Infliximab; Piperidines; Pyrimidines

Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We aimed to estimate the overall incidence of safety events in patients with UC in a real-life population cohort for comparison with the tofacitinib UC clinical trial program.. Clinical trial-like criteria were applied to an IBM MarketScan® claims database population-based cohort (n = 22,967) of patients with UC (October 2010 to September 2015) to identify a UC trial-like cohort treated with tumor necrosis factor inhibitors (TNFi; n = 6366) to compare with the tofacitinib UC clinical trial cohort (n = 1157).. Incidence rates (events per 100 patient-years; [95% confidence interval]) in the UC trial-like cohort were as follows: serious infections, 3.33 (2.73-4.02); opportunistic infections (OIs; excluding herpes zoster [HZ]), 1.45 (1.06-1.93); HZ, 1.77 (1.34-2.29); malignancies (excluding nonmelanoma skin cancer [NMSC]), 0.63 (0.43-0.90); NMSC, 1.69 (1.35-2.10); major adverse cardiovascular events (MACE), 0.51 (0.31-0.79); pulmonary embolism (PE), 0.54 (0.30-0.89); deep vein thrombosis (DVT), 1.41 (1.00-1.93); and gastrointestinal perforations, 0.31 (0.16-0.54). Compared with the UC trial-like cohort, tofacitinib-treated patients had numerically lower incidence rates for serious infections (1.75 [1.27-2.36]), OIs (excluding HZ; 0.16 [0.04-0.42]), NMSC (0.78 [0.47-1.22]), PE (0.16 [0.04-0.41]), and DVT (0.04 [0.00-0.23]), and a higher rate for HZ (3.57 [2.84-4.43]); rates for malignancies (excluding NMSC), MACE, and gastrointestinal perforations were similar.. When acknowledging limitations of comparing claims data with controlled clinical trial data, incidence rates for HZ among TNFi-treated patients in the UC trial-like cohort were lower than in the tofacitinib UC clinical trial cohort; rates for serious infections, OIs, NMSC, PE, and DVT were numerically higher.. NCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612.

Topics: Colitis, Ulcerative; Humans; Neoplasms; Opportunistic Infections; Piperidines; Product Surveillance, Postmarketing; Pyrimidines; Randomized Controlled Trials as Topic

Tofacitinib, an oral Janus kinase inhibitor, is approved for the treatment of moderate to severe ulcerative colitis (UC). We evaluated clinical and endoscopic efficacy, safety and drug survival of tofacitinib up to one year in a real-world cohort.. In this retrospective cohort study, 36 UC patients were included who received tofacitinib. The primary outcome was combined with steroid-free clinical remission [Simple Clinical Colitis Activity Index (SCCAI) ≤2] and endoscopic improvement (Mayo score ≤1) at 52 weeks. Secondary outcomes included clinical (SCCAI drop ≥3) and endoscopic response (Mayo score drop ≥1), biochemical remission [fecal calprotectin (FC) ≤150 mg/kg and C-reactive protein ≤5 mg/L), safety and drug survival.. Median disease duration was 7 (3-14) years and 89 and 42% of patients failed prior anti-tumor necrosis factor (anti-TNF) and vedolizumab treatment, respectively. Combined corticosteroid-free clinical remission and endoscopic improvement were observed in 8/36 patients (22%), 6/35 (17%) and 12/31 (39%), at 16, 36 and 52 weeks, respectively. Corresponding combined clinical and endoscopic response rates were 15/36 (42%), 12/35 (34%), 15/31 (48%) and biochemical remission rates were 11/33 (33%), 10/32 (31%) and 10/29 (34%). Nine infections (two herpes zoster) led to dose reduction or (temporary) drug withdrawal. Permanent withdrawal occurred in 14/36 patients (33%) after a median duration of 9 (5-30) weeks. Drug survival at 1 year was 60%. Patients that failed anti-TNF were less likely to discontinue tofacitinib treatment early compared to patients without prior anti-TNF use (hazard ratio 0.20, 95% confidence interval 0.06-0.65).. In a refractory UC population, combined steroid-free clinical remission and endoscopic improvement were found in 39% of patients at 1 year.

Topics: Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Remission Induction; Retrospective Studies; Tumor Necrosis Factor Inhibitors

Topics: Colectomy; Colitis, Ulcerative; Humans; Inpatients; Piperidines; Pyrimidines; Treatment Outcome; Tumor Necrosis Factor Inhibitors

Topics: Alopecia Areata; Colitis, Ulcerative; Humans; Piperidines; Pyoderma Gangrenosum; Pyrimidines

Ulcerative colitis (UC) is an inflammatory bowel disease of autoimmune origin with an estimated prevalence in Spain of 0.39%. Current treatments for UC do not achieve high long-term efficacy. Treatment recommendations in moderate and severe disease involve drugs, but when these options fail, the alternatives are scarce, and surgery is intended to be reserved for the last option. We present the case of a 48-year-old male patient with UC for 23 years, who had failed several lines of treatment. The patient started combined therapy with tofacitinib and vedolizumab. These drugs have different mechanisms of action, achieving an immune response and reducing gastrointestinal inflammation. The patient's disease symptoms improved 11 months after starting this treatment, and he is now entirely asymptomatic. Analytical parameters related to the disease have also shown improvement, and the patient has so far avoided the need for surgical intervention.

Topics: Antibodies, Monoclonal, Humanized; Colitis, Ulcerative; Humans; Male; Middle Aged; Piperidines; Pyrimidines

Topics: Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Pyrroles

Topics: Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Pyrroles; Treatment Outcome

Pyoderma gangrenosum (PG) is a difficult-to-manage ulcero-necrotizing dermatosis associated with inflammatory bowel disease (IBD). In this article, we report a refractory PG in a patient with severe ulcerative colitis (UC) that responded to tofacitinib 10 mg/12 h.

Topics: Colitis, Ulcerative; Humans; Inflammatory Bowel Diseases; Piperidines; Pyoderma Gangrenosum; Pyrimidines

Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis. Here, we evaluate the efficacy and safety of tofacitinib re-treatment following treatment interruption in patients with ulcerative colitis.. Here, patients with clinical response to tofacitinib 10 mg b.d. induction therapy were randomised to receive placebo in OCTAVE Sustain. Those experiencing treatment failure after Week 8 of OCTAVE Sustain entered OCTAVE Open and re-initiated tofacitinib 10 mg b.d. [re-treatment subpopulation]; efficacy and safety data are presented up to Month 36 of OCTAVE Open.. Median time to treatment failure following interruption was 169 (95% confidence interval [CI], 94.0-179.0) and 123 [95% CI, 91.0-168.0] days for induction remitters, and induction responders but non-remitters, respectively. Following re-treatment with tofacitinib, rates (non-responder imputation after a patient discontinued; latest observation carried forward imputation after a patient advanced to a subsequent study [NRI-LOCF]) of clinical response, remission, and endoscopic improvement were 74.0%, 39.0%, and 55.0% at Month 2, and 48.5%, 37.4%, and 42.4% at Month 36, respectively. Among induction remitters and induction responders but non-remitters, clinical response rates at Month 36 were 60.6% and 42.4% [NRI-LOCF], respectively. Efficacy was recaptured regardless of prior tumour necrosis factor inhibitor failure status. The safety profile of tofacitinib 10 mg b.d. re-treatment was consistent with the overall cohort and demonstrated no new safety risks associated with exposure of ≤36 months.. Median time to treatment failure was numerically higher in induction remitters versus induction responders but non-remitters. Following treatment interruption, efficacy was safely and successfully recaptured with tofacitinib 10 mg b.d. re-treatment in a substantial proportion of patients [ClinicalTrials.gov:NCT01458574;NCT01470612].

Topics: Adult; Colitis, Ulcerative; Female; Humans; Janus Kinase Inhibitors; Male; Middle Aged; Outcome Assessment, Health Care; Piperidines; Pyrimidines; Treatment Adherence and Compliance; Treatment Outcome

The literature regarding monoclonal antibodies and increased postoperative complications in inflammatory bowel disease remains controversial. There have been no studies investigating tofacitinib. The aim of this work was to determine preoperative exposure to the small-molecule inhibitor tofacitinib and postoperative outcomes.. We conducted a retrospective review of all adult patients exposed to tofacitinib within 4 weeks of total abdominal colectomy for medically refractory ulcerative colitis between 1 January 2018 and 1 September 2020 at four inflammatory bowel disease referral centres. Data collected included patient demographics and 90-day postoperative morbidity, readmission and reoperation rates.. Fifty-three patients (32 men, 60%) with ulcerative colitis underwent a total abdominal colectomy (n = 50 laparoscopic, 94%) for medically refractory disease. Previous exposure to monoclonal antibodies included infliximab (n = 34), adalimumab (n = 35), certolizumab pegol (n = 5), vedolizumab (n = 33) and ustekinumab (n = 10). Twenty-seven (51%) patients were on concurrent prednisone at a median daily dose of 30 mg by mouth (range 5-60 mg). There were no postoperative deaths. Ninety-day postoperative complications included ileus (n = 7, 13.2%), superficial surgical site infection (n = 4, 7.5%), intra-abdominal abscess (n = 2, 3.8%) and venous thromboembolism (VTE) (n = 7, 13.2%). Locations of VTE included portomesenteric venous thrombus (n = 4), internal iliac vein (n = 2) and pulmonary embolism (n = 1). Nine (17%) patients were readmitted to hospital and five (9%) patients had a reoperation.. Mirroring the recently issued US Food and Drug Administration black box warning of an increased risk of VTE in medically treated ulcerative colitis patients taking tofacitinib, preoperative tofacitinib exposure may present an increased risk of postoperative VTE events. Consideration should be given for prolonged VTE prophylaxis on hospital discharge.

