Prebiotics for induction and maintenance of remission in ulcerative colitis.

BACKGROUND: People affected by ulcerative colitis (UC) are interested in dietary therapies as treatments that can improve their health and quality of life. Prebiotics are a category of food ingredients theorised to have health benefits for the gastrointestinal system through their effect on the growth and activity of intestinal bacteria and probiotics. OBJECTIVES: To assess the efficacy and safety of prebiotics for the induction and maintenance of remission in people with active UC. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, and WHO ICTRP on 24 June 2023. SELECTION CRITERIA: We included randomised controlled trials (RCTs) on people with UC. We considered any type of standalone or combination prebiotic intervention, except those prebiotics combined with probiotics (known as synbiotics), compared to any control intervention. We considered interventions of any dose and duration. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. MAIN RESULTS: We included 9 RCTs involving a total of 445 participants. Study duration ranged from 14 days to 2 to 3 months for induction and 1 to 6 months for maintenance of remission. All studies were on adults. Five studies were on people with mild to moderate active disease, three in remission or mild activity, and one did not mention. We judged only one study as at low risk of bias in all areas. Two studies compared prebiotics with placebo for induction of remission. We cannot draw any conclusions about clinical remission (70% versus 67%; risk ratio (RR) 1.05, 95% confidence interval (CI) 0.57 to 1.94); clinical improvement (mean Rachmilewitz score on day 14 of 4.1 versus 4.5; mean difference (MD) -0.40, 95% CI -2.67 to 1.87); faecal calprotectin levels (mean faecal calprotectin on day 14 of 1211 µg/mL versus 3740 µg/mL; MD -2529.00, 95% CI -6925.38 to 1867.38); interleukin-8 (IL-8) levels (mean IL-8 on day 7 of 2.9 pg/mL versus 5.0 pg/mL; MD -2.10, 95% CI -4.93 to 0.73); prostaglandin E2 (PGE-2) levels (mean PGE-2 on day 7 of 7.1 ng/mL versus 11.5 ng/mL; MD -4.40, 95% CI -20.25 to 11.45); or withdrawals due to adverse events (21% versus 8%; RR 2.73, 95% CI 0.51 to 14.55). All evidence was of very low certainty. No other outcomes were reported. Two studies compared inulin and oligofructose 15 g with inulin and oligofructose 7.5 g for induction of remission. We cannot draw any conclusions about clinical remission (53% versus 12.5%; RR 4.27, 95% CI 1.07 to 16.96); clinical improvement (67% versus 25%; RR 2.67, 95% CI 1.06 to 6.70); total adverse events (53.5% versus 31%; RR 1.71, 95% CI 0.72 to 4.06); or withdrawals due to adverse events (13% versus 25%; RR 0.53, 95% CI 0.11 to 2.50). All evidence was of very low certainty. No other outcomes were reported. One study compared prebiotics and anti-inflammatory therapy with anti-inflammatory therapy alone for induction of remission. We cannot draw any conclusions about clinical improvement (mean Lichtiger score at 4 weeks of 6.2 versus 10.3; MD -4.10, 95% CI -8.14 to -0.06) or serum C-reactive protein (CRP) levels (mean CRP levels at 4 weeks 0.55 ng/mL versus 0.50 ng/mL; MD 0.05, 95% CI -0.37 to 0.47). All evidence was of very low certainty. No other outcomes were reported. Three studies compared prebiotics with placebo for maintenance of remission. There may be no difference between groups in rate of clinical relapse (44% versus 33%; RR 1.36, 95% CI 0.79 to 2.31), and prebiotics may lead to more total adverse events than placebo (77% versus 46%; RR 1.68, 95% CI 1.18 to 2.40). The evidence was of low certainty. We cannot draw any conclusions about clinical improvement (mean partial Mayo score at day 60 of 0.428 versus 1.625; MD -1.20, 95% CI -2.17 to -0.22); faecal calprotectin levels (mean faecal calprotectin level at day 60 of 214 µg/mL versus 304 µg/mL; MD -89.79, 95% CI -221.30 to 41.72); quality of life (mean Inflammatory Bowel Disease Questionnaire (IBDQ) score at day 60 of 193.5 versus 188.0; MD 5.50, 95% CI -8.94 to 19.94); or withdrawals due to adverse events (28.5% versus 11%; RR 2.57, 95% CI 1.15 to 5.73). The evidence for these outcomes was of very low certainty. No other outcomes were reported. One study compared prebiotics with synbiotics for maintenance of remission. We cannot draw any conclusions about quality of life (mean IBDQ score at 4 weeks 182.4 versus 176.1; MD 6.30, 95% CI -6.61 to 19.21) or withdrawals due to adverse events (23% versus 20%; RR 1.13, 95% CI 0.48 to 2.62). All evidence was of very low certainty. No other outcomes were reported. One study compared prebiotics with probiotics for maintenance of remission. We cannot draw any conclusions about quality of life (mean IBDQ score at 4 weeks 182.4 versus 168.6; MD 13.60, 95% CI 1.22 to 25.98) or withdrawals due to adverse events (22.5% versus 22.5%; RR 1.00, 95% CI 0.44 to 2.26). All evidence was of very low certainty. No other outcomes were reported. AUTHORS' CONCLUSIONS: There may be no difference in occurrence of clinical relapse when adjuvant treatment with prebiotics is compared with adjuvant treatment with placebo for maintenance of remission in UC. Adjuvant treatment with prebiotics may result in more total adverse events when compared to adjuvant treatment with placebo for maintenance of remission. We could draw no conclusions for any of the other outcomes in this comparison due to the very low certainty of the evidence. The evidence for all other comparisons and outcomes was also of very low certainty, precluding any conclusions. It is difficult to make any clear recommendations for future research based on the findings of this review given the clinical and methodological heterogeneity among studies. It is recommended that a consensus is reached on these issues prior to any further research.

Infliximab for maintenance of medically-induced remission in Crohn's disease.

BACKGROUND: Infliximab is a monoclonal antibody that binds and neutralises tumour necrosis factor-alpha (TNF-α) which is present in high levels in the blood serum, mucosa and stool of patients with Crohn's disease. OBJECTIVES: To determine the efficacy and safety of infliximab for maintaining remission in patients with Crohn's disease. SEARCH METHODS: On 31 August, 2021 and 23 June, 2023, we searched CENTRAL, Embase, MEDLINE, ClinicalTrials.gov, and WHO ICTRP. SELECTION CRITERIA: Randomised controlled trials (RCTs) in which infliximab was compared to placebo or another active comparator for maintenance, remission, or response in patients with Crohn's disease. DATA COLLECTION AND ANALYSIS: Pairs of review authors independently selected studies and conducted data extraction and risk of bias assessment. We expressed outcomes as risk ratios and mean differences with 95% confidence intervals. We assessed the certainty of the evidence using GRADE. Our primary outcome was clinical relapse. Secondary outcomes were loss of clinical response, endoscopic relapse, and withdrawal due to serious and adverse events. MAIN RESULTS: Nine RCTs with 1257 participants were included. They were conducted between 1999 and 2022; seven RCTs included biologically-naive patients, and the remaining two included a mix of naive/not naive patients. Three studies included patients in clinical remission, five included patients with a mix of activity scores, and one study included biologic responders with active disease at baseline. All studies allowed some form of concomitant medication during their duration. One study exclusively included patients with fistulating disease. The age of the participants ranged from 18 to 69 years old. All but one single-centre RCT were multicentre RCTs. Four studies were funded by pharmaceutical companies, two had a mix of commercial and public funding, and two had public funding. Infliximab is probably superior to placebo in preventing clinical relapse in patients who have mixed levels of clinical disease activity at baseline, and are not naive to biologics (56% vs 75%, RR 0.73, 95% CI 0.63 to 0.84, NNTB = 5, moderate-certainty evidence). We cannot draw any conclusions on loss of clinical response (RR 0.59, 95% CI 0.37 to 0.96), withdrawals due to adverse events (RR 0.66, 95% CI 0.37 to 1.19), or serious adverse events (RR 0.60, 95% CI 0.36 to 1.00) because the evidence is very low certainty. Infliximab combined with purine analogues is probably superior to purine analogues for clinical relapse (12% vs 59%, RR 0.20, 95% CI 0.10 to 0.42, NNTB = 2, moderate-certainty evidence), for patients in remission, and who are not naive to biologics. We cannot draw any conclusions on withdrawals due to adverse events (RR 0.47, 95% CI 0.15 to 1.49), and serious adverse events (RR 1.19, 95% CI 0.54 to 2.64) because the evidence is very low certainty. We cannot draw any conclusions about the effects of infliximab on serious adverse events compared to purine analogues (RR 0.79, 95% CI 0.37 to 1.68) for a population in remission at baseline because the evidence is very low certainty. There was no evidence available for the outcomes of clinical relapse, loss of clinical response, and withdrawal due to adverse events. Infliximab may be equivalent to biosimilar for clinical relapse (47% vs 40% RR 1.18, 95% CI 0.82 to 1.69), and it may be slightly less effective in averting loss of clinical response (49% vs 32%, RR 1.50, 95% CI 1.01 to 2.23, low-certainty evidence), for a population with mixed/low disease activity at baseline. Infliximab may be less effective than biosimilar in averting withdrawals due to adverse events (27% vs 0%, RR 20.73, 95% CI 2.86 to 150.33, low-certainty evidence). Infliximab may be equivalent to biosimilar for serious adverse events (10% vs 10%, RR 0.99, 95% CI 0.39 to 2.50, low-certainty evidence). We cannot draw any conclusions on the effects of subcutaneous biosimilar compared with intravenous biosimilar on clinical relapse (RR 1.01, 95% CI 0.65 to 1.57), loss of clinical response (RR 0.94, 95% CI 0.70 to 1.25), and withdrawals due to adverse events (RR 0.77, 95% CI 0.30 to 1.97) for an active disease population with clinical response at baseline because the evidence is of very low certainty. We cannot draw any conclusions on the effects of infliximab compared to adalimumab on loss of clinical response (RR 0.68, 95% CI 0.29 to 1.59), withdrawals due to adverse events (RR 0.10, 95% CI 0.01 to 0.72), serious adverse events (RR 0.09, 95% CI 0.01 to 1.54) for an active disease population with clinical response at baseline because the evidence is of very low certainty. There was no evidence available for the outcome of clinical relapse. AUTHORS' CONCLUSIONS: Infliximab is probably more effective in preventing clinical relapse than placebo (moderate-certainty evidence). Infliximab in combination with purine analogues is probably more effective in preventing clinical and endoscopic relapse than purine analogues alone (moderate-certainty evidence). No conclusions can be drawn regarding prevention of loss of clinical response, occurrence of withdrawals due to adverse events, or total adverse events due to very low-certainty evidence for both of these comparisons. There may be little or no difference in prevention of clinical relapse, withdrawal due to adverse events or total adverse events between infliximab and a biosimilar (low-certainty evidence). Infliximab may lead to more loss of clinical response than a biosimilar (low-certainty evidence). We were unable to draw meaningful conclusions about other comparisons and outcomes related to missing data or very low-certainty evidence due to serious concerns about imprecision and risk of bias. Further research should focus on comparisons with other active therapies for maintaining remission, as well as ensuring adequate power calculations and reporting of methods.

