Low-Dose Interleukin 2 for the Treatment of Moderate to Severe Ulcerative Colitis.
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ABSTRACT:
SUBMITTER: Allegretti JR
PROVIDER: S-EPMC10523991 | biostudies-literature | 2023 Aug
REPOSITORIES: biostudies-literature
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Low-Dose Interleukin 2 for the Treatment of Moderate to Severe Ulcerative Colitis.
Allegretti Jessica R JR Mitsialis Vanessa V Canavan James B JB Snapper Scott B SB
Gastroenterology 20230407 2
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Project description:Curcumin was shown in placebo-controlled trials to induce remission in mild-moderate ulcerative colitis (UC). QingDai (QD, Indigo), another herbal extract, showed efficacy in two UC trials from Japan, but evidence in the Western population is scant. We report on the use of curcumin-QingDai combination (CurQD) for the treatment of moderate-severe UC. Patient 1 was a 24-year-old male with severe UC refractory to cyclosporine and corticosteroids. He partially responded to infliximab but later lost response to an optimized dose of infliximab in combination with 6-mercaptopurine, presenting with worsening symptoms and severe Mayo 3 mucosal inflammation. Initiation of CurQD 2.5 g/day resulted in rapid cessation of blood per rectum. Complete clinical remission ensued within few weeks. Follow-up endoscopies performed 12 weeks later showed only minimal residual inflammation. Infliximab was later stopped due to reimbursement issues, and the patient was successfully maintained on lower doses of CurQD and 6-mercaptopurine for 31 months. Two flares have responded to a temporary increase in QD component dose. Patient 2 was a 59-year-old female with extensive UC not responding to maximal oral + topical 5-ASA and corticosteroids. Despite severe mucosal ulceration (Mayo 3) found on endoscopy, she refused the recommendation for biologics and opted for a short-term limited trial of CurQD. This was initiated at 2,000 mg/day and induced rapid clinical remission. Lower endoscopies performed after 2 and 5 months on CurQD showed complete mucosal healing, and the patient maintained her clinical remission on low-dose CurQD for 49 months. No adverse events were noted in the 2 patients.
| S-EPMC9941783 | biostudies-literature
Project description:Background and aimsFilgotinib is a small molecule that selectively inhibits Janus kinase [JAK] type 1. It is already approved for the treatment of rheumatoid arthritis and is being evaluated for the management of patients with moderate to severe ulcerative colitis [UC]. The purpose of this review is to provide an overview of the currently available data on filgotinib and to define how to position this new drug in the treatment algorithm of patients with UC.MethodsThe Pubmed, Embase and Scopus databases were searched up to June 25, 2021 in order to identify studies reporting efficacy and safety data of filgotinib in patients with UC.ResultsData from a phase III study enrolling UC patients with moderate to severe disease show that filgotinib is effective with a reassuring safety profile. Filgotinib treatment is not associated with a greater risk of thrombosis and herpes zoster infections compared to other JAK inhibitors. However, animal studies reported impaired spermatogenesis and histopathological effects on male reproductive organs, making it necessary to deepen this aspect in dedicated human studies.ConclusionsFilgotinib is an effective and safe drug for treatment of both biologic-naive and biologic-experienced patients with moderate to severe UC and may soon be available.
| S-EPMC9228886 | biostudies-literature
Project description:ObjectiveThe aim of this study was to evaluate the cost effectiveness of tofacitinib versus other treatment options currently available in Colombia in naïve to biologics (first-line) and exposed to biologics (second-line) patients with moderate to severe active ulcerative colitis (UC).MethodsA Markov model was constructed with 8-week cycles, simulating a cohort of patients in a 5-year time horizon. The health states included remission, treatment response, active UC, and colectomy. The transition probabilities for the induction and maintenance phase were obtained from a network meta-analysis, and effectiveness was measured using quality-adjusted life-years (QALYs). Unit costs were derived from official national sources.ResultsFor first line, the incremental cost-effectiveness ratio (ICER) per QALY was $883 for tofacitinib and $3619 for infliximab, compared with adalimumab. Sensitivity analysis showed that tofacitinib is cost effective in 45% of the iterations, adalimumab in 5%, and infliximab in 50%. Meanwhile, the ICER of adalimumab was $14,927 compared with tofacitinib in second-line treatment. In the sensitivity analysis, tofacitinib was cost effective in 64% of the iterations, followed by adalimumab in 36%. Infliximab and golimumab were not included due to data limitations in the network meta-analysis of second-line treatment.ConclusionThe analysis suggests that in Colombia, treatment with tofacitinib for patients with moderate-to-severe UC is a cost-effective option in both lines compared with other treatment options.
