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BACKGROUND AND AIMS: Risks of peri- and postoperative complications after bowel surgery in patients with inflammatory bowel disease (IBD) receiving biologics are still discussed controversially. We therefore addressed the safety of different biologics that were applied in our IBD center before surgery. METHODS: Data of IBD patients who underwent bowel resections between 2012 and 2022 at our hospital were analyzed retrospectively. Exposure to biologics was defined by receiving biologics within 12 weeks before resective abdominal surgery. Safety considerations included minor complications, such as infections and wound healing disorders and major complications, e.g., anastomotic insufficiency or abscess formation. RESULTS: A total of 447 IBD patients (334 with Crohn's disease, 113 with ulcerative colitis), 51.9% female, were included and followed for a median follow-up of 45 months [range 0-113]. A total of 73.9% (326/447) were undergoing medical treatment at date of surgery, 61.5% (275/447) were treated with biologics within 3 months and 42.3% (189/447) within 4 weeks before surgery. Most surgeries (97.1%) were planned electively and 67.8% were performed laparoscopically. Major and minor complications occurred in 20.8% (93/447) of patients. Serious complications were rare: Six patients had acute postoperative bleeding, one CD patient developed peritonitis and two CD patients died postoperatively. After adjusting for age, disease duration, disease activity, Montreal classification, and medical treatment at date of surgery, no significant differences were observed regarding complications and exposure to biologics. CONCLUSIONS: This retrospective single center study of 447 IBD patients goes to demonstrate that perioperative use of biologics is not associated with a higher risk of complications.
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Produtos Biológicos , Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Humanos , Feminino , Masculino , Estudos Retrospectivos , Produtos Biológicos/efeitos adversos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/cirurgia , Doença de Crohn/tratamento farmacológico , Doença de Crohn/cirurgia , Fatores BiológicosRESUMO
Background: COVID-19 represents one of the most significant medical problems of our time. Aims: This study is focused on the question whether patients with inflammatory bowel disease (IBD) who receive immunotherapies are more vulnerable to respiratory tract infections and SARS-CoV-2 infections in comparison to medical staff, as a cohort with an increased infection risk, and to the general population in a COVID-19 hotspot. Methods: We analysed data regarding respiratory tract infections that were collected in our IBD registry and compared them with corresponding data from medical employees in our associated Isarklinikum hospital and from the healthy general population in Munich, Germany, over the same time frame in April and June 2020. Patients were tested for SARS-CoV-2 immunoglobulins (Ig). Results: Symptoms of respiratory tract infections occurred equally frequent in IBD patients with immunotherapies as compared to those without. Older age (>49 years), TNF-inhibitor, and ustekinumab treatment showed a significantly protective role in preventing respiratory tract symptomatic COVID-19 infections that occurred in 0.45% of all our 1.091 IBD patients. Of those, 1.8% were positive for SARS-CoV-2 Ig, identically to the general population of Munich with also 1.8% positivity. Whilst more than 3% of all COVID-19 subjects of the general population died during the first wave, none of our IBD patients died or needed referral to the ICU or oxygen treatment. Conclusions: In our study, IBD patients are as susceptible to respiratory tract infections or SARS-CoV-2 as the normal population. There is no evidence of an association between IBD therapies and increased risk of COVID-19. Interestingly, a reduced rate of COVID-19 deaths in IBD patients, the majority on immunomodulator therapy, was observed, compared to the general population. Therefore, no evidence was found to suggest that IBD medication should be withheld, and adherence should be encouraged to prevent flares. In addition to older age (>49 years), TNF inhibitors and ustekinumab show a protective role in preventing respiratory tract infections. In addition, these results add to the growing evidence that supports further investigation of TNF inhibitors as a possible treatment in the early course of severe COVID-19.
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COVID-19 , Doenças Inflamatórias Intestinais , COVID-19/epidemiologia , Humanos , Imunoterapia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/terapia , SARS-CoV-2 , Estações do Ano , Inibidores do Fator de Necrose Tumoral , Ustekinumab/uso terapêuticoRESUMO
INTRODUCTION: Iron deficiency and vitamin D deficiency are common comorbidities in inflammatory bowel disease (IBD). Accumulating evidence indicates that active 1,25-dihydroxyvitamin D (1,25(OH)D) may enhance iron absorption by suppressing hepcidin. We investigated the influence of vitamin D on iron metabolism in patients with IBD and on the expression of genes facilitating intestinal epithelial iron absorption. METHODS: Iron parameters and serum levels of 25-hydroxyvitamin D (25(OH)D), 1,25(OH)D, and hepcidin were measured in 104 adult patients with IBD (67 with Crohn's disease and 37 with ulcerative colitis). Genes involved in iron absorption were tested for induction by 1,25(OH)D in Caco-2 cells, which resemble the small intestinal epithelium. RESULTS: In multiple regression models controlling for age, sex, body mass index, smoking status, disease activity, and C-reactive protein levels, low 25(OH)D levels were associated with iron deficiency in patients with IBD (ß [SE] = -0.064 [0.030], P = 0.029). Vitamin D sufficiency was associated with increased levels of ferritin (ß [SE] = 0.25 [0.11], P = 0.024) and transferrin saturation (ß [SE] = 8.41 [4.07], P = 0.044). Higher 1,25(OH)D:25(OH)D ratios were associated with lower hepcidin levels (ß [SE] = -4.31 [1.67], P = 0.012). Especially in Crohn's disease, increased 1,25(OH)D correlated with higher transferrin saturation (ß [SE] = 0.43 [0.18], P = 0.027). Furthermore, 1,25(OH)D strongly induced the expression of the ferroxidase ceruloplasmin in Caco-2 cells. DISCUSSION: Low vitamin D levels in IBD correlate with iron deficiency. Vitamin D may ameliorate iron deficiency, potentially by downregulating hepcidin and upregulating ceruloplasmin, enhancing intestinal iron absorption.
