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The most recent and promising therapeutic strategies for inflammatory bowel disease (IBD) have engaged biologics targeting single effector components involved in major steps of the immune-inflammatory processes, such as tumor necrosis factor, interleukins or integrins. Nevertheless, these molecules have not yet met expectations regarding efficacy and safety, resulting in a significant percentage of refractory or relapsing patients. Thus, novel treatment options are urgently needed. The minor isoform of the complement inhibitor C4b-binding protein, C4BP(ß-), has been shown to confer a robust anti-inflammatory and immunomodulatory phenotype over inflammatory myeloid cells. Here we show that C4BP(ß-)-mediated immunomodulation can significantly attenuate the histopathological traits and preserve the intestinal epithelial integrity in dextran sulfate sodium (DSS)-induced murine colitis. C4BP(ß-) downregulated inflammatory transcripts, notably those related to neutrophil activity, mitigated circulating inflammatory effector cytokines and chemokines such as CXCL13, key in generating ectopic lymphoid structures, and, overall, prevented inflammatory immune cell infiltration in the colon of colitic mice. PRP6-HO7, a recombinant curtailed analogue with only immunomodulatory activity, achieved a similar outcome as C4BP(ß-), indicating that the therapeutic effect is not due to the complement inhibitory activity. Furthermore, both C4BP(ß-) and PRP6-HO7 significantly reduced, with comparable efficacy, the intrinsic and TLR-induced inflammatory markers in myeloid cells from both ulcerative colitis and Crohn's disease patients, regardless of their medication. Thus, the pleiotropic anti-inflammatory and immunomodulatory activity of PRP6-HO7, able to "reprogram" myeloid cells from the complex inflammatory bowel environment and to restore immune homeostasis, might constitute a promising therapeutic option for IBD.
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Colite , Doenças Inflamatórias Intestinais , Animais , Humanos , Camundongos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Colite/induzido quimicamente , Colite/tratamento farmacológico , Imunomodulação , Inflamação , Doenças Inflamatórias Intestinais/induzido quimicamente , Doenças Inflamatórias Intestinais/tratamento farmacológico , Células MieloidesRESUMO
INTRODUCTION: The objective of this study was to assess the durability, short-term and long-term effectiveness, and safety of tofacitinib in ulcerative colitis (UC) in clinical practice. METHODS: This is a retrospective multicenter study including patients with UC who had received the first tofacitinib dose at least 8 weeks before the inclusion. Clinical effectiveness was based on partial Mayo score. RESULTS: A total of 408 patients were included. Of them, 184 (45%) withdrew tofacitinib during follow-up (mean = 18 months). The probability of maintaining tofacitinib was 67% at 6 m, 58% at 12 m, and 49% at 24 m. The main reason for tofacitinib withdrawal was primary nonresponse (44%). Older age at the start of tofacitinib and a higher severity of clinical activity were associated with tofacitinib withdrawal. The proportion of patients in remission was 38% at week 4, 45% at week 8, and 47% at week 16. Having moderate-to-severe vs mild disease activity at baseline and older age at tofacitinib start were associated with a lower and higher likelihood of remission at week 8, respectively. Of 171 patients in remission at week 8, 83 (49%) relapsed. The probability of maintaining response was 66% at 6 m and 54% at 12 m. There were 93 adverse events related to tofacitinib treatment (including 2 pulmonary thromboembolisms [in patients with risk factors] and 2 peripheral vascular thrombosis), and 29 led to tofacitinib discontinuation. DISCUSSION: Tofacitinib is effective in both short-term and long-term in patients with UC. The safety profile is similar to that previously reported.