| S-EPMC9596638 | biostudies-literature
Project description:Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We characterized tofacitinib pharmacokinetics in patients with moderate to severe UC, and the effects of covariates on variability in pharmacokinetic parameter estimates. Data were pooled from 1 8-week phase 2 and 2 8-week phase 3 induction studies, and a 52-week phase 3 maintenance study (N = 1096). Population pharmacokinetic analysis was conducted using nonlinear mixed-effects modeling. Potential predictors of apparent oral clearance (CL/F) and volume of distribution (V/F) were evaluated. The PK was described by a 1-compartment model parameterized in terms of CL/F (26.3 L/hour [h]) and V/F (115.8 L), with first-order absorption (Ka ; 9.85 h-1 ) and lag time (0.236 h). The derived elimination half-life was approximately 3.05 h. In the final model, baseline creatinine clearance, sex, and race (Asian vs non-Asian) were significant covariates for CL/F; significant covariates for V/F were age, sex, and body weight; baseline albumin and baseline Mayo score were not significant covariates. CL/F between-patient variability was estimated at 22%. Tofacitinib exposure did not change significantly over the duration of induction/maintenance treatment in patients with UC. Although statistically significant covariate effects on CL/F and V/F were observed, the magnitude of the effects are not clinically significant. Therefore, dose adjustment/restrictions for age, body weight, sex, race, or baseline disease severity are not required during tofacitinib treatment. ClinicalTrials.gov numbers: NCT00787202, NCT01465763, NCT01458951, NCT01458574.
| S-EPMC7986169 | biostudies-literature
Project description:A subset of patients with ulcerative colitis (UC) present with, or progress to, moderate to severe disease activity. These patients are at high risk for colectomy, hospitalization, corticosteroid dependence, and serious infections. The risk of life-threatening complications and emergency colectomy is particularly high among those patients hospitalized with acute severe ulcerative colitis. Optimal management of outpatients or inpatients with moderate to severe UC often requires the use of immunomodulator and/or biologic therapies, including thiopurines, methotrexate, cyclosporine, tacrolimus, TNF-α antagonists, vedolizumab, tofacitnib, or ustekinumab, either as monotherapy or in combination (with immunomodulators), to mitigate these risks. Decisions about optimal drug therapy in moderate to severe UC are complex, with limited guidance on comparative efficacy and safety of different treatments, leading to considerable practice variability. Therefore, the American Gastroenterological Association prioritized development of clinical guidelines on this topic. To inform the clinical guidelines, this technical review was completed in accordance with the Grading of Recommendations Assessment, Development and Evaluation framework. Focused questions in adult outpatients with moderate to severe UC included: (1) overall and comparative efficacy of different medications for induction and maintenance of remission in patients with or without prior exposure to TNF-α antagonists, (2) comparative efficacy and safety of biologic monotherapy vs combination therapy with immunomodulators, (3) comparative efficacy of top-down (upfront use of biologics and/or immunomodulator therapy) vs step-up therapy (acceleration to biologic and/or immunomodulator therapy only after failure of 5-aminosalicylates, and (4) role of continuing vs stopping 5-aminosalicylates in patients being treated with immunomodulator and/or biologic therapy for moderate to severe UC. Focused questions in adults hospitalized with acute severe ulcerative colitis included: (5) overall and comparative efficacy of pharmacologic interventions for inpatients refractory to corticosteroids, in reducing risk of colectomy, (6) optimal dosing regimens for intravenous corticosteroids and infliximab in these patients, and (7) role of adjunctive antibiotics in the absence of confirmed infections.
| S-EPMC7117094 | biostudies-literature
Project description:AimsTofacitinib 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.MethodsOne- 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 [Cav,ss ] and trough plasma concentration at steady state [Ctrough,ss ]) and week 8 efficacy endpoints were characterized using logistic regression analysis. Baseline disease, demographics, prior and concurrent UC treatment were evaluated as covariates.ResultsPlasma tofacitinib concentrations increased proportionately with dose and estimated oral clearance, and Cav,ss values were not significantly different between baseline and week 8. Dose, Cav,ss and Ctrough,ss performed similarly as predictors of efficacy based on statistical criteria for model fit and comparison of model predictions for each endpoint. Individual Cav,ss values were similar between clinical remitters and nonremitters at predicted efficacious doses (10 and 15 mg twice daily). Baseline Mayo score was a significant determinant of efficacy. Predicted differences from placebo in clinical remission at 10 mg twice daily for patients with baseline Mayo score >8 and ≤8 were 39% (95% CI: 7-70) and 21% (-2-50), respectively.ConclusionsExposure-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.
