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Thoracic manifestations of inflammatory bowel disease (IBD) are rare, occurring in less than 1% of patients. Unlike most other extra-intestinal manifestations, they predominate in patients with ulcerative colitis rather than in Crohn's disease. In most patients, thoracic involvement follows the onset of IBD by several years. However, thoracic involvement may also occur synchronously or even precede the onset of digestive symptoms. The thoracic manifestations of IBD include airway involvement and parenchymal lung abnormalities. Airways are the most frequent anatomical site for thoracic involvement in IBD. Airway manifestations usually develop several years after the onset of intestinal manifestations, preferentially when the latter are stable or in remission. Airway manifestations include bronchial wall thickening, bronchiectasis, small airway disease, and tracheal wall thickening. Parenchymal lung abnormalities are less prevalent in IBD and include organizing pneumonia, necrobiotic nodules, noncaseating granulomatous nodules, drug-induced pneumonia, and rarely interstitial lung diseases. The differential diagnosis between organizing pneumonia, necrobiotic nodules, and noncaseating granulomatous nodules is difficult and usually requires histopathological analysis for a definite diagnosis. Radiologists play a key role in the detection of thoracic manifestations of Crohn's disease and ulcerative colitis and, therefore, need to be familiar with their imaging findings. This article aims to offer an overview of the imaging findings of thoracic manifestations in patients with Crohn's disease or ulcerative colitis. CRITICAL RELEVANCE STATEMENT: Thoracic manifestations of Crohn's disease and ulcerative colitis include tracheal involvement, bronchiectasis, small airway disease, and parenchymal lung abnormalities such as organizing pneumonia and necrobiotic nodules. These rare manifestations (< 1% of patients) more often affect patients with ulcerative colitis. KEY POINTS: Thoracic manifestations of inflammatory bowel disease are rare, occurring in less than 1% of patients. Thoracic manifestations are more frequent in patients with ulcerative colitis than Crohn's disease. Bronchial disease is the most frequent thoracic manifestation of Crohn's disease and ulcerative colitis.
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BACKGROUND/AIM: We aimed to assess gastrointestinal cancers risks in a large cohort of individuals with primary antibody deficiency (PAD) and their association with risk of autoimmune and inflammatory gastrointestinal diseases. METHODS: Investigating a French national database of inpatient admissions between 2010 and 2018, we identified 12,748 patients with PAD and 38,244 control non-exposed individuals. We performed multiple exposed-non-exposed studies using conditional logistic regression. RESULTS: In comparison with non-exposed patients, PAD patients had increased risk of in situ gastric carcinoma (Odds Ratio (OR) =10.5 [95 % CI 2.2; 50.5]), malignant gastric tumor (OR=3.2 [95 % CI 2.2; 4.4]) and colorectal cancer (OR=1.2 [95 % CI 1; 1.5]). PAD patients had also increased risk of pernicious anaemia (OR=8 |95 % CI 5.6; 11.5]), Crohn's disease (OR= 4.4 [95 % CI 3.5; 5.6]), ulcerative colitis (OR=2.9 [95 % CI 2.4; 3.6]) and coeliac disease (OR=13.3 [95 % CI 9.1; 19.5]). Within patients with gastric cancer, those with PAD had increased risk of pernicious anaemia (OR=8.4 [95 % CI 1.5; 215]; p = 0.01) but not of H. pylori infection. CONCLUSIONS: Risk of gastric cancer is particularly high in PAD patients and notably risk of in situ gastric carcinoma in association with pernicious anaemia. It supports indication of early endoscopic screening in these patients.
