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Introduction: Collagenous colitis (CC) is a disabling disease primarily affecting elderly women. Sparse, well-documented treatment modalities exist, except for budesonide. Long-term and repetitive treatment with budesonide is often necessary. Rifaximin is a poorly absorbed antibiotic with a positive modulatory effect on gut microbiota. In this randomised, double-blind, placebo-controlled single-centre trial, we test the effect of adding rifaximin in continuation to budesonide on relapse rates in CC. Methods: Eligible patients with active, biopsy-verified CC received oral budesonide during a 6-week open-label induction phase. Patients in clinical remission after 4 weeks of treatment were randomised to receive either rifaximin or placebo for 4 weeks. Results: Fifteen patients were randomised to receive either rifaximin (n = 7) or placebo (n = 8). At 12-week follow-up, 2 patients in the rifaximin group were still in remission and none in the placebo group (p = 0.2). The median number of days in remission in the rifaximin group was 42 (interquartile range [IQR] 33-126) compared to 18.5 (IQR 10.5-51.5) in the placebo group (p = 0.189). At 12-week follow-up, the relapse rate per 100 person-days in the placebo group was higher (3.25 [1.40-6.41]) than in the rifaximin group (1.33 [0.43-3.10]). Conclusion: Although not statistically significant (p = 0.0996), the study suggests a potential improvement in relapse rates within the rifaximin group compared to the placebo group. A major limitation in the study is the small sample size.
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BACKGROUND AND AIMS: Patient-reported outcome measures [PROMs] aim to measure patients' perception of how their disorder influences everyday functioning. The objective of this study was to develop a PROM to assess disease activity in microscopic colitis [MC] fulfilling the requirements of the Food and Drug Administration [FDA]. METHODS: The European Microscopic Colitis Activity Index [E-MCAI] was developed in four steps. [1] A list of symptoms associated with active MC was created by a group of experts in the field. [2] Content validity of the symptoms was performed by experts [n = 14] and patients [n = 79] using the Content Validity Index. [3] Questions and response alternatives were created for each symptom, and validity of the E-MCAI was evaluated with cognitive interviews with patients [n = 7] and by the experts. [4] A pilot postal survey was performed to ensure usability. RESULTS: Seven of the symptoms related to active MC fulfilled the criteria for content validity and were included in the E-MCAI: stool consistency, stool frequency, stools at night, feel a need to pass more stools shortly after a bowel movement, urgent need to empty the bowel, leakage of stool and abdominal pain. The development and validation process resulted in the current version of the E-MCAI consisting of six questions related to MC. CONCLUSIONS: The E-MCAI was developed using the methods advocated by the FDA. The evaluation indicates good content validity. Further evaluation will be performed to achieve construct validity, reliability and responsiveness in future cross-sectional and longitudinal studies.
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Colite Microscópica , Medidas de Resultados Relatados pelo Paciente , Colite Microscópica/diagnóstico , Estudos Transversais , Humanos , Reprodutibilidade dos Testes , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: Microscopic colitis [MC], encompassing collagenous colitis [CC] and lymphocytic colitis [LC], is an increasingly prevalent gastrointestinal disease with an unknown aetiology. Previous research has reported significant differences in the incidence of MC within Denmark, with the lowest incidence found in the most populated region [Capital Region of Denmark]. Our aim was to elucidate the causes of these regional differences. DESIGN: All incident MC patients [nâ =â 14 302] with a recorded diagnosis of CC [nâ =â 8437] or LC [nâ =â 5865] entered in The Danish Pathology Register between 2001 and 2016 were matched to 10 reference individuals [nâ =â 142 481]. Information regarding drug exposure, including proton pump inhibitors [PPIs], selective serotonin reuptake inhibitors [SSRIs], statins, and nonsteroidal anti-inflammatory drugs [NSAIDs], were retrieved from The Danish National Prescription Registry. Information regarding endoscopy rate, smoking-related diseases, and immune-mediated inflammatory diseases were acquired from The Danish National Patient Registry. RESULTS: Smoking, immune-mediated inflammatory diseases, exposure to PPIs, SSRIs, statins, and NSAIDs were significantly associated with MC in all Danish regions. The association between drug exposure and MC was weakest in the Capital Region of Denmark with an odds ratio of 1.8 (95% confidence interval [CI]: 1.61-2.01). The relative risk of undergoing a colonoscopy with biopsy was significantly increased in sex- and age-matched controls in all regions compared with controls from the Capital Region of Denmark, with the greatest risk found in the Region of Southern Denmark, 1.37 [95% CI: 1.26-1.50]. CONCLUSIONS: The cause of the regional differences in MC incidence in Denmark seems to be multifactorial, including variations in disease awareness and distribution of risk factors.
