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BACKGROUND & AIMS: Clostridioides difficile infection (CDI) is associated with high mortality. Fecal microbiota transplantation (FMT) is an established treatment for recurrent CDI, but its use for first or second CDI remains experimental. We aimed to investigate the effectiveness of FMT for first or second CDI in a real-world clinical setting. METHODS: This multi-site Danish cohort study included patients with first or second CDI treated with FMT from June 2019 to February 2023. The primary outcome was cure of C. difficile-associated diarrhea (CDAD) 8 weeks after the last FMT treatment. Secondary outcomes included CDAD cure 1 and 8 weeks after the first FMT treatment and 90-day mortality following positive C. difficile test. RESULTS: We included 467 patients, with 187 (40%) having their first CDI. The median patient age was 73 years (interquartile range [IQR], 58-82 years). Notably, 167 (36%) had antibiotic-refractory CDI, 262 (56%) had severe CDI, and 89 (19%) suffered from fulminant CDI. Following the first FMT treatment, cure of CDAD was achieved in 353 patients (76%; 95% confidence interval [CI], 71%-79%) at week 1. At week 8, 255 patients (55%; 95% CI, 50%-59%) maintained sustained effect. In patients without initial effect, repeated FMT treatments led to an overall cure of CDAD in 367 patients (79%; 95% CI, 75%-82%). The 90-day mortality was 10% (95% CI, 8%-14%). CONCLUSION: Repeated FMT treatments demonstrate high effectiveness in managing patients with first or second CDI. Forwarding FMT in CDI treatment guidelines could improve patient survival. CLINICALTRIALS: gov, Number: NCT03712722.
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BACKGROUND: Evidence on ustekinumab safety in pregnancy is gradually expanding, but its clearance in the postnatal period is unknown. The aim of this study was to investigate ustekinumab concentrations in umbilical cord blood and rates of clearance after birth, as well as how these correlate with maternal drug concentrations, risk of infection, and developmental milestones during the first year of life. METHODS: Pregnant women with inflammatory bowel disease were prospectively recruited from 19 hospitals in Denmark and the Netherlands between 2018 and 2022. Infant infections leading to hospitalization/antibiotics and developmental milestones were assessed. Serum ustekinumab concentrations were measured at delivery and specific time points. Nonlinear regression analysis was applied to estimate clearance. RESULTS: In 78 live-born infants from 76 pregnancies, we observed a low risk of adverse pregnancy outcomes and normal developmental milestones. At birth, the median infant-mother ustekinumab ratio was 2.18 (95% confidence interval, 1.69-2.81). Mean time to infant clearance was 6.7 months (95% confidence interval, 6.1-7.3 months). One in 4 infants at 6 months had an extremely low median concentration of 0.015 µg/mL (range 0.005-0.12 µg/mL). No variation in median ustekinumab concentration was noted between infants with (2.8 [range 0.4-6.9] µg/mL) and without (3.1 [range 0.7-11.0] µg/mL) infections during the first year of life (P = .41). CONCLUSIONS: No adverse signals after intrauterine exposure to ustekinumab were observed with respect to pregnancy outcome, infections, or developmental milestones during the first year of life. Infant ustekinumab concentration was not associated with risk of infections. With the ustekinumab clearance profile, live attenuated vaccination from 6 months of age seems of low risk.
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The 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.
