Dose intensification strategy influences infliximab pharmacokinetics but not clinical response after the same number of doses.

BACKGROUND: The optimal infliximab dose intensification strategy to address secondary loss of response (LOR) remains unclear. This study aimed to compare clinical and pharmacokinetic outcomes following (i) upfront infliximab re-induction with (ii) ongoing 6-weekly dose interval shortening (DIS), after the same number of doses. METHODS: A prospective parallel cohort study of inflammatory bowel disease patients who required infliximab dose intensification for secondary LOR using (i) re-induction (i.e., repeat 5 mg/kg 0, 2, 6-week dosing) followed by 8-weekly maintenance or (ii) 6-weekly 5 mg/kg DIS was undertaken. Week 32 clinical response was the primary outcome, with secondary evaluation of infliximab pharmacokinetics and predictors of response. RESULTS: Of 104 patients, 54 underwent re-induction, and 50 underwent 6-weekly DIS; 43 per cohort had clinically active disease, with comparable baseline infliximab levels (2.03 vs 2.02 ug/mL, P = 0.83). Clinical response was similar across re-induction and DIS cohorts at weeks 12 (69.8 vs 65.1%) and 32 (53.5 vs 62.8%, each P > 0.50); however, both strategies demonstrated distinct pharmacokinetic profiles at weeks 6 (18.45 vs 5.36 ug/mL, P < 0.01), 12 (8.94 vs 5.96 ug/mL, P = 0.02) and 30 (3.89 vs 6.35 ug/mL, P = .0.02). In multivariable analyses, objectively verified active disease at baseline (OR 12.92, 95% CI [1.84-90.84], P = 0.01), subtherapeutic week 6 infliximab levels (OR 0.12, 95% CI [0.01, 0.99], P = 0.049) and week 12 clinical response (OR 5.44, 95% CI [1.20-19.97], P = 0.04) were associated with week 32 response, as were week 2 infliximab levels (OR 1.34, 95% CI [1.02-1.47], P = 0.04) following re-induction. Following re-induction, week 2 infliximab levels <15.6 ug/mL (AUROC 0.76, 95% CI [0.54-0.99], P < 0.05) predicted nonresponse at week 32. CONCLUSION: Dose intensification strategy impacted immediate and sustained infliximab levels but not clinical response. Upfront intensification was associated with short-term pharmacokinetic advantages, including predictors of response, that diminished with time. Hence, when applying upfront dose intensification, clinicians should consider continuing intensified dosing to sustain early pharmacokinetic advantages based on predictors of (non)response.

Proactive Metabolite Testing in Patients on Thiopurine May Yield Long-Term Clinical Benefits in Inflammatory Bowel Disease.

BACKGROUND: The thiopurine medications are well established in the treatment of inflammatory bowel disease (IBD). There is significant variation in levels of toxic and therapeutic metabolites. Current data from small or short-term studies support therapeutic drug monitoring (TDM) in assessing azathioprine (AZA) and 6-mercaptopurine (6MP). TDM of thiopurines involves measurement and interpretation of metabolites 6-TGN and 6-MMPR. AIMS: This study aimed to assess long-cterm outcomes of patients on thiopurines following therapeutic drug monitoring. METHODS: A multicenter retrospective observational study of outcomes post thiopurine TDM was conducted. Demographics, disease characteristics, physician global assessment, IBD therapy at baseline TDM and again at 12 months were collected. Clinical outcomes were analyzed according to TDM result, and indication for TDM including proactive and other indications. RESULTS: The study included 541 patients. Only 39% of patients had appropriate dosing of thiopurines. AZA/6MP TDM informed a management change in 61.9%, and enabled 88.8% of the cohort to continue AZA/6MP following TDM. At 12 months following TDM the majority (74.1%) of the cohort remained on AZA/6MP. Clinical remission was higher at 12-months following thiopurines TDM (68%) compared to baseline (37%), including proactive TDM. Post TDM, 13.0% of patients were identified as shunters and commenced on thiopurine-allopurinol co-therapy. CONCLUSION: Thiopurine TDM resulted in a change in management for the majority of patients. Post TDM significantly more patients were in remission. TDM allowed the identification of non-adherence and shunters who, without intervention, would not reach therapeutic drug levels. Proactive TDM allowed identification and management of inappropriate dosing, and was associated with increased levels of clinical 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.

