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1.
Artigo em Inglês | MEDLINE | ID: mdl-31676360

RESUMO

In the last decade, several new therapies with different mechanisms of action have been approved for the management of moderate to severe Crohn's disease (CD). However, there is limited guidance on optimal positioning of agents as first- or second-line therapies due to the absence of head-to-head trials. Furthermore, given the lack of comparative studies, treatment guidelines provide limited insight. In this review, we will discuss data on key treatment attributes, comparative efficacy and safety, factors predictive of response to each agent and propose an algorithm for positioning therapies for the management of patients with low-risk and high-risk CD.

2.
Gastroenterology ; 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31711921

RESUMO

BACKGROUND AND AIMS: Etrasimod (APD334) is an oral, selective sphingosine 1-phosphate receptor modulator in development for immune-mediated inflammatory disorders. We assessed the efficacy and safety of etrasimod in patients with moderately to severely active ulcerative colitis (UC). METHODS: In a phase 2, proof of concept, double-blind, parallel-group study, adult outpatients with modified Mayo Clinic scores (MCSs; stool frequency, rectal bleeding, and endoscopy findings) of 4-9, endoscopic subscores of 2 or more, and rectal bleeding subscores of 1 or more were randomly assigned to groups given once-daily etrasimod 1 mg (n=52), etrasimod 2 mg (n=50), or placebo (n=54) for 12 weeks. The study was performed from October 15, 2015 through February 14, 2018 at 87 centers in 17 countries. The primary endpoint was an increase in the mean improvement in modified MCS from baseline to week 12. Secondary endpoints included the proportion of patients with endoscopic improvement (subscores of 1 or less) from baseline to week 12. Exploratory endpoints, including clinical remission, are reported in the manuscript, although the study was only statistically powered to draw conclusions on the primary endpoint. RESULTS: At week 12, the etrasimod 2 mg group met the primary and all secondary endpoints. Etrasimod 2 mg led to a significantly greater increase in mean improvement in modified MCS from baseline than placebo (difference from placebo, 0.99 points; 90% CI, 0.30-1.68; P=.009), and etrasimod 1 mg led to an increase in mean improvement from baseline in modified MCS of 0.43 points more than placebo (90% CI, reduction of 0.24 to increase of 1.11; nominal P=.15). Endoscopic improvement occurred in 41.8% of patients receiving etrasimod 2 mg vs 17.8% receiving placebo (P=.003). Most adverse events were mild to moderate. Three patients had a transient, asymptomatic, low-grade atrioventricular block that resolved spontaneously and did not recur with further dosing; 2 of the 3 patients had evidence of atrioventricular block prior to etrasimod exposure. CONCLUSIONS: In patients with moderately to severely active UC, etrasimod 2 mg was more effective than placebo in producing clinical and endoscopic improvements. Further clinical development is warranted. Clinicaltrials.gov no: NCT02447302.

