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.

The synergy of dual faecal immunochemical and faecal calprotectin testing for accurate assessment of endoscopic and histological activity in inflammatory bowel disease.

Background: Faecal biomarkers are increasingly utilized for disease assessment in inflammatory bowel disease (IBD). Objectives: To characterize the relative and combined accuracy of faecal calprotectin (FC) and faecal immunochemical testing (FIT) for detecting endoscopic and histologically active disease in Crohn's disease (CD) and ulcerative colitis (UC), subdivided by disease location. Design: A prospective cohort study. Methods: Patients with confirmed IBD undergoing routine ileocolonoscopy for activity assessment were prospectively recruited and performed both FC and FIT ±30 days of ileocolonoscopy. Endoscopic activity was assessed via the simplified endoscopic score for CD, Mayo endoscopic score for UC and histological activity graded as nil/mild/moderate. Receiver-operator curve analyses were utilized to assess the performance of FC and FIT per disease subtype and location. Results: In all, 137 (79 CD, 57 UC) patients were recruited. FC was more sensitive than FIT in detecting active endoscopic (CD: 91% versus 69%, UC: 94% versus 82%) and histological (CD: 86% versus 55%, UC 88% versus 56%) disease. However, FIT was more specific than FC in detecting active endoscopic (CD: 94% versus 56%, UC: 85% versus 69%) and histological (CD: 93% versus 55%, UC: 96% versus 70%) diseases. FIT was more sensitive and specific than FC in detecting active colonic CD (endoscopic activity: 94% versus 93%, histological activity: 92% versus 77%, respectively); however, it was poorly sensitive for active ileal CD (43% versus 89%). Conclusion: FC demonstrated higher sensitivity and FIT higher specificity for active IBD. Hence, dual testing was synergistic, displaying excellent performance characteristics across most IBD locations and subtypes, holding promise for future clinical application. Trial registration: Not applicable.

Therapeutic Drug Monitoring for Biologic and Small-Molecule Therapies for Inflammatory Bowel Disease.

Background: Inflammatory bowel disease (IBD), encompassing ulcerative colitis and Crohn's disease, necessitates long-term medical therapy to manage symptoms and prevent complications. Therapeutic drug monitoring (TDM) has emerged as a strategy to optimize treatment efficacy, particularly with anti-tumour necrosis factor (anti-TNF) alpha drugs. This review explores the role of TDM for non-anti-TNF advanced therapies in IBD, focusing on vedolizumab, ustekinumab, tofacitinib, upadacitinib, risankizumab and ozanimod. Methods: The literature search, conducted through OVID (Medline) and PubMed, delves into proactive versus reactive TDM, timing of monitoring and methods for measuring drug levels and anti-drug antibodies. Results: While ustekinumab and vedolizumab exhibit exposure-response relationships, consensus on target levels and the role of TDM adjustments remains elusive. Limited data on risankizumab suggest a dose-dependent response, while for small molecule therapies (janus kinase inhibitors and ozanimod), the absence of real-world data and commercially available TDM tools pose challenges. Conclusion: At present, with the available data, there is a limited role for TDM in non-anti-TNF biologic and small-molecule therapies. This review underscores the need for further research to delineate the utility of TDM in guiding treatment decisions for these agents.

Assessing quality of magnetic resonance enterography and its impact on disease assessment of ileal Crohn's disease.