Faecal microbiota transplantation for recurrent Clostridioides difficile infection: an Australian experience - effective, safe, yet room for improvement.

Faecal microbiota transplantation (FMT) is reportedly effective and safe for the management of recurrent or refractory Clostridioides difficile infection (CDI), yet real-world data of outcomes of FMT in Australia are limited. In this series, FMT safely resulted in resolution of CDI in 19 patients with reduced healthcare utilisation after 25 FMT, but one patient was diagnosed with an anti-nuclear antibody-positive constitutional illness and Hashimoto thyroiditis following FMT. Further prospective evaluation of the utility of FMT earlier in CDI treatment algorithms to minimise cost and morbidity, and recipient follow up for immune-mediated conditions, is required.

Higher Mucosal Healing with Tumor Necrosis Factor Inhibitors in Combination with Thiopurines Compared to Methotrexate in Crohn's Disease.

BACKGROUND: The differential impact of anti-tumor necrosis factor (anti-TNF) therapy with methotrexate versus thiopurine co-therapy on endoscopic remission remains uncertain. AIMS: To compare rates of endoscopic remission based on methotrexate or thiopurine co-therapy used with anti-TNF therapy in Crohn's disease. METHODS: A retrospective observational study at two tertiary centers between 2010 and 2016 compared endoscopic remission rates and persistence on anti-TNF therapy in combination with methotrexate versus thiopurines for at least 3 months. RESULTS: Of 412 patients on anti-TNF therapy, 278 (67%) received immunomodulator co-therapy for ≥ 3 months and 269 (65%) had complete data for analysis. Methotrexate was used in 77 (29%) and thiopurines in 192 (71%) patients plus either infliximab (156, 58%) or adalimumab (113, 42%), with median follow-up of 2.8 years. The methotrexate group had greater prior immunomodulator intolerance (62% vs 20%, p < 0.01). Endoscopic remission rates were higher in those treated with thiopurine compared to methotrexate co-therapy at 12 m (58% vs 17%, p < 0.01) and at last review (59% vs 40%, p = 0.03). Endoscopic remission rates were higher with thiopurines than methotrexate when combined with adalimumab (49% vs 6%, p < 0.01) but not with infliximab (65% vs 54%, p = 0.09). In multivariate analysis, thiopurine co-therapy, elevated baseline CRP, and therapeutic anti-TNF drug levels were each associated with longer persistence of co-therapy (each p < 0.05). There were no significant differences in adverse events, malignancy or infection rates. CONCLUSION: In this cohort, anti-TNF and thiopurine co-therapy resulted in higher rates of mucosal healing than methotrexate, the difference is most pronounced with adalimumab and conversely with low-dose methotrexate.

Faecal calprotectin delivers on convenience, cost reduction and clinical decision-making in inflammatory bowel disease: a real-world cohort study.

BACKGROUND: Faecal calprotectin (FC) is an accurate biomarker of disease activity in inflammatory bowel disease (IBD), yet the cost/resource implications of incorporating FC into 'real-world' practice remain uncertain. AIM: To evaluate the utility of FC in clinical decision-making and on healthcare costs in IBD. METHODS: Retrospective data, including colonoscopy/other investigations, medication, admission and surgical data, were collected from hospital records and compared between two groups: pre-FC historical cohort (2005-2009) where colonoscopy was used to assess IBD activity versus the cohort where FC was used first instead (2010-2014). Post-test costs were also compared. RESULTS: A total of 357 FC tests (246 patients, 2010-2014) and 450 colonoscopies (268 patients, 2005-2009) were performed. On subsequent review, both FC and colonoscopy (in their respective cohorts) were associated with changes in management in 50.7 versus 56.2% (P = 0.14), respectively, with similar proportions of subsequent IBD-related investigations within 6 months (21.8 vs 21.9%, P = 1.0). Prior to FC availability (2005-2009), a colonoscopy for disease reassessment cost AU$606 578 (cost per patient-year $1887.34) versus AU$282 048 (cost per patient-year $968.60) when FC ± colonoscopy was used (2010-2014). Within the FC cohort, 73.6% did not proceed to colonoscopy within 6 months post-FC, and 60.6% had not undergone colonoscopy post-FC by the end of follow up (median 1.8 years (0.1, 4.6) post-FC). Those with FC ≥ 250 were scoped earlier than those with FC < 100 µg/mL (median 0.49 vs 1.0 years, P = 0.03). CONCLUSION: Introduction of FC into routine IBD care aided changes in clinical management in a similar proportion, yet at potentially half the total cost, compared to a historical colonoscopy-only cohort at the same centre.

