Clinical Update on the Prevention and Management of Postoperative Crohn's Disease Recurrence.

PURPOSE OF REVIEW: Despite advances in therapeutics, a significant portion of patients with Crohn's disease still require surgical management. In this article, we present updates to the natural history, prognostication and postoperative monitoring, and novel therapeutics in the prevention and treatment of postoperative Crohn's disease recurrence. RECENT FINDINGS: Clinical risk factors have been associated with higher rates of postoperative recurrence (POR), and in recent studies demonstrate an increased cumulative risk with presence of additional risk factors. Additional novel clinical, histologic, and "-omic" risk factors for recurrence have recently been elucidated, including the role of the mesentery on recurrence and perioperative intraabdominal septic complications. High-risk patients benefit most from medical prophylaxis, including anti-TNF with or without immunomodulator therapy to prevent recurrence. New biologics such as vedolizumab and ustekinumab have emerging evidence in the use of prophylaxis, especially with recent REPREVIO trial data. Non-invasive disease monitoring, such as cross-sectional enterography, intestinal ultrasound, and fecal calprotectin, have been validated against ileocolonoscopy. Recent advances in the prediction, prevention, and monitoring algorithms of postoperative Crohn's disease may be leading to a reduction in postoperative recurrence. Ongoing trials will help determine optimal monitoring and management strategies for this at-risk population.

Comparative Persistence of Non-tumor Necrosis Factor (TNF) vs. TNF Antagonists for Post-operative Prophylaxis in Crohn's Disease (CD).

BACKGROUND: The comparative safety and effectiveness of available biologics for post-operative prophylaxis in Crohn's disease (CD) is uncertain. Drug persistence may serve as a real-world proxy for tolerability and effectiveness. We evaluated the comparative persistence of non-TNF and TNF antagonists for post-operative prophylaxis and their comparative effectiveness for preventing early endoscopic post-operative recurrence (POR). METHODS: We conducted a single-center, retrospective study of surgically naïve CD subjects undergoing ileocecal or small bowel resection between 1/1/2000 and 12/31/2021 and prescribed a biologic for post-operative prophylaxis. We compared the risk of prophylaxis failure (requiring recurrent surgery or discontinuation of therapy due to persistent POR despite optimized drug level or dose escalation, immunogenicity, and/or adverse event) and early endoscopic POR (Rutgeert's score ≥ i2 within 15 months postoperatively) between non-TNF and TNF antagonist prophylaxis using Cox proportional hazard and logistic regression, respectively, adjusting for demographic and disease characteristics. RESULTS: The study included 291 subjects (81% TNF antagonists). After multivariable adjustment, non-TNF antagonist prophylaxis was associated with a significantly lower risk of prophylaxis failure than TNF antagonists (hazard ratio 0.26; 95% confidence interval (CI) [0.13-0.53]). Prophylaxis with non-TNF and TNF antagonists had similar risk of early endoscopic POR (odds ratio 0.66; 95% CI [0.32-1.36]). Stratifying the non-TNF antagonists by anti-integrin and anti-IL12/23 yielded similar results. CONCLUSION: In a cohort of surgically naïve CD subjects prescribed a biologic for post-operative prophylaxis, non-TNF antagonists had greater persistence than TNF antagonists with similar risk for early endoscopic POR. If confirmed by large, prospective studies, these findings can inform post-operative management strategies in CD.

Real-World Surgical and Endoscopic Recurrence Based on Risk Profiles and Prophylaxis Utilization in Postoperative Crohn's Disease.

BACKGROUND & AIMS: Preoperative risk stratification may help guide prophylactic biologic utilization for the prevention of postoperative Crohn's disease (CD) recurrence; however, there are limited data exploring and validating proposed clinical risk factors. We aimed to explore the preoperative clinical risk profiles, quantify individual risk factors, and assess the impact of biologic prophylaxis on postoperative recurrence risk in a real-world cohort. METHODS: In this multicenter retrospective analysis, patients with CD who underwent ileocolonic resection (ICR) from 2009 to 2020 were identified. High-risk (active smoking, ≥2 prior surgeries, penetrating disease, and/or perianal disease) and low-risk (nonsmokers and age >50 y) features were used to stratify patients. We assessed the risk of endoscopic (Rutgeert score, ≥i2b) and surgical recurrence by risk strata and biologic prophylaxis (≤90 days postoperatively) with logistic and time-to-event analyses. RESULTS: A total of 1404 adult CD patients who underwent ICR were included. Of the high-risk factors, 2 or more ICRs (odds ratio [OR], 1.71; 95% CI, 1.13-2.57), active smoking (OR, 1.73; 95% CI, 1.17-2.53), penetrating disease (OR, 1.41; 95% CI, 1.02-1.94), and history of perianal disease alone (OR, 1.99; 95% CI, 1.42-2.79) were associated with surgical but not endoscopic recurrence. Surgical recurrence was lower in high-risk patients receiving prophylaxis vs not (10.2% vs 16.7%; P = .02), and endoscopic recurrence was lower in those receiving prophylaxis irrespective of risk strata (high-risk, 28.1% vs 37.4%; P = .03; and low-risk, 21.1% vs 38.3%; P = .002). CONCLUSIONS: Clinical risk factors accurately illustrate patients at risk for surgical recurrence, but have limited utility in predicting endoscopic recurrence. Biologic prophylaxis may be of benefit irrespective of risk stratification and future studies should assess this.