3.
Gastroenterology ; 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31711925

RESUMO

BACKGROUND & AIMS: Non-invasive tests to measure endoscopic activity in patients with Crohn's disease (CD) have limitations. We aimed to develop a test to identify patients in remission, based on endoscopic analysis, and monitor CD activity based on serum levels of proteins. METHODS: We developed a test to measure 13 proteins in blood (ANG1, ANG2, CRP, SAA1, IL7, EMMPRIN, MMP1, MMP2, MMP3, MMP9, TGFA, CEACAM1, and VCAM1), called the endoscopic healing index [EHI] using samples from 278 patients with CD from multi-national training cohort. We validated the test using 2 independent cohorts of patients with CD: 116 biologic-naïve patients with early-stage CD (validation cohort 1) and 195 biologic-exposed patients with chronic CD (validation cohort 2). The ability of the test to identify patients with active disease vs patients in remission (defined as a simple endoscopic score for CD of ≤ 2 and ≤ 1 in each segment, or a total CD endoscopic index of severity score < 3) was assessed using area under receiver operating characteristic curve (AUROC) analysis. The diagnostic accuracy of the test was compared with that of measurement of serum CRP and fecal calprotectin (FC). RESULTS: The EHI scores range from 0 to 100 units; higher scores indicate more severe CD activity, based on endoscopy findings. The EHI identified patients in remission with an AUROC of 0.962 in validation cohort 1 (95% CI, 0.942-0.982) and an AUROC of 0.693 in validation cohort 2 (95% CI, 0.619-0.767), regardless of CD location or phenotype. A cut-off value of 20 points identified patients in remission with the highest level of sensitivity (97.1% in validation cohort 1 and 83.2% in validation cohort 2), with specificity values of 69.0% and 36.6%, respectively. A cut-off value of 50 points identified patients in remission with the highest level of specificity (100% in validation cohort 1 and 87.8% in validation cohort 2), with sensitivity values of 37.3% and 30.0%, respectively. The EHI identified patients in remission with a significantly higher AUROC value than the test for CRP (0.876, P<.001 in validation cohort 1 and 0.624, P=.109 in validation cohort 2). In analysis of patients with available FC measurements, the AUROC value for the EHI did not differ significantly from that of measurement of FC (AUROC, 0.950 for EHI vs AUROC, 0.923 for FC, P=.147 in validation cohort 1 and AUROC, 0.803 for EHI vs AUROC, 0.854 for FC, P=.298 in validation cohort 2). CONCLUSIONS: We developed an index to identify patients with CD in endoscopic remission based on blood levels of 13 proteins, called the EHI. The EHI identified patients with resolution of endoscopic disease activity, with good overall accuracy, although with variation between the 2 cohorts assessed. The EHI AUROC values were comparable to measurement of FC and higher than measurement of serum CRP. The test might be used in practice for assessing endoscopic activity in patients with CD.

4.
Inflamm Bowel Dis ; 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31748806

RESUMO

BACKGROUND: Longer disease duration is associated with inferior response to biologic therapy in Crohn's disease. However, the effect of disease duration on response to biologic therapy in ulcerative colitis (UC) has not been well studied. METHODS: In a single-center retrospective cohort study of outpatients with UC starting a biologic agent, we evaluated treatment response by disease duration. The primary outcome was treatment failure (composite outcome of inflammatory bowel disease [IBD]-related surgery/hospitalization or treatment modification including dose escalation, treatment discontinuation, or addition of corticosteroids); secondary outcomes were risk of IBD-related surgery/hospitalization and endoscopic remission. We conducted multivariate Cox proportional hazard analyses to evaluate the independent impact of disease duration on clinical outcomes. RESULTS: We included 160 biologic-treated UC patients (73% biologic-naïve) with a median age (interquartile range) of 36 (26-52) years and disease duration (range) of 4.5 (1-9) years. After adjusting for immunosuppressive medications, albumin, and body mass index, each 1-year increase in disease duration was associated with a 5% lower risk of treatment failure (adjusted hazard ratio, 0.95; 95% confidence interval [CI], 0.91-0.99) and a 9% higher risk of achieving endoscopic remission (adjusted odds ratio, 1.09; 95% CI, 1.01-1.18). This association of short disease duration with treatment failure was observed only in biologic-naïve patients, but not biologic-experienced patients. No significant association was seen between disease duration and risk of surgery or hospitalization. CONCLUSION: Shorter disease duration is independently associated with increased risk of treatment failure in biologic-treated patients with UC. Requirement of biologic therapy early in the course of disease may be a negative prognostic marker in patients with UC.

5.
Genome Biol ; 20(1): 226, 2019 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-31672156

RESUMO

As metagenomic studies move to increasing numbers of samples, communities like the human gut may benefit more from the assembly of abundant microbes in many samples, rather than the exhaustive assembly of fewer samples. We term this approach leaderboard metagenome sequencing. To explore protocol optimization for leaderboard metagenomics in real samples, we introduce a benchmark of library prep and sequencing using internal references generated by synthetic long-read technology, allowing us to evaluate high-throughput library preparation methods against gold-standard reference genomes derived from the samples themselves. We introduce a low-cost protocol for high-throughput library preparation and sequencing.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31755121

RESUMO

BACKGROUND: 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. AIM: To quantify the prevalence of endoscopic improvement and remission amongst ulcerative colitis patients with various permutations of patient-reported outcomes. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

7.
Artigo em Inglês | MEDLINE | ID: mdl-31660640

RESUMO

BACKGROUND: 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. AIMS: To assess the efficacy and safety of tofacitinib dose de-escalation and escalation in patients with UC. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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).