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Doenças Inflamatórias Intestinais , Deficiências de Ferro , Células CACO-2 , Ceruloplasmina , Hepcidinas , Humanos , Vitamina DRESUMO
Background: Over 10 years ago, the step-up/top-down trial demonstrated favorable outcomes of Crohn's disease (CD) after early initiation of infliximab (IFX) in patients with CD. However, data on long-term effects of this treatment strategy in daily clinical practice are scarce. Methods: This retrospective study investigated effects of early (<24 months after diagnosis) versus late intervention (>24 months) of IFX in CD on endoscopic remission (ER) rates, surgery rates, and course of CD, long term. Results: Overall, 242 CD patients (94 early, 148 late intervention) were started on IFX and followed for 24 months. Sixty-one patients with early and 86 with late intervention underwent endoscopy after start of IFX. After IFX induction, 90.3% of patients with early versus 87.8% with late intervention were in clinical remission (P = .676), compared to 89.1% versus 85.8% after 24 months (P = .554). Almost half of patients with early IFX (45.9%, n = 28/61) achieved ER within 24 months compared to only one forth with late IFX intervention (25.6%, n = 22/86, P = .013). In addition, significantly less patients with early IFX intervention (9.8%, n = 6/61) developed intestinal stenosis during 24 months follow-up compared to late IFX start (29.1%, n = 25/86, P = .007). Logistic regression revealed early IFX intervention as only relevant factor achieving ER with an odds ratio of 2.386 (95% confidence interval [1.1180; 4.825], P = .016). Conclusions: Our data on early IFX therapy in CD support early IFX intervention with more patients achieving ER, and less patients developing stricturing disease behavior. Early IFX intervention could therefore change the course of CD.
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BACKGROUND: NOD2 variants are the strongest genetic predictors for susceptibility to Crohn's disease (CD). However, the clinical value of NOD2 on an individual patient level remains controversial. We aimed to define the predictive power of the major NOD2 mutations regarding complicated CD in a large single center cohort. METHODS: 1076 CD patients were prospectively genotyped for the three common CD-associated NOD2 mutations rs2066844, rs2066845, and rs2066847, followed by detailed genotype-phenotype analyses. RESULTS: Overall, 434 CD patients (40.3%) carried at least one of the three main NOD2 mutations. A significantly higher minor allele frequency (15.6%) of the NOD2 frameshift mutation p.Leu1007fsX1008 (rs2066847) was seen in patients with aggressive disease compared to 8.2% in patients with mild disease (p = 2.6 x 10-5). Moreover, a total of 54 CD patients (5.0%) were homozygous for this NOD2 frameshift mutation. 100% of these patients had ileal disease compared to 82% of NOD2 wild-type carriers (p<0.0001). In homozygous carriers of the NOD2 frameshift mutation, 87% presented with ileal stenosis, 68.5% had fistulas, and 72.2% required CD-related surgery despite immunosuppressive therapy in 87% of these patients. All homozygous carriers of the 1007fs mutation who were active smokers had ileal stenosis and required CD-related surgery. CONCLUSION: Homozygosity for Leu1007fsX1008 is an excellent biomarker for predicting complicated CD on an individual patient level. Active smoking and homozygosity for this mutation is associated with a 100% risk for developing ileal stenosis requiring CD-related surgery. In these patients, smoking cessation and early initiation of immunosuppressive strategies may be beneficial.