Calprotectina fecal no monitoramento de pacientes com Doença de Crohn envolvendo o cólon / Fecal calprotectin in monitoring patients with Crohn's disease involving the colon

INTRODUÇÃO: Considerada uma doença crônica e sem cura que acomete adolescentes e adultos jovens, as principais características clínicas da DC incluem febre, palidez, perda de peso, massas abdominais, fístulas e fissuras perianais. Devido à heterogeneidade das manifestações clínicas, seu diagnóstico e monitoramento é obtido através de uma avaliação combinada das características clínicas com os achados endoscópicos, histopatológicos, laboratoriais e de imagem. De maneira geral, as análises laboratoriais contribuem na avaliação de sinais de resposta inflamatória aguda e/ou crônica, essenciais para o direcionamento do início e da manutenção do tratamento farmacológico. Atualmente, devido às suas correlações com alterações na atividade inflamatória, os testes laboratoriais de proteína C reativa (PCR) e velocidade de hemossedimentação (VHS) estão disponíveis no SUS. A CF apresenta boa correlação com a atividade inflamatória do trato intestinal, fazendo dela um importante marcador inflamatório na DC, especialmente quando o objetivo a monitorização do tratamento, a fim de reduzir o número de colonoscopias indesejadas. PERGUNTA: No monitoramento de pacientes com doença de Crohn (DC) envolvendo o cólon em atividade, a calprotectina fecal (CF) é mais sensível e/ou específica que a proteína C reativa (PCR) ou a velocidade de hemossedimentação (VHS) para identificar e/ou afastar doença com atividade endoscópica? EVIDÊNCIAS CLÍNICAS: A colonoscopia foi considerada padrão ouro no monitoramento da atividade da DC em todos os estudos que avaliaram marcadores inflamatórios, como possível substituto no monitoramento dos pacientes com DC. Quatro revisões sistemáticas foram incluídas, sendo duas com meta-análises. Para síntese de resultados e realização do GRADE foi escolhida a revisão sistemática mais recente, a qual teve maior número de estudos incluídos na síntese de dados. A partir da mesma, foi observado uma sensibilidade de 0,83 (IC 95% 0,77 a 0,87) e especificidade de 0,76 (0,68 a 0,82) no monitoramento da atividade da DC. A síntese de resultados mostrou que a CF apresenta um odds ratio diagnóstico de 13,8 (IC 95% 9,1-20,9) no monitoramento da atividade da doença, o que significa dizer que o exame apresenta 14 vezes mais chances de identificar o paciente que está com doença ativa comparado com aquele com doença inativa. Os estudos foram considerados como de qualidade da evidência criticamente baixa a baixa. O nível de certeza da evidência foi moderado. AVALIAÇÃO ECONÔMICA: Ao comparar a sensibilidade da CF com PCR para o desfecho de colonoscopias evitadas, observou-se equivalência entre as tecnologias. Consequentemente, a eficácia das duas tecnologias resulta em números iguais de colonoscopias evitadas. Portanto, a principal diferença nesta análise foi o custo adicional do teste de CF em relação ao PCR, que foi de R$ 450,90. No entanto, em contrapartida, a eficácia da CF para o desfecho de monitoramento adequado da atividade da Doença de Crohn (DC) foi ligeiramente maior (∆ 0,03263), resultando em uma RCEI de R$ 13.818,57 por indivíduo adequadamente monitorado. O valor de RCEI por número de colonoscopia evitadas e monitoramento adequado ao comparar com VSH foi de R$ 10.046,73 e R$ 7.525,00, respectivamente. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: O horizonte temporal estabelecido para a análise de impacto orçamentário foi de cinco anos. Para o cálculo da população elegível, partiu-se do número de pacientes com DC que estão em tratamento no DATASUS e, a partir de então, definiu-se o número de pacientes que necessitam de monitoramento da atividade da DC. O market share utilizado para o cenário proposto foi de 5% a 25%, assumindo que 74% dos pacientes com DC fazem o monitoramento com PCR e 26% com VHS. Considerando a incorporação do teste de CF no SUS houve um incremento de custo de R$ 39.675,00 no primeiro ano, chegando a R$ 231.755,00 no quinto ano de análise, resultando em um total acumulado de R$ 660.907,00 ao longo de cinco anos. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Realizaram-se buscas estruturadas nos campos de pesquisa das bases de dados ClinicalTrials.gov e Cortellis™, a fim de se localizar demais dispositivos médicos utilizados no procedimento de testagem para a calprotectina fecal no monitoramento de pacientes com doença de crohn envolvendo o cólon. As pesquisas nas bases de dados não apresentaram resultados para novos dispositivos médicos utilizados em procedimentos de análises laboratoriais que realizem a testagem da calprotectina fecal. CONSIDERAÇÕES FINAIS: Não houve estudos que comparassem diretamente a CF com os outros marcadores inflamatórios. Para determinar a sensibilidade e especificidade da CF, os estudos disponíveis utilizavam os escores endoscópicos como