Treatments for intractable constipation in childhood.

BACKGROUND: Constipation that is prolonged and does not resolve with conventional therapeutic measures is called intractable constipation. The treatment of intractable constipation is challenging, involving pharmacological or non-pharmacological therapies, as well as surgical approaches. Unresolved constipation can negatively impact quality of life, with additional implications for health systems. Consequently, there is an urgent need to identify treatments that are efficacious and safe. OBJECTIVES: To evaluate the efficacy and safety of treatments used for intractable constipation in children. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and two trials registers up to 23 June 2023. We also searched reference lists of included studies for relevant studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing any pharmacological, non-pharmacological, or surgical treatment to placebo or another active comparator, in participants aged between 0 and 18 years with functional constipation who had not responded to conventional medical therapy. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were symptom resolution, frequency of defecation, treatment success, and adverse events; secondary outcomes were stool consistency, painful defecation, quality of life, faecal incontinence frequency, abdominal pain, hospital admission for disimpaction, and school absence. We used GRADE to assess the certainty of evidence for each primary outcome. MAIN RESULTS: This review included 10 RCTs with 1278 children who had intractable constipation. We assessed one study as at low risk of bias across all domains. There were serious concerns about risk of bias in six studies. One study compared the injection of 160 units botulinum toxin A (n = 44) to unspecified oral stool softeners (n = 44). We are very uncertain whether botulinum toxin A injection improves treatment success (risk ratio (RR) 37.00, 95% confidence interval (CI) 5.31 to 257.94; very low certainty evidence, downgraded due to serious concerns with risk of bias and imprecision). Frequency of defecation was reported only for the botulinum toxin A injection group (mean interval of 2.6 days). The study reported no data for the other primary outcomes. One study compared erythromycin estolate (n = 6) to placebo (n = 8). The only primary outcome reported was adverse events, which were 0 in both groups. The evidence is of very low certainty due to concerns with risk of bias and serious imprecision. One study compared 12 or 24 µg oral lubiprostone (n = 404) twice a day to placebo (n = 202) over 12 weeks. There may be little to no difference in treatment success (RR 1.29, 95% CI 0.87 to 1.92; low certainty evidence). We also found that lubiprostone probably results in little to no difference in adverse events (RR 1.05, 95% CI 0.91 to 1.21; moderate certainty evidence). The study reported no data for the other primary outcomes. One study compared three-weekly rectal sodium dioctyl sulfosuccinate and sorbitol enemas (n = 51) to 0.5 g/kg/day polyethylene glycol laxatives (n = 51) over a 52-week period. We are very uncertain whether rectal sodium dioctyl sulfosuccinate and sorbitol enemas improve treatment success (RR 1.33, 95% CI 0.83 to 2.14; very low certainty evidence, downgraded due to serious concerns with risk of bias and imprecision). Results of defecation frequency per week was reported only as modelled means using a linear mixed model. The study reported no data for the other primary outcomes. One study compared biofeedback therapy (n = 12) to no intervention (n = 12). We are very uncertain whether biofeedback therapy improves symptom resolution (RR 2.50, 95% CI 1.08 to 5.79; very low certainty evidence, downgraded due to serious concerns with risk of bias and imprecision). The study reported no data for the other primary outcomes. One study compared 20 minutes of intrarectal electromotive botulinum toxin A using 2800 Hz frequency and botulinum toxin A dose 10 international units/kg (n = 30) to 10 international units/kg botulinum toxin A injection (n = 30). We are very uncertain whether intrarectal electromotive botulinum toxin A improves symptom resolution (RR 0.96, 95% CI 0.76 to 1.22; very low certainty evidence) or if it increases the frequency of defecation (mean difference (MD) 0.00, 95% CI -1.87 to 1.87; very low certainty evidence). We are also very uncertain whether intrarectal electromotive botulinum toxin A has an improved safety profile (RR 0.20, 95% CI 0.01 to 4.00; very low certainty evidence). The evidence for these results is of very low certainty due to serious concerns with risk of bias and imprecision. The study did not report data on treatment success. One study compared the injection of 60 units botulinum toxin A (n = 21) to myectomy of the internal anal sphincter (n = 21). We are very uncertain whether botulinum toxin A injection improves treatment success (RR 1.00, 95% CI 0.75 to 1.34; very low certainty evidence). No adverse events were recorded. The study reported no data for the other primary outcomes. One study compared 0.04 mg/kg oral prucalopride (n = 107) once daily to placebo (n = 108) over eight weeks. Oral prucalopride probably results in little or no difference in defecation frequency (MD 0.50, 95% CI -0.06 to 1.06; moderate certainty evidence); treatment success (RR 0.96, 95% CI 0.53 to 1.72; moderate certainty evidence); and adverse events (RR 1.15, 95% CI 0.94 to 1.39; moderate certainty evidence). The study did not report data on symptom resolution. One study compared transcutaneous electrical stimulation to sham stimulation, and another study compared dietitian-prescribed Mediterranean diet with written instructions versus written instructions. These studies did not report any of our predefined primary outcomes. AUTHORS' CONCLUSIONS: We identified low to moderate certainty evidence that oral lubiprostone may result in little to no difference in treatment success and adverse events compared to placebo. Based on moderate certainty evidence, there is probably little or no difference between oral prucalopride and placebo in defecation frequency, treatment success, or adverse events. For all other comparisons, the certainty of the evidence for our predefined primary outcomes is very low due to serious concerns with study limitations and imprecision. Consequently, no robust conclusions could be drawn.