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Nonresponsive celiac disease (CeD) is relatively common. It is generally attributed to persistent gluten exposure and resolves after correction of diet errors. However, other complications of CeD and disorders clinically mimicking CeD need to be excluded. Novel therapies are being evaluated to facilitate mucosal recovery, which might benefit patients with nonresponsive CeD. Refractory CeD (RCeD) is rare and is divided into 2 types. The etiology of type I RCeD is unclear. A switch to gluten-independent autoimmunity is suspected in some patients. In contrast, type II RCeD represents a low-grade intraepithelial lymphoma. Type I RCeD remains a diagnosis of exclusion, requiring ruling out gluten intake and other nonmalignant causes of villous atrophy. Diagnosis of type II RCeD relies on the demonstration of a clonal population of neoplastic intraepithelial lymphocytes with an atypical immunophenotype. Type I RCeD and type II RCeD generally respond to open-capsule budesonide, but the latter has a dismal prognosis due to severe malnutrition and frequent progression to enteropathy-associated T-cell lymphoma; more efficient therapy is needed.
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Doença Celíaca , Doença Celíaca/diagnóstico , Doença Celíaca/terapia , Doença Celíaca/imunologia , Doença Celíaca/dietoterapia , Humanos , Dieta Livre de Glúten , Mucosa Intestinal/patologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/efeitos dos fármacos , Glutens/imunologia , Glutens/efeitos adversos , Resultado do Tratamento , Budesonida/uso terapêuticoRESUMO
BACKGROUND & AIMS: The management of intra-abdominal abscesses complicating Crohn's disease (CD) is challenging, and surgery with delayed intestinal resection is often recommended. The aims of this study were to estimate the success rate of adalimumab (ADA) in patients with CD with an intra-abdominal abscess resolved without surgery, and to identify predictive factors for success. METHODS: A multicenter, prospective study was conducted in biologic-naïve patients with CD with resolved intra-abdominal abscess treated with ADA with a 2-year follow-up. The primary endpoint was ADA failure at week (W) 24 defined as a need for steroids after W12, intestinal resection, abscess recurrence, and clinical relapse. Secondary post-hoc endpoint was the long-term success defined as the survival without abscess relapse or intestinal resection at W104. The factors associated with ADA failure at W24 and W104 were identified using a logistic and a Cox regression, respectively. RESULTS: From April 2013 to December 2017, 190 patients from 27 GETAID centers were screened, and 117 were included in the analysis. Fifty-eight patients (50%) were male, and the median age at baseline was 28 years. At W24, 87 patients (74%; 95% confidence interval [CI], 65.5%-82.0%; n = 117) achieved ADA success. Among the 30 patients with ADA failure, 15 underwent surgery. At W104, the survival rate without abscess recurrence or surgery was 72.9% (95% CI, 62.1%-79.8%; n = 109). Abscess drainage was significantly associated with ADA failure at W24 (odds ratio, 4.18; 95% CI, 1.06-16.5; P =0 .043). Disease duration (hazard ratio [HR], 1.32; 95% CI, 1.09-1.59; P = .008), abscess drainage (HR, 5.59; 95% CI, 2.21-14.15; P = .001), and inflammatory changes in mesenteric fat (HR, 0.4; 95% CI, 0.17-0.94; P = .046) were significantly associated with ADA failure at W104. CONCLUSION: Provided that the abscess was carefully managed before initiating medical treatment, this study showed the high efficacy of ADA in the short and long term in biologic-naïve patients with CD complicated by an intra-abdominal abscess. CLINICALTRIALS: gov, Number: NCT02856763.