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Colite Microscópica/diagnóstico , Colite Microscópica/epidemiologia , Colonoscopia/estatística & dados numéricos , Idoso , Estudos de Casos e Controles , Dinamarca/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prevalência , Sistema de Registros , Fatores de RiscoRESUMO
INTRODUCTION: Microscopic colitis is a chronic inflammatory bowel disease characterised by normal or almost normal endoscopic appearance of the colon, chronic watery, nonbloody diarrhoea and distinct histological abnormalities, which identify three histological subtypes, the collagenous colitis, the lymphocytic colitis and the incomplete microscopic colitis. With ongoing uncertainties and new developments in the clinical management of microscopic colitis, there is a need for evidence-based guidelines to improve the medical care of patients suffering from this disorder. METHODS: Guidelines were developed by members from the European Microscopic Colitis Group and United European Gastroenterology in accordance with the Appraisal of Guidelines for Research and Evaluation II instrument. Following a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the certainty of the evidence. Statements and recommendations were developed by working groups consisting of gastroenterologists, pathologists and basic scientists, and voted upon using the Delphi method. RESULTS: These guidelines provide information on epidemiology and risk factors of microscopic colitis, as well as evidence-based statements and recommendations on diagnostic criteria and treatment options, including oral budesonide, bile acid binders, immunomodulators and biologics. Recommendations on the clinical management of microscopic colitis are provided based on evidence, expert opinion and best clinical practice. CONCLUSION: These guidelines may support clinicians worldwide to improve the clinical management of patients with microscopic colitis.
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BACKGROUND AND AIMS: The disease course of microscopic colitis [MC], encompassing collagenous colitis [CC] and lymphocytic colitis [LC], is not well known. In a Danish nationwide cohort, we evaluated the disease activity patterns as well as the risk of colorectal cancer [CRC] and mortality based on disease severity. METHODS: All incident MC patients [nâ =â 14 302] with a recorded diagnosis of CC [nâ =â 8437] or LC [nâ =â 5865] in the Danish Pathology Register, entered between 2001 and 2016, were matched to 10 reference individuals [nâ =â 142 481]. Incident cases of CRC after the index date were captured from the Danish Cancer Registry. Mortality data were ascertained from the Danish Registry of Causes of Death, and information about treatment was obtained from the Danish National Prescription Registry. The risk of CRC and mortality analyses were investigated by Cox regression and Kaplan-Meier estimates. RESULTS: We identified a self-limiting or transient disease course in 70.6% of LC patients and in 59.9% of CC patients, pâ <0.001. Less than 5% of MC patients experienced a budesonide-refractory disease course and were treated with immunomodulators or biologic treatment. A total of 2926 [20.5%] MC patients and 24 632 [17.3%] reference individuals died during the study period. MC patients with a severe disease had a relative risk [RR] of mortality of 1.41 (95% confidence interval [CI]: 1.32-1.50) compared with reference individuals. Only 90 MC patients were diagnosed with CRC during follow-up, corresponding to an RR of 0.48 [95% CI: 0.39-0.60]. CONCLUSIONS: A majority of MC patients experience an indolent disease course with a lower risk of developing CRC compared with the background population.