Patient education interventions for the management of inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) is a life-long condition for which currently there is no cure. Patient educational interventions deliver structured information to their recipients. Evidence suggests patient education can have positive effects in other chronic diseases. OBJECTIVES: To identify the different types of educational interventions, how they are delivered, and to determine their effectiveness and safety in people with IBD. SEARCH METHODS: On 27 November 2022, we searched CENTRAL, Embase, MEDLINE, ClinicalTrials.gov, and WHO ICTRP with no limitations to language, date, document type, or publication status. Any type of formal or informal educational intervention, lasting for any time, that had content focused directly on knowledge about IBD or skills needed for direct management of IBD or its symptoms was included. Delivery methods included face-to-face or remote educational sessions, workshops, guided study via the use of printed or online materials, the use of mobile applications, or any other method that delivers information to patients. SELECTION CRITERIA: All published, unpublished and ongoing randomised control trials (RCTs) that compare educational interventions targeted at people with IBD to any other type of intervention or no intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently conducted data extraction and risk of bias assessment of the included studies. We analysed data using Review Manager Web. We expressed dichotomous and continuous outcomes as risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs). We assessed the certainty of the evidence using GRADE methodology. MAIN RESULTS: We included 14 studies with a total of 2708 randomised participants, aged 11 to 75 years. Two studies examined populations who all had ulcerative colitis (UC); the remaining studies examined a mix of IBD patients (UC and Crohn's disease). Studies considered a range of disease activity states. The length of the interventions ranged from 30 minutes to 12 months. Education was provided in the form of in-person workshops/lectures, and remotely via printed materials or multimedia, smartphones and internet learning. Thirteen studies compared patient education interventions plus standard care against standard care alone. The interventions included seminars, information booklets, text messages, e-learning, a multi professional group-based programme, guidebooks, a staff-delivered programme based on an illustrated book, a standardised programme followed by group session, lectures alternating with group therapy, educational sessions based on an IBD guidebook, internet blog access and text messages, a structured education programme, and interactive videos. Risk of bias findings were concerning in all judgement areas across all studies. No single study was free of unclear or high of bias judgements. Reporting of most outcomes in a homogeneous fashion was limited, with quality of life at study end reported most commonly in six of the 14 studies which allowed for meta-analysis, with all other outcomes reported in a more heterogeneous manner that limited wider analysis. Two studies provided data on disease activity. There was no clear difference in disease activity when patient education (n = 277) combined with standard care was compared to standard care (n = 202). Patient education combined with standard care is probably equivalent to standard care in reducing disease activity in patients with IBD (standardised mean difference (SMD) -0.03, 95% CI -0.25 to 0.20), moderate-certainty evidence. Two studies provided continuous data on flare-up/relapse. There was no clear difference for flare-ups or relapse when patient education (n = 515) combined with standard care was compared to standard care (n = 507), as a continuous outcome. Patient education combined with standard care is probably equivalent to standard care in reducing flare-ups or relapse in patients with IBD (MD -0.00, 95% CI -0.06 to 0.05; moderate-certainty evidence). Three studies provided dichotomous data on flare-up/relapse. The evidence is very uncertain on whether patient education combined with standard care (n = 157) is different to standard care (n = 150) in reducing flare-ups or relapse in patients with IBD (RR 0.94, 95% CI 0.41 to 2.18; very low-certainty evidence). Six studies provided data on quality of life. There was no clear difference in quality of life when patient education combined with standard care (n = 721) was compared to standard care (n = 643). Patient education combined with standard care is probably equivalent to standard care in improving quality of life in patients with IBD (SMD 0.08, 95% CI -0.03 to 0.18; moderate-certainty evidence). The included studies did not report major differences on healthcare access. Medication adherence, patient knowledge and change in quality of life showed conflicting results that varied between no major differences and differences in favour of the educational interventions. Only five studies reported on adverse events. Four reported zero total adverse events and one reported one case of breast cancer and two cases of surgery in their interventions groups, and zero adverse events in their control group. Two studies compared delivery methods of patient education, specifically: web-based patient education interventions versus colour-printed books or text messages; and one study compared frequency of patient education, specifically: weekly educational text messages versus once every other week educational text messages. These did not show major differences for disease activity and quality of life. Other outcomes were not reported. AUTHORS' CONCLUSIONS: The ways in which patient educational support surrounding IBD may impact on disease outcomes is complex. There is evidence that education added to standard care is probably of no benefit to disease activity or quality of life when compared with standard care, and may be of no benefit for occurrence of relapse when compared with standard care. However, as there was a paucity of specific information regarding the components of education or standard care, the utility of these findings is questionable. Further research on the impact of education on our primary outcomes of disease activity, flare-ups/relapse and quality of life is probably not indicated. However, further research is necessary, which should focus on reporting details of the educational interventions and study outcomes that educational interventions could be directly targeted to address, such as healthcare access and medication adherence. These should be informed by direct engagement with stakeholders and people affected by Crohn's and colitis.

ANTECEDENTES: La enfermedad inflamatoria intestinal (EII) es una enfermedad crónica para la que no existe cura en la actualidad. Las intervenciones educativas para pacientes proporcionan información estructurada a sus destinatarios. La evidencia sugiere que la educación del paciente puede tener efectos positivos en otras enfermedades crónicas. OBJETIVOS: Identificar los diferentes tipos de intervenciones educativas, cómo se realizan y determinar su eficacia y seguridad en personas con EII. MÉTODOS DE BÚSQUEDA: El 27 de noviembre de 2022 se realizaron búsquedas en CENTRAL, Embase, MEDLINE, ClinicalTrials.gov y la ICTRP de la OMS sin limitaciones de idioma, fecha, tipo de documento o estado de publicación. Se incluyó cualquier tipo de intervención educativa formal o informal, de cualquier duración, cuyo contenido se centrara directamente en los conocimientos sobre la EII o en las habilidades necesarias para el control directo de la EII o sus síntomas. Los métodos de entrega incluyeron sesiones educativas presenciales o a distancia, talleres, estudio guiado mediante el uso de materiales impresos o en línea, el uso de aplicaciones móviles o cualquier otro método que proporcionara información a los pacientes. CRITERIOS DE SELECCIÓN: Todos los ensayos controlados aleatorizados (ECA) publicados, no publicados y en curso que comparen intervenciones educativas dirigidas a personas con EII con cualquier otro tipo de intervención o ninguna intervención. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Dos autores de la revisión realizaron de forma independiente la extracción de los datos y la evaluación del riesgo de sesgo de los estudios incluidos. Los datos se analizaron mediante Review Manager Web. Los desenlaces dicotómicos y continuos se expresaron como razones de riesgos (RR) y diferencias de medias (DM) con intervalos de confianza (IC) del 95%. La certeza de la evidencia se evaluó mediante el método GRADE. RESULTADOS PRINCIPALES: Se incluyeron 14 estudios con un total de 2708 participantes asignados al azar, de edades comprendidas entre los 11 y los 75 años. Dos estudios examinaron poblaciones que tenían todas colitis ulcerosa (CU); los estudios restantes examinaron una mezcla de pacientes con EII (CU y enfermedad de Crohn). Los estudios consideraron una serie de estados de actividad de la enfermedad. La duración de las intervenciones osciló entre 30 minutos y 12 meses. La educación se impartió en forma de talleres/conferencias presenciales y a distancia mediante material impreso o multimedia, teléfonos inteligentes y aprendizaje por Internet. Trece estudios compararon las intervenciones educativas para pacientes más la atención estándar con la atención estándar sola. Las intervenciones incluyeron seminarios, folletos informativos, mensajes de texto, aprendizaje electrónico, un programa multiprofesional basado en grupos, guías, un programa impartido por el personal basado en un libro ilustrado, un programa estandarizado seguido de una terapia grupal, conferencias alternadas con terapia grupal, sesiones educativas basadas en una guía sobre la EII, acceso a blogs de Internet y mensajes de texto, un programa educativo estructurado y vídeos interactivos. Los hallazgos de riesgo de sesgo fueron preocupantes en todas las áreas de valoración en todos los estudios. Ningún estudio estuvo libre de valoraciones de sesgo incierto o alto. El informe de la mayoría de los desenlaces de forma homogénea fue limitado, con la calidad de vida al final del estudio informada con mayor frecuencia en seis de los 14 estudios que permitieron el metanálisis, y todos los demás desenlaces fueron informados de forma más heterogénea, lo que impidió un análisis más amplio. Dos estudios proporcionaron datos sobre la actividad de la enfermedad. No hubo diferencias claras en la actividad de la enfermedad cuando se comparó la educación del paciente (n = 277) combinada con la atención estándar con la atención estándar sola (n = 202). La educación del paciente combinada con la atención estándar es probablemente equivalente a la atención estándar en la reducción de la actividad de la enfermedad en pacientes con EII (diferencia de medias estandarizada [DME] ­0,03; IC del 95%: ­0,25 a 0,20), evidencia de certeza moderada. Dos estudios proporcionaron datos continuos sobre las exacerbaciones/recaídas. No hubo diferencias claras en las exacerbaciones o recaídas cuando se comparó la educación del paciente (n = 515) combinada con la atención estándar con la atención estándar sola (n = 507), como desenlace continuo. La educación del paciente combinada con la atención estándar es probablemente equivalente a la atención estándar en la reducción de las exacerbaciones o recaídas en pacientes con EII (DM ­0,00; IC del 95%: ­0,06 a 0,05; evidencia de certeza moderada). Tres estudios proporcionaron datos dicotómicos sobre las exacerbaciones/recaídas. La evidencia es muy incierta en cuanto a si la educación del paciente combinada con la atención estándar (n = 157) es diferente de la atención estándar (n = 150) en la reducción de las exacerbaciones o recaídas en pacientes con EII (RR 0,94; IC del 95%: 0,41 a 2,18; evidencia de certeza muy baja). Seis estudios proporcionaron datos sobre la calidad de vida. No hubo diferencias claras en la calidad de vida cuando se comparó la educación del paciente combinada con la atención estándar (n = 721) con la atención estándar sola (n = 643). La educación del paciente combinada con la atención estándar es probablemente equivalente a la atención estándar para mejorar la calidad de vida en los pacientes con EII (DME 0,08; IC del 95%: ­0,03 a 0,18; evidencia de certeza moderada). Los estudios incluidos no informaron de diferencias importantes en el acceso a la asistencia sanitaria. La adherencia a la medicación, el conocimiento de los pacientes y el cambio en la calidad de vida mostraron resultados contradictorios que oscilaron entre la falta de diferencias importantes y las diferencias a favor de las intervenciones educativas. Solo cinco estudios informaron sobre los eventos adversos. Cuatro informaron cero eventos adversos totales y uno informó un caso de cáncer de mama y dos casos de cirugía en sus grupos de intervención, y cero eventos adversos en su grupo de control. Dos estudios compararon los métodos de entrega de la educación del paciente, en concreto: intervenciones educativas para pacientes a través de la web versus libros impresos a color o mensajes de texto; y un estudio comparó la frecuencia de la educación del paciente, en concreto: mensajes de texto educativos semanales versus mensajes de texto educativos una vez cada dos semanas. Estos no mostraron diferencias importantes en cuanto a la actividad de la enfermedad y la calidad de vida. No se informaron otros desenlaces. CONCLUSIONES DE LOS AUTORES: Las formas en que el apoyo educativo al paciente en torno a la EII podría influir en los desenlaces de la enfermedad son complejas. Existe evidencia de que la educación añadida a la atención estándar probablemente no tenga efectos beneficiosos en la actividad de la enfermedad o la calidad de vida en comparación con la atención estándar, y podría no tener beneficios en la aparición de recaídas en comparación con la atención estándar. Sin embargo, como hubo escasa información específica sobre los componentes de la educación o la atención estándar, la utilidad de estos hallazgos es cuestionable. Probablemente no esté indicado investigar más sobre el impacto de la educación en los desenlaces principales de la actividad de la enfermedad, las exacerbaciones/recaídas ni la calidad de vida. Sin embargo, se necesitan más estudios de investigación que deberían centrarse en informar sobre los detalles de las intervenciones educativas y estudiar los desenlaces que las intervenciones educativas podrían abordar directamente, como el acceso a la atención sanitaria y la adherencia a la medicación. Éstas deben basarse en el compromiso directo con las partes interesadas y las personas afectadas por la enfermedad de Crohn y la colitis.