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Abscesso Abdominal , Produtos Biológicos , Doença de Crohn , Humanos , Masculino , Adulto , Feminino , Adalimumab/uso terapêutico , Doença de Crohn/complicações , Doença de Crohn/tratamento farmacológico , Estudos Prospectivos , Abscesso/tratamento farmacológico , Resultado do Tratamento , Abscesso Abdominal/tratamento farmacológico , Recidiva , Produtos Biológicos/uso terapêuticoRESUMO
Coeliac disease (CD) is a frequent immune enteropathy induced by gluten in genetically predisposed individuals. Its pathogenesis has been extensively studied and CD has emerged as a model disease to decipher how the interplay between environmental and genetic factors can predispose to autoimmunity and promote lymphomagenesis. The keystone event is the activation of a gluten-specific immune response that is driven by molecular interactions between gluten, the indispensable environmental factor, HLA-DQ2/8, the main predisposing genetic factor and transglutaminase 2, the CD-specific autoantigen. The antigluten response is however not sufficient to induce epithelial damage which requires the activation of cytotoxic CD8+ intraepithelial lymphocytes (IEL). In a plausible scenario, cooperation between cytokines released by gluten-specific CD4+ T cells and interleukin-15 produced in excess in the coeliac gut, licenses the autoimmune-like attack of the gut epithelium, likely via sustained activation of the Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway in IEL. Demonstration that lymphomas complicating CD arise from IEL that have acquired gain-of-function JAK1 or STAT3 mutations stresses the key role of this pathway and explains how gluten-driven chronic inflammation may promote this rare but most severe complication. If our understanding of CD pathogenesis has considerably progressed, several questions and challenges remain. One unsolved question concerns the considerable variability in disease penetrance, severity and presentation, pointing to the role of additional genetic and environmental factors that remain however uneasy to untangle and hierarchize. A current challenge is to transfer the considerable mechanistic insight gained into CD pathogenesis into benefits for the patients, notably to alleviate the gluten-free diet, a burden for many patients.
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BACKGROUND AND AIMS: There is no consensus on the management of immune checkpoint inhibitor (ICI) for treating cancer in patients with pre-existing inflammatory bowel disease (IBD). The Groupe d'Étude Thérapeutique des Affections Inflammatoires du tube Digestif (GETAID) aimed to provide recommendations on this topic. METHODS: A dedicated working group performed a comprehensive expert-based review of the literature, generated clinical key question and shaped recommendations that were further voted for approval by the educational and scientific committees of the GETAID. Using consensus methods, treatment modalities were defined by vote. RESULTS: Majority of patients with IBD in clinical remission can be treated with ICI after cancer diagnosis. The rate of relapse or immune-related diarrhoea or colitis upon ICI treatment is up to 39.8% and is maximal with ICI combination therapy compared to monotherapies. When starting ICI in a patient with IBD, it is recommended to assess disease activity and pursue ongoing maintenance therapy. In case of relapse or immune-related diarrhoea or colitis upon ICI treatment, treatment depends on grading of diarrhoea or colitis and may include corticosteroid therapy, infliximab and/or vedolizumab. CONCLUSIONS: In the present publication, we provided recommendations, which may assist gastroenterologists, haematologists, and oncologists for a better management of patients with pre-existing IBD before and during cancer treatment with ICI.
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Colite , Doenças Inflamatórias Intestinais , Neoplasias , Diarreia , Humanos , Inibidores de Checkpoint Imunológico , Recidiva , Estudos RetrospectivosRESUMO
OBJECTIVE: Differential diagnosis of villous atrophy (VA) without coeliac antibodies in adults includes seronegative coeliac disease (CD) and chronic enteropathies unrelated to gluten, ie. non-coeliac enteropathies (NCEs). There is currently no international consensus on the nomenclature and diagnostic criteria for these enteropathies. In this work, a Delphi process was conducted to address this diagnostic and clinical uncertainty. DESIGN: An international task force of 13 gastroenterologists from six countries was recruited at the 16th International Coeliac Disease Symposium, Paris, 2019. Between September 2019 and July 2021, a Delphi process was conducted through mail surveys to reach a consensus on which conditions to consider in the differential diagnosis of VA with negative coeliac serology and the clinical diagnostic approaches required for these conditions. A 70% agreement threshold was adopted. RESULTS: Chronic enteropathies characterised by VA and negative coeliac serology can be attributed to two main clinical scenarios: forms of CD presenting with negative serology, which also include seronegative CD and CD associated with IgA deficiency, and NCEs, with the latter recognising different underlying aetiologies. A consensus was reached on the diagnostic criteria for NCEs assisting clinicians in differentiating NCEs from seronegative CD. Although in adults seronegative CD is the most common aetiology in patients with VA and negative serology, discriminating between seronegative CD and NCEs is key to avoid unnecessary lifelong gluten-free diet, treat disease-specific morbidity and contrast poor long-term outcomes. CONCLUSION: This paper describes the Paris consensus on the definitions and diagnostic criteria for seronegative CD and chronic NCEs in adults.