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Colite Microscópica/epidemiologia , Neoplasias Colorretais/epidemiologia , Idoso , Estudos de Coortes , Colite Microscópica/mortalidade , Neoplasias Colorretais/mortalidade , Dinamarca/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Risco , Índice de Gravidade de DoençaRESUMO
PURPOSE: The diagnosis microscopic colitis (MC) consisting of collagenous colitis (CC) and lymphocytic colitis (LC) relies on histological assessment of mucosal biopsies from the colon. The optimal biopsy strategy for reliable diagnosis of MC is controversial. The aim of this study was to evaluate the distribution of histopathological features of MC throughout the colon. METHODS: Mucosal biopsies from multiple colonic segments of patients with MC who participated in one of the three prospective European multicenter trials were analyzed. Histological slides were stained with hematoxylin-and-eosin, a connective tissue stain, and CD3 in selected cases. RESULTS: In total, 255 patients were included, 199 and 56 patients with CC and LC, respectively. Both groups exhibited a gradient with more pronounced inflammation in the lamina propria in the proximal colon compared with the distal colon. Similarly, the thickness of the subepithelial collagenous band in CC showed a gradient with higher values in the proximal colon. The mean number of intraepithelial lymphocytes was > 20 in all colonic segments in patients within both subgroups. Biopsies from 86 to 94% of individual segments were diagnostic, rectum excluded. Biopsies from non-diagnostic segments often showed features of another subgroup of MC. CONCLUSION: Conclusively, although the severity of the histological changes in MC differed in the colonic mucosa, the minimum criteria required for the diagnosis were present in the random biopsies from the majority of segments. Thus, our findings show MC to be a pancolitis, rectum excluded, questioning previously proclaimed patchiness throughout the colon.
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Colite Colagenosa , Colite Microscópica , Colite , Biópsia , Colo , Humanos , Estudos ProspectivosRESUMO
BACKGROUND AND AIMS: Epidemiological studies suggest an increasing global incidence of microscopic colitis, including collagenous colitis and lymphocytic colitis. We aimed to investigate the incidence and prevalence of microscopic colitis in Denmark. METHODS: In a nationwide cohort study, we included all incident patients with a recorded diagnosis of collagenous colitis or lymphocytic colitis in the Danish Pathology Register between 2001 and 2016. RESULTS: A total of 14 302 patients with microscopic colitis-8437 [59%] with collagenous and 5865 [41%] with lymphocytic colitis-were identified during the study period. The prevalence in December 2016 was estimated to be 197.9 cases per 100 000 inhabitants. Microscopic colitis was more prevalent among females (n = 10 127 [71%]), with a mean annual incidence of 28.8, compared with 12.3 per 100 000 person-years among males. The overall mean incidence during the study period was 20.7 per 100 000 person-years. Mean age at time of diagnosis was 65 years (standard deviation [SD]:14) for microscopic colitis, 67 [SD:13] for collagenous colitis, and 63 [SD:15] for lymphocytic colitis. The overall incidence increased significantly from 2.3 cases in 2001 to 24.3 cases per 100 000 person-years in 2016. However, the highest observed incidence of microscopic colitis was 32.3 cases per 100 000 person-years in 2011. Large regional differences were found, with the highest incidence observed in the least populated region. CONCLUSIONS: The incidence of microscopic colitis in Denmark has increased 10-fold during the past 15 years and has now surpassed that of Crohn's disease and ulcerative colitis. However, incidence has stabilised since 2012, suggesting that a plateau has been reached.
