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  • 1. Almer, Sven
    et al.
    Granerus, Göran
    Ström, Magnus
    Olaison, Gunnar
    Bonnet, Joëlle
    Lémann, Marc
    Smedh, Kennet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland.
    Franzén, Lennart
    Bertheau, Philippe
    Cattan, Pierre
    Rain, Jean-Didier
    Modigliani, Robert
    Leukocyte scintigraphy compared to intraoperative small bowel enteroscopy and laparotomy findings in Crohn's disease2007In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 13, no 2, p. 164-174Article in journal (Refereed)
    Abstract [en]

    Background: Leukocyte scintigraphy is a noninvasive investigation to assess inflammation. We evaluated the utility of labeled leukocytes to detect small bowel inflammation and disease complications in Crohn's disease and compared it to whole small bowel enteroscopy and laparotomy findings.Methods: Scintigraphy with technetium-99m exametazime-labeled leukocytes was prospectively performed in 48 patients with Crohn's disease a few days before laparotomy; 41 also had an intraoperative small bowel enteroscopy. The same procedures were performed in 8 control patients. Independent grading of scans was compared with the results of enteroscopy and with surgical, histopathologic, and clinical data.Results: In the 8 control patients leukocyte scan, endoscopy, and histopathology were all negative for the small bowel. In patients with Crohn's disease and small bowel inflammation seen at enteroscopy and/or laparotomy (n = 39) the scan was positive in 33. In 8 patients without macroscopic small bowel inflammation, the scan was positive for the small bowel in 3 patients; at histology, 2 of 3 had inflammation. When combining results for patients and controls, the sensitivity of leukocyte scan for macroscopically evident small bowel inflammation was 0.85, specificity 0.81, accuracy 0.84, positive predictive value 0.92, and negative predictive value 0.68. Scintigraphy detected inflammatory lesions not known before laparotomy in 16 of 47 (34%) Crohn's disease patients and showed uptake in 25 of 35 (71%) bowel strictures. It was diagnostic regarding 4 of 8 abscesses and 9 of 15 fistulas. In 6 patients (13%) lesions first demonstrated by leukocyte scintigraphy were treated during the surgery performed.Conclusions: Leukocyte scintigraphy reliably detects small bowel inflammation in Crohn's disease. It gives additional information on the presence of inflammatory lesions in a fraction of patients planned for surgery.

  • 2.
    Ardesjö, Brita
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Portela-Gomes, Guida M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Rorsman, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gerdin, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Lööf, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ekwall, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Immunoreactivity against goblet cells in patients with inflammatory bowel disease2008In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 14, no 5, p. 652-661Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A number of autoantibodies have been reported in inflammatory bowel disease (IBD). The aim of this study was to investigate to what extent sera from patients with IBD contain autoantibodies directed against normal human gastrointestinal mucosa. METHODS: Samples of sera from 50 patients with IBD and 50 healthy subjects were used for immunostaining of normal and affected human gastrointestinal tissues. RESULTS: Eighty-four percent of the sera from IBD patients showed immunoreactivity against goblet cells in the appendix compared with 8% of the sera from healthy subjects. Goblet cell reactivity of IBD patient sera varied between regions in the gastrointestinal tract. Sera from healthy subjects only reacted with goblet cells in the appendix. In the colon and the appendix, goblet cell reactivity of IBD sera was generally weak at the base of the crypts and gradually increased toward the lumen. Three IBD sera samples reacted with gastrin cells in the antrum. In colon biopsies from patients with ulcerative colitis, immunoreactivity against the remaining goblet cells showed an inverse correlation with inflammatory activity. CONCLUSIONS: These findings suggest that immunoreactivity against goblet cells may be of central importance in the pathogenesis of IBD. Identification of goblet cell antigens could lead to a better understanding of IBD and provide a new diagnostic tool.

