Quality of Life and Work Productivity Improvements with Upadacitinib: Phase 2b Evidence from Patients with Moderate to Severe Crohn’s Disease

Introduction: In the phase 2 CELEST study, positive efficacy results were obtained with the Janus kinase 1 inhibitor upadacitinib for adult patients with moderate to severe Crohn’s disease. We present the health-related quality of life and work productivity improvement results with upadacitinib from CELEST. Methods: CELEST (NCT02365649) was a double-blind study where patients were randomized 1:1:1:1:1:1 in the 16-week induction period to placebo or upadacitinib 3 mg twice daily (BID), 6 mg BID, 12 mg BID, 24 mg BID, or 24 mg once daily (QD). Patients completing the induction period were re-randomized 1:1:1 to receive upadacitinib 3 mg BID, 12 mg BID, or 24 mg QD for 36 weeks or 3 mg BID, 6 mg BID, or 12 mg BID (after amendment). Inflammatory Bowel Disease Questionnaire (IBDQ), European Quality of Life-5 Dimensions visual analog scale (EQ-5D VAS), and Work Productivity and Activity Impairment (WPAI) questionnaire outcomes were assessed at baseline and Weeks 8, 16, and 52. Results: At Week 16, a significant percentage (P ≤ 0.05) of patients receiving upadacitinib 6-mg BID dose or higher achieved IBDQ response (IBDQ score change ≥ 16 points; 49%–57% for upadacitinib vs. 24% for placebo) and IBDQ remission, except 24 mg QD (IBDQ score ≥ 170; 26%–39% for upadacitinib vs. 11% for placebo). Greater improvements in IBDQ total score, EQ-5D VAS, and activity impairment from baseline (P ≤ 0.1) versus placebo were also observed. Larger improvements (P ≤ 0.1) in IBDQ response and total score and EQ-5D VAS were observed at Week 8 with 6 and 24 mg BID versus placebo, with improvements for all dosages maintained or greater at Week 52 for IBDQ, EQ-5D VAS, and WPAI endpoints, in particular for the 12-mg BID group. Conclusion: Improvements in health-related quality of life and work productivity were achieved and sustained with upadacitinib in patients with moderate to severe Crohn’s disease. Trial Registration: ClinicalTrials.gov identifier, NCT02365649. © 2021, The Author(s)

Comparative performances of machine learning methods for classifying Crohn Disease patients using genome-wide genotyping data

© 2019, The Author(s). Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people according to their genomic information. The Immunochip dataset containing 18,227 CD patients and 34,050 healthy controls enrolled and genotyped by the international Inflammatory Bowel Disease genetic consortium (IIBDGC) has been re-analyzed using a set of ML methods: penalized logistic regression (LR), gradient boosted trees (GBT) and artificial neural networks (NN). The main score used to compare the methods was the Area Under the ROC Curve (AUC) statistics. The impact of quality control (QC), imputing and coding methods on LR results showed that QC methods and imputation of missing genotypes may artificially increase the scores. At the opposite, neither the patient/control ratio nor marker preselection or coding strategies significantly affected the results. LR methods, including Lasso, Ridge and ElasticNet provided similar results with a maximum AUC of 0.80. GBT methods like XGBoost, LightGBM and CatBoost, together with dense NN with one or more hidden layers, provided similar AUC values, suggesting limited epistatic effects in the genetic architecture of the trait. ML methods detected near all the genetic variants previously identified by GWAS among the best predictors plus additional predictors with lower effects. The robustness and complementarity of the different methods are also studied. Compared to LR, non-linear models such as GBT or NN may provide robust complementary approaches to identify and classify genetic markers

Composite Outcomes in Observational Studies of Ulcerative Colitis: a Systematic Review and Meta‐Analysis

