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1.
Ann Pathol ; 43(3): 252-265, 2023 Jun.
Artigo em Francês | MEDLINE | ID: mdl-37156715

RESUMO

The gastrointestinal tract is the site of exciting immunological interactions between the epithelium and the mucosa-associated lymphoid tissue, leading to the immune response to food and microbial antigens in the digestive lumen. The objective of this review is to present the main dysimmune pathologies of the digestive tract leading to an enteropathy. As examples, we describe celiac and non-celiac enteropathies to clarify a florid diagnostic framework, by identifying a spectrum of elementary lesions, which must be confronted with the clinico biological context of the patient to orient the diagnosis. The microscopic lesions observed are most often non-specific and may be encountered in several diagnostic settings. Moreover, it is a set of elementary lesions in each clinical context that will orient the diagnostic framework. Celiac disease is the main etiology of enteropathy with villous atrophy, its diagnosis is multidisciplinary and there are many differential diagnoses. We will discuss celiac disease lymphomatous complications as enteropathy associated T-cell lymphoma including refractory sprue type 2. We will then present the non-celiac enteropathies. Among these, enteropathies of unknown etiology may be associated with a primary immune deficiency that may be reflected by florid lymphoid hyperplasia of the gastrointestinal tract and/or be associated with an infectious etiology that should also be constantly sought. Finally, we will discuss of induced enteropathy by new immunomodulatory treatments.


Assuntos
Doença Celíaca , Humanos , Doença Celíaca/complicações , Doença Celíaca/diagnóstico , Intestino Delgado/patologia , Hiperplasia/patologia
2.
Gut ; 71(3): 497-508, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-33579790

RESUMO

OBJECTIVE: Enteropathy-associated T-cell lymphoma (EATL) is a rare but severe complication of coeliac disease (CeD), often preceded by low-grade clonal intraepithelial lymphoproliferation, referred to as type II refractory CeD (RCDII). Knowledge on underlying oncogenic mechanisms remains scarce. Here, we analysed and compared the mutational landscape of RCDII and EATL in order to identify genetic drivers of CeD-associated lymphomagenesis. DESIGN: Pure populations of RCDII-cells derived from intestinal biopsies (n=9) or sorted from blood (n=2) were analysed by whole exome sequencing, comparative genomic hybridisation and RNA sequencing. Biopsies from RCDII (n=50), EATL (n=19), type I refractory CeD (n=7) and uncomplicated CeD (n=18) were analysed by targeted next-generation sequencing. Moreover, functional in vitro studies and drug testing were performed in RCDII-derived cell lines. RESULTS: 80% of RCDII and 90% of EATL displayed somatic gain-of-functions mutations in the JAK1-STAT3 pathway, including a remarkable p.G1097 hotspot mutation in the JAK1 kinase domain in approximately 50% of cases. Other recurrent somatic events were deleterious mutations in nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) regulators TNFAIP3 and TNIP3 and potentially oncogenic mutations in TET2, KMT2D and DDX3X. JAK1 inhibitors, and the proteasome inhibitor bortezomib could block survival and proliferation of malignant RCDII-cell lines. CONCLUSION: Mutations activating the JAK1-STAT3 pathway appear to be the main drivers of CeD-associated lymphomagenesis. In concert with mutations in negative regulators of NF-κB, they may favour the clonal emergence of malignant lymphocytes in the cytokine-rich coeliac intestine. The identified mutations are attractive therapeutic targets to treat RCDII and block progression towards EATL.


Assuntos
Doença Celíaca/complicações , Doença Celíaca/genética , Linfoma de Células T Associado a Enteropatia/etiologia , Mutação com Ganho de Função/genética , Linfócitos/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença Celíaca/patologia , Estudos de Coortes , Linfoma de Células T Associado a Enteropatia/patologia , Feminino , França , Humanos , Janus Quinase 1/genética , Masculino , Pessoa de Meia-Idade , Fator de Transcrição STAT3/genética , Adulto Jovem
3.
Gut ; 68(8): 1396-1405, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30448772