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Doença Celíaca , Doenças Inflamatórias Intestinais , Adulto , Tomada de Decisão Clínica , Consenso , Dieta Livre de Glúten , Humanos , IncertezaRESUMO
Due to the potential role of the gut microbiota and bile acids in the pathogenesis of both inflammatory bowel disease (IBD) and sporadic colorectal cancer, we aimed to determine whether these factors were associated with colorectal cancer in IBD patients. 215 IBD patients and 51 non-IBD control subjects were enrolled from 10 French IBD centers between September 2011 and July 2018. Fecal samples were processed for bacterial 16S rRNA gene sequencing and bile acid profiling. Demographic, clinical, endoscopic, and histological outcomes were recorded. Characteristics of IBD patients included: median age: 41.6 (IQR 22); disease duration 13.2 (13.1); 47% female; 21.9% primary sclerosing cholangitis; 109 patients with Crohn's disease (CD); 106 patients with ulcerative colitis (UC). The prevalence of cancer was 2.8% (6/215: 1 CD; 5 UC), high-grade dysplasia 3.7% (8/215) and low-grade dysplasia 7.9% (17/215). Lachnospira was decreased in IBD patients with cancer, while Agathobacter was decreased and Escherichia-Shigella increased in UC patients with any neoplasia. Bile acids were not associated with cancer or neoplasia. Unsupervised clustering identified three gut microbiota clusters in IBD patients associated with bile acid composition and clinical features, including a higher risk of neoplasia in UC in two clusters when compared to the third (relative risk (RR) 4.07 (95% CI 1.6-10.3, P < .01) and 3.56 (95% CI 1.4-9.2, P < .01)). In this multicentre observational study, a limited number of taxa were associated with neoplasia and exploratory microbiota clusters co-associated with clinical features, including neoplasia risk in UC. Given the very small number of cancers, the robustness of these findings will require assessment and validation in future studies.
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Colite Ulcerativa , Neoplasias Colorretais , Doença de Crohn , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Adulto , Ácidos e Sais Biliares , Colite Ulcerativa/microbiologia , Neoplasias Colorretais/etiologia , Doença de Crohn/microbiologia , Detecção Precoce de Câncer/efeitos adversos , Feminino , Humanos , Doenças Inflamatórias Intestinais/microbiologia , Masculino , RNA Ribossômico 16S/genéticaRESUMO
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.
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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 JovemRESUMO
The mechanisms that maintain intestinal homeostasis despite constant exposure of the gut surface to multiple environmental antigens and to billions of microbes have been scrutinized over the past 20 years with the goals to gain basic knowledge, but also to elucidate the pathogenesis of inflammatory bowel diseases (IBD) and to identify therapeutic targets for these severe diseases. Considerable insight has been obtained from studies based on gene inactivation in mice as well as from genome wide screens for genetic variants predisposing to human IBD. These studies are, however, not sufficient to delineate which pathways play key nonredundant role in the human intestinal barrier and to hierarchize their respective contribution. Here, we intend to illustrate how such insight can be derived from the study of human Mendelian diseases, in which severe intestinal pathology results from single gene defects that impair epithelial and or hematopoietic immune cell functions. We suggest that these diseases offer the unique opportunity to study in depth the pathogenic mechanisms leading to perturbation of intestinal homeostasis in humans. Furthermore, molecular dissection of monogenic intestinal diseases highlights key pathways that might be druggable and therapeutically targeted in common forms of IBD.