Background/Aims: Assessment of quality of magnetic resonance enterography (MRE) in small bowel Crohn's disease (CD) activity evaluation has received little attention. We assessed the impact of bowel distention and motion artifact on MRE activity indices in ileal CD. Methods: A cohort of patients who underwent contemporaneous MRE and colonoscopy for ileal CD assessment between 2014 and 2021 at 2 centers were audited. An abdominal radiologist blinded to clinical data reviewed each MRE, graded bowel distention and motion artifact upon a pre-specified 3-point scale and calculated the original magnetic resonance index of activity (MaRIA) and simplified MaRIA (sMaRIA), London index and CD MRE index (CDMI). Ileal endoscopic activity was graded via the Simplified Endoscopy Score for CD (SES-CD). The performance of MRE indices in discriminating active disease (SES-CD ≥3) stratified by MRE quality was measured by receiver operator characteristic analyses. Results: One hundred and thirty-seven patients had MRE and colonoscopy within a median of 16 days (range, 0-30 days) with 63 (46%) exhibiting active disease (SES-CD ≥3). Forty-four MREs (32%) were deemed low quality due to motion artifact and/or moderate to poor distention. Low-quality MREs demonstrated reduced discriminative performance between ileal SES-CD ≥3 and MRE indices (MaRIA 0.838 vs. 0.634, sMaRIA 0.834 vs. 0.527, CDMI 0.850 vs. 0.595, London 0.748 vs. 0.511, P<0.05 for all). Individually the presence of any motion artifact markedly impacted the discriminative performance (e.g., sMaRIA area under the curve 0.544 vs. 0.814, P<0.05). Conclusions: Image quality parameters can significantly impact MRE disease activity interpretation. Quality metrics should be reported, enabling cautious interpretation in lower-quality studies.

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).

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.

Systematic Review and Meta-analysis: The Association Between Serum Ustekinumab Trough Concentrations and Treatment Response in Inflammatory Bowel Disease.

BACKGROUND: Optimizing therapy and monitoring response are integral aspects of inflammatory bowel disease treatment. We conducted a systematic review and meta-analysis to determine whether serum ustekinumab trough concentrations during maintenance therapy were associated with ustekinumab treatment response in patients with inflammatory bowel disease. METHODS: A systematic review was performed to March 21, 2022, to identify studies using MEDLINE, EMBASE, and the Cochrane library. We included studies that reported the association between serum ustekinumab trough concentrations with clinical or endoscopic remission. Outcome measures were combined across studies using the random-effects model with an odds ratio (OR) for binary outcomes of endoscopic and clinical remission. RESULTS: We identified 14 observational studies that were included in the analysis for clinical remission (919 patients, 63% with Crohn's disease) or endoscopic remission (290 patients, all with Crohn's disease). Median ustekinumab trough concentrations were higher amongst individuals achieving clinical remission compared with those not achieving remission (mean difference, 1.6 ug/mL; 95% confidence interval [CI], 0.21-3.01 ug/mL). Furthermore, individuals with median serum trough concentration in the fourth quartile were significantly more likely to achieve clinical (OR, 3.61; 95% CI, 2.11-6.20) but not endoscopic remission (OR, 4.67; 95% CI, 0.86-25.19) compared with those with first quartile median trough concentrations. CONCLUSION: Based on the results of this meta-analysis primarily relating to patients with Crohn's disease on maintenance ustekinumab treatment, it appears that there is an association between higher ustekinumab trough concentration and clinical outcomes. Prospective studies are required to determine whether proactive dose adjustments of ustekinumab therapy provides additional clinical benefit.

This meta-analysis of 14 observational studies found an association between better clinical outcomes and higher trough ustekinumab levels for maintenance treatment in inflammatory bowel disease.

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.

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.

Challenges and Strategies to Optimising the Quality of Small Bowel Magnetic Resonance Imaging in Crohn's Disease.

Magnetic resonance enterography (MRE) is one of the most highly utilised tools in the assessment of patients with small bowel Crohn's disease (CD). As a non-invasive modality, it has both patient and procedure-related advantages over ileocolonoscopy which is the current gold standard for Crohn's disease activity assessment. MRE relies upon high-quality images to ensure accurate disease activity assessment; however, few studies have explored the impact of image quality on the accuracy of small bowel CD activity assessment. Bowel distension and motion artifacts are two key imaging parameters that impact the quality of images obtained through MRE. Multiple strategies have been employed to both minimise the effects of motion artifacts and improve bowel distension. This review discusses the definitions of bowel distension and motion artifacts within the literature with a particular focus on current strategies to improve bowel distension and limit motion artifacts in MRE.