RESUMO
Inflammatory bowel disease (IBD) is characterized by chronic inflammation in the gut. There is growing evidence in Crohn's disease (CD) of the existence of a preclinical period characterized by immunological changes preceding symptom onset that starts years before diagnosis. Gaining insight into this preclinical phase will allow disease prediction and prevention. Analysis of preclinical serum samples, up to 6 years before IBD diagnosis (from the PREDICTS cohort), revealed the identification of a unique glycosylation signature on circulating antibodies (IgGs) characterized by lower galactosylation levels of the IgG fragment crystallizable (Fc) domain that remained stable until disease diagnosis. This specific IgG2 Fc glycan trait correlated with increased levels of antimicrobial antibodies, specifically anti-Saccharomyces cerevisiae (ASCA), pinpointing a glycome-ASCA hub detected in serum that predates by years the development of CD. Mechanistically, we demonstrated that this agalactosylated glycoform of ASCA IgG, detected in the preclinical phase, elicits a proinflammatory immune pathway through the activation and reprogramming of innate immune cells, such as dendritic cells and natural killer cells, via an FcγR-dependent mechanism, triggering NF-κB and CARD9 signaling and leading to inflammasome activation. This proinflammatory role of ASCA was demonstrated to be dependent on mannose glycan recognition and galactosylation levels in the IgG Fc domain. The pathogenic properties of (anti-mannose) ASCA IgG were validated in vivo. Adoptive transfer of antibodies to mannan (ASCA) to recipient wild-type mice resulted in increased susceptibility to intestinal inflammation that was recovered in recipient FcγR-deficient mice. Here we identify a glycosylation signature in circulating IgGs that precedes CD onset and pinpoint a specific glycome-ASCA pathway as a central player in the initiation of inflammation many years before CD diagnosis. This pathogenic glyco-hub may constitute a promising new serum biomarker for CD prediction and a potential target for disease prevention.
Assuntos
Doença de Crohn , Imunoglobulina G , Manose , Polissacarídeos , Doença de Crohn/imunologia , Doença de Crohn/sangue , Imunoglobulina G/imunologia , Imunoglobulina G/sangue , Animais , Humanos , Glicosilação , Manose/metabolismo , Manose/imunologia , Camundongos , Polissacarídeos/imunologia , Polissacarídeos/metabolismo , Feminino , Saccharomyces cerevisiae/imunologia , Masculino , Adulto , Anticorpos Antifúngicos/sangue , Anticorpos Antifúngicos/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Biomarcadores/sangue , Pessoa de Meia-Idade , Fragmentos Fc das Imunoglobulinas/imunologia , GlicoproteínasRESUMO
BACKGROUND AND AIMS: No consensus exists on optimal strategy to prevent postoperative recurrence [POR] after ileocaecal resection [ICR] for Crohn's disease [CD]. We compared early medical prophylaxis versus expectant management with treatment driven by findings at elective endoscopy 6-12 months after ICR. METHODS: A retrospective, multicentric, observational study was performed. CD patients undergoing first ICR were assigned to Cohort 1 if a biologic or immunomodulator was [re]started prophylactically after ICR, or to Cohort 2 if no postoperative prophylaxis was given and treatment was started as reaction to elective endoscopic findings. Primary endpoint was rate of endoscopic POR [Rutgeerts >i1]. Secondary endpoints were severe endoscopic POR [Rutgeerts i3/i4], clinical POR, surgical POR, and treatment burden during follow-up. RESULTS: Of 346 included patients, 47.4% received prophylactic postoperative treatment [proactive/Cohort 1] and 52.6% did not [reactive/Cohort 2]. Endoscopic POR [Rutgeertsâ >i1] rate was significantly higher in Cohort 2 [41.5% vs 53.8%, OR 1.81, pâ =â 0.039] at endoscopy 6-12 months after surgery. No significant difference in severe endoscopic POR was found [OR 1.29, pâ =â 0.517]. Cohort 2 had significantly higher clinical POR rates [17.7% vs 35.7%, OR 3.05, pâ =â 0.002] and numerically higher surgical recurrence rates [6.7% vs 13.2%, OR 2.59, pâ =â 0.051]. Cox proportional hazards regression analysis showed no significant difference in time to surgical POR of proactive versus expectant/reactive approach [HR 2.50, pâ =â 0.057]. Quasi-Poisson regression revealed a significantly lower treatment burden for immunomodulator use in Cohort 2 [mean ratio 0.53, pâ =â 0.002], but no difference in burden of biologics or combination treatment. CONCLUSIONS: The PORCSE study showed lower rates of endoscopic POR with early postoperative medical treatment compared with expectant management after first ileocaecal resection for Crohn's disease.