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Artrite Reumatoide , Produtos Biológicos , Fumar , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Estudos Prospectivos , Fumar/efeitos adversos , Produtos Biológicos/uso terapêutico , Resultado do Tratamento , Artrite Reumatoide/tratamento farmacológico , Psoríase/tratamento farmacológico , Colite Ulcerativa/tratamento farmacológico , Doença Crônica , Doença de Crohn/tratamento farmacológico , Estudos de Coortes , Artrite Psoriásica/tratamento farmacológico , Idoso , InflamaçãoRESUMO
OBJECTIVE: To compare the number of contacts to general practice across 11 types of abdominal cancer in the 12 months preceding a diagnosis. DESIGN: Nationwide register study. SETTING: Danish general practice. SUBJECTS: Forty-seven thousand eight hundred and ninety-eight patients diagnosed with oesophageal, gastric, colon, rectal, liver, gall bladder/biliary tract, pancreatic, endometrial, ovarian, kidney or bladder cancer in 2014-2018. MAIN OUTCOME MEASURES: Monthly contact rates and incidence rate ratios (IRRs) of daytime face-to-face, email and telephone consultations in general practice across different abdominal cancers. The analyses were conducted for each sex and adjusted for age, comorbidity, marital status and education. RESULTS: Compared to women with colon cancer, women with rectal cancer had the lowest number of contacts to general practice (IRR 12 months pre-diagnostic (IRR-12)=0.86 (95% CI: 0.80-0.92); IRR 1 month pre-diagnostic (IRR-1)=0.85 (95% CI: 0.81-0.89)), whereas women with liver (IRR-12=1.23 (95% CI: 1.09-1.38); IRR-1=1.11 (95% CI: 1.02-1.20)), pancreatic (IRR-12=1.08 (95% CI: 1.01-1.16); IRR1=1.52 (95% CI: 1.45-1.58)) and kidney cancer (IRR-12=1.14 (95% CI: 1.05-1.23); IRR-1=1.18 (95% CI: 1.12-1.24)) had the highest number of contacts. Men showed similar patterns. From seven months pre-diagnostic, an increase in contacts to general practice was seen in bladder cancer patients, particularly women, compared to colon cancer. CONCLUSIONS: Using pre-diagnostic contact rates unveiled that liver, pancreatic, kidney and bladder cancers had a higher and more prolonged use of general practice. This may suggest missed opportunities of diagnosing cancer. Thus, pre-diagnostic contact rates may indicate symptoms and signs for cancer that need further research to ensure early cancer diagnosis.Key pointsThe majority of cancer patients attend their general practitioner (GP) before diagnosis; however, little is known about the use of general practice across different abdominal cancers.This study suggests that a potential exists to detect some abdominal cancers at an earlier point in time.The contact patterns in general practice seem to be shaped by the degree of diagnostic difficulty.GPs may need additional diagnostic opportunities to identify abdominal cancer in symptomatic patients.
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Neoplasias do Colo , Medicina Geral , Clínicos Gerais , Neoplasias da Bexiga Urinária , Estudos de Coortes , Dinamarca/epidemiologia , Feminino , Humanos , Masculino , Neoplasias da Bexiga Urinária/diagnósticoRESUMO
BACKGROUND: Abdominal cancers represent 30% of all diagnosed cancers. Nevertheless, it is unknown if the general practitioner's (GP's) initial cancer suspicion varies for different abdominal cancer types and how this is associated with referrals to standardized cancer patient pathways (CPPs). OBJECTIVES: To explore initial cancer suspicion in GPs and to investigate how this was associated with GP referrals to CPPs and the duration of the primary care interval (PCI) in 10 different abdominal cancer types. METHODS: We conducted a cohort study on 1104 incident abdominal cancer patients diagnosed in Denmark in 2016 using a combination of survey and register-based data. Poisson regression was used to estimate associations between GP cancer suspicion, CPP referral and PCI duration. RESULTS: The GPs initially suspected cancer or other serious disease in 46-78% of cases, lowest in kidney cancer, and referred 35-65% to a CPP, lowest in oesophageal cancer. The GP's suspicion at the first presentation was strongly associated with referral to a CPP. The median (0-11 days) and 75th percentile (3-32 days) PCIs varied between the abdominal cancer types. The likelihood of a long PCI was more than 3-fold higher when the GP did not initially suspect cancer. CONCLUSION: In up to half of abdominal cancer patients, there is no initial suspicion of cancer or serious disease. CPPs were used in only one-third to two-thirds of patients, depending on cancer type. For kidney cancer, as well as several abdominal cancers, we need better diagnostic strategies to support GPs to enable effective and efficient referral.
This study investigates how often a suspicion of cancer is raised by the general practitioner (GP) at the first consultation leading up to a diagnosis for several abdominal cancer types. The study also explores how often the GPs refer these patients to a cancer patient pathway (CPP). Moreover, the length of the primary care interval is measured, that is, the interval from the first time when the patient presents with symptoms to their GP until referral to a hospital or another specialist. The results show that the GPs initially suspected cancer or other serious disease in 4678% of 10 selected types of abdominal cancer; lowest suspicion was seen for kidney cancer, and referred 3565% to a CPP; lowest CPP use was seen for oesophageal cancer. The median time from the first visit to the GP until referral to a hospital or another specialist was 011 days, depending on the cancer type. The most important factor for a prompt referral was the GP's initial cancer suspicion; this was seen independent of the diagnosed cancer type. These findings call for the development of new cancer pathways that better target the patients in whom the GP does not initially suspect cancer.