RESUMO

OBJECTIVES: Primary GI T-cell lymphoproliferative diseases (T-LPD) are heterogeneous entities, which raise difficult diagnosis and therapeutic challenges. We have recently provided evidences that lymphomas complicating coeliac disease (CD) arise from innate-like lymphocytes, which may carry NK receptors (NKRs). DESIGN: NKRs expression was compared by flow cytometry in intraepithelial lymphocytes (IEL) from CD, type I or type II refractory CD (RCD). NKp46 was next assessed by immunohistochemistry in paraffin-embedded biopsies from 204 patients with CD, RCDI, RCDII or GI T-cell lymphomas and from a validation cohort of 61 patients. The cytotoxic properties of an anti-NKp46 monoclonal antibody conjugated to pyrrolobenzodiazepine (PBD) was tested ex vivo in human primary tumour cells isolated from fresh duodenal biopsies. RESULTS: NKp46 (but not CD94, NKG2A, NKG2C, NKG2D) was significantly more expressed by malignant RCDII IEL than by normal IEL in CD and RCDI. In paraffin biopsies, detection of >25 NKp46+ IEL per 100 epithelial cells discriminated RCDII from CD and RCDI. NKp46 was also detected in enteropathy-associated T-cell lymphomas (EATL, 24/29) and in monomorphic epitheliotropic intestinal T-cell lymphomas (MEITL, 4/4) but not in indolent T-LPD (0/15). Treatment with anti-NKp46-PBD could efficiently and selectively kill human NKp46+ primary IEL ex vivo. CONCLUSION: NKp46 is a novel biomarker useful for diagnosis and therapeutic stratification of GI T-LPD. Strong preclinical rationale identifies anti-NKp46-PBD as a promising therapy for RCDII, EATL and MEITL.


Assuntos
Doença Celíaca , Linfoma de Células T Associado a Enteropatia , Mucosa Intestinal , Células Matadoras Naturais/imunologia , Receptor 1 Desencadeador da Citotoxicidade Natural/imunologia , Anticorpos Monoclonais/imunologia , Biomarcadores/sangue , Biópsia/métodos , Doença Celíaca/complicações , Doença Celíaca/diagnóstico , Doença Celíaca/imunologia , Doença Celíaca/patologia , Células Cultivadas , Linfoma de Células T Associado a Enteropatia/diagnóstico , Linfoma de Células T Associado a Enteropatia/etiologia , Linfoma de Células T Associado a Enteropatia/imunologia , Linfoma de Células T Associado a Enteropatia/patologia , Feminino , França , Humanos , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Intestino Delgado/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico
5.
BMC Med Inform Decis Mak ; 17(1): 140, 2017 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-28962565

RESUMO

BACKGROUND: Data collected in EHRs have been widely used to identifying specific conditions; however there is still a need for methods to define comorbidities and sources to identify comorbidities burden. We propose an approach to assess comorbidities burden for a specific disease using the literature and EHR data sources in the case of autoimmune diseases in celiac disease (CD). METHODS: We generated a restricted set of comorbidities using the literature (via the MeSH® co-occurrence file). We extracted the 15 most co-occurring autoimmune diseases of the CD. We used mappings of the comorbidities to EHR terminologies: ICD-10 (billing codes), ATC (drugs) and UMLS (clinical reports). Finally, we extracted the concepts from the different data sources. We evaluated our approach using the correlation between prevalence estimates in our cohort and co-occurrence ranking in the literature. RESULTS: We retrieved the comorbidities for 741 patients with CD. 18.1% of patients had at least one of the 15 studied autoimmune disorders. Overall, 79.3% of the mapped concepts were detected only in text, 5.3% only in ICD codes and/or drugs prescriptions, and 15.4% could be found in both sources. Prevalence in our cohort were correlated with literature (Spearman's coefficient 0.789, p = 0.0005). The three most prevalent comorbidities were thyroiditis 12.6% (95% CI 10.1-14.9), type 1 diabetes 2.3% (95% CI 1.2-3.4) and dermatitis herpetiformis 2.0% (95% CI 1.0-3.0). CONCLUSION: We introduced a process that leveraged the MeSH terminology to identify relevant autoimmune comorbidities of the CD and several data sources from EHRs to phenotype a large population of CD patients. We achieved prevalence estimates comparable to the literature.