  • 3.
    Ardesjö, Brita
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Portela-Gomes, Guida M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Rorsman, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ekwall, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Identification of a novel staining pattern of bile duct epithelial cells in primary sclerosing cholangitis2010In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 16, no 2, p. 305-311Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Primary sclerosing cholangitis (PSC) is an inflammatory disease of the bile ducts with an unknown etiology. A number of autoantigens have been proposed, but an early diagnostic marker is still lacking. Our aim was to identify such an autoantigen. METHODS: Immunostaining was performed on normal human bile duct with sera from patients with PSC and controls. To identify an autoantigen a cDNA library from normal human choledochus was constructed and immunoscreened with patient sera. Using in vitro transcription and translation and immunoprecipitation we examined the immunoreactivity against PDZ domain containing 1 (PDZK1) in 35 patients with PSC, 198 control patients, and 94 healthy controls. RESULTS: We observed a previously unpublished staining pattern in which cytoplasmatic granules and apical cell membranes of biliary epithelial cells were stained by PSC sera. Strong immunoreactivity to these structures was obtained with 12 out of 35 PSC sera (34%) but not with sera from healthy controls. By screening the cDNA library we identified PDZK1 as a candidate antigen. Immunoreactivity against PDZK1 was detected in 9% of PSC patients, 2% of inflammatory bowel disease (IBD) patients, 8% of autoimmune pancreatitis patients, 18% of Grave's disease patients, and 1% of healthy controls. CONCLUSIONS: Previously unpublished, specific, and strong autoantibodies against epithelial cells of the bile duct in PSC sera were identified. Furthermore, PDZK1 is suggested as a potential new autoantigen.

  • 4. de Ridder, Lissy
    et al.
    Turner, Dan
    Wilson, David C.
    Koletzko, Sibylle
    Martin-de-Carpi, Javier
    Fagerberg, Ulrika L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Spray, Christine
    Sladek, Malgorzata
    Shaoul, Ron
    Roma-Giannikou, Eleftheria
    Bronsky, Jiri
    Serban, Daniela E.
    Cucchiara, Salvatore
    Veres, Gabor
    Ruemmele, Frank M.
    Hojsak, Iva
    Kolho, Kaija L.
    Davies, Ieuan H.
    Aloi, Marina
    Lionetti, Paolo
    Veereman-Wauters, Gigi
    Braegger, Christian P.
    Trindade, Eunice
    Wewer, Anne V.
    Hauer, Almuthe
    Levine, Arie
    Malignancy and Mortality in Pediatric Patients with Inflammatory Bowel Disease: A Multinational Study from the Porto Pediatric IBD Group2014In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 20, no 2, p. 291-300Article in journal (Refereed)
    Abstract [en]

    Background: The combination of the severity of pediatric-onset inflammatory bowel disease (IBD) phenotypes and the need for intense medical treatment may increase the risk of malignancy and mortality, but evidence regarding the extent of the problem is scarce. Therefore, the Porto Pediatric IBD working group of ESPGHAN conducted a multinational-based survey of cancer and mortality in pediatric IBD. Methods: A survey among pediatric gastroenterologists of 20 European countries and Israel on cancer and/or mortality in the pediatric patient population with IBD was undertaken. One representative from each country repeatedly contacted all pediatric gastroenterologists from each country for reporting retrospectively cancer and/or mortality of pediatric patients with IBD after IBD onset, during 2006-2011. Results: We identified 18 cases of cancers and/or 31 deaths in 44 children (26 males) who were diagnosed with IBD (ulcerative colitis, n = 21) at a median age of 10.0 years (inter quartile range, 3.0-14.0). Causes of mortality were infectious (n = 14), cancer (n = 5), uncontrolled disease activity of IBD (n = 4), procedure-related (n = 3), other non-IBD related diseases (n = 3), and unknown (n = 2). The most common malignancies were hematopoietic tumors (n = 11), of which 3 were hepatosplenic T-cell lymphoma and 3 Ebstein-Barr virus-associated lymphomas. Conclusions: Cancer and mortality in pediatric IBD are rare, but cumulative rates are not insignificant. Mortality is primarily related to infections, particularly in patients with 2 or more immunosuppressive agents, followed by cancer and uncontrolled disease. At least 6 lymphomas were likely treatment-associated by virtue of their phenotype.