Topics: Adult; Colitis, Ulcerative; Humans; Male; Piperidines; Postoperative Complications; Pyrimidines; Retrospective Studies

Topics: Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Pyrroles

Topics: Colitis, Ulcerative; Humans; Piperidines; Propensity Score; Pyrimidines; Treatment Outcome; Ustekinumab

Topics: Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Pyrroles

Topics: Biological Products; Colitis, Ulcerative; Humans; Piperidines; Pyrimidines

Electronic health records (EHR) are receiving growing attention from regulators, biopharmaceuticals and payors as a potential source of real-world evidence. However, their suitability for the study of diseases with complex activity measures is unclear. We sought to evaluate the use of EHR data for estimating treatment effectiveness in inflammatory bowel disease (IBD), using tofacitinib as a use case.. Records from the University of California, San Francisco (6/2012 to 4/2019) were queried to identify tofacitinib-treated IBD patients. Disease activity variables at baseline and follow-up were manually abstracted according to a preregistered protocol. The proportion of patients meeting the endpoints of recent randomised trials in ulcerative colitis (UC) and Crohn's disease (CD) was assessed.. 86 patients initiated tofacitinib. Baseline characteristics of the real-world and trial cohorts were similar, except for universal failure of tumour necrosis factor inhibitors in the former. 54% (UC) and 62% (CD) of patients had complete capture of disease activity at baseline (month -6 to 0), while only 32% (UC) and 69% (CD) of patients had complete follow-up data (month 2 to 8). Using data imputation, we estimated the proportion achieving the trial primary endpoints as being similar to the published estimates for both UC (16%, p value=0.5) and CD (38%, p-value=0.8).. This pilot study reproduced trial-based estimates of tofacitinib efficacy despite its use in a different cohort but revealed substantial missingness in routinely collected data. Future work is needed to strengthen EHR data and enable real-world evidence in complex diseases like IBD.

Topics: Adult; Colitis, Ulcerative; Crohn Disease; Electronic Health Records; Female; Humans; Inflammatory Bowel Diseases; Male; Middle Aged; Pilot Projects; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies

To analyse adverse events (AEs) of special interest across tofacitinib clinical programmes in rheumatoid arthritis (RA), psoriatic arthritis (PsA), ulcerative colitis (UC) and psoriasis (PsO), and to determine whether the incidence rates (IRs; unique patients with events per 100 patient-years) of these events are consistent across diseases.. The analysis included data from patients exposed to ≥1 dose of tofacitinib in phase 1, 2, 3 or 3b/4 clinical trials and long-term extension (LTE) studies (38 trials) in RA (23 trials), PsA (3 trials), UC (5 trials) and PsO (7 trials). All studies were completed by or before July 2019, except for one ongoing UC LTE study (data cut-off May 2019). IRs were obtained for AEs of special interest.. 13 567 patients were included in the analysis (RA: n=7964; PsA: n=783; UC: n=1157; PsO: n=3663), representing 37 066 patient-years of exposure. Maximum duration of exposure was 10.5 years (RA). AEs within the 'infections and infestations' System Organ Class were the most common in all diseases. Among AEs of special interest, IRs were highest for herpes zoster (non-serious and serious; 3.6, 1.8, 3.5 and 2.4 for RA, PsA, UC and PsO, respectively) and serious infections (2.5, 1.2, 1.7 and 1.3 for RA, PsA, UC and PsO, respectively). Age-adjusted and sex-adjusted mortality ratios (weighted for country) were ≤0.2 across cohorts.. The tofacitinib safety profile in this analysis was generally consistent across diseases and with longer term follow-up compared with previous analyses.

Topics: Arthritis, Psoriatic; Arthritis, Rheumatoid; Colitis, Ulcerative; Humans; Piperidines; Psoriasis; Pyrimidines; Treatment Outcome

Despite rescue therapy, more than 30% of patients with acute severe ulcerative colitis (ASUC) require colectomy. Tofacitinib is a rapidly acting Janus kinase inhibitor with proven efficacy in ulcerative colitis. Tofacitinib may provide additional means for preventing colectomy in patients with ASUC.. A retrospective case-control study was performed evaluating the efficacy of tofacitinib induction in biologic-experienced patients admitted with ASUC requiring intravenous corticosteroids. Tofacitinib patients were matched 1:3 to controls according to gender and date of admission. Using Cox regression adjusted for disease severity, we estimated the 90-day risk of colectomy. Rates of complications and steroid dependence were examined as secondary outcomes.. Forty patients who received tofacitinib were matched 1:3 to controls (n = 113). Tofacitinib was protective against colectomy at 90 days compared with matched controls (hazard ratio [HR], 0.28, 95% confidence interval [CI], 0.10-0.81; P = .018). When stratifying according to treatment dose, 10 mg three times daily (HR, 0.11; 95% CI, 0.02-0.56; P = .008) was protective, whereas 10 mg twice daily was not significantly protective (HR, 0.66; 95% CI, 0.21-2.09; P = .5). Rate of complications and steroid dependence were similar between tofacitinib and controls.. Tofacitinib with concomitant intravenous corticosteroids may be an effective induction strategy in biologic-experienced patients hospitalized with ASUC. Prospective trials are needed to identify the safety, optimal dose, frequency, and duration of tofacitinib for ASUC.

Topics: Biological Products; Case-Control Studies; Colectomy; Colitis, Ulcerative; Humans; Piperidines; Prospective Studies; Pyrimidines; Retrospective Studies

Tofacitinib, a selective Janus kinase inhibitor, effectively induces and maintains remission in adults with inflammatory bowel disease (IBD), but data are limited in children. This study aimed to evaluate the efficacy and safety of tofacitinib for medically refractory pediatric-onset IBD.. This single-center retrospective study included subjects ages 21 years and younger who started tofacitinib for medically refractory IBD. Clinical activity indices, clinical response, steroid-free remission, biochemical response, and adverse events (AEs) were evaluated over 52 weeks.. Twenty-one subjects, 18 with ulcerative colitis or indeterminate IBD, received tofacitinib. At the end of the 12-week induction period, 9 out of 21 (42.9%) subjects showed clinical response and 7 out of 21 (33.3%) were in steroid-free remission. Of evaluable subjects at 52 weeks, 7 out of 17 (41.2%) showed clinical response and were in steroid-free remission. Of those remaining on tofacitinib at 1 year, none required concomitant systemic corticosteroids. Tofacitinib was discontinued in 8 subjects because of refractory disease, including 8 who ultimately underwent colectomy, and in 1 subject who developed a sterile intra-abdominal abscess. There were no instances of thrombi, zoster reactivation, or clinically significant hyperlipidemia, all of which were AEs of interest.. There is limited experience with tofacitinib in pediatric IBD. In this cohort, tofacitinib induced rapid clinical response with sustained efficacy in nearly half of subjects. This study provides encouraging evidence for the efficacy and safety of tofacitinib as part of the treatment paradigm for young individuals with moderate-to-severe IBD. Larger, well-powered, prospective studies are warranted.

Topics: Adult; Child; Colitis, Ulcerative; Humans; Inflammatory Bowel Diseases; Piperidines; Pyrimidines; Retrospective Studies; Young Adult

Topics: Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Treatment Outcome

The pathogenesis of immune checkpoint inhibitor (ICI)-colitis remains incompletely understood. We sought to identify key cellular drivers of ICI-colitis and their similarities to idiopathic ulcerative colitis, and to determine potential novel therapeutic targets.. We used a cross-sectional approach to study patients with ICI-colitis, those receiving ICI without the development of colitis, idiopathic ulcerative colitis, and healthy controls. A subset of patients with ICI-colitis were studied longitudinally. We applied a range of methods, including multiparameter and spectral flow cytometry, spectral immunofluorescence microscopy, targeted gene panels, and bulk and single-cell RNA sequencing.. Interferon gamma-producing CD8

Topics: Case-Control Studies; CD8-Positive T-Lymphocytes; Colitis; Colitis, Ulcerative; Colon; Cross-Sectional Studies; CTLA-4 Antigen; Gene Expression Profiling; Humans; Immune Checkpoint Inhibitors; Immunologic Memory; Interferon-gamma; Longitudinal Studies; Lymphocyte Activation; Memory T Cells; Phenotype; Piperidines; Programmed Cell Death 1 Receptor; Prospective Studies; Pyrimidines; RNA-Seq; Single-Cell Analysis; Transcriptome

Up to 25% of patients with ulcerative colitis (UC) will require hospitalization for severe flare. In patients hospitalised for severe flare, who previously experienced multiple drug failures, including steroids and anti-TNF agents, new quick-acting medical options are needed. Tofacitinib is effective in refractory UC and has a rapid onset of action.. To evaluate effectiveness and safety of tofacitinib as rescue therapy in patients hospitalised for UC flare.. We conducted an observational and multicentre study with both retrospective and prospective collections in 14 GETAID centres. The primary objective was to assess the survival without colectomy following tofacitinib initiation in patients hospitalised for a UC flare. We determined rates of clinical response, clinical remission, and steroid-free clinical remission at week 6 and week 14 and safety.. Fifty-five patients were included (49 with prior infliximab failure and 19 previously exposed to ciclosporin). With a median follow-up of 6.5 months (interquartile range [IQR] [3-12.3]), rate of colectomy-free survival was estimated at 78.9% (95 CI [68.5-90.9]) and 73.6% (95 CI [61.9-87.3]) at 3 and 6 months, respectively. Rates of clinical response, clinical remission and steroid-free clinical remission were 60%, 45.5% and 37.5% at week 6 and 41.8%, 34.5% and 32.7% at week 14. Regarding safety, no death was observed, three patients withdrew tofacitinib due to adverse events. Two herpes zoster infections occurred in patients aged over 60 years old. No venous thrombotic or major adverse cardiovascular events occurred.. Tofacitinib appears as a promising option in patients hospitalised with a UC flare but needs further validation in controlled trials.

