362 research outputs found
Altered colonic glycoprotein expression in unaffected monozygotic twins of inflammatory bowel disease patients
No full textBackground and aims: Previous chromatographic analysis of colonic mucins from monozygotic twins with inflammatory bowel disease (IBD) suggested a genetic mucin alteration in ulcerative colitis (UC). This study explores this further by assessing mucosal expression of the oncofetal carbohydrate antigen TF (galactose ?1, 3 N-acetylgalactosamine ?-), among the same IBD twins. Materials and methods: Formalin fixed paraffin embedded rectal biopsies were studied from 22 monozygotic twin pairs with IBD. These included eight UC twin pairs and 14 Crohn’s disease (CD) twin pairs, with six pairs concordant for disease and 16 unaffected twin siblings. Closely adjacent sections were assessed by peanut lectin histochemistry for TF expression and immunohistochemically for nuclear factor ?B (NF?B) activation with investigators blinded to the diagnosis. Results: Unaffected twins were almost all TF positive (15/16) compared with 5/29 histologically normal controls (p<0.0001). Unaffected UC (7/8) and CD twins (8/8) were similarly TF positive. TF positivity was confined mainly to the superficial epithelium and absent from the stem cell compartment of the lower crypts, suggesting that glycosylation changes are acquired rather than genetically determined. Activated NF?B was present in the surface epithelium of mucosal biopsies from 13/14 unaffected IBD twins but in only 6/22 histologically normal controls (p?=?0.0004). All 22 affected IBD twins were TF positive and 18 were positive for activated NF?B. Conclusions: Altered mucosal glycosylation in unaffected identical twins of IBD patients was confirmed in this study. This occurred in both UC and CD twins. The changes are probably acquired rather than congenital and may reflect “preinflammatory” NF?B activation. <br/
The Future of Biosimilars: Maximizing Benefits Across Immune-Mediated Inflammatory Diseases
No full textBiologics have transformed the treatment of immune-mediated inflammatory diseases such as rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). Biosimilars—biologic medicines with no clinically meaningful differences in safety or efficacy from licensed originators—can stimulate market competition and have the potential to expand patient access to biologics within the parameters of treatment recommendations. However, maximizing the benefits of biosimilars requires cooperation between multiple stakeholders. Regulators and developers should collaborate to ensure biosimilars reach patients rapidly without compromising stringent quality, safety, or efficacy standards. Pharmacoeconomic evaluations and payer policies should be updated following biosimilar market entry, minimizing the risk of imposing nonmedical barriers to biologic treatment. In RA, disparities between treatment guidelines and national reimbursement criteria could be addressed to ensure more uniform patient access to biologics and enable rheumatologists to effectively implement treat-to-target strategies. In IBD, the cost-effectiveness of biologic treatment earlier in the disease course is likely to improve when biosimilars are incorporated into pharmacoeconomic analyses. Patient understanding of biosimilars is crucial for treatment success and avoiding nocebo effects. Full understanding of biosimilars by physicians and carefully considered communication strategies can help support patients initiating or switching to biosimilars. Developers must operate efficiently to be sustainable, without undermining product quality, the reliability of the supply chain, or pharmacovigilance. Developers should also facilitate information sharing to meet the needs of other stakeholders. Such collaboration will help to ensure a sustainable future for both the biosimilar market and healthcare systems, supporting the availability of effective treatments for patient
Birth weight, sex, and celiac disease: a nationwide twin study
No full textRalf Kuja-Halkola,1 Benjamin Lebwohl,1,2 Jonas Halfvarson,3 Louise Emilsson,4–6 Patrik K Magnusson,1 Jonas F Ludvigsson1,2,7,8 1Department Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; 2Department of Medicine, Celiac Disease Center, Columbia University Medical Center, Columbia University, New York, NY, USA; 3Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; 4Department of Health Management and Health Economy, Institute of Health and Society, University of Oslo, Oslo, Norway; 5Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; 6Centre for Clinical Research, Vårdcentralen Värmlands Nysäter, County Council of Värmland, Värmland, 7Department of Pediatrics, Örebro University Hospital, Örebro, Sweden; 8Division of Epidemiology and Public Health, School of Medicine, City Hospital, University of Nottingham, Nottingham, UK Objective: Earlier research suggests that birth weight may be associated with celiac disease (CD), but the direction of association has been unclear potentially due to confounding effect from genetic and intrafamilial factors. Through within-twin analyses, we aimed to minimize confounding effects such as twins that share genetic and early environmental exposures.Materials and methods: Using the Swedish Twin Registry, we examined the birth weight of 146,830 twins according to the