RESUMO
Crohn's disease (CD) is a chronic inflammatory disorder affecting the bowel wall. Tissue-resident memory T (Trm) cells are implicated in CD, yet their characteristics remain unclear. We aimed to investigate the transcriptional profiles and functional characteristics of Trm cells in the small bowel of CD and their interactions with immune cells. Seven patients with CD and four with ulcerative colitis as controls were included. Single-cell RNA sequencing and paired T cell receptor sequencing assessed T cell subsets and transcriptional signatures in lamina propria (LP) and submucosa/muscularis propria-enriched fractions (SM/MP) from small bowel tissue samples. We detected 58,123 T cells grouped into 16 populations, including the CD4+ Trm cells with a Th17 signature and CD8+ Trm clusters. In CD, CD4+ Trm cells with a Th17 signature, termed Th17 Trm, showed significantly increased proportions within both the LP and SM/MP areas. The Th17 Trm cluster demonstrated heightened expression of tissue-residency marker genes (ITGAE, ITGA1, and CXCR6) along with elevated levels of IL17A, IL22, CCR6, and CCL20. The clonal expansion of Th17 Trm cells in CD was accompanied by enhanced transmural dynamic potential, as indicated by significantly higher migration scores. CD-prominent Th17 Trm cells displayed an increased interferon gamma (IFNγ)-related signature possibly linked with STAT1 activation, inducing chemokines (i.e., CXCL10, CXCL8, and CXCL9) in myeloid cells. Our findings underscored the elevated Th17 Trm cells throughout the small bowel in CD, contributing to disease pathogenesis through IFNγ induction and subsequent chemokine production in myeloid cells.
Assuntos
Doença de Crohn , Memória Imunológica , Células T de Memória , Células Th17 , Humanos , Doença de Crohn/imunologia , Doença de Crohn/genética , Doença de Crohn/patologia , Células Th17/imunologia , Células Th17/metabolismo , Células T de Memória/imunologia , Células T de Memória/metabolismo , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Biomarcadores , Perfilação da Expressão Gênica , Adulto JovemRESUMO
INTRODUCTION: Metastatic disease affects approximately 15% to 17% of patients with pheochromocytomas and paragangliomas (PPGLs). Unfortunately, treatment options for metastatic PPGLs are limited and rely on small, nonrandomized clinical trials. The impact of germline mutation status on systemic treatment outcomes remains unclear. To address these gaps, we retrospectively evaluated treatment outcomes in patients with PPGL. PATIENTS AND METHODS: Between December 2004 and December 2021, 33 patients were diagnosed with metastatic PPGLs and received systemic treatment at the Department of Oncology, Asan Medical Center, Seoul, South Korea. RESULTS: The median age of the patients was 49. Germline mutations were revealed in nine patients (39.1%) out of 23 who underwent germline testing, with SDHB mutation being the most frequent in 5 patients. Cyclophosphamide, vincristine, and dacarbazine (CVD) chemotherapy was administered to 18 patients, with an objective response rate (ORR) of 22% and a disease control rate (DCR) of 67%. The median progression-free survival (PFS) was 7.9 and the median overall survival (OS) was 36.2 months. Sunitinib was given to 6 patients, which had an ORR of 33%, a DCR of 83%, and a median PFS of 14.6 months. Notably, patients with SDHB/SDHD mutation (4 patients and one patient, respectively) who received CVD treatment had a significantly better OS than those without (median OS 94.0 months vs. 13.7 months, P = .01). CONCLUSION: Our study reveals that CVD and sunitinib are effective treatments for metastatic PPGLs. The results are consistent with previous studies and patients with SDHB and SDHD mutations may benefit most from CVD treatment.