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Neoplasias Abdominais , Clínicos Gerais , Neoplasias Abdominais/diagnóstico , Estudos de Coortes , Humanos , Atenção Primária à Saúde , Encaminhamento e Consulta , Inquéritos e QuestionáriosRESUMO
Rheumatoid arthritis (RA) is an inflammatory joint disease leading to cartilage damage and ultimately impaired joint function. To gain new insight into the systemic immune manifestations of RA, we characterized the colon mucosa proteome from 11 RA-patients and 10 healthy controls. The biopsies were extracted by colonoscopy and analyzed by label-free quantitative proteomics, enabling the quantitation of 5366 proteins. The abundance of dihydrofolate reductase (DHFR) was statistically significantly increased in RA-patient biopsies compared with controls and correlated with the administered dosage of methotrexate (MTX), the most frequently prescribed immunosuppressive drug for RA. Additionally, our data suggest that treatment with Leflunomide, a common alternative to MTX, increases DHFR. The findings were supported by immunohistochemistry with confocal microscopy, which furthermore demonstrated that DHFR was located in the cytosol of the intestinal epithelial and interstitial cells. Finally, we identified 223 citrullinated peptides from 121 proteins. Three of the peptides were unique to RA. The list of citrullinated proteins was enriched in extracellular and membrane proteins and included known targets of anticitrullinated protein antibodies (ACPAs). Our findings support that the colon mucosa could trigger the production of ACPAs, which could contribute to the onset of RA. The MS data have been deposited to ProteomeXchange with identifiers PXD001608 and PXD003082.
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Antirreumáticos/efeitos adversos , Artrite Reumatoide/genética , Autoanticorpos/biossíntese , Mucosa Intestinal/imunologia , Proteoma/genética , Tetra-Hidrofolato Desidrogenase/genética , Adulto , Idoso , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Estudos de Casos e Controles , Citrulina/metabolismo , Colo/efeitos dos fármacos , Colo/imunologia , Colo/patologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Células Epiteliais/patologia , Feminino , Regulação da Expressão Gênica , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Isoxazóis/efeitos adversos , Leflunomida , Masculino , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Peptídeos Cíclicos/biossíntese , Peptídeos Cíclicos/genética , Peptídeos Cíclicos/imunologia , Proteoma/imunologia , Tetra-Hidrofolato Desidrogenase/imunologiaAssuntos
Anti-Infecciosos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Clostridioides difficile/efeitos dos fármacos , Infecções por Clostridium/tratamento farmacológico , Colite Ulcerativa/complicações , Doença de Crohn/complicações , Anti-Infecciosos/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Anticorpos Neutralizantes/efeitos adversos , Anticorpos Amplamente Neutralizantes , Ensaios Clínicos Fase III como Assunto , Clostridioides difficile/patogenicidade , Infecções por Clostridium/diagnóstico , Infecções por Clostridium/microbiologia , Colite Ulcerativa/diagnóstico , Doença de Crohn/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
INTRODUCTION: The macrophage activation marker soluble (s)CD163 is associated with disease severity and prognosis in patients with primary biliary cholangitis (PBC). Ursodeoxycholic acid (UDCA) treatment attenuates fibrosis progression in PBC patients, but its effect on macrophage activation is unclear. We examined the effect of UDCA on macrophage activation, as determined by sCD163 levels. METHODS: We included 2 cohorts of PBC patients; 1 cohort with prevalent PBC patients, and 1 cohort of incident PBC patients before start of UDCA treatment and with follow-up after 4 weeks and 6 months. We measured sCD163 and liver stiffness in both cohorts. Further, we measured sCD163 and TNF-α shedding in vitro in monocyte-derived macrophages after UDCA and lipopolysaccharide incubation. RESULTS: We included 100 patients with prevalent PBC [93% women, median age 63 y (interquartile range: 51-70)] and 47 patients with incident PBC [77% women, median age 60 y (49-67)]. Prevalent PBC patients had a lower median sCD163 of 3.54 mg/L (2.77-4.72) than incident PBC patients with a median sCD163 of 4.33 mg/L (2.83-5.99) at inclusion. Patients with an incomplete response to UDCA and patients with cirrhosis had higher sCD163 than responders to UDCA and noncirrhosis patients. After 4 weeks and 6 months of UDCA treatment median sCD163 decreased by 4.6% and 9.0%, respectively. In in vitro experiments, UDCA attenuated shedding of TNF-α, but not sCD163, from monocyte-derived macrophages. CONCLUSION: In PBC patients, sCD163 levels correlated with liver disease severity and treatment response to UDCA. Further, after 6 months of UDCA treatment, we observed a decrease in sCD163, which may be related to the treatment.
