Effects of Thiopurine Withdrawal on Vedolizumab-Treated Patients With Ulcerative Colitis: A Randomized Controlled Trial.

BACKGROUND & AIMS: The impact of thiopurine de-escalation while on vedolizumab versus continuing thiopurine therapy in ulcerative colitis (UC) is unclear. We aimed to determine the effect of thiopurine withdrawal for patients with UC in remission on vedolizumab. METHODS: This multicenter randomized controlled trial recruited UC patients on vedolizumab 300 mg intravenously every 8 weeks and a thiopurine. Patients in steroid-free clinical remission for ≥6 months and endoscopic remission/improvement (Mayo endoscopic subscore ≤1) were randomized 2:1 to withdraw or continue thiopurine. Primary outcome was comparing week 48 vedolizumab trough concentrations. Secondary outcomes were clinical relapse (partial Mayo score ≥3 and fecal calprotectin >150 µg/g or increase in Mayo endoscopic subscore ≥1 from baseline), fecal calprotectin remission (<150 µg/g), C-reactive protein remission (<5 mg/L), centrally read endoscopic remission (Mayo endoscopic subscore = 0), histologic remission (Nancy index = 0), histo-endoscopic remission, and adverse events. RESULTS: In total, 62 patients were randomized to continue (n = 20) or withdraw (n = 42) thiopurine. At week 48, vedolizumab trough concentrations were not significantly different between continue and withdrawal groups (14.7 µg/mL, interquartile rate [IQR], 12.3-18.5 µg/mL versus 15.9 µg/mL, IQR, 10.1-22.7 µg/mL, respectively, P = 0.36). The continue group had significantly higher fecal calprotectin remission (95.0%, 19/20 versus 71.4%, 30/42; P = .03), histologic remission (80.0%, 16/20 versus 48.6%, 18/37; P = .02), and histo-endoscopic remission (75.0%, 15/20 versus 32.4%, 12/37; P = .002) than the withdrawal group. Histologic activity (hazard ratio [HR], 15.5; 95% confidence interval [CI], 1.6-146.5; P = .02) and prior anti-tumor necrosis factor exposure (HR, 6.5; 95% CI, 1.3-33.8; P = .03) predicted clinical relapse after thiopurine withdrawal. CONCLUSIONS: Thiopurine withdrawal did not affect vedolizumab trough concentrations. However, it may increase fecal calprotectin, histologic, and histo-endoscopic activity. Histologic activity and prior anti-tumor necrosis factor exposure may predict disease relapse on thiopurine withdrawal for patients using vedolizumab for UC. Australian and New Zealand Trial Registry, number ACTRN12618000812291.

Vedolizumab and Ustekinumab Levels in Pregnant Women With Inflammatory Bowel Disease and Infants Exposed In Utero.

BACKGROUND & AIMS: Vedolizumab and ustekinumab pharmacokinetics in pregnancy and the infant after in utero exposure remain incompletely defined. We aim to define the antenatal stability of ustekinumab and vedolizumab levels and the time at which infant drug levels become undetectable. METHODS: This multicenter prospective observational cohort study recruited pregnant or preconception women with inflammatory bowel disease receiving vedolizumab or ustekinumab. Trough drug levels, clinical data, and biochemical data were documented preconception, during each trimester of pregnancy, and postpartum. Maternal and cord blood drug levels were measured at delivery and in infants until undetectable. Infant outcomes were assessed until 2 years of age. RESULTS: A total of 102 participants (vedolizumab, n = 58) were included. The majority of mothers were, and remained, in clinical and biochemical remission. Maternal vedolizumab levels decreased over the course of pregnancy in association with increasing weight, rather than increasing gestation. Maternal ustekinumab levels remained stable. The median time to drug becoming undetectable in the infant was shorter for vedolizumab (11 wk; range, 5-19 wk; n = 32) than ustekinumab (14 wk; range, 9-36 wk; n = 17) and correlated positively with infant delivery level. Thirty-two of 41 (88%) and 17 of 30 (67%) vedolizumab- and ustekinumab-exposed infants had undetectable drug levels by 15 weeks of age, respectively. Pregnancy and infant outcomes were favorable. Twenty infants with undetectable drug levels received the rotavirus vaccine, with no adverse reactions reported. CONCLUSIONS: Maternal vedolizumab levels decreased, whereas ustekinumab levels remained stable over the course of pregnancy. Most vedolizumab- and approximately half of ustekinumab-exposed infants had undetectable drug levels by 15 weeks of age. No concerning maternal or infant safety signals were identified.