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Doença de Crohn/genética , Doença de Crohn/patologia , Doenças do Íleo/cirurgia , Obstrução Intestinal/etiologia , Obstrução Intestinal/cirurgia , Mutação/genética , Proteína Adaptadora de Sinalização NOD2/genética , Fumar/efeitos adversos , Adolescente , Adulto , Estudos de Coortes , Doença de Crohn/complicações , Feminino , Dosagem de Genes , Frequência do Gene/genética , Marcadores Genéticos , Predisposição Genética para Doença , Heterozigoto , Homozigoto , Humanos , Doenças do Íleo/etiologia , Modelos Logísticos , Masculino , Fenótipo , Fatores de Risco , Índice de Gravidade de Doença , Adulto JovemRESUMO
BACKGROUND: Recently, ustekinumab a monoclonal antibody targeting interleukin-12 and -23 and successfully used in Crohn's disease also has been shown to be effective in induction and maintaining remission in patients with moderate to severe ulcerative colitis in a large phase 3 trial. However, no observational data on the use of ustekinumab in ulcerative colitis in daily clinical practice is available. AIM: The purpose of this study was to assess the clinical outcomes achieved with ustekinumab as rescue treatment in therapy-refractory or -intolerant ulcerative colitis in a real-life setting. METHODS: A retrospective data analysis was performed in 19 ulcerative colitis patients who were intolerant or refractory to all of the following drugs: steroids, purine-analogues, tumour necrosis factor antibodies and vedolizumab. To all patients ustekinumab was provided as a rescue treatment (intravenous induction with 6 mg/kg, followed by week subcutaneous injection once every eight weeks of 90 mg). The primary outcome was achievement of clinical remission at one year, defined as score of ≤ 3 points in the Lichtiger score (colitis activity index). Patients were evaluated regularly and a colonoscopy was performed before the start and at the end of the observation. Ethical approval was provided by Ethikkommission Ärztekammer Hamburg (PV 5539). RESULTS: In five patients, therapy was stopped due to refractory disease or side effects. In all remaining 14 patients the median colitis activity index dropped from 8.5 points (range 1-12) at start to 2.0 points at one year (range 0-5.5) and Mayo endoscopy scores fell from a median of two points (range 1-3, mean of 2.3) at start to a median of one point (range 1-3, mean of 1.4) at one year. Including the five drop-outs, clinical remission was achieved in 53% of the 19 patients at one year. CONCLUSIONS: In accordance with the UNIFI (A Study to Evaluate the Safety and Efficacy of Ustekinumab Induction and Maintenance Therapy in Participants With Moderately to Severely Active Ulcerative Colitis) trial our real-life data support ustekinumab as an effective and safe treatment option in therapy refractory moderate to severe ulcerative colitis with a history of biological therapies.
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Produtos Biológicos/farmacologia , Colite Ulcerativa/tratamento farmacológico , Fármacos Gastrointestinais/farmacologia , Imunossupressores/farmacologia , Ustekinumab/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Produtos Biológicos/uso terapêutico , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/imunologia , Colonoscopia , Esquema de Medicação , Resistência a Medicamentos , Feminino , Fármacos Gastrointestinais/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Infusões Intravenosas , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Indução de Remissão/métodos , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do Tratamento , Ustekinumab/efeitos adversosRESUMO
BACKGROUND: Lipocalin-2 (LCN2) is a potent bacteriostatic protein. We aimed to investigate its role as a disease activity marker in patients with inflammatory bowel disease (IBD) and its induction by the Th17 cytokines IL-17A, IL-22, and TNF-α in colonic epithelial cells. Moreover, we analyzed the influence of IBD-associated IL23R alleles on LCN2 serum levels in IBD patients. METHODS: LCN2 serum levels were determined in 131 IBD patients (71 with Crohn's disease [CD], 60 with ulcerative colitis [UC]) and 63 healthy controls. IBD patients were genotyped for 10 IBD-associated IL23R polymorphisms. LCN2 expression after stimulation with IL-17A, IL-22, and TNF-α was measured in human colonic epithelial cell lines. RESULTS: A significant upregulation of serum LCN2 in active IBD (median [IQR], 36.84 [21.17-73.74] ng/mL; P = 0.01) compared with healthy controls (24.22 [17.76-35.25] ng/mL) was confined to active UC (42.21 [28.97-73.74] ng/mL; P = 0.0006). LCN2 proved to be a marker of UC disease activity (area under the curve 0.75, sensitivity 0.83, specificity 0.63; P = 0.0002). IL-17A showed a synergistic effect with IL-22 and TNF-α in inducing colonic epithelial expression of LCN2 and its essential transcription factor IKBZ. In CD, LCN2 concentrations were significantly modulated by IL23R genotype status with homozygous carriers of IBD risk-increasing alleles showing particularly low LCN2 levels. CONCLUSIONS: Serum LCN2 proves to be a biomarker of active UC. Lower LCN2 levels in CD patients carrying IBD risk-increasing IL23R variants may result from a restricted upregulation of LCN2 due to an impaired Th17 immune response.