Assuntos
Doença de Crohn , Prevenção Secundária , Humanos , Doença de Crohn/cirurgia , Doença de Crohn/prevenção & controle , Feminino , Estudos Retrospectivos , Masculino , Adulto , Prevenção Secundária/métodos , Prevenção Secundária/estatística & dados numéricos , Íleo/cirurgia , Recidiva , Pessoa de Meia-Idade , Fatores Imunológicos/uso terapêutico , Produtos Biológicos/uso terapêutico , Europa (Continente) , Ceco/cirurgia , Colonoscopia/estatística & dados numéricos , Colonoscopia/métodosRESUMO
Background: Colorectal cancer (CRC) is a leading cause of cancer. The detection of pre-malignant lesions by colonoscopy is associated with reduced CRC incidence and mortality. Narrow band imaging has shown promising but conflicting results for the detection of serrated lesions. Methods: We performed a randomized clinical trial to compare the mean detection of serrated lesions and hyperplastic polyps ≥10 mm with NBI or high-definition white light (HD-WL) withdrawal. We also compared all sessile serrated lesions (SSLs), adenoma, and polyp prevalence and rates. Results: Overall, 782 patients were randomized (WL group 392 patients; NBI group 390 patients). The average number of serrated lesions and hyperplastic polyps ≥10 mm detected per colonoscopy (primary endpoint) was similar between the HD-WL and NBI group (0.118 vs. 0.156, p = 0.44). Likewise, the adenoma detection rate (55.2% vs. 53.2%, p = 0.58) and SSL detection rate (6.8% vs. 7.5%, p = 0.502) were not different between the two study groups. Withdrawal time was higher in the NBI group (10.88 vs. 9.47 min, p = 0.004), with a statistically nonsignificant higher total procedure time (20.97 vs. 19.30 min, p = 0.052). Conclusions: The routine utilization of narrow band imaging does not improve the detection of serrated class lesions or any pre-malignant lesion and increases the withdrawal time.
Introdução: O cancro do cólon e reto é a neoplasia mais frequente considerando os dois géneros. . A deteção de lesões pré-malignas por colonoscopia está associada a uma redução da incidência e da mortalidade. Estudos sobre a utilização da luz de banda estreita (NBI) na deteção de lesões serreadas tiveram resultados promissores, mas heterogéneos. Métodos: Realizámos um ensaio clínico randomizado para comparar o número médio de lesões serreadas e lesões hiperplásicas ≥10 mm com NBI ou luz branca de alta-definição (HD-WL). Como resultados secundários comparámos a prevalência e as taxas de deteção de lesões serreadas sésseis, adenomas e todas as lesões. Resultados: Foram randomizados 782 doentes (392 no grupo HD-WL e 390 no grupo NBI). O número médio de lesões serreadas e hiperplásicas ≥10 mm não apresentou diferença estatisticamente significativa entre dois grupos (0.118 vs. 0.156, p = 0.44). A taxa de deteção de adenomas (55.2% vs. 53.2%, p = 0.58) e a taxa de deteção de lesões serreadas sésseis (6.8% vs. 7.5%, p = 0.502) também não foram diferentes. O tempo de retirada foi maior no grupo NBI (10.88 vs. 9.47 min, p = 0.004) e o tempo total de procedimento teve um ligeiro aumento não atingindo significância estatística (20.97 vs. 19.30 min, p = 0.052). Conclusão: A utilização da luz NBI por rotina não aumenta a deteção de lesões serreadas nem de qualquer lesão pré-maligna e aumenta o tempo de retirada na colonoscopia.