  • 5.
    Drobin, Kimi
    et al.
    Royal Inst Technol, KTH, Sch Biotechnol, Affin Prote, SciLifeLab, Stockholm, Sweden.
    Assadi, Ghazaleh
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden.
    Hong, Mun-Gwan
    Royal Inst Technol, KTH, Sch Biotechnol, Affin Prote, SciLifeLab, Stockholm, Sweden.
    Andersson, Eni
    Royal Inst Technol, KTH, Sch Biotechnol, Affin Prote, SciLifeLab, Stockholm, Sweden.
    Fredolini, Claudia
    Royal Inst Technol, KTH, Sch Biotechnol, Affin Prote, SciLifeLab, Stockholm, Sweden.
    Forsström, Björn
    Royal Inst Technol, KTH, Sch Biotechnol, Affin Prote, SciLifeLab, Stockholm, Sweden.
    Reznichenko, Anna
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden.
    Akhter, Tahmina
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden.
    Ek, Weronica E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden.
    Bonfiglio, Ferdinando
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden; Biodonostia Hlth Res Inst, Dept Gastrointestinal & Liver Dis, San Sebastian, Spain.
    Berner Hansen, Mark
    AstraZeneca R&D, Innovat & Global Med, Mölndal, Sweden; Univ Copenhagen, Bispebjerg Hosp, Ctr Digest Dis, Copenhagen, Denmark.
    Sandberg, Kristian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden.
    Greco, Dario
    Univ Helsinki, Inst Biotechnol, Helsinki, Finland.
    Repsilber, Dirk
    Örebro Univ, Sch Med Sci, Örebro, Sweden.
    Schwenk, Jochen M.
    Royal Inst Technol, KTH, Sch Biotechnol, Affin Prote, SciLifeLab, Stockholm, Sweden.
    D’Amato, Mauro
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden; BioDonostia Hlth Res Inst, San Sebastian, Spain; Ikerbasque, Basque Fdn Sci, Bilbao, Spain.
    Halfvarson, Jonas
    Örebro Univ, Fac Med & Hlth, Dept Gastroenterol, Örebro, Sweden.
    Targeted Analysis of Serum Proteins Encoded at Known Inflammatory Bowel Disease Risk Loci2019In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 25, no 2, p. 306-316Article in journal (Refereed)
    Abstract [en]

    Background: Few studies have investigated the blood proteome of inflammatory bowel disease (IBD). We characterized the serum abundance of proteins encoded at 163 known IBD risk loci and tested these proteins for their biomarker discovery potential.

    Methods: Based on the Human Protein Atlas (HPA) antibody availability, 218 proteins from genes mapping at 163 IBD risk loci were selected. Targeted serum protein profiles from 49 Crohn’s disease (CD) patients, 51 ulcerative colitis (UC) patients, and 50 sex- and age-matched healthy individuals were obtained using multiplexed antibody suspension bead array assays. Differences in relative serum abundance levels between disease groups and controls were examined. Replication was attempted for CD-UC comparisons (including disease subtypes) by including 64 additional patients (33 CD and 31 UC). Antibodies targeting a potentially novel risk protein were validated by paired antibodies, Western blot, immuno-capture mass spectrometry, and epitope mapping.

    Results: By univariate analysis, 13 proteins mostly related to neutrophil, T-cell, and B-cell activation and function were differentially expressed in IBD patients vs healthy controls, 3 in CD patients vs healthy controls and 2 in UC patients vs healthy controls (q < 0.01). Multivariate analyses further differentiated disease groups from healthy controls and CD subtypes from UC (P < 0.05). Extended characterization of an antibody targeting a novel, discriminative serum marker, the laccase (multicopper oxidoreductase) domain containing 1 (LACC1) protein, provided evidence for antibody on-target specificity.

    Conclusions: Using affinity proteomics, we identified a set of IBD-associated serum proteins encoded at IBD risk loci. These candidate proteins hold the potential to be exploited as diagnostic biomarkers of IBD.

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  • 6.
    Englund, Gunilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Jacobson, Annica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rorsman, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rönnblom, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Efflux transporters in ulcerative colitis: decreased expression of BCRP (ABCG2) and Pgp (ABCB1)2007In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 13, no 3, p. 291-297Article in journal (Refereed)
    Abstract [en]