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Biomarcadores/sangue , Colite Ulcerativa/genética , Doença de Crohn/genética , Lipocalinas/sangue , Proteínas Proto-Oncogênicas/sangue , Receptores de Interleucina/genética , Proteínas de Fase Aguda , Proteínas Adaptadoras de Transdução de Sinal , Adolescente , Adulto , Idoso , Colite Ulcerativa/sangue , Colite Ulcerativa/imunologia , Colo/metabolismo , Doença de Crohn/sangue , Doença de Crohn/imunologia , Células Epiteliais/metabolismo , Feminino , Genótipo , Voluntários Saudáveis , Humanos , Proteínas I-kappa B/metabolismo , Interleucina-17/metabolismo , Interleucinas/metabolismo , Lipocalina-2 , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/metabolismo , Polimorfismo Genético , Receptores de Interleucina/metabolismo , Células Th17/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima , Adulto Jovem , Interleucina 22RESUMO
BACKGROUND: Currently, limited data of the outcome of inflammatory bowel disease (IBD) in patients after solid organ transplantation (SOT) are available. We aimed to analyze effects of SOT on the IBD course in a large IBD patient cohort. METHODS: Clinical data from 1537 IBD patients were analyzed for patients who underwent SOT (n = 31) between July 2002 and May 2014. Sub-analyses included SOT outcome parameters, IBD activity before and after SOT, and efficacy of IBD treatment. RESULTS: 4.74% of patients with ulcerative colitis (UC) and 0.84% of patients with Crohn's disease (CD) underwent SOT (p = 2.69 x 10(-6), UC vs. CD). 77.4% of patients with SOT underwent liver transplantation (LTx) with tacrolimus-based immunosuppressive therapy after SOT. All LTx were due to primary sclerosing cholangitis (PSC) or PSC overlap syndromes. Six patients (19.4%) required renal transplantation and one patient (3.2%) heart transplantation. A survival rate of 83.9% after a median follow-up period of 103 months was observed. Before SOT, 65.0% of patients were in clinical remission and 5 patients received immunosuppressive therapy (16.1%). After SOT, 61.0% of patients were in remission (p = 1.00 vs. before SOT) and 29.0% required IBD-specific immunosuppressive or anti-TNF therapy (p = 0.54 vs. before SOT). 42.9% of patients with worsening of IBD after SOT were at higher risk of needing steroid therapy for increased IBD activity (p = 0.03; relative risk (RR): 10.29; 95% CI 1.26-84.06). Four patients (13.0%) needed anti-TNF therapy after SOT (response rate 75%). CONCLUSIONS: SOT was more common in UC patients due to the higher prevalence of PSC-related liver cirrhosis in UC. Despite mainly tacrolimus-based immunosuppressive regimens, outcome of SOT and IBD was excellent in this cohort. In this SOT cohort, concomitant immunosuppressive therapy due to IBD was well tolerated.
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Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Transplante de Coração/efeitos adversos , Transplante de Rim/efeitos adversos , Transplante de Fígado/efeitos adversos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Idoso , Colite Ulcerativa/patologia , Doença de Crohn/patologia , Feminino , Humanos , Terapia de Imunossupressão , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Tacrolimo/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: A previous study suggested an association of the single nucleotide polymorphism (SNP) rs72796353 (IVS4+10 A>C) in the NOD2 gene with susceptibility to Crohn's disease (CD). However, this finding has not been confirmed. Given that NOD2 variants still represent the most important predictors for CD susceptibility and phenotype, we evaluated the association of rs72796353 with inflammatory bowel disease (IBD) susceptibility and the IBD phenotype. METHODOLOGY: Genomic DNA from 2256 Caucasians, including 1073 CD patients, 464 patients with ulcerative colitis (UC), and 719 healthy controls, was genotyped for the NOD2 SNP rs72796353 and the three main CD-associated NOD2 mutations rs2066844, rs2066845, and rs2066847. Subsequently, IBD association and genotype-phenotype analyses were conducted. RESULTS: In contrast to the strong associations of the NOD2 SNPs rs2066844 (p=3.51 x 10(-3)), rs2066845 (p=1.54 x 10(-2)), and rs2066847 (p=1.61 x 10(-20)) with CD susceptibility, no significant association of rs72796353 with CD or UC susceptibility was found. However, in CD patients without the three main CD-associated NOD2 mutations, rs72796353 was significantly associated with the development of perianal fistulas (p=2.78 x 10(-7), OR 5.27, [95% CI 2.75-10.12] vs. NOD2 wild-type carriers). CONCLUSION/SIGNIFICANCE: Currently, this study represents the largest genotype-phenotype analysis of the impact of the NOD2 variant rs72796353 on the disease phenotype in IBD. Our data demonstrate that in CD patients the IVS4+10 A>C variant is strongly associated with the development of perianal fistulas. This association is particularly pronounced in patients who are not carriers of the three main CD-associated NOD2 mutations, suggesting rs72796353 as additional genetic marker for the CD disease behaviour.