Assuntos
Neoplasias das Glândulas Suprarrenais , Doenças Cardiovasculares , Paraganglioma , Feocromocitoma , Humanos , Feocromocitoma/tratamento farmacológico , Feocromocitoma/genética , Feocromocitoma/diagnóstico , Mutação em Linhagem Germinativa , Estudos Retrospectivos , Sunitinibe/uso terapêutico , Succinato Desidrogenase/genética , Paraganglioma/tratamento farmacológico , Paraganglioma/genética , Dacarbazina/uso terapêutico , Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/diagnóstico , Ciclofosfamida/uso terapêuticoRESUMO
BACKGROUND AND AIMS: Creeping fat [CF] is a poorly understood feature of Crohn's disease [CD], characterized by the wrapping of mesenteric adipose tissue [MAT] around the inflamed intestine. The aim of this study was to investigate the transcriptional profile and compositional features of CF. METHODS: We collected 59 MAT samples: 23 paired samples from patients with CD (CF [CD-CF] and MAT around the uninflamed intestine [CD-MAT]) and 13 MAT samples from non-CD patients [Con-MAT]. Differentially expressed gene [DEG], functional pathway, cell deconvolution, and gene co-expression network analyses were performed. RESULTS: By comparing three different MAT samples, we identified a total of 529 DEGs [|log2FoldChange| > 1.5; false discovery rate < 0.05]. Of these, 323 genes showed an incremental pattern from Con-MAT to CD-MAT, and to CD-CF, while 105 genes displayed a decremental pattern. Genes with an incremental pattern were related to immune cell responses, including B- and T-cell activation, while genes with a decremental pattern were involved in cell trafficking and migration. Cell deconvolution analysis revealed significant changes in cellular composition between the CD-CF and Con-MAT groups, with increased proportions of B-cells/plasma cells [pâ =â 1.16â ×â 10-4], T-cells [pâ =â 3.66â ×â 10-3], and mononuclear phagocytes [pâ =â 3.53â ×â 10-2] in the CD-CF group. In contrast, only the B-cell/plasma cell component showed a significant increase [pâ =â 1.62â ×â 10-2] in the CD-MAT group compared to Con-MAT. CONCLUSION: The distinct transcriptional profiles and altered cellular components of each MAT found in our study provide insight into the mechanisms behind CF and highlight its possible role in the pathogenesis of CD.
Assuntos
Doença de Crohn , Humanos , Doença de Crohn/patologia , Intestinos/patologia , Tecido Adiposo/metabolismo , Linfócitos T/metabolismo , Perfilação da Expressão GênicaRESUMO
BACKGROUND: Sex is an integral variable often overlooked in complex disease genetics. Differences between sexes have been reported in natural history, disease complications, and age of onset in inflammatory bowel disease (IBD). While association studies have identified >230 IBD loci, there have been a limited number of studies investigating sex differences underlying these genetic associations. METHODS: We report the first investigation of sex-dimorphic associations via meta-analysis of a sex-stratified association study (34 579 IBD cases, 39 125 controls). In addition, we performed chromosome (chr) X-specific analyses, considering models of X inactivation (XCI) and XCI escape. Demographic and clinical characteristics were also compared between sexes. RESULTS: We identified significant differences between sexes for disease location and perianal complication in Crohn's disease and disease extent in ulcerative colitis. We observed genome-wide-significant sex-dimorphic associations (Pâ <â 5â ×â 10-8) at loci not previously reported in large-scale IBD genetic studies, including at chr9q22, CARMIL1, and UBASH3A. We identified variants in known IBD loci, including in chr2p15 and within the major histocompatibility complex on chr6, exhibiting sex-specific patterns of association (Pâ <â 5â ×â 10-7 in one sex only). We identified 3 chrX associations with IBD, including a novel Crohn's disease susceptibility locus at Xp22. CONCLUSIONS: These analyses identified novel IBD loci, in addition to characterizing sex-specific patterns of associations underlying sex-dimorphic associations. By elucidating the role of sex in IBD genetics, our study will help enhance our understanding of the differences between the sexes in IBD biology and underscores a need to move beyond conventional sex-combined analyses to appreciate the genetic architecture of IBD more comprehensively.
Sex-dimorphic meta-analyses of sex-stratified case-control (nâ =â 73 704) regression identified 3 novel inflammatory bowel disease loci reaching genome-wide significance and highlighted chromosome 2 and major histocompatibility complex variants exhibiting sex-specific association. In addition, a novel chromosome X Crohn's disease susceptibility locus was identified.
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Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Humanos , Feminino , Masculino , Predisposição Genética para Doença , Doenças Inflamatórias Intestinais/genética , Doença de Crohn/genética , Colite Ulcerativa/genética , Caracteres Sexuais , Estudo de Associação Genômica AmplaRESUMO
Inflammatory bowel diseases (IBDs) are chronic disorders of the gastrointestinal tract with the following two subtypes: Crohn's disease (CD) and ulcerative colitis (UC). To date, most IBD genetic associations were derived from individuals of European (EUR) ancestries. Here we report the largest IBD study of individuals of East Asian (EAS) ancestries, including 14,393 cases and 15,456 controls. We found 80 IBD loci in EAS alone and 320 when meta-analyzed with ~370,000 EUR individuals (~30,000 cases), among which 81 are new. EAS-enriched coding variants implicate many new IBD genes, including ADAP1 and GIT2. Although IBD genetic effects are generally consistent across ancestries, genetics underlying CD appears more ancestry dependent than UC, driven by allele frequency (NOD2) and effect (TNFSF15). We extended the IBD polygenic risk score (PRS) by incorporating both ancestries, greatly improving its accuracy and highlighting the importance of diversity for the equitable deployment of PRS.