Assuntos
Doenças Autoimunes/epidemiologia , Doença Celíaca/epidemiologia , Registros Eletrônicos de Saúde , Adulto , Comorbidade , Efeitos Psicossociais da Doença , Mineração de Dados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Fluxo de Trabalho
7.
Nat Rev Gastroenterol Hepatol ; 21(3): 198-215, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38110546

RESUMO

Coeliac disease (CeD) is an immunological disease triggered by the consumption of gluten contained in food in individuals with a genetic predisposition. Diagnosis is based on the presence of small bowel mucosal atrophy and circulating autoantibodies (anti-type 2 transglutaminase antibodies). After diagnosis, patients follow a strict, life-long gluten-free diet. Although the criteria for diagnosis of this disease are well defined, the monitoring phase has been studied less and there is a lack of specific guidelines for this phase. To develop a set of clinical guidelines for CeD monitoring, we followed the Grading of Recommendations Assessment, Development and Evaluation methodology. Statements and recommendations with the level of evidence were developed and approved by the working group, which comprised gastroenterologists, pathologists, dieticians and biostatisticians. The proposed guidelines, endorsed by the North American and European coeliac disease scientific societies, make recommendations for best practices in monitoring patients with CeD based on the available evidence. The evidence level is low for many topics, suggesting that further research in specific aspects of CeD would be valuable. In conclusion, the present guidelines support clinicians in improving CeD treatment and follow-up and highlight novel issues that should be considered in future studies.


Assuntos
Doença Celíaca , Gastroenterologistas , Adulto , Humanos , Doença Celíaca/diagnóstico , Autoanticorpos , Dieta Livre de Glúten , Predisposição Genética para Doença
8.
Diagnostics (Basel) ; 12(7)2022 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-35885608

RESUMO

(1) Background: Villous atrophy is an indication for small bowel capsule endoscopy (SBCE). However, SBCE findings are not described uniformly and atrophic features are sometimes not recognized; (2) Methods: The Delphi technique was employed to reach agreement among a panel of SBCE experts. The nomenclature and definitions of SBCE lesions suggesting the presence of atrophy were decided in a core group of 10 experts. Four images of each lesion were chosen from a large SBCE database and agreement on the correspondence between the picture and the definition was evaluated using the Delphi method in a broadened group of 36 experts. All images corresponded to histologically proven mucosal atrophy; (3) Results: Four types of atrophic lesions were identified: mosaicism, scalloping, folds reduction, and granular mucosa. The core group succeeded in reaching agreement on the nomenclature and the descriptions of these items. Consensus in matching the agreed definitions for the proposed set of images was met for mosaicism (88.9% in the first round), scalloping (97.2% in the first round), and folds reduction (94.4% in the first round), but granular mucosa failed to achieve consensus (75.0% in the third round); (4) Conclusions: Consensus among SBCE experts on atrophic lesions was met for the first time. Mosaicism, scalloping, and folds reduction are the most reliable signs, while the description of granular mucosa remains uncertain.

9.
J Med Liban ; 58(2): 86-90, 2010.
Artigo em Francês | MEDLINE | ID: mdl-20549894

RESUMO

Graves' ophthalmopathy is a debilitating disease impairing the quality of life of affected individuals. The management of moderate-to-severe active Graves' ophthalmopathy is a major therapeutic challenge, and the treatment outcome is often unsatisfactory. We have carried out a retrospective study to assess the efficacy of combined orbital irradiation and systemic corticosteroids. Ten patients were included; all patients had received 20 Grays to the retrobulbar tissues in ten fractions, and oral or intravenous glucocorticoids. The main therapeutic outcome measures were the criteria of Donaldson and co-workers and a self-assessment evaluation. The quality of life outcome was also evaluated by the GO-QOL (Graves' ophthalmopathy quality of life) questionnaire. Seven patients (70%) demonstrated improvement in ocular parameters; the response was excellent in three cases, good in three cases and fair in one case. Three patients showed no response to the treatment. The self-assessment evaluation showed that 75% of patients were satisfied with the results of the treatment. Proptosis was the most responsive sign to radiation and steroids. A duration of the eye disease of more than 18 months was associated with less improvement and a higher failure of the treatment. Concerning the quality of life, the score for visual fonctionning was 882 +/- 18.2 after treatment, while the score for appearance was 63.3 +/- 23.3. In conclusion, a combination of orbital irradiation and systemic steroids is associated with 70% of favorable responses, but the quality of life is not restored in the same proportions and remains impaired after treatment.