8.
Aliment Pharmacol Ther ; 50(10): 1068-1076, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31599001

RESUMO

BACKGROUND: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). AIM: To report incidence of deep vein thrombosis (DVT) and pulmonary embolism (PE) in the tofacitinib UC programme. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

9.
Inflamm Bowel Dis ; 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31644790

RESUMO

BACKGROUND: The Crohn's Disease Activity Index (CDAI) has been criticized for being weakly correlated with bowel inflammation. We assessed correlation between Simple Endoscopic Score for Crohn's Disease (SES-CD) and individual CDAI items stratified by disease location to better understand this relationship. METHODS: We pooled patient-level data from 3 placebo-controlled Crohn's disease (CD) trials that tested adalimumab, upadacitinib, and risankizumab. Disease location was defined as ileum only, colon only, or ileocolonic based upon colonoscopy at study entry. Pearson correlation coefficients and linear regression assessed correlations between items of the CDAI and SES-CD. RESULTS: A total of 353 patients were included (20.7% ileal, 30.6% colonic, 48.7% ileocolonic disease). Crohn's Disease Activity Index and SES-CD scores were moderately correlated (R = 0.33; P < 0.001). Among CDAI items, the strongest correlations with SES-CD were seen with very soft or liquid stool frequency (SF) and patient-reported outcome 2 (PRO2; which includes SF and abdominal pain score; both R = 0.36; P < 0.001); these correlations were numerically stronger in colonic disease (SF: R = 0.46; P < 0.001; PRO2: R = 0.44; P < 0.001) than in ileal disease (SF: R = 0.14; P = 0.23; PRO2: R = 0.21; P = 0.07), although a test for interaction was not significant. In adjusted linear regression models, the proportion of mucosa that was inflamed and the proportion of mucosa with ulceration were positively correlated, whereas the presence of strictures was inversely correlated with SF. CONCLUSIONS: The SF item of the CDAI is moderately correlated with SES-CD and independently correlated with mucosal ulceration, inflammation, and strictures. Understanding why bowel inflammation as measured endoscopically does not correlate more strongly with patients' symptoms could help develop scales that link CD pathology to patient experience.

10.
Gastroenterology ; 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31593701

RESUMO

Since 2010, substantial progress has been made in artificial intelligence (AI) and its application to medicine. AI is explored in gastroenterology for endoscopic analysis of lesions, in detection of cancer, and to facilitate the analysis of inflammatory lesions or gastrointestinal bleeding during wireless capsule endoscopy. AI is also tested to assess liver fibrosis and to differentiate patients with pancreatic cancer from those with pancreatitis. AI might also be used to establish prognoses of patients or predict their response to treatments, based on multiple factors. We review the ways in which AI may help physicians make a diagnosis or establish a prognosis and discuss its limitations, knowing that further randomized controlled studies will be required before the approval of AI techniques by the health authorities.