Upadacitinib Salvage Therapy for Infliximab-Experienced Patients with Acute Severe Ulcerative Colitis.

BACKGROUND AND AIMS: Acute severe ulcerative colitis [ASUC] is a medical emergency treated with intravenous steroids followed by infliximab or cyclosporin in the case of steroid failure with emergent colectomy required in refractory or severe cases. Case series have reported on the effectiveness of tofacitinib for refractory disease, but data regarding the effectiveness of upadacitinib in this setting have not been previously reported. We describe the use of upadacitinib therapy for steroid-refractory ASUC in patients with prior loss of response to infliximab. METHODS: Six patients who received upadacitinib for steroid-refractory ASUC were identified at two Australian tertiary inflammatory bowel disease centres. Patients were followed for up to 16 weeks after discharge with clinical, biochemical and intestinal ultrasound [IUS] outcomes. RESULTS: All six patients demonstrated clinical response to upadacitinib induction during their inpatient admission. Four patients achieved corticosteroid-free clinical remission by week 8, including complete resolution of rectal bleeding and transmural healing assessed by IUS, and sustained clinical remission at week 16. One patient proceeded to colectomy at week 15 due to refractory disease. No adverse events directly attributable to upadacitinib were identified. CONCLUSIONS: Upadacitinib may have a role as a safe and effective salvage therapy for steroid-refractory ASUC in patients who have previously failed to respond to infliximab therapy. Prospective studies are required to determine the safety and efficacy of upadacitinib use in this setting before routine use can be recommended.

Comprehensive systematic review and pooled analysis of real-world studies evaluating immunomodulator and biologic therapies for chronic pouchitis treatment.

Background and Aim: Pouchitis is a common complication after restorative ileal pouch-anal anastomosis following proctocolectomy for ulcerative colitis. Antibiotic-dependent or antibiotic-refractory chronic pouchitis (CP), which is a common cause of pouch failure affecting 15-20% of patients, is challenging to treat. The efficacy of second-line immunomodulator and biologic therapy remains poorly defined. We present a pooled analysis of real-world efficacy data from peer-reviewed full-text manuscripts, focusing on immunomodulator and biologic therapies in CP. Methods: Embase and PubMed databases were searched for full-text articles describing the treatment of CP. We performed a systematic review and pooled analysis of published studies to assess the efficacy of immunomodulators, including thiopurines and methotrexate, and biologics including antitumor necrosis factor, anti-integrin, and interleukin-12/23 antagonists. Clinical and endoscopic response and remission rates were combined for pooled analyses. Rates of treatment discontinuation and safety were also assessed. Results: Pooled analysis comprised 20 full-text articles (485 patients). Overall clinical response rate was 46% (95% CI: 35-59%) and clinical remission rate was 35% (95% CI: 21-52%). Overall endoscopic response and remission rates were 41% (95% CI: 18-68%) and 15% (95% CI: 5-39%), respectively. Individual agents' safety profile was reassuring, with vedolizumab being the most favorable. Conclusion: The real-world efficacy data of immunomodulators in the treatment of CP is insufficient. Vedolizumab and ustekinumab appeared effective and safe for CP, whereas anti-TNFs showed higher rates of adverse events. The high heterogeneity within the studies is attributed to the real-world study design, obfuscating drug efficacy comparisons across the studies. Further studies are required to define the comparative effectiveness of available treatments of CP.

Refractory fulminant colitis following ocrelizumab therapy requiring colectomy in a patient with multiple sclerosis.

A woman in her 40s was referred for acute and chronic postprandial abdominal cramps on a background of relapsing remitting multiple sclerosis on ocrelizumab therapy as well as coeliac disease on a gluten-free diet, with a family history of ulcerative colitis. Initial colonoscopy demonstrated mild patchy colitis. The patient was trialled on mesalazine, which was ceased due to intolerance. Subsequently, she continued on mercaptopurine monotherapy for management of mild symptoms. Despite this, her symptoms rapidly progressed, with endoscopic and histological evidence of severe rectal-sparing pancolonic inflammation, consistent with severe ocrelizumab-induced colitis. This was refractory to intravenous methylprednisolone and intravenous cyclosporine rescue therapy, requiring surgical management with a subtotal colectomy and subsequent ileorectal anastomosis, after which she remained in clinical, endoscopic and histological remission.