CD status. CD was defined as having villous atrophy according to a small intestinal biopsy reports.Results: The prevalence of diagnosed CD was 0.5% (n=669), and we included 407 discordant pairs of CD–non-CD twins. Comparing the 669 CD patients with non-CD twins, the association between birth weight and future CD was not statistically significant (odds ratio [OR] per 1000 g increase in birth weight: 1.16; 95% confidence interval [CI]=0.97–1.38). In males, the association was positive and statistically significant (OR=1.50; 95% CI=1.11–2.02). However, the association was not significant in within-pair analyses for both dizygotic and monozygotic twins and for both sexes.Conclusion: This population-based study found that in male twins, higher birth weight was associated with higher risk of CD. However, when comparing discordant twin pairs in within-twin pair analyses, there was no statistically significant association between birth weight, intrauterine growth, and future risk of CD. Keywords: autoimmune, gestational age, gluten, registries, risk factors, twin
Metabolomics reveals metabolic biomarkers of Crohn's disease
No full textThe causes and etiology of Crohn's disease (CD) are currently unknown although both host genetics and environmental factors play a role. Here we used non-targeted metabolic profiling to determine the contribution of metabolites produced by the gut microbiota towards disease status of the host. Ion Cyclotron Resonance Fourier Transform Mass Spectrometry (ICR-FT/MS) was used to discern the masses of thousands of metabolites in fecal samples collected from 17 identical twin pairs, including healthy individuals and those with CD. Pathways with differentiating metabolites included those involved in the metabolism and or synthesis of amino acids, fatty acids, bile acids and arachidonic acid. Several metabolites were positively or negatively correlated to the disease phenotype and to specific microbes previously characterized in the same samples. Our data reveal novel differentiating metabolites for CD that may provide diagnostic biomarkers and/or monitoring tools as well as insight into potential targets for disease therapy and prevention
Should we use vedolizumab as mono or combo therapy in ulcerative colitis?
No full textRandomized controlled trials comparing the efficacy of vedolizumab monotherapy with combination therapy of vedolizumab and an immunomodulator in patients with ulcerative colitis (UC) are lacking. Emerging pharmacokinetic data indicate that vedolizumab concentrations correlate with clinical outcomes, although the correlation may be less strong for vedolizumab compared with an anti-TNF agents. Associations between concomitant use of immunomodulators and decreased immunogenicity of vedolizumab have been reported, but this does not appear to translate into enhanced therapeutic effect of combination therapy, at least not based on present data. However, data are sparse and often based on post-hoc analyses. Future comparative effectiveness studies of patients with UC, naive to vedolizumab as well as immunomodulators, are needed. This might be of specific relevance for subgroups of UC patients, such as young men and the elderly, in whom combination versus monotherapy therapy may have a different risk-benefit ratio, given the risk of malignancy associated with immunomodulators. (C) 2018 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).</p
Defining Comprehensive Disease Control for Use as a Treatment Target for Ulcerative Colitis in Clinical Practice: International Delphi Consensus Recommendations
No full textBackground and Aims: Treatment of ulcerative colitis [UC] requires a patient-centric definition of comprehensive disease control that considers improvements in aspects not typically captured by classical landmark trial endpoints. In an international initiative, we reviewed aspects of UC that affect patients and/or indicate mucosal inflammation, to achieve consensus on which aspects to combine in a definition of comprehensive disease control, using a modified Delphi process. Methods: The Delphi panel comprised 12 gastroenterologists and one patient advocate. Two gastroenterologists were elected as chairs and did not vote. To inform statements, we asked 18 patients and the panel members about their experiences of remission and reviewed published literature. Panel members voted on statements anonymously in three rounds, with a live discussion before Round 3. Consensus was met if ≥67% of the panel agreed. Statements without consensus in Rounds 1 and 2 were revised or discarded after Round 3. Results: The panel agreed to measure individual patient benefit using a definition of comprehensive disease control that combines aspects currently measured in trials [rectal bleeding, stool frequency, disease-related quality of life, endoscopy, histological inflammatory activity, inflammatory biomarkers, and corticosteroid use] with additional patient-reported symptoms [bowel urgency, abdominal pain, extraintestinal manifestations, fatigue, and sleep disturbance]. The panel agreed on scoring systems and thresholds for many aspects. Conclusions: Using a robust methodology, we defined comprehensive disease control in UC. Next, we will combine the measurement and scoring of these aspects into a multicomponent tool and will adopt comprehensive disease control as a treatment target in clinical practice and trials.</p
