Induction and Maintenance of Clinical Remission by Adalimumab in Patients With Moderate-to-Severe Ulcerative Colitis

Abstract Background To perform a systematic review and meta-analysis discussing the efficacy and safety of vedolizumab (VDZ) treatment in patients with active moderate to severe ulcerative colitis (UC). Methods Using relevant keywords, we searched PubMed, Web of Science, Scopus, and Cochrane Central databases, until June 2020. We included interventional and observational cohort studies which assessed the safety and effectiveness of VDZ 300 mg intravenous infusion, in patients with active moderate to severe UC. We used the Cochrane risk of bias assessment tool and the Newcastle-Ottawa scale to assess the quality of included interventional and cohort studies, respectively. Dichotomous outcomes were pooled as proportion, 95% Confidence interval (CI), and p-value under the random-effects model in the open meta-analyst software. Results We found 10 interventional studies and 35 cohort studies, including 4,794 patients eligible for our review. Most of the included citations were single-arm studies. Our meta-analysis showed that VDZ therapy could induce a significant clinical response in UC patients up to 54 weeks (proportion 0.516, 95% CI [0.453, 0.578], p < 0.001). VDZ was associated with clinically significantly clinical remission and steroid-free clinical remission after 54 weeks (p < 0.0001). Durable clinical remission, histological remission, and endoscopic response rates were maintained in UC patients taking VDZ at the 52nd week. There was no significant difference between VDZ and placebo regarding the incidence of drug-related serious adverse events (p = 0.113) and death rates (p = 0.085). Conclusion Our systematic review and meta-analysis showed that the use of VDZ in patients with active moderate to severe UC was associated with high percentages of clinical response and remission rates in induction and maintenance treatment stages. VDZ seems to be well tolerated in UC patients, apart from some infections and inflammations. Future RCTs should compare VDZ to active treatments for longer follow-up periods with larger sample size.

Download Full-text

S906 Clinical Remission Using the Patient-Reported Ulcerative Colitis Electronic Diary (UC e-Diary) in Adults With Moderate-to-Severe Ulcerative Colitis

The American Journal of Gastroenterology ◽

10.14309/01.ajg.0000777156.87814.06 ◽

2021 ◽

Vol 116 (1) ◽

pp. S428-S428

Author(s):

Muna J. Tahir ◽

Saeid Shahraz ◽

Pravin Kamble ◽

Song Wang ◽

Peter Nagy

Keyword(s):

Ulcerative Colitis ◽

Clinical Remission ◽

Electronic Diary ◽

Severe Ulcerative Colitis ◽

Patient Reported

Download Full-text

A232 EFFICACY OF TOFACITINIB FOR THE TREATMENT OF MODERATE-TO-SEVERE ULCERATIVE COLITIS: REAL-WORLD DATA

Journal of the Canadian Association of Gastroenterology ◽

10.1093/jcag/gwz047.231 ◽

2020 ◽

Vol 3 (Supplement_1) ◽

pp. 108-109

Author(s):

Y Xiao ◽

P L Lakatos ◽

R Bourdages ◽

A Bitton ◽

W Afif ◽

...

Keyword(s):