padrão ouro. Foi observado uma sensibilidade de 0,83 (IC 95% 0,77 a 0,87) e especificidade de 0,76 (0,68 a 0,82) no monitoramento da atividade da DC com CF. A síntese de resultados mostrou que o exame apresenta 14 vezes mais chances de identificar o paciente que está com doença ativa comparado com aquele com doença inativa. A qualidade metodológica das revisões sistemáticas incluídas foi considerada criticamente baixa (25%) a baixa (75%). Pelo GRADE, considerando uma corte simulada com 1.000 pacientes testados com prevalência de, 10, 40 e 80% de doença ativa, a certeza da evidência gerada foi julgada como moderada. O CADTH e o SBU destacam o uso da CF no monitoramento da atividade das DII. De maneira geral, ao ser utilizado no monitoramento da atividade da DC, o teste de CF pode resultar em um incremento de R$660.907,00 em cinco anos. PERSPECTIVA DO PACIENTE: Foi aberta Chamada Pública nº 26/2023 para inscrição de participantes para a Perspectiva do Paciente, durante o período de 13/07/2023 a 23/07/2023, e 148 pessoas se inscreveram. A seleção dos representantes titular e suplente ocorreu por meio de sorteio em plataforma on-line. Durante seu relato, a representante destacou os aspectos positivos de realizar o monitoramento da doença de Crohn com o exame de calprotectina fecal. Pontuou que com a sua realização, não tem sido mais necessário realizar colonoscopia - exame que exige todo um preparo anterior e que a deixa debilitada. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Os membros do Comitê de Produtos e Procedimentos presentes na 16ª Reunião Extraordinária da Conitec, realizada no dia 31 de outubro de 2023, deliberaram por unanimidade que a matéria fosse disponibilizada em consulta pública com recomendação preliminar desfavorável à incorporação no SUS da Calprotectina Fecal (CF) no monitoramento de pacientes com doença de Crohn envolvendo o cólon. O comitê considerou que é necessário aguardar o retorno da consulta pública, na expectativa de que as contribuições forneçam uma melhor compreensão dos benefícios da tecnologia para a indicação em avaliação. CONSULTA PÚBLICA: A Consulta Pública nº 64/2023 foi realizada entre os dias 29/12/2023 e 17/01/2024. Foram recebidas 266 contribuições, sendo 161 pelo formulário para contribuições técnico-científicas e 105 pelo formulário para contribuições sobre experiência ou opinião de pacientes, familiares, amigos ou cuidadores de pacientes, profissionais de saúde ou pessoas interessadas no tema. Dentre estas, 100% das contribuições expressaram discordância em relação à recomendação preliminar da Conitec e opinaram pela incorporação da tecnologia no SUS. Após análise do conteúdo das contribuições técnico-científicas, mais 126 contribuições do formulário técnico-científico foram consideradas como de experiência ou opinião. Dessa forma, a análise foi realizada sobre o total de 231 contribuições sobre experiência e opinião. Os respondentes destacaram que a tecnologia deve ser incorporada por ser um procedimento menos invasivo, mais seguro e acessível, contribuindo para melhor acompanhamento da doença e resultando em menor custo em relação à tecnologia disponível atualmente no SUS para diagnóstico e monitoramento da doença (colonoscopia). Foram consideradas para análise 31 contribuições técnico-científicas, sendo 28 realizadas por profissionais da Saúde e 2 por empresa fabricante da tecnologia. Foram recebidos 15 anexos com documentos solicitando a incorporação com referências de Consensos Nacionais e Internacionais, diretrizes e outros estudos demonstrando a importância e a necessidade do exame na prática clínica. RECOMENDAÇÃO FINAL DA CONITEC: Os membros do Comitê de Produtos e Procedimentos presentes na 127ª Reunião Ordinária da Conitec, realizada no dia 08 de março de 2024, deliberaram por unanimidade, recomendar a incorporação no SUS da calprotectina fecal no monitoramento de pacientes com doença de Crohn envolvendo o cólon, conforme Protocolo Clínico do Ministério da Saúde. Para essa recomendação os membros do Comitê consideraram fundamental as contribuições advindas da consulta pública, que apresentaram a importância da realização do exame no monitoramento dos pacientes em tratamento, por ser de fácil acesso, menos invasivo e custo-efetivo. Consideraram também as opiniões dos especialistas presentes na reunião que apresentaram estudo recentemente publicado e confirmaram que a realização do exame de calprotectina fecal poderá diminuir a realização de exames de colonoscopias no monitoramento dos pacientes, diminuindo filas de espera para a realização do exame. Foi assinado o Registro de Deliberação nº 885/2024. DECISÃO: incorporar, no âmbito do Sistema Único de Saúde - SUS, o exame de calprotectina fecal no monitoramento de pacientes com doença de Crohn envolvendo o cólon, conforme Protocolo Clínico do Ministério da Saúde, publicada no Diário Oficial da União nº 77, seção 1, página 177, em 22 de abril de 2024.