Examining maintenance care following infliximab salvage therapy for acute severe ulcerative colitis.

BACKGROUND AND AIM: Data supporting the optimal maintenance drug therapy and strategy to monitor ongoing response following successful infliximab (IFX) induction, for acute severe ulcerative colitis (ASUC), are limited. We aimed to evaluate maintenance and monitoring strategies employed in patients post-IFX induction therapy. METHODS: Patients in six Australian tertiary centers treated with IFX for steroid-refractory ASUC between April 2014 and May 2015 were identified via hospital IBD and pharmacy databases. Patients were followed up for 1 year with clinical data over 12 months recorded. Analysis was limited to patient outcomes beyond 3 months. RESULTS: Forty one patients were identified. Five of the 41 (12%) patients underwent colectomy within 3 months, and one patient was lost to follow-up. Six of 35 (17%) of the remaining patients progressed to colectomy by 12 months. Maintenance therapy: Patients maintained on thiopurine monotherapy (14/35) versus IFX/thiopurine therapy (15/35) were followed up. Two of 15 (13%) patients who received combination maintenance therapy underwent a colectomy at 12 months, compared with 1/14 (7%) patients receiving thiopurine monotherapy (P = 0.610). Monitoring during maintenance: Post-discharge, thiopurine metabolites were monitored in 15/27 (56%); fecal calprotectin in 11/32 (34%); and serum IFX levels in 4/20 (20%). Twenty of 32 (63%) patients had an endoscopic evaluation after IFX salvage with median time to first endoscopy of 109 days (interquartile range 113-230). CONCLUSION: Following IFX induction therapy for ASUC, the uptake of maintenance therapy in this cohort and strategies to monitor ongoing response were variable. These data suggest that the optimal maintenance and monitoring strategy post-IFX salvage therapy remains to be defined.

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.

Poor predictive value of breath hydrogen response for probiotic effects in IBS.

BACKGROUND AND AIMS: Previous observations suggested that an early rise in breath hydrogen after lactulose (ERBHAL) may identify patients with irritable bowel syndrome (IBS) likely to respond to probiotics. Therefore, we aimed to (i) investigate whether treatment with a probiotic changes breath hydrogen response in patients with ERBHAL and (ii) whether these changes identify patients who may benefit symptomatically from probiotics. METHODS: In a randomized, double-blind, placebo-controlled trial, patients with IBS (Rome III) were randomized to either 65 mL/day fermented milk product containing probiotic (FMPP) or placebo for 6 weeks, followed by 6 weeks' open-label treatment and 6 weeks' withdrawal. Breath hydrogen responses to lactulose (15 g) and liquid-gastric emptying time were evaluated before and at the end of each treatment period. Symptoms were measured using a 100-mm visual analog scale. RESULTS: Loss of ERBHAL occurred in 36% of 23 patients receiving FMPP and 41% of 22 receiving placebo (P = 1.00). Amongst 40 patients who completed open-label FMPP treatment, ERBHAL was lost in a further 38%, continued in 25%, and regained in 10%. Similar variability occurred in the withdrawal phase. Variability was unrelated to changes in gastric emptying. No differences in symptom response were seen between treatment groups nor in relation to the loss or retention of ERBHAL. CONCLUSIONS: Breath hydrogen patterns after lactulose are poorly reproducible. No FMPP-specific effects on fermentation patterns or symptoms were observed. The presence of ERBHAL is not useful to predict symptomatic response to probiotic therapy in patients with IBS.