Probiotics for management of functional abdominal pain disorders in children.

BACKGROUND: Functional abdominal pain is pain occurring in the abdomen that cannot be fully explained by another medical condition and is common in children. It has been hypothesised that the use of micro-organisms, such as probiotics and synbiotics (a mixture of probiotics and prebiotics), might change the composition of bacterial colonies in the bowel and reduce inflammation, as well as promote normal gut physiology and reduce functional symptoms. OBJECTIVES: To assess the efficacy and safety of probiotics in the treatment of functional abdominal pain disorders in children. SEARCH METHODS: We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL) and two clinical trials registers from inception to October 2021. SELECTION CRITERIA: Randomised controlled trials (RCTs) that compare probiotic preparations (including synbiotics) to placebo, no treatment or any other interventional preparation in patients aged between 4 and 18 years of age with a diagnosis of functional abdominal pain disorder according to the Rome II, Rome III or Rome IV criteria. DATA COLLECTION AND ANALYSIS: The primary outcomes were treatment success as defined by the primary studies, complete resolution of pain, improvement in the severity of pain and improvement in the frequency of pain. Secondary outcomes included serious adverse events, withdrawal due to adverse events, adverse events, school performance or change in school performance or attendance, social and psychological functioning or change in social and psychological functioning, and quality of life or change in quality life measured using any validated scoring tool. For dichotomous outcomes, we calculated the risk ratio (RR) and corresponding 95% confidence interval (95% CI). For continuous outcomes, we calculated the mean difference (MD) and corresponding 95% CI. MAIN RESULTS: We included 18 RCTs assessing the effectiveness of probiotics and synbiotics in reducing the severity and frequency of pain, involving a total of 1309 patients. Probiotics may achieve more treatment success when compared with placebo at the end of the treatment, with 50% success in the probiotic group versus 33% success in the placebo group (RR 1.57, 95% CI 1.05 to 2.36; 554 participants; 6 studies; I2 = 70%; low-certainty evidence).  It is not clear whether probiotics are more effective than placebo for complete resolution of pain, with 42% success in the probiotic group versus 27% success in the placebo group (RR 1.55, 95% CI 0.94 to 2.56; 460 participants; 6 studies; I2 = 70%; very low-certainty evidence). We judged the evidence to be of very low certainty due to high inconsistency and risk of bias. We were unable to draw meaningful conclusions from our meta-analyses of the pain severity and pain frequency outcomes due to very high unexplained heterogeneity leading to very low-certainty evidence. None of the included studies reported serious adverse events. Meta-analysis showed no difference in withdrawals due to adverse events between probiotics (1/275) and placebo (1/269) (RR 1.00, 95% CI 0.07 to 15.12). The results were identical for the total patients with any reported adverse event outcome. However, these results are of very low certainty due to imprecision from the very low numbers of events and risk of bias. Synbiotics may result in more treatment success at study end when compared with placebo, with 47% success in the probiotic group versus 35% success in the placebo group (RR 1.34, 95% CI 1.03 to 1.74; 310 participants; 4 studies; I2 = 0%; low certainty). One study used Bifidobacterium coagulans/fructo-oligosaccharide, one used Bifidobacterium lactis/inulin, one used Lactobacillus rhamnosus GG/inulin and in one study this was not stated).  Synbiotics may result in little difference in complete resolution of pain at study end when compared with placebo, with 52% success in the probiotic group versus 32% success in the placebo group (RR 1.65, 95% CI 0.97 to 2.81; 131 participants; 2 studies; I2 = 18%; low-certainty evidence). We were unable to draw meaningful conclusions from our meta-analyses of pain severity or frequency of pain due to very high unexplained heterogeneity leading to very low-certainty evidence.  None of the included studies reported serious adverse events. Meta-analysis showed little to no difference in withdrawals due to adverse events between synbiotics (8/155) and placebo (1/147) (RR 4.58, 95% CI 0.80 to 26.19), or in any reported adverse events (3/96 versus 1/93, RR 2.88, 95% CI 0.32 to 25.92). These results are of very low certainty due to imprecision from the very low numbers of events and risk of bias. There were insufficient data to analyse by subgroups of specific functional abdominal pain syndrome (irritable bowel syndrome, functional dyspepsia, abdominal migraine, functional abdominal pain - not otherwise specified) or by specific strain of probiotic. There was insufficient evidence on school performance or change in school performance/attendance, social and psychological functioning, or quality of life to draw conclusions about the effects of probiotics or synbiotics on these outcomes. AUTHORS' CONCLUSIONS: The results from this review demonstrate that probiotics and synbiotics may be more efficacious than placebo in achieving treatment success, but the evidence is of low certainty. The evidence demonstrates little to no difference between probiotics or synbiotics and placebo in complete resolution of pain. We were unable to draw meaningful conclusions about the impact of probiotics or synbiotics on the frequency and severity of pain as the evidence was all of very low certainty due to significant unexplained heterogeneity or imprecision. There were no reported cases of serious adverse events when using probiotics or synbiotics amongst the included studies, although a review of RCTs may not be the best context to assess long-term safety. The available evidence on adverse effects was of very low certainty and no conclusions could be made in this review. Safety will always be a priority in paediatric populations when considering any treatment. Reporting of all adverse events, adverse events needing withdrawal, serious adverse events and, particularly, long-term safety outcomes are vital to meaningfully move forward the evidence base in this field. Further targeted and appropriately designed RCTs are needed to address the gaps in the evidence base. In particular, appropriate powering of studies to confirm the safety of specific strains not yet investigated and studies to investigate long-term follow-up of patients are both warranted.

Remote care through telehealth for people with inflammatory bowel disease.