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Doença de Crohn/genética , Predisposição Genética para Doença , Mutação , Proteína Adaptadora de Sinalização NOD2/genética , Polimorfismo de Nucleotídeo Único , Fístula Retal/genética , Adulto , Estudos de Casos e Controles , Doença de Crohn/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fístula Retal/complicaçõesRESUMO
BACKGROUND: Very recently, a sub-analysis of genome-wide association scans revealed that the non-coding single nucleotide polymorphism (SNP) rs12212067 in the FOXO3A gene is associated with a milder course of Crohn's disease (CD) (Cell 2013;155:57-69). The aim of our study was to evaluate the clinical value of the SNP rs12212067 in predicting the severity of CD by correlating CD patient genotype status with the most relevant complications of CD such as stenoses, fistulas, and CD-related surgery. METHODOLOGY/PRINCIPAL FINDINGS: We genotyped 550 CD patients for rs12212067 (FOXO3A) and the three common CD-associated NOD2 mutations rs2066844, rs2066847, and rs2066847 and performed genotype-phenotype analyses. RESULTS: No significant phenotypic differences were found between the wild-type genotype TT of the FOXO3A SNP rs12212067 and the minor genotypes TG and GG independently from NOD2 variants. The allele frequency of the minor G allele was 12.7%. Age at diagnosis, disease duration, body mass index, surgery rate, stenoses, fistula, need for immunosuppressive therapy, and disease course were not significantly different. In contrast, the NOD2 mutant p.Leu1007fsX1008 (rs2066847) was highly associated with penetrating CD (pâ=â0.01), the development of fistulas (pâ=â0.01) and stenoses (pâ=â0.01), and ileal disease localization (pâ=â0.03). Importantly, the NOD2 SNP rs2066847 was a strong separator between an aggressive and a mild course of CD (pâ=â2.99×10(-5)), while the FOXO3A SNP rs12212067 did not separate between mild and aggressive CD behavior in our cohort (pâ=â0.35). 96.2% of the homozygous NOD2 p.Leu1007fsX1008 carriers had an aggressive disease behavior compared to 69.3% of the patients with the NOD2 wild-type genotype (pâ=â0.007). CONCLUSION/SIGNIFICANCE: In clinical practice, the NOD2 variant p.Leu1007fsX1008 (rs2066847), in particular in homozygous form, is a much stronger marker for a severe clinical phenotype than the FOXO3A rs12212067 SNP for a mild disease course on an individual patient level despite its important impact on the inflammatory response of monocytes.
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Doença de Crohn/diagnóstico , Doença de Crohn/genética , Fatores de Transcrição Forkhead/genética , Predisposição Genética para Doença , Íntrons , Mutação , Proteína Adaptadora de Sinalização NOD2/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Criança , Feminino , Proteína Forkhead Box O3 , Estudos de Associação Genética , Genótipo , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Prognóstico , Índice de Gravidade de Doença , Adulto JovemRESUMO
OBJECTIVE: Mucosal healing (MH) is an important treatment goal in patients with inflammatory bowel disease (IBD), but factors predicting MH under medical therapy are largely unknown. In this study, we aimed to characterize predictive factors for MH in anti-TNF-alpha antibody-treated IBD patients. METHODS: We retrospectively analyzed 248 IBD patients (61.3% CD, 38.7% UC) treated with anti-TNF-alpha antibodies (infliximab and/or adalimumab) for MH, defined as macroscopic absence of inflammatory lesions (Mayo endoscopy score 0 or SES-CD score 0) in colonoscopies which were analyzed before and after initiation of an anti-TNF-alpha antibody treatment. RESULTS: In patients treated with only one anti-TNF-alpha antibody ("TNF1 group", nâ=â202), 56 patients (27.7%) achieved complete MH at follow-up colonoscopy (median overall follow-up time: 63 months). In a second cohort (nâ=â46), which comprised patients who were consecutively treated with two anti-TNF-alpha antibodies ("TNF2 group"), 13 patients (28.3%) achieved complete MH (median overall follow-up time: 64.5 months). Compared to patients without MH, CRP values at follow-up colonoscopy were significantly lower in patients with MH (TNF1 group: pâ=â8.35×10-5; TNF2 group: pâ=â0.002). Multivariate analyses confirmed CRP at follow-up colonoscopy as predictor for MH in the TNF1 group (pâ=â0.012). Overall need for surgery was lower in patients with MH (TNF1 group: pâ=â0.01; TNF2 group: pâ=â0.03). CONCLUSIONS: We identified low serum CRP level at follow-up colonoscopy as predictor for MH, while MH was an excellent negative predictor for the need for surgery.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Fármacos Gastrointestinais/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Mucosa Intestinal/patologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/farmacologia , Proteína C-Reativa/análise , Criança , Colonoscopia , Procedimentos Cirúrgicos do Sistema Digestório/estatística & dados numéricos , Quimioterapia Combinada , Feminino , Fármacos Gastrointestinais/administração & dosagem , Fármacos Gastrointestinais/farmacologia , Hospitalização , Humanos , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/patologia , Doenças Inflamatórias Intestinais/cirurgia , Infliximab , Mucosa Intestinal/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo , Adulto JovemRESUMO
PURPOSE: We aimed to analyse malignancy rates and predictors for the development of malignancies in a large German inflammatory bowel disease (IBD) cohort treated with thiopurines and/or anti-tumour necrosis factor (TNF) antibodies. METHODS: De novo malignancies in 666 thiopurine-treated and/or anti-TNF-treated IBD patients were analysed. Patients (n = 262) were treated with thiopurines alone and never exposed to anti-TNF antibodies (TP group). In addition, patients (n = 404) were exposed to anti-TNF antibodies (TNF+ group) with no (7.4%), discontinued (80.4%) or continued (12.1%) thiopurine therapy. RESULTS: In the TP group, 20 malignancies were observed in 18 patients compared with 8 malignancies in 7 patients in the TNF+ group (hazard ratio 4.15; 95% CI 1.82-9.44; p = 0.0007; univariate Cox regression). Moreover, 18.2% of all patients in the TP group ≥50 years of age developed a malignancy, compared with 3.8% of all patients <50 years of age (p = 0.0008). In the TNF+ group, 6.5% of all patients ≥50 years of age developed malignancies compared with 0.3% of all patients <50 years of age (p = 0.0007). In both groups combined, thiopurine treatment duration ≥4 years was associated with the risk for skin cancer (p = 0.0024) and lymphoma (p = 0.0005). CONCLUSIONS: Our data demonstrate an increased risk for the development of malignancies in IBD patients treated with thiopurines in comparison with patients treated with anti-TNF antibodies with or without thiopurines.