Ulcerative Colitis ◽

Clinical Response ◽

Clinical Remission ◽

Preliminary Analysis ◽

Kinase Inhibitor ◽

Significant Proportion ◽

Real Life ◽

Janus Kinase ◽

Severe Ulcerative Colitis ◽

Mayo Score

Abstract Background A significant proportion of patients with moderate to severe ulcerative colitis (UC) do not respond to therapy, which includes thiopurines, glucocorticoids, and antagonists to tumour necrosis factor-α and integrin. Tofacitinib, a Janus Kinase inhibitor, has emerged as an efficacious and safe treatment for moderate to severe ulcerative colitis. However, it is not known if this efficacy translates into real-life effectiveness in a regular clinical practice. Aims We aimed to assess the rate of clinical response and clinical remission at 3 and 6 months after tofacitinib initiation. Secondary endpoints included rate of biomarker normalization, corticosteroids-free clinical remission and severe infections. Methods We conducted a multi-center retrospective observational study of adult patients with active UC started on tofacitinib from January 1, 2015 to October 1, 2019 at the McGill University Health Center and Hotel-Dieu de Lévis. A positive clinical response was defined as a decrease of ≥3 in the partial Mayo score. Clinical remission was defined as partial Mayo score of ≤2. Biomarker normalization was defined as fecal calprotectin ≤250ug/g. Severe infection was defined as an infection requiring hospitalization. Results During the study period, 40 patients with UC were started on tofacitinib. Amongst the patients, 85% (n=34) had failed ≥1 biologic and 50% (n=20) had failed ≥3 biologics. At the time of this preliminary analysis, 38 patients had undergone 3 months of treatment and 30 patients had undergone 6 months of treatment. At 3 months, a clinical response was seen in 89.5% of patients (n=34) and clinical remission occurred in 63.2% (n=24). At 6 months, clinical response occurred in 73.3% of patients (n=22) and clinical remission was sustained in 53.33% (n=16). Biochemical normalization occurred in 29.0% (n=11) and 30.0% (n=9) at 3 and 6 months, respectively. Additionally, 63.2% (n=24) and 43.3% of patients (n=13) achieved steroid-free clinical remission at 3 and 6 months, respectively. In the interim, one patient developed a serious infection requiring discontinuation of drug. Conclusions Our preliminary analysis demonstrates that in a real-life setting, tofacitinib is an effective treatment for inducing clinical remission in refractory UC patients. Further data will be complied to better assess the efficacy over a longer follow up. Funding Agencies None

Download Full-text

ANTI-TNF PHARMACOKINETICS AND RESPONSE TO THERAPY IN PEDIATRIC ACUTE SEVERE ULCERATIVE COLITIS (THE ARCH STUDY)

Inflammatory Bowel Diseases ◽

10.1093/ibd/izaa347.132 ◽

2021 ◽

Vol 27 (Supplement_1) ◽

pp. S55-S56

Author(s):

Kaitlin Whaley ◽

Vivian Xiong ◽

Rebekah Karns ◽

Jeffrey Hyams ◽

Subra Kugathasan ◽

...

Keyword(s):

Ulcerative Colitis ◽

Clinical Remission ◽

Pediatric Population ◽

Controlled Trial ◽

Positive Association ◽

Volume Of Distribution ◽

Response To Therapy ◽

Parameter Estimates ◽

Time Curve ◽

Severe Ulcerative Colitis

Abstract Background and Aims 25% of children hospitalized with acute severe ulcerative colitis (ASUC) rescued with infliximab (IFX) at labeled dosing undergo a colectomy prior to discharge. Our aim was to determine whether IFX pharmacokinetics (PK) are associated with treatment response in pediatric ASUC. Methods We prospectively enrolled hospitalized pediatric patients initiating IFX for ASUC or IBD-U (PUCAI ≥65) at 7 North American centers and followed for 26 weeks in this pilot and feasibility cohort study. Serial IFX levels (Prometheus Biosciences, Inc.) were obtained and individual PK parameter estimates, such as volume of distribution, clearance (CL), elimination half-life (T1/2) and IFX exposure (area under the concentration-time curve) were estimated using Bayesian methodology. The primary outcome was Day 7 clinical response (CR-D7, PUCAI <35). Key secondary outcomes were Week 8 clinical remission (CR-W8, PUCAI <10) and Week 26 corticosteroid-free clinical remission (CFR-W26). Results 38 participants (mean age 14.5 years, 50% female, 95% UC, 87% extensive/pancolitis) were treated with IFX at a mean higher than labeled dosing of 9.9 [9.3,10.3] mg/kg, and 16% received an early second dose 4–6 days after the first infusion. CR-D7, CR-W8, and CFR-W26 were achieved in 71%, 55%, and 41%, respectively. Only one participant (2.7%) underwent colectomy by week 26. Using 304 IFX level measurements, we developed a novel pediatric population PK model for IFX in ASUC that incorporated albumin, antibodies to IFX, CRP, and height to characterize the PK profile for participants. The median IFX T1/2 was 5.8 [4.2,7.0] days at Day 7 and lengthened to 7.4 [5.4,8.4] days by Week 26 (P=0.014), but notably remained below the median 10.8 [8.6, 15.4] days reported in a randomized controlled trial of IFX for moderate to severe pediatric UC (Fig. 1). IFX exposure was not associated with CR-D7, CR-W8, or CSR-W26. More rapid IFX CL at Week 26 was significantly associated with inability to achieve CFR-W26 (P=.013). This finding was in line with a higher, but not statistically significant, median trough IFX level nearest Week 26 in those with (19.5 [13.6, 30.3]) versus without (14.2 [6.0, 21.3] μg/ml) CFR-W26 (P=.13) (Fig. 2). Conclusion At the higher than standard IFX dosing used to treated children with ASUC in this observational study, we observed a lower colectomy rate compared to prior studies but did not observe a positive association between IFX exposure and clinical outcomes. Albumin, CRP, height, and ATI were associated with IFX PK and incorporated into a new pediatric ASUC PK model. Initial 10 mg/kg IFX dosing may be sufficient to optimize early outcomes in pediatric ASUC. Additional studies are needed to determine if sustained intensification of maintenance IFX regimens can overcome persistent rapid clearance and improve later outcomes in pediatric ASUC.