Higher Anti-tumor Necrosis Factor-α Levels Correlate With Improved Radiologic Outcomes in Crohn's Perianal Fistulas.

BACKGROUND & AIMS: Higher anti-tumor necrosis factor-α (TNF) drug levels are associated with improved clinical healing of Crohn's perianal fistulas. It is unclear whether this leads to improved healing on radiologic assessment. We aimed to evaluate the association between anti-TNF drug levels and radiologic outcomes in perianal fistulising Crohn's disease. METHODS: A cross-sectional retrospective multicenter study was undertaken. Patients with perianal fistulising Crohn's disease on maintenance infliximab or adalimumab, with drug levels within 6 months of perianal magnetic resonance imaging were included. Patients receiving dose changes or fistula surgery between drug level and imaging were excluded. Radiologic disease activity was scored using the Van Assche Index, with an inflammatory subscore calculated using indices: T2-weighted imaging hyperintensity, collections >3 mm diameter, rectal wall involvement. Primary endpoint was radiologic healing (inflammatory subscore ≤6). Secondary endpoint was radiologic remission (inflammatory subscore = 0). RESULTS: Of 193 patients (infliximab, n = 117; adalimumab, n = 76), patients with radiologic healing had higher median drug levels compared with those with active disease (infliximab 6.0 vs 3.9 µg/mL; adalimumab 9.1 vs 6.2 µg/mL; both P < .05). Patients with radiologic remission also had higher median drug levels compared with those with active disease (infliximab 7.4 vs 3.9 µg/mL; P < .05; adalimumab 9.8 vs 6.2 µg/mL; P = .07). There was a significant incremental reduction in median inflammatory subscores with higher anti-TNF drug level tertiles. CONCLUSIONS: Higher anti-TNF drug levels were associated with improved radiologic outcomes on magnetic resonance imaging in perianal fistulising Crohn's disease, with an incremental improvement at higher drug level tertiles for both infliximab and adalimumab.

Switching Australian patients with moderate to severe inflammatory bowel disease from originator to biosimilar infliximab: a multicentre, parallel cohort study.

OBJECTIVE: To examine whether non-medical switching of patients with inflammatory bowel disease (IBD) from originator infliximab to a biosimilar (CT-P13, Inflectra) is safe and clinically non-inferior to continued treatment with originator infliximab. DESIGN: Prospective, open label, multicentre, parallel cohort, non-inferiority study in seven Australian hospitals over 48 weeks, May 2017 - October 2019. PARTICIPANTS: Adults (18 years or older) with IBD receiving maintenance originator infliximab (Remicade) who had been in steroid-free clinical remission for at least 12 weeks. INTERVENTION: Managed program for switching patients in four hospitals from originator to biosimilar infliximab (CT-P13); patients in three other hospitals continued to receive originator infliximab (control). MAIN OUTCOME MEASURES: Clinical disease worsening requiring infliximab dose escalation or change in therapy. RESULTS: The switch group included 204 patients, the control group 141 patients with IBD. Ten patients in the control group (7%) and 16 patients switched to CT-P13 (8%) experienced clinical deterioration; the adjusted risk difference (control v switch group) was -1.1 percentage points (95% CI, -6.1 to 8.2 percentage points), within our pre-specified non-inferiority margin of 15 percentage points. Serious adverse events leading to infliximab discontinuation were infrequent in both the switch (six, 3%) and control (six, 4%) groups. CONCLUSION: Switching patients with IBD from originator to biosimilar infliximab is safe and non-inferior to continuing treatment with originator infliximab. Moreover, the introduction of biosimilar infliximab, by increasing market competition, has resulted in substantial cost savings for the Pharmaceutical Benefits Scheme.

Monitoring Inflammatory Bowel Disease in Pregnancy Using Gastrointestinal Ultrasonography.

