Ultrasound muscle assessment for sarcopenia detection in inflammatory bowel disease: A prospective study.

BACKGROUND: Sarcopenia is prevalent in patients with inflammatory bowel disease (IBD) and impacts surgical and therapeutic outcomes; thus, effective diagnostic tools are needed to assess muscle mass and function in this population. METHODS: 153 consecutive patients were included, 100 in the training cohort and 53 in the study cohort. Three superficial muscles (rectus femoris = RF, rectus abdominis = RA, and biceps brachii = BB) were selected for the detection of sarcopenia using muscle ultrasound (US). The training cohort consisted of consecutive patients with or without IBD and was used to evaluate the feasibility and inter- and intra-observer variability of the US measurement. The study cohort consisted of only IBD patients and served to test US diagnostic accuracy. In the latter, muscle US, bioelectrical impedance analysis (BIA), and magnetic resonance imaging (MRI) were used to measure muscle parameters. RESULTS: Sarcopenia prevalence in IBD patients was 50%. Muscle US showed excellent inter-rater and intra-rater reliability (ICC >0.95) and a good diagnostic accuracy in detecting sarcopenia compared to BIA with area under the receiver operating characteristic curve (AUROC) values of 80% and 85% for RA and BB thickness, respectively. Moreover, an Ultrasound Muscle Index (USMI) was defined as the sum of the RA, BB, and RF thickness divided by the square of the patient's height, resulting in an AUROC of 81%. Muscle thresholds for sarcopenia were detected, with RA and USMI values correlated with the highest positive (84.3%) and negative (99%) predictive values, respectively. Additionally, the agreement between the US and MRI measurements of RA was excellent (ICC 0.96). CONCLUSIONS: The findings of this study emphasize the potential of muscle US as a reliable diagnostic tool for assessing sarcopenia in IBD patients. This research has significant implications for disease management in IBD patients and underscores the need for further investigations to validate these findings in larger cohorts.

Magnetic Resonance Enterography Assessment of Transmural Healing with Vedolizumab in Moderate to Severe Crohn's Disease: Feasibility in the VERSIFY Phase 3 Clinical Trial.

Purpose: The VERSIFY phase 3 trial in patients with Crohn's disease (CD) treated with vedolizumab was the first to include a substudy that used a standardized magnetic resonance enterography (MRE) protocol to assess features of transmural inflammation (bowel edema and wall thickness) and extramural disease activity (enlarged lymph nodes). Patients and Methods: Patients received intravenous vedolizumab (300 mg) at weeks 0 (baseline), 2, and 6, and then every 8 weeks for 26 or 52 weeks. Post hoc analyses included a subpopulation with a Magnetic Resonance Index of Activity score of ≥7 in at least one bowel segment at baseline and at least one postbaseline MRE assessment. Changes in transmural inflammation, including intramural bowel edema and wall thickness, were evaluated. Patient-level and segment-level analyses were performed. Results: MRE images were evaluated in 27 patients with 83 evaluable bowel segments at baseline and week 26, and 13 patients with 38 evaluable segments at baseline, week 26, and week 52. At baseline, all patients had bowel wall edema and wall thickness of >3 mm in at least one bowel segment. The proportion of patients with edema decreased at weeks 26 (17/27 [63.0%]) and 52 (4/13 [30.8%]) and the proportion with bowel wall thickness of >3 mm decreased at weeks 26 (25/27 [92.6%]) and 52 (10/13 [76.9%]). Conclusion: In patients with CD treated with vedolizumab for 26 and 52 weeks, the number of patients, and bowel segments, with MRE-detected transmural inflammation was reduced. These results highlight the impact of vedolizumab on components of transmural inflammation in CD and demonstrate that using MRE in CD multicenter clinical trials is feasible. Trial Registration: ClinicalTrials.gov NCT02425111, April 23, 2015, http://www.clinicaltrials.gov NCT02425111; EU Clinical Trials Register EudraCT 2014-003509-13, https://www.clinicaltrialsregister.eu.

Leveraging the holistic benefits of biosimilars in Europe - part 2: how payers can safeguard the future of a healthy biosimilar market environment.