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Cirrose Hepática Biliar , Ácido Ursodesoxicólico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Colagogos e Coleréticos/uso terapêutico , Cirrose Hepática Biliar/tratamento farmacológico , Gravidade do Paciente , Fator de Necrose Tumoral alfa/uso terapêutico , Ácido Ursodesoxicólico/uso terapêutico , IdosoRESUMO
Strictures and abdominal pain often complicate Crohn's disease (CD). The primary aim was to explore whether parameters obtained by preoperative contrast-enhanced (CE) ultrasonography (US) and dynamic CE MR Enterography (DCE-MRE) of strictures associates with biomechanical properties. CD patients undergoing elective small intestinal surgery were preoperatively examined with DCE-MRE and CEUS. The excised intestine was distended utilizing a pressure bag. Luminal and outer bowel wall cross-sectional areas were measured with US. The circumferential stricture stiffness (Young's modulus E) was computed. Stiffness was associated with the initial slope of enhancement on DCE-MRE (ρ = 0.63, p = 0.007), reflecting active disease, but lacked association with CEUS parameters. For structural imaging parameters, inflammation and stricture stiffness were associated with prestenotic dilatation on US (τb = 0.43, p = 0.02) but not with MRE (τb = 0.01, p = 1.0). Strictures identified by US were stiffer, 16.8 (14.0-20.1) kPa, than those graded as no or uncertain strictures, 12.6 (10.5-15.1) kPa, p = 0.02. MRE global score (activity) was associated with E (ρ = 0.55, p = 0.018). Elastography did not correlate with circumferential stiffness. We conclude that increasing activity defined by the initial slope of enhancement on DCE-MRE and MRE global score were associated with stricture stiffness. Prestenotic dilatation on US could be a potential biomarker of CD small intestinal stricture stiffness.
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INTRODUCTION: Magnetic resonance enterography (MRE) is useful for detecting bowel strictures, whereas a number of imaging biomarkers may reflect severity of fibrosis burden in Crohn's disease (CD). This study aimed to verify the association of MRE metrics with histologic fibrosis independent of inflammation. METHODS: This prospective European multicenter study performed MRE imaging on 60 patients with CD with bowel strictures before surgical resection. Locations of 61 histological samples were annotated on MRE examinations, followed by central readings using the Chiorean score and measurement of delayed gain of enhancement (DGE), magnetization transfer ratio, T2-weighted MRI sequences (T2R), apparent diffusion coefficient (ADC), and the magnetic resonance index of activity (MaRIA). Correlations of histology and MRE metrics were assessed. Least Absolute Shrinkage and Selection Operator and receiver operator characteristic (ROC) curve analyses were used to select composite MRE scores predictive of histology and to estimate their predictive value. RESULTS: ADC and MaRIA correlated with fibrosis (R = -0.71, P < 0.0001, and 0.59, P < 0.001) and more moderately with inflammation (R = -0.35, P < 0.01, and R = 0.53, P < 0.001). Lower or no correlations of fibrosis or inflammation were found with DGE, magnetization transfer ratio, or T2R. Least Absolute Shrinkage and Selection Operator and ROC identified a composite score of MaRIA, ADC, and DGE as a very good predictor of histologic fibrosis (ROC area under the curve = 0.910). MaRIA alone was the best predictor of histologic inflammation with excellent performance in identifying active histologic inflammation (ROC area under the curve = 0.966). DISCUSSION: MRE-based scores for histologic fibrosis and inflammation may assist in the characterization of CD stenosis and enable development of fibrosis-targeted therapies and clinical treatment of stenotic patients.
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Doença de Crohn , Constrição Patológica/diagnóstico por imagem , Doença de Crohn/complicações , Doença de Crohn/diagnóstico por imagem , Fibrose , Humanos , Inflamação/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética , Estudos ProspectivosRESUMO
BACKGROUND AND AIMS: The health consequences of coronavirus disease 2019 [COVID-19] among patients with ulcerative colitis [UC] and Crohn's disease [CD] remain largely unknown. We aimed to investigate the outcomes and long-term effects of COVID-19 in patients with UC or CD. METHODS: We conducted a prospective, population-based study covering all Danish patients with CD or UC and confirmed COVID-19 between January 28, 2020 and April 1, 2021, through medical records and questionnaires. RESULTS: All 319 patients with UC and 197 patients with CD who developed COVID-19 in Denmark were included in this study and compared with the Danish background population with COVID-19 [N = 230 087]. A significantly higher risk of COVID-19-related hospitalization was observed among patients with UC (N = 46 [14.4%], relative risk [RR] = 2.49 [95% confidence interval, CI, 1.91-3.26]) and CD (N = 24 [12.2%], RR = 2.11 [95% CI 1.45-3.07]) as compared with the background population (N = 13 306 [5.8%]). A similar pattern was observed for admission to intensive care (UC: N = 8 [2.51%], RR = 27.88 [95% CI 13.88-56.00]; CD: N = 3 [1.52%], RR = 16.92 [95% CI 5.46-52.46]). After a median of 5.1 months (interquartile range [IQR] 4.5-7.9), 58 [42.3%] and 39 [45.9%] patients with UC and CD, respectively, reported persisting symptoms which were independently associated with discontinuation of immunosuppressive therapies during COVID-19 (odds ratio [OR] = 1.50 [95% CI 1.07-10.22], p = 0.01) and severe COVID-19 (OR = 2.76 [95% CI 1.05-3.90], p = 0.04), but not with age or presence of comorbidities. CONCLUSION: In this population-based study of 516 patients with IBD and COVID-19, 13.6% needed hospitalization and 2.1% required intensive care. Furthermore, sequelae were frequent, affecting 43.7% of COVID-19-infected patients. These findings might have implications for planning the healthcare of patients in the post-COVID-19 era.