BACKGROUND AND AIMS: Inflammatory bowel disease [IBD] affects women during their childbearing years. Gastrointestinal ultrasonography [GIUS] accurately identifies disease activity in non-pregnant patients with IBD. The utility of GIUS in pregnancy has not been established. We aimed to determine the feasibility and accuracy of GIUS in the assessment of IBD during pregnancy progression. METHODS: A multicentre observational study of women with IBD undergoing GIUS during pregnancy. Clinicians assessed the adequacy of bowel views and disease activity in four colonic segments and the terminal ileum. Location[s] in which views were impeded by the uterus were documented. GIUS disease activity [bowel wall thickness >3 mm] was compared with biochemical disease activity [faecal calprotectin >100 µg/g]. RESULTS: Ninety patients and 127 GIUS examinations were included [median gestation 19 weeks, range 4-33]. Adequate colonic views were obtained in 116/127 [91%] scans. Adequate ileal views were obtained in 62/67 [93%] scans <20 weeks and 30/51 [59%] scans at 20-26 weeks. There was a positive correlation between bowel wall thickness and calprotectin [r = 0.26, p = 0.03]. GIUS delivered a specificity of 83%, sensitivity of 74%, and negative predictive value of 90% compared with calprotectin. CONCLUSIONS: GIUS is a feasible and accurate modality for monitoring IBD in pregnancy. Adequate GIUS views of the colon and terminal ileum can be obtained in the majority of patients up to 20 weeks of gestation. Beyond 20 weeks, GIUS provides good views of the colon but the terminal ileum becomes difficult to assess.

Gastrointestinal ultrasound in inflammatory bowel disease care: Patient perceptions and impact on disease-related knowledge.

BACKGROUND AND AIM: Objective monitoring of disease activity is integral to therapeutic decision-making in inflammatory bowel disease (IBD). Data are sparse on patients' perspectives of tools used to monitor disease activity in IBD. To evaluate patients' perspectives of gastrointestinal ultrasound (GIUS) performed during routine IBD clinical care, along with its impact on IBD-specific knowledge. METHODS: Patients with a formal diagnosis of IBD who underwent GIUS at two tertiary IBD services between March 2017 and January 2019 participated in this prospective study. Participants completed a questionnaire measuring the acceptability, tolerability, and usefulness of GIUS using a visual analogue scale (VAS) from 0 (disagree) to 10 (strongly agree). Comparative acceptability of IBD monitoring tools and the impact of GIUS on IBD-specific knowledge was measured. RESULTS: A total of 121 participants completed the questionnaire, with a mean age of 42 years (range 17-78), 54 (45%) males, and 79 (65%) Crohn's disease patients. In the overall population, GIUS was scored as highly acceptable for monitoring IBD (mean 9.20 ± 1.37) compared to colonoscopy (7.94 ± 2.30), stool sampling (8.17 ± 1.96), blood sampling (8.87 ± 1.62), and imaging (8.67 ± 1.60); P < 0.01 for each comparison. GIUS caused little patient discomfort (1.88 ± 1.83), and 98 (81%) participants ranked GIUS as their preferred IBD monitoring tool. GIUS also improved patients' overall IBD-specific knowledge (VAS IBD-specific knowledge 7.96 ± 1.92), including their understanding of the need for medical therapy and disease extent. CONCLUSION: GIUS is a highly acceptable and well-tolerated tool for monitoring disease activity in IBD patients. GIUS is preferred by patients and enhances IBD-specific knowledge.

Faecal calprotectin testing for identifying patients with organic gastrointestinal disease: systematic review and meta-analysis.

OBJECTIVES: To assess the clinical effectiveness of faecal calprotectin (FC) testing for distinguishing between organic gastrointestinal diseases (organic GID), such as inflammatory bowel disease (IBD), and functional gastrointestinal disorders (functional GIDs). STUDY DESIGN: Studies that assessed the accuracy of FC testing for differentiating between IBD or organic GID and functional GIDs were reviewed. Articles published in English during January 1998 - June 2018 that compared diagnostic FC testing in primary care and outpatient hospital settings with a reference test and employed the standard enzyme-linked immunosorbent FC assay method with a cut-off of 50 or 100 µg/g faeces were included. Study quality was assessed with QUADAS-2, an evidence-based quality assessment tool for diagnostic accuracy studies. DATA SOURCES: MEDLINE and EMBASE; reference lists of screened articles. DATA SYNTHESIS: Eighteen relevant studies were identified. For distinguishing patients with organic GID (including IBD) from those with functional GIDs (16 studies), the estimated sensitivity of FC testing was 81% (95% CI, 74-86%), the specificity 81% (95% CI, 71-88%); area under the curve (AUC) was 0.87. For distinguishing IBD from functional GIDs (ten studies), sensitivity was 88% (95% CI, 80-93%), specificity 72% (95% CI, 59-82%), and AUC 0.89. Assuming a population prevalence of organic GID of 1%, the positive predictive value was 4.2%, the negative predictive value 100%. The difference in sensitivity and specificity between FC testing cut-offs of 50 µg/g and 100 µg/g faeces was not statistically significant (P = 0.77). CONCLUSIONS: FC testing is clinically useful for distinguishing organic GID (including IBD) from functional GIDs, and its incorporation into clinical practice for evaluating patients with lower gastrointestinal symptoms could lead to fewer patients with functional GIDs undergoing colonoscopy, reducing costs for both patients and the health system. PROSPERO REGISTRATION: CRD4201810507.