BACKGROUND: People with inflammatory bowel disease (IBD) require intensive follow-up with frequent consultations after diagnosis. IBD telehealth management includes consulting by phone, instant messenger, video, text message, or web-based services. Telehealth can be beneficial for people with IBD, but may have its own set of challenges. It is important to systematically review the evidence on the types of remote or telehealth approaches that can be deployed in IBD. This is particularly relevant following the coronavirus disease 2019 (COVID-19) pandemic, which led to increased self- and remote-management. OBJECTIVES: To identify the communication technologies used to achieve remote healthcare for people with inflammatory bowel disease and to assess their effectiveness. SEARCH METHODS: On 13 January 2022, we searched CENTRAL, Embase, MEDLINE, three other databases, and three trials registries with no limitations on language, date, document type, or publication status. SELECTION CRITERIA: All published, unpublished, and ongoing randomised controlled trials (RCTs) that evaluated telehealth interventions targeted at people with IBD versus any other type of intervention or no intervention. We did not include studies based on digital patient information resources or education resources, unless they formed part of a wider package including an element of telehealth. We excluded studies where remote monitoring of blood or faecal tests was the only form of monitoring. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from the included studies and assessed their risk of bias. We analysed studies on adult and paediatric populations separately. We expressed the effects of dichotomous outcomes as risk ratios (RRs) and the effects of continuous outcomes as mean differences (MDs) or standardised mean differences (SMDs), each with their 95% confidence intervals (CIs). We assessed the certainty of the evidence using GRADE methodology. MAIN RESULTS: We included 19 RCTs with a total of 3489 randomised participants, aged eight to 95 years. Three studies examined only people with ulcerative colitis (UC), two studies examined only people with Crohn's disease (CD), and the remaining studies examined a mix of IBD patients. Studies considered a range of disease activity states. The length of the interventions ranged from six months to two years. The telehealth interventions were web-based and telephone-based. Web-based monitoring versus usual care Twelve studies compared web-based disease monitoring to usual care. Three studies, all in adults, provided data on disease activity. Web-based disease monitoring (n = 254) is probably equivalent to usual care (n = 174) in reducing disease activity in people with IBD (SMD 0.09, 95% CI -0.11 to 0.29). The certainty of the evidence is moderate. Five studies on adults provided dichotomous data that we could use for a meta-analysis on flare-ups. Web-based disease monitoring (n = 207/496) is probably equivalent to usual care (n = 150/372) for the occurrence of flare-ups or relapses in adults with IBD (RR 1.09, 95% CI 0.93 to 1.27). The certainty of the evidence is moderate. One study provided continuous data. Web-based disease monitoring (n = 465) is probably equivalent to usual care (n = 444) for the occurrence of flare-ups or relapses in adults with CD (MD 0.00 events, 95% CI -0.06 to 0.06). The certainty of the evidence is moderate. One study provided dichotomous data on flare-ups in a paediatric population. Web-based disease monitoring (n = 28/84) may be equivalent to usual care (n = 29/86) for the occurrence of flare-ups or relapses in children with IBD (RR 0.99, 95% CI 0.65 to 1.51). The certainty of the evidence is low. Four studies, all in adults, provided data on quality of life. Web-based disease monitoring (n = 594) is probably equivalent to usual care (n = 505) for quality of life in adults with IBD (SMD 0.08, 95% CI -0.04 to 0.20). The certainty of the evidence is moderate. Based on continuous data from one study in adults, we found that web-based disease monitoring probably leads to slightly higher medication adherence compared to usual care (MD 0.24 points, 95% CI 0.01 to 0.47). The results are of moderate certainty. Based on continuous data from one paediatric study, we found no difference between web-based disease monitoring and usual care in terms of their effect on medication adherence (MD 0.00, 95% CI -0.63 to 0.63), although the evidence is very uncertain. When we meta-analysed dichotomous data from two studies on adults, we found no difference between web-based disease monitoring and usual care in terms of their effect on medication adherence (RR 0.87, 95% CI 0.62 to 1.21), although the evidence is very uncertain. We were unable to draw any conclusions on the effects of web-based disease monitoring compared to usual care on healthcare access, participant engagement, attendance rate, interactions with healthcare professionals, and cost- or time-effectiveness. The certainty of the evidence is very low. AUTHORS' CONCLUSIONS: The evidence in this review suggests that web-based disease monitoring is probably no different to standard care in adults when considering disease activity, occurrence of flare-ups or relapse, and quality of life. There may be no difference in these outcomes in children, but the evidence is limited. Web-based monitoring probably increases medication adherence slightly compared to usual care. We are uncertain about the effects of web-based monitoring versus usual care on our other secondary outcomes, and about the effects of the other telehealth interventions included in our review, because the evidence is limited. Further studies comparing web-based disease monitoring to standard care for the clinical outcomes reported in adults are unlikely to change our conclusions, unless they have longer follow-up or investigate under-reported outcomes or populations. Studies with a clearer definition of web-based monitoring would enhance applicability, enable practical dissemination and replication, and enable alignment with areas identified as important by stakeholders and people affected by IBD.

Infliximab for medical induction of remission in Crohn's disease.

BACKGROUND: Infliximab is a monoclonal antibody that binds and neutralises tumour necrosis factor-alpha (TNF-α), which is present in high levels in the blood serum, mucosa and stool of people with Crohn's disease. OBJECTIVES: To evaluate the benefits and harms of infliximab alone or in combination with another agent for induction of remission in Crohn's disease compared to placebo or active medical therapies. SEARCH METHODS: On 31 August 2021 and 4 March 2023, we searched CENTRAL, MEDLINE, Embase, ClinicalTrials.gov and World Health Organization ICTRP. SELECTION CRITERIA: Randomised control trials (RCTs) comparing infliximab alone or in combination with another agent to placebo or another active comparator in adults with active Crohn's disease. DATA COLLECTION AND ANALYSIS: Pairs of review authors independently selected studies and conducted data extraction and risk of bias assessment. We expressed outcomes as risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI). We assessed the certainty of the evidence using GRADE. Our primary outcomes were clinical remission, clinical response and withdrawals due to adverse events. Our secondary outcomes were endoscopic remission, histological remission, endoscopic response, and serious and total adverse events. MAIN RESULTS: The search identified 10 RCTs with 1101 participants. They were conducted between 1999 and 2019, and 7/10 RCTs included biologically naive participants. All but one RCT, which did not provide information, were multicentre and funded by pharmaceutical companies, and their authors declared conflicts. The age of the participants ranged from 26 to 65 years. Results were based on one study unless otherwise stated. Infliximab 5 mg/kg to 10 mg/kg may be more effective than placebo at week four for clinical remission (30/55 versus 3/25; RR 4.55, 95% CI 1.53 to 13.50; number needed to treat for an additional beneficial outcome (NNTB) 3) and response (36/55 versus 4/25; RR 4.09, 95% CI 1.63 to 10.25, NNTB 3). The evidence was low certainty. The study did not report withdrawals due to adverse events. We could not draw conclusions on the effects of infliximab 5 mg/kg to 10 mg/kg compared to placebo for fistulating participants for clinical remission (29/63 versus 4/31; RR 3.57, 95% CI 1.38 to 9.25; NNTB 4), response (48/106 versus 15/75; RR 1.94, 95% CI 1.10 to 3.41; NNTB 6; 2 studies) or withdrawals due to adverse events (2/63 versus 0/31; RR 2.50, 95% CI 0.12 to 50.54). The evidence was very low certainty. Infliximab used in combination with purine analogues is probably more effective than purine analogues alone for clinical remission at weeks 24 to 26 (182/301 versus 95/302; RR 1.92, 95% CI 1.59 to 2.32, NNTB 4; 4 studies; moderate-certainty evidence) and clinical response at week 26 (107/177 versus 66/178; RR 1.64, 95% CI 1.31 to 2.05; NNTB 5; 2 studies; moderate-certainty evidence). There may be little or no difference in withdrawals due to adverse events at week 26 (62/302 versus 53/301; RR 0.87, 95% CI 0.63 to 1.21; 4 studies; low-certainty evidence). Infliximab alone may be more effective than purine analogues alone at week 26 for clinical remission (85/177 versus 57/178; RR 1.50, 95% CI 1.15 to 1.95; NNTB 7; 2 studies) and response (94/177 versus 66/178; RR 1.44, 95% CI 1.13 to 1.82; NNTB 7; 2 studies). There may be little or no difference in withdrawals due to adverse events (30/177 versus 43/178; RR 0.70, 95% CI 0.46 to 1.06; 4 studies). The evidence was low certainty. We could not draw any conclusions on the effects of infliximab 5 mg/kg compared to 10 mg/kg for clinical remission (19/27 versus 11/28; RR 1.79, 95% CI 1.06 to 3.02) and response (22/27 versus 24/28; RR 1.63, 95% CI 1.08 to 2.46). The evidence was very low certainty. Withdrawals due to adverse events were not reported. We could not draw any conclusions on the effects of infliximab 5 mg/kg compared to 10 mg/kg in an exclusively fistulating population for clinical remission (17/31 versus 12/32; RR 1.46, 95% CI 0.84 to 2.53), response (21/31 versus 18/32; RR 1.20, 95% CI 0.82 to 1.78), or withdrawals due to adverse events (1/31 versus 1/32; RR 1.03, 95% CI 0.07 to 15.79). The evidence was very low certainty. We could not draw any conclusions on the effects of infliximab 5 mg/kg compared to 20 mg/kg for clinical remission (19/27 versus 11/28; RR 1.79, 95% CI 1.06 to 3.02) or response (22/27 versus 18/28; RR 1.27, 95% CI 0.91 to 1.76). The evidence was very low certainty. Withdrawals due to adverse events were not reported. We could not draw any conclusions on the effects of infliximab 10 mg/kg compared to 20 mg/kg for clinical remission (11/28 versus 11/28; RR 1.00, 95% CI 0.52 to 1.92) or response (14/28 versus 18/28; RR 0.78, 95% CI 0.49 to 1.23). The evidence was very low certainty. Withdrawals due to adverse events were not reported. There may be little or no difference between infliximab and a CT-P13 biosimilar at week six for clinical remission (47/109 versus 49/111; RR 0.98, 95% CI 0.72 to 1.32), response (67/109 versus 70/111; RR 0.97, 95% CI 0.79 to 1.20) and withdrawals due to adverse events (21/109 versus 17/111; RR 1.26, 95% CI 0.70 to 2.25). The evidence was low certainty. AUTHORS' CONCLUSIONS: Infliximab in combination with purine analogues is probably more effective than purine analogues alone in inducing clinical remission and clinical response. Infliximab alone may be more effective in inducing clinical remission and response than purine analogues alone or placebo. Infliximab may be similar in efficacy to a CT-P13 biosimilar and there may be little or no difference in withdrawals due to adverse events. We were unable to draw meaningful conclusions as to whether infliximab alone is effective when used for exclusively fistulating populations. There was evidence that there may be little or no difference in withdrawal due to adverse events between infliximab plus purines compared with purines alone, as well as infliximab alone compared with purines alone. Meaningful conclusions cannot be drawn on all other outcomes related to adverse events due to very low certainty evidence.

Antibiotics for the induction and maintenance of remission in ulcerative colitis.