    Background: Efflux transport proteins are important components of the intestinal barrier against bacterial toxins, carcinogens, and drugs. This investigation was conducted to determine the expression of Breast Cancer Resistance Protein (BCRP/ABCG2), P-glycoprotein (Pgp/MDR1/ABCB1), and Multidrug Resistance Protein 2 (MRP2/ABCC2) in the gut mucosa of patients with ulcerative colitis (UC). Methods: Patients were thoroughly diagnosed according to well-established clinical, endoscopic, and histologic criteria to be included in the group of patients with active UC (n = 16) or UC in remission (n = 17). Colonic and rectal mucosa from patients with UC were compared with tissues from control subjects (n = 15). The mRNA expression (TaqMan) of the efflux transporters and the proinflammatory cytokines interleukin (IL)-1β and IL-6 was determined. Western blot was used in the analysis of protein expression and the tissue localization of BCRP was determined with confocal microscopy. Results: BCRP and Pgp expression was strongly reduced in individuals with active inflammation compared with controls and was negatively correlated with the levels of IL-6 mRNA. The BCRP staining of colonic epithelium seen in healthy mucosa was diminished in inflamed tissues, with concurrent disruption of epithelial F-actin structure. Conclusions: Two of the efflux transporters of importance for the barrier function of the gut mucosa, Pgp and BCRP, are expressed at strongly reduced levels during active inflammation in patients with UC. Investigations are warranted to determine whether the low levels of efflux transporters during active UC contribute to altered transport and tissue exposure of carcinogens, bacterial toxins, and drugs.

  • 7.
    Hanzel, Jurij
    et al.
    Univ Ljubljana, Univ Med Ctr Ljubljana, Fac Med, Ljubljana, Slovenia.;Amsterdam UMC, Dept Gastroenterol & Hepatol, Amsterdam, Netherlands..
    Dreesen, Erwin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Katholieke Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Leuven, Belgium.
    Vermeire, Severine
    Univ Hosp Leuven, Dept Gastroenterol & Hepatol, Leuven, Belgium..
    Lowenberg, Mark
    Amsterdam UMC, Dept Gastroenterol & Hepatol, Amsterdam, Netherlands..
    Hoentjen, Frank
    Radboud UMC, Dept Gastroenterol & Hepatol, Nijmegen, Netherlands..
    Bossuyt, Peter
    Imelda Gen Hosp, Imelda GI Clin Res Ctr, Bonheiden, Belgium..
    Clasquin, Esme
    Amsterdam UMC, Dept Gastroenterol & Hepatol, Amsterdam, Netherlands..
    Baert, Filip J.
    AZ Delta, Div Gastroenterol, Roeselare, Belgium..
    D'Haens, Geert R.
    Amsterdam UMC, Dept Gastroenterol & Hepatol, Amsterdam, Netherlands..
    Mathot, Ron
    Amsterdam UMC, Dept Hosp Pharm Clin Pharmacol, Amsterdam, Netherlands..
    Pharmacokinetic-Pharmacodynamic Model of Vedolizumab for Targeting Endoscopic Remission in Patients With Crohn Disease: Posthoc Analysis of the LOVE-CD Study2022In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 28, no 5, p. 689-699Article in journal (Refereed)
    Abstract [en]

    Background

    Higher serum concentrations of vedolizumab have been associated with improved outcomes in inflammatory bowel disease. It is unclear how vedolizumab exposure is linked to endoscopic remission in Crohn disease (CD). We aimed to develop a pharmacokinetic-pharmacodynamic model linking vedolizumab exposure to endoscopic remission in CD.

    Methods

    Data were obtained from the first 110 patients participating in a phase 4 prospective multicenter trial (LOVE-CD; ClinicalTrials.gov identifier: NCT02646683), where vedolizumab was dosed at 300 mg every 8 weeks and serum concentrations and antibodies to vedolizumab were measured before each infusion. Concentration-time profiles were described by a 2-compartment model with parallel linear and nonlinear elimination. A first-order discrete-time Markov model was used to describe the relationship between pharmacokinetic exposure metrics and the probability of endoscopic remission (Simple Endoscopic Score for CD < 4).

    Results

    Linear clearance was 0.215 L/d, and the volume of distribution of the central compartment was 4.92 L. Linear clearance was higher and vedolizumab exposure was lower in patients with lower serum albumin concentrations, in the presence of antibodies to vedolizumab, and in patients with previous exposure to other biologic therapy. A week 22 vedolizumab concentration of 20.0 mg/L was predicted to yield a 35% probability of achieving endoscopic remission at week 26. Model-based simulations suggested that endoscopic remission rates of 46.5% or 40.0% could be reached with every-4-weeks dosing in patients who were naive or previously exposed to biologic therapy, respectively.

