9 research outputs found
Prognostic factors in Chronic Inflammatory Diseases:A PhD study within clinical epidemiology
Get PDFBaggrund: Kroniske inflammatoriske sygdomme (CIDs) associeret med en vestlig livsstil inkluderer Crohn’s sygdom, colitis ulcerosa, reumatoid artrit, axial spondylartrit, psoriasis artrit og psoriasis, der alle er tæt relaterede. De er en stor byrde for patienterne og sundhedssystemet og er desværre ikke mulige at kurere. Derfor er målet med behandlingen af disse sygdomme at dæmpe symptomer og forhindre sygdomsforværring og komplikationer. Biologiske lægemidler har revolutioneret behandlingen af CIDs, men succes raten er langt fra optimal.Formål: Det overordnede formål for dette Ph.d. projekt var derfor at forbedre behandlingen af disse sygdomme ved at identificere prognostiske kost faktorer og sikre troværdig evidens. Formålene for de enkelte studier var:I. At undersøge om behandlingsrespons til biologiske lægemidler var associeret med det relative indtag af kostfibre og rødt og forarbejdet kød i patienter med CIDs II. At identificere og karakterisere kostmønstre blandt patienter med CIDs and undersøge om patient karakteristika var associeret med disse mønstre III. At undersøge indflydelsen af patient frafald i randomiserede kliniske forsøg af patienter med CIDs behandlet med biologiske og syntetiske targeterede lægemidler Metode: Patienter med CIDs der skulle opstarte i biologisk behandling blev løbende inkluderet i en prospektiv kohorte. De gennemgik en klinisk undersøgelse inden opstart og efter 14-16 ugers behandling for at vurdere sygdoms aktivitet. Inden behandlingsstart besvarede de et kostspørgeskema hvorfra vi kunne estimere deres kost indtag. Baseret på de longitudinelle data fra kohorten (studie I) undersøgte vi om behandlingsrespons til de biologiske lægemidler var associeret med indtag af kostfibre og rødt og forarbejdet kød ved at opdele patienterne i to grupper baseret på fibre/kød ratioen (en gruppe med højt fibre- og lavt rødt/forarbejdet kød indtag og en gruppe med det modsatte).I en tværsnits analyse af baseline data (studie II) identificerede og karakteriserede vi kostmønstre og de dertil hørende patienter ved hjælp af specifikke statistiske analyser (eksploratorisk faktor analyse, latent profil analyse og deskriptive analyser).I et meta-epidemiologisk studie (studie III) samlede vi randomiserede forsøg, der undersøgte effekten af biologiske og targeterede syntetiske lægemidler til behandling af CIDs. Fra disse indsamlede vi information om behandlingseffekt og patient frafald. Vi kombinerede studierne ved hjælp af metaregressions modeller hvorved vi kunne analysere om frafald og behandlingsrespons var associeret og derved få et mål for frafalds indflydelse på studieresultaterne.Resultater I studie I fandt vi ud af, at et højt indtag af kostfibre i kombination med et lavt indtag af rødt og forarbejdet kød ikke var associeret med behandlingsrespons på tværs af de seks sygdomme (OR=1.48, 95% konfidens interval 0.72-3.05). Men vores resultater indikerede, at der var en gavnlig effekt blandt patienter med reumatoid artrit (OR=9.84, 1.35-71.56). I studie II identificerede vi tre kostmønstre (’Kød og Salt’, ’Grønt’ og ’Blandet’), som varierede i de ernærings-relaterede men ikke i de patient-relaterede karakteristika. Fælles for alle tre kostmønstre var at indtaget af specifikke næringsstoffer og fødevarer var enten for højt eller for lavt som typisk for den vestlige kost.I studie III fandt vi en høj grad af differentieret frafald mellem interventions og kontrol grupperne (OR=0.45, 0.41-0.50) i de randomiserede studier med mere frafald blandt kontrol grupperne. Odds for behandlingseffekt var 4.39 gange højere i interventionsgrupperne (OR=3.94-4.89). Dette estimat var negativt associeret med estimatet for differentieret frafald, hvilket betyder, at studier med et højere frafald i kontrol gruppen viste bedre estimater for behandlingseffekt.Konklusion: Patienterne med CIDs spiste generelt ikke svarende til anbefalingerne for sund kost, og kostmønstre blandt dem var ikke forbundet med en bestemt patient fænotype. Et højt kostfiber- og lavt rødt/forarbejdet kød indtag var ikke prognostisk for bedre behandlingsrespons på tværs af de seks CIDs, men viste et potentiale for patienter med reumatoid artrit, hvilket kræver yderligere bekræftelse i randomiserede forsøg.Målrettede kostændringer som en del af behandlingen af CIDs har et lovende potentiale, men der er brug for evidens-baserede retningslinjer. For at skabe denne evidens base er det vigtigt at vurdere den eksisterende evidens kritisk, hvilket bl.a. involverer en vurdering af om patient frafald har indflydelse på resultaterne.Background: Chronic inflammatory diseases (CIDs) associated with the Western lifestyle include Crohn’s disease, ulcerative colitis, rheumatoid arthritis, axial spondyloarthritis, psoriatic arthritis and