BACKGROUND: Antibiotics have been considered to treat ulcerative colitis (UC) due to their antimicrobial properties against intestinal bacteria linked to inflammation. However, there are concerns about their efficacy and safety. OBJECTIVES: To determine whether antibiotic therapy is safe and effective for the induction and maintenance of remission in people with UC. SEARCH METHODS: We searched five electronic databases on 10 December 2021 for randomised controlled trials (RCTs) comparing antibiotic therapy to placebo or an active comparator. SELECTION CRITERIA: We considered people with UC of all ages, treated with antibiotics of any type, dose, and route of administration for inclusion. Induction studies required a minimum duration of two weeks for inclusion. Maintenance studies required a minimum duration of three months to be considered for inclusion. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our primary outcome for induction studies was failure to achieve remission and for maintenance studies was relapse, as defined by the primary studies. MAIN RESULTS: We included 12 RCTs (847 participants). One maintenance of remission study used sole antibiotic therapy compared with 5-aminosalicylic acid (5-ASA). All other trials used concurrent medications or standard care regimens and antibiotics as an adjunct therapy or compared antibiotics with other adjunct therapies to examine the effect on induction of remission. There is high certainty evidence that antibiotics (154/304 participants) compared to placebo (175/304 participants) result in no difference in failure to achieve clinical remission (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.74 to 1.06). A subgroup analysis found no differences when steroids, steroids plus 5-ASA, or steroids plus 5-ASA plus probiotics were used as additional therapies to antibiotics and placebo. There is low certainty evidence that antibiotics (102/168 participants) compared to placebo (121/175 participants) may result in no difference in failure to achieve clinical response (RR 0.75, 95% CI 0.47 to 1.22). A subgroup analysis found no differences when steroids or steroids plus 5-ASA were used as additional therapies to antibiotics and placebo. There is low certainty evidence that antibiotics (6/342 participants) compared to placebo (5/349 participants) may result in no difference in serious adverse events (RR 1.19, 95% CI 0.38 to 3.71). A subgroup analysis found no differences when steroids were additional therapies to antibiotics and placebo. There is low certainty evidence that antibiotics (3/342 participants) compared to placebo (1/349 participants) may result in no difference in withdrawals due to adverse events (RR 2.06, 95% CI 0.27 to 15.72). A subgroup analysis found no differences when steroids or steroids plus 5-ASA were additional therapies to antibiotics and placebo. It is unclear if there is any difference between antibiotics in combination with probiotics compared to no treatment or placebo for failure to achieve clinical remission (RR 0.68, 95% CI 0.39 to 1.19), serious adverse events (RR 1.00, 95% CI 0.07 to 15.08), or withdrawals due to adverse events (RR 1.00, 95% CI 0.07 to 15.08). The certainty of the evidence is very low. It is unclear if there is any difference between antibiotics compared to 5-ASA for failure to achieve clinical remission (RR 2.20, 95% CI 1.17 to 4.14). The certainty of the evidence is very low. It is unclear if there is any difference between antibiotics compared to probiotics for failure to achieve clinical remission (RR 0.47, 95% CI 0.23 to 0.94). The certainty of the evidence is very low. It is unclear if there is any difference between antibiotics compared to 5-ASA for failure to maintain clinical remission (RR 0.71, 95% CI 0.47 to 1.06). The certainty of the evidence is very low. It is unclear if there is any difference between antibiotics compared to no treatment for failure to achieve clinical remission in a mixed population of people with active and inactive disease (RR 0.56, 95% CI 0.29 to 1.07). The certainty of the evidence is very low. For all other outcomes, no effects could be estimated due to a lack of data. AUTHORS' CONCLUSIONS: There is high certainty evidence that there is no difference between antibiotics and placebo in the proportion of people who achieve clinical remission at the end of the intervention period. However, there is evidence that there may be a greater proportion of people who achieve clinical remission and probably a greater proportion who achieve clinical response with antibiotics when compared with placebo at 12 months. There may be no difference in serious adverse events or withdrawals due to adverse events between antibiotics and placebo. No clear conclusions can be drawn for any other comparisons. A clear direction for future research appears to be comparisons of antibiotics and placebo (in addition to standard therapies) with longer-term measurement of outcomes. Additionally. As there were single studies of other head-to-head comparisons, there may be scope for future studies in this area.

Tacrolimus (FK506) for induction of remission in corticosteroid-refractory ulcerative colitis.

BACKGROUND: There are a limited number of treatment options for people with corticosteroid-refractory ulcerative colitis. Animal models of inflammatory bowel disease and uncontrolled studies in humans suggest that tacrolimus may be an effective treatment for ulcerative colitis. OBJECTIVES: To evaluate the efficacy and safety of tacrolimus for induction of remission in people with corticosteroid-refractory ulcerative colitis. SEARCH METHODS: We searched the Cochrane Gut group specialised register, CENTRAL, MEDLINE (PubMed), Embase, Clinicaltrials.gov and WHO ICTRP from inception to October 2021 to identify relevant randomised controlled trials (RCT). SELECTION CRITERIA: Two review authors independently selected potentially relevant studies to determine eligibility based on the prespecified criteria. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and analysed them using Review Manager Web. The primary outcomes were induction of remission and clinical improvement, as defined by the studies and expressed as a percentage of the participants randomised (intention-to-treat analysis). MAIN RESULTS: This review included five RCTs with 347 participants who had active ulcerative colitis or ulcerative proctitis. The duration of intervention varied between two weeks and eight weeks. Tacrolimus versus placebo Tacrolimus (oral and rectal) may be superior in achieving clinical remission compared to placebo (oral and rectal) (14/87 participants with tacrolimus versus 1/61 participants with placebo; risk ratio (RR) 3.76, 95% confidence interval (CI) 1.03 to 13.73; 3 studies). These results are of low certainty due to imprecision and risk of bias. Tacrolimus (oral and rectal) may be superior for clinical improvement compared to placebo (oral and rectal) (45/87 participants with tacrolimus versus 7/61 participants with placebo; RR 4.47, 95% CI 2.15 to 9.29; 3 studies). These results are of low certainty due to imprecision and risk of bias. The evidence is very uncertain about the effects of tacrolimus (oral and rectal) on serious adverse events compared to placebo (oral and rectal) (2/87 participants with tacrolimus versus 0/61 participants with placebo; RR 2.44, 95% CI 0.12 to 48.77; 3 studies). These results are of very low certainty due to high imprecision and risk of bias. Tacrolimus versus ciclosporin One study compared oral tacrolimus to intravenous ciclosporin, with an intervention lasting two weeks and 113 randomised participants. The evidence is very uncertain about the effect of tacrolimus on achievement of clinical remission compared to ciclosporin (15/33 participants with tacrolimus versus 24/80 participants with ciclosporin; RR 1.52, 95% CI 0.92 to 2.50). The results are of very low certainty due to risk of bias and high imprecision. The evidence is very uncertain about the effect of tacrolimus on clinical improvement compared to intravenous ciclosporin (23/33 participants with tacrolimus versus 62/80 participants with ciclosporin; RR 0.90, 95% CI 0.70 to 1.16). The results are of very low certainty due to risk of bias and imprecision. Tacrolimus versus beclometasone One study compared tacrolimus suppositories with beclometasone suppositories in an intervention lasting four weeks with 88 randomised participants. There may be little to no difference in achievement of clinical remission (16/44 participants with tacrolimus versus 15/44 participants with beclometasone; RR 1.07, 95% CI 0.60 to 1.88). The results are of low certainty due to high imprecision. There may be little to no difference in clinical improvement when comparing tacrolimus suppositories to beclometasone suppositories (22/44 participants with tacrolimus versus 22/44 with beclometasone; RR 1.00, 95% CI 0.66 to 1.52). The results are of low certainty due to high imprecision. There may be little to no difference in serious adverse events when comparing tacrolimus suppositories to beclometasone suppositories (1/44 participants with tacrolimus versus 0/44 with beclometasone; RR 3.00, 95% CI 0.13 to 71.70). These results are of low certainty due to high imprecision. There may be little to no difference in total adverse events when comparing tacrolimus suppositories to beclometasone suppositories (21/44 participants with tacrolimus versus 14/44 participants with beclometasone; RR 1.50, 95% CI 0.88 to 2.55). These results are of low certainty due to high imprecision. No secondary outcomes were reported for people requiring rescue medication or to undergo surgery. AUTHORS' CONCLUSIONS: There is low-certainty evidence that tacrolimus may be superior to placebo for achievement of clinical remission and clinical improvement in corticosteroid-refractory colitis or corticosteroid-refractory proctitis. The evidence is very uncertain about the effect of tacrolimus compared to ciclosporin for achievement of clinical remission or clinical improvement. There may be no difference between tacrolimus and beclometasone for inducing clinical remission or clinical improvement. The cohorts studied to date were small, with missing data sets, offered short follow-up and the clinical endpoints used were not in line with those suggested by regulatory bodies. Therefore, no clinical practice conclusions can be made. This review highlights the need for further research that targets the relevant clinical questions, uses appropriate trial methodology and reports key findings in a systematic manner that facilitates future integration of findings with current evidence to better inform clinicians and patients. Future studies need to be adequately powered and of pertinent duration so as to capture the efficacy and effectiveness of tacrolimus in the medium to long term. Well-structured efficacy studies need to be followed up by long-term phase 4 extensions to provide key outputs and inform in a real-world setting.