Systematic Review and Meta-analysis: Optimal Salvage Therapy in Acute Severe Ulcerative Colitis.

BACKGROUND: Infliximab is an effective salvage therapy in acute severe ulcerative colitis; however, the optimal dosing strategy is unknown. We performed a systematic review and meta-analysis to examine the impact of infliximab dosage and intensification on colectomy-free survival in acute severe ulcerative colitis. METHODS: Studies reporting outcomes of hospitalized steroid-refractory acute severe ulcerative colitis treated with infliximab salvage were identified. Infliximab use was categorized by dose, dose number, and schedule. The primary outcome was colectomy-free survival at 3 months. Pooled proportions and odds ratios with 95% confidence intervals were reported. RESULTS: Forty-one cohorts (n = 2158 cases) were included. Overall colectomy-free survival with infliximab salvage was 79.7% (95% confidence interval [CI], 75.48% to 83.6%) at 3 months and 69.8% (95% CI, 65.7% to 73.7%) at 12 months. Colectomy-free survival at 3 months was superior with 5-mg/kg multiple (≥2) doses compared with single-dose induction (odds ratio [OR], 4.24; 95% CI, 2.44 to 7.36; P < 0.001). However, dose intensification with either high-dose or accelerated strategies was not significantly different to 5-mg/kg standard induction at 3 months (OR, 0.70; 95% CI, 0.39 to 1.27; P = 0.24) despite being utilized in patients with a significantly higher mean C-reactive protein and lower albumin levels. CONCLUSIONS: In acute severe ulcerative colitis, multiple 5-mg/kg infliximab doses are superior to single-dose salvage. Dose-intensified induction outcomes were not significantly different compared to standard induction and were more often used in patients with increased disease severity, which may have confounded the results. This meta-analysis highlights the marked variability in the management of infliximab salvage therapy and the need for further studies to determine the optimal dose strategy.

Predicting response after infliximab salvage in acute severe ulcerative colitis.

BACKGROUND AND AIM: Acute severe ulcerative colitis (ASUC) is a medical emergency requiring prompt therapeutic intervention. Although infliximab has been used as salvage therapy for over 15 years, clinical predictors of treatment success are lacking. We performed a retrospective analysis to identify factors that predict colectomy and may guide dose intensification. METHODS: Fifty-four hospitalized patients received infliximab for ASUC at seven Australian centers (April 2014-May 2015). Follow-up was over 12 months. The data were primarily analyzed for predictors of colectomy. Accelerated (AI) versus standard (SI) infliximab induction strategies were also compared. RESULTS: Of 54 patients identified, the overall colectomy rate was 15.38% (8/52) at 3 months and 26.92% (14/52) at 12 months. Two patients were lost to follow-up. There was a numerically higher colectomy rate in those treated with AI compared with SI (P = 0.3); however, those treated with AI had more severe biochemical disease. A C-reactive protein (CRP)/albumin ratio cut-off of 0.37 post-commencement of infliximab and before discharge was a significant predictor of colectomy with an area under receiver operating curve of 0.73. Pretreatment CRP and albumin levels were not predictive of colectomy. A Mayo Endoscopic Score of 2 had a 94% PPV for avoidance of colectomy following infliximab salvage. CONCLUSIONS: The baseline Mayo Endoscopic Score and the CRP/albumin ratio following infliximab salvage are significant predictors of treatment response for ASUC and identify patients at high risk of colectomy. Whether this risk can be mitigated using infliximab dose intensification requires prospective evaluation before the CRP/albumin ratio can be integrated into ASUC management algorithms.