Assuntos
Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Humanos , Colite Ulcerativa/genética , Doença de Crohn/genética , População do Leste Asiático , População Europeia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Doenças Inflamatórias Intestinais/genética , Polimorfismo de Nucleotídeo Único/genética , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genéticaRESUMO
BACKGROUND AND AIMS: Reduced body muscle mass is a poor prognostic factor for inflammatory bowel disease (IBD). In this study, we investigated the prevalence of sarcopenia at diagnosis and its clinical significance in Korean patients with IBD. METHODS: The prevalence of sarcopenia in IBD patients between June 1989 and December 2016 was investigated using a well-characterized referral center-based cohort. Abdominopelvic computed tomography within six months from IBD diagnosis was used for the evaluation. Sarcopenia was defined as an L3 skeletal muscle index of < 49 cm2/m2 for male and < 31 cm2/m2 for female. The clinical characteristics and outcomes were evaluated with respect to sarcopenia. RESULTS: A total of 1,027 patients (854 Crohn's disease [CD]; 173 ulcerative colitis [UC]) were evaluated. Sarcopenia was found in 56.8% of the population (CD, 57.5%; UC, 53.2%), and male were more likely to be sarcopenic (CD, 94.3%; UC, 91.6%). There were no significant differences in the cumulative risk of using steroids, immunomodulators, biologics, and bowel resections (or colectomy) with or without sarcopenia during follow-up (median: CD, 5.8 years; UC, 3.7 years). In sarcopenic patients with CD, there was a significantly higher cumulative risk of perianal surgeries than in non-sarcopenic patients with CD (Log-rank test; P = 0.001). However, the risk of perianal surgeries was not significant in multivariate analysis (Odds ratio 1.368; 95% confidence interval 0.782-2.391; P = 0.272). CONCLUSION: Sarcopenia at diagnosis may have no significant prognostic value for medical treatment and bowel resection, but it may be associated with perianal CD.
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Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Sarcopenia , Humanos , Masculino , Feminino , Sarcopenia/diagnóstico por imagem , Sarcopenia/epidemiologia , Doenças Inflamatórias Intestinais/diagnóstico , Colite Ulcerativa/complicações , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/epidemiologia , Doença de Crohn/complicações , Doença de Crohn/diagnóstico , Doença de Crohn/epidemiologia , Colectomia , Progressão da Doença , República da Coreia/epidemiologiaRESUMO
Crohn's disease (CD) and ulcerative colitis (UC), two major subtypes of inflammatory bowel disease, show substantial differences in their clinical course and treatment response. To identify the genetic factors underlying the distinct characteristics of these two diseases, we performed a genome-wide association study (GWAS) between CD (n = 2359) and UC (n = 2175) in a Korean population, followed by replication in an independent sample of 772 CD and 619 UC cases. Two novel loci were identified with divergent effects on CD and UC: rs9842650 in CD200 and rs885026 in NCOR2. In addition, the seven established susceptibility loci [major histocompatibility complex (MHC), TNFSF15, OTUD3, USP12, IL23R, FCHSD2 and RIPK2] reached genome-wide significance. Of the nine loci, six (MHC, TNFSF15, OTUD3, USP12, IL23R and CD200) were replicated in the case-case GWAS of European populations. The proportion of variance explained in CD-UC status by polygenic risk score analysis was up to 22.6%. The area under the receiver-operating characteristic curve value was 0.74, suggesting acceptable discrimination between CD and UC. This CD-UC GWAS provides new insights into genetic differences between the two diseases with similar symptoms and might be useful in improving their diagnosis and treatment.
Assuntos
Colite Ulcerativa , Doença de Crohn , Humanos , Colite Ulcerativa/genética , Doença de Crohn/genética , Estudo de Associação Genômica Ampla , Predisposição Genética para Doença , Loci Gênicos , Polimorfismo de Nucleotídeo Único/genética , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Proteínas de Transporte/genética , Proteínas de Membrana/genética , Proteases Específicas de Ubiquitina/genéticaRESUMO
Background/Aims: Chronic enteropathy associated with SLCO2A1 gene (CEAS), an inherited disease characterized by nonspecific intestinal ulcers, has emerged in the Japanese population via loss-of-function mutations in the SLCO2A1 gene. We aimed to investigate the clinical and genetic characteristics of Korean patients diagnosed with CEAS. Methods: From July 2018 to July 2021, we performed Sanger sequencing of the SLCO2A1 gene in 46 patients with chronic intestinal ulcers. CEAS was confirmed based on known SLCO2A1 mutations. We summarized the clinical characteristics of patients with confirmed CEAS. Results: Fourteen out of 46 patients (30.4%) had genetically confirmed CEAS, and two SLCO2A1 variants were detected (splicing site variant c.940+1G>A and nonsense mutation [p.R603X] in SLCO2A1). Twelve patients (85.7%) were females and the median age at diagnosis of CEAS was 44.5 years. All patients presented with abdominal pain, and 13 patients (92.9%) presented with anemia (median hemoglobin, 9.6 g/dL). Ten patients (71.4%) had hypoalbuminemia (median, 2.7 g/dL). The most commonly involved site was the ileum (13/14, 92.9%). Manifestations of primary hypertrophic osteoarthropathy (PHO), such as digital clubbing, pachydermia, and periostosis were observed in five patients (28.6%) and two male patients and one female patient satisfied all major PHO diagnostic criteria. Conclusions: The clinical and genetic characteristics of Korean patients with confirmed CEAS were similar to those reported in the literature. CEAS should be considered in the differential diagnosis for patients with unexplained chronic nonspecific ulcers of the small intestine.