Probiotics for treatment of chronic constipation in children.

BACKGROUND: Functional constipation is defined as chronic constipation with no identifiable underlying cause. It is a significant cause of morbidity in children, accounting for up to 25% of visits to paediatric gastroenterologists. Probiotic preparations may sufficiently alter the gut microbiome and promote normal gut physiology in a way that helps relieve functional constipation. Several studies have sought to address this hypothesis, as well as the role of probiotics in other functional gut disorders. Therefore, it is important to have a focused review to assess the evidence to date. OBJECTIVES: To evaluate the efficacy and safety of probiotics for the management of chronic constipation without a physical explanation in children. SEARCH METHODS: On 28 June 2021, we searched CENTRAL, MEDLINE, Embase, CINAHL, AMED, WHO ICTR, and ClinicalTrials.gov, with no language, date, publication status, or document type limitations. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that assessed probiotic preparations (including synbiotics) compared to placebo, no treatment or any other interventional preparation in people aged between 0 and 18 years old with a diagnosis of functional constipation according to consensus criteria (such as Rome IV). DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 14 studies (1127 randomised participants): 12 studies assessed probiotics in the treatment of functional constipation, whilst two studies investigated synbiotic preparations. Three studies compared probiotics to placebo in relation to the frequency of defecation at study end, but we did not pool them as there was very significant unexplained heterogeneity. Four studies compared probiotics to placebo in relation to treatment success. There may be no difference in global improvement/treatment success (RR 1.29, 95% CI 0.73 to 2.26; 313 participants; low-certainty evidence). Five studies compared probiotics to placebo in relation to withdrawals due to adverse events, with the pooled effect suggesting there may be no difference (RR 0.64, 95% CI 0.21 to 1.95; 357 participants; low-certainty evidence). The pooled estimate from three studies that compared probiotics plus an osmotic laxative to osmotic laxative alone found there may be no difference in frequency of defecation (MD -0.01, 95% CI -0.57 to 0.56; 268 participants; low-certainty evidence). Two studies compared probiotics plus an osmotic laxative to osmotic laxative alone in relation to global improvement/treatment success, and found there may be no difference between the treatments (RR 0.95, 95% CI 0.79 to 1.15; 139 participants; low-certainty evidence). Three studies compared probiotics plus osmotic laxative to osmotic laxative alone in relation to withdrawals due to adverse events, but it is unclear if there is a difference between them (RR 2.86, 95% CI 0.12 to 68.35; 268 participants; very low-certainty evidence). Two studies compared probiotics versus magnesium oxide. It is unclear if there is a difference in frequency of defecation (MD 0.28, 95% CI -0.58 to 1.14; 36 participants), treatment success (RR 1.08, 95% CI 0.74 to 1.57; 36 participants) or withdrawals due to adverse events (RR 0.50, 95% CI 0.05 to 5.04; 77 participants). The certainty of the evidence is very low for these outcomes. One study assessed the role of a synbiotic preparation in comparison to placebo. There may be higher treatment success in favour of synbiotics compared to placebo (RR 2.32, 95% CI 1.54 to 3.47; 155 participants; low-certainty evidence). The study reported that there were no withdrawals due to adverse effects in either group. One study assessed a synbiotic plus paraffin compared to paraffin alone. It is uncertain if there is a difference in frequency of defecation (MD 0.74, 95% CI -0.96, 2.44; 66 participants; very low-certainty evidence), or treatment success (RR 0.91, 95% CI 0.71 to 1.17; 66 participants; very low-certainty evidence). The study reported that there were no withdrawals due to adverse effects in either group. One study compared a synbiotic preparation to paraffin. It is uncertain if there is a difference in frequency of defecation (MD -1.53, 95% CI -3.00, -0.06; 60 participants; very low-certainty evidence) or in treatment success (RR 0.86, 95% CI 0.65, 1.13; 60 participants; very low-certainty evidence). The study reported that there were no withdrawals due to adverse effects in either group. All secondary outcomes were either not reported or reported in a way that did not allow for analysis. AUTHORS' CONCLUSIONS: There is insufficient evidence to conclude whether probiotics are efficacious in successfully treating chronic constipation without a physical explanation in children or changing the frequency of defecation, or whether there is a difference in withdrawals due to adverse events when compared with placebo. There is limited evidence from one study to suggest a synbiotic preparation may be more likely than placebo to lead to treatment success, with no difference in withdrawals due to adverse events. There is insufficient evidence to draw efficacy or safety conclusions about the use of probiotics in combination with or in comparison to any of the other interventions reported. The majority of the studies that presented data on serious adverse events reported that no events occurred. Two studies did not report this outcome. Future studies are needed to confirm efficacy, but the research community requires guidance on the best context for probiotics in such studies, considering where they should be best considered in a potential treatment hierarchy and should align with core outcome sets to support future interpretation of findings.

Inflammatory Bowel Disease Treatments and Predictive Biomarkers of Therapeutic Response.

Inflammatory bowel disease (IBD) is a chronic immune-mediated inflammation of the gastrointestinal tract with a highly heterogeneous presentation. It has a relapsing and remitting clinical course that necessitates lifelong monitoring and treatment. Although the availability of a variety of effective therapeutic options including immunomodulators and biologics (such as TNF, CAM inhibitors) has led to a paradigm shift in the treatment outcomes and clinical management of IBD patients, some patients still either fail to respond or lose their responsiveness to therapy over time. Therefore, according to the recent Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE-II) recommendations, continuous disease monitoring from symptomatic relief to endoscopic healing along with short- and long-term therapeutic responses are critical for providing IBD patients with a tailored therapy algorithm. Moreover, considering the high unmet need for novel therapeutic approaches for IBD patients, various new modulators of cytokine signaling events (for example, JAK/TYK inhibitors), inhibitors of cytokines (for example IL-12/IL-23, IL-22, IL-36, and IL-6 inhibitors), anti-adhesion and migration strategies (for example, ß7 integrin, sphingosine 1-phosphate receptors, and stem cells), as well as microbial-based therapeutics to decolonize the bed buds (for example, fecal microbiota transplantation and bacterial inhibitors) are currently being evaluated in different phases of controlled clinical trials. This review aims to offer a comprehensive overview of available treatment options and emerging therapeutic approaches for IBD patients. Furthermore, predictive biomarkers for monitoring the therapeutic response to different IBD therapies are also discussed.

Interventions for the management of abdominal pain in ulcerative colitis.

BACKGROUND: Ulcerative colitis (UC) is a chronic inflammation of the colon characterised by periods of relapse and remission. It starts in the rectum and can extend throughout the colon. UC and Crohn's disease (CD) are the most common inflammatory bowel diseases (IBDs). However, UC tends to be more common than CD. It has no known cure but can be managed with medication and surgery. However, studies have shown that abdominal pain persists in up to one-third of people with UC in remission. Abdominal pain could be a symptom of relapse of the disease due to adverse effects of medication, surgical complications and strictures or adhesions secondary to UC. OBJECTIVES: To assess the efficacy and safety of interventions for managing abdominal pain in people with ulcerative colitis. SEARCH METHODS: We searched CENTRAL, MEDLINE and five other databases and clinical trials registries on 28 April 2021. We contacted authors of relevant studies and ongoing or unpublished trials that may be relevant to the review. We also searched references of trials and systematic reviews for any additional trials. SELECTION CRITERIA: All published, unpublished and ongoing randomised trials that compared interventions for the management of abdominal pain with other active interventions or standard therapy, placebo or no therapy were included. People with both active and inactive disease were included. We excluded studies that did not report on any abdominal pain outcomes. DATA COLLECTION AND ANALYSIS: Two review authors independently conducted data extraction and 'Risk of bias' assessments. We analysed data using Review Manager 5. We expressed dichotomous and continuous outcomes as risk ratios (RRs) and mean differences (MDs), respectively, with 95% confidence intervals. We assessed the certainty of the evidence using the GRADE methodology. MAIN RESULTS: We included five studies (360 randomised participants). Studies considered mainly participants in an inactive state of the disease.   No conclusions could be drawn about the efficacy of any of the interventions on pain frequency, pain intensity, and treatment success. The certainty of the evidence was very low for all comparisons because of imprecision due to sparse data, and risk of bias. One study compared a low FODMAPs diet (n=13) to a sham diet (n=13). The evidence is very uncertain about the effect of this treatment on pain frequency (MD -4.00, 95% CI -20.61 to 12.61) and intensity (MD -9.00, 95% CI -20.07 to 2.07). Treatment success was not reported. One study compared relaxation training (n=20) to wait-list (n=20). The evidence is very uncertain about the effect of this treatment on pain frequency at end of intervention (MD 2.60, 95% CI 1.14 to 4.06) and 6-month follow-up (MD 3.30, 95% CI 1.64 to 4.96). Similarly, the evidence is very uncertain about the effect of this treatment on pain intensity at end of intervention (MD -1.70, 95% CI -2.92 to -0.48) and 6-month follow-up (MD -2.30, 95% CI -3.70 to -0.90). Treatment success was not reported. One study compared yoga (n=30) to no intervention (n=30). The study defined treatment success as the presence or absence of pain; however, the data they provided was unclear. Pain frequency and intensity were not reported. One study compared a kefir diet (Lactobacillus bacteria, n=15) to no intervention (n=15). The evidence is very uncertain about the effect of this treatment on pain intensity (MD -0.17, 95% CI -0.91 to 0.57). Pain frequency and treatment success were not reported. One study compared a stellate ganglion block treatment (n=90) to sulfasalazine treatment (n=30). The study defined treatment success as "stomachache"; however, the data they provided was unclear. Pain frequency and intensity were not reported. Two studies reported withdrawals due to adverse events. One study reported withdrawals due to adverse events as zero. Two studies did not report this outcome.  We cannot draw any conclusions about the effects of any of the interventions on withdrawals due to adverse events because of the very limited evidence. The reporting of secondary outcomes was inconsistent. Adverse events tended to be very low or zero. However, we can make no clear judgements about adverse events for any of the interventions, due to the low number of events. Anxiety was measured and reported at end of intervention in only one study (yoga versus no intervention), and depression was not measured in any of the studies. We can therefore draw no meaningful conclusions about these outcomes. AUTHORS' CONCLUSIONS: We found very low-certainty evidence on the efficacy and safety of interventions for the management of abdominal pain in ulcerative colitis. Pervasive issues with very serious imprecision from small samples size and high risk of bias have led to very low-certainty outcomes, precluding conclusions. While few adverse events and no serious adverse events were reported, the certainty of these findings was again very low for all comparisons, so no conclusions can be drawn. There is a need for further research. We have identified eight ongoing studies in this review, so an update will be warranted. It is key that future research addresses the issues leading to reduced certainty of outcomes, specifically sample size and reporting that leads to high risk of bias. It is also important that if researchers are considering pain as a critical outcome, they should report clearly if participants were pain-free at baseline; in that case, data would be best presented as separate subgroups throughout their research.