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COVID-19 , Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , COVID-19/epidemiologia , Estudos de Coortes , Colite Ulcerativa/diagnóstico , Doença de Crohn/complicações , Doença de Crohn/epidemiologia , Doença de Crohn/terapia , Dinamarca/epidemiologia , Humanos , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/epidemiologia , Doenças Inflamatórias Intestinais/terapia , Estudos ProspectivosRESUMO
Background: 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].
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BACKGROUND AND AIMS: Intestinal stenosis is a common complication of Crohn's Disease (CD). Stenosis is associated with alteration of bowel mechanical properties. This study aims to quantitate the mechanical properties of the intestinal stenosis and to explore associations between histology and mechanical remodeling at stenotic intestinal sites in CD patients. METHODS: Intestinal segments from stenotic sites were studied in vitro from 19 CD patients. A luminal catheter with a bag was used to stepwise pressurize the intestinal segments from 0-100 cmH2O with 10 cmH2O increments. B-mode ultrasound images were obtained at the narrowest part of the stenosis at each pressure level and morphometric parameters were obtained from ultrasound images. The mechanical behavior of the stenotic tissue were characterized by using an isotropic three dimensional strain energy function in Demiray model form, the mechanical constants were obtained by fitting the model to the recorded intraluminal pressure and the inner radius of the stenotic segment of the small bowel. Grading scores were used for histological analysis of inflammation, fibrosis, muscular hypertrophy and adipocyte proliferation in the intestinal layers. The collagen area fraction in intestinal layers was also calculated. Associations between histological and the mechanical constants (stiffness) were analyzed. RESULTS: Chronic inflammation was mainly located in mucosa whereas fibrosis was found in submucosa. The mechanical remodeling was performed with changed mechanical constants ranged between 0.35-13.68kPa. The mechanical properties changes were associated mainly with chronic inflammation, fibrosis and combination of inflammation and fibrosis (R>0.69, P<0.001). Furthermore, the mechanical properties correlated with the collagen fraction in submucosa and muscular layers (R>0.53, P<0.05). CONCLUSIONS: We quantitated the intestinal stenosis stiffness. Associations were found between bowel mechanical remodeling and histological changes at the stenotic site in CD patients. STATEMENT OF SIGNIFICANCE: Although intestinal ultrasonography, CT and MRI can be used to diagnose Crohn's Disease (CD)-associated bowel strictures, these techniques may not have sufficient accuracy and resolution to differentiate predominantly inflammatory strictures from predominantly fibrotic strictures. The present study aims to quantitate the mechanical remodeling of intestinal stenosis and to explore the associations between histological parameters and mechanical properties at the intestinal stenotic sites in CD patients. For the first time, we quantitatively demonstrated that the mechanical properties of the intestinal wall in CD stenosis are associated with the chronic inflammation, fibrosis and collagen fraction in the intestinal layers. The results of this study may facilitate design and development of artificial biomaterials for gastrointestinal organs. The potential clinical implication of this study is that the histological characteristics in patients with CD can be predicted clinically by means of inflammation and fibrosis assessment in conjunction with tissue stiffness measurement.