Assuntos
Doenças Inflamatórias Intestinais , Transportadores de Ânions Orgânicos , Humanos , Masculino , Feminino , Adulto , Úlcera , Transportadores de Ânions Orgânicos/genética , Intestino Delgado , Mutação , República da CoreiaRESUMO
Genome-wide association studies (GWAS) of Crohn's disease (CD) in European and leprosy in Chinese population have shown that CD and leprosy share genetic risk loci. As these shared loci were identified through cross-comparisons across different ethnic populations, we hypothesized that meta-analysis of GWAS on CD and leprosy in East Asian populations would increase power to identify additional shared loci. We performed a cross-disease meta-analysis of GWAS data from CD (1621 cases and 4419 controls) and leprosy (2901 cases 3801 controls) followed by replication in additional datasets comprising 738 CD cases and 488 controls and 842 leprosy cases and 925 controls. We identified one novel locus at 7p22.3, rs77992257 in intron 2 of ADAP1, shared between CD and leprosy with genome-wide significance (P = 3.80 × 10-11) and confirmed 10 previously established loci in both diseases: IL23R, IL18RAP, IL12B, RIPK2, TNFSF15, ZNF365-EGR2, CCDC88B, LACC1, IL27, NOD2. Phenotype variance explained by the polygenic risk scores derived from Chinese leprosy data explained up to 5.28% of variance of Korean CD, supporting similar genetic structures between the two diseases. Although CD and leprosy shared a substantial number of genetic susceptibility loci in East Asians, the majority of shared susceptibility loci showed allelic effects in the opposite direction. Investigation of the genetic correlation using cross-trait linkage disequilibrium score regression also showed a negative genetic correlation between CD and leprosy (rg [SE] = -0.40[0.13], P = 2.6 × 10-3). These observations implicate the possibility that CD might be caused by hyper-sensitive reactions toward pathogenic stimuli.
Assuntos
Doença de Crohn , Hanseníase , Humanos , Estudo de Associação Genômica Ampla , Doença de Crohn/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Povo Asiático/genética , Loci Gênicos , Hanseníase/genética , Estudos de Casos e Controles , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genéticaRESUMO
Background/Aims: : Although pediatric ulcerative colitis (UC) has a different phenotype and clinical course than adult UC, its clinical features and outcomes are poorly defined, especially in Asian populations. This study investigated the clinical features and long-term outcomes of pediatric UC in a Korean population. Methods: We retrospectively analyzed 208 patients aged <18 years diagnosed with UC between 1987 and 2013. The patient characteristics at diagnosis according to the Paris classification and the clinical course were analyzed. Results: The male-to-female ratio was 1.3:1, and the median patient age was 15.5 years. At diagnosis, 28.8% of patients had proctitis (E1), 27.8%, left-sided colitis (E2); 5.2%, extensive colitis (E3); and 38.2%, pancolitis (E4). The cumulative probabilities of extension after 5, 10, 15, and 20 years were 32.7%, 40.4%, 52.5%, and 65.8%, respectively. Eighteen patients underwent colectomy, and three patients had colorectal cancer. The cumulative probabilities of colectomy after 5, 10, 15, and 20 years were 7.1%, 8.9%, 12.6%, and 15.6%, and those of colorectal cancer after 10, 15, and 20 years were 0%, 2.1%, and 12.0%, respectively. The disease extent, Pediatric Ulcerative Colitis Activity Index severity, and systemic corticosteroid therapy were significant risk factors for colectomy. The development of primary sclerosing cholangitis was significantly associated with colorectal cancer. Conclusions: This study provides detailed information on the disease phenotype and long-term clinical outcomes in a large cohort of Korean children with UC. They have extensive disease at diagnosis, a high rate of disease extension, and a low rate of cumulative colectomy.