11.
N Engl J Med ; 381(13): 1201-1214, 2019 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-31553833

RESUMO

BACKGROUND: The efficacy of ustekinumab, an antagonist of the p40 subunit of interleukin-12 and interleukin-23, as induction and maintenance therapy in patients with ulcerative colitis is unknown. METHODS: We evaluated ustekinumab as 8-week induction therapy and 44-week maintenance therapy in patients with moderate-to-severe ulcerative colitis. A total of 961 patients were randomly assigned to receive an intravenous induction dose of ustekinumab (either 130 mg [320 patients] or a weight-range-based dose that approximated 6 mg per kilogram of body weight [322]) or placebo (319). Patients who had a response to induction therapy 8 weeks after administration of intravenous ustekinumab were randomly assigned again to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 12 weeks [172 patients] or every 8 weeks [176]) or placebo (175). The primary end point in the induction trial (week 8) and the maintenance trial (week 44) was clinical remission (defined as a total score of ≤2 on the Mayo scale [range, 0 to 12, with higher scores indicating more severe disease] and no subscore >1 [range, 0 to 3] on any of the four Mayo scale components). RESULTS: The percentage of patients who had clinical remission at week 8 among patients who received intravenous ustekinumab at a dose of 130 mg (15.6%) or 6 mg per kilogram (15.5%) was significantly higher than that among patients who received placebo (5.3%) (P<0.001 for both comparisons). Among patients who had a response to induction therapy with ustekinumab and underwent a second randomization, the percentage of patients who had clinical remission at week 44 was significantly higher among patients assigned to 90 mg of subcutaneous ustekinumab every 12 weeks (38.4%) or every 8 weeks (43.8%) than among those assigned to placebo (24.0%) (P = 0.002 and P<0.001, respectively). The incidence of serious adverse events with ustekinumab was similar to that with placebo. Through 52 weeks of exposure, there were two deaths (one each from acute respiratory distress syndrome and hemorrhage from esophageal varices) and seven cases of cancer (one each of prostate, colon, renal papillary, and rectal cancer and three nonmelanoma skin cancers) among 825 patients who received ustekinumab and no deaths and one case of cancer (testicular cancer) among 319 patients who received placebo. CONCLUSIONS: Ustekinumab was more effective than placebo for inducing and maintaining remission in patients with moderate-to-severe ulcerative colitis. (Funded by Janssen Research and Development; UNIFI ClinicalTrials.gov number, NCT02407236.).


Assuntos
Anti-Inflamatórios/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Ustekinumab/uso terapêutico , Adulto , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Quimioterapia de Indução , Infusões Intravenosas , Injeções Subcutâneas , Quimioterapia de Manutenção , Masculino , Gravidade do Paciente , Indução de Remissão/métodos , Ustekinumab/administração & dosagem , Ustekinumab/efeitos adversos
12.
Artigo em Inglês | MEDLINE | ID: mdl-31546056

RESUMO

BACKGROUND & AIMS: Little is known about the association between rectal bleeding and increased stool frequency with endoscopic findings in patients with mild to moderate ulcerative colitis (UC). We evaluated the associations between rectal bleeding or stool frequency and endoscopic remission in this population. METHODS: We performed a post-hoc analysis of data from a phase 3 non-inferiority trial of 817 adults with mild to moderate UC who received treatment with mesalazine. We obtained information on rectal bleeding, stool frequency, and Mayo endoscopic subscores (MESs) at weeks 0, 8, and 38. The sensitivity, specificity, and positive and negative predictive values with which rectal bleeding and stool frequency identified patients with MESs of 0 and/or 1 were calculated at weeks 8 and 38 of treatment. The associations between change in rectal bleeding and stool frequency and change in MES after treatment were quantified using the Spearman's rank correlation coefficient. RESULTS: Among patients with a MES of 0, 7/82 patients (9%) had a rectal bleeding score of 1 or more and 40/82 patients (49%) had a stool frequency score of 1 or more at week 8; at week 38, 6/167 patients (4%) had a rectal bleeding score of 1 or more and 63/167 patients (38%) had a stool frequency score of 1 or more. Among patients with MESs of 0 or 1, 50/310 patients (16%) had a rectal bleeding score of 1 or more and 162/310 patients (52%) had had a stool frequency score of 1 or more at week 8; at week 38, 18/363 patients (5%) had a rectal bleeding score of 1 or more and 141/363 patients (39%) had a stool frequency score of 1 or more. The Spearman rank correlation coefficients for change in rectal bleeding and stool frequency with change in MES at week 8 were 0.39 (95% CI, 0.32-0.45) and 0.34 (95% CI, 0.27-0.40), respectively. In patients with reduced MESs at week 8, 39/389 patients (10%) had unchanged or worsening rectal bleeding and 81/389 patients (21%) had unchanged or increasing stool frequencies. CONCLUSIONS: In a post-hoc analysis of data from a phase 3 trial of adults with mild to moderate UC treated with mesalazine, we found absence of rectal bleeding to identify patients in endoscopic remission. However, many patients in remission still have increased stool frequency, indicating that it may not be a sensitive marker of disease activity in patients with mild to moderate UC.