Topics: Aged; Colectomy; Colitis, Ulcerative; Humans; Infliximab; Middle Aged; Piperidines; Prospective Studies; Pyrimidines; Retrospective Studies; Salvage Therapy; Treatment Outcome; Tumor Necrosis Factor Inhibitors

Obesity may affect efficacy and safety of biologic treatments for ulcerative colitis (UC). Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of UC.. To assess efficacy and safety of tofacitinib in patients with UC, by baseline body mass index (BMI).. This post hoc analysis evaluated patients with UC receiving placebo or tofacitinib from the 8-week OCTAVE Induction 1 and 2 (NCT01465763, NCT01458951) and 52-week OCTAVE Sustain (NCT01458574) studies. Patients were stratified by BMI at OCTAVE Induction 1 and 2 baseline (<25, 25 to <30 and ≥30 kg/m. At Week 8 of OCTAVE Induction 1 and 2, and Week 52 of OCTAVE Sustain, higher proportions of patients receiving tofacitinib 5 or 10 mg twice daily (b.d.) achieved clinical response vs placebo, regardless of baseline BMI subgroup (all P < 0.05). Proportions of patients achieving efficacy endpoints were generally similar across BMI subgroups; in univariate and multivariate regression analyses, BMI was not a significant predictor (all P ≥ 0.05; univariate BMI [continuous] odds ratio for remission: 0.98 [95% confidence interval 0.95, 1.02]). There was no consistent trend between BMI and adverse events. Among patients receiving tofacitinib 10 mg b.d. in OCTAVE Induction 1 and 2, serious infections were numerically greater in the BMI ≥30 subgroup (3.2%) vs other subgroups (0.4%). Limitations included small patient numbers in the BMI ≥30 subgroup.. Efficacy and safety of tofacitinib were similar in patients with UC regardless of baseline BMI.

Topics: Body Mass Index; Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Pyrroles

Topics: Body Mass Index; Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Pyrroles

Topics: Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Pyrroles

Topics: Biological Products; Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Pyrroles

Topics: Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Pyrroles

At present, the conventional therapies for acute severe ulcerative colitis (ASUC) mainly include corticosteroids, cyclosporin, and biological agents. However, the treatment of patients with severe steroid-refractory ulcerative colitis remains a serious challenge to clinicians. This study reports a case of steroid-refractory ASUC treated with cyclosporin combined with tofacitinib after treatment failure with infliximab.

Topics: Colitis, Ulcerative; Cyclosporine; Humans; Piperidines; Pyrimidines; Steroids

A 26-year-old man was admitted to our institution for ulcerative colitis treatment. He used mesalamine, steroid, immunomodulators, and anti-TNFα anti-body, but it was difficult to maintain remission. We started induction therapy with tofacitinib (TOF) 10 mg twice daily. He maintained clinical remission but had chest pain 44 days after the start of TOF. Esophagogastroduodenoscopy showed multiple ulcers from middle to lower esophagus. Although rare, TOF induced esophageal ulcers were considered based on his clinical course and endoscopic findings.

Topics: Adult; Colitis, Ulcerative; Esophageal Diseases; Esophagoscopy; Esophagus; Humans; Male; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Ulcer

Phase III trials demonstrated effectiveness of tofacitinib, an oral Janus kinase inhibitor, to induce and maintain remission in patients with moderate-to-severe active ulcerative colitis (UC).. We report the real-world effectiveness and safety of tofacitinib in patients with UC in France.. From February 2017 to December 2018, we performed a national French cohort study, which included all consecutive patients with an active UC refractory to anti-TNF and vedolizumab, who received tofacitinib. Outcomes were survival without colectomy, survival without tofacitinib discontinuation and steroid-free clinical remission at weeks 14, 24 and 48.. Thirty-eight patients were included, with a median follow-up of 41.5 (18.5-56.8) weeks. Survival without colectomy was 77% [95% confidence interval (95%CI): 59.3-87.9] at week 24 and 70% (95%CI: 50.9-82.8) at week 48. Survival without treatment discontinuation was 70% (95%CI: 52.6-82.3) at week 24. Steroid-free clinical remission was observed in 13 (34%) patients at week 48. Adverse events occurred in 14 (37%) patients, including 6 severe adverse events and three herpes zoster infections.. In a highly refractory UC population, one third of patients treated with tofacitinib achieved steroid-free clinical remission at week 14 and 70% of patients avoided colectomy at one year, with an acceptable safety profile. These data confirm tofacitinib effectiveness in UC, especially after multiple biologic failures.

Topics: Adult; Antibodies, Monoclonal, Humanized; Colectomy; Colitis, Ulcerative; Female; France; Humans; Janus Kinase Inhibitors; Kaplan-Meier Estimate; Male; Medication Adherence; Middle Aged; Piperidines; Pyrimidines; Remission Induction; Retrospective Studies; Tumor Necrosis Factor Inhibitors

Topics: Bronchiectasis; Colitis, Ulcerative; Humans; Piperidines; Pyrimidines

Treatment targets for ulcerative colitis are evolving towards achievement of endoscopic improvement and remission in addition to symptom resolution. It remains to be accurately quantified what proportion of patients with symptom resolution have residual endoscopic activity that might warrant treatment modification.. To quantify the prevalence of endoscopic improvement and remission amongst ulcerative colitis patients with various permutations of patient-reported outcomes.. Individual participant data from active intervention and placebo arms of clinical trials of infliximab, golimumab, vedolizumab and tofacitinib were pooled to estimate the prevalence of endoscopic improvement (Mayo endoscopic sub-score [MES] 0 or 1) and remission (MES 0) scores with various permutations of the rectal bleeding sub-score (RBS) and stool frequency sub-score (SFS) of the Mayo score, following induction (6-8 weeks) and maintenance (30-54 weeks) therapy. Subgroup analyses were performed by year of publication and centrally read endoscopy scoring.. Data from 2586 trial participants were analysed. Using locally scored endoscopy, the prevalence of endoscopic improvement and remission was highest among participants with a RBS 0 + SFS 0 post-induction (MES 0/1:81%, [95% CI 78-84]; MES 0:29% [26-33]) and during maintenance (MES 0/1:91% [87-93]; MES 0:57% [52-62]). Prevalence estimates were lower for more recently performed trials (P < .01). In comparison to locally scored endoscopy, when using central endoscopy scoring, the prevalence of endoscopic improvement and remission was lower post-induction (MES 0/1 57% [50-64], P < .001; MES 0 15% [11-21], P = .09) and during maintenance (MES 0/1 74% [67-81], P = .001; MES 0 31% [24-38], P = .001) for participants achieving a RBS 0 + SFS 0.. Approximately 8 of 10 patients with normalisation of rectal bleeding and stool frequency have improvement in endoscopic disease activity, whereas approximately only half of these patients have endoscopic remission.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Clinical Trials as Topic; Cohort Studies; Colitis, Ulcerative; Endoscopy, Gastrointestinal; Female; Gastrointestinal Agents; Gastrointestinal Hemorrhage; Humans; Induction Chemotherapy; Infliximab; Maintenance Chemotherapy; Male; Middle Aged; Patient Reported Outcome Measures; Piperidines; Prevalence; Pyrimidines; Pyrroles; Remission Induction; Young Adult

Topics: Adolescent; Colitis, Ulcerative; Female; Humans; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Takayasu Arteritis; Treatment Outcome

Acute severe ulcerative colitis is a high stakes event with significant numbers still requiring emergent colectomy, representing a need to establish alternative medical management options. We report a case series of tofacitinib as rescue therapy in biologic-experienced patients with acute severe ulcerative colitis.. Four patients were identified over a 1-year period at our institution who initiated tofacitinib for acute severe ulcerative colitis. All four had previously failed at least two biologics, including infliximab, and were failing high-dose oral prednisone therapy before admission. All patients had Mayo disease activity index of at least 10 at admission. After no significant improvement despite receiving a minimum of 3 days of intravenous methylprednisolone and based on elevated Ho and Travis indices at Day 3, patients were offered rescue tofacitinib for induction of remission, or colectomy. Standard induction of tofacitinib was used [10 mg twice daily], and one patient was escalated to 15 mg twice daily after inadequate response.. All patients experienced improvement in objective symptoms and laboratory markers, and were discharged without colectomy on tofacitinib as maintenance therapy and prednisone taper; 30-day and 90-day colectomy rates on tofacitinib maintenance therapy were zero and 90-day readmission rate was also zero. Two of four patients achieved steroid-free remission on maintenance tofacitinib monotherapy based on clinical symptoms and follow-up endoscopy. No major adverse reaction was reported during induction or maintenance therapy.. Tofacitinib may be an acceptable rescue agent in biologic-experienced patients with acute severe ulcerative colitis. Tofacitinib may also be safely continued as maintenance therapy once remission has been achieved.