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Colite Ulcerativa , Neoplasias Colorretais , Colectomia , Colite Ulcerativa/tratamento farmacológico , Progressão da Doença , Feminino , Humanos , Masculino , República da Coreia/epidemiologia , Estudos RetrospectivosRESUMO
BACKGROUND & AIMS: In this nationwide population-based study, we investigated the risk of vertebral and hip fractures in patients with inflammatory bowel disease (IBD). METHODS: Using data from the Korean National Health Insurance claims database gathered between 2007 and 2016, we calculated the incidence rate ratios (IRRs) of vertebral and hip fractures in patients with newly diagnosed IBD (n = 18,228; 64.1% male, 65.9% ulcerative colitis) compared with an age- and sex-matched control population (matching ratio, 1:10; n = 186,871). RESULTS: During a median follow-up period of 4.5 years, the incidence rate and IRR of vertebral and hip fractures in patients with IBD were 2.88 per 1000 person-years and 1.24 (95% CI, 1.08-1.42), respectively. The cumulative risk of vertebral and hip fractures in IBD patients was 0.6%, 1.4%, and 1.9% at 2, 5, and 7 years after diagnosis, respectively, and this risk of fracture in IBD patients was higher than that in matched controls (P = .002). The use of corticosteroids further increased the risk of fractures in IBD patients (IRR, 1.37; 95% CI, 1.13-1.65) compared with matched controls. The risk of fractures was significantly higher in patients with Crohn's disease (CD) (IRR, 1.56; 95% CI, 1.19-2.04) than in matched controls, and this risk remained higher in patients with CD without corticosteroid exposure (IRR, 1.62; 95% CI, 1.12-2.34). The risk of fracture increased with age and was particularly high in females and in those with comorbidities. CONCLUSIONS: The risk of fractures was significantly high in newly diagnosed IBD patients, especially in those with CD regardless of corticosteroid exposure.
Assuntos
Colite Ulcerativa , Doença de Crohn , Fraturas do Quadril , Doenças Inflamatórias Intestinais , Corticosteroides , Estudos de Casos e Controles , Colite Ulcerativa/complicações , Colite Ulcerativa/epidemiologia , Feminino , Fraturas do Quadril/epidemiologia , Fraturas do Quadril/etiologia , Humanos , Incidência , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/epidemiologia , Masculino , Fatores de RiscoRESUMO
ABSTRACT: This study aimed to evaluate self-reported vaccination rates, immunity, knowledge of and attitudes toward vaccination among Korean patients with inflammatory bowel disease (IBD) as well as to identify factors associated with proper vaccination.Between November 2013 and February 2015, consecutive patients with IBD were invited to complete a standardized questionnaire on vaccination. Moreover, immune status for common vaccine-preventable diseases was evaluated via serologic tests.A total of 310 patients with IBD were invited to the questionnaire survey and 287 patients (92.6%) who completed the questionnaires were finally enrolled (men, 188 [65.5%], median age at survey, 29.9âyears [interquartile range, 22.3-39.2], ulcerative colitis: Crohn diseaseâ=â165:122]. Self-reported vaccine uptake rates were as follows: hepatitis A virus (HAV; 13.2%), hepatitis B virus (HBV; 35.2%), seasonal influenza (43.2%), pneumococcus (4.9%). Most of the patients (87.1%) did not know that proper vaccination has been recommended for patients with IBD. Up to 64.8% and 32.8% of patients were negative for IgG anti-HAV antibody and IgG HBV surface antibody, respectively. In a multivariable analysis, newspaper subscription (aOR [adjusted odds ratio] 2.185, 95% confidence interval [CI] 1.136-4.203, Pâ=â.019), ever recommendation of vaccination by a physician (aOR 2.456, 95% CI 1.240-4.862, Pâ=â.010), and use of anti-tumor necrosis factor agents (aOR 4.966, 95% CI 1.098-22.464, Pâ=â.037) showed a significant association with uptake of adult vaccines recommended for patients with IBD.Vaccine uptake rates, positivity of antibody to HAV and HBV, and knowledge of patients with IBD regarding vaccination were not sufficient. Proper educational information and recommendation from physicians could enhance awareness among patients with IBD about the need for vaccination and thereby improve vaccination rates.Trial registration number: NCT01984879.