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Doença de Crohn , Obstrução Intestinal , Constrição Patológica/patologia , Doença de Crohn/complicações , Doença de Crohn/patologia , Fibrose , Humanos , Obstrução Intestinal/patologia , IntestinosRESUMO
BACKGROUND: More than 11,500 abdominal cancers are yearly diagnosed in Denmark. Nevertheless, little is known about which investigations the patients undergo before a diagnosis of abdominal cancer. We aimed to investigate the frequency and timing of selected diagnostic investigations during the year preceding an abdominal cancer diagnosis. METHODS: We conducted a nationwide registry-based cohort study of patients aged ≥ 18 years who were diagnosed with a first-time abdominal cancer in 2014-2018. We included the following cancer types: oesophageal, gastric, colon, rectal, liver, gall bladder/biliary tract, pancreatic, endometrial, ovarian, kidney, and bladder cancer. Investigations of interest were transvaginal ultrasound, abdominal ultrasound, colonoscopy, gastroscopy, endoscopic retrograde cholangiopancreatography, cystoscopy, hysteroscopy, abdominal computed tomography and abdominal magnetic resonance imaging. Generalised linear models were used to calculate incidence rate ratios to enable comparison of monthly rates of investigations. RESULTS: All types of investigations were performed, with varying frequency, across the 11 abdominal cancer types in the year preceding the diagnosis. Increased use of investigations revealed that the timing of the onset differed for the different abdominal cancers, with increases seen 2-6 months before the diagnosis. Abdominal ultrasound, colonoscopy and computed tomography were the investigations with the earliest increase. CONCLUSION: In the year before a diagnosis of an abdominal cancer, some patients appear to undergo investigations typically used to detect another cancer type. This indicates that a window of opportunity exists to diagnose some abdominal cancers at an earlier time point. Future studies should explore an alternative clinical pathway to promote earlier diagnosis of abdominal cancers.
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Neoplasias Abdominais/diagnóstico , Técnicas e Procedimentos Diagnósticos/estatística & dados numéricos , Neoplasias Abdominais/epidemiologia , Adolescente , Adulto , Idoso , Estudos de Coortes , Dinamarca/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Adulto JovemRESUMO
RATIONALE: Vitamin D has been shown to be involved in the host immune response toward Mycobacterium tuberculosis. OBJECTIVES: To test whether vitamin D supplementation of patients with tuberculosis (TB) improved clinical outcome and reduced mortality. METHODS: We conducted a randomized, double-blind, placebo-controlled trial in TB clinics at a demographic surveillance site in Guinea-Bissau. We included 365 adult patients with TB starting antituberculosis treatment; 281 completed the 12-month follow-up. The intervention was 100,000 IU of cholecalciferol or placebo at inclusion and again 5 and 8 months after the start of treatment. MEASUREMENTS AND MAIN RESULTS: The primary outcome was reduction in a clinical severity score (TBscore) for all patients with pulmonary TB. The secondary outcome was 12-month mortality. No serious adverse effects were reported; mild hypercalcemia was rare and present in both arms. Reduction in TBscore and sputum smear conversion rates did not differ among patients treated with vitamin D or placebo. Overall mortality was 15% (54 of 365) at 1 year of follow-up and similar in both arms (30 of 187 for vitamin D treated and 24 of 178 for placebo; relative risk, 1.19 [0.58-1.95]). HIV infection was seen in 36% (131 of 359): 21% (76 of 359) HIV-1, 10% (36 of 359) HIV-2, and 5% (19 of 357) HIV-1+2. CONCLUSIONS: Vitamin D does not improve clinical outcome among patients with TB and the trial showed no overall effect on mortality in patients with TB; it is possible that the dose used was insufficient. Clinical trial registered with www.controlled-trials.com/isrctn (ISRCTN35212132).
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Colecalciferol/uso terapêutico , Tuberculose Pulmonar/tratamento farmacológico , Vitaminas/uso terapêutico , Adulto , Antituberculosos/uso terapêutico , Contagem de Linfócito CD4 , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Guiné-Bissau/epidemiologia , Infecções por HIV/epidemiologia , Humanos , Masculino , Tuberculose Pulmonar/mortalidade , Vitamina D/sangue , Deficiência de Vitamina D/tratamento farmacológico , Deficiência de Vitamina D/epidemiologia , Aumento de PesoRESUMO
The aim was to examine anti-tumor necrosis factor α (anti-TNFα) therapy influence changes on Th17 and Th22 cells in patients with spondyloarthritis (SpA), and its correlation with changes in clinical and magnetic resonance imaging (MRI) activity and chronicity scores. The Th17 and Th22 cells were assessed at baseline, after 12 and 52 weeks of anti-TNFα therapy by flow cytometry (ClinicalTrials.gov NCT4682724). The percentages of both Th17 and Th22 cells were increased by 70% at baseline compared with healthy controls (both p < 0.01). During treatment, these two subsets increased further to be 170% (Th17) and 123% (Th22) above levels in healthy controls (both p < 0.01). The same subsets decrease their expression of IL-23R significantly during the observation period (p < 0.05). High levels of Th17 and Th22 cells at baseline were associated with the degree of chronic changes in the sacroiliac joints on MRI and a good clinical response to anti-TNFα treatment after one year. Plasma levels were not associated with clinical changes. Th17 cells, and Th22 subsets, increased during one year of anti-TNF-α therapy in SpA, regardless of their clinical improvement. This supports that both the Th17 and Th22 subsets could be involved in the progression in SpA.