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Colite Ulcerativa , Humanos , Colite Ulcerativa/tratamento farmacológico , Resultado do Tratamento , Indução de Remissão , Estudos RetrospectivosRESUMO
INTRODUCTION: The pandemic caused by the SARS-CoV-2 virus has had a serious impact on the functioning of gastrointestinal endoscopy Units. The Asociación Española de Gastroenterología (AEG) and the Sociedad Española de Endoscopia Digestiva (SEED) have proposed the EPAGE guidelines for managing postponed colonoscopies. OBJECTIVE: To evaluate the EPAGE guidelines as a management tool compared to the immunologic faecal occult blood test (iFOBT) and compared to risk score (RS) that combines age, sex and the iFOBT for the detection of colorectal cancer (CRC) and significant bowel disease (SBD). METHODS: A prospective, single-centre study enrolling 743 symptomatic patients referred for a diagnostic colonoscopy. Each order was classified according to the EPAGE guidelines as appropriate, indeterminate or inappropriate. Patients underwent an iFOBT and had their RS calculated. RESULTS: The iFOBT (p<0.001), but not the EPAGE guidelines (p = 0.742), was an independent predictive factor of risk of CRC. The ROC AUCs for the EPAGE guidelines, the iFOBT and the RS were 0.61 (95% CI 0.49-0.75), 0.95 (0.93-0.97) and 0.90 (0.87-0.93) for CRC, and 0.55 (0.49-0.61), 0.75 (0.69-0.813) and 0.78 (0.73-0.83) for SBD, respectively. The numbers of colonoscopies needed to detect a case of CRC and a case of SBD were 38 and seven for the EPAGE guidelines, seven and two for the iFOBT, and 19 and four for a RS ≥5 points, respectively. CONCLUSION: The EPAGE guidelines, unlike the iFOBT, is not suitable for screening candidate patients for a diagnostic colonoscopy to detect CRC. The iFOBT, in combination with age and sex, is the most suitable strategy for managing demand for endoscopy in a restricted-access situation.
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COVID-19/epidemiologia , Colonoscopia/normas , Neoplasias Colorretais/diagnóstico , Sangue Oculto , Pandemias , Guias de Prática Clínica como Assunto , Adulto , Fatores Etários , Idoso , Análise de Variância , COVID-19/prevenção & controle , Colonoscopia/estatística & dados numéricos , Endoscopia Gastrointestinal/normas , Feminino , Gastroenterologia/normas , Humanos , Enteropatias/diagnóstico , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores de Risco , Fatores Sexuais , Sociedades MédicasRESUMO
Background Blood loss from the gastrointestinal (GI) tract is the most common cause of iron deficiency anaemia (IDA) in adult men and postmenopausal women. Gastroduodenal endoscopy (GDE) and colonoscopy are frequently recommended, despite uncertainty regarding the coexistence of lesions in the upper and lower GI tract. The faecal immunochemical test (FIT) measures the concentration of faecal haemoglobin (f-Hb) originating only from the colon or rectum. We aimed to assess whether the FIT was able to select the best endoscopic procedure for detecting the cause of IDA. Methods A prospective study of 120 men and postmenopausal women referred for a diagnostic study of IDA were evaluated with an FIT, GDE and colonoscopy. The endoscopic finding of a significant upper lesion (SUL) or a significant bowel lesion (SBL) was considered to be the cause of the IDA. Results The diagnoses were 35.0% SUL and 20.0% SBL, including 13.3% GI cancer. In the multivariate analysis, the concentration of blood haemoglobin (b-Hb) <9 g/dL (OR: 2.60; 95% CI 1.13-6.00; p = 0.025) and non-steroidal anti-inflammatory drugs NSAIDs (2.56; 1.13-5.88; p = 0.024) were associated with an SUL. Age (0.93; 0.88-0.99; p = 0.042) and f-Hb ≥ 15 µg Hb/g faeces (38.53; 8.60-172.50; p < 0.001) were associated with an SBL. A "FIT plus gastroscopy" strategy, in which colonoscopy is performed only when f-Hb ≥15 µg Hb/g faeces, would be able to detect 92.4% of lesions and be 100% accurate in the detection of cancer while avoiding 71.6% of colonoscopies. Conclusions The FIT is an accurate method for selecting the best endoscopy study for the evaluation of IDA. An FIT-based strategy is more cost-effective than the current bidirectional endoscopy-based strategy and could improve endoscopic resource allocation.