Background: Ulcerative colitis (UC) has been the focus of numerous observational studies over the years and a common strategy employed in their design is the use of composite and aggregate outcomes. Objective: This systematic review and meta-analysis aims to identify composite and aggregate outcomes of observational studies in UC and to evaluate how the number and type of variables included and the length of follow-up affect the frequency of patients that achieve these outcomes. Methods: A systematic literature search was carried out using MEDLINE [via PubMed], Scopus, and Web of Science online databases. Observational studies that included UC patients and reported composite or aggregate outcomes were identified. A set of variables considered to be representative of progressive or disabling UC was defined, the proportion of patients attaining the outcomes was determined and a random-effects meta-analysis was performed by dividing the identified studies into subgroups according to different criteria of interest. Results: A total of 10,264 records were identified in the systematic search, of which 33 were retained for qualitative analysis and 20 were included in the meta-analysis. The mean frequency for composite outcomes was 0.363 [95% confidence interval (CI) 0.323-0.403]. The frequency of composite outcome for the subgroup of studies that included the variable "Biologics" was significantly higher than for those in which this variable was not reported [0.410; 95% CI 0.364-0.457 versus 0.298; 95% CI 0.232-0.364; p = 0.006]. Composite outcomes were also more frequent as the follow-up duration increased. Conclusion: The frequency of composite outcomes in observational studies of UC is dependent on the specific identity of the variables being reported. Moreover, longer follow-up periods are associated with higher frequencies of composite outcomes. The evidence provided here is useful for the design of future observational studies of UC that aim to maximize the frequency of patients that achieve composite outcomes.info:eu-repo/semantics/publishedVersio

A systematic review of factors associated with non-adherence to treatment for immune-mediated inflammatory diseases.

Background: Non-adherence impacts negatively on patient health outcomes and has associated economic costs. Understanding drivers of treatment adherence in immune-mediated inflammatory diseases is key for the development of effective strategies to tackle non-adherence. Objective: To identify factors associated with treatment non-adherence across diseases in three clinical areas: rheumatology, gastroenterology, and dermatology. Design: Systematic review Data sources: Articles published in PubMed, Science Direct, PsychINFO and the Cochrane Library from 1 January 1980 to 14 February 2014. Study selection: Studies were eligible if they included patients with a diagnosis of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease, or psoriasis and included statistics to examine associations of factors with non-adherence. Data extraction: Data were extracted by the first reviewer using a standardised 23-item form and verified by a second/ third reviewer. Quality assessment was carried out for each study using a 16-item quality checklist. Results: 73 studies were identified for inclusion in the review. Demographic or clinical factors were not consistently associated with non-adherence. Limited evidence was found for an association between non-adherence and treatment factors such as dosing frequency. Consistent associations with adherence were found for psychosocial factors, with the strongest evidence for the impact of the healthcare professional-patient relationship, perceptions of treatment concerns and depression, lower treatment self-efficacy and necessity beliefs, and practical barriers to treatment. Conclusions: While examined in only a minority of studies, the strongest evidence found for non-adherence were psychosocial factors. Interventions designed to address these factors may be most effective in tackling treatment non-adherence

Unmet Medical Needs in Ulcerative Colitis: An Expert Group Consensus

BACKGROUND The authors aimed to conduct an extensive literature review and consensus meeting to identify unmet needs in ulcerative colitis (UC) and ways to overcome them. UC is a relapsing and remitting inflammatory bowel disease with varied, and changing, incidence rates worldwide. UC has an unpredictable disease course and is associated with a high health economic burden. During 2016 and 2017, a panel of experts was convened to identify, discuss and address areas of unmet need in UC. METHODS PubMed and Cochrane Library databases were searched for relevant articles describing studies performed in patients with UC. These findings were used to generate a set of statements relating to unmet needs in UC. Consensus on these statements was then sought from a panel of 9 expert gastroenterologists using a modified Delphi review process that consisted of anonymous surveys followed by live meetings. RESULTS In 2 literature reviews, over 5,000 unique records were identified and a total of 138 articles were fully reviewed. These were used to consider 26 areas of unmet need, which were explored in 2 face-to-face meetings, in which the statements were debated and amended, resulting in consensus on 30 final statements. The unmet needs identified were categorised into 7 areas: impact of UC on patients' daily life; importance of early diagnosis and treatment; drawbacks of existing treatments; urgent need for new treatments; and disease-, practice- or patient-focused unmet needs. CONCLUSIONS These expert group meetings found a number of areas of unmet needs in UC, which is an important first step in tackling them in the future. Future research and development should be focused in these areas for the management of patients with UC

Development of Red Flags Index for Early Referral of Adults with Symptoms and Signs Suggestive of Crohn's Disease: An IOIBD Initiative