Topics: Adult; Anti-Inflammatory Agents; Colectomy; Colitis, Ulcerative; Female; Humans; Immunosuppressive Agents; Infliximab; Maintenance Chemotherapy; Male; Middle Aged; Piperidines; Prednisone; Protein Kinase Inhibitors; Pyrimidines; Retreatment; Severity of Illness Index; Treatment Outcome; Young Adult

Topics: Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Pyrroles

The aim was to compare outcomes in adult patients with inflammatory bowel disease (IBD) who switched to infliximab-dyyb with those who remained on reference product (RP) infliximab in the United States (US) in a retrospective, propensity score-matched, non-inferiority cohort trial.. This study was a retrospective, non-inferiority study conducted within a US integrated healthcare system and included adult patients with a confirmed diagnosis of Crohn's disease or ulcerative colitis. A 1:1 propensity score matching was utilized to match patients who switched to infliximab-dyyb during the period April 2016-March 2018 to patients who remained on RP infliximab. The non-inferiority margin was set at + 10% of the upper limit. The primary outcome was a composite measure of disease worsening requiring acute care after the index date of switching to infliximab-dyyb or continuing RP infliximab. Disease worsening requiring acute care was defined as any IBD-related emergency room visit, hospitalization, or surgery. The secondary outcome was the composite measure of disease worsening requiring acute care or treatment failure. A switch to another biologic or tofacitinib was a proxy for treatment failure. All patients were followed for up to 9 months.. After propensity score matching, the matched cohort included 1409 patients in the infliximab-dyyb group and 1409 patients in the RP infliximab group. The overall mean age (± standard deviation) was 47.7 ± 17.0 years, 50.9% of patients were of male gender, and 51.8% of patients had Crohn's disease, while the remainder of the cohort had ulcerative colitis. There were 144 patients (10.2%) in the infliximab-dyyb group and 245 patients (17.4%) in the RP infliximab group who experienced disease worsening requiring acute care (P < 0.01 for non-inferiority). There were 347 patients (24.6%) in the infliximab-dyyb group who experienced disease worsening requiring acute care or treatment failure compared to 375 patients (26.6%) who remained on RP infliximab (P < 0.01 for non-inferiority).. There was no increased risk of (1) disease worsening requiring acute care or (2) disease worsening requiring acute care or treatment failure in patients with IBD who switched from RP infliximab to infliximab-dyyb when compared to patients who remained on RP infliximab in this US population. Infliximab-dyyb is an option for patients with IBD who need to use RP infliximab.

Topics: Adult; Aged; Antibodies, Monoclonal; Biosimilar Pharmaceuticals; Cohort Studies; Colitis, Ulcerative; Crohn Disease; Delivery of Health Care, Integrated; Drug Substitution; Female; Humans; Infliximab; Male; Middle Aged; Piperidines; Propensity Score; Pyrimidines; Retrospective Studies; Treatment Outcome; United States

We describe a case of refractory pouchitis successfully treated with tofacitinib. The patient was a 20-year-old woman diagnosed with ulcerative colitis at the age of 14 years. She underwent surgery at the age of 18 years for chronic active inflammation, despite an optimal medication regimen. Ten months after surgery, she was diagnosed with pouchitis. She did not respond to conventional conservative treatment; thus, the case was considered as that of refractory chronic pouchitis. Anti-tumor necrosis factor-α (TNF-α) therapy was administered, which led to some improvement; however, pouchitis recurred. Systemic steroid and vedolizumab were also administered, but the response was unsatisfactory. Therefore, surgery was considered; however, the patient refused to undergo surgery. As identical therapies are recommended for ulcerative colitis and pouchitis, they are considered to have a common etiology. Therefore, we considered tofacitinib therapy in this case. After obtaining the patient's informed consent, tofacitinib treatment was initiated. The therapy led to improvement in her symptoms as well as in the appearance of the pouch when observed on endoscopy, and surgery was avoided. Thus, tofacitinib may be considered a therapy option for refractory chronic pouchitis.

Topics: Adolescent; Adult; Colitis, Ulcerative; Female; Humans; Piperidines; Pouchitis; Proctocolectomy, Restorative; Pyrimidines; Pyrroles; Young Adult

Topics: Anti-Inflammatory Agents; Arthritis, Psoriatic; Arthritis, Rheumatoid; Cardiovascular Diseases; Colitis, Ulcerative; Humans; Piperidines; Pyrimidines

Topics: Adult; Colitis, Ulcerative; Female; Humans; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Remission Induction; Takayasu Arteritis

Topics: Adult; Ambulatory Care; Biological Products; Clinical Decision-Making; Colitis, Ulcerative; Decision Support Techniques; Drug Therapy, Combination; Humans; Immunologic Factors; Methotrexate; Piperidines; Practice Guidelines as Topic; Pyrimidines; Pyrroles; Severity of Illness Index

Tofacitinib is a Janus kinase inhibitor approved for the treatment of ulcerative colitis (UC).. To evaluate effectiveness, safety and use of tofacitinib in daily practice.. UC patients initiating tofacitinib were prospectively enrolled in 15 hospitals in the Netherlands. Corticosteroid-free clinical remission (short clinical colitis activity index [SCCAI] ≤2), biochemical remission (faecal calprotectin level ≤250 µg/g), combined corticosteroid-free clinical and biochemical remission, predictors of remission, safety outcomes, treatment dose and effect on lipids were determined at weeks 12 and 24. Endoscopic outcomes were evaluated in centres with routine endoscopic evaluation.. In total, 123 UC patients (95% anti-TNF, 62% vedolizumab and 3% ustekinumab experienced) were followed for a median duration of 24 weeks (interquartile range 12-26). The proportion of patients in corticosteroid-free clinical, biochemical, and combined corticosteroid-free clinical and biochemical remission rate at week 24 was 29% (n: 22/77), 25% (n: 14/57), and 19% (n: 11/57) respectively. Endoscopic remission (Mayo = 0) was achieved in 21% of patients at week 12 (n: 7/33). Prior vedolizumab exposure was associated with reduced clinical remission (odds ratio 0.33, 95% confidence interval [CI] 0.11-0.94). At week 24, 33% (n: 14/42) of patients still on tofacitinib treatment used 10 mg twice daily. In total, 33 tofacitinib-related adverse events (89 per 100 patient years) occurred, 7 (6% of total cohort) resulted in discontinuation. Cholesterol, HDL and LDL levels increased during induction treatment by 18% (95% CI 9-26), 18% (95% CI 8-28) and 21% (95% CI 14-39) respectively.. Tofacitinib is an effective treatment for UC after anti-TNF and vedolizumab failure. However, a relatively high rate of adverse events was observed resulting in discontinuation in 6% of patients.

Topics: Adult; Antibodies, Monoclonal, Humanized; Colitis, Ulcerative; Crohn Disease; Female; Humans; Male; Middle Aged; Netherlands; Piperidines; Prospective Studies; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Registries; Treatment Outcome; Tumor Necrosis Factor-alpha; Ustekinumab

Topics: Arthritis, Rheumatoid; Azetidines; Betacoronavirus; Colitis, Ulcerative; Coronavirus Infections; COVID-19; Cytokines; Dermatitis, Atopic; Heterocyclic Compounds, 3-Ring; Humans; Immunomodulation; Janus Kinases; Nitriles; Pandemics; Piperidines; Pneumonia, Viral; Primary Myelofibrosis; Purines; Pyrazoles; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; SARS-CoV-2; STAT Transcription Factors; Sulfonamides

Tofacitinib is a partially selective Janus kinase inhibitor approved for the treatment of refractory moderate to severe ulcerative colitis [UC]. We sought to define the effectiveness and adverse effects of tofacitinib in a real-world cohort.. We conducted a retrospective observational cohort study of 134 patients with UC [64% male; median age 37 years [range 16-81]; 83% of patients had previously received at least one biologic] treated with tofacitinib from October 2018 to October 2019 in four UK centres. Disease activity was assessed using the Simple Clinical Colitis Activity Index [SCCAI] or partial Mayo score [PMS], depending on study site. Response and remission were defined as a reduction in SCCAI or PMS of ≥3and SCCAI ≤2 or a PMS ≤1, respectively.. Overall, 74% (88/119; 95 confidence interval [CI] 65-81%] patients responded to tofacitinib at Week 8 and steroid-free remission was observed in 44% [47/108; 95% CI 3453%] patients at Week 26. Primary non-response was independently associated with younger age [p = 0.014] and higher C-reactive protein [CRP] levels at baseline [p = 0.004]. Only 23% [3/13] of patients who continued tofacitinib in the setting of primary non-response were in steroid-free remission at Week 26. Prior biologic exposure did not influence response or remission rates. Dose escalation, however, recaptured response in approximately half of patients who had lost response. Dyslipidaemia was observed in 20% [27/134; 95% CI 1428%] of patients, but adverse events necessitating drug withdrawal were uncommon and no venous thromboembolic events occurred.. In this multicentre real-world cohort, tofacitinib was well tolerated and clinically effective in a treatment-refractory UC population.

Topics: Adult; Age Factors; Colitis, Ulcerative; Female; Humans; Janus Kinase 3; Janus Kinase Inhibitors; Male; Outcome and Process Assessment, Health Care; Patient Acuity; Piperidines; Pyrimidines; Remission Induction; Retrospective Studies; Severity of Illness Index; United Kingdom

The aim: To investigate the transcolonoscopic pH-metry and calprotectin in patients with ulcerative colitis.. Materials and methods: the research included 110 patients both male and female between the ages of 18 to 75 years old, who were treated for UC of medium and severe activity, in active phase. All patients were divided into 3 groups. The first group received standard therapy (ST; n=50), the second group received adalimumab (ADA; n=32), and the third group was treated with tofacitinib (TOF; n=28). The control group consisted of healthy individuals between the ages of 18 and 65 years old.. Results: UC patients had lower pH levels in all sections of the large intestine, compared to the control group (р<0,05). Calprotectin level is a better predictor of the course of the disease.. Conclusions:Tofacitinib, compared to adalimumab and budesonide, has better influence on clinical, endoscopic and laboratory parameters of UC.