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Anti-Inflamatórios/uso terapêutico , Espondilartrite/tratamento farmacológico , Linfócitos T Auxiliares-Indutores/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Anti-Inflamatórios/farmacologia , Feminino , Citometria de Fluxo , Humanos , Interleucina-17/metabolismo , Interleucinas/metabolismo , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Receptores de Interleucina/metabolismo , Espondilartrite/diagnóstico por imagem , Espondilartrite/imunologia , Espondilartrite/patologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Células Th17/metabolismo , Resultado do Tratamento , Interleucina 22RESUMO
BACKGROUND AND AIMS: Increased small intestinal wall thickness correlates with both inflammatory activity and fibrosis in Crohn's disease [CD]. Assessment of perfusion holds promise as an objective marker distinguishing between the two conditions. Our primary aim was to determine if relative bowel wall perfusion measurements correlate with histopathological scores for inflammation or fibrosis in CD. METHODS: A total of 25 patients were investigated before elective surgery for small intestinal CD. Unenhanced ultrasonography [US] and magnetic resonance enterography [MRE] were applied to describe bowel wall thickness. Perfusion was assessed with contrast-enhanced US [CEUS] and dynamic contrast-enhanced MRE [DCE-MRE]. Histopathology was used as gold standard. RESULTS: Compared with histopathology, the mean wall thickness was 0.4 mm greater on US [range -0.3 to 1.0, p = 0.24] and 1.4 mm greater on MR [0.4 to 2.3, p = 0.006]. No correlation was found between the severity of inflammation or fibrosis on histopathology, and either DCE-MRE [r = -0.13, p = 0.54 for inflammation and r = 0.41, p = 0.05 for fibrosis] or CEUS [r = 0.16, p = 0.45 for inflammation and r = -0.28, p = 0.19 for fibrosis]. Wall thickness assessed with US was correlated with both histological inflammation [r = 0.611, p = 0.0012] and fibrosis [r = 0.399, p = 0.048]. The same was not true for MR [r = 0.41, p = 0.047 for inflammation and r = 0.29, p = 0.16 for fibrosis]. CONCLUSIONS: Bowel wall thickness assessed with US is a valid marker of inflammation in small intestinal CD. However, relative contrast enhancement of US or of MRE cannot distinguish between inflammatory activity and fibrosis.
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Doença de Crohn/diagnóstico por imagem , Doença de Crohn/patologia , Intestinos/patologia , Imageamento por Ressonância Magnética/métodos , Úlcera/diagnóstico por imagem , Ultrassonografia , Adulto , Idoso , Proteína C-Reativa/metabolismo , Meios de Contraste , Doença de Crohn/complicações , Fezes/química , Feminino , Fibrose , Humanos , Inflamação/sangue , Inflamação/diagnóstico por imagem , Inflamação/patologia , Complexo Antígeno L1 Leucocitário/análise , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Úlcera/etiologia , Úlcera/patologia , Adulto JovemRESUMO
INTRODUCTION: An unbalanced intestinal microbiota may mediate activation of the inflammatory pathways seen in psoriatic arthritis (PsA). A randomised, placebo-controlled trial of faecal microbiota transplantation (FMT) infused into the small intestine of patients with PsA with active peripheral disease who are non-responsive to methotrexate (MTX) treatment will be conducted. The objective is to explore clinical aspects associated with FMT performed in patients with PsA. METHODS AND ANALYSIS: This trial is a randomised, two-centre stratified, double-blind (patient, care provider and outcome assessor), placebo-controlled, parallel-group study. Eighty patients will be included and randomised (1:1) to either placebo (saline) or FMT provided from an anonymous healthy donor. Throughout the study, both groups will continue the weekly self-administered subcutaneous MTX treatment, remaining on the preinclusion dosage (15-25 mg/week). The clinical measures of psoriasis and PsA disease activity used include the Short (2-page) Health Assessment Questionnaire, the Dermatology Quality of Life Index, the Spondyloarthritis Research Consortium of Canada Enthesitis Index, the Psoriasis Area Severity Index, a dactylitis digit count, a swollen/tender joint count (66/68), plasma C reactive protein as well as visual analogue scales for pain, fatigue and patient and physician global assessments. The primary end point is the proportion of patients who experience treatment failure during the 6-month trial period. The number of adverse events will be registered throughout the study. ETHICS AND DISSEMINATION: This is a proof-of-concept clinical trial and will be performed in agreement with Good Clinical Practice standards. Approvals have been obtained from the local Ethics Committee (DK-S-20150080) and the Danish Data Protection Agency (15/41684). The study has commenced in May 2017. Dissemination will be through presentations at national and international conferences and through publications in international peer-reviewed journal(s). TRIAL REGISTRATION NUMBER: NCT03058900; Pre-results.