13.
Aliment Pharmacol Ther ; 50(8): 848-857, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31483522

RESUMO

BACKGROUND: There has been limited evaluation of the association between vedolizumab trough concentration and clinical outcomes in patients with inflammatory bowel diseases (IBD). AIM: To perform a systematic review and meta-analysis to evaluate the potential role of therapeutic drug monitoring (TDM) for vedolizumab. METHODS: Through a systematic literature search through 28 February 2019, we identified five cohort studies (558 patients, 42% with ulcerative colitis) reporting the association between vedolizumab trough concentration and clinical outcomes in patients with IBD. We calculated mean difference (MD) in vedolizumab trough concentration in patients achieving vs not achieving clinical outcomes, and qualitatively synthesized thresholds associated with favourable outcomes. RESULTS: In patients with UC, median vedolizumab trough concentrations were consistently higher in patients achieving clinical remission (median, 14.3 µg/mL vs 10.5 µg/mL; MD, 5.1 µg/mL, 95% CI, 2.8-7.4) or endoscopic remission (median, 13.0 µg/mL vs 9.7; MD, 5.1 µg/mL, 95% CI, 2.2-7.9). In patients with CD, there was no significant difference in median vedolizumab trough concentrations in patients achieving vs not achieving clinical remission (MD, 2.0 µg/mL; 95% CI, -0.5 to 4.5) or endoscopic remission (MD, 3.6 µg/mL; 95% CI, -1.4 to 8.6). In patients with UC, week 6 vedolizumab trough concentrations ≥18.5-20.8 µg/mL, and maintenance trough concentrations ≥9.0-12.6 µg/mL were associated with favourable clinical outcomes. Antibodies to vedolizumab were reported in 1.7%-3.0% patients on maintenance therapy. CONCLUSION: Based on meta-analysis, patients with UC who achieve endoscopic and clinical remission have significantly higher vedolizumab trough concentration during maintenance therapy. Vedolizumab trough concentration >20 µg/mL at week 6, and >12 µg/mL during maintenance may be associated with better outcomes, though cause-effect relationship remains unclear. Prospective studies on reactive and proactive therapeutic drug monitoring of vedolizumab (vs empiric dose escalation) are warranted.

14.
Gastroenterology ; 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31493397

RESUMO

BACKGROUND & AIMS: Interleukin 23 (IL23) contributes to pathogenesis of ulcerative colitis (UC). We investigated the effects of mirikizumab, a monoclonal antibody against the p19 subunit of IL23, in a phase 2 study of patients with UC. METHODS: We performed a trial of the efficacy and safety of mirikizumab in patients with moderate to severely active UC, enrolling patients from 14 countries from January 2016 through September 2017. Patients were randomly assigned to groups given intravenous placebo (n=63), mirikizumab 50 mg (n=63) or 200 mg (n=62) with exposure-based dosing, or mirikizumab 60 mg with fixed dosing (n=61), at weeks 0, 4, and 8. Of assigned patients, 63% had prior exposure to a biologic agent. Clinical responders (decrease in 9-point Mayo score, including ≥2 points and ≥35% from baseline with either a decrease of rectal bleeding subscore of ≥1 or a rectal bleeding subscore of 0 or 1) at week 12 who had received mirikizumab were randomly assigned to groups that received maintenance treatment with mirikizumab 200 mg subcutaneously every 4 weeks (n=47) or every 12 weeks (n=46). The primary endpoint was clinical remission (Mayo subscores of 0 for rectal bleeding, with 1-point decrease from baseline for stool frequency, and 0 or 1 for endoscopy) at week 12. A multiple testing procedure was used that began with the 600-mg dose group, and any non-significant comparison result ended the formal statistical testing procedure. RESULTS: At week 12, 15.9% (P=.066), 22.6% (P=.004), and 11.5% (P=.142) of patients in the 50-mg, 200-mg, and 600-mg groups achieved clinical remission, respectively, compared with 4.8% of patients given placebo. The primary endpoint was not significant (comparison to 600 mg, P>.05). Clinical responses occurred in 41.3% (P=.014), 59.7% (P<.001), and 49.2% (P=.001) of patients in the 50-mg, 200-mg, and 600-mg groups, respectively, compared to 20.6% of patients given placebo. At week 52, 46.8% of patients given subcutaneous mirikizumab 200 mg every 4 weeks and 37.0% given subcutaneous mirikizumab 200 mg every 12 weeks were in clinical remission. CONCLUSIONS: In a randomized trial of patients with UC, mirikizumab was effective in inducing a clinical response after 12 weeks. Additional studies are required to determine the optimal dose for induction of remission. Mirikizumab demonstrated durable efficacy throughout the maintenance period. Clinicaltrials.gov no: NCT02589665.