Topics: Adalimumab; Adolescent; Adult; Aged; Colitis, Ulcerative; Female; Humans; Hydrogen-Ion Concentration; Leukocyte L1 Antigen Complex; Male; Middle Aged; Piperidines; Pyrimidines; Pyrroles; Young Adult

Topics: Adrenal Cortex Hormones; Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Pyrroles

Topics: Adrenal Cortex Hormones; Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Pyrroles

Topics: Adult; Betacoronavirus; Colitis, Ulcerative; Colonoscopy; Comorbidity; Coronavirus Infections; COVID-19; Female; Humans; Medication Therapy Management; Pandemics; Patient Acuity; Piperidines; Pneumonia, Viral; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; SARS-CoV-2; Symptom Assessment; Treatment Outcome

We applied the Grading of Recommendations, Assessment, Development, and Evaluation framework to evaluate the performance of fecal calprotectin (FC) as an alternative to endoscopy in patients with moderate-to-severe ulcerative colitis (UC) treated with a biologic agent or tofacitinib.. Individual participant data from the trials of infliximab, golimumab, vedolizumab, and tofacitinib for UC were pooled to generate prevalence of endoscopic activity (Mayo endoscopy score) across different combinations of the rectal bleeding score (RBS) and stool frequency score (SFS). These estimates were then combined with the data from an updated systematic review of the operating properties of FC to generate clinical scenario-specific assessments of the performance of FC as a predictor of endoscopic disease activity. A prespecified threshold of acceptability for false-negative (FN) and false-positive (FP) test results was set at 5%.. For patients with UC achieving RBS 0 + SFS 0/1, FC ≤ 50 μg/g may avoid endoscopy in 50% patients with a FN rate <5%. Similarly, for patients with RBS 2/3 + SFS 2/3, FC ≥ 250 μg/g potentially avoids endoscopy in approximately 50% patients with an FP rate <5%. The greatest uncertainty in the diagnostic performance for FC was observed in patients with UC achieving RBS 0 but having SFS 2/3, where FN and FP rates were consistently >10%, and endoscopic evaluation may be warranted.. Two clinical scenarios were identified where FC can be used with confidence for monitoring treatment response to biologics or tofacitinib in patients with UC without the requirement for endoscopy.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Biological Products; Colitis, Ulcerative; Colonoscopy; Feces; Gastrointestinal Agents; Humans; Infliximab; Leukocyte L1 Antigen Complex; Outcome Assessment, Health Care; Patient Reported Outcome Measures; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Severity of Illness Index; Treatment Outcome

Topics: Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Pyrroles

Topics: Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Pyrroles

Topics: Colitis; Colitis, Ulcerative; Humans; Piperidines; Programmed Cell Death 1 Receptor; Pyrimidines; Pyrroles

Topics: Acute Disease; Adult; Colitis, Ulcerative; Female; Humans; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Severity of Illness Index; Tertiary Care Centers; Treatment Outcome; Young Adult

A 40-year-old woman (case 1) visited the hospital complaining of diarrhea and was diagnosed with ulcerative colitis (UC). She was administered 5-aminosalicylic acid (5-ASA), but developed intolerance. Prednisolone (PSL) was administered, and her symptoms improved. However, alopecia areata developed as the PSL was tapered, and her UC relapsed. Adalimumab, Infliximab (IFX), and golimumab were used, but all showed insufficient efficacy. Therefore, we started tofacitinib (TOF). Her bloody stools and diarrhea improved 3 days after TOF administration, and clinical remission occurred on day 14. Her alopecia areata improved 14 days after starting TOF and improved completely during TOF maintenance therapy. A 19-year-old man (case 2) had developed alopecia areata at 10 years old and was diagnosed with UC at 17 years old. He achieved sustained remission with IFX, but then stopped IFX to receive a live vaccination. His UC relapsed 4 months later, immediately after the live vaccine was administered. Vedolizumab was administered, but was ineffective, as was re-administration of IFX. TOF was administered, and his clinical symptoms improved 7 days later. He achieved clinical remission on day 20. In addition, his hair began to regrow 14 days after starting TOF.

Topics: Adult; Alopecia Areata; Colitis, Ulcerative; Female; Humans; Infliximab; Male; Piperidines; Pyrimidines; Pyrroles; Young Adult

Topics: Antibodies, Monoclonal, Humanized; Colitis, Ulcerative; Drug Therapy, Combination; Female; Gastrointestinal Agents; Humans; Middle Aged; Piperidines; Pyrimidines; Spondylarthritis

Topics: Administration, Oral; Biomarkers; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Colitis, Ulcerative; Crohn Disease; Dose-Response Relationship, Drug; Drug Monitoring; Humans; Janus Kinase Inhibitors; Meta-Analysis as Topic; Piperidines; Pyrimidines; Treatment Outcome

Topics: Anus Neoplasms; Colitis, Ulcerative; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Papillomaviridae; Papillomavirus Infections; Piperidines; Precancerous Conditions; Protein Kinase Inhibitors; Pyrimidines

Topics: Antibodies, Monoclonal, Humanized; Colitis, Ulcerative; Comparative Effectiveness Research; Cost-Benefit Analysis; Dermatologic Agents; Humans; Piperidines; Placebos; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Safety; Treatment Outcome; Tumor Necrosis Factor-alpha; Ustekinumab

Topics: Adrenal Cortex Hormones; Colitis, Ulcerative; Herpesvirus 3, Human; Humans; Nocardia Infections; Opportunistic Infections; Piperidines; Pneumonia, Pneumocystis; Pyrimidines; Varicella Zoster Virus Infection; Virus Activation

Despite the biological drugs, the treatment of moderate to severe ulcerative colitis is still a challenge, particularly in resource-limited settings. The aim of this study was to assess the efficiency of biological drugs and tofacitinib for moderate to severe ulcerative colitis in the Spanish context.. A Markov model was built to simulate the progression of moderate to severe ulcerative colitis in a cohort of patients. The model used a time horizon of 10 years. The perspective chosen was the National Health Service, with a discount rate of 3%, and a threshold of €30,000/quality adjusted life-year (QALY). It carried out a one-way sensitivity analysis and probabilistic sensitivity analysis.. The comparison of infliximab with adalimumab and golimumab estimated an incremental cost-effectiveness ratio (ICER) of €43,928.07/QALY and €31,340.69/QALY, with a difference of - 0.43 and - 0.82 QALY, respectively. Vedolizumab vs infliximab achieved an ICER of €122,890.19/QALY with a gain of 0.46 QALY. The comparison of infliximab with tofacitinib yielded an estimated ICER of €270,503.19/QALY, with a slight gain in QALY (0.16). The one-way sensitivity analysis showed a robust study.. For a threshold of €30,000/QALY, adalimumab was the most cost-effective treatment versus infliximab for moderate to severe ulcerative colitis in Spain.

Topics: Adalimumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Colitis, Ulcerative; Cost-Benefit Analysis; Drug Costs; Gastrointestinal Agents; Humans; Infliximab; Markov Chains; Piperidines; Pyrimidines; Severity of Illness Index; Spain

Topics: Colitis, Ulcerative; Colonoscopy; Humans; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Treatment Outcome

Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC).. To report incidence of deep vein thrombosis (DVT) and pulmonary embolism (PE) in the tofacitinib UC programme.. DVT and PE were evaluated from one phase 2 and two phase 3 induction studies, one phase 3 maintenance study and an ongoing, open-label, long-term extension (OLE) study (September 2018 datacut). Data were analysed in induction, maintenance and overall (patients receiving ≥ 1 dose of tofacitinib 5 or 10 mg b.d. in any phase 2, 3 or OLE study) cohorts.. 1157 patients (2404 patient-years' exposure; ≤ 6.1 years' tofacitinib treatment) were evaluated in the overall cohort. In induction, one placebo-treated patient had DVT and one had PE; no tofacitinib-treated patients had DVT/PE. In maintenance, one placebo-treated patient had DVT and one had PE; no tofacitinib-treated patients had DVT/PE. In the overall cohort, one patient had DVT (incidence rate [patients with events/100 patient-years; 95% CI]: 0.04 [0.00-0.23]); four had PE (0.16 [0.04-0.41]); all received predominant dose tofacitinib 10 mg b.d.; all had venous thromboembolism risk factors alongside UC.. In this post hoc analysis of patients with UC, during tofacitinib exposure, one patient had DVT and four had PE, all during the OLE study, on predominant dose 10 mg b.d. (83% of overall cohort patients received predominant dose 10 mg b.d.) with venous thromboembolism risk factors. This analysis is limited by small sample size and limited drug exposure; further studies are needed. ClinicalTrials.gov: NCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612.

Topics: Adult; Aged; Cohort Studies; Colitis, Ulcerative; Female; Humans; Incidence; Male; Middle Aged; Piperidines; Pulmonary Embolism; Pyrimidines; Pyrroles; Retrospective Studies; Risk Factors; Venous Thromboembolism; Venous Thrombosis; Young Adult

Tofacitinib is an oral, small molecule inhibitor of JAK for the treatment of ulcerative colitis (UC). We evaluated the onset of symptom improvement in post-hoc analyses of data from 2 phase 3 trials of induction therapy with tofacitinib in patients with UC (OCTAVE Induction 1 and 2).. The studies comprised patients with moderate to severe active UC who were intolerant to, or failed by previous treatment with, corticosteroids, thiopurines, and/or tumor necrosis factor (TNF) antagonists. Patients received tofacitinib (10 mg twice daily, n = 905) or placebo (n = 234) for 8 weeks. Daily Mayo stool frequency and rectal bleeding subscores were calculated using diary data from the first 15 days of therapy. We analyzed data from subgroups including failure of prior anti-TNF therapy, baseline corticosteroid use, and baseline serum levels of C-reactive protein.. Mean changes were significantly greater in patients given tofacitinib vs placebo in reductions from baseline stool frequency subscore (tofacitinib: -0.27 vs placebo: -0.11; P < .01), total number of daily bowel movements (-1.06 vs -0.27; P < .0001), and rectal bleeding subscore (-0.30 vs -0.14; P < .01) by day 3. Compared with placebo, more tofacitinib-treated patients had reductions from baseline in stool frequency subscore (by ≥1 point for tofacitinib, 241/837, 28.8% vs placebo, 39/218, 17.9%) (P < .01) and rectal bleeding subscore (by ≥1 point for tofacitinib, 266/830, 32.0% vs placebo, 43/214, 20.1%) (P < .01) by day 3. A consistent effect of tofacitinib was observed in all subgroups.. In a post-hoc analysis of data from phase 3 trials of induction therapy with tofacitinib in patients with UC, we found significant improvements in symptoms among patients given tofacitinib compared with placebo within 3 days. These findings indicate the rapid onset of effect of this drug in patients with UC. ClinicalTrials.gov no: NCT01465763 and NCT01458951.