Early life exposure to broccoli sprouts confers stronger protection against enterocolitis development in an immunological mouse model of inflammatory bowel disease.

IMPORTANCE: To our knowledge, IL-10-KO mice have not previously been used to investigate the interactions of host, microbiota, and broccoli, broccoli sprouts, or broccoli bioactives in resolving symptoms of CD. We showed that a diet containing 10% raw broccoli sprouts increased the plasma concentration of the anti-inflammatory compound sulforaphane and protected mice to varying degrees against disease symptoms, including weight loss or stagnation, fecal blood, and diarrhea. Younger mice responded more strongly to the diet, further reducing symptoms, as well as increased gut bacterial richness, increased bacterial community similarity to each other, and more location-specific communities than older mice on the diet intervention. Crohn's disease disrupts the lives of patients and requires people to alter dietary and lifestyle habits to manage symptoms. The current medical treatment is expensive with significant side effects, and a dietary intervention represents an affordable, accessible, and simple strategy to reduce the burden of symptoms.

Higher dietary fibre intake is associated with lower risk of inflammatory bowel disease: prospective cohort study.

BACKGROUND: Limited prospective studies that have examined the association of dietary fibre with IBD have provided inconsistent evidence. AIM: To examine any associations between dietary fibre intake and subsequent incidence of IBD, Crohn's disease (CD) and ulcerative colitis (UC) METHODS: We conducted a prospective cohort study of 470,669 participants from the UK Biobank and estimated dietary fibre intake from a valid food frequency questionnaire at baseline. Incident IBD was ascertained from primary care data and inpatient data. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between dietary fibre intake and the risk of IBD, CD and UC. RESULTS: During an average follow-up of 12.1 years, we ascertained 1473 incident IBD cases, including 543 cases of CD and 939 cases of UC. Comparing the lowest quintiles, an inverse association was observed between dietary fibre intake and risk of IBD (HR 0.74, 95% CI 0.58-0.93, p = 0.011) and CD (HR 0.48, 95% CI 0.32-0.72, p < 0.001), but not UC (HR 0.92, 95% CI 0.69-1.24, p = 0.595). For specified sources, dietary fibre intake from fruit and bread decreased the risk of CD, while dietary fibre intake from cereal decreased the risk of UC. CONCLUSIONS: Higher consumption of dietary fibre was associated with a lower risk of IBD and CD, but not UC. Our findings support current recommendations to increase the intake of dietary fibre.

Anti-TNF Agents and New Biological Agents (Vedolizumab and Ustekinumab) in the Prevention and Treatment of Postoperative Recurrence After Surgery in Crohn's Disease.