15.
Inflamm Bowel Dis ; 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31504528

RESUMO

BACKGROUND: We summarized the protocol-specified corticosteroid tapering regimens in clinical trials of moderate-severe ulcerative colitis (UC) and Crohn's disease (CD) and calculated differences in rates of clinical remission vs corticosteroid-free clinical remission (CSF-CR). METHODS: Through a systematic literature review through February 28, 2019, we identified 16 randomized controlled trials (RCTs) of biologics or small molecules in patients with moderate-severe UC or CD who reported CSF-CR as an outcome. We estimated the relative risk and 95% confidence interval of achieving CSF-CR vs overall clinical remission in patients treated with active intervention or placebo through random-effects meta-analysis. RESULTS: Across trials of UC (11 trials) and CD (5 trials), a median of 53% and 49% of participants were on corticosteroids at the time of trial entry, respectively. Participants were allowed to enter trials at a median corticosteroid dose (range) of 35 (20-40) mg/d. Doses were kept stable for a median (range) of 8 (5-10) weeks during induction therapy, after which a mandatory and structured taper was implemented, albeit with the investigators' discretion depending on clinical status. Pooled rates of CSF-CR in patients with UC and CD treated with placebo were 9.7% and 19.1%, respectively. In UC and CD trials, the rate of CSF-CR was 24% and 18% lower than the rate of overall clinical remission, respectively. CONCLUSIONS: Protocol-specified corticosteroid tapering regimens vary across trials. These findings will help to inform the design and interpretation of future clinical trials and highlight the need for standardization.

16.
Artigo em Inglês | MEDLINE | ID: mdl-31473359

RESUMO

Endoscopic evaluation for postoperative recurrence of Crohn's disease (CD) is routinely integrated into clinical practice. The Rutgeerts score (RS) was developed to grade the severity of endoscopic postoperative CD recurrence and has been integrated into clinical practice guidelines and utilized as an endpoint in interventional trials.1,2 However, the operating properties of the RS have not been fully assessed. Furthermore, the RS i2 grade groups purely anastomotic ulcerations with those in the neoterminal ileum, whereas the modified Endoscopic Postoperative Recurrence Score (mEPRS) distinguishes lesions limited to the ileocolic anastomosis (i2a) from those in the neoterminal ileum (i2b). Accurate characterization of endoscopic recurrence is an important determinant for initiating postoperative medical therapy. Therefore, variability in endoscopic scoring may result in inappropriate therapeutic decisions.3 We evaluated the reliability of endoscopic assessment of postoperative CD recurrence among independent blinded central readers.

17.
Artigo em Inglês | MEDLINE | ID: mdl-31470176

RESUMO

BACKGROUND & AIMS: We investigated 30- and 90-day rates and causes of, risk factors for, and interventions to reduce hospital readmission in patients who received medical treatment for inflammatory bowel diseases (IBD). METHODS: We performed a systematic search of publications through July 1, 2018 for studies of rates of hospital readmission and associated causes and risk factors in patients who received medical treatments for IBD. Our final analysis included 17 cohort studies (6324 patients) of hospitalized adults with IBD who had received medical treatment, along with reported readmission rates with detailed chart review. We performed random effects meta-analysis to estimate 30- and 90-day rates of readmission and identified causes and risk factors associated with readmission. We also performed qualitative analyses of studies that focused on interventions to reduce readmission. RESULTS: Overall, the 30-day rate of readmission was 18.1% (95% CI, 14.4-22.4) and the 90-day rate was 26.0% (95% CI, 22.7-29.6). On meta-regression, studies with higher proportions of patients with ulcerative colitis than Crohn's disease reported higher risks for readmission. Most common reasons for readmission were IBD flare, infection, or complications from unplanned surgeries during hospitalizations. Consistent risk factors for 30-day readmission were admission for pain control (odds ratio [OR], 2.27; 95% CI, 1.69-3.03), need for total parenteral nutrition on discharge (OR, 2.13; 95% CI, 1.36-3.35), and prior or unplanned surgery during admission (OR, 3.11; 95% CI, 2.27-4.25). Only 1 study focused on interventions (specialized inpatient IBD service) to reduce risk of readmission. CONCLUSIONS: Overall 30- and 90-day rates of readmission for patients who received medical treatment for IBD are 18.1% and 26.0%, respectively. IBD flares and infections are common reasons for readmission, and inadequate pain control and need for parenteral nutrition were common risk factors. Interventional studies to reduce risk of readmission are needed.