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Imunossupressores/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Neoplasias/epidemiologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/uso terapêutico , Azatioprina/administração & dosagem , Azatioprina/efeitos adversos , Azatioprina/uso terapêutico , Estudos de Coortes , Quimioterapia Combinada , Feminino , Alemanha/epidemiologia , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Neoplasias/etiologia , Neoplasias/patologia , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND AND AIMS: We analyzed iron deficiency and the therapeutic response following intravenous ferric carboxymaltose in a large single-center inflammatory bowel disease (IBD) cohort. METHODS: 250 IBD patients were retrospectively analyzed for iron deficiency and iron deficiency anemia. A subgroup was analyzed regarding efficacy and side effects of iron supplementation with ferric carboxymaltose. RESULTS: In the cohort (n = 250), 54.4% of the patients had serum iron levels ≤60 µg/dl, 81.2% had ferritin ≤100 ng/ml, and 25.6% had hemoglobin (Hb) of ≤12 g/dl (females) or ≤13 g/dl (males). In the treatment subcohort (n = 80), 83.1% of the patients had iron ≤60 µg/dl, 90.4% had ferritin ≤100 ng/ml, and 66.7% had Hb ≤12/13 g/dl before ferric carboxymaltose treatment. After a median dose of 500 mg ferric carboxymaltose, 74.7% of the patients reached iron >60 µg/dl, 61.6% had ferritin >100 ng/ml, and 90.7% reached Hb >12/13 g/dl at follow-up (p < 0.0001 for all parameters vs. pretreatment values). The most frequent adverse event was a transient increase of liver enzymes with male gender as risk factor (p = 0.008, OR 8.62, 95% CI 1.74-41.66). CONCLUSIONS: Iron deficiency and anemia are frequent in IBD patients. Treatment with ferric carboxymaltose is efficious, safe and well tolerated in iron-deficient IBD patients.
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Anemia Ferropriva/tratamento farmacológico , Compostos Férricos/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Maltose/análogos & derivados , Adolescente , Adulto , Idoso , Anemia Ferropriva/sangue , Estudos de Coortes , Feminino , Compostos Férricos/administração & dosagem , Compostos Férricos/efeitos adversos , Compostos Férricos/sangue , Ferritinas/sangue , Hemoglobinas , Humanos , Doenças Inflamatórias Intestinais/sangue , Infusões Intravenosas , Ferro/sangue , Masculino , Maltose/administração & dosagem , Maltose/efeitos adversos , Maltose/sangue , Maltose/uso terapêutico , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Infliximab (IFX) and adalimumab (ADA) are attractive treatment options in patients with inflammatory bowel disease (IBD) also during pregnancy but there is still limited data on the benefit/risk profile of IFX and ADA during pregnancy. METHODS: This observational study assessed pregnancy outcomes in 212 women with IBD under antitumor necrosis factor alpha (TNF) treatment at our IBD unit. Pregnancy outcomes in 42 pregnancies with direct exposure to anti-TNF treatment (35 IFX, 7 ADA) were compared with that in 23 pregnancies prior to IBD diagnosis, 78 pregnancies before start of IFX, 53 pregnancies with indirect exposure to IFX, and 56 matched pregnancies in healthy women. RESULTS: Thirty-two of the 42 pregnancies ended in live births with a median gestational age of 38 weeks (interquartile range [IQR] 37-39). There were seven premature deliveries, six children had low birth weight, and there was one stillbirth. One boy weighed 1640 g delivered at week 33, died at age of 13 days because of necrotizing enterocolitis. A total of eight abortions (one patient wish) occurred in seven women. Trisomy 18 was diagnosed in one fetus of a mother with CD at age 37 under ADA treatment (40 mg weekly) and pregnancy was terminated. Pregnancy outcomes after direct exposure to anti-TNF treatment were not different from those in pregnancies before anti-TNF treatment or with indirect exposure to anti-TNF treatment but outcomes were worse than in pregnancies before IBD diagnosis. CONCLUSIONS: Direct exposure to anti-TNF treatment during pregnancy was not related to a higher incidence of adverse pregnancy outcomes than IBD overall.
Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Fator de Necrose Tumoral alfa/imunologia , Adalimumab , Adolescente , Adulto , Estudos de Casos e Controles , Estudos de Coortes , Colite Ulcerativa/imunologia , Doença de Crohn/imunologia , Feminino , Seguimentos , Humanos , Infliximab , Gravidez , Resultado da Gravidez , Estudos Prospectivos , Taxa de Sobrevida , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto JovemRESUMO
BACKGROUND & AIMS: Infliximab is an antibody against tumor necrosis factor-α that is used to treat patients with moderate to severe Crohn's disease (CD). C-reactive protein (CRP) is a marker used to identify and follow individuals with CD. We analyzed changes in levels of CRP in a large cohort of patients with CD undergoing treatment with infliximab. METHODS: Serial levels of CRP were analyzed in 718 CD patients. Blood was collected before each infusion; a total of 8845 CRP levels were available for analysis. The correlations between CRP levels and need for dose adjustment, outcomes, and mucosal healing (based on endoscopic analysis of 253 patients) were evaluated. Therapy adjustment was considered successful if therapy continued without need for change. Subgroup analysis was performed by using data from 268 patients who received 8 weeks of maintenance therapy. RESULTS: More patients with high baseline levels of CRP responded to infliximab than patients with normal levels (90.8% vs 82.6%; P = .014). Early normalization of CRP levels correlated with sustained long-term response (P < .001). CRP levels remained significantly higher among patients who lost their response to infliximab, compared with those with a sustained response (P = .001). At time of loss of response, CRP levels were significantly increased (median, 11.2 mg/L) and did not return to baseline levels (median, 18.2 mg/L; P = .039). CRP correlated with mucosal healing (P = .033). CONCLUSIONS: CRP is a good marker of disease activity in patients treated with infliximab. Increased levels of CRP indicate mucosal inflammation and a likelihood of clinical relapse.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Biomarcadores/sangue , Proteína C-Reativa/análise , Doença de Crohn/diagnóstico , Doença de Crohn/tratamento farmacológico , Monitoramento de Medicamentos/métodos , Fatores Imunológicos/administração & dosagem , Adulto , Estudos de Coortes , Doença de Crohn/patologia , Feminino , Humanos , Infliximab , Masculino , Mucosa/patologia , Resultado do TratamentoRESUMO
BACKGROUND: Anti-tumor necrosis factor (TNF) therapy used in patients with inflammatory bowel disease (IBD) has been associated with induction of autoantibodies including antinuclear antibodies (ANA), double-strand (ds) DNA antibodies, and the occurrence of lupus-like syndrome (LLS). However, the clinical relevance of autoantibody formation and predictive factors are unclear. METHODS: 180 IBD patients treated with anti-TNF antibodies (infliximab or adalimumab, or infliximab and adalimumab consecutively) were analyzed regarding ANA and dsDNA antibody values and the development of LLS, including factors predicting the development of LLS. RESULTS: In all, 44.4% of anti-TNF-treated patients had ANA titers ≥1:240, while 15.6% had dsDNA serum levels ≥9 U/mL. However, only a minority of these patients experienced clinical symptoms of LLS; 8.9% presented with mild lupus-like symptoms with no need for intervention; 1.1% had severe symptoms consistent with LLS requiring immediate stop of anti-TNF therapy. Multivariate logistic regression analyses identified age as an independent risk factor for developing ANA ≥1:240 (P < 0.001) and LLS (P = 0.002), while concomitant immunosuppressive therapy was protective against autoantibody formation (ANA: P = 0.05) and LLS development (P = 0.04). There was a significant association between dsDNA antibody values ≥9 U/mL and LLS (P = 0.02) but not between ANA titers and LLS. CONCLUSIONS: dsDNA antibody levels ≥9 U/mL, but not ANA titers ≥1:240, are associated with clinical symptoms of LLS. IBD patients of higher age treated with anti-TNF-α antibodies are at increased risk for development of ANA and LLS, while concomitant immunosuppressive therapy may have a protective effect.
Assuntos
Anticorpos Antinucleares/imunologia , Anticorpos Monoclonais/efeitos adversos , Autoanticorpos/sangue , DNA/imunologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Lúpus Eritematoso Sistêmico/imunologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab , Adolescente , Adulto , Idoso , Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Estudos de Coortes , Feminino , Humanos , Doenças Inflamatórias Intestinais/imunologia , Infliximab , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto JovemRESUMO
BACKGROUND AND AIMS: We analyzed the prevalence of concomitant intestinal stenosis in patients with fistulizing Crohn's disease (CD), including the NOD2/CARD15 and IL23R genotype status. METHODS: Medical records of n = 1,110 patients with inflammatory bowel diseases were screened for patients with fistulizing and stricturing CD. Study inclusion required diagnosis of stenosis made within 6 months of diagnosing fistulas. CD-associated NOD2 and IL23R variants were genotyped. Similarly, we prospectively investigated 42 patients presenting with fistulizing CD. RESULTS: In the retrospective study (n = 333 CD patients), fistulas were found in 145 (43.5%) patients and stenoses in 223 (67.0%) patients. Concomitant stenosis was diagnosed in 125 patients with fistulas resulting in a positive predictive value (PPV) of 86.2% for fistulas predicting intestinal stenosis (p = 5.53 x 10(-11); OR 5.74, 95% CI 3.22-10.50). In logistic regression analysis, presence of fistulas (OR 4.51; 95% CI 2.54-8.01, p = 2.68 x 10(-7)) and disease duration (OR 1.09; 95% CI 1.05-1.13; p = 3.19 x 10(-6)) were strongly associated with intestinal stenosis. NOD2 genotype information, but not IL23R status, increased the PPV for the correct diagnosis of stenosis (PPV = 89.9%). All homozygous carriers (100%) of NOD2 variants with fistulizing CD were diagnosed with stenosis; 1007fs homozygotes were found more often among patients with fistulas and stenoses than in patients without stenoses and fistulas (p = 0.00037). Similar results were found in the prospective analysis, in which 83.3% of the patients with fistulizing CD had concomitant stenosis. CONCLUSION: Fistulizing CD is strongly associated with concomitant intestinal stenosis, particularly in homozygous carriers of NOD2 mutations.