Assuntos
Oftalmopatia de Graves/terapia , Adulto , Feminino , Glucocorticoides/uso terapêutico , Humanos , Metilprednisolona/uso terapêutico , Qualidade de Vida , Dosagem Radioterapêutica , Estudos Retrospectivos
10.
Therap Adv Gastroenterol ; 13: 1756284820934314, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32774463

RESUMO

BACKGROUND AND AIMS: The role of small bowel neoplasia (SBN) screening in asymptomatic patients with Lynch syndrome (LS) is uncertain. The aim of our study was to assess the effectiveness of screening by capsule endoscopy (CE) in these patients. METHODS: This study was an observational, analytical, and retrospective single-center study within the PRED-IdF network. All consecutive asymptomatic patients older than 35 years-old with confirmed LS and no personal history of SBN who started the screening from 2010-2015 were included. The baseline screening and 24 months follow-up were performed by CE. The CE diagnostic yield (positive tumor or polyp) and accuracy, using the follow-up as gold standard, were evaluated. RESULTS: A total of 150 patients underwent the SBN screening program and 135 (52.7 ± 11.2 years-old, 37.8% male) met the inclusion criteria. The baseline CE diagnostic yield was 4.4% (3 polyps, 3 tumors) and the proximal small bowel was the most common location (n = 4, 66.7%). In total, 87 patients underwent follow-up and the diagnostic yield was 4.6%.Four patients were considered positive at follow-up (2 adenomas, 2 adenocarcinomas). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of CE were 60%, 100%, 100%, 96.9%, and 97%, respectively. CONCLUSIONS: CE is an accurate procedure for baseline screening of SBN in LS patients and may be efficient for follow-up procedures. However, the optimal starting age of screening and intervals of follow-up must be clarified.

11.
Lancet Gastroenterol Hepatol ; 4(12): 960-970, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31494097

RESUMO

BACKGROUND: Refractory coeliac disease type 2 is a rare subtype of coeliac disease with high mortality rates; interleukin 15 (IL-15) is strongly implicated in its pathophysiology. This trial aimed to investigate the effects of AMG 714, an anti-IL-15 monoclonal antibody, on the activity and symptoms of refractory coeliac disease type 2. METHODS: This was a randomised, double-blind, placebo-controlled, phase 2a study of adults with a confirmed diagnosis of refractory coeliac disease type 2. Patients were randomly assigned at a 2:1 ratio to receive seven intravenous doses over 10 weeks of AMG 714 (8 mg/kg) or matching placebo. Biopsy samples were obtained at baseline and week 12 for cellular analysis and histology. The change in the proportion of aberrant intraepithelial lymphocytes from baseline to week 12 with respect to all intraepithelial lymphocytes was the primary endpoint and was quantified using flow cytometry. Secondary endpoints were the change in aberrant intraepithelial lymphocytes with respect to intestinal epithelial cells; intestinal histological scores (villous height-to-crypt depth ratio; VHCD); intraepithelial lymphocyte counts; Marsh score; and patient-reported symptom measures, including the Bristol stool form scale (BSFS) and gastrointestinal symptom rating scale (GSRS). Main analyses were done in the per-protocol population of patients who received their assigned treatment, provided evaluable biopsy samples, and did not have major protocol deviations; only patients with non-atypical disease were included in the analyses of aberrant intraepithelial lymphocytes, including the primary analysis. Safety was assessed in all patients who received at least one dose of study drug. This study is registered at ClinicalTrials.gov (NCT02633020) and EudraCT (2015-004063-36). FINDINGS: From April 13, 2016, to Jan 19, 2017, 28 patients were enrolled and randomly assigned to AMG 714 (n=19) and placebo (n=9). Six patients were not included in the primary analysis because of protocol deviation (one in the AMG 714 group), insufficient biopsy samples (one in the AMG 714 group), and atypical intraepithelial lymphocytes (three in the AMG 714 group and one in the placebo group). At 12 weeks, the least square mean difference between AMG 714 and placebo in the relative change from baseline in aberrant intraepithelial lymphocyte percentage was -4·85% (90% CI -30·26 to 20·56; p=0·75). The difference between the AMG 714 and placebo groups in aberrant intraepithelial lymphocytes with respect to epithelial cells at 12 weeks was -38·22% (90% CI -95·73 to 19·29; nominal p=0·18); the difference in change in Marsh score from baseline was 0·09% (95% CI -1·60-1·90; nominal p=0·92); the difference in VHCD ratio was 10·67% (95% CI -38·97 to 60·31; nominal p=0·66); and the difference in change in total intraepithelial lymphocyte count was -12·73% (95% CI -77·57-52·12); nominal p=0·69). Regarding symptoms, the proportion of patients with diarrhoea per the BSFS score decreased from ten (53%) of 19 at baseline to seven (37%) of 19 at week 12 in the AMG 714 group and increased from two (22%) of nine at baseline to four (44%) of nine at week 12 in the placebo group (nominal p=0·0008); and the difference between the groups in change in GSRS score was -0·14 (SE 0·19; nominal p=0·48). Eight (89%) patients in the placebo group and 17 (89%) in the AMG 714 group had treatment-emergent adverse events, including one (11%) patient in the placebo group and five (26%) in the AMG 714 group who had serious adverse events. The most common adverse event in the AMG 714 group was nasopharyngitis (eight [42%] patients vs one [11%] in the placebo group). INTERPRETATION: In patients with refractory coeliac disease type 2 who were treated with AMG 714 or placebo for 10 weeks, there was no difference between the groups in terms of the primary endpoint of aberrant intraepithelial lymphocyte reduction from baseline. Effects on symptoms and other endpoints suggest that further research of AMG 714 may be warranted in patients with refractory coeliac disease type 2. FUNDING: Celimmune and Amgen.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Interleucina-15/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Doença Celíaca/patologia , Método Duplo-Cego , Europa (Continente) , Feminino , Citometria de Fluxo , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Estados Unidos , Adulto Jovem
12.
Therap Adv Gastroenterol ; 11: 1756284818775058, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29872454