18.
Artigo em Inglês | MEDLINE | ID: mdl-31442599

RESUMO

BACKGROUND & AIMS: Endoscopy is used to measure activity of Crohn's disease (CD) and determine eligibility and outcomes of participants in randomized controlled trials of therapeutic agents. We aimed to estimate the rate of response to placebo in trials, based on endoscopic evaluation of CD activity, and identify factors that affect this response. METHODS: We collected patient-level data from randomized, double-blind, placebo-controlled trials of therapeutic agents for CD that included centrally-read endoscopic assessments with validated scoring indices. We analyzed data from induction trials of eldelumab, filgotinib, risankizumab, and ustekinumab (from 188 patients given placebo). The primary outcome was the rate of response to placebo, based on endoscopic assessment of CD activity (>50% reduction in the simple endoscopic score for CD). Rate of remission rate, based on endoscopic score, was a secondary outcome. Overall rates of response to placebo were calculated using the inverse variance-weighted average method and presented with 95% CIs. We performed a multi-variable meta-regression analysis to identify determinants of response to placebo, determined endoscopically, using patient-level data from the filgotinib and ustekinumab trials. RESULTS: The pooled rate of response among patients given placebo was 16.2% (95% CI, 10.5%-22.0%) and the rate of remission in this group was 5.2% (95% CI, 1.7%-8.8%). Prior exposure to tumor necrosis factor antagonists (odds ratio, 0.31; 95% CI, 0.10-0.93; P=.036) and increased concentration of C-reactive protein at baseline (odds ratio, 0.93; 95% CI, 0.87-0.98; P=.014 per 10 mg/L increase) were independently associated with lower rates of response to placebo. CONCLUSIONS: Rates of response and remission to placebo, determined by centrally-read endoscopy, in induction trials of therapies for CD are low. These estimates are important for sample size calculations for randomized placebo-controlled trials that use the Simple Endoscopic Score for CD as an endpoint. They also provide a benchmark to interpret findings from non-placebo controlled, prospective, randomized, unblinded trials.

19.
Gastroenterology ; 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31470005

RESUMO

BACKGROUND & AIMS: Maintenance treatment with vedolizumab, a monoclonal antibody that inhibits the gut-selective α4ß7 integrin, is administered intravenously. Some patients might prefer a subcutaneous formulation of vedolizumab for maintenance treatment. Subcutaneous vedolizumab was investigated as maintenance treatment in patients with moderately to severely active ulcerative colitis. METHODS: We performed a phase 3, double-blind, double-dummy trial at 141 sites in 29 countries from December 18, 2015 through August 21, 2018. Patients with moderately to severely active ulcerative colitis received open-label treatment with intravenous vedolizumab 300 mg at weeks 0 and 2. At week 6, patients with clinical response were randomly assigned maintenance treatment with subcutaneous vedolizumab (108 mg) every 2 weeks, intravenous vedolizumab 300 mg every 8 weeks, or placebo. The primary end point was clinical remission at week 52, which was defined as a total Mayo score of ≤2 or lower and no subscore >1. RESULTS: Among 216 patients randomly assigned to groups, clinical remission at week 52 was achieved by 46.2%, 42.6%, and 14.3% of patients in the subcutaneous vedolizumab, intravenous vedolizumab, and placebo groups, respectively (subcutaneous vedolizumab vs placebo: Δ32.3%; 95% confidence interval, 19.7%-45.0%; P < .001). The subcutaneous vedolizumab group also had greater endoscopic improvement and durable clinical response at week 52 compared with placebo (both P < .001). The incidence of injection-site reactions was more frequent in patients given subcutaneous vedolizumab (10.4%) than intravenous vedolizumab (1.9%) or placebo (0%); these were not treatment limiting, most were mild, and none resulted in discontinuation. Subcutaneous and intravenous vedolizumab safety profiles were otherwise similar. CONCLUSIONS: Subcutaneous vedolizumab is effective as maintenance therapy in patients with moderately to severely active ulcerative colitis who had a clinical response to intravenous vedolizumab induction therapy. It has a favorable safety and tolerability profile. ClinicalTrials.gov ID: NCT02611830; EudraCT 2015-000480-14.