psoriasis and are all closely related. These diseases are a considerable burden for patients and society; unfortunately, there is no cure. Thus, the therapeutic goal is to relieve symptoms and prevent disease progression and morbidity. Biological disease-modifying drugs have revolutionised the treatment of CIDs, but remission rates are less than optimal.Aim: Therefore, the generic aim of this PhD was to improve the treatment of these CIDs by identifying dietary prognostic factors and ensuring trustworthy evidence. The aims of the individual studies were: I. To investigate if the treatment response of biological therapy is associated with habitual dietary intakes of fibre and red/processed meat in patients with CIDs II. To identify and characterise dietary patterns among patients with CIDs and investigate whether patient characteristics were associated with these patterns III. To explore the impact of attrition rates in randomised trials of patients with CIDs treated with biological and targeted synthetic disease-modifying drugsMethods: We prospectively enrolled patients with one of the six CID diagnoses and a plan to initiate biological therapy. The patients were clinically assessed before and after 14-16 weeks of treatment. At baseline, patients completed a food frequency questionnaire enabling estimation of habitual dietary intake. Based on the cohort’s longitudinal data, we stratified patients into two groups determined by the ratio of fibre to red/processed meat (a high fibre/low meat group and a low fibre/high meat group) to compare the proportion of clinical response after 14-16 of treatment (study I).In a cross-sectional analysis of the baseline data, we identified and characterised dietary patterns and the dietary pattern membership for each patient using explorative factor, latent profile and descriptive analyses (study II).In a meta-epidemiological study, we synthesised randomised trials testing the effect of biological and synthetic targeted disease-modifying drugs in patients with CIDs (study III). We extracted information on treatment effects and attrition and combined the trials using meta-regression models to analyse the associations between treatment effects and attrition.ResultsIn study I, we found that a high intake of ‘dietary fibre and low intake of red/processed meat’ was not associated with better treatment response across the group of CIDs (OR=1.48, 95% CI 0.72 to 3.05). However, the results indicated a beneficial effect among rheumatoid arthritis patients (OR=9.84, 1.35 to 71.56). In study II, we identified and characterised three dietary patterns, i.e., the ‘Meat and Salt’, the ‘Vegetables’ and the ‘Mixed’ dietary pattern, which varied in nutrient profiles but were similar in patient characteristics. Common for all three patterns were excessive and deficient intake of nutrients typical of the Western diet.In study III, differential attrition prevailed among randomised trials, with more attrition in control than intervention groups (OR=0.45, 0.41 to 0.50). The odds of treatment benefit were 4.39 (3.94 to 4.89) higher in the intervention groups. This estimate was inversely associated with the OR for differential attrition, meaning that trials with the most attrition in the control groups were connected to better treatment effect estimates.Conclusion: In conclusion, CID patients do not generally eat according to recommendations for healthy eating and prevailing dietary patterns among them were not associated with specific phenotypes. A high intake of fibre in combination with a low intake of red/processed meat did not affect the clinical response to biological treatment across the six CIDs but showed a beneficial effect among RA patients, warranting confirmation in randomised trials. Targeting diet as one of the modifiable risk factors for treating CIDs has promising potentials, but evidence-based guidelines are urgently needed. The validity of research findings must be critically appraised to establish such an evidence base, which encompasses assessing the risk of attrition bias, including evaluating the presence of differential attrition. <br/
Stored Intestinal Biopsies in Inflammatory Bowel Disease Research: A Danish Nationwide Population-Based Register Study