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Anemia Ferropriva/diagnóstico , Fezes/química , Hemoglobinas/análise , Anti-Inflamatórios não Esteroides/uso terapêutico , Colonoscopia , Endoscopia Gastrointestinal , Feminino , Seguimentos , Neoplasias Gastrointestinais/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de RiscoRESUMO
BACKGROUND: Histological remission has been proposed as a new treatment goal in patients with ulcerative colitis (UC) although no universal definition for microscopic activity exists. AIM: We evaluated the accuracy of histological activity to predict clinical relapse in UC patients with both clinical and endoscopic remission. METHODS: Asymptomatic UC patients in endoscopic remission (Mayo endoscopic sub-score 0 or 1) undergoing surveillance colonoscopy in two referral hospitals were prospectively recruited. All colonic biopsies were analyzed according to the Geboes' score (GS) and the presence of basal plasmacytosis (BP). RESULTS: Ninety-six patients were included (38% women, median (interquartile range) age 50.0 (39.0-58.5) years, median disease duration 12.0 (6.5-19.5) years). Histological activity defined as GS ≥ 2B.1, GS ≥ 3.1, or BP was present in, respectively, 26%, 23% and 12%. Within 12 months from index endoscopy, 23% of the patients presented with clinical relapse. In multivariate analysis, active histological disease was the only risk factor predicting clinical relapse (odds ratio (95% confidence interval) 4.29 (1.55-11.87); p = 0.005 for GS ≥ 2B.1 and 4.31 (1.52-12.21); p = 0.006 for GS ≥ 3.1). CONCLUSIONS: In patients with UC in clinical and endoscopic remission, histological activity is an independent risk factor for clinical relapse. Further prospective studies need to clarify whether treatment optimization is justified in this context.
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The aim of our work was to test the usability of fecal calprotectin (FC) home-based test in inflammatory bowel disease (IBD) patients. METHODS: IBD patients were prospectively recruited. They had to measure FC with a dedicated tool and smartphone application, 5 times at two weeks intervals over an 8 weeks period. They had to fill in a usability questionnaire at the first and the last FC measurement. A System Usability Scale (SUS: 0-100) and the Global Score of Usability (GSU: 0-85) were calculated. FC was also centrally measured by ELISA. RESULTS: Fifty-eight patients were recruited. Forty-two performed at least one FC measurement and 27 performed all the FC requested measurements. The median (IQR) SUS (0-100) at the first and last use were 85 (78-90) and 81 (70-88), respectively; the median (IQR) GSU (0-85) at the first and last use were 74 (69-80) and 77 (68-83), respectively. Adherence to the planned measurements and usability of the tool were higher in females and in less severe disease. The intra-class correlation coefficient between home-based and centrally measured FC was 0.88. CONCLUSION: The adherence to home-based measurement of FC was fair. Usability scores for the home-based test were high. There was a good correlation with the centrally measured FC by ELISA.
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Fezes/química , Doenças Inflamatórias Intestinais/diagnóstico , Complexo Antígeno L1 Leucocitário/análise , Autocuidado , Adulto , Doenças Assintomáticas , Bélgica , Biomarcadores/análise , Feminino , Humanos , Modelos Lineares , Modelos Logísticos , Masculino , Noruega , Cooperação do Paciente , Valor Preditivo dos Testes , Índice de Gravidade de Doença , Espanha , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Controlled studies show high efficacy of budesonide in inducing short-term clinical remission in collagenous colitis (CC), but relapses are common after its withdrawal. AIM: To evaluate the need for high-dose budesonide (≥6mg/d) to maintain clinical remission in CC. METHODS: Analysis of a multicentre retrospective cohort of 75 patients with CC (62.3±1.5years; 85% women) treated with budesonide in a clinical practice setting between 2013 and 2015. Frequency of budesonide (9mg/d) refractoriness and safety, and the need for high-dose budesonide to maintain clinical remission, were evaluated. Drugs used as budesonide-sparing, including azathioprine and mercaptopurine, were recorded. Logistic regression analysis was performed to evaluate the risk factors associated with the need for high-dose budesonide (≥6mg/d) to maintain clinical remission. RESULTS: Budesonide induced clinical remission in 92% of patients, with good tolerance. Fourteen of 68 patients (21%; 95% CI, 13-32%) needed high-dose budesonide to maintain remission. Only intake of NSAIDs at diagnosis (OR, 8.6; 95% CI, 1.6-44) was associated with the need for high-dose budesonide in the multivariate analysis. TREATMENT: with thiopurines was effective in 5 out of 6 patients (83%; 95% CI, 44-97%), allowing for withdrawal from or a dose decrease of budesonide. CONCLUSIONS: One fifth of CC patients, especially those with NSAID intake at diagnosis, require high-dose budesonide (≥6mg/d) to maintain clinical remission. In this setting, thiopurines might be effective as budesonide-sparing drugs.