RESUMO
BACKGROUND: Early biologic therapy within the first 18-24 months after diagnosis is associated with improved clinical outcomes in Crohn's disease [CD]. However, the definition of the best time to initiate biologic therapy remains unclear. We aimed to assess if there is an optimal timing for early biologic therapy initiation. METHODS: This was a multicentre retrospective cohort study including newly diagnosed CD patients who started anti-tumour necrosis factor [TNF] therapy within 24 months from diagnosis. The timing of initiation of biologic therapy was categorised asâ ≤6, 7-12, 13-18, and 19-24 months. The primary outcome was CD-related complications defined as a composite of progression of Montreal disease behaviour, CD-related hospitalisations, or CD-related intestinal surgeries. Secondary outcomes included clinical, laboratory, endoscopic, and transmural remission. RESULTS: We included 141 patients where 54%, 26%, 11%, and 9% started biologic therapy atâ ≤6, 7-12, 13-18, and 19-24 months after diagnosis, respectively. A total of 34 patients [24%] reached the primary outcome: 8% had progression of disease behaviour, 15% were hospitalised, and 9% required surgery. There was no difference in the time to a CD-related complication according to the time of initiation of biologic therapy within the first 24 months. Clinical, endoscopic, and transmural remission was achieved in 85%, 50%, and 29%, respectively, but no differences were found according to the time of initiation of biologic therapy. CONCLUSION: Starting anti-TNF therapy within the first 24 months after diagnosis was associated with a low rate of CD-related complications and high rates of clinical and endoscopic remission, although we found no differences with earlier initiation within this window of opportunity.
Assuntos
Doença de Crohn , Humanos , Doença de Crohn/tratamento farmacológico , Doença de Crohn/diagnóstico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Estudos Retrospectivos , Imunoterapia , Prevenção SecundáriaRESUMO
A 46-year-old woman without previous history of hepatobiliary disease was admitted to the intensive care unit due to SARS-CoV-2 infection. Admission blood tests revealed impending hyperinflammation in the context of systemic inflammatory response syndrome. She required 12 days of mechanical ventilation and vasopressor support. After admission, liver function tests became deranged in a cholestatic pattern and continued to worsen despite overall clinical improvement. Magnetic resonance cholangiopancreatography revealed liver abscesses, intrahepatic bile duct dilation with multiple strictures and some linear repletion defects at the bifurcation of the common hepatic duct. During endoscopic retrograde cholangiopancreatography, biliary casts were retrieved confirming the diagnosis of secondary sclerosing cholangitis in the critically ill patient triggered by a severe SARS-CoV-2 infection. Other causes of cholestasis and secondary sclerosing cholangitis were properly excluded. We present an illustrative case and discuss the current literature, focusing on SARS-CoV-2 infection contribution to the development of this potentially underdiagnosed and severe condition.
Uma mulher de 46 anos sem antecedentes de patologia hepatobiliar foi admitida na unidade de cuidados intensivos no contexto de infeção por SARS-CoV-2. Apresentava alterações analíticas interpretadas no contexto de síndrome de resposta inflamatória sistémica. Houve necessidade de suporte vasopressor e ventilação mecânica invasiva durante 12 dias. Após a admissão, verificou-se uma alteração das provas hepáticas com padrão colestático, com agravamento contínuo apesar da melhoria do quadro infecioso. A colangiografia por ressonância magnética revelou a presença de abcessos hepáticos, dilatação das vias biliares intrahepáticas com múltiplas estenoses e com alguns defeitos de repleção lineares na bifurcação do ducto hepático comum. Na colangiopancreatografia endoscópica retrógrada foram removidos cilindros bilares da via biliar, confirmando o diagnóstico de colangite esclerosante secundária associada aos cuidados intensivos, no contexto de uma infeção grave por SARS-CoV-2. Foram excluídas outras causas de colestase e colangite esclerosante secundária de forma exaustiva. Apresentamos um caso clínico ilustrativo com respetiva iconografia e revisão da literatura, com especial enfoque na contribuição da infeção por SARS-CoV-2 no desenvolvimento desta entidade clínica, potencialmente grave e subdiagnosticada.