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Colite Microscópica/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Colite Microscópica/epidemiologia , Colite Microscópica/fisiopatologia , Dinamarca/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , PrevalênciaRESUMO
BACKGROUND: Due to a substantial first-pass metabolism of oral budesonide, systemic bioavailability is low compared to other oral corticosteroids, thereby possibly avoiding adverse effects of systemic corticosteroid use. AIM: To determine whether use of oral budesonide is associated with osteoporotic fractures in patients with microscopic colitis (MC). METHODS: Applying data from the Danish nationwide health registries, we conducted a case-control study nested within a cohort of patients with MC from 2004 to 2012. We estimated odds ratios (ORs) for the association between budesonide use and osteoporotic fractures (hip, wrist and spinal fractures). RESULTS: We identified 417 cases with a first occurrence of an osteoporotic fracture. Eighty-six per cent were women and the median age was 78 years. The OR for the overall association between ever-use of budesonide and any osteoporotic fractures did not reach statistical significance (OR 1.13, CI: 0.88-1.47). The highest risk was observed for spinal fractures (OR 1.98, CI: 0.94-4.17), where a dose-response association seemed to exist, followed by hip and wrist fractures (OR 1.17 [CI: 0.79-1.73] and OR 0.99 [CI: 0.66-1.47] respectively). We generally found modestly increased ORs across subgroups at suspected high or low risk of fractures (1.00-2.49). No overall dose-response association was evident (OR for doubling of cumulative dose 0.93 (CI: 0.84-1.03). CONCLUSION: No overall association between use of oral budesonide and osteoporotic fractures was demonstrated among individuals with MC. There seemed to be an isolated adverse effect of budesonide on the risk of spinal fractures, which appears to be dose related.
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Budesonida/administração & dosagem , Budesonida/efeitos adversos , Colite Microscópica/tratamento farmacológico , Colite Microscópica/epidemiologia , Fraturas por Osteoporose/induzido quimicamente , Fraturas por Osteoporose/epidemiologia , Administração Oral , Corticosteroides/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Estudos de Coortes , Colite Microscópica/patologia , Feminino , Humanos , Assistência de Longa Duração , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Fatores de TempoRESUMO
In this case report a 48-year-old man presented with nausea and abdominal pain. Ten days prior he had been treated with an endoscopic epinephrine/saline injection for haemostasis of a bleeding duodenal ulcer and was discharged the following day. At readmission, an abdominal CT revealed severe gastric distention and a gastroscopy showed total duodenal obstruction. Subsequent post-contrast CT revealed that a massive intramural duodenal haematoma was the cause of the total duodenal occlusion. Also, acute pancreatitis was seen. The treatment was conservative, and follow-up gastroscopy showed total resolution of the haematoma.
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Duodenopatias/etiologia , Hematoma/etiologia , Hemostase Endoscópica/efeitos adversos , Doença Aguda , Duodenopatias/diagnóstico por imagem , Duodenopatias/terapia , Obstrução Duodenal/diagnóstico por imagem , Obstrução Duodenal/etiologia , Obstrução Duodenal/terapia , Úlcera Duodenal/terapia , Epinefrina/administração & dosagem , Epinefrina/efeitos adversos , Epinefrina/uso terapêutico , Hematoma/diagnóstico por imagem , Hematoma/terapia , Humanos , Injeções/efeitos adversos , Masculino , Pessoa de Meia-Idade , Pancreatite/etiologia , Pancreatite/terapia , Solução Salina/administração & dosagem , Solução Salina/efeitos adversos , Solução Salina/uso terapêutico , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND & AIMS: Lymphocytic colitis is a common cause of chronic, nonbloody diarrhea. However, the effects of treatment are unclear and randomized placebo-controlled trials were requested in a Cochrane review. We performed a randomized, placebo-controlled, multicenter study to evaluate budesonide and mesalazine as induction therapy for lymphocytic colitis. METHODS: Patients with active lymphocytic colitis were randomly assigned to groups given budesonide 9 mg once daily (Budenofalk granules), mesalazine 3 g once daily (Salofalk granules), or placebo for 8 weeks in a double-blind, double-dummy design. The primary endpoint was clinical remission, defined as ≤21 stools (including ≤6 watery stools), in the 7 days before week 8. RESULTS: The final analysis included 57 patients (19 per group). Most patients were female (72%) and the mean age was 59 years. The proportion of patients in clinical remission at week 8 was significantly higher in the budesonide group than in the placebo group (intention-to-treat analysis, 79% vs 42%; P = .01). The difference in proportions of patients in clinical remission at week 8 between the mesalazine (63%) and placebo groups was not significant (P = .09). The proportion of patients with histologic remission at week 8 was significantly higher in the budesonide group (68%) vs the mesalazine (26%; P = .02) or placebo (21%; P = .008) groups. The incidence of adverse events was 47.4% in the budesonide group, 68.4% in the mesalazine group, and 42.1% in the placebo group. CONCLUSIONS: In a randomized multicenter study, we found oral budesonide 9 mg once daily to be effective and safe for induction of clinical and histologic remission in patients with lymphocytic colitis, compared with placebo. Oral mesalazine 3 g once daily was not significantly better than placebo. ClinicalTrials.gov no: NCT01209208.