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Anti-Inflamatórios/administração & dosagem , Budesonida/administração & dosagem , Colite Colagenosa/tratamento farmacológico , Quimioterapia de Manutenção , Anti-Inflamatórios não Esteroides/uso terapêutico , Azatioprina/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Humanos , Modelos Logísticos , Masculino , Mercaptopurina/uso terapêutico , Pessoa de Meia-Idade , Análise Multivariada , Recidiva , Indução de Remissão , Estudos Retrospectivos , Fatores de Risco , EspanhaRESUMO
BACKGROUND AND AIM: Intravenous corticosteroids remain the first line therapy for severe attacks of ulcerative colitis although up to 30-40% of patients do not respond to treatment. The availability of alternative therapies to colectomy and the knowledge of early predictors of response to corticosteroids should have improved the clinical outcomes of patients with severe refractory ulcerative colitis. The aim of the study is to describe the current need, way of use, and efficacy of rescue therapies, as well as colectomy rates in patients with severe ulcerative colitis flares. METHODS: Between January 2005 and December 2011, all patients admitted in three referral centres for a severe ulcerative colitis flare who received intravenous corticosteroids were identified and clinical and biological data were accurately collected. Patients were followed-up until colectomy, death, or date of data collection. RESULTS: Sixty-two flares were included. Initial efficacy of intravenous corticosteroids (mild activity or inactive disease without rescue treatment, at day 7 after starting intravenous corticosteroids) was achieved in 50% of flares, and rescue therapies were used in 27 episodes (43%). After a median follow-up of 18 months, the colectomy rate was 6.5%. Failed oral corticosteroids for the index flare were the only baseline feature that predicted the need for rescue therapy and colectomy. CONCLUSIONS: There is a marked reduction in the colectomy rate and an increased use of medical rescue therapies as compared to historical series. Patients worsening while on oral corticosteroids for a moderate flare are at high risk of rescue therapy and colectomy and, therefore, should be directly treated with rescue therapies instead of attempting intravenous corticosteroids.
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Corticosteroides/uso terapêutico , Colite Ulcerativa/terapia , Fármacos Gastrointestinais/uso terapêutico , Imunossupressores/uso terapêutico , Administração Intravenosa , Adulto , Colectomia , Ciclosporina/uso terapêutico , Feminino , Seguimentos , Humanos , Infliximab/uso terapêutico , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença , Espanha , Centros de Atenção Terciária , Falha de TratamentoRESUMO
Chronic diarrhoea is a common presenting symptom in both primary care medicine and in specialized gastroenterology clinics. It is estimated that >5% of the population has chronic diarrhoea and nearly 40% of these patients are older than 60 years. Clinicians often need to select the best diagnostic approach to these patients and choose between the multiple diagnostic tests available. In 2014 the Catalan Society of Gastroenterology formed a working group with the main objective of creating diagnostic algorithms based on clinical practice and to evaluate diagnostic tests and the scientific evidence available for their use. The GRADE system was used to classify scientific evidence and strength of recommendations. The consensus document contains 28 recommendations and 6 diagnostic algorithms. The document also describes criteria for referral from primary to specialized care.