International audience; BACKGROUND AND AIMS:Diagnostic delay is frequent in patients with Crohn's disease (CD). We developed a tool to predict early diagnosis.METHODS:A systematic literature review and 12 CD specialists identified 'Red Flags', i.e. symptoms or signs suggestive of CD. A 21-item questionnaire was administered to 36 healthy subjects, 80 patients with irritable bowel syndrome (non-CD group) and 85 patients with recently diagnosed (<18 months) CD. Patients with CD were asked to recall symptoms and signs they experienced during the 12 months before diagnosis. Multiple logistic regression analyses selected and weighted independent items to construct the Red Flags index. A receiver operating characteristic curve was used to assess the threshold that discriminated CD from non-CD. Association with the Red Flags index relative to this threshold was expressed as the odds ratios (OR).RESULTS:Two hundred and one subjects, CD and non-CD, answered the questionnaire. The multivariate analysis identified eight items independently associated with a diagnosis of CD. A minimum Red Flags index value of 8 was highly predictive of CD diagnosis with sensitivity and specificity bootstrap estimates of 0.94 (95% confidence interval 0.88-0.99) and 0.94 (0.90-0.97), respectively. Positive and negative likelihood ratios were 15.1 (9.3-33.6) and 0.066 (0.013-0.125), respectively. The association between CD diagnosis and a Red Flags index value of ≥8 corresponds to an OR of 290 (p < 0.0001).CONCLUSIONS:The Red Flags index using early symptoms and signs has high predictive value for the diagnosis of CD. These results need prospective validation prior to introduction into clinical practice

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

The LUCID study: living with ulcerative colitis; identifying the socioeconomic burden in Europe

Background Ulcerative colitis (UC) is an inflammatory bowel disease with increasing prevalence worldwide. Current treatment strategies place considerable economic and humanistic burdens on patients. The aim of this study was to determine the socioeconomic burden of UC in adult patients in European countries in a real-world setting. Methods In this retrospective, cross-sectional and observational pan-European study, patients with moderate or severe UC were assigned to ARM 1 and patients who had moderate or severe UC but achieved mild or remission status 12 months before index date (or clinical consultation date), were assigned to ARM 2. Clinical and medical resource use data were collected via electronic case report forms, and data on non-medical and indirect costs, and health-related quality of life (HRQoL) were collected via patient and public involvement and engagement (PPIE) questionnaires. Per-patient annual total costs per ARM and per country were calculated using the collated resource use in the last 12 months (between the start of the documentation period and patient consultation or index date) and country specific unit costs. Quality of life was described by arm and by country. Results In the physician-reported eCRF population (n = 2966), the mean annual direct medical cost was €4065 in ARM 1 (n = 1835) and €2935 in ARM 2 (n = 1131). In the PPIE population (ARM 1, n = 1001; ARM 2, n = 647), mean annual direct cost was €4526 in ARM 1 and €3057 in ARM 2, mean annual direct non-medical cost was €1162 in ARM 1 and €1002 in ARM 2, mean annual indirect cost was €3098 in ARM 1 and €2309 ARM 2, and mean annual total cost was in €8787 in ARM 1 and €6368 in ARM 2. HRQoL scores showed moderate to high burden of UC in both groups. Conclusions The cost and HRQoL burden were high in patients in both ARM 1 and ARM 2 indicating unmet needs in the UC active population

I-CARE, a European Prospective Cohort Study Assessing Safety and Effectiveness of Biologics in Inflammatory Bowel Disease

Background and aims: There is a need to evaluate the benefit-risk ratio of current therapies in inflammatory bowel disease (IBD) patients to provide the best quality of care. The primary objective of I-CARE (IBD Cancer and serious infections in Europe) was to assess prospectively safety concerns in IBD, with specific focus on the risk of cancer/lymphoma and serious infections in patients treated with anti-tumor necrosis factor and other biologic monotherapy as well as in combination with immunomodulators.. Methods: I-CARE was designed as a European prospective longitudinal observational multicenter cohort study to include patients with a diagnosis of Crohn's disease, ulcerative colitis, or IBD unclassified established at least 3 months prior to enrollment. Results: A total of 10,206 patients were enrolled between March 2016 and April 2019, including 6169 (60.4%) patients with Crohn's disease, 3853 (37.8%) with ulcerative colitis, and 184 (1.8%) with a diagnosis of IBD unclassified. Thirty-two percent of patients were receiving azathioprine/thiopurines, 4.6% 6-mercaptopurine, and 3.2% methotrexate at study entry. At inclusion, 47.3% of patients were treated with an anti-tumor necrosis factor agent, 8.8% with vedolizumab, and 3.4% with ustekinumab. Roughly one-quarter of patients (26.8%) underwent prior IBD-related surgery. Sixty-six percent of patients had been previously treated with systemic steroids. Three percent of patients had a medical history of cancer prior to inclusion and 1.1% had a history of colonic, esophageal, or uterine cervix high-grade dysplasia.. Conclusions: I-CARE is an ongoing investigator-initiated observational European prospective cohort study that will provide unique information on the long-term benefits and risks of biological therapies in IBD patients