| S-EPMC5980553 | biostudies-literature
Project description:BackgroundSustaining clinical remission is an important treatment goal in moderate-to-severe UC. This post hoc exploratory analysis assessed the long-term efficacy of vedolizumab in the subset of patients with UC in the GEMINI 1 study who were in clinical remission by week 14 after 3 induction doses, administered at weeks 0, 2, and 6.MethodsSustained clinical remission (primary endpoint) was evaluated using 2 definitions: (1) a partial Mayo Score (pMS) of ≤2 with no subscore >1 and (2) a rectal bleeding subscore (RBS) of 0 throughout weeks 14, 26, 38, and 52.ResultsThe proportion of patients in clinical remission at week 14 was significantly higher in patients receiving vedolizumab (n = 620) compared with placebo (n = 149) (pMS: 32.7% vs 20.1% [percentage-point difference (∆) 12.6%; 95% confidence interval [CI], 5.2-20.0]; RBS: 47.3% vs 28.9% [∆18.4%; 95% CI, 10.1-26.7]). Of patients in clinical remission at week 14, a significantly higher proportion of vedolizumab-treated patients achieved sustained clinical remission compared with placebo (pMS: 66.5% vs 26.7%; ∆39.8%; 95% CI, 22.7-56.9; RBS: 56.7% vs 20.9%; ∆35.7%; 95% CI, 22.3-49.1). Findings were consistent in tumor necrosis factor (TNF) antagonist-naive and antagonist-failure patients.ConclusionCompared with placebo, 35%-40% more patients receiving a full induction course of vedolizumab had sustained clinical remission after 52 weeks of therapy. This result was observed irrespective of TNF antagonist treatment history. Clinical remission at week 14 may therefore be a predictor for sustained clinical remission with vedolizumab.
| S-EPMC6499937 | biostudies-literature
Project description:BackgroundTofacitinib 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.MethodsPatients 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).ResultsAmong 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.ConclusionsAmong 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.
| S-EPMC8994921 | biostudies-literature
Project description:Mirikizumab is a p19-directed anti-interleukin-23 antibody approved for the treatment of adults with moderate-to-severe ulcerative colitis (UC). Here, we report the first data of mirikizumab pharmacokinetics (PK) and exposure-response (E/R) relationships in pediatric participants (aged 2 to <18 years weighing >10 kg) with moderate-to-severe UC from the phase II, open-label study SHINE-1 (NCT04004611). PK parameters were analyzed using a model developed previously in adults with fixed-exponent allometry for body weight. Serum samples collected from 26 participants during the 12-week induction and 40-week maintenance periods of SHINE-1 were analyzed. Estimated body weight-adjusted systemic clearance, volume of distribution, and subcutaneous bioavailability were 0.021 L/h, 0.069 L/kg, and 49.8%, respectively. Covariate analysis identified no clinically significant covariates other than body weight. In the exposure range studied, E/R analysis using post hoc grouping by average concentration quartile and comparison of observed change from baseline in modified Mayo Score (MMS) at Week 12 with the adult model prediction revealed no obvious E/R relationship in clinical response, clinical remission, or endoscopic response, consistent with observations in adults. The E/R relationship for observed change from baseline in MMS at Week 12 is also similar to the adult model prediction. The PK modeling and E/R analyses suggested optimal doses of intravenous mirikizumab 300 mg for weight >40 kg, 5 mg/kg for weight ≤40 kg every 4 weeks (Q4W) during induction, and subcutaneous mirikizumab 200 mg (>40 kg), 100 mg (>20 to ≤40 kg), or 50 mg (≤20 kg) Q4W during maintenance therapy for pediatric patients with moderate-to-severe UC.
| S-EPMC11919259 | biostudies-literature
Project description:BackgroundViral infections have been suggested as possible triggers for the onset of ulcerative colitis (UC).MethodsWe employed VirCapSeq-Vert, a high-throughput sequencing virus capture platform, to examine the stool virome of children with newly diagnosed moderate to severe UC. We surveyed fecal samples collected at presentation, after symptom remission, and from a control group diagnosed with irritable bowel syndrome.ResultsSeventy subjects with UC (mean age 13 years, 45 had moderate symptoms, 25 had severe, 69 of 70 had a Mayo endoscopy subscore 2/3) were studied. We detected a wide range of animal viruses that were taxonomically classified into 12 viral families. A virus was present in 50% of fecal samples collected at presentation, 41% of samples collected after remission, and 40% of samples in our control group. The most frequently identified viruses were diet-based gyroviruses. The UC cohort had a significantly higher prevalence of anelloviruses compared with the control cohort. However, we did not identify a single virus that can be implicated in the onset of UC and did not find an association between UC disease severity and viral presence.ConclusionPresence of virus in stool was not associated with the onset of pediatric UC.
| S-EPMC7108593 | biostudies-literature