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Diarreia , Algoritmos , Antidiarreicos/uso terapêutico , Doença Crônica , Colite/complicações , Colite/diagnóstico , Técnicas de Diagnóstico do Sistema Digestório , Diarreia/classificação , Diarreia/diagnóstico , Diarreia/etiologia , Diarreia/terapia , Dieta , Açúcares da Dieta/efeitos adversos , Gerenciamento Clínico , Insuficiência Pancreática Exócrina/complicações , Insuficiência Pancreática Exócrina/diagnóstico , Hipersensibilidade Alimentar/complicações , Hipersensibilidade Alimentar/diagnóstico , Gastroenteropatias/diagnóstico , Microbioma Gastrointestinal , Motilidade Gastrointestinal , Humanos , Síndromes de Malabsorção/complicações , Síndromes de Malabsorção/diagnósticoRESUMO
BACKGROUND: European health systems have developed referral guidelines for the selection of patients for the urgent investigation of suspected colorectal cancer. AIM: To evaluate whether quantitative faecal immunochemical testing performs better than commonly used high-risk symptoms based strategies for fast-tracking cancer referrals. METHODS: We prospectively studied 1054 symptomatic patients referred for a colonoscopy who provided a sample for faecal immunochemical testing. The usefulness of faecal immunochemical testing and two current guidelines for urgent referral were compared for their efficacy in the detection of colorectal cancer and advanced neoplasia. RESULTS: The guidelines detected 46.7% and 43.3% of cases of colorectal cancer while faecal haemoglobin concentration ≥15µg Hb/g detected 96.7% of cases. The diagnostic accuracy of both the guidelines and faecal haemoglobin concentration ≥15µg Hb/g for the detection of advanced neoplasia was: sensitivity 38.3%, 36.1%, 57.1% and specificity 71.8%, 69.5%, 86.6%, respectively. Male gender (OR 2.35; p<0.001), age (1.34; p=0.002), and faecal haemoglobin concentration ≥10µg Hb/g (7.81; p<0.001) were independent predictive factors of advanced neoplasia. CONCLUSIONS: A faecal immunochemical test based-strategy performs better than current high-risk symptoms based strategies for fast-tracking cancer referrals. A score that combines gender, age and a faecal immunochemical test could accurately estimate the risk of advanced neoplasia.
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Neoplasias Colorretais/diagnóstico , Sangue Oculto , Guias de Prática Clínica como Assunto/normas , Encaminhamento e Consulta/normas , Adulto , Idoso , Colonoscopia , Feminino , Humanos , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Análise Multivariada , Estudos Prospectivos , Curva ROC , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Oral corticosteroids remain the mainstay of treatment for moderately active ulcerative colitis (UC). In patients who fail to respond to oral corticosteroids, attempting the intravenous route before starting rescue therapies is an alternative, although no evidence supports this strategy. AIM: To evaluate clinical outcomes after a course of intravenous corticosteroids for moderate attacks of UC according to the failed oral corticosteroids or not. METHODS: All episodes of active UC admitted to three university hospitals between January 2005 and December 2011 were identified and retrospectively reviewed. Only moderately active episodes treated with intravenous corticosteroids were included. Treatment outcome was compared between episodes which failed to outpatient oral corticosteroids for the index flare and those directly treated by intravenous corticosteroids. RESULTS: 110 episodes were included, 45% of which failed to outpatient oral corticosteroids (median dose 60mg/day [IQR 50-60], median length of course 10days [IQR 7-17]). Initial response (defined as mild severity or inactive disease at day 7 after starting intravenous corticosteroids, without rescue therapy) was achieved in 75%, with no between-group differences (78% vs. 75%). After a median follow-up of 12months (IQR 4-24), 35% of the initial responders developed steroid-dependency and up to 13% required colectomy. Unsuccessful response to oral corticosteroids was the only factor associated with steroid-dependency in the long term (P=0.001). CONCLUSIONS: Intravenous corticosteroids are efficient for inducing remission in moderately active UC unresponsive to oral corticosteroids, but almost half of these patients develop early steroid-dependency. Alternative therapeutic strategies should be assessed in this clinical setting.