INTRODUCTION: Biosimilars have improved access to biologic medicines; however, historical thinking may jeopardize the viability of future markets. AREAS COVERED: An expert panel of eight diverse European stakeholders provided insights about rethinking biosimilars and cost-savings, reducing patient access inequalities, increasing inter-market equity, and improving education. The insights reported here (Part 2) follow a study that provides perspectives on leveraging the holistic benefits of biosimilars for market sustainability based on independent survey results and telephone interviews of stakeholders from diverse biosimilar markets (Part 1). Directional recommendations are provided for payers. EXPERT OPINION: The panel's market maturity framework for biosimilars has three stages: 'Invest,' 'Expand' and 'Harvest.' Across market stages, re-thinking the benefits of biosimilars beyond cost-savings, considering earlier or expanded access/new indications, product innovations, and re-investment of biosimilar-generated cost-savings should be communicated to stakeholders to promote further engagement. During 'Expand' and 'Harvest' stages, development of efficient, forward-looking procurement systems and mechanisms that drive uptake and stabilize competition between manufacturers are key. Future biosimilars will target various therapy areas beyond those targeted by existing biosimilars. To ensure a healthy, accessible future market, stakeholders must align their objectives, communicate, collaborate, and coordinate via education, incentivization, and procurement, to maximize the totality of benefits.

The influence of subclinical active inflammation on IFX pharmacokinetic modeling and disease progression assessment: findings from a prospective real-world study in inflammatory bowel disease patients.

BACKGROUND AND AIMS: Effective management of inflammatory bowel disease (IBD) relies on a comprehensive understanding of infliximab (IFX) pharmacokinetics (PK). This study's primary goal was to develop a robust PK model, identifying key covariates influencing IFX clearance (CL), while concurrently evaluating the risk of disease progression during the maintenance phase of IBD treatment. METHODS: The multicenter, prospective, real-world DIRECT study was conducted in several care centers, which included 369 IBD patients in the maintenance phase of IFX therapy. A two-compartment population PK model was used to determine IFX CL and covariates. Logistic and Cox regressions were applied to elucidate the associations between disease progression and covariates embedded in the PK model. RESULTS: The PK model included the contributions of weight, albumin, antidrug antibody (ADA), and fecal calprotectin (FC). On average, higher ADA, FC concentration and weight, and lower albumin concentration resulted in higher IFX CL. In the multivariate regression analyses, FC levels influenced the odds of disease progression in all its different definitions, when adjusted for several confounding factors. Additionally, alongside FC, both IFX and CL demonstrated a significant impact on the temporal aspect of disease progression. CONCLUSION: In this 2-year real-world study, readily available clinical covariates, notably FC, significantly impacted IFX availability in IBD patients. We demonstrated that subclinical active inflammation, as mirrored by FC or CRP, substantially influenced IFX clearance. Importantly, FC emerged as a pivotal determinant, not only of IFX pharmacokinetics but also of disease progression. These findings underscore the need to integrate FC into forthcoming IFX pharmacokinetic models, amplifying its clinical significance.

Reliability and Responsiveness of Histologic Indices for the Assessment of Crohn's Disease Activity.

BACKGROUND & AIMS: The operating properties of histologic indices for evaluating Crohn's disease (CD) activity are poorly characterized. We assessed the reliability and responsiveness of existing histologic indices/items used in CD and ulcerative colitis (UC), in addition to 3 novel items, and developed exploratory ileal, colonic, and colonic-ileal CD instruments. METHODS: Blinded central readers independently reviewed paired baseline and week 12 image sets from the EXTEND trial. Disease activity was scored using 4 indices (the Global Histologic Activity Score, Geboes Score, Nancy Histological Index, and Robarts Histopathology Index) and 3 items identified by an expert panel (mucin depletion, basal plasmacytosis, and ileal pyloric gland metaplasia). Reliability and responsiveness were quantified using the intraclass correlation coefficient (ICC) and area under the receiver operating curve (AUC), respectively. Exploratory indices were developed using backward stepwise linear regression analysis. Candidate independent variables were items with an inter-rater ICC ≥0.40 and AUC ≥0.56. The dependent variable was histologic disease activity measured by a 100-mm visual analogue scale. RESULTS: Paired image sets were available from 55 patients. Substantial to almost perfect inter-rater reliability (ICC, 0.63-0.87) and some responsiveness (AUC, 0.57-0.94) were observed for all existing indices regardless of whether individual colonic and ileal segments, combined colonic segments, or combined colonic and ileal segments were assessed and the calculation method used. Five items were tested as candidate items, and exploratory colonic, ileal, and colonic-ileal indices were developed. CONCLUSIONS: CD and UC indices were similarly reliable and responsive in measuring histologic CD activity. Exploratory index development did not offer benefit over current histologic instruments.