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Anti-Inflamatórios/uso terapêutico , Budesonida/uso terapêutico , Colite Linfocítica/tratamento farmacológico , Mesalamina/uso terapêutico , Administração Oral , Anti-Inflamatórios/administração & dosagem , Budesonida/administração & dosagem , Colite Linfocítica/patologia , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Quimioterapia de Indução , Masculino , Mesalamina/administração & dosagem , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
BACKGROUND: Microscopic colitis causes chronic watery diarrhoea and has previously been associated with the use of proton pump inhibitors. AIM: To explore the association between proton pump inhibitor use and microscopic colitis, including its dependency on timing, dose and choice of proton pump inhibitor. METHODS: Within a 10-year period, we identified 10 652 patients with a first-time diagnosis of microscopic colitis, including 6254 (59%) with collagenous colitis and 4398 (41%) with lymphocytic colitis. All microscopic colitis cases were histologically confirmed in the Danish Pathology Register. Information on proton pump inhibitor use was obtained from the Danish Prescription Register. In this case-control study, we estimated the adjusted odds ratios (aOR) for the association between proton pump inhibitor use and risk of microscopic colitis using conditional logistic regression while adjusting for potential confounders. RESULTS: We found strong associations between current proton pump inhibitor use and both collagenous colitis (aOR 6.98; 95% CI: 6.45-7.55) and lymphocytic colitis (aOR 3.95; 95% CI: 3.60-4.33). This association was observed with all PPIs. The strongest association was with the current use of lansoprazole for both collagenous colitis (aOR 15.74; 95% CI: 14.12-17.55) and lymphocytic colitis (aOR 6.87; 95% CI: 6.00-7.86). When considering timing, ORs were highest for current use of proton pump inhibitor and lower for recent or past exposure. No clear dose-response pattern was observed. CONCLUSIONS: We found a strong association between microscopic colitis and ongoing use of proton pump inhibitors, especially lansoprazole.
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Colite Microscópica/tratamento farmacológico , Inibidores da Bomba de Prótons/classificação , Inibidores da Bomba de Prótons/uso terapêutico , Idoso , Estudos de Casos e Controles , Colite Colagenosa/tratamento farmacológico , Colite Colagenosa/epidemiologia , Colite Linfocítica/tratamento farmacológico , Colite Linfocítica/epidemiologia , Colite Microscópica/epidemiologia , Dinamarca/epidemiologia , Feminino , Humanos , Lansoprazol/uso terapêutico , Masculino , Pessoa de Meia-Idade , Sistema de RegistrosRESUMO
OBJECTIVES: Patients with microscopic colitis (MC) have several risk factors for osteoporosis. The prevalence of osteopenia and osteoporosis in MC is unknown. The primary purpose of this study was to evaluate bone mineral status in MC. METHODS: Patients with MC and disease activity within the last 2 years were included. Bone turnover markers were analyzed and bone mineral density (BMD) was measured with Dual Energy X-ray Absorptiometry (DXA) at inclusion and after one year. Medical history, demographics, risk factors for osteoporosis, disease activity and treatment with cumulative budesonide dosage at least 3 years before inclusion was registered. Adrenal function was tested by adrenocortico-tropic hormone (ACTH) and an ACTH stimulation test at inclusion. Results were compared with age and sex-matched controls. RESULTS: Fifty MC patients (44 women) were included. Median age 67 (range 45-93); median disease duration 28 month (range 2-163); median cumulative budesonide dosage 702 mg (range 0-5400). No difference in number of patients with osteoporosis or osteopenia and BMD was detected between groups. The bone mineral formation marker specific alkaline phosphatase was lower in MC than controls 12 (5-69) µg/l versus 16 (10-35) µg/l (p < 0.005). Patients more often smoked (34% versus 10%, p = 0.001). Disease duration and cumulative budesonide dose was associated with lower BMD and T-score in hip (Spearman's rho; p < 0.05) with a cut of point of 2500 mg budesonide predicting osteopenia. Budesonide treatment did not affect adrenal gland function. CONCLUSION: The risk of osteoporosis in patients with MC is not increased. However, DXA scan is recommended in MC patients with known risk factors or active disease requiring longstanding budesonide treatment. Supplementation of calcium and vitamin-D in patients treated with budesonide is recommended.