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Conhecimentos, Atitudes e Prática em Saúde , Doenças Inflamatórias Intestinais , Vacinas contra Influenza , Vacinação , Adulto , Humanos , Imunização , Imunoglobulina G , Doenças Inflamatórias Intestinais/imunologia , Masculino , República da CoreiaRESUMO
BACKGROUND: Anti-tumor necrosis factor (TNF) treatment for inflammatory bowel disease (IBD) increases the risk of tuberculosis (TB) infection. In the present study, we analyzed the clinical characteristics and risks of TB in Korean patients with IBD who received anti-TNF treatment. METHODS: The study included patients with IBD who were treated using anti-TNF agents between January 2001 and June 2018 at the Asan Medical Center. Overall, 1434 patients with ulcerative colitis or Crohn's disease were enrolled. We calculated the incidence of active TB infection after anti-TNF treatment and compared the clinical characteristics of the TB group with those of the non-TB group. RESULTS: Twenty-one patients (1.46%) developed active TB infection, and the incidence rate of active TB was 366.73 per 100,000 person-years. In total, 198 patients (14.9%) were positive for latent tuberculosis infection (LTBI), of whom only eight (4%) did not complete LTBI treatment. The age at which the anti-TNF therapy was started was significantly higher in the TB group than in the non-TB group (HR 1.041, 95% CI 1.014-1.069, p = 0.002), and as age increased, so did the incidence rate of active TB infection (linearity p < 0.001). There was no significant difference in the incidence rate of LTBI between the TB and non-TB groups (HR 0.896, 95% CI 0.262-3.066, p = 0.862). CONCLUSIONS: In patients with IBD, the incidence rate of TB increased with age at anti-TNF therapy initiation. Active treatment of LTBI may lower the incidence of TB in patients with IBD who are to undergo anti-TNF therapy.
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Doenças Inflamatórias Intestinais , Tuberculose , Estudos de Coortes , Hospitais , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/epidemiologia , Infliximab/efeitos adversos , República da Coreia/epidemiologia , Tuberculose/epidemiologia , Inibidores do Fator de Necrose TumoralRESUMO
Methods: We retrospectively reviewed the medical records of IBD patients who visited Asan Medical center. We used a large, well-characterized referral center-based cohort. The clinical features of IBD patients with body mass index (BMI) over 30 and matched controls with BMI under 30 were compared. Results: Among the 6,803 IBD patients enrolled in the Asan IBD Registry between June 1989 and December 2016, we identified 16 patients with Crohn's disease (CD) and 27 patients with ulcerative colitis (UC) whose BMI was over 30 at the time of diagnosis. Their clinical characteristics and course were compared with those of 64 and 108 matched patients with CD and UC, respectively. There were no significant differences in the risk of using steroids (hazards ratio (HR) = 0.633 and P=0.254), immunomodulators (HR = 0.831 and P=0.517), and anti-tumor necrosis factor (TNF) therapy (HR = 1.539 and P=0.351) and risk of bowel resections (HR = 1.858 and P=0.231) between CD patients with BMI over 30 and those with BMI under 30; similarly, UC patients did not show significant differences in the risk of using steroids (HR = 0.613 and P=0.145), immunomodulators (HR = 0.492 and P=0.111), anti-TNF therapy (HR = 0.385 and P=0.095), and risk of colectomy (HR = 0.262 and P=0.104). In the subgroup analysis, under-weight UC patients had a higher cumulative probability of needing steroids (HR = 0.2510 and P=0.042), needing immunomodulators (HR = 0.097 and P=0.014), and a higher risk of receiving colectomy (HR = 0.024 and P=0.019) than obese UC patients. Conclusions: Obese IBD patients with CD or UC did not show significantly different clinical features from nonobese IBD patients.
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Colite Ulcerativa , Doenças Inflamatórias Intestinais , Colite Ulcerativa/complicações , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/epidemiologia , Humanos , Obesidade/complicações , Obesidade/epidemiologia , Estudos Retrospectivos , Inibidores do Fator de Necrose TumoralRESUMO
OBJECTIVE: Dysfunctional resolution of intestinal inflammation and altered mucosal healing are essential features in the pathogenesis of inflammatory bowel disease (IBD). Intestinal macrophages are vital in the process of inflammation resolution, but the mechanisms underlying their mucosal healing capacity remain elusive. DESIGN: We investigated the role of the prostaglandin E2 (PGE2) receptor PTGER4 on the differentiation of intestinal macrophages in patients with IBD and mouse models of intestinal inflammation. We studied mucosal healing and intestinal epithelial barrier regeneration in Csf1r-iCre Ptger4fl/fl mice during dextran sulfate sodium (DSS)-induced colitis. The effect of PTGER4+ macrophage secreted molecules was investigated on epithelial organoid differentiation. RESULTS: Here, we describe a subset of PTGER4-expressing intestinal macrophages with mucosal healing properties both in humans and mice. Csf1r-iCre Ptger4fl/fl mice showed defective mucosal healing and epithelial barrier regeneration in a model of DSS colitis. Mechanistically, an increased mucosal level of PGE2 triggers chemokine (C-X-C motif) ligand 1 (CXCL1) secretion in monocyte-derived PTGER4+ macrophages via mitogen-activated protein kinases (MAPKs). CXCL1 drives epithelial cell differentiation and proliferation from regenerating crypts during colitis. Specific therapeutic targeting of macrophages with liposomes loaded with an MAPK agonist augmented the production of CXCL1 in vivo in conditional macrophage PTGER4-deficient mice, restoring their defective epithelial regeneration and favouring mucosal healing. CONCLUSION: PTGER4+ intestinal macrophages are essential for supporting the intestinal stem cell niche and regeneration of the injured epithelium. Our results pave the way for the development of a new class of therapeutic targets to promote macrophage healing functions and favour remission in patients with IBD.