Assessment of the effectiveness of Budesonide MMX® for active, mild-to-moderate ulcerative colitis in the Polish sub-group of the CORE Practice prospective multi-centre observational study.

Introduction: Budesonide MMX® is approved for induction of remission in mild-to-moderate active ulcerative colitis (UC) in adults in whom 5-ASA is not sufficient. There is a lack of data on its effectiveness and safety in clinical practice. Material and methods: The CORE Practice study was a multi-centre prospective, observational study of mild-to-moderate UC-patients treated with Budesonide MMX® 9 mg for up to 8 weeks (induction). Enrolled patients had previously been prescribed Budesonide MMX® 9 mg in accordance with the SmPC within a 5-day time window. The primary endpoint was the percentage of patients achieving a decrease ≥ 3 points in the UCDAI clinical sub-score at the end of the induction treatment. Other endpoints were clinical remission (decrease ≤ 1 in UCDAI clinical sub-score), resolution of symptoms, change in Short Inflammatory Bowel Disease Questionnaire (SIBD-Q) score, treatment satisfaction, and tolerability. This report presents results from the Polish study sites. Results: The data from a Polish subgroup of 181 patients with mild-to-moderate UC were analysed. Clinical improvement ≥ 3 points in the UCDAI at the end of treatment induction was achieved in 63.8% patients. Clinical remission was observed in 55.9% of patients at the end of the induction treatment. Full resolution of symptoms (rectal bleeding = 0 and stool frequency = 0) at the end of the Budesonide MMX® treatment was achieved in 52.5% of patients. Significant improvement in quality of life was seen in mean SIBD-Q total score from 40 points at baseline to 56 points at last assessment (p < 0.001). A treatment satisfaction score of more than 8 out of 10 was observed in 72.9% of patients. One patient discontinued Budesonide MMX® due to an adverse event that was related to the study drug, which counted for less than 1% of patients. Conclusions: The data from the Polish subgroup of the real-life study CORE Practice confirms the clinical efficacy of Budesonide MMX® 9 mg in the majority of patients with active mild-to-moderate UC. Budesonide MMX® was safe and well tolerated. The therapy was satisfactory for patients and showed a beneficial effect on the patients' quality of life.

Diverticular Inflammation and Complication Assessment classification, CODA score and fecal calprotectin in clinical assessment of patients with diverticular disease: A decision curve analysis.

BACKGROUND AND AIMS: The Diverticular Inflammation and Complication Assessment (DICA) classification and the Combined Overview on Diverticular Assessment (CODA) were found to be effective in predicting the outcomes of Diverticular Disease (DD). We ascertain whether fecal calprotectin (FC) can further aid in improving risk stratification. METHODS: A three-year international, multicentre, prospective cohort study was conducted involving 43 Gastroenterology and Endoscopy centres. Survival methods for censored observations were used to estimate the risk of acute diverticulitis (AD) in newly diagnosed DD patients according to basal FC, DICA, and CODA. The net benefit of management strategies based on DICA, CODA and FC in addition to CODA was assessed with decision curve analysis, which incorporates the harms and benefits of using a prognostic model for clinical decisions. RESULTS: At the first diagnosis of diverticulosis/DD, 871 participants underwent FC measurement. FC was associated with the risk of AD at 3 years (HR per each base 10 logarithm increase: 3.29; 95% confidence interval, 2.13-5.10) and showed moderate discrimination (c-statistic: 0.685; 0.614-0.756). DICA and CODA were more accurate predictors of AD than FC. However, FC showed high discrimination capacity to predict AD at 3 months, which was not maintained at longer follow-up times. The decision curve analysis comparing the combination of FC and CODA with CODA alone did not clearly indicate a larger net benefit of one strategy over the other. CONCLUSIONS: FC measurement could be used as a complementary tool to assess the immediate risk of AD. In all other cases, treatment strategies based on the CODA score alone should be recommended.