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Glândulas Suprarrenais/metabolismo , Colite Microscópica/epidemiologia , Osteoporose/epidemiologia , Absorciometria de Fóton , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/efeitos adversos , Biomarcadores , Densidade Óssea , Doenças Ósseas Metabólicas/epidemiologia , Budesonida/administração & dosagem , Budesonida/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Índice de Gravidade de Doença , Fumar/epidemiologia , Fatores Socioeconômicos , Fatores de TempoRESUMO
BACKGROUND: Intravenous iron allows for efficient and well-tolerated treatment in iron deficiency and is routinely used in diseases of the gastrointestinal tract. OBJECTIVE: The aims of this study were to determine the probability of relapse of iron deficiency over time and to investigate treatment routine, effectiveness, and safety of iron isomaltoside. METHODS: A total of 282 patients treated with iron isomaltoside were observed for two treatments or a minimum of one year. RESULTS: Out of 282 patients, 82 had Crohn's disease and 67 had ulcerative colitis. Another 133 patients had chronic blood loss, malabsorption, or malignancy. Patients who received an iron isomaltoside dose above 1000 mg had a 65% lower probability of needing retreatment compared with those given 1000 mg. A clinically significant treatment response was shown, but in 71/191 (37%) of patients, anaemia was not corrected. The mean dose given was 1100 mg, lower than the calculated total iron need of 1481 mg. Adverse drug reactions were reported in 4% of patients. CONCLUSION: Iron isomaltoside is effective with a good safety profile, and high doses reduce the need for retreatment over time. Several patients were anaemic after treatment, indicating that doses were inadequate for full iron correction. This trial is registered with NCT01900197.
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The datasets presented in this article are related to the research articles entitled "Neutrophil Extracellular Traps in Ulcerative Colitis: A Proteome Analysis of Intestinal Biopsies" (Bennike et al., 2015 [1]), and "Proteome Analysis of Rheumatoid Arthritis Gut Mucosa" (Bennike et al., 2017 [2]). The colon mucosa represents the main interacting surface of the gut microbiota and the immune system. Studies have found an altered composition of the gut microbiota in rheumatoid arthritis patients (Zhang et al., 2015; Vaahtovuo et al., 2008; Hazenberg et al., 1992) [5], [6], [7] and inflammatory bowel disease patients (Morgan et al., 2012; Abraham and Medzhitov, 2011; Bennike, 2014) [8], [9], [10]. Therefore, we characterized the proteome of colon mucosa biopsies from 10 inflammatory bowel disease ulcerative colitis (UC) patients, 11 gastrointestinal healthy rheumatoid arthritis (RA) patients, and 10 controls. We conducted the sample preparation and liquid chromatography mass spectrometry (LC-MS/MS) analysis of all samples in one batch, enabling label-free comparison between all biopsies. The datasets are made publicly available to enable critical or extended analyses. The proteomics data and search results, have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifiers PXD001608 for ulcerative colitis and control samples, and PXD003082 for rheumatoid arthritis samples.