Prospective Evaluation of Serum Free Thiols in Inflammatory Bowel Disease: A Candidate to Replace C-Reactive Protein for Disease Activity Assessment?

BACKGROUND: Serum free thiols (SFTs) reflecting oxidative stress appear to correlate with inflammatory bowel disease (IBD) activity. We aimed to evaluate the performance of SFTs concentrations vs endoscopic and histological activity, compare SFTs with established biomarkers, and identify clinical and laboratory parameters independently associated with SFT levels in IBD patients. METHODS: Patients with confirmed IBD undergoing routine ileocolonoscopy for activity assessment were prospectively recruited, with serum samples obtained concurrently for SFTs and routine bloods, plus fecal calprotectin and immunochemical tests were collected ±30 days from ileocolonoscopy. Endoscopic activity was assessed via established indices and histological activity graded as inactive/mild/moderate. Receiver-operating characteristic curve analyses were utilized to assess performance of SFTs vs endoscopic activity, and multiple regression analysis was used to identify factors associated with SFT levels. RESULTS: A total of 141 (80 Crohn's disease, 61 ulcerative colitis) patients were recruited. Median SFTs were significantly lower in moderate vs inactive/mild endoscopic activity (309 µM vs 433/471 µM, respectively; P < .01). There was no significant difference in median SFTs across inactive/mild/moderate histological activity. SFTs achieved higher sensitivity than C-reactive protein in predicting moderate, endoscopically active disease (89% vs 78%; area under the curve, 0.80 each) yet was outperformed by fecal calprotectin (100%; area under the curve, 0.93). Advancing age and increasing albumin levels were independently associated with SFT levels, and thus are possible confounders. CONCLUSIONS: This prospective study has demonstrated the potential of SFTs as a serum biomarker in IBD. It was more sensitive than C-reactive protein, yet less sensitive than fecal biomarkers for prediction of endoscopically active IBD.

Clinical trial: Combination allopurinol-thiopurine versus standard thiopurine in patients with IBD escalating to immunomodulators (the DECIDER study).

BACKGROUND: Thiopurines are established treatments for inflammatory bowel disease (IBD), yet concerns remain regarding their safety. AIM: To evaluate the use of thiopurine-allopurinol combination therapy compared to standard thiopurine therapy in IBD. METHODS: We performed a multicentre, randomised, placebo-controlled trial to compare the efficacy and safety of thiopurine-allopurinol versus thiopurine with placebo for adults commencing a thiopurine for IBD. Patients had active disease at baseline; dosing of therapy was based on a pre-specified regimen and subsequent metabolites. The primary outcome was the proportion of patients achieving a composite of symptomatic disease activity remission (Harvey Bradshaw Index <5 for Crohn's disease, Simple Clinical Colitis Activity Index <4 for ulcerative colitis) and a faecal calprotectin <150 µg/g after 26 weeks of treatment. RESULTS: The trial was terminated early due to slow recruitment. We randomised 102 participants (54 thiopurine-allopurinol, 48 thiopurine with placebo) with similar age (median 42 vs 48 years) and sex distribution (46% women per group). A higher proportion achieved the primary outcome in the thiopurine-allopurinol group (50% vs 35%, p = 0.14) and fewer participants stopped their allocated therapy due to adverse events (11% vs 29%, p = 0.02). Also, within the thiopurine-allopurinol group, thiopurine dose adjustments were less frequent (69% vs 92%, p = 0.03), a higher proportion achieved an early therapeutic 6-TGN level at week 6 (71% vs 53%, p = 0.19), and adverse events attributed to therapy were less frequent (15% vs 44%, p = 0.002). CONCLUSION: Thiopurine-allopurinol therapy is safe and mitigates thiopurine adverse effects, thus enhancing tolerability without compromising efficacy (ACTRN12613001347752).

Replacing Endoscopy with Magnetic Resonance Enterography for Mucosal Activity Assessment in Terminal Ileal Crohn's Disease: Are We There Yet?