Neutrophil-only Histological Assessment of Ulcerative Colitis Correlates with Endoscopic Activity and Predicts Long-term Outcomes in a Multicentre Study.

BACKGROUNDS AND AIMS: Absence of neutrophils is the minimum standard to consider histological remission of ulcerative colitis [UC]. The PICaSSO Histological Remission Index [PHRI] is a new simple index for UC, based only on the detection of neutrophils. We evaluate PHRI's correlation with endoscopy and its prognostic value compared with other established indices. METHODS: Consecutive patients with UC underwent colonoscopy at two referral centres [Birmingham, UK, and Milan, Italy,] and were followed up for 2 years. Correlation between histology (PHRI, Nancy [NHI], and Robarts [RHI] indexes) and endoscopy (Mayo Endoscopic Score [MES], Ulcerative Colitis Endoscopic Index of Severity [UCEIS], and PICaSSO index) was calculated as Spearman coefficients. Diagnostic performance of endoscopy was assessed with receiver operating characteristic [ROC] curves and outcome stratification with Kaplan-Meier curves. RESULTS: A total of 192 patients with UC was enrolled, representing all grades of endoscopic severity. Correlation between histology and endoscopy did not differ significantly when using PHRI instead of NHI or RHI. In particular, PHRI's correlation with MES, UCEIS, and PICaSSO was 0.745, 0.718, and 0.694, respectively. Endoscopically-assessed remission reflected the absence of neutrophils [PHRI = 0] with areas under the ROC curve of 0.905, 0.906, and 0.877 for MES, UCEIS, and PICaSSO, respectively. The hazard ratio for disease flare between patients in histological activity/remission was statistically similar [p >0.05] across indexes [2.752, 2.706, and 2.871 for RHI, NHI, and PHRI, respectively]. CONCLUSION: PHRI correlates with endoscopy and stratifies risk of relapse similarly to RHI and NHI. Neutrophil-only assessment of UC is a simple yet viable alternative to established histological scores.

Content Validity and Psychometric Evaluation of the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) in Patients with Crohn's Disease and Ulcerative Colitis.

BACKGROUND: Patients with Crohn's disease (CD) or ulcerative colitis (UC) frequently experience fatigue, although it is often overlooked in medical research and practice. AIMS: To explore patients' experience of fatigue and evaluate content validity, psychometric properties, and score interpretability of the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) in patients with CD or UC. METHODS: Concept elicitation and cognitive interviews were conducted with participants aged ≥ 15 years with moderately-to-severely active CD (N = 30) or UC (N = 33). To evaluate psychometric properties (reliability and construct validity) and interpretation of FACIT-Fatigue scores, data from two clinical trials were analyzed [ADVANCE (CD): N = 850; U-ACHIEVE (UC): 248]. Meaningful within-person change was estimated using anchor-based methods. RESULTS: Almost all interview participants reported experiencing fatigue. Over 30 unique fatigue-related impacts were reported per condition. The FACIT-Fatigue was interpretable for most patients. FACIT-Fatigue items had good internal consistency (Cronbach's α 0.86-0.88 for CD and 0.94-0.96 for UC); the total score displayed acceptable test-retest reliability (intraclass correlation coefficients > 0.60 for CD and > 0.90 for UC). FACIT-Fatigue scores had acceptable convergent validity with similar measures. A 7-10 point improvement for CD and 4-9 point improvement for UC on the FACIT-Fatigue total score may represent meaningful improvements. CONCLUSIONS: These results highlight the importance of fatigue among adolescents and adults with CD or UC and provide evidence that the FACIT-Fatigue is content valid and produces reliable, valid, and interpretable scores in these populations. Care should be taken if using the questionnaire with adolescents who may be less familiar with the word "fatigue." Clinical trial registration numbers NCT03105128 (date of registration: 4 April 2017) and NCT02819635 (date of registration: 28 June 2016).

Non-invasive monitoring and treat-to-target approach are cost-effective in patients with mild-moderate ulcerative colitis.