RESUMO

BACKGROUND: Despite colonoscopic screening, colorectal cancer (CRC) remains frequent in patients with Lynch syndrome (LS). The objective of this study was to evaluate the impact of an optimized colorectal screening program within a French dedicated network. METHODS: All LS patients followed at our institution were consecutively included in the Prédisposition au Cancer Colorectal-Ile de France (PRED-IdF) network. Patients were offered an optimized screening program allowing an adjustment of the interval between colonoscopies, depending on bowel preparation, chromoendoscopy achievement and adenoma detection. Colonoscopies were defined as optimal when all the screening criteria were respected. We compared colonoscopy quality and colonoscopy detection rate before and after PRED-IdF inclusion, including polyp detection rate (PDR), adenoma detection rate (ADR) and cancer detection rate (CDR). RESULTS: Between January 2010 and January 2016, 144 LS patients were consecutively included (male/female = 50/94, mean age = 51 ± 13 years and mutations: MLH1 = 39%, MSH2 = 44%, MSH6 = 15%, PMS2 = 1%). A total of 564 colonoscopies were analyzed, 353 after inclusion and 211 before. After PRED-IdF inclusion, 98/144 (68%) patients had optimal screening colonoscopies versus 33/132 (25%) before (p < 0.0005). The optimal colonoscopy rate was 304/353 (86%) after inclusion versus 87/211 (41%) before, (p < 0.0001). PRED-IdF inclusion was associated with a reduction of CRC occurrence with a CDR of 1/353 (0.3%) after inclusion versus 6/211 (2.8%) before (p = 0.012). ADR and PDR were 99/353 (28%) versus 60/211 (28.8%) (p > 0.05) and 167/353 (48.1%) versus 90/211 (42.2%) (p > 0.05), respectively after and before inclusion. CONCLUSIONS: An optimized colonoscopic surveillance program in LS patients seems to improve colonoscopic screening quality and might possibly decrease colorectal interval cancer occurrence. Long-term cohort studies are needed to confirm these results.

13.
Endosc Int Open ; 5(5): E389-E394, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28508033

RESUMO

Background and study aims Over-the-scope clip (OTSC) has been recently used in management of gastrointestinal perforations, but data on it are still limited. The aim of this study was to compare management of iatrogenic perforations before and after the OTSC was available in our endoscopy unit. Patients and methods We conducted a monocentric retrospective study from June 2007 to June 2015. All iatrogenic gastrointestinal perforations detected during endoscopy were included. Two time periods were compared in terms of surgery and mortality rates: before use of OTSC (June 2007 to June 2011) and after OTSC became available (June 2011 to June 2015). Results During the first period, 24 perforations were recorded. Fifteen (62.5 %) were managed with surgery. The mortality rate was 8 %. During the second period, 16 perforations occurred. In 11 patients (68.7 %), an OTSC was used to close the perforation, with complete sealing of the perforation in 100 % of cases. However, 2 patients with sigmoid perforation had to undergo surgery due to right ureteral obstruction by the clip in 1 case and to presence of a localized peritonitis in the other. The surgery rate during this period was 12.5 % (2 /16), with a statistically significant difference compared to the first period (P = 0.002). There was no mortality in the second period versus 8 % in the first one (P = 0.23). Conclusions OTSC is effective for endoluminal closure of iatrogenic perforations and results in a significant decrease in surgery rate.

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