20.
Gastroenterology ; 157(4): 1019-1031.e7, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31279870

RESUMO

BACKGROUND & AIMS: Although ustekinumab is an effective therapy for moderate to severe Crohn's disease (CD), its effects on the microscopic manifestations of CD are unknown. METHODS: We evaluated the effects of ustekinumab on histologic CD activity in an analysis of data from 251 participants in phase 3 induction and maintenance studies. Two endoscopic biopsy samples were collected at weeks 0, 8, and 44 from the ileum, splenic flexure, and rectum (18 biopsy samples from each patient). Histologic activity was assessed based on global histology activity scores (GHASs). RESULTS: At week 8, the mean GHAS was significantly reduced after ustekinumab induction treatment (from 10.4 ± 7.0 to 7.1 ± 5.9; P < .001) but not in patients who received placebo (from 9.2 ± 6.4 to 7.8 ± 6.2). At week 44 in the randomized maintenance therapy population, the mean GHAS remained reduced from week 8 in patients who received subcutaneous ustekinumab (90 mg every 8 weeks; from 7.4 ± 7.7 to 6.1 ± 4.7) but not every 12 weeks (from 5.3 ± 3.9 to 8.7 ± 4.1) or placebo (from 9.2 ± 3.8 to 10.9 ± 7.1). In the pooled (randomized and nonrandomized) maintenance therapy population, histologic improvement continued in patients given ustekinumab every 8 weeks (from 7.1 ± 6.2 to 5.2 ± 4.2; P < .0001) but not in those given ustekinumab every 12 weeks (from 6.1 ± 5.7 to 7.2 ± 5.1) or placebo (from 8.2 ± 4.2 to 8.9 ± 6.8). A significantly greater proportion of patients achieved histologic response (≥50% decrease in GHAS from baseline) at week 44 if they received ustekinumab every 8 weeks (50% in the randomized maintenance population and 54% in the pooled maintenance population) compared with every 12 weeks (17% and 39% in the randomized and pooled populations, respectively) or placebo (0% and 22% in the randomized and pooled populations, respectively) (P = .0137 for every 8 weeks vs placebo and P = .3529 for every 12 weeks vs placebo in the randomized population; P = .0168 for every 8 weeks vs placebo and P = .3069 for every 12 weeks vs placebo in the pooled population). Regional and overall mean GHASs correlated with the simple endoscopic score for CD (r = .6255, P < .0001). Multivariate analysis found an association between histologic improvement and endoscopic or histologic burden at baseline. CONCLUSIONS: In an analysis of data from participants in phase 3 induction and maintenance trials, we found histologic improvement in a greater proportion of patients given ustekinumab vs placebo. The largest improvements occurred in patients who received ustekinumab maintenance therapy every 8 weeks. ClinicalTrials.gov nos. NCT01369329, NCT01369342, and NCT01369355.


Assuntos
Anti-Inflamatórios/administração & dosagem , Doença de Crohn/tratamento farmacológico , Fármacos Gastrointestinais/administração & dosagem , Mucosa Intestinal/efeitos dos fármacos , Ustekinumab/administração & dosagem , Cicatrização/efeitos dos fármacos , Adulto , Anti-Inflamatórios/efeitos adversos , Biópsia , Doença de Crohn/patologia , Esquema de Medicação , Endoscopia Gastrointestinal , Feminino , Fármacos Gastrointestinais/efeitos adversos , Humanos , Quimioterapia de Indução , Mucosa Intestinal/patologia , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Fatores de Tempo , Resultado do Tratamento , Ustekinumab/efeitos adversos
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