Surgery for Crohn's disease (CD) is not curative, as postoperative recurrence (POR) after ileocolonic resection is the rule in the absence of prophylactic treatment. In the present article, we critically review available data on the role of anti-tumour necrosis factor (TNF) agents and new biologics (including vedolizumab and ustekinumab) in the prevention and treatment of POR after surgery in CD. Several studies (summarised in various meta-analyses) have confirmed the efficacy of anti-TNFs in the prevention of POR. We identified 37 studies, including 1863 CD patients, with mean endoscopic POR at 6-12 months of 29%. Only few randomised controlled trials (RCTs) have directly compared thiopurines and anti-TNFs, with controversial results, although the superiority of the latter is supported by several meta-analyses. Infliximab and adalimumab seem equally effective. The combination of anti-TNFs and immunosuppressives should be considered in patients previously exposed to anti-TNFs. Several studies have shown that anti-TNFs remain an effective option to prevent POR also in patients with anti-TNF failure before surgery. In fact, the use of the same anti-TNF before and after surgery might be effective for the prevention of POR. Prophylactic anti-TNF treatment, once started, should be continued long term. Anti-TNFs are also effective for the treatment of established POR. Retreatment with anti-TNFs for POR is a valid strategy even after their preoperative failure. In six studies (including 156 patients) evaluating vedolizumab, mean endoscopic POR at 6-12 months was 41%. The non-randomised comparison of anti-TNFs and vedolizumab has provided controversial results. One placebo-controlled RCT confirmed that vedolizumab is quite effective in preventing POR in CD patients with increased risk of recurrence. Seven studies (including 162 patients) evaluated ustekinumab, with a mean endoscopic POR at 6-12 months of 41%. The comparative efficacy of ustekinumab and anti-TNFs is still unclear. Ustekinumab and vedolizumab seem to be equally effective, although the experience is very limited. In conclusion, to date, anti-TNFs are the most effective agents in preventing and treating POR in CD. Anti-TNFs remain an effective option to prevent POR also in patients with anti-TNF failure before surgery. Vedolizumab seems to be quite effective in the prevention of POR in patients with increased risk of recurrence. Ustekinumab is probably also effective in the postoperative setting, although the comparative efficacy with anti-TNFs or vedolizumab is still unclear.

Results of the Eighth Scientific Workshop of ECCO: Prevention and Treatment of Postoperative Recurrence in Patients With Crohn's Disease Undergoing an Ileocolonic Resection With Ileocolonic Anastomosis.

Despite the introduction of biological therapies, an ileocolonic resection is often required in patients with Crohn's disease [CD]. Unfortunately, surgery is not curative, as many patients will develop postoperative recurrence [POR], eventually leading to further bowel damage and a decreased quality of life. The 8th Scientific Workshop of ECCO reviewed the available scientific data on both prevention and treatment of POR in patients with CD undergoing an ileocolonic resection, dealing with conventional and biological therapies, as well as non-medical interventions, including endoscopic and surgical approaches in case of POR. Based on the available data, an algorithm for the postoperative management in daily clinical practice was developed.

Ustekinumab and vedolizumab for the prevention of postoperative recurrence of Crohn's disease: Results from the ENEIDA registry.

BACKGROUND: Anti-TNF agents are the only effective biological agents for the prevention of postoperative recurrence (POR) in Crohn's disease (CD). However, they are contraindicated or have been shown to fail in some patients. Although ustekinumab and vedolizumab were licensed for CD some years ago, data in this setting are scarce. METHODS: All CD patients in whom ustekinumab or vedolizumab was prescribed for the prevention of POR within three months of ileocolonic resection with anastomosis were identified from the ENEIDA registry. The development of endoscopic, clinical and surgical POR was registered. RESULTS: Forty patients were treated for the prevention of POR with ustekinumab and 25 were treated with vedolizumab. Eighty per cent had at least one risk factor for POR (prior resections, active smoking, perianal disease or penetrating disease behaviour). All the patients had been exposed to anti-TNF therapy. After a median follow-up of 17 and 26 months, the cumulative probability of clinical POR at 12 months after surgery was 32% and 30% for ustekinumab and vedolizumab, respectively. Endoscopic assessment within the first 18 months after surgery was available for 80% of the patients on ustekinumab and 70% for those on vedolizumab. The rate of endoscopic POR was 42% for ustekinumab and 40% for vedolizumab. One patient treated with ustekinumab and two with vedolizumab underwent a new intestinal resection. CONCLUSIONS: Ustekinumab and vedolizumab seem to be effective in the prevention of POR in patients at high risk. Our results warrant controlled trials comparing these drugs with conventional therapies.

Diet Quality and Risk of Older-onset Crohn's Disease and Ulcerative Colitis.

BACKGROUND: We aimed to assess the relationship between diet quality and risk of older-onset Crohn's disease [CD] and ulcerative colitis [UC]. METHODS: We conducted a prospective cohort study of 83 147 participants from the Swedish Mammography Cohort and the Cohort of Swedish Men. We used food frequency questionnaires to calculate adherence scores to multiple derived healthy diet patterns: Alternate Healthy Eating Index [AHEI], Healthy Eating Index-2015 [HEI-2015], Healthful Plant-Based Diet Index [HPDI], and modified Mediterranean Diet Score [mMED] at baseline in 1997 in both cohorts. Diagnoses of CD and UC were retrieved from the Swedish Patient Register. We used Cox proportional hazards modelling to estimate the adjusted hazard ratios [HRs] and 95% confidence intervals [CIs]. RESULTS: Through December of 2017, we confirmed 164 incident cases of CD and 395 incident cases of UC. Comparing the highest with the lowest quartiles, the adjusted HRs of CD were 0.73 [95% CI, 0.48, 1.12, ptrend = 0.123] for AHEI; 0.90 [0.57, 1.41, ptrend = 0.736] for HEI 2015; 0.52 [95% CI 0.32, 0.85, ptrend = 0.011] for HPDI; and 0.58 [95% CI 0.32, 1.06, ptrend = 0.044] for mMED. In contrast, we did not observe an association between any diet quality score and risk of UC. CONCLUSIONS: We found that several healthy eating patterns were associated with a lower risk of older-onset CD. Our findings provide a rationale for adapting different healthy dietary patterns based on individuals' food preferences and traditions in designing future prevention strategies for IBD.