BACKGROUND: There are no data to assess the value associated with a treat-to-target (T2T) strategy based on tight control of mild-moderate ulcerative colitis (UC). AIM: To assess the cost-effectiveness of a T2T approach based on the normalisation of clinical signs and faecal calprotectin (FC) METHODS: A decision analytical Markov model was developed to compare T2T algorithm combining clinical symptoms and FC levels to define treatment response and the possible switch to the next treatment line (T2T-FC), and the reference strategy based only on symptoms. The model included five treatment lines and was conducted from the Italian national health service (NHS) perspective using a 3-year time horizon. The model calculated the incremental cost-effectiveness ratio as € per relapse avoided. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS: The cost-effectiveness analysis produced an increased time spent by a patient in clinical remission and FC ≤ 100 level (+0.177 years; about 2 months) and a decreasing number of relapses (-0.1937; -20.9%) per patient using a T2T-FC approach compared to only symptoms. Furthermore, the T2T-FC was associated with higher cost (+€1795). The ICER estimated was €9263 per relapse avoided. These results were confirmed by sensitivity analyses. CONCLUSIONS: T2T-FC approach resulted in a higher benefit for mild-moderate UC patients in terms of time in remission and incidence of relapse but was associated with higher costs. Clinical trials and real-world clinical studies are needed to provide additional data on the cost-benefit of this approach.

Noninvasive Assessment of Postoperative Disease Recurrence in Crohn's Disease: A Multicenter, Prospective Cohort Study on Behalf of the Italian Group for Inflammatory Bowel Disease.

BACKGROUND & AIMS: Colonoscopy (CS) is the gold standard to assess postoperative recurrence (POR) in Crohn's disease (CD). However, CS is invasive and may be poorly tolerated by patients. The aim of this study was to prospectively assess the diagnostic accuracy of a noninvasive approach in detecting POR, using the endoscopic Rutgeerts' score (RS) as the reference standard. METHODS: Consecutive patients with CD who underwent ileo-cecal resection were prospectively enrolled in 3 referral Italian centers. Patients underwent CS and bowel ultrasound within 1 year of surgery. Uni- and multivariable analyses were used to assess the correlation between noninvasive parameters and endoscopic recurrence, defined by a RS ≥2. RESULTS: Ninety-one patients were enrolled. Sixty patients (66%) experienced endoscopic POR. The multivariable analysis identified bowel wall thickness (BWT) per 1-mm increase (odds ratio [OR], 2.43; 95% confidence interval [CI], 1.21-4.89; P = .012), the presence of mesenteric lymph nodes (OR, 15.63; 95% CI, 1.48-164.54; P = .022), and fecal calprotectin (FC) values ≥50 mcg/g (OR, 8.58; 95% CI, 2.45-29.99; P < .001) as independent predictors for endoscopic recurrence. The presence of lymph nodes or the combination of BWT ≥3 mm and FC values ≥50 mcg/g correctly classified 56% and 75% of patients, with less than 5% of patients falsely classified as having endoscopic recurrence. Conversely, the combination of BWT <3 mm and FC <50 mcg/g correctly classified 74% of patients with only 4.5% of patients falsely classified as not having endoscopic recurrence. CONCLUSIONS: A noninvasive approach combining bowel ultrasound and FC can be used with confidence for detecting POR in patients with CD without the requirement for CS.

Available Methods for Benefit-risk Assessment: Lessons for Inflammatory Bowel Disease Drugs.

BACKGROUND AND AIMS: Medical treatment for inflammatory bowel disease has advanced significantly over the two past decades. The advent of biologics and small molecules has revolutionised outcomes for patients with inflammatory bowel disease. Knowledge of drug pharmacology, indications, and adverse events is essential to ensure the best clinical care while minimising toxicity. Our aim was to review the literature on current methods of benefit-risk assessment, and consider their practical applicability to inflammatory bowel disease. METHODS: A literature search was conducted to investigate studies documenting benefit-risk assessment. RESULTS: Several structured frameworks and quantitative methodologies have been developed to evaluate benefit-risk profiles of drugs in a more comprehensive and consistent framework. Quantitative methods integrate benefit and risk outcome measures or incorporate preference weights for benefit and risk criteria into the evaluation. Incorporation of preference weights from patients is an essential aspect of quantitative benefit-risk assessment. Benefit-risk assessment is still evolving in inflammatory bowel disease. CONCLUSIONS: The risks and benefits of each medical therapy must be discussed with the patient and a shared decision-making process is recommended. Future initiatives should be developed to perform a benefit-risk assessment considering the characteristics of inflammatory bowel disease drugs.