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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/imunologiaRESUMO
BACKGROUND: The relationship between clinical and histological parameters in collagenous colitis (CC) is poorly understood. Smoking is a risk factor for CC, whereas its impact on clinical activity and outcome is not well known. METHODS: In a post hoc analysis of pooled data from two randomized controlled trials we assessed the association between demographic data (gender, age, smoking habits, family history of inflammatory bowel disease), clinical variables (duration of symptoms, mean number of stools/watery stools per day, abdominal pain, clinical remission) and histological data (thickness of the collagen band, inflammation of the lamina propria, total numbers of intraepithelial lymphocytes, degeneration). Moreover, we analysed the predictive value of baseline parameters for clinical outcome in a logistic regression model. RESULTS: Pooled data were available from 202 patients with active CC, of whom 36% were current smokers, 29% former smokers and 35% non-smokers. Smoking status was associated with decreased ability to achieve clinical remission (current smokers vs non-smokers: odds ratio [OR] 0.31, 95% confidence interval [CI] 0.10-0.98, p = 0.045; former smokers vs non-smokers: OR 0.19, 95% CI 0.05-0.73, p = 0.016). Current smokers had an increased mean number of watery stools at baseline compared with non-smokers (p = 0.051) and increased mean number of watery stools per se was associated with decreased likelihood of obtaining clinical remission (OR 0.63, 95% CI 0.47-0.86, p = 0.003). Patient characteristics and histology at baseline had no association with clinical parameters and no predictive value for clinical outcome. CONCLUSION: Smoking worsens clinical symptoms in CC and is associated with an increased number of watery stools and decreased likelihood of achieving clinical remission. There is no significant association between histology and clinical data.
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Colite Colagenosa/etiologia , Fumar/efeitos adversos , Idoso , Budesonida/uso terapêutico , Colite Colagenosa/diagnóstico , Colite Colagenosa/tratamento farmacológico , Colite Colagenosa/patologia , Colo/patologia , Feminino , Fármacos Gastrointestinais/uso terapêutico , Humanos , Masculino , Mesalamina/uso terapêutico , Pessoa de Meia-Idade , Prognóstico , Indução de Remissão , Resultado do TratamentoRESUMO
OBJECTIVE: This 1-year study aimed to assess low-dose budesonide therapy for maintenance of clinical remission in patients with collagenous colitis. DESIGN: A prospective, randomised, placebo-controlled study beginning with an 8-week open-label induction phase in which patients with histologically confirmed active collagenous colitis received budesonide (Budenofalk, 9â mg/day initially, tapered to 4.5â mg/day), after which 92 patients in clinical remission were randomised to budesonide (mean dose 4.5â mg/day; Budenofalk 3 mg capsules, two or one capsule on alternate days) or placebo in a 12-month double-blind phase with 6â months treatment-free follow-up. Primary endpoint was clinical remission throughout the double-blind phase. RESULTS: Clinical remission during open-label treatment was achieved by 84.5% (93/110 patients). The median time to remission was 10.5â days (95% CI (9.0 to 14.0â days)). The maintenance of clinical remission at 1â year was achieved by 61.4% (27/44 patients) in the budesonide group versus 16.7% (8/48 patients) receiving placebo (treatment difference 44.5% in favour of budesonide; 95% CI (26.9% to 62.7%), p<0.001). Health-related quality of life was maintained during the 12-month double-blind phase in budesonide-treated patients. During treatment-free follow-up, 82.1% (23/28 patients) formerly receiving budesonide relapsed after study drug discontinuation. Low-dose budesonide over 1â year resulted in few suspected adverse drug reactions (7/44 patients), all non-serious. CONCLUSIONS: Budesonide at a mean dose of 4.5â mg/day maintained clinical remission for at least 1â year in the majority of patients with collagenous colitis and preserved health-related quality of life without safety concerns. Treatment extension with low-dose budesonide beyond 1â year may be beneficial given the high relapse rate after budesonide discontinuation. TRIAL REGISTRATION NUMBERS: http://www.clinicaltrials.gov (NCT01278082) and http://www.clinicaltrialsregister.eu (EudraCT: 2007-001315-31).