Top-down Versus Step-up Strategies to Prevent Postoperative Recurrence in Crohn's Disease.

BACKGROUND: The best management after ileocolonic resection is still unknown in Crohn's disease (CD). We compared step-up and top-down approaches to prevent short and long-term postoperative recurrences in CD patients. METHODS: From a comprehensive database, consecutive CD patients who underwent intestinal resection (2014-2021) were included. Top-down (biologics started within the first month after surgery) or step-up strategies (no biologic between surgery and colonoscopy at 6 months) were performed with systematic colonoscopy at 6 months and therapeutic escalation if Rutgeerts index was ≥i2a (endoscopic postoperative recurrence). Propensity score analysis was applied for each comparison. RESULTS: Among 115 CD patients, top-down was the most effective strategy to prevent endoscopic postoperative recurrence (46.8% vs 65.9%, P = .042) and to achieve complete endoscopic remission (Rutgeerts index = i0; 45.3% vs 19.3%; P = .004) at 6 months. We did not observe any significant difference between the 2 groups regarding clinical postoperative recurrence (hazard ratio [HR], .86 [0.44-1.66], P = .66) and progression of bowel damage (HR, 0.81 [0.63-1.06], P = .12). Endoscopic postoperative recurrence at 6 months was associated with increased risk of clinical postoperative recurrence (HR, 1.97 [1.07-3.64], P 0.029) and progression of bowel damage (HR, 3.33 [1.23-9.02], P = .018). Among the subgroup without endoscopic postoperative recurrence at 6 months, the risks of clinical postoperative recurrence and progression of bowel damage were significantly improved in the top-down group (HR, 0.59 [0.37-0.94], P = .025; and HR, 0.73 [0.63-0.83], P < .001, respectively). CONCLUSIONS: Top-down strategy should be the preferred management to prevent short and long-term postoperative recurrence in CD.

Our data suggest that top-down strategy should be preferred to step-up approach to prevent endoscopic postoperative recurrence, as well as clinical postoperative recurrence and progression of bowel damage in most of the patients with Crohn's disease after bowel resection.

Prevention of post-operative recurrence of Crohn's disease among patients with prior anti-TNFα failure: A retrospective multicenter study.

BACKGROUND: Anti-TNFα are recommended for preventing Crohn's disease (CD) postoperative recurrence (POR) in patients with risk factors. However, few data exploring anti-TNFα efficacy in patients with preoperative anti-TNFα failure are available so far. AIMS: The aim of the present study was to compare the efficacy of anti-TNFα with other biologics and immunosuppressants to prevent POR in this setting. METHODS: Consecutive CD patients who underwent bowel resection between January 2010 and December 2019 after failure of at least one anti-TNFα were retrospectively included among three tertiary centers if they started a postoperative medical prophylaxis within the three months after index surgery. The main outcome was to compare rates of objective recurrence (endoscopic or radiological recurrence in absence of colonoscopy) between patients treated with an anti-TNFα agent or another treatment as prevention of POR. RESULTS: Among the 119 patients included, 71 patients received an anti-TNFα (26 infliximab, 45 adalimumab) and 48 another treatment (18 ustekinumab, 7 vedolizumab, 20 azathioprine and 3 methotrexate) to prevent POR. Rates of objective recurrence at two years were 23.9% in patients treated with anti-TNFα and 44.9% in the others (p = 0.011). CONCLUSION: Anti-TNFα remained an effective option to prevent POR for patients operated upon with previous anti-TNFα failure.

Benefit of Risk-stratified Prophylactic Treatment on Clinical Outcome in Postoperative Crohn's Disease.