    Conclusions

    Model-informed dosing of vedolizumab in CD provides a foundation for future research aiming to maximize endoscopic remission rates.

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  • 8. Sjoberg, Daniel
    et al.
    Holmstrom, Tommy
    Larsson, Marit
    Nielsen, Anne-Lie
    Holmquist, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Rönnblom, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Anemia in a Population-based IBD Cohort (ICURE): Still High Prevalence After 1 Year, Especially Among Pediatric Patients2014In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 20, no 12, p. 2266-2270Article in journal (Refereed)
    Abstract [en]

    Background:Prevalence of anemia in patients with inflammatory bowel disease (IBD) is uncertain because of scarcity of population-based studies. The aim of this study was to evaluate prevalence of anemia in a population-based cohort of newly diagnosed patients with IBD to identify risk factors for anemia and to describe contemporary anemia-specific treatment during the first year.Methods:All patients with ulcerative colitis or Crohn's disease in the IBD Cohort of Uppsala Region cohort (n = 790) and hemoglobin levels at the time of diagnosis were eligible for inclusion. The WHO definition of anemia was used.Results:Seven hundred forty-nine (95%) of the patients with IBD were included. Five hundred eighty of 749 (77%) patients had measured hemoglobin levels at 12-month follow-up. The prevalence of anemia at the time of diagnosis was 227/749 (30%). After 1 year, it was 102/580 (18%). Anemia was more common among newly diagnosed patients with Crohn's disease compared with ulcerative colitis (42% versus 24%, P < 0.0001), but after 1 year, there was no difference (18% versus 18%, P = NS). Children had more often anemia compared with adults, both at diagnosis and after 1 year (diagnosis: 55% versus 27%, P < 0.0001; follow-up: 28% versus 16%, P < 0.05). Anemia was associated with colonic engagement in Crohn's disease and the extent of inflammation in ulcerative colitis. Only 46% of patients with anemia were treated with iron supplementation or blood transfusion.Conclusions:The overall prevalence of anemia in patients with IBD at the time of diagnosis was high. A large proportion was still anemic after 1 year. Children were more at risk compared with adults. More efforts are needed to treat patients with anemia.

  • 9. Sjöberg, Mats
    et al.
    Walch, Andrea
    Meshkat, Mina
    Gustavsson, Anders
    Järnerot, Gunnar
    Vogelsang, Harald
    Hertervig, Erik
    Novacek, Gottfried
    Friis-Liby, Ingalill
    Blomquist, Lars
    Angelberger, Sieglinde
    Karlen, Per
    Grännö, Christer
    Vilien, Mogens
    Ström, Magnus
    Verbaan, Hans
    Hellström, Per M.
    Dejaco, Clemens
    Magnuson, Anders
    Halfvarson, Jonas
    Reinisch, Walter
    Tysk, Curt
    Infliximab or cyclosporine as rescue therapy in hospitalized patients with steroid-refractory ulcerative colitis: a retrospective observational study2012In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 18, no 2, p. 212-218Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Cyclosporine (CsA) or infliximab (IFX) are used as rescue therapies in steroid-refractory, severe attacks of ulcerative colitis (UC). There are no data comparing the efficacy of these two alternatives.

    METHODS:

    Outcome of rescue therapy was retrospectively studied in two cohorts of patients hospitalized due to steroid-refractory moderate to severe UC: 1) a Swedish-Danish cohort (n = 49) treated with a single infusion of IFX; 2) an Austrian cohort (n = 43) treated with intravenous CsA. After successful rescue therapy, maintenance immunomodulator treatment was given to 27/33 (82%) of IFX patients and to 31/40 (78%) of CsA patients. Endpoints were colectomy-free survival at 3 and 12 months. Kaplan-Meier and Cox regression models were used to evaluate the association between treatment groups and colectomy.