Assuntos
Doença de Crohn/fisiopatologia , Fístula Intestinal/etiologia , Proteína Adaptadora de Sinalização NOD2/genética , Receptores de Interleucina/genética , Constrição Patológica/etiologia , Constrição Patológica/genética , Doença de Crohn/genética , Genótipo , Humanos , Fístula Intestinal/genética , Obstrução Intestinal/etiologia , Obstrução Intestinal/genética , Modelos Logísticos , Mutação , Valor Preditivo dos Testes , Estudos Prospectivos , Estudos RetrospectivosRESUMO
OBJECTIVES: We analyzed the efficacy and safety of the antitumor necrosis factor-alpha antibody infliximab (IFX) for induction therapy in patients with moderate-to-severe ulcerative colitis (UC) in a large single-center cohort. METHODS: A total of 90 UC patients treated with IFX for 14 weeks were analyzed retrospectively. Colitis activity index (CAI) and markers of inflammation were measured during IFX induction therapy. Genotyping for UC-associated variants in the IL23R gene and in the IL2/IL21 region was performed. RESULTS: At week 2 (after the first IFX infusion), 64.1% of IFX-treated patients had clinical response to IFX and 52.6% were in remission. At week 14 (after three infusions), 61.0% showed clinical response and 52.5% were in remission. The mean CAI decreased significantly from 10.4 points at week 0 to 5.1 at week 2 (P<0.001), to 4.4 at week 6 (P<0.001), and to 5.0 at week 14 (P<0.001). Similarly, IFX therapy significantly decreased C-reactive protein levels and leukocyte counts (P=0.01 and P=0.001 at week 2 and week 0, respectively). Multivariate regression analysis identified high CAI before IFX therapy (P=0.01) and negative antineutrophil cytoplasmatic autoantibody (ANCA) status (P=0.01) as independent positive predictors for response to IFX. Homozygous carriers of inflammatory bowel disease (IBD) risk-increasing IL23R variants were more likely to respond to IFX than were homozygous carriers of IBD risk-decreasing IL23R variants (74.1 vs. 34.6%; P=0.001). No serious adverse IFX-related events requiring hospitalization were recorded. CONCLUSIONS: Our findings suggest that IFX therapy is safe and effective in patients with moderate-to-severe UC. A high CAI before IFX therapy, ANCA seronegativity, and the IL23R genotype were predictors of early response to IFX.
Assuntos
Anticorpos Anticitoplasma de Neutrófilos/análise , Anticorpos Monoclonais/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Receptores de Interleucina/genética , Adulto , Biomarcadores/análise , Colectomia/estatística & dados numéricos , Colite Ulcerativa/genética , Colite Ulcerativa/imunologia , Colite Ulcerativa/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Variação Genética , Genótipo , Humanos , Infliximab , Modelos Logísticos , Masculino , Indução de Remissão , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Infliximab (IFX) treatment induces mucosal healing (MH) in patients with Crohn's disease (CD) but the impact of MH on the long-term outcome of IFX treatment in CD is still debated. METHODS: We studied MH during long-term treatment with IFX in 214 CD patients. A total of 183 patients (85.5%) responded to induction therapy and 31 patients (14.5%) were primary nonresponders. They underwent lower gastrointestinal (GI) endoscopy within a median of 0.7 months (interquartile range [IQR] 0.1-6.8) prior to first IFX and after a median of 6.7 months (IQR 1.4-24.6) after start of IFX and were further analyzed. The relationship between the outcome of IFX treatment long-term and MH was studied. RESULTS: MH was observed in 67.8% of the 183 initial responders (n = 124), with 83 patients having complete healing (45.4%) and 41 having partial healing (22.4%). Scheduled IFX treatment from the start resulted in MH more frequently (76.9% MH rate) than episodic treatment (61.0% MH rate; P = 0.0222, odds ratio [OR] 2.14, 95% confidence interval [CI] 1.11-4.12). Concomitant treatment with corticosteroids (CS) had a negative impact on MH (37.9% in patients with CS versus 63.2% in patients without CS; P = 0.021, OR 0.36, 95% CI 0.16-0.80). MH was associated with a significantly lower need for major abdominal surgery (MAS) during long-term follow-up (14.1% of patients with MH needed MAS versus 38.4% of patients without MH; P < 0.0001). CONCLUSIONS: MH induced by long-term maintenance IFX treatment is associated with an improved long-term outcome of the disease especially with a lower need for major abdominal surgeries.