BACKGROUND AND AIMS: Whereas immediate postoperative treatment has shown effectiveness in reducing endoscopic postoperative recurrence [POR], evidence regarding the clinical benefit is limited. We compared rates of clinical POR in Crohn's disease [CD] patients receiving immediate prophylactic treatment with rates in patients receiving endoscopy-driven treatment. METHODS: We retrospectively collected data from 376 consecutive CD patients who underwent an ileocaecal resection with anastomosis between 2007 and 2018 with at least 3 years of follow-up at three sites. Subsequently, high- and low-risk patients categorised by established guidelines, who underwent endoscopy within 12 months postoperatively, were grouped according to a prophylactic- or endoscopy-driven approach and compared for incidence and time till endoscopic and clinical POR. RESULTS: Prophylactic treatment reduced rates of and time till endoscopic POR within 1 year in high-risk (hazard ratio [HR] 0.48, 95% confidence interval [CI] 0.27-0.86, p = 0.04, number needed to treat [NNT] = 5) but not low-risk [HR 0.90, 95% CI 0.32-2.56, p = 0.85] patients. Conversely, no significant differences in clinical POR within 3 years between prophylactic- and endoscopy-driven low-risk [HR 1.17, 95% CI 0.41-3.29, p = 0.75] and high-risk patients were observed [HR 1.06, 95% CI 0.63-1.79, p = 0.82, NNT = 22]. However, a large numerical albeit not statistical significant difference in 3-year clinical POR [28.6% vs. 62.5%, p = 0.11] in a subset of high-risk patients with three or more ECCO-defined risk factors was observed, indicating a cumulative effect of having multiple risk factors. CONCLUSION: Our observations favour step-up treatment guided by early endoscopic evaluation with prophylactic treatment reserved for carefully selected high-risk patients, in order to avoid potential overtreatment of a significant number of patients.

Selected Aspects of Nutrition in the Prevention and Treatment of Inflammatory Bowel Disease.

Inflammatory bowel disease has become a global health problem at the turn of the 21st century. The pathogenesis of this disorder has not been fully explained. In addition to non-modifiable genetic factors, a number of modifiable factors such as diet or gut microbiota have been identified. In this paper, the authors focus on the role of nutrition in the prevention of inflammatory bowel disease as well as on the available options to induce disease remission by means of dietary interventions such as exclusive and partial enteral nutrition in Crohn's disease, the efficacy of which is reported to be comparable to that of steroid therapy. Diet is also important in patients with inflammatory bowel disease in the remission stage, during which some patients report irritable bowel disease-like symptoms. In these patients, the effectiveness of diets restricting the intake of oligo-, di-, monosaccharides, and polyols is reported.

Endoscopic Postoperative Recurrence in Crohn's Disease After Curative Ileocecal Resection with Early Prophylaxis by Anti-TNF, Vedolizumab or Ustekinumab: A Real-World Multicentre European Study.

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.

Prophylactic Antitubercular Therapy Is Associated With Accelerated Disease Progression in Patients With Crohn's Disease Receiving Anti-TNF Therapy: A Retrospective Multicenter Study.

INTRODUCTION: Prophylactic antitubercular therapy (ATT) is widely prescribed in patients with Crohn's disease (CD) receiving antitumor necrosis factor (anti-TNF) treatment. However, antitubercular agents have been demonstrated to possess profibrotic effects. We aimed to evaluate whether ATT accelerated disease progression in patients with CD receiving anti-TNF treatment. METHODS: A retrospective, multicenter study was performed in CD patients presented with inflammatory behavior (B1) and treated with anti-TNF agents. Disease progression was defined as the development of a stricturing (B2) or penetrating (B3) phenotype. ATT users were propensity score-matched with non-ATT users. Survival and multivariable Cox analyses were used to identify factors associated with disease progression. RESULTS: We enrolled 441 patients, including 295 ATT users and 146 non-ATT users, with a median follow-up of 3.15 years (interquartile range: 1.6-4.7). The cumulative rates of disease progression in the ATT group were constantly higher than those in the non-ATT group after 1-, 3-, 5-, and 10-year follow-ups, respectively (P = 0.031). Multivariable Cox analysis identified ATT as an independent risk factor for disease progression using both the whole (hazard ratio = 2.22; 95% confidence interval: 1.11-4.48; P = 0.025) and propensity score-matched cohorts (hazard ratio = 2.35; 95% confidence interval: 1.07-5.14; P = 0.033). In subgroup analysis, patients receiving ATT ≥4.5 months had a significantly higher rate of disease progression compared with patients receiving ATT <4.5 months (P = 0.005) and non-ATT treatment (P = 0.036). DISCUSSION: Prophylactic ATT with duration over 4.5 months was associated with disease progression in patients with CD receiving anti-TNF treatment.

Rate and risk factors of postoperative endoscopic recurrence of moderate- to high-risk Crohn's disease patients - A real-world experience from a Middle Eastern cohort.