    RESULTS:

    At 15 days, colectomy-free survival in the IFX cohort was 36/49 (73%) versus 41/43 (95%) in the CsA cohort (P = 0.005), at 3 months 33/49 (67%) versus 40/43 (93%) (P = 0.002), and at 12 months 28/49 (57%) versus 33/43 (77%) (P = 0.034). After adjusting for potential confounding factors, Cox regression analysis yielded adjusted hazard ratios for risk of colectomy in IFX-treated patients of 11.2 (95% confidence interval [CI] 2.4-53.1, P = 0.002) at 3 months and of 3.0 (95% CI 1.1-8.2, P = 0.030) at 12 months in comparison with CsA-treated patients. There were no opportunistic infections or mortality.

    CONCLUSIONS:

    Colectomy frequencies were significantly lower after rescue therapy with CsA than with a single infusion of IFX both at 3 and 12 months' follow-up. The superiority of CsA was seen principally during the first 15 days.

  • 10. Torkvist, Leif
    et al.
    Halfvarson, Jonas
    Ong, Rick T. H.
    Lordal, Mikael
    Sjoqvist, Urban
    Bresso, Francesca
    Bjork, Jan
    Befrits, Ragnar
    Lofberg, Robert
    Blom, Johannes
    Carlson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Padyukov, Leonid
    D'Amato, Mauro
    Seielstad, Mark
    Pettersson, Sven
    Analysis of 39 Crohn's Disease Risk Loci in Swedish Inflammatory Bowel Disease Patients2010In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 16, no 6, p. 907-909Article in journal (Refereed)
  • 11.
    Torkzad, Michael R
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ullberg, Ulla
    Nyström, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Blomqvist, Lennart
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Fagerberg, Ulrika L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland.
    Manifestations of small bowel disease in pediatric Crohn's disease on magnetic resonance enterography2012In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 18, no 3, p. 520-528Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    We report the manifestations of Crohn's disease (CD) observed on magnetic resonance enterography (MRE) in a pediatric population at the time of CD diagnosis.

    METHODS:

    MRE of 95 consecutive pediatric patients with inflammatory bowel disease (IBD) examined in 2006-2009 were retrospectively analyzed, with documentation of findings based on type and location of the small bowel (SB) disease.

    RESULTS:

    In all, 51 were boys and 44 girls. 54 had CD, 31 non-CD IBD, and 10 no IBD. The most common site of SB involvement in CD was the terminal ileum seen in 29 (53.7%) patients, followed by ileum in 10 (18.5%) and jejunum in 9 (16.7%) patients. Solitary jejunal inflammation (3.7%), SB stenoses (1.9%), fistula formation (0.95%), and abscess (0.95%) were much less common. Perienteric lymphadenopathy was seen in 30 (55.6%) patients and fatty proliferation in 9 (16.7%). The most common manifestation of SB inflammation was increased contrast enhancement of bowel wall (93.5%), thickening of the bowel wall (90.3%), and derangement of bowel shape with saccular formations (25.8%).

    CONCLUSIONS:

    MRE in the pediatric population often demonstrates increased contrast uptake, bowel wall thickening, and perienteral lymphadenopathy in CD. More chronic small bowel changes seen commonly in adults and solitary jejunal involvements are less commonly seen.

  • 12.
    Wagner, Michael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lampinen, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sangfelt, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Agnarsdóttir, Margrét
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Carlson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Budesonide Treatment of Patients With Collagenous Colitis Restores Normal Eosinophil and T-cell Activity in the Colon2010In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 16, no 7, p. 1118-1126Article in journal (Refereed)
    Abstract [en]

    Objective: The aim of this study was to assess the activity of eosinophils, neutrophils and CD4+ as well as CD8+ T-cells in eleven patients with active collagenous colitis (CC) before and after eight weeks of budesonide treatment (9 mg once daily) compared to ten healthy individuals.

    Methods: Clinical symptoms were recorded and intestinal biopsy samples were taken and analysed by flow cytometry. Eosinophils with a high surface expression of CD44 and low CD9 expression were classified as activated. Neutrophil activity was assessed by their expression of CD66b and CD69 was used as an activation marker for T cells.

    Results: All patients responded to the treatment. The eosinophils in active CC showed increased activity compared to controls. The activity was back to control levels after treatment. Neutrophils were not activated in CC patients before or after treatment.

    CD8+ T cells from untreated CC patients had a lower activity than controls, and a tendency of lower activity was observed on CD4+ T cells. After treatment, the activity was increased on both types of T cells and was not different from controls.