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Artrite Psoriásica , Transplante de Microbiota Fecal , Antirreumáticos , Artrite Psoriásica/terapia , Canadá , Método Duplo-Cego , Humanos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
INTRODUCTION: Chronic inflammatory diseases (CIDs) are frequently treated with biological medications, specifically tumour necrosis factor inhibitors (TNFi)). These medications inhibit the pro-inflammatory molecule TNF alpha, which has been strongly implicated in the aetiology of these diseases. Up to one-third of patients do not, however, respond to biologics, and lifestyle factors are assumed to affect treatment outcomes. Little is known about the effects of dietary lifestyle as a prognostic factor that may enable personalised medicine. The primary outcome of this multidisciplinary collaborative study will be to identify dietary lifestyle factors that support optimal treatment outcomes. METHODS AND ANALYSIS: This prospective cohort study will enrol 320 patients with CID who are prescribed a TNFi between June 2017 and March 2019. Included among the patients with CID will be patients with inflammatory bowel disease (Crohn's disease and ulcerative colitis), rheumatic disorders (rheumatoid arthritis, axial spondyloarthritis, psoriatic arthritis), inflammatory skin diseases (psoriasis, hidradenitis suppurativa) and non-infectious uveitis. At baseline (pretreatment), patient characteristics will be assessed using patient-reported outcome measures, clinical assessments of disease activity, quality of life and lifestyle, in addition to registry data on comorbidity and concomitant medication(s). In accordance with current Danish standards, follow-up will be conducted 14-16 weeks after treatment initiation. For each disease, evaluation of successful treatment response will be based on established primary and secondary endpoints, including disease-specific core outcome sets. The major outcome of the analyses will be to detect variability in treatment effectiveness between patients with different lifestyle characteristics. ETHICS AND DISSEMINATION: The principle goal of this project is to improve the quality of life of patients suffering from CID by providing evidence to support dietary and other lifestyle recommendations that may improve clinical outcomes. The study is approved by the Ethics Committee (S-20160124) and the Danish Data Protecting Agency (2008-58-035). Study findings will be disseminated through peer-reviewed journals, patient associations and presentations at international conferences. TRIAL REGISTRATION NUMBER: NCT03173144; Pre-results.
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Fibras na Dieta/administração & dosagem , Inflamação , Produtos da Carne/efeitos adversos , Carne Vermelha/efeitos adversos , Doença Crônica , Dieta , Humanos , Doenças Inflamatórias Intestinais/terapia , Estilo de Vida , Medidas de Resultados Relatados pelo Paciente , Medicina de Precisão , Prognóstico , Estudos Prospectivos , Qualidade de Vida , Projetos de Pesquisa , Doenças Reumáticas/terapia , Dermatopatias/terapia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Uveíte/terapiaRESUMO
BACKGROUND: Little is known regarding vitamin D deficiency (VDD) in African populations and in tuberculosis (TB) patients. VDD has been shown to be associated with TB. OBJECTIVE: We aimed to compare the degree of vitamin D insufficiency (VDI) and VDD in TB patients and healthy adult controls in a West African population. DESIGN: An unmatched case-control study was performed at a Demographic Surveillance Site in Guinea-Bissau. Serum 25-hydroxyvitamin D(3) [25(OH)D(3)] concentrations were measured in 362 TB patients and in 494 controls. RESULTS: Hypovitaminosis D [25(OH)D(3) = 75 nmol/L] was more common in TB patients, but VDD [25(OH)D(3) = 50 nmol/L] was more common and more severe in controls. We observed hypovitaminosis D in 46% (167/362) of the TB patients and in 39% (193/494) of the controls; the relative risk (RR) of hypovitaminosis D was 1.18 (95% CI: 1.01, 1.38). VDD was observed in 8.5% (31/362) of the TB patients and in 13.2% (65/494) of the controls. The RR was 0.65 (95% CI: 0.43, 0.98), mainly because severe VDD [25(OH)D(3) = 25 nmol/L] was observed in only 1 of 362 TB patients (0.2%) and in 24 of 494 controls (4.9%). After adjustment for background factors, hypovitaminosis D was not more frequent in TB patients than in healthy controls, but the mean serum 25(OH)D(3) concentration remained lower. CONCLUSIONS: Hypovitaminosis D was highly prevalent in TB patients and in healthy controls living at 12 degrees N; severe VDD was rare in TB patients. The finding indicates that the serum 25(OH)D(3) concentration is associated with TB infection, but whether this role is a symptom or is causal was not established.