RESUMO
INTRODUCTION: Anti-SARS-CoV-2 vaccine clinical trials did not include patients with immune-mediated conditions such as inflammatory bowel disease [IBD]. We aimed to describe the implementation of anti-SARS-CoV-2 vaccination among IBD patients, patients' concerns, and the side effect profile of the anti-SARS-CoV-2 vaccines, using real-world data. METHODS: An anonymous web-based self-completed survey was distributed in 36 European countries between June and July 2021. The results of the patient characteristics, concerns, vaccination status, and side effect profile were analysed. RESULTS: In all 3272 IBD patients completed the survey, 79.6% had received at least one dose of anti-SARS-CoV-2 vaccine, and 71.7% had completed the vaccination process. Patients over 60 years old had a significantly higher rate of vaccination [pâ <â 0.001]. Patients' main concerns before vaccination were the possibility of having worse vaccine-related adverse events due to their IBD [24.6%], an IBD flare after vaccination [21.1%], and reduced vaccine efficacy due to IBD or associated immunosuppression [17.6%]. After the first dose of the vaccine, 72.4% had local symptoms and 51.4% had systemic symptoms [five patients had non-specified thrombosis]. Adverse events were less frequent after the second dose of the vaccine and in older patients. Only a minority of the patients were hospitalised [0.3%], needed a consultation [3.6%], or had to change IBD therapy [13.4%] after anti-SARS-CoV-2 vaccination. CONCLUSIONS: Although IBD patients raised concerns about the safety and efficacy of anti-SARS-CoV-2 vaccines, the implementation of vaccination in those responding to our survey was high and the adverse events were comparable to the general population, with minimal impact on their IBD.
Assuntos
Vacinas contra COVID-19 , COVID-19 , Doenças Inflamatórias Intestinais , Idoso , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Europa (Continente) , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Internet , Pessoa de Meia-Idade , Inquéritos e Questionários , Vacinação/efeitos adversosRESUMO
BACKGROUND: Endoscopic-post-operative-recurrence [ePOR] in Crohn's disease [CD] after ileocecal resection [ICR] is a major concern. We aimed to evaluate the effectiveness of early prophylaxis with biologics and to compare anti-tumour necrosis factor [anti-TNF] therapy to vedolizumab [VDZ] and ustekinumab [UST] in a real-world setting. METHODS: A retrospective multicentre study of CD-adults after curative ICR on early prophylaxis was undertaken. ePOR was defined as a Rutgeerts score [RS] ≥ i2 or colonic-segmental-SES-CD ≥ 6. Multivariable logistic regression was used to evaluate risk factors, and inverse probability treatment weighting [IPTW] was applied to compare the effectiveness between agents. RESULTS: The study included 297 patients (53.9% males, age at diagnosis 24 years [19-32], age at ICR 34 years [26-43], 18.5% smokers, 27.6% biologic-naïve, 65.7% anti-TNF experienced, 28.6% two or more biologics and 17.2% previous surgery). Overall, 224, 39 and 34 patients received anti-TNF, VDZ or UST, respectively. Patients treated with VDZ and UST were more biologic experienced with higher rates of previous surgery. ePOR rates within 1 year were 41.8%. ePOR rates by treatment groups were: anti-TNF 40.2%, VDZ 33% and UST 61.8%. Risk factors for ePOR at 1 year were: past-infliximab (adjusted odds ratio [adj.OR] = 1.73 [95% confidence interval, CI: 1.01-2.97]), past-adalimumab [adj.OR = 2.32 [95% CI: 1.35-4.01] and surgical aspects. After IPTW, the risk of ePOR within 1 year of VDZ vs anti-TNF or UST vs anti-TNF was comparable (OR = 0.55 [95% CI: 0.25-1.19], OR = 1.86 [95% CI: 0.79-4.38]), respectively. CONCLUSION: Prevention of ePOR within 1 year after surgery was successful in ~60% of patients. Patients treated with VDZ or UST consisted of a more refractory group. After controlling for confounders, no differences in ePOR risk were seen between anti-TNF prophylaxis and other groups.