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Anti-Inflamatórios/administração & dosagem , Colite Ulcerativa/tratamento farmacológico , Metilprednisolona/administração & dosagem , Administração Intravenosa , Administração Oral , Adulto , Idoso , Anti-Inflamatórios não Esteroides/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Colectomia , Colite Ulcerativa/cirurgia , Ciclosporina/uso terapêutico , Feminino , Seguimentos , Humanos , Imunossupressores/uso terapêutico , Infliximab , Masculino , Metilprednisolona/efeitos adversos , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Retratamento , Estudos Retrospectivos , Índice de Gravidade de Doença , Falha de TratamentoRESUMO
BACKGROUND: The short-term efficacy of infliximab (IFX) and cyclosporine A (CsA) in steroid-refractory ulcerative colitis (SRUC) has been recently shown to be similar, but long-term outcomes are still unclear. Moreover, the need for further rescue therapies in patients treated with IFX or CsA for SRUC has not been reported. The aims of our study were to compare short-term and long-term efficacy between 2 different strategies based on initial treatment with CsA or IFX for SRUC attacks. PATIENTS AND METHODS: Between January 2005 and December 2011, all patients admitted for SRUC who required medical rescue therapy were identified from the electronic databases of 3 referral centers and grouped according to whether they received CsA or IFX as first-line rescue therapy, and retrospectively reviewed. RESULTS: Among 50 SRUC attacks, 20 were treated with CsA as first-line rescue therapy and 30 with IFX. The CsA group had a higher proportion of patients with severe UC activity immediately before rescue therapy (P = 0.03) and a shorter median time from intravenous corticosteroids to rescue therapy (P = 0.03). A higher proportion of patients in the CsA group received second-line drug therapy (switch) as compared with the IFX group (P = 0.04). Fifteen patients (30%) were colectomized during the study period, with no between-group differences. Previous thiopurine exposure (P = 0.004; odds ratio = 6.1 [1.7-20.9]) was the only independent predictor of colectomy. CONCLUSIONS: CsA- and IFX-based strategies for SRUC seem similarly effective in preventing colectomy in the short and long term, although second-line drug therapy is more often required with CsA-based strategies.
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Corticosteroides/farmacologia , Anticorpos Monoclonais/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Ciclosporina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Adulto , Idoso , Gerenciamento Clínico , Feminino , Seguimentos , Fármacos Gastrointestinais/uso terapêutico , Hospitalização , Humanos , Imunossupressores/uso terapêutico , Infliximab , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
BACKGROUND & AIMS: Histologic recovery of patients with ulcerative colitis (UC) often is incomplete, even among those in clinical and endoscopic remission. Persistent active microscopic inflammation is associated with an increased risk of relapse and colorectal neoplasia. A high level of fecal calprotectin (FC) is a reliable marker of endoscopic lesions in patients with UC. We evaluated the accuracy of FC in identifying patients with UC in clinical and endoscopic remission who still have histologic features of inflammation. METHODS: We performed a prospective observational study of 59 patients with UC in clinical and endoscopic remission undergoing colonoscopy. Several biopsy specimens were collected from each colonic segment. Endoscopic remission was defined as a Mayo endoscopic subscore with a grade of 0 or 1. Active histologic inflammation was defined by the presence of neutrophils infiltrating crypt epithelial cells. FC was determined by enzyme-linked immunosorbent assay analysis. RESULTS: Eighteen patients (30.5%) showed evidence of active histologic inflammation. Patients with active histologic inflammation had a significantly higher median level of FC (278 µg/g; interquartile range, 136-696 µg/g) than those without active histologic inflammation (68 µg/g; interquartile range, 30-172 µg/g) (P = .002). In multivariate analysis, the FC and Mayo endoscopic subscore (0 or 1) were each independent predictors of histologic inflammation. The level of FC identified active histologic inflammation in patients in clinical and endoscopic remission, with an area under the receiver operator characteristic curve value of 0.754. CONCLUSIONS: Histologic inflammation is common among patients with UC in clinical and endoscopic remission. Patients with histologic features of inflammation can be identified reliably based on their fecal level of calprotectin.