Multiple Polymorphisms Affect Expression and Function of the Neuropeptide S Receptor (NPSR1)
No full textPeer reviewe
Medical and surgical treatment of inflammatory bowel disease
No full textInflammatory bowel disease (IBD), with its two main entities Crohn's disease (CD) and ulcerative colitis (UC), is a chronic and relapsing inflammatory condition affecting the entire gastrointestinal tract. IBD is associated with reduced health-related quality of life, substantial loss of work productivity and increased morbidity. In Sweden alone, around 70 000 persons are estimated to be affected by IBD. Treatment includes both medical and surgical therapy. In case of failure or intolerance to conventional medical therapies, remaining treatment options are surgery or newer medical therapies such as biological agents. However, a sizeable number of patients do not respond or lose response to a certain biological agent, hence there is still a need to expand the knowledge about therapeutic options in IBD. This thesis therefore aimed to explored real-world clinical outcomes of a recent biological therapy. Using registered-based data, the thesis also investigated epidemiological aspects of IBD including the validity of IBD-related surgical procedure codes and the incidence of IBD in Sweden.In Study I, we validated IBD-related surgical procedure codes in the Swedish National Patient Register (NPR). We conducted the validation through patient chart review in a nationwide random sample of 262 patients with registered IBD diagnoses in the NPR between 1966 and 2014. We found high validity and high sensitivity for IBD-related surgical procedure codes in the NPR with a positive predictive value of 96.8% and a sensitivity of 94.5%. Our study indicated that the NPR is a reliable data source for researchers wanting to identify patients with a history of IBD-related surgery.In Studies II and III, we conducted a nationwide prospective observational real-world study of clinical, biochemical and health-related quality of life outcomes in CD patients treated with ustekinumab according to clinical practice. We included a total of 114 patients initiated on ustekinumab treatment during 2017 and 2018 at 20 different hospitals. We found significant improvements of almost all outcome measures and both short-term (Study II) and long-term (Study III) response and remission to treatment. Our study contributes to the knowledge about the real-world effectiveness and safety of ustekinumab for treatment of moderate to severe CD.In Study IV, we estimated the nationwide incidence of IBD and subtypes (CD, UC and IBDunclassified) and investigated differences between age-groups and sexes in Sweden 1990- 2014. We used a combination of diagnostic codes for IBD in the NPR and biopsy data from the ESPRESSO histopathology cohort to identify incident cases (N=65 908) during the study period. We found evidence of increasing incidence rates (IRs) in all subtypes 1990-2001, but signs of stabilising or decreasing IRs 2002-2014. We also showed differences in IRs between males and females related to age and calendar period. Our results contribute to the knowledge about temporal trends of IBD incidence in Sweden of importance for future research, and possibly also for healthcare resource planners.In conclusion, this thesis gave evidence of the NPR as a reliable and valid data source for researchers wanting to identify patients with previous IBD-related surgery. It also enhanced knowledge about the real-world effectiveness of ustkinumab, beneficial for patients suffering from CD. Finally, it shed light on previous contradicting estimates of the temporal trends of the incidence of IBD in Sweden.List of scientific papersI. Forss, A, Myrelid, P, Olén, O, Everhov H, Å, Nordenvall, C, Halfvarson, J, Ludvigsson, JF. Validating surgical procedure codes for inflammatory bowel disease in the Swedish National Patient Register. BMC Medical Informatics and Decision Making. 19:217 (2019). https://doi.org/10.1186/s12911-019-0948-z II. Forss, A, Clements, M, Myrelid, P, Strid, H, Söderman, C, Wagner, A, Andersson, D, Hjelm, F, The PROSE SWIBREG study group, Olén, O, Ludvigsson, JF, Halfvarson, J. Prospective observational study on Stelara (ustekinumab) assessing effectiveness in Crohn’s disease (PROSE): a 16-week follow-up. Scandinavian Journal of Gastroenterology. 56:6;680-686 (2021). https://doi.org/10.1080/00365521.2021.1906946 III. Forss, A, Clements, M, Myrelid, P, Strid, H, Söderman, C, Wagner, A, Andersson, D, Hjelm, F, The PROSE SWIBREG study group, Olén, O, Halfvarson, J, Ludvigsson, JF. A two-year prospective observational study on ustekinumab assessing effectiveness and health-related quality of life in Crohn’s disease (PROSE). [Submitted]IV. Forss, A, Clements, M, Bergman, D, Roelstraete, B, Kaplan, G, Myrelid, P, Halfvarson, J, Olén, O, Ludvigsson, JF. A nationwide cohort study of the incidence of inflammatory bowel disease in Sweden from 1990-2014. Alimentary Pharmacology & Therapeutics. https://doi.org/10.1111/apt.16735 </p
I-CARE, a European Prospective Cohort Study Assessing Safety and Effectiveness of Biologics in Inflammatory Bowel Disease
No full textBackground 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
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