Crohn's disease (CD) is a chronic immune mediated disorder that most commonly affects the small bowel and/or the large bowel. Treatment targets in CD include mucosal healing assessed via ileocolonoscopy and transmural healing assessed through cross-sectional imaging modalities such as magnetic resonance enterography (MRE). More recently, histological healing in CD has emerged as a treatment target, though it is made cumbersome given its reliance on frequent endoscopic examinations. With expert guidelines now recommending regular objective assessments as part of a treat-to-target approach, accurate non-invasive assessment will become increasingly critical. MRE has an established role in the assessment of small bowel CD, with growing data supportive of its ability in detecting disease activity at mucosal and histological levels. This could therefore potentially reduce the need for serial endoscopic assessment. Thus, this review will assess the capacity of individual MRE parameters and MRE indices for detecting mucosal and histological small bowel CD activity. Furthermore, challenging scenarios, such as CD activity detection in post-operative clinical scenarios and abnormal findings in the context of a normal ileocolonoscopy, will be explored.

The Utility of Faecal Calprotectin, Lactoferrin and Other Faecal Biomarkers in Discriminating Endoscopic Activity in Crohn's Disease: A Systematic Review and Meta-Analysis.

INTRODUCTION: Currently, faecal calprotectin (FC) is the predominate faecal biomarker utilised in clinical practice to monitor Crohn's disease (CD) activity. However, there are several potential faecal biomarkers described in the literature. We performed a meta-analysis to determine the accuracy of faecal biomarkers in discriminating endoscopic activity and mucosal healing in CD. METHODS: We searched the medical literature using MEDLINE, EMBASE, and PubMed from 1978 to 8 August 2022. Descriptive statistics, including sensitivity, specificity of the primary studies, their positive and negative likelihood ratios, and their diagnostic odds ratio (DOR), were calculated. The methodological quality of the included studies was evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS) criteria. RESULTS: The search found 2382 studies, of which 33 were included for analysis after screening. FC was found to have a pooled sensitivity and specificity, DOR, and negative predictive value (NPV) in discriminating active endoscopic disease (versus inactive) of 81%, 74%, 13.93, and 0.27, respectively. Faecal lactoferrin (FL) had a pooled sensitivity and specificity, DOR, and NPV in discriminating active endoscopic disease of 75%, 80%, 13.41, and 0.34, respectively. FC demonstrated a pooled sensitivity and specificity, DOR, and NPV of 88%, 72%, 18.17, and 0.19 in predicting mucosal healing. CONCLUSION: FC remains an accurate faecal biomarker. Further evaluation of the utility of novel faecal biomarkers is needed.

Utility of panenteric capsule endoscopy for the detection of small-bowel Crohn's disease in patients with a normal magnetic resonance enterography: A prospective observational pilot study.

Background and Aim: Capsule endoscopy allows the direct visualization of the small bowel. We examined the diagnostic utility of a new modality, namely panenteric Crohn's capsule endoscopy (CE), in detecting active small-bowel Crohn's disease (CD) in those with normal magnetic resonance enterography (MRE). Methods: We prospectively recruited patients with a diagnosis of CD or suspected small-bowel CD in whom the MRE was normal. Inclusion criteria included abdominal symptoms and abnormal serum or fecal biomarkers. The primary outcome was the detection of active small-bowel CD (measured through the Lewis score [LS]). Secondary outcomes included change in Montreal classification for those with a pre-existing CD diagnosis, change in medical therapy, clinical activity, and biomarkers at baseline and 6 months, and quality-of-life measures. Results: A total of 22 patients with a diagnosis of CD or suspected new diagnosis were recruited, with CE complete to the caecum in 21 and 18/21 (86%) showing evidence of active small-bowel CD (LS > 135). Of the patients with a pre-existing diagnosis of CD, 9/11 (82%) had a change in Montreal classification. At 6 months following CE, 17/18 (94%) had clinician-directed change in therapy. This correlated with an improvement in the quality of life (P < 0.05 as per the Short Inflammatory Bowel Disease Questionnaire), a reduction in the Harvey Bradshaw index (median: 7-4, P < 0.001), and favorable CRP and albumin response. Conclusion: Crohn's CE is a useful diagnostic test for assessing active small-bowel CD when imaging is normal but clinical suspicion is high. Crohn's CE should be integrated into the diagnostic algorithm for small-bowel CD.