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Interações entre Hospedeiro e Microrganismos/imunologia , Imunidade nas Mucosas , Imunomodulação , Mucosa Intestinal/fisiologia , Imunidade Adaptativa , Animais , Transporte Biológico , Biomarcadores , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Suscetibilidade a Doenças , Enterócitos/citologia , Enterócitos/imunologia , Enterócitos/metabolismo , Regulação da Expressão Gênica , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/imunologia , Predisposição Genética para Doença , Hematopoese/genética , Hematopoese/imunologia , Homeostase , Interações entre Hospedeiro e Microrganismos/genética , Humanos , Imunidade Inata , Mutação , Transdução de SinaisRESUMO
Indolent T cell lymphoproliferative disorder (LPD) of the gastrointestinal tract (GI-TLPD) is a rare human primary gastrointestinal T cell lymphoma that was recently included in the 2016 revision of the World Health Organization classification of lymphoid neoplasms. Low-grade intestinal T cell lymphoma (LGITL), an emerging disease in the domestic cat, shares a number of features with human GI-TLPD. In this prospective study, we determined whether feline LGITL might serve as a model of human GI-TLPD. We analyzed clinical, laboratory, and radiological data and performed histopathological and molecular studies on small intestinal biopsies from 22 domestic cats diagnosed with LGITL. This cancer mostly affects aging cats, is associated with nonspecific gastrointestinal tract signs, and is usually characterized by an indolent course. A histopathological analysis indicated that LGITL was mainly located in the jejunum. The small intestinal lamina propria was infiltrated by large numbers of small CD3+ T cell lymphocytes with various CD4 and CD8 expression profiles (CD4+ CD8- (4 out of 11, 36%), CD4- CD8+ (3 out of 11, 27%), and CD4- CD8- (4 out of 11, 36%)). Intraepithelial lymphocyte (IEL) counts were elevated in all cases. Ki67 was expressed in lamina propria lymphocytes and IELs at a low level (<30%). Most LGITLs were labelled by antibodies against phosphorylated STAT5, but were negative for CD56 and phosphorylated STAT3. T cell receptor gamma chain gene monoclonality was found in 86% of cases. These findings confirmed that feline LGITL shares clinical and histopathological features with human GI-TLPD. Feline LGITL may therefore constitute a relevant model of the human disease.
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Modelos Animais de Doenças , Gastroenteropatias/imunologia , Mucosa Intestinal/imunologia , Linfoma de Células T , Animais , Gatos , Feminino , Gastroenteropatias/patologia , Mucosa Intestinal/patologia , Jejuno/patologia , MasculinoRESUMO
BACKGROUND: There are few data regarding multiple switching from the originator Infliximab to its biosimilars. AIM: To assess outcomes and patient perspectives in a prospective manner after double switching from Infliximab to the biosimilars CT-P13 and SB2. METHODS: A total of 158 consecutive patients with inflammatory bowel disease (IBD) receiving CT-P13 maintenance therapy were switched to SB2 and followed for 54 weeks. Patients were stratified according to previous switch from the originator Infliximab to CT-P13 (double switch group) or not (single switch group). RESULTS: The drug persistence was high (94.9%) after 54 weeks. In total, 17 (10.8%) patients experienced loss of response to SB2, including 10 patients who were managed through dose optimisation and continued treatment. No changes were observed in clinical activity scores, fatigue, biological activity and pharmacokinetical parameters after the switch. The safety profile was in line with the current knowledge of Infliximab. According to the Beliefs about Medicines Questionnaire, the patients' perspectives did not change after switching from CT-P13 to SB2. The primary patient concerns remained after the switch, which were focused on effectiveness and safety rather than on the molecular differences between originator and biosimilars or socioeconomic benefits. There were also no differences in the concerns and beliefs between the double and single switch groups. CONCLUSION: Double switching from the originator Infliximab to CT-P13 and then to SB2 was not associated with an impairment in patient beliefs, while the effectiveness, immunogeniity and safety of anti-TNF therapy remained stable after 54 weeks of follow-up.
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Medicamentos Biossimilares , Doenças Inflamatórias Intestinais , Anticorpos Monoclonais , Medicamentos Biossimilares/efeitos adversos , Substituição de Medicamentos , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Infliximab/uso terapêutico , Estudos Prospectivos , Resultado do Tratamento , Fator de Necrose Tumoral alfa/uso terapêuticoRESUMO
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.