Topics: Adult; Clinical Trials, Phase III as Topic; Colitis, Ulcerative; Female; Gastrointestinal Agents; Humans; Induction Chemotherapy; Male; Middle Aged; Piperidines; Placebos; Pyrimidines; Pyrroles; Treatment Outcome

Topics: Antibodies, Monoclonal, Humanized; Biological Products; Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Pyrroles; Spondylarthropathies

As many as 25% of patients diagnosed with ulcerative colitis are hospitalized with an episode of acute severe ulcerative colitis (ASUC).

Topics: Adult; Animals; Colitis, Ulcerative; Female; Hospitals; Humans; Immunologic Factors; Induction Chemotherapy; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Treatment Outcome; Young Adult

Many inflammatory bowel disease (IBD) patients do not respond to medical therapy. Tofacitinib is a first-in-class, partially selective inhibitor of Janus kinase, recently approved for treating patients with ulcerative colitis (UC). We describe our experience with the use of tofacitinib for treatment of patients with moderate-to-severe IBD.. This is a retrospective, observational study of the use of tofacitinib in IBD. Patients with medically resistant IBD were treated orally with 5 mg or 10 mg twice daily. Clinical response and adverse events were assessed at 8, 26, and 52 weeks. Objective response was assessed endoscopically, radiologically, and biochemically.. 58 patients (53 UC, 4 Crohn's, 1 pouchitis) completed at least 8 weeks of treatment with tofacitinib. 93% of the patients previously failed treatment with anti-TNF. At 8 weeks of treatment, 21 patients (36%) achieved a clinical response, and 19 (33%) achieved clinical remission. Steroid-free remission at 8 weeks was achieved in 15 patients (26%). Of the 48 patients followed for 26 weeks, 21% had clinical, steroid-free remission. Of the 26 patients followed for 12 months, 27% were in clinical, steroid-free remission. Twelve episodes of systemic infections were noted, mostly while on concomitant steroids. One episode of herpes zoster infection was noted during follow-up.. In this cohort of patients with moderate-to-severe, anti-TNF resistant IBD, tofacitinib induced clinical response in 69% of the patients. 27% were in clinical, steroid-free remission by 1 year of treatment. Tofacitinib is an effective therapeutic option for this challenging patient population.

Topics: Administration, Oral; Adult; Colitis; Colitis, Ulcerative; Drug Administration Schedule; Female; Humans; Janus Kinase Inhibitors; Male; Middle Aged; Piperidines; Pouchitis; Pyrimidines; Pyrroles; Remission Induction; Retrospective Studies; Tertiary Care Centers; Time Factors; Treatment Outcome

Tofacitinib (Tofa) has been approved for moderately to severely active ulcerative colitis (UC). To improve its therapeutic efficacy and limit dose-dependent toxicity, we developed a macromolecular prodrug of Tofa (P-Tofa). If the prodrug design improves the potency and duration of Tofa therapy, it would widen its therapeutic window, potentially leading to improved safety and better clinical management of UC.. P-Tofa was synthesized by conjugating Tofa to N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer via a cleavable carbamate linker. DSS-induced UC mouse model were treated with Tofa (daily oral gavage, from day 8), P-Tofa (single intravenous administration on day 8, dose equivalent to Tofa treatment) and saline. Healthy mice were used as a positive control. The therapeutic efficacy was evaluated using disease activity index (DAI), endoscopic score and end-point histology. The optical imaging, immunohistochemistry and flow cytometry were used to understand P-Tofa's working mechanism.. DAI results suggested that a single dose P-Tofa treatment was more efficacious than dose equivalent daily Tofa treatment. Endoscopic evaluation and histology analyses confirmed that while both P-Tofa and Tofa protected the colon, P-Tofa treated group was observed with better colon integrity with less tissue damage. Optical imaging, flow cytometry and immunohistochemistry results showed that P-Tofa passively targeted the inflamed colon and being retained via cellular sequestration.. Single intravenous administration of P-Tofa was more effective than dose equivalent daily oral Tofa gavage in ameliorating DSS-induced colitis. This observed superior therapeutic efficacy may be attributed to P-Tofa's passive targeting to and retention by the inflamed colon.

Topics: Animals; Colitis, Ulcerative; Colon; Dextran Sulfate; Disease Models, Animal; Inflammation; Janus Kinases; Male; Methacrylates; Mice; Piperidines; Polymers; Prodrugs; Pyrimidines; Pyrroles

Treatment pathways for ulcerative colitis (UC) and Crohn's disease (CD) are shifting to a more individualized, risk-stratified approach. The perception is that insurance policies may not have implemented this paradigm shift, particularly regarding access to newer agents. We evaluated patient access to advanced therapies by analyzing policy information from the Managed Markets Insight and Technology database.. Coverage status as of December 2018 for all US lives was queried for adalimumab, infliximab, infliximab-dyyb, tofacitinib, ustekinumab, and vedolizumab by indication (UC and/or CD) and medical or pharmacy coverage benefit. Coverage status was classified by the number of biologic steps before access to specified drug as "No Biologic," "1 Prior Biologic," "2+ Prior Biologics," "Not Covered." Unknown lives were excluded from the analyses.. Coverage analysis was available for approximately 302 million lives under each medical and pharmacy benefit. Our analysis indicates that approximately half of covered lives had access to all agents (except tofacitinib) as first-line therapy; two-thirds had access after one biologic exposure. Among newer agents, vedolizumab had the widest coverage. For indications of UC and CD, 81% of known lives had access to vedolizumab with no prior biologic exposure required ("No Biologic"), 95% after "No Biologic" + "1 prior Biologic." Geographic variations were identified for coverage patterns.. This US-based healthcare policy analysis points to an increased access to advanced therapies for UC and CD. An individualized, risk-stratified treatment approach integrating advanced therapies, including those recently approved, into treatment pathways for UC and CD is feasible.

Topics: Adalimumab; Antibodies, Monoclonal, Humanized; Biological Products; Colitis, Ulcerative; Crohn Disease; Databases, Factual; Gastrointestinal Agents; Health Services Accessibility; Humans; Infliximab; Insurance Coverage; Insurance, Health; Piperidines; Pyrimidines; Pyrroles; United States; Ustekinumab

Topics: Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Pyrroles

Nicotinamide phosphoribosyltransferase (NAMPT, also referred to as pre-B cell colony-enhancing factor or visfatin) is critically required for the maintenance of cellular nicotinamide adenine dinucleotide (NAD) supply catalysing the rate-limiting step of the NAD. We investigated the impact of NAMPT inhibition by the small-molecule inhibitor FK866 in the dextran sulfate sodium (DSS) model of colitis and the azoxymethane/DSS model of colitis-associated cancer. The impact of NAD depletion on differentiation of mouse and human primary monocytes/macrophages was studied in vitro. Finally, we tested the efficacy of FK866 compared with dexamethasone and infliximab in lamina propria mononuclear cells (LPMNC) isolated from patients with IBD.. Our data emphasise the importance of NAD immunometabolism for mucosal immunity and highlight FK866-mediated NAMPT blockade as a promising therapeutic approach in acute intestinal inflammation.

Topics: Acrylamides; Animals; Cell Differentiation; Colitis, Ulcerative; Colonic Neoplasms; Dexamethasone; Energy Metabolism; Gastrointestinal Agents; Humans; Infliximab; Intestinal Mucosa; Macrophages; Mice; Monocytes; NAD; Nicotinamide Phosphoribosyltransferase; Piperidines

Topics: Biological Products; Biological Therapy; Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Pyrroles

Topics: Biological Products; Biological Therapy; Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Pyrroles

Knowledge regarding the economic outcomes of anti-tumour necrosis factor-α (anti-TNFα) and oral Janus kinase inhibitor (JAKi) therapies for the treatment of ulcerative colitis (UC) is limited. We conducted this analysis to assess the economic outcomes of anti-TNFα, antiadhesion molecule inhibitors (anti-AMi), and oral JAKi therapies for the treatment of UC from the perspectives of the United Kingdom (UK) and China, which are the representatives of high-income and middle-income regions, respectively.. A Markov model-based economic analysis was performed by incorporating effectiveness and utility data obtained from the literature and costs based on publicly available reports. The UK and Chinese health care perspectives were adopted to evaluate different intervention treatment sequences, including 14 treatment sequences consisting of conventional therapy, tofacitinib, adalimumab, vedolizumab, golimumab, and infliximab. The participants were the patients with moderate-to-severe UC eligible for anti-TNFα, anti-Ami, and JAKi treatment. Cost, quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER) were reported.. Compared to other alternatives comprising adalimumab, golimumab, and infliximab, the use of a treatment sequence comprising tofacitinib and vedolizumab always had better health outcomes. The most cost-effective options in the UK included the sequences comprising tofacitinib and vedolizumab, and the most cost-effective treatment option in China was tofacitinib. There were uncertainties surrounding the results, the key drivers of which being the utility values, effectiveness of conventional therapy, and relative efficacy of the active treatments.. The treatment with tofacitinib and vedolizumab for moderate-to-severe UC is likely to be the most favorable cost-effective option in the high-income UK, and tofacitinib is the most cost-effective option in the middle-income China.