Get PDFBackground. Inflammatory bowel disease (IBD), encompassing Crohn’s disease (CD) and ulcerative colitis (UC), is a complex inflammatory condition affecting the intestinal tract. Currently, immune-modulating treatments are inadequate for 30–50% of patients and often cause significant side effects, highlighting the urgent need for a personalized medicine approach. Real-world data and archived gut biological material from clinical repositories could be a resource for identifying new drug candidates and biomarkers. This study assesses the extent of stored formalin-fixed, paraffin-embedded (FFPE) gut biopsies from patients with IBD that could be leveraged for research efforts. Methods. Data from the Danish National Patient Register and the Danish Pathology Register were used to construct a cohort of patients diagnosed with IBD between 1 January 2005, and 30 June 2013, and followed for five years. Results. Among 14,512 IBD patients, 13,936 (96%) had at least one biopsy visit within five years after their initial diagnosis (CD 94%, UC 97%), and 13,598 (94%) had their first biopsy visit as part of the diagnostic process. Biopsies were taken from the colon (82%) or multiple locations (46%). Patients with severe disease had more biopsy visits than those with non-severe disease (IBD 3.3 vs. 2.0 visits, CD 2.9 vs. 1.9 visits, UC 3.6 vs. 2.0 visits). Conclusions. Thus, the vast majority of patients with IBD have biopsies taken. These findings demonstrate the feasibility and applicability of combining real-world data and archived gut biopsies for research, highlighting it as a valuable but underutilized resource for identifying new drug candidates and biomarkers, with huge potential for enhancing personalized medicine within IBD for the benefit of patients and society
Bovine Milk Oligosaccharides with Sialyllactose Improves Cognition in Preterm Pigs
Get PDFOptimal nutrition is important after preterm birth to facilitate normal brain development. Human milk is rich in sialic acid and preterm infants may benefit from supplementing formula with sialyllactose to support neurodevelopment. Using pigs as models, we hypothesized that sialyllactose supplementation improves brain development after preterm birth. Pigs (of either sex) were delivered by cesarean section at 90% gestation and fed a milk diet supplemented with either an oligosaccharide-enriched whey with sialyllactose (n = 20) or lactose (n = 20) for 19 days. Cognitive performance was tested in a spatial T-maze. Brains were collected for ex vivo magnetic resonance imaging (MRI), gene expression, and sialic acid measurements. For reference, term piglets (n = 14) were artificially reared under identical conditions and compared with vaginally born piglets naturally reared by the sow (n = 12). A higher proportion of sialyllactose supplemented preterm pigs reached the T-maze learning criteria relative to control preterm pigs (p <0.05), and approximated the cognition level of term reference pigs (p <0.01). Furthermore, supplemented pigs had upregulated genes related to sialic acid metabolism, myelination, and ganglioside biosynthesis in hippocampus. Sialyllactose supplementation did not lead to higher levels of sialic acid in the hippocampus or change MRI endpoints. Contrary, these parameters were strongly influenced by postconceptional age and postnatal rearing conditions. In conclusion, oligosaccharide-enriched whey with sialyllactose improved spatial cognition, with effects on hippocampal genes related to sialic acid metabolism, myelination, and ganglioside biosynthesis in preterm pigs. Dietary sialic acid enrichment may improve brain development in infants
Impact of Obesity on Treatment Response in Patients With Chronic Inflammatory Disease Receiving Biologic Therapy:Secondary Analysis of the Prospective Multicentre BELIEVE Cohort Study
Get PDFBiological therapy is used to treat chronic inflammatory diseases (CIDs); however, up to 50% of patients fail to achieve an adequate clinical response. This study aimed to access the impact of obesity on clinical treatment response in CID patients after 14–16 weeks of biological therapy. This multicentre prospective cohort study enrolled 233 adults between 2017 and 2020 diagnosed with Crohn disease, ulcerative colitis (UC), rheumatoid arthritis, axial spondyloarthritis (PsA), psoriatic arthritis or psoriasis scheduled for biologic therapy. The main analysis population included patients with BMI data before treatment initiation, categorising patients as either obese (BMI ≥ 30 kg/m2) or non-obese (BMI < 30 kg/m2). The primary endpoint was the proportion of patients achieving clinical treatment response after 14–16 weeks. Main analyses were based on logistic regression with a factor for obesity, while adjusted for sex and age. Of the 228 patients eligible for the main analyses, 125 (55%) responded to biologic therapy. In the obese group (n = 59), 30 (51%) patients responded compared to the 95 (56%) individuals categorised as non-obese (n = 169), with no difference between groups (OR: 0.82, 95% CI: 0.43 to 1.60). This study did not find a lower likelihood of response to biologics in obese individuals compared with non-obese counterparts. Trial Registration: ClinicalTrials.gov identifier: NCT03173144.</p
Impact of gluten intake on clinical outcomes in patients with chronic inflammatory diseases initiating biologics:Secondary analysis of the prospective multicentre BELIEVE cohort study