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Doenças Inflamatórias Intestinais/metabolismo , Mucosa Intestinal/citologia , Mucosa Intestinal/metabolismo , Ativação de Macrófagos , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Animais , Diferenciação Celular , Quimiocina CXCL1/metabolismo , Modelos Animais de Doenças , Camundongos , Regeneração , Transdução de SinaisRESUMO
BACKGROUND: Previous studies have shown vitamin D status to be associated with disease activity in patients with inflammatory bowel disease (IBD), but its influence on the clinical course of IBD has not been established. AIMS: We aimed to analyze whether the serum 25-hydroxyvitamin D3 [25(OH)D] status is associated with clinical characteristics and affects the risk of surgery in patients with IBD. METHODS: From the IBD registry of the Asan Medical Center, we identified all patients who had at least one 25(OH)D measurement; we then analyzed the association between clinical factors and 25(OH)D status. 25(OH)D was considered borderline deficient, deficient, and severely deficient at levels of < 30, < 20, and < 10 ng/mL, respectively. RESULTS: We included 711 Crohn's disease (CD) and 764 ulcerative colitis (UC) patients who had not undergone surgery before 25(OH)D was measured. Both in CD and in UC patients, reduced 25(OH)D was associated with higher disease activity scores and CRP levels (p < 0.001). Severe 25(OH)D deficiency was associated with ileocolonic disease and complicated behavior in CD (p < 0.05) and was relevant to the disease extent in UC (p < 0.001). Additionally, severe 25(OH)D deficiency was associated with CMV colitis in patients with UC (p < 0.001). In multivariable analysis, severe deficiency of 25(OH)D was an independent risk factor for surgery in both CD (HR 1.93, 95% confidence interval [CI] 1.38-2.70) and UC (HR 2.77, 95% CI 1.14-6.74). CONCLUSION: Severe 25(OH)D deficiency may be a marker of a more aggressive clinical course of IBD.
Assuntos
Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/metabolismo , Índice de Gravidade de Doença , Deficiência de Vitamina D/diagnóstico , Deficiência de Vitamina D/metabolismo , Vitamina D/metabolismo , Adolescente , Adulto , Estudos de Coortes , Feminino , Humanos , Doenças Inflamatórias Intestinais/epidemiologia , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Deficiência de Vitamina D/epidemiologia , Adulto JovemRESUMO
BACKGROUND AND AIM: The clinical impact of perianal Crohn's disease (CD) (pCD), a well-known poor prognostic factor of CD, has not been fully evaluated in Asian patients. We investigated the outcomes of CD in Korean patients according to the presence of pCD at CD diagnosis. METHODS: Using 2010-2014 data from the national health insurance claims database, we evaluated the disease course of CD according to the presence of pCD at CD diagnosis. The results were verified in a hospital-based cohort of 2923 patients. RESULTS: The cumulative risk of intestinal resection was lower in patients with pCD at diagnosis than in those without, in the population-based cohort (9.1% vs 14.7% at 5 years after diagnosis, P < 0.001), but it was similar between the two groups in the hospital-based cohort (36.8% vs 36.8% at 10 years after diagnosis, P = 0.950). Moreover, the cumulative risk of behavioral progression was not significantly different between the two groups in the hospital-based cohort (43.4% vs 41.6% at 10 years after diagnosis, P = 0.366). On multivariable analysis, pCD at CD diagnosis was not a predictor of intestinal resection, behavioral progression, CD-related hospital admission, or diverting surgery; however, it was an independent predictor of proctectomy (hazard ratio [HR] 3.210, P < 0.001) and anorectal cancer (HR 3.104, P = 0.047). CONCLUSIONS: Although the presence of pCD increased the risk of proctectomy and anorectal cancer in Asian patients, the clinical impact of pCD on the overall outcomes of patients with CD may be less significant in Asian patients compared with Western patients.