Topics: Adult; Antibodies, Monoclonal, Humanized; China; Colitis, Ulcerative; Cost-Benefit Analysis; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Piperidines; Prognosis; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Quality-Adjusted Life Years; Severity of Illness Index; Tumor Necrosis Factor-alpha; United Kingdom

Active inflammatory bowel disease increases the risk of adverse pregnancy outcomes. Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). As a small molecule, tofacitinib is likely to cross the placental barrier; however, information on the effects of tofacitinib on pregnancy outcomes is limited. We report pregnancy and newborn outcomes among patients in UC clinical studies with prenatal (maternal/paternal) exposure to tofacitinib.. Pregnancies with maternal/paternal exposure to tofacitinib were identified and outcomes reported in 5 tofacitinib UC interventional studies (up to March 2017). Outcomes from tofacitinib rheumatoid arthritis (RA), psoriasis, and psoriatic arthritis interventional studies, and RA noninterventional postapproval safety studies, spontaneous adverse event reporting, and registry data are also reported.. Of 1157 patients enrolled in the UC interventional studies, 301 were women of childbearing age. Eleven cases of maternal exposure and 14 cases of paternal exposure to tofacitinib (doses of 5 mg or 10 mg twice daily) before/at the time of conception or during pregnancy were identified. Outcomes included 15 healthy newborns, no fetal deaths, no neonatal deaths, no congenital malformations, 2 spontaneous abortions, and 2 medical terminations. Outcomes across other tofacitinib studies and postmarketing cases were consistent, with a healthy newborn being the most common outcome and no fetal deaths.. Based on the limited data available, pregnancy and newborn outcomes among patients with prenatal (maternal/paternal) exposure to tofacitinib in UC studies appear similar to those reported for other tofacitinib clinical study populations and the general population.

Topics: Adult; Colitis, Ulcerative; Databases, Factual; Female; Humans; Infant, Newborn; Janus Kinase Inhibitors; Male; Maternal Exposure; Paternal Exposure; Piperidines; Pregnancy; Pregnancy Outcome; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Young Adult

Topics: Colitis, Ulcerative; Drug Approval; Humans; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles

Topics: Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Pyrroles

Tofacitinib, a non-selective Janus kinase (JAK) inhibitor, is effective in inducing clinical and endoscopic remission in patients with active ulcerative colitis (UC). Tofacitinib inhibits cytokine signalling through blockade of JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2). Adverse events including neutropenia and anaemia resulting from JAK2 inhibition have been observed in actively treated patients. By selectively targeting JAK1, such adverse events could be expected to be avoided. This open label study was designed to enrol 15 patients with UC, however the trial was discontinued after two inclusions due to safety concerns with the agent in a parallel trial for systemic lupus erythematosus. GSK2586184 was administered in two patients with moderate-to-severe UC. The JAK1 selective inhibitor GSK2586184 was well tolerated and induced clinical and endoscopic response in two patients with moderate-to-severe UC. In addition, treatment with GSK2586184 decreased histology scores and faecal calprotectin levels at early withdrawal.

Topics: Adult; Azetidines; C-Reactive Protein; Clinical Trials as Topic; Colitis, Ulcerative; Humans; Janus Kinase 1; Leukocyte L1 Antigen Complex; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Severity of Illness Index; Triazoles

Topics: Administration, Oral; Anti-Inflammatory Agents; Colitis, Ulcerative; Crohn Disease; Humans; Immunologic Factors; Indans; Inflammatory Bowel Diseases; Oxadiazoles; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Quinolones; Randomized Controlled Trials as Topic; Treatment Outcome; Tumor Necrosis Factor-alpha

Ulcerative colitis (UC) is a chronic inflammatory bowel disease that is chronically present in patients throughout their lives. Hence, the chronic nature of the disease invariably requires continuous medical treatment. Advances in medical therapy over the last decades and current developments offer increasing options and are closely associated with a better life quality in patients.. Recent developments in understanding the pathogenesis of UC are discussed. The current standard therapeutic regimens are outlined and recent developments and upcoming strategies introduced.. (1) Environmental factors that are yet to be defined contribute to the pathogenesis of UC. (2) An accelerated step-up therapy represents the current standard in UC. (3) Anti-integrins represent the most recently introduced pharmacological class in the therapy of UC. (4) Novel strategies including Janus kinase inhibitors are in the near future.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal, Humanized; Biosimilar Pharmaceuticals; Colitis, Ulcerative; Gastrointestinal Agents; Glucocorticoids; Humans; Immunosuppressive Agents; Infliximab; Integrins; Janus Kinases; Mercaptopurine; Mesalamine; Piperidines; Pyrimidines; Pyrroles; Remission Induction; Tumor Necrosis Factor-alpha

Piperine, a main component of Piper longum Linn. and Piper nigrum Linn., is a plant alkaloid with a long history of medicinal use. Piperine exhibits antidepressant, hepatoprotective, anti-metastatic, anti-thyroid, immunomodulatory, antitumor and anti-inflammatory activities, However its therapeutic potential in amelioration of ulcerative colitis and the underlying mechanism for anti-inflammatory activity remains unknown.The objective of the present investigation was to unravel the therapeutic potential of piperine on amelioration of IBD using acetic acid induced experimental animal model for ulcerative colitis and to determine the role of TLR4 receptor in signalling pathway of inflammatory gene expression in ulcerative colitis.. We induced colitis using acetic acid (150µl of 5% once, intrarectally) in mice and estimated disease activity index (DAI), which took into account weight loss, stool consistency, and occult/gross bleeding. Colon length, spleen weights, ulcer area and ulcer index were measured; histological changes were observed by H&E staining. Effect of piperine on various antioxidant parameter of mice colon such as tissue myeloperoxidase (MPO) accumulation, SOD concentrations, reduced GSH and lipid peroxidation were determined. Pro-inflammatory mediators, namely, nitric oxide (NO), tumour necrosis factor-α (TNF-α) were determined by a TNF-α ELISA kit obtained from Thermo fisher scientific India Pvt. Ltd. Effect of piperine on haematological parameters of mice in acetic acid induced IBD was also determined which involves the estimation of FFA using a commercial free fatty acid fluorometric assay kit.. Piperine significantly attenuated acetic acid induced DAI score which implies that it suppresses weight loss, diarrhoea, gross bleeding and infiltration of immune cells. Piperine administration also effectively and dose dependently prevented shortening of colon length and enlargement of spleen size. Histological examination indicated that piperine reduces oedema in sub-mucosa, cellular infiltration, reduced haemorrhages and ulceration as compare to acetic acid induced colitis in mice. Furthermore piperine inhibited abnormal secretion of pro-inflammatory mediators namely NO, cytokines TNF-α and reduces FFA induced TLR4 mediated inflammation.. These results suggest that piperine has an anti-inflammatory effect at colorectal sites that is due to down- regulations of the productions and expression of inflammatory mediators and it also reduces FFA induced TLR4 mediated inflammation. Thus it may have therapeutic potential on amelioration of IBD.

Topics: Acetic Acid; Alkaloids; Animals; Anti-Inflammatory Agents; Benzodioxoles; Colitis, Ulcerative; Colon; Fatty Acids, Nonesterified; Glutathione; Lipid Peroxidation; Male; Malondialdehyde; Mice; Nitric Oxide; Piperidines; Polyunsaturated Alkamides; Superoxide Dismutase; Toll-Like Receptor 4; Toxicity Tests, Acute; Tumor Necrosis Factor-alpha

Curcumin (CUR) is a poorly water-soluble drug and its absorption is very low. In this study, CUR and piperine (PIP) were co-encapsulated into the nanoformulation called self-microemulsifying drug delivery system (SMEDDS) to improve the stability and water-solubility of CUR and enhance its anti-colitis activity. The formulation of CUR-PIP-SMEDDS was prepared to encapsulate two hydrophobic components CUR and PIP, and then was characterized by assessing appearance, morphology, particle size, zeta potential and drug encapsulation efficiency. The appearance of CUR-PIP-SMEDDS remained clarified and transparent, and the microemulsion droplets appeared spherical without aggregation. The mean size of microemulsion droplet formed from CUR-PIP-SMEDDS was 15.87 ± 0.76 nm, and the drug encapsulation efficiency of SMEDDS for CUR and PIP were (94.34 ± 2.18)% and (90.78 ± 2.56)%, respectively. The vitro stability investigation of CUR-PIP-SMEDDS in colon tissue suggested that using SMEDDS as a delivery vehicle and co-encapsulated with PIP, CUR was more stable than drug solution in colons site. Meanwhile, the anti-inflammatory activity of CUR-PIP-SMEDDS was evaluated on DSS-induced colitis model. The results showed that CUR-PIP-SMEDDS exhibited definite anti-colitis activity by directing CUR-PIP-SMEDDS to inflammatory colon tissue through retention enema administration. Our study illustrated that the developed CUR-PIP-SMEDDS formulation was a potential carrier for developing colon-specific drug delivery system of CUR for ulcerative colitis treatment.