Assuntos
Produtos Biológicos , Doença de Crohn , Adulto , Feminino , Humanos , Masculino , Produtos Biológicos/uso terapêutico , Doença de Crohn/tratamento farmacológico , Doença de Crohn/prevenção & controle , Doença de Crohn/cirurgia , Estudos Retrospectivos , Resultado do Tratamento , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Ustekinumab/uso terapêutico , Adulto JovemRESUMO
Despite the recent developments in the diagnosis and management of inflammatory bowel diseases (IBD), patients still suffer from disabling bowel symptoms and significant disease complications and many questions remain to improve their care. IBD is a chronic disease, whose management could be divided into the five different stages of chronic diseases, ranging from the pre-treatment evaluation phase to the induction therapy, maintenance therapy, monitor and re-establishment of control and the cessation of the disease. Reconciling these phases with the current unmet needs in IBD could help tailor priorities for research. In this review, some of the unanswered questions in the management of both Crohn's Disease and Ulcerative Colitis will be addressed, by following this paradigm of chronic diseases' management.
RESUMO
INTRODUCTION: Patients with inflammatory bowel disease (IBD) do not seem to be at increased risk of infection by SARS-CoV-2, but there is a concern whether immunosuppressive therapy may be associated with more severe disease. Several clinical practice recommendations have been published to help guide IBD care during the COVID-19 pandemic. Nonetheless, few studies have addressed patients' perspectives and fears. We aimed to evaluate Portuguese IBD patients' perspectives on the clinical management of their disease during the SARS-CoV-2 pandemic as well as the impact on their professional life. METHODS: An anonymous electronic survey was created using REDCap and was distributed by the Portuguese Association of Inflammatory Bowel Disease (APDI) between May and August 2020. Patients' perspectives on immunosuppressive therapy, disease management, interaction with gastroenterology departments, and the impact of the pandemic in their professional life were assessed. Patients' proposals to improve medical care were also evaluated. Descriptive analysis and logistic regression were performed. RESULTS: A total of 137 participants answered the survey (79.6% females, mean age 41.7 ± 12.1 years). Although having IBD and receiving treatment with immunosuppressors (thiopurines, steroids, or biologics) were considered promotors of anxiety, most patients (85.4%) agreed that disease remission was a priority and only a minority of patients interrupted their treatment during the pandemic. In multivariate analysis, active disease, biologic treatment, and use of corticosteroids in the last 3 months were perceived by the patients as high-risk features for increased risk of SARS-Cov-2 infection and more severe disease. Fifty-nine patients (44%) believed that their follow-up was influenced by the pandemic and only 58.8% felt that they had the opportunity to discuss their therapeutic options with their doctor. Sixty-three patients (46.0%) were working from home during the pandemic, although this decision was related to IBD and immunosuppressive therapy in only 36.5 and 39.7% of the cases, respectively. Areas where care could have been improved during the pandemic were identified by patients, namely enhancement of the communication with IBD professionals, conciliation of telemedicine with face-to-face appointments, and facilitation of the interaction between patients and employers. CONCLUSION: Most patients agreed that maintaining IBD remission is crucial, and only a minority of the patients stopped their treatment as per their own initiative. IBD status only had a small influence on patients' professional activity during the COVID-19 outbreak, with most changes being related to the pandemic itself.