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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 JovemRESUMO
Celiac disease (CeD), defined as gluten-induced enteropathy, is a frequent and largely underdiagnosed disease. Diagnosis relies on the detection of highly specific serum IgA anti-transglutaminase auto-antibodies and on the demonstration of duodenal villous atrophy. Treatment necessitates a strict gluten-free diet, which resolves symptoms and enables histological recovery. However, regular follow-up is necessary to assess mucosal healing, which emerges as an important prognostic factor. Recent work on CeD pathogenesis has highlighted how the cross-talk between gluten-specific CD4 + T cells and interleukin-15 can activate cytotoxic intraepithelial lymphocytes and trigger epithelial lesions. Moreover, acquisition by a subset of intraepithelial lymphocytes of somatic gain-of-function mutations in the JAK-STAT pathway was shown to be a decisive step in the progression toward lymphomas complicating CeD, thus opening new therapeutic perspectives for these rare but life-threatening complications.
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Doença Celíaca , Doença Celíaca/imunologia , Doença Celíaca/metabolismo , Doença Celíaca/terapia , Dieta Livre de Glúten , Progressão da Doença , Glutens , Humanos , TransglutaminasesRESUMO
Refractory celiac disease (RCD) refers to persistence of malnutrition and intestinal villous atrophy for more than 1 to 2 years despite strict gluten-free diet in patients with celiac disease. Diagnosis remains difficult and impacts treatment and follow-up. RCD has been subdivided into 2 subgroups according to the normal (RCDI) or abnormal phenotype of intraepithelial lymphocytes (IELs) (RCDII). RCDII is considered as a low-grade intraepithelial lymphoma and has a poor prognosis due to gastrointestinal and extraintestinal dissemination of the abnormal IELs, and high risk of overt lymphoma.
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Budesonida/administração & dosagem , Doença Celíaca/diagnóstico , Doença Celíaca/terapia , Doença Celíaca/etiologia , Doença Celíaca/patologia , Endoscopia Gastrointestinal , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Intestino Delgado/citologia , Intestino Delgado/diagnóstico por imagem , Intestino Delgado/patologia , Linfócitos Intraepiteliais/imunologia , Linfócitos Intraepiteliais/patologia , Desnutrição/etiologia , Prognóstico , Risco , Índice de Gravidade de DoençaRESUMO
Celiac disease is a chronic inflammation of the small intestine with villous atrophy that can become refractory to a gluten-free diet. Two categories of refractory celiac disease can be distinguished by the phenotype of intraepithelial lymphocytes and the status of TRG genes. Their distinction is important because 30% to 50% of type II but only 0% to 14% of type I evolve to an aggressive enteropathy-associated T-cell lymphoma and therefore require intensive treatment. Currently, differential diagnosis integrates immunohistochemistry, immunophenotyping, and TRG clonality analyses, but each has limitations. A single-tube multiplex TRG PCR (ECN) was prospectively compared to an in-house two-tube TRG PCR (N2T) in 73 samples, including 67 cryopreserved intestine tissues. Thirteen formalin-fixed, paraffin-embedded (FFPE) samples were also analyzed retrospectively. The ECN PCR had comparable efficiency to detect major clonal rearrangements in highly infiltrated tissues from T-cell lymphoproliferative disorders and type II refractory celiac disease and to detect the persistence of minor clones in type II refractory celiac disease follow-up samples. The ECN PCR abolished the risk of amplification of false-positive weak clonal rearrangements in cryopreserved specimens and allowed improved detection of clonal rearrangements in DNA from FFPE samples. The ECN PCR allows robust assessment of cryopreserved and FFPE digestive tissues at diagnosis and follow-up of enteropathies with villous atrophy, thus guiding therapeutic management.
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Doença Celíaca/genética , Rearranjo Gênico , Linfoma de Células T/genética , Reação em Cadeia da Polimerase Multiplex/métodos , Doença Celíaca/diagnóstico , Doença Celíaca/patologia , Formaldeído , Humanos , Linfoma de Células T/diagnóstico , Linfoma de Células T/patologia , Inclusão em Parafina , Estudos Prospectivos , Fixação de TecidosRESUMO
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.