New magnetic resonance imaging sequences for fibrosis assessment in Crohn's disease: a pilot study.

BACKGROUND AND OBJECTIVE: Patients with Crohn's disease can develop intestinal strictures, containing various degrees of inflammation and fibrosis. Differentiation of the main component of a structuring lesion is the key for defining the therapeutic management. We evaluated new magnetic resonance imaging sequences (IVIM (Intravoxel Incoherent Motion imaging) and T1 mapping) for assessing fibrosis in Crohn's disease. METHODS: This was a prospective, single-center study of adult patients with Crohn's disease and magnetic resonance imaging examination, including IVIM and T1 mapping sequences, between March 2021 and April 2021. The association between the perfusion fraction (IVIM), reduction of relaxation time between pre- and postcontrast enhancement (T1 mapping), and the degree of fibrosis assessed by a visual analog scale from 0 to 10 was evaluated. RESULTS: A total of 33 patients were included. The perfusion fraction was significantly correlated with fibrosis, with lower perfusion fraction in severe fibrosis (p = .002). T1 mapping sequence was also correlated with the degree of fibrosis, reduction of relaxation time was higher in patients with severe fibrosis than in patients with mild fibrosis (p = .05). CONCLUSION: In Crohn's disease, these new tools could improve the performance of magnetic resonance imaging for transmural fibrosis quantification, and may be useful for improving care.

Ultrasound Elastography in Inflammatory Bowel Diseases: A Systematic Review of Accuracy Compared with Histopathological Assessment.

BACKGROUND AND AIMS: Ultrasound elastography [USE] is an innovative, non-invasive, promptly available, ancillary technique that has been proposed in the evaluation of intestinal fibrosis as a monitorable biomarker, in terms of stiffness. The non-invasive estimate of fibrosis by USE appears appealing for dedicated physicians, in order to optimise the treatments for inflammatory bowel disease [IBD] patients [surgical vs non-surgical]. We aimed to systematically review literature evidence on ultrasound elastography in IBD patients. METHODS: For this qualitative systematic review, we searched PubMed, EMBASE, and Scopus to identify all studies, published until October 2021, investigating the application of USE in IBD patients compared with histopathological assessment. RESULTS: Overall, 12 papers published between 2011 and 2019 were included. A total of 275 IBD patients were included: 272 Crohn's disease [CD] [98.9%] and three ulcerative colitis [UC] [1.1%]. Seven [58.3%] and four [41.6%] studies investigated strain elastography [SE] and shear wave elastography [SWE], respectively; in one study [0.1%] both techniques were addressed. The histological evaluation was largely conducted on surgical specimens and in two studies endoscopic biopsies were also included. The histological assessment was semi-quantitative in all the included studies, except for two where the fibrosis was evaluated only qualitatively. In 10/12 publications USE could accurately distinguish inflammation from fibrosis in the examined bowel tracts. CONCLUSIONS: From the preliminary available data, an overall moderate-to-good accuracy of USE in detecting histological fibrosis [10/12 studies] was found. Point-shear wave elastography has been shown to perform superiorly. Further studies are needed to confirm these evidences.

Long-term Safety and Efficacy of the Anti-MAdCAM-1 Monoclonal Antibody Ontamalimab [SHP647] for the Treatment of Ulcerative Colitis: The Open-label Study TURANDOT II.