Assuntos
Doença de Crohn/diagnóstico , Adulto , Neoplasias do Ânus/epidemiologia , Neoplasias do Ânus/etiologia , Povo Asiático , Estudos de Coortes , Doença de Crohn/complicações , Doença de Crohn/epidemiologia , Doença de Crohn/cirurgia , Feminino , Humanos , Masculino , Protectomia , Prognóstico , Neoplasias Retais/epidemiologia , Neoplasias Retais/etiologia , Risco , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND AND AIM: Fucosyltransferase 2 (FUT2) at 19q13 is a well-established susceptibility locus for Crohn's disease (CD) in Caucasians. FUT2 encodes α-1,2-fucosyltransferase that regulates the secretion of the α-1-2-N-acetylgalactosaminyltransferase and α-1-3-galactosyltransferase (ABO) antigens in both the gastrointestinal mucosa and secretory glands. Given that CD is thought to arise from dysregulated mucosal immune responses to the gut flora and both the ABO blood group and the FUT2 secretor status affect the composition of the gut microbiota, the goal of this study was to evaluate the associations of variants of FUT2 and ABO with CD in Koreans. METHODS: Three single-nucleotide polymorphisms from the FUT2 and ABO genes were genotyped in 1735 patients with CD and 8074 healthy controls. RESULTS: The FUT2 non-secretor allele showed genome-wide significant association with CD in Koreans (rs1047781, odds ratio [OR] = 1.30, Pcombined = 3.52 × 10-12 ). The ABO locus showed genome-wide significant association with CD in Asians (Pmeta = 2.35 × 10-8 ). A moderate association was observed with the A and B groups (OR = 1.40, P = 2.26 × 10-6 ; and OR = 1.32, P = 1.92 × 10-4 , respectively) compared with the O group. Following stratification on the basis of FUT2 genotype, carriers of the secretor O blood group were significantly protective against CD than were those of the secretor non-O blood group (OR = 0.63, 95% confidence interval = 0.54-0.73, P = 2.86 × 10-9 ). CONCLUSIONS: These are the first results indicating that the O blood group and FUT2 secretor status are protective factors against CD in Asians.
Assuntos
Sistema ABO de Grupos Sanguíneos/genética , Doença de Crohn/genética , Fucosiltransferases/genética , Galactosiltransferases/genética , Povo Asiático , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Galactosídeo 2-alfa-L-FucosiltransferaseRESUMO
BACKGROUND: Little is known about the natural history of perianal fistulas in Asian populations with Crohn's disease (CD). AIMS: We investigated the incidence and outcomes of perianal CD (pCD) in Korean CD patients. METHODS: A nationwide population-based cohort of 6265 CD patients diagnosed in 2010-2014 was analyzed to investigate the incidence and outcomes of pCD. The results were validated in a hospital-based cohort of 2923 CD patients diagnosed in 1981-2015. Factors associated with pCD development were analyzed. The incidence and outcomes of pCD were compared between the prebiologic and biologic eras. RESULTS: pCD occurred in 39.2% of the population-based cohort and 56.1% of the hospital-based cohort during the median follow-up of 4.2 and 8.5 years, respectively. The cumulative incidence of pCD was 40.0% at 5 years after CD diagnosis in the population-based cohort and 62.5% at 20 years in the hospital-based cohort. In multivariate analysis, pCD development was positively associated with male sex, younger age and colonic involvement at diagnosis, early diagnosis, and CD diagnosis in the prebiologic era. The cumulative probability of proctectomy at 10, 20, and 30 years after pCD diagnosis was 2.9%, 12.2%, and 16.2%, respectively. The cumulative incidence of pCD occurring after CD diagnosis and the cumulative probability of proctectomy were significantly lower in the biologic era than in the prebiologic era (p < 0.001 and p = 0.03, respectively). CONCLUSIONS: Compared with Western patients with CD, Korean patients show a high incidence of pCD but have a low probability of proctectomy, suggesting the favorable course of pCD.
Assuntos
Povo Asiático , Doença de Crohn/epidemiologia , Vigilância da População , Fístula Retal/epidemiologia , Estudos de Coortes , Doença de Crohn/diagnóstico , Doença de Crohn/cirurgia , Feminino , Seguimentos , Hospitalização/tendências , Humanos , Incidência , Masculino , Vigilância da População/métodos , Fístula Retal/diagnóstico , Fístula Retal/cirurgia , República da Coreia/epidemiologia , Fatores de Risco , Resultado do TratamentoRESUMO
Inflammatory bowel disease (IBD) is a heterogeneous disorder in terms of age at onset, clinical phenotypes, severity, disease course, and response to therapy. This underlines the need for predictive and precision medicine that can optimize diagnosis and disease management, provide more cost-effective strategies, and minimize the risk of adverse events. Ideally, we can leverage molecular profiling to predict the risk to develop IBD and disease progression. Despite substantial successes of genome-wide association studies in the identification of genetic variants affecting IBD susceptibility, molecular profiling of disease onset and progression as well as of treatment responses has lagged behind. Still, thanks to technological advances and good study designs, predicting phenotypes using genomics and transcriptomics in IBD has been rapidly evolving. In this review, we summarize the current status of prediction of disease risk, clinical course, and response to therapy based on clinical case presentations. We also discuss the potential and limitations of the currently used approaches.