Get PDFChronic inflammatory diseases (CIDs) pose a growing healthcare challenge, with a substantial proportion of patients showing inadequate response to biological treatment. There is renewed interest in dietary changes to optimize treatment regimens, with a growing body of evidence suggesting beneficial effects with adherence to a gluten-free diet. This study compared the likelihood of achieving clinical response to biological treatment after 14–16 weeks in patients with CID with high versus low-to-medium gluten intake. Secondary outcomes of interest included changes in disease activity, health-related quality of life and C-reactive protein. The study was a multicentre prospective cohort of 193 participants with a CID diagnosis (i.e. Crohn's Disease, Ulcerative Colitis, Rheumatoid Arthritis, Axial Spondyloarthritis, Psoriatic Arthritis or Psoriasis) who initiated biological treatment between 2017 and 2020. Participants were stratified based on their habitual gluten intake: the upper 33.3% (high gluten intake) and the remaining 66.6% (low-to-medium gluten intake). The proportion of patients achieving clinical response to biological treatment after 14–16 weeks was compared using logistic regression models. The median gluten intake differed significantly between groups (12.5 g/day vs. 5.9 g/day, standardized mean difference = 1.399). In total, 108 (56%) achieved clinical response to treatment, with no difference between 35 (55%) in the high gluten group and 73 (57%) in the medium-to-low gluten group (OR = 0.96 [0.51–1.79], p = 0.897). No differences were found with secondary outcomes. In conclusion, this study found no association between gluten intake and response to biological treatment in patients with CID.</p
Effects of smoking on clinical treatment outcomes amongst patients with chronic inflammatory diseases initiating biologics:secondary analyses of the prospective BELIEVE cohort study
Get PDFThe prevalence and disease burden of chronic inflammatory diseases (CIDs) are predicted to rise. Patients are commonly treated with biological agents, but the individual treatment responses vary, warranting further research into optimizing treatment strategies. This study aimed to compare the clinical treatment responses in patients with CIDs initiating biologic therapy based on smoking status, a notorious risk factor in CIDs. In this multicentre cohort study including 233 patients with a diagnosis of Crohn's disease, ulcerative colitis, rheumatoid arthritis, axial spondyloarthritis, psoriatic arthritis or psoriasis initiating biologic therapy, we compared treatment response rates after 14 to 16 weeks and secondary outcomes between smokers and non-smokers. We evaluated the contrast between groups using logistic regression models: (i) a “crude” model, only adjusted for the CID type, and (ii) an adjusted model (including sex and age). Among the 205 patients eligible for this study, 53 (26%) were smokers. The treatment response rate among smokers (n = 23 [43%]) was lower compared to the non-smoking CID population (n = 92 [61%]), corresponding to a “crude” OR of 0.51 (95% CI: [0.26;1.01]) while adjusting for sex and age resulted in consistent findings: 0.51 [0.26;1.02]. The contrast was apparently most prominent among the 38 RA patients, with significantly lower treatment response rates for smokers in both the “crude” and adjusted models (adjusted OR 0.13, [0.02;0.81]). Despite a significant risk of residual confounding, patients with CIDs (rheumatoid arthritis in particular) should be informed that smoking probably lowers the odds of responding sufficiently to biological therapy. Registration: Clinical.Trials.gov NCT03173144.</p
Impact of fibre and red/processed meat intake on treatment outcomes among patients with chronic inflammatory diseases initiating biological therapy: A prospective cohort study
Get PDFBACKGROUND: Biologic disease-modifying drugs have revolutionised the treatment of a number of chronic inflammatory diseases (CID). However, up to 60% of the patients do not have a sufficient response to treatment and there is a need for optimization of treatment strategies. OBJECTIVE: To investigate if the treatment outcome of biological therapy is associated with the habitual dietary intake of fibre and red/processed meat in patients with a CID. METHODS: In this multicentre prospective cohort study, we consecutively enrolled 233 adult patients with a diagnosis of Crohn's Disease, Ulcerative Colitis, Rheumatoid Arthritis (RA), Axial Spondyloarthritis, Psoriatic Arthritis and Psoriasis, for whom biologic therapy was planned, over a 3 year period. Patients with completed baseline food frequency questionnaires were stratified into a high fibre/low red and processed meat exposed group (HFLM) and an unexposed group (low fibre/high red and processed meat intake = LFHM). The primary outcome was the proportion of patients with a clinical response to biologic therapy after 14–16 weeks of treatment. RESULTS: Of the 193 patients included in our primary analysis, 114 (59%) had a clinical response to biologic therapy. In the HFLM group (N = 64), 41 (64%) patients responded to treatment compared to 73 (56%) in the LFHM group (N = 129), but the difference was not statistically significant (OR: 1.48, 0.72–3.05). For RA patients however, HFLM diet was associated with a more likely clinical response (82% vs. 35%; OR: 9.84, 1.35–71.56). CONCLUSION: Habitual HFLM intake did not affect the clinical response to biological treatment across CIDs. HFLM diet in RA patients might be associated with better odds for responding to biological treatment, but this would need confirmation in a randomised trial. TRIAL REGISTRATION: (clinicaltrials.gov), identifier [NCT03173144]
Data_Sheet_1_Impact of fibre and red/processed meat intake on treatment outcomes among patients with chronic inflammatory diseases initiating biological therapy: A prospective cohort study.pdf
No full textBackgroundBiologic disease-modifying drugs have revolutionised the treatment of a number of chronic inflammatory diseases (CID). However, up to 60% of the patients do not have a sufficient response to treatment and there is a need for optimization of treatment strategies.ObjectiveTo investigate if the treatment outcome of biological therapy is associated with the habitual dietary intake of fibre and red/processed meat in patients with a CID.MethodsIn this multicentre prospective cohort study, we consecutively enrolled 233 adult patients with a diagnosis of Crohn's Disease, Ulcerative Colitis, Rheumatoid Arthritis (RA), Axial Spondyloarthritis, Psoriatic Arthritis and Psoriasis, for whom biologic therapy was planned, over a 3 year period. Patients with completed baseline food frequency questionnaires were stratified into a high fibre/low red and processed meat exposed group (HFLM) and an unexposed group (low fibre/high red and processed meat intake = LFHM). The primary outcome was the proportion of patients with a clinical response to biologic therapy after 14–16 weeks of treatment.ResultsOf the 193 patients included in our primary analysis, 114 (59%) had a clinical response to biologic therapy. In the HFLM group (N = 64), 41 (64%) patients responded to treatment compared to 73 (56%) in the LFHM group (N = 129), but the difference was not statistically significant (OR: 1.48, 0.72–3.05). For RA patients however, HFLM diet was associated with a more likely clinical response (82% vs. 35%; OR: 9.84, 1.35–71.56).ConclusionHabitual HFLM intake did not affect the clinical response to biological treatment across CIDs. HFLM diet in RA patients might be associated with better odds for responding to biological treatment, but this would need confirmation in a randomised trial.Trial registration(clinicaltrials.gov), identifier [NCT03173144].</p
Data_Sheet_2_Impact of fibre and red/processed meat intake on treatment outcomes among patients with chronic inflammatory diseases initiating biological therapy: A prospective cohort study.pdf
No full textBackgroundBiologic disease-modifying drugs have revolutionised the treatment of a number of chronic inflammatory diseases (CID). However, up to 60% of the patients do not have a sufficient response to treatment and there is a need for optimization of treatment strategies.ObjectiveTo investigate if the treatment outcome of biological therapy is associated with the habitual dietary intake of fibre and red/processed meat in patients with a CID.MethodsIn this multicentre prospective cohort study, we consecutively enrolled 233 adult patients with a diagnosis of Crohn's Disease, Ulcerative Colitis, Rheumatoid Arthritis (RA), Axial Spondyloarthritis, Psoriatic Arthritis and Psoriasis, for whom biologic therapy was planned, over a 3 year period. Patients with completed baseline food frequency questionnaires were stratified into a high fibre/low red and processed meat exposed group (HFLM) and an unexposed group (low fibre/high red and processed meat intake = LFHM). The primary outcome was the proportion of patients with a clinical response to biologic therapy after 14–16 weeks of treatment.ResultsOf the 193 patients included in our primary analysis, 114 (59%) had a clinical response to biologic therapy. In the HFLM group (N = 64), 41 (64%) patients responded to treatment compared to 73 (56%) in the LFHM group (N = 129), but the difference was not statistically significant (OR: 1.48, 0.72–3.05). For RA patients however, HFLM diet was associated with a more likely clinical response (82% vs. 35%; OR: 9.84, 1.35–71.56).ConclusionHabitual HFLM intake did not affect the clinical response to biological treatment across CIDs. HFLM diet in RA patients might be associated with better odds for responding to biological treatment, but this would need confirmation in a randomised trial.Trial registration(clinicaltrials.gov), identifier [NCT03173144].</p