BACKGROUND AND AIMS: Ontamalimab, a fully-human monoclonal antibody targeting MAdCAM-1, induced remission in patients with moderate-to-severe ulcerative colitis [UC] in the TURANDOT study. We aimed to assess long-term safety, tolerability, and efficacy of ontamalimab in TURANDOT II. METHODS: TURANDOT II was a phase 2, multicentre, open-label [OL] study in patients with moderate-to-severe UC who completed TURANDOT on placebo or ontamalimab (NCT01771809). Patients were randomised to 75 mg or 225 mg ontamalimab every 4 weeks for 72 weeks [OL1]. The dosage could be increased to 225 mg from Week 8 at the investigator's discretion. All patients then received 75 mg every 4 weeks for 72 weeks [OL2], followed by 6-month safety follow-up. The primary objective was safety, measured by adverse events [AEs], serious AEs [SAEs], and AEs leading to withdrawal. Mucosal healing [MH; centrally read endoscopy] was assessed. RESULTS: Of 330 patients, 180 completed OL1; 94 escalated to 225 mg; 127 completed OL2. Overall, 36.1% experienced drug-related AEs. The most common SAE [10.0%] was worsening/ongoing UC; 5.5% of patients had serious infections, the most common being gastroenteritis [0.9%]. One death and four cancers [all unrelated to ontamalimab] occurred. No PML [progressive multifocal leukoencephalopathy]/lymphoproliferative disorders occurred. Geometric mean high-sensitivity C-reactive protein [hsCRP] and faecal calprotectin decreased across OL1 in both dose groups. The proportion of patients assigned to placebo in TURANDOT achieving MH increased from 8.8% [6/68] at baseline to 35.3% at Week 16 [24/68; non-responder imputation]. The corresponding increase in the ontamalimab group was from 23.3% [61/262] to 26.7% [70/262]. CONCLUSIONS: Ontamalimab was well tolerated up to 144 weeks in patients with moderate-to-severe UC, with good safety and efficacy.

Innovative approaches to biologic development on the trail of CT-P13: biosimilars, value-added medicines, and biobetters.

The biosimilar concept is now well established. Clinical data accumulated pre- and post-approval have supported biosimilar uptake, in turn stimulating competition in the biologics market and increasing patient access to biologics. Following technological advances, other innovative biologics, such as "biobetters" or "value-added medicines," are now reaching the market. These innovative biologics differ from the reference product by offering additional clinical or non-clinical benefits. We discuss these innovative biologics with reference to CT-P13, initially available as an intravenous (IV) biosimilar of reference infliximab. A subcutaneous (SC) formulation, CT-P13 SC, has now been developed. Relative to CT-P13 IV, CT-P13 SC offers clinical benefits in terms of pharmacokinetics, with comparable efficacy, safety, and immunogenicity, as well as increased convenience for patients and reduced demands on healthcare system resources. As was once the case for biosimilars, nomenclature and regulatory pathways for innovative biologics require clarification to support their uptake and ultimately benefit patients.

Assessment of extraintestinal manifestations in inflammatory bowel diseases: A systematic review and a proposed guide for clinical trials.

BACKGROUND AND AIMS: Extraintestinal manifestations are common in inflammatory bowel disease patients, although there are few data available on their diagnosis, management and follow-up. We systematically reviewed the literature evidence to evaluate tools and investigations used for the diagnosis and for the assessment of the treatment response in inflammatory bowel disease patients with extraintestinal manifestations. METHODS: We searched in PubMed, Embase and Web of Science from January 1999-December 2019 for all interventional and non-interventional studies published in English assessing diagnostic tools and investigations used in inflammatory bowel disease patients with extraintestinal manifestations. RESULTS: Forty-five studies (16 interventional and 29 non-interventional) were included in our systematic review, enrolling 7994 inflammatory bowel disease patients. The diagnostic assessment of extraintestinal manifestations was performed by dedicated specialists in a percentage of cases ranging from 60-100% depending on the specific condition. The clinical examination was the most frequent diagnostic strategy, accounting for 35 studies (77.8%). In patients with primary sclerosing cholangitis or rheumatological symptoms, biochemical and imaging tests were also performed. Anti-TNF agents were the most used biological drugs for the treatment of extraintestinal manifestations (20 studies, 44.4%), and the treatment response varied from 59.1% in axial spondyloarthritis to 88.9% in ocular manifestations. No benefit was detected in primary sclerosing cholangitis patients after treatment with biologics. CONCLUSIONS: In the clinical management of inflammatory bowel disease patients with extraintestinal manifestations the collaboration of dedicated specialists for diagnostic investigations and follow-up is key to ensure the best of care approach. However, international guidelines are needed to homogenise and standardise the assessment of extraintestinal manifestations.