Download Full-text

Tofacitinib in Treatment-Refractory Moderate to Severe Ulcerative Colitis: Real-World Experience from a Retrospective Multicenter Observational Study

Journal of Clinical Medicine ◽

10.3390/jcm9072177 ◽

2020 ◽

Vol 9 (7) ◽

pp. 2177

Author(s):

Peter Hoffmann ◽

Anna-Maria Globig ◽

Anne K. Thomann ◽

Maximilian Grigorian ◽

Johannes Krisam ◽

...

Keyword(s):

Ulcerative Colitis ◽

Adverse Events ◽

Clinical Response ◽

Real World ◽

Clinical Remission ◽

Safety Data ◽

Colon Perforation ◽

Severe Ulcerative Colitis ◽

Emergency Colectomy

(1) Background: Tofacitinib is approved in Europe for the treatment of adults with moderately to severely active ulcerative colitis since 2018. Real-world efficacy and safety data are currently scarce. (2) Methods: We performed a retrospective multicenter study at three German tertiary outpatient clinics for inflammatory bowel diseases and included all patients who started tofacitinib therapy between August 2018 and March 2020. The primary endpoint was a combined endpoint of steroid-free clinical remission, steroid-free clinical response, or clinical response at week 8. Secondary endpoints were biochemical response at week 8, as well as steroid-free clinical remission, steroid-free clinical response or clinical response at week 24, respectively, adverse events by week 24, and need for colectomy by the end of follow-up. (3) Results: Thirty-eight patients with moderate-to-severe ulcerative colitis were included. Eleven patients (28.9%) achieved steroid-free clinical remission at week 8. Fifty-three percent of the patients were primary non-responders at week 8. Three severe adverse events (pneumonia, hospitalization for aggravation of ulcerative colitis, emergency colectomy due to colon perforation), and 12 adverse events were documented by week 8 of therapy. By the end of follow-up, seven patients (18.4%) had undergone colectomy.

Download Full-text

P662 Efficacy and safety of tofacitinib in patients with moderate-to-severe ulcerative colitis: A real-world retrospective study

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.790 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S545-S545

Author(s):

N Yoshimura ◽

Soh Okano ◽

Minako Sako ◽

Masakazu Takazoe

Keyword(s):

Ulcerative Colitis ◽

Total Cholesterol ◽

Clinical Response ◽

Clinical Remission ◽

Janus Kinase ◽

Remission Induction ◽

Efficacy And Safety ◽

Response Level ◽

Severe Ulcerative Colitis ◽

Mayo Score

Abstract Background Tofacitinib is an orally active, small-molecule Janus kinase inhibitor, recently approved for the treatment of moderate to severe ulcerative colitis (UC) refractory to corticosteroid. However, currently, there is inadequate evidence for efficacy of Tofacitinib in UC patients. Therefore, our objective was to evaluate the efficacy and safety of Tofacitinib for inducing and maintaining remission in UC patients. Methods In a single-centre retrospective setting, 71 consecutive patients with UC who had failed to respond to corticosteroid or biologics were included. All patients had received 10mg Tofacitinib orally twice daily for at least 8 weeks as remission induction therapy and then, the responders received 5mg twice daily as maintenance therapy for up to 26 weeks. The clinical response and adverse events were evaluated at weeks 8 (induction) and 26 (maintenance). UC activity was assessed by the partial Mayo score. Clinical remission was defined as p-Mayo score ≤1 and the bleeding subscore = 0. Clinical response was defined as p-Mayo score ≤4 and a decrease of ≥3 points relative to baseline. Furthermore, the cumulative remission rates up to 26 weeks were determined by the Kaplan–Meier survival analysis. Results At week 8, 24 of 71 patients (33.8%) achieved clinical remission and 20 (28.2%) achieved response level. The mean p-Mayo score fell from 5.8 ± 1.1 at entry to 3.5 ± 2.3 at week 2 (p < 0.01) and 2.3 ± 1.9 at week 8 (P<0.01). The average total cholesterol increased from 180.8 ± 36.0 mg/dl at entry to 206.8±39.3 mg/dl (p < 0.01). In anti-tumour necrosis factor (TNF)-α or vedolizumab (VDZ) naïve subgroup (n = 14), 8 patients (57.1%) achieved response level, while in biologic failure subgroup (n = 57), 36 patients (63.2%) achieved response level. In single biologic failure subgroup (n = 27), 19 patients (70.4%), in double biologics failure subgroup, 14 of 24 patients (58.3%), and in 3 biologics failure subgroup, 3 of 6 patients (50.0%) achieved response level, showing a decrease in the efficacy of Tofacitinib in patients who had failed more than one biologic. Furthermore, of the 25 patients followed for 26 weeks, 23 (92.0%) sustained remission at week 16 and 19 (76.0%) at week 26. Herpes virus infection occurred in 4 patients. The increase in total cholesterol was observed in 68.8% of the patients. Conclusion Our retrospective efficacy assessment indicated that Tofacitinib was effective and safe for inducing and maintaining remission in corticosteroid refractory UC patients, regardless of biologic naïve or failure background. The efficacy of 10mg twice daily was rapid and observed within 2 weeks of starting the treatment.