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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 , PrognósticoRESUMO
BACKGROUND: Low-grade alimentary lymphoma (LGAL) is characterised by the infiltration of neoplastic T-lymphocytes, typically in the small intestine. The incidence of LGAL has increased over the last ten years and it is now the most frequent digestive neoplasia in cats and comprises 60 to 75% of gastrointestinal lymphoma cases. Given that LGAL shares common clinical, paraclinical and ultrasonographic features with inflammatory bowel diseases, establishing a diagnosis is challenging. A review was designed to summarise current knowledge of the pathogenesis, diagnosis, prognosis and treatment of feline LGAL. Electronic searches of PubMed and Science Direct were carried out without date or language restrictions. RESULTS: A total of 176 peer-reviewed documents were identified and most of which were published in the last twenty years. 130 studies were found from the veterinary literature and 46 from the human medicine literature. Heterogeneity of study designs and outcome measures made meta-analysis inappropriate. The pathophysiology of feline LGAL still needs to be elucidated, not least the putative roles of infectious agents, environmental factors as well as genetic events. The most common therapeutic strategy is combination treatment with prednisolone and chlorambucil, and prolonged remission can often be achieved. Developments in immunohistochemical analysis and clonality testing have improved the confidence of clinicians in obtaining a correct diagnosis between LGAL and IBD. The condition shares similarities with some diseases in humans, especially human indolent T-cell lymphoproliferative disorder of the gastrointestinal tract. CONCLUSIONS: The pathophysiology of feline LGAL still needs to be elucidated and prospective studies as well as standardisation of therapeutic strategies are needed. A combination of conventional histopathology and immunohistochemistry remains the current gold-standard test, but clinicians should be cautious about reclassifying cats previously diagnosed with IBD to lymphoma on the basis of clonality testing. Importantly, feline LGAL could be considered to be a potential animal model for indolent digestive T-cell lymphoproliferative disorder, a rare condition in human medicine.
Assuntos
Doenças do Gato/patologia , Modelos Animais de Doenças , Linfoma não Hodgkin/veterinária , Linfoma de Células T Periférico , Animais , Doenças do Gato/diagnóstico , Doenças do Gato/terapia , Gatos , Sistema Digestório/patologia , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/veterinária , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/patologia , Linfoma não Hodgkin/terapiaRESUMO
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.
RESUMO
BACKGROUND: Approximately 5% of patients with celiac disease (CeD) do not respond to a gluten-free diet and progress to refractory celiac disease (RCD), a severe progression that is characterized by infiltration of intraepithelial T lymphocytes. Patients with RCD type II (RCDII) show clonal expansions of intraepithelial T lymphocytes that result in a poor prognosis and a high mortality rate through development of aggressive enteropathy-associated T-cell lymphoma. It is not known whether genetic variations play a role in severe progression of CeD to RCDII. PATIENTS AND METHODS: We performed the first genome-wide association study to identify the causal genes for RCDII and the molecular pathways perturbed in RCDII. The genome-wide association study was performed in 38 Dutch patients with RCDII, and the 15 independent top-associated single nucleotide polymorphism (SNP) variants (P<5×10) were replicated in 56 independent French and Dutch patients with RCDII. RESULTS: After replication, SNP rs2041570 on chromosome 7 was significantly associated with progression to RCDII (P=2.37×10, odds ratio=2.36) but not with CeD susceptibility. SNP rs2041570 risk allele A was associated with lower levels of FAM188B expression in blood and small intestinal biopsies. Stratification of RCDII biopsies based on rs2041570 genotype showed differential expression of innate immune and antibacterial genes that are expressed in Paneth cells. CONCLUSION: We have identified a novel SNP associated with the severe progression of CeD to RCDII. Our data suggest that genetic susceptibility to CeD might be distinct from the progression to RCDII and suggest a role for Paneth cells in RCDII progression.