Topics: Alkaloids; Animals; Benzodioxoles; Chemistry, Pharmaceutical; Colitis, Ulcerative; Curcumin; Drug Delivery Systems; Drug Stability; Emulsions; Male; Mice; Mice, Inbred BALB C; Particle Size; Piperidines; Polyunsaturated Alkamides; Solubility

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

Pharmacological treatment and/or maintenance of remission in inflammatory bowel diseases (IBD) is currently one of the biggest challenge in the field of gastroenterology. Available therapies are mostly limited to overcoming the symptoms, but not the cause of the disease. Recently, the endocannabinoid system has been proposed as a novel target in the treatment of IBD. Here we aimed to assess the anti-inflammatory action of the novel fatty acid amide hydrolase (FAAH) inhibitor PF-3845 and its effect on the endocannabinoid and related lipid metabolism during the course of experimental colitis.. We used two models of experimental colitis in mice (TNBS- and DSS-induced) and additionally, we employed LC/MS/MS spectrometry to determine the changes in biolipid levels in the mouse colon during inflammation.. We showed that the FAAH inhibitor PF-3845 reduced experimental TNBS-induced colitis in mice and its anti-inflammatory action is associated with altering the levels of selected biolipids (arachidonic and oleic acid derivatives, prostaglandins and biolipids containing glycine in the mouse colon).. We show that FAAH is a promising pharmacological target and the FAAH-dependent biolipids play a major role in colitis. Our results highlight and promote therapeutic strategy based on targeting FAAH-dependent metabolic pathways in order to alleviate intestinal inflammation.

Topics: Amidohydrolases; Animals; Cannabinoids; Colitis, Ulcerative; Disease Models, Animal; Dose-Response Relationship, Drug; Indoles; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Piperidines; Pyrazoles; Pyridines; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Treatment Outcome

The present work was undertaken to determine the effects of Amaranthus roxburghianus Nevski. (Amaranthaceae) root alone and in combination with piperine in treating ulcerative colitis (UC) in mice.. Swiss albino mice were divided into seven groups (n = 6). Standard group received prednisolone (5 mg/kg, intraperitoneally). Treatment groups received hydroalcoholic extract of roots of A. roxburghianus (50 and 100 mg/kg, per oral) and a combination of hydroalcoholic extract of roots of A. roxburghianus (50 and 100 mg/kg, per oral) and piperine (5 mg/kg, per oral). Ulcer index, colitis severity, myeloperoxidase (MPO), malondialdehyde and glutathione were estimated from blood and tissue. Column chromatography of the extract was done and purified fractions were analyzed by gas chromatography-mass spectroscopy (GC-MS).. Treatment with the combination of hydroalcoholic extract of A. roxburghianus and piperine showed minimal ulceration, hemorrhage, necrosis and leucocyte infiltration by histopathological observation. Acetic acid increased MPO levels in blood and colon tissue to 355 U/mL and 385 U/mg, respectively. The combination of hydroalcoholic extract of A. roxburghianus (100 mg/kg) and piperine (5 mg/kg) significantly decreased MPO in blood and tissue to 182 U/mL and 193 U/mg, respectively (P < 0.05). Similarly, this combination significantly reduced malondialdehyde levels and increased glutathione levels in blood and tissue. Various phytoconstituents were detected by GC-MS.. The combination of hydroalcoholic extract of A. roxburghianus and piperine is effective in the treatment of UC and the effects are comparable with the standard drug prednisolone. 4H-pyran-4-one, 2,3-dihydro-3,5-dihydroxy-6-methyl, eugenol and benzene, and 1-(1,5-dimethyl-4-hexenyl)-4-methyl are reported having analgesic, anti-inflammatory, and antioxidant properties; they may play a role in the biological activity of A. roxburghianus root.

Topics: Alkaloids; Amaranthus; Animals; Benzodioxoles; Colitis, Ulcerative; Colon; Drug Therapy, Combination; Glutathione; Humans; Male; Malondialdehyde; Mice; Peroxidase; Piperidines; Plant Extracts; Plant Roots; Polyunsaturated Alkamides

Lafutidine, a histamine H2-receptor antagonist, exhibits gastric mucosal protective action mediated by capsaicin-sensitive afferent neurons, in addition to a potent antisecretory effect. In this study we examined the effect of lafutidine on dextran sulfate Na (DSS)-induced ulcerative colitis in rats, in relation to capsaicin-sensitive afferent neurons. Experimental colitis was induced in rats by daily treatment with 3% DSS in drinking water for 7 days. Lafutidine, capsaicin, and cimetidine were administered per os twice daily for 6 days. The ulceration area, colon length, and myeloperoxidase (MPO) activity were measured on day 7 after the onset of DSS treatment. DSS caused severe mucosal lesions in the colon, accompanied by an increase in MPO activity as well as a decrease in body weight gain and colon length. Daily administration of lafutidine dose-dependently reduced the severity of DSS-induced colitis and significantly mitigated changes in the colon length and MPO activity. The effects of lafutidine were mimicked by daily administration of capsaicin but not cimetidine and were totally abolished by chemical ablation of capsaicin-sensitive afferent neurons. In contrast, desensitization of afferent neurons significantly worsened the colonic inflammation induced by DSS. It was also found that both lafutidine and capsaicin increased the secretion of mucus in the colonic mucosa. These results suggest that lafutidine is effective against the ulcerative colitis induced by DSS through capsaicin-sensitive afferent neurons. This action might be attributable at least partly to the enhancement of colonic mucus secretion.

Topics: Acetamides; Animals; Capsaicin; Colitis, Ulcerative; Dextran Sulfate; Histamine H2 Antagonists; Intestinal Mucosa; Male; Neurons, Afferent; Peroxidase; Piperidines; Pyridines; Rats; Rats, Wistar

1. This in vitro study was designed to determine the potential use of the NK(1) antagonist, SR140333 as an anti-diarrhoeal treatment for food allergy or inflammatory bowel disease. The effect of various immune and neuronal stimuli on human colonic substance P (SP) release and the effect of SR140333 on subsequently stimulated mucosal ion transport was investigated. 2. Submucosal and sensory nerve fibre stimulation using electrical field stimulation (1 ms/7 Hz/7 V) and capsaicin (50 microM) respectively, mast cell activation by anti-IgE (1/250 dilution) and granulocyte stimulation using fMLP (50 microM) each released SP and evoked a secretory response. 3. SP and the NK(1) selective agonist, Sar-SP (0.1 - 1000 nM) stimulated an increase in colonic secretion which was antagonized by SR140333 (pD'(2)=6.7 and 7.25 versus SP and Sar-SP respectively). 4. SR140333, at a concentration that blocked NK(1)-mediated secretion (500 nM), also reduced the secretory response to both alphaIgE and capsaicin. This suggests a pathophysiologic role for NK(1) receptors. 5. Capsaicin evoked SP release was increased in tissue taken from Crohn's disease but not ulcerative colitis patients. The response to SP was however reduced by 70 and 89% respectively. 6. Mast cells and sensory afferents contribute to allergic diarrhoea. Since SR140333 reduced the secretory response to mast cell and afferent stimulation this compound may be particularly useful in reducing the symptoms of food allergy.

Topics: Animals; Antidiarrheals; Capsaicin; Colitis, Ulcerative; Colon; Crohn Disease; Epithelial Cells; Food Hypersensitivity; Guinea Pigs; Humans; Immunoglobulin E; Inflammatory Bowel Diseases; Male; Mast Cells; Neurokinin A; Neurokinin B; Neurokinin-1 Receptor Antagonists; Piperidines; Quinuclidines; Rats; Receptors, Neurokinin-1; Species Specificity; Substance P; Tachykinins

19 consecutive patients admitted with severe chronic diarrhoea which had failed to respond to standard therapeutic regimen were treated with 4 to 8 mg of loperamide daily for up to 50 weeks. A marked improvement was achieved in 13 out of the 19 patients (68%). The best results were observed in patients with ulcerative colitis and Crohn's disease. Patients with secretory diarrhoea did not improve. No major side effects were observed. It is concluded that loperamide is a highly effective and safe new drug in the treatment of patients with chronic inflammatory bowel diseases.

Topics: Adult; Aged; Carcinoid Tumor; Chronic Disease; Colitis, Ulcerative; Crohn Disease; Diarrhea; Exocrine Pancreatic Insufficiency; Female; Humans; Loperamide; Male; Middle Aged; Piperidines; Short Bowel Syndrome; Time Factors

Topics: Adult; Chronic Disease; Colitis, Ulcerative; Humans; Loperamide; Male; Megacolon, Toxic; Peristalsis; Piperidines

Topics: Adult; Aged; Biliary Tract Diseases; Colitis, Ulcerative; Dioxoles; Dysmenorrhea; Female; Humans; Male; Middle Aged; Parasympatholytics; Piperidines; Tablets; Urinary Calculi

Topics: Adolescent; Adrenal Cortex Hormones; Arthritis; Child; Chlordiazepoxide; Colitis, Ulcerative; Female; Humans; Infant; Male; Methylprednisolone; Parent-Child Relations; Piperidines; Purpura; Pyoderma; Sulfasalazine; Vitamins

Topics: Adult; Barium; Colectomy; Colitis, Ulcerative; Female; Humans; Hydrocortisone; Ileostomy; Middle Aged; Penicillins; Piperidines; Prednisone; Proctoscopy; Radiography; Streptomycin; Sulfasalazine; Sulfisoxazole

Topics: Biomedical Research; Colchicine; Colectomy; Colitis; Colitis, Ulcerative; Colonic Diseases; Colonic Diseases, Functional; Crohn Disease; Diabetic Neuropathies; Diarrhea; Diphenoxylate; Diverticulitis; Diverticulitis, Colonic; Drug Therapy; Dysentery; Dysentery, Amebic; Enteritis; Gastroenteritis; Humans; Piperidines; Postgastrectomy Syndromes; Postoperative Complications; Toxicology; Virus Diseases

Topics: Benzilates; Colic; Colitis; Colitis, Ulcerative; Colonic Diseases; Humans; Hydrocarbons, Brominated; Parasympatholytics; Piperidines