Download Full-text

DOP69 Ozanimod for induction treatment of Moderate-to-Severe Ulcerative Colitis: Results from a systematic literature review and network meta-analyses

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjab073.108 ◽

2021 ◽

Vol 15 (Supplement_1) ◽

pp. S103-S105

Author(s):

K Eaton ◽

C Duperrouzel ◽

P Bhandari ◽

S Craigie ◽

A Bonner ◽

...

Keyword(s):

Ulcerative Colitis ◽

Literature Review ◽

Clinical Response ◽

Systematic Literature Review ◽

Clinical Remission ◽

Similar Efficacy ◽

Induction Treatment ◽

Induction Phase ◽

Severe Ulcerative Colitis ◽

Meta Analyses

Abstract Background Ozanimod (OZA) is an orally administered, selective sphingosine-1-phosphate receptor modulator that has been evaluated versus placebo (PBO) in the phase 3 True North trial in the treatment of adult patients with moderate-to-severe ulcerative colitis (UC). The objective of this study was to compare the relative efficacy of OZA versus other approved moderate-to-severe UC therapies via network meta-analyses (NMA). Methods A systematic literature review was conducted to identify randomised clinical trials published from Jan 1, 2000 to Oct 21, 2020 that evaluated biological therapies (infliximab [IFX], adalimumab [ADA], golimumab [GOL], vedolizumab [VEDO], and ustekinumab [UST]) or an oral small molecule (tofacitinib [TOF]) for adults with moderate-to-severe UC. Bayesian NMAs were performed to determine the comparative efficacy of these therapies based on clinical remission, clinical response, and endoscopic improvement in the induction phase (6 to 14 weeks). Three populations were considered: all patients (overall), first-line (biologic-naïve), or those with exposure to or failure of prior biologic therapy (biologic-experienced). All six comparator therapies were included in the overall and biologic-naive populations, whereas the biologic-experienced population included ADA, VEDO, UST, and TOF due to lack of biologic-experienced data for IFX and GOL. Results Twenty-two RCTs examining 10,269 patients in the induction phase were included (Figure 1). All therapies offered significant improvement over PBO across networks apart from ADA in the analysis of clinical remission and clinical response in the biologic-experienced population and ADA, VEDO, and OZA in the analysis of endoscopic improvement in the biologic-experienced population. In the overall and biologic-naïve populations, OZA offered similar efficacy to all other therapies across endpoints except for a significant improvement in endoscopic improvement over ADA (overall: OR 2.01, 95% CrI 1.14, 3.66 [Figure 2]; biologic-naïve: OR 2.13, 95% CrI 1.02, 4.50 [Figure 3]). OZA also offered similar efficacy to all other therapies across endpoints in the biologic-experienced population except for an improvement in clinical remission (OR 4.16, 95% CrI 1.55, 11.24) and clinical response (OR 3.11, 95% CrI 1.40, 7.08) over ADA (Figure 4). Conclusion This NMA suggests that OZA provides similar induction efficacy on clinical remission, clinical response, and endoscopic improvement versus other approved moderate-to-severe UC therapies regardless of prior biologic treatment status.

Download Full-text