Background: Crohn's disease (CD) frequently recurs after intestinal resection. Azathioprine (AZA) and biological therapies have shown efficacy in preventing postoperative recurrence (POR). Data on POR from Middle Eastern populations is lacking. This study aimed to evaluate the rate of endoscopic POR in a cohort of CD patients who underwent ileocecal resection (ICR), and to assess the effectiveness of AZA and biological therapies in reducing the risk of disease recurrence. Methods: We performed a retrospective cohort study on 105 CD patients followed at our center, who underwent ileal resection and were at moderate to high risk for POR. Clinical and laboratory data were collected; the primary endpoint was post ICR endoscopic recurrence at 24 months defined by Rutgeerts' score of i2 or more despite treatment. Results: In total, 105 patients with Crohn's disease met our inclusion criteria; 76.2% were in remission and did not have endoscopic POR at 24 months. Further, 41.9% were on biological therapy, and 34.3% were mainly on AZA. Out of the 28.2% who had POR, approximately 15% were on biological therapies. Penetrating phenotype was the only predictive factor for decreasing POR (OR = 0.19, 95% CI: 0.04-0.98, P = 0.04) as identified in multiple logistic regression analysis. Conclusions: The use of biological therapies post-surgery was not superior than AZA in reducing the endoscopic POR for mod- high risk CD patients. Only penetrating behavior of the CD was associated with significantly lower risk of endoscopic recurrence. This finding is worth further investigation in more robust study designs and among larger samples of patients.

Risk Prediction and Comparative Efficacy of Anti-TNF vs Thiopurines, for Preventing Postoperative Recurrence in Crohn's Disease: A Pooled Analysis of 6 Trials.

BACKGROUND & AIMS: The superiority of anti-TNF-α agents to thiopurines for the prevention of postoperative recurrence of Crohn's disease (CD) after ileocolonic resection remains controversial. In this meta-analysis of individual participant data (IPD), the effect of both strategies was compared and assessed after risk stratification. METHODS: After a systematic literature search, IPD were requested from randomized controlled trials investigating thiopurines and/or anti-TNF-α agents after ileocolonic resection. Primary outcome was endoscopic recurrence (ER) (Rutgeerts score ≥i2) and secondary outcomes were clinical recurrence (Harvey-Bradshaw Index/Crohn's Disease Activity Index score) and severe ER (Rutgeerts score ≥i3). A fixed effect network meta-analysis was performed. Subgroup effects were assessed and a prediction model was established using Poisson regression models, including sex, smoking, Montreal classification, CD duration, history of prior resection and previous exposure to anti-TNF-α or thiopurines. RESULTS: In the meta-analysis of IPD, 645 participants from 6 studies were included. In the total population, a superior effect was demonstrated for anti-TNF-α compared with thiopurine prophylaxis for ER (relative risk [RR], 0.52; 95% confidence interval [CI], 0.33-0.80), clinical recurrence (RR, 0.50; 95% CI, 0.26-0.96), and severe ER (RR, 0.41; 95% CI, 0.21-0.79). No differential subgroup effects were found for ER. In Poisson regression analysis, previous exposure to anti-TNF-α and penetrating disease behavior were associated with ER risk. The advantage of anti-TNF-α agents as compared with thiopurines was observed in low- and high-risk groups. CONCLUSIONS: Anti-TNF-α is superior to thiopurine prophylaxis for the prevention of endoscopic and clinical postoperative CD recurrence after ileocolonic resection. The advantage of anti-TNF-α agents was confirmed in subgroup analysis and after risk stratification.

Continued Postoperative Use of Tumor Necrosis Factor-α Inhibitors for the Prevention of Crohn's Disease Recurrence.

Background/Aims: Many patients with Crohn's disease (CD) undergo intestinal resection during the disease course. Despite surgery, postoperative recurrence (POR) commonly occurs. Although postoperative use of tumor necrosis factor α (TNF-α) inhibitors is known to be effective in preventing POR, few studies have evaluated the effectiveness of continuing the same TNF-α inhibitors postoperatively in patients who received TNF-ɑ inhibitors before surgery. Methods: This retrospective observational study was performed in a single tertiary medical center. We retrospectively reviewed patients who had undergone the first intestinal resection due to CD and divided them into two groups: TNF-α inhibitor users in both the preoperative and postoperative periods, and TNF-α inhibitor users in only the preoperative period. We compared the clinical outcomes between these two groups. Results: In total, 45 patients who used TNF-α inhibitors preoperatively were recruited. Among them, TNF-α inhibitors were used postoperatively in 20 patients (44.4%). The baseline characteristics except age at diagnosis were similar in both groups. The rates of surgical and endoscopic recurrence were not different between the two groups, but the cumulative clinical recurrence rate was significantly lower in the postoperative TNF-α inhibitors group (log-rank p=0.003). In multivariate Cox regression analysis, postoperative TNF-α inhibitors use was significantly associated with a decreased risk of clinical recurrence (adjusted hazard ratio, 0.204; 95% confidence interval, 0.060 to 0.691; p=0.011). Conclusions: Continuing TNF-α inhibitors postoperatively in patients who were receiving TNF-α inhibitors before surgery significantly reduced the rate of clinical recurrence. For patients with CD who received TNF-α inhibitors preoperatively, continuing their use after surgery could be recommended.