    Conclusions: In the present study we demonstrated that the inflammation in CC is characterized by activated eosinophils but there is no neutrophil activity. CD4+ and CD8+ T cells are increased in numbers in active CC but, surprisingly, they had a lower grade of activity than in control subjects. The major finding in this study is that budesonide treatment restores the normal activation of eosinophils and T-cells, accompanied by clinical remission.

  • 13. Willing, Ben
    et al.
    Halfvarson, Jonas
    Dicksved, Johan
    Rosenquist, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Järnerot, Gunnar
    Engstrand, Lars
    Tysk, Curt
    Jansson, Janet K.
    Twin studies reveal specific imbalances in the mucosa-associated microbiota of patients with ileal Crohn's disease2009In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 15, no 5, p. 653-660Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Large interindividual variation in the composition of the intestinal microbiota between unrelated individuals has made it challenging to identify specific aspects of dysbiosis that lead to Crohn's disease (CD). METHODS: To reduce variations in exposure during establishment of the gut flora and the influence of genotype, we studied the mucosa-associated microbiota of monozygotic twin pairs that were discordant (n = 6) or concordant (n = 4) for CD. DNA was extracted from biopsies collected from 5 locations between the ileum and rectum. Bacterial 16S ribosomal RNA genes were amplified and community composition assessed by terminal-restriction fragment length polymorphism, cloning and sequencing, and quantitative real-time polymerase chain reaction (PCR). RESULTS: The microbial compositions at all biopsy locations for each individual were similar, regardless of disease state, but there were differences between individuals. In particular, individuals with predominantly ileal CD had a dramatically lower abundance (P < 0.001) of Faecalibacterium prausnitzii and increased abundance (P < 0.03) of Escherichia coli compared to healthy co-twins and those with CD localized in the colon. This dysbiosis was significantly correlated to the disease phenotype rather than genotype. CONCLUSIONS: The reduced abundance of F. prausnitzii and increased abundance of E. coli are indicative of an ileal CD phenotype, distinct from colonic CD, and the relative abundances of these specific bacterial populations are promising biomarker candidates for differential diagnosis of CD and eventually customized treatment.

  • 14. Zhulina, Yaroslava
    et al.
    Hahn-Stromberg, Victoria
    Shamikh, Alia
    Peterson, Christer G. B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Gustavsson, Anders
    Nyhlin, Nils
    Wickbom, Anna
    Bohr, Johan
    Bodin, Lennart
    Tysk, Curt
    Carlson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Halfvarson, Jonas
    Subclinical Inflammation with Increased Neutrophil Activity in Healthy Twin Siblings Reflect Environmental Influence in the Pathogenesis of Inflammatory Bowel Disease2013In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 19, no 8, p. 1725-1731Article in journal (Refereed)
    Abstract [en]

    Background:The mechanisms behind increased fecal calprotectin (FC) in healthy relatives of patients with inflammatory bowel disease (IBD) are unknown. Our aims were to explore if there is a subclinical inflammation with increased neutrophil activity in healthy twin siblings in discordant twin pairs with IBD and to assess the influence of genetics in this context.Methods:Nuclear factor kappa B (NF-B) and neutrophil activity, based on myeloperoxidase (MPO) and FC, were analyzed in healthy twin siblings in discordant twin pairs with IBD and compared with healthy controls. NF-B and MPO were assessed by immunohistochemistry and FC by enzyme-linked immunosorbent assay.Results:In total, 33 of 34 healthy twin siblings were histologically normal. Increased NF-B was more often observed in healthy twin siblings in discordant twin pairs with Crohn's disease (13/18 [73%]) and with ulcerative colitis (12/16 [75%]) than in healthy controls (8/45 [18%]). MPO was more often increased in healthy twin siblings in discordant pairs with Crohn's disease (12/18 [67%]) than in healthy controls (11/45 [24%]) and FC more often in healthy twin siblings in discordant pairs with ulcerative colitis (14/21 [67%]) than in healthy controls (6/31 [19%]). Interestingly, the observed differences remained when healthy monozygotic and dizygotic twin siblings were analyzed separately.Conclusions:We observed increased NF-B, MPO, and FC in healthy twins in both monozygotic and dizygotic discordant pairs with IBD. These novel findings speak for an ongoing subclinical inflammation with increased neutrophil activity in healthy first-degree relatives.

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