The Nocebo Effect in a Non-Medical Switching Program from Originator to Biosimilar Infliximab in Inflammatory Bowel Disease.

BACKGROUND: Despite growing awareness of the nocebo effect, few studies have evaluated the nocebo effect using combined assessment of patient-reported outcome measures (PROMs), clinical indices, and objective biomarkers in inflammatory bowel disease (IBD) patients switching from originator to biosimilar medicines. OBJECTIVE: This study aimed to compare these outcomes across switch and non-switch cohorts to evaluate the nocebo effect in patients with IBD. METHODS: Parallel cohorts of IBD patients who (1) switched from originator to biosimilar (CT-P13) infliximab and (2) continued biosimilar (CT-P13) infliximab were evaluated over 32 weeks. Clinical disease activity, objective biomarkers and PROMs were assessed at baseline, and weeks 16 and 32 across both cohorts. The PROM of interest was patient-perceived disease activity evaluated using a 0-100 visual analogue scale (VAS) per the IBD-Control Questionnaire. RESULTS: Of 81 patients, 47 switched from originator to biosimilar (CT-P13) infliximab. A negative change from baseline patient-reported disease control was observed across the switch cohort compared with the non-switch cohort at week 16 (mean VAS - 8.21 vs. 1.26; p = 0.03), but not at week 32 (mean VAS - 1.21 vs. 1.38; p = 0.58). Corresponding clinical and objective biomarker assessments over these timepoints were comparable across both cohorts. CONCLUSION: This study demonstrated a temporary yet discernible nocebo effect in the first 16 weeks following non-medical switching that was not sustained at week 32. Negative patient perceptions may be overcome by a patient-inclusive approach to non-medical switching in conjunction with close clinical follow-up and disease monitoring.

Systematic review and meta-analysis: evaluating response to empiric anti-TNF dose intensification for secondary loss of response in Crohn's disease.

INTRODUCTION: Anti-tumor necrosis factor (TNF) dose intensification represents an effective method of overcoming secondary loss of response (LOR); however, a subset of patients may not respond (tertiary non-response), or fail to demonstrate durable response (tertiary LOR) to intensified dosing. This systematic review and meta-analysis aimed to evaluate these outcomes to determine the clinical effectiveness of empiric dose intensification in Crohn's disease. METHODS: Multiple databases including MEDLINE and EMBASE were interrogated to identify studies that reported outcomes following anti-TNF dose intensification to address secondary LOR in Crohn's disease. Studies that used anti-TNF levels as the primary basis for dose intensification were excluded. Studies that reported (1) tertiary response and tertiary non-response within 6 months or (2) tertiary response and tertiary LOR beyond 6 months, were pooled using a random effects model with risk ratio (RR) derived, quantifying the effect of each comparison. RESULTS: Twenty-six studies reported outcomes following anti-TNF dose intensification to address secondary LOR. Short-term response within 12 weeks of any dose-intensification strategy was 33-90%, while sustained response (⩾48 weeks) was achieved in 25-85%. Tertiary non-response occurred in up to 45% of intensified patients within 6 months of anti-TNF dose intensification, while tertiary LOR beyond 6 months occurred in up to 64% of patients. Tertiary response was more likely than tertiary non-response within 6 months (RR 2.58, 95% CI (1.76, 3.79), I 2 = 82%, 12 studies), while sustained response beyond 6 months compared to tertiary LOR (RR 1.10 (0.75, 1.61) I 2 = 85%, 7 studies) was less convincing. CONCLUSION: Although anti-TNF dose intensification is clinically effective in patients with Crohn's disease, particularly within the first 6 months, a proportion of patients will fail to demonstrate short-term and/or sustained clinical response. Hence, clinical reassessment following anti-TNF dose intensification, particularly beyond 6 months, remains important to differentiate between effective and ineffective dose-intensification strategies.