Interventions for the management of abdominal pain in Crohn's disease and inflammatory bowel disease.

BACKGROUND: Crohn's disease is a remitting and relapsing disorder that can affect the whole gastrointestinal tract. Active disease symptoms include abdominal pain, fatigue, weight loss, and diarrhoea. There is no known cure; however, the disease can be managed, and therefore places a huge financial burden on healthcare systems. Abdominal pain is a common and debilitating symptom of Crohn's and other inflammatory bowel diseases (IBDs), and is multifaceted. Abdominal pain in Crohn's disease could be a symptom of disease relapse or related to medication adverse effects, surgical complications and strictures or adhesions secondary to IBD. In the absence of these factors, around 20 to 50% of people with Crohn's in remission still experience pain. OBJECTIVES: To assess the efficacy and safety of interventions for managing abdominal pain in people with Crohn's disease and IBD (where data on ulcerative colitis and Crohn's disease could not be separated). SEARCH METHODS: We searched CENTRAL, MEDLINE, three other databases, and clinical trials registries on 29 April 2021. We also searched the references of trials and systematic reviews for any additional trials. SELECTION CRITERIA: All published, unpublished, and ongoing randomised trials that compared interventions for the management of abdominal pain in the setting of Crohn's disease and IBD, with other active interventions or standard therapy, placebo, or no therapy were included. We excluded studies that did not report on any abdominal pain outcomes. DATA COLLECTION AND ANALYSIS: Five review authors independently conducted data extraction and 'Risk of bias' assessment of the included studies. We analysed data using Review Manager 5. We expressed dichotomous and continuous outcomes as risk ratios and mean differences with 95% confidence intervals. We assessed the certainty of the evidence using GRADE methodology. MAIN RESULTS: We included 14 studies (743 randomised participants). Five studies evaluated participants with Crohn's disease; seven studies evaluated participants with IBD where the data on ulcerative colitis and Crohn's disease could not be separated; and two studies provided separate results for Crohn's disease participants. Studies considered a range of disease activity states. Two studies provided intervention success definitions, whilst the remaining studies measured pain as a continuous outcome on a rating scale. All studies except one measured pain intensity, whilst three studies measured pain frequency. Withdrawals due to adverse events were directly or indirectly reported in 10 studies. No conclusions could be drawn about the efficacy of the majority of the interventions on pain intensity, pain frequency, and treatment success, except for the comparison of transcranial direct current stimulation to sham stimulation. The certainty of the evidence was very low in all but one comparison because of imprecision due to sparse data and risk of bias assessed as unclear or high risk. Two studies compared a low FODMAP diet (n=37) to a sham diet (n=45) in IBD patients. The evidence on pain intensity was of very low certainty (MD -12.00, 95% CI -114.55 to 90.55). One study reported pain intensity separately for CD participants in the low FODMAP group [n=14, mean(SD)=24 (82.3)] and the sham group [n=12, mean(SD)=32 (69.3)]. The same study also reported pain frequency for IBD participants in the low FODMAP group [n=27, mean(SD)=36 (26)] and sham group [n=25, mean(SD)=38(25)] and CD participants in the low FODMAP group [n=14, mean(SD)=36 (138.4)] and sham group [n=12, mean(SD)=48 (128.2)]. Treatment success was not reported. One study compared a low FODMAP diet (n=25) to high FODMAP/normal diet (n=25) in IBD patients. The data reported on pain intensity was unclear. Treatment success and pain frequency were not reported. One study compared medicine-separated moxibustion combined with acupuncture (n=51) versus wheat bran-separated moxibustion combined with shallow acupuncture (n=51) in CD patients. The data reported on pain intensity and frequency were unclear. Treatment success was not reported. One study compared mindfulness with CBT (n=33) versus no treatment (n=33) in IBD patients. The evidence is very uncertain about the effect of this treatment on pain intensity and frequency (MD -37.00, 95% CI -87.29 to 13.29). Treatment success was not reported. One study compared soft non-manipulative osteopathic treatment (n=16) with no treatment besides doctor advice (n=14) in CD patients. The evidence is very uncertain about the effect of this treatment on pain intensity (MD 0.01, 95% CI -1.81 to 1.83). Treatment success and pain frequency were not reported. One study compared stress management (n=15) to self-directed stress management(n=15) and to standard treatment (n=15) in CD patients. The evidence is very uncertain about the effect of these treatments on pain intensity (MD -30.50, 95% CI -58.45 to -2.55 and MD -34.30, 95% CI -61.99 to -6.61). Treatment success and pain frequency were not reported. One study compared enteric-release glyceryl trinitrate (n=34) with placebo (n=36) in CD patients. The data reported on pain intensity was unclear. Treatment success and pain frequency were not reported.  One study compared 100 mg olorinab three times per day (n=8) with 25 mg olorinab three times per day (n=6) in CD patients. Pain intensity was measured as a 30% reduction in weekly average abdominal pain intensity score for the 100mg group (n=5) and the 25mg group (n=6). The evidence is very uncertain about the effect of this treatment on pain intensity (RR 0.66, 95% CI 0.38 to 1.15). Treatment success and pain frequency were not reported. One study compared relaxation training (n=28) to a waitlist (n=28) in IBD patients. The evidence is very uncertain about the effect of this treatment on pain intensity (MD -0.72, 95% CI -1.85 to 0.41). Treatment success and pain frequency were not reported. One study compared web-based education (n=30) with a book-based education (n=30) in IBD patients. The evidence is very uncertain about the effect of this treatment on pain intensity (MD -0.13, 95% CI -1.25 to 0.99). Treatment success and pain frequency were not reported. One study compared yoga (n=50) with no treatment (n=50) in IBD patients. The data reported on treatment success were unclear. Pain frequency and intensity were not reported. One study compared transcranial direct current stimulation (n = 10) to sham stimulation (n = 10) in IBD patients. There may be an improvement in pain intensity when transcranial direct current is compared to sham stimulation (MD -1.65, 95% CI -3.29 to -0.01, low-certainty evidence). Treatment success and pain frequency were not reported. One study compared a kefir diet (Lactobacillus bacteria) to no intervention in IBD patients and provided separate data for their CD participants. The evidence is very uncertain about the effect of this treatment on pain intensity in IBD (MD 0.62, 95% CI 0.17 to 1.07) and CD (MD -1.10, 95% CI -1.67 to -0.53). Treatment success and pain frequency were not reported. Reporting of our secondary outcomes was inconsistent. The most adverse events were reported in the enteric-release glyceryl trinitrate and olorinab studies.  In the enteric-release glyceryl trinitrate study, the adverse events were higher in the intervention arm. In the olorinab study, more adverse events were observed in the higher dose arm of the intervention.  In the studies on non-drug interventions, adverse events tended to be very low or zero. However, no clear judgements regarding adverse events can be drawn for any interventions due to the low number of events. Anxiety and depression were measured and reported at the end of intervention in only one study; therefore, no meaningful conclusions can be drawn for this outcome. AUTHORS' CONCLUSIONS: We found low certainty evidence that transcranial direct current stimulation may improve pain intensity compared to sham stimulation. We could not reach any conclusions on the efficacy of any other interventions on pain intensity, pain frequency, and treatment success. The certainty of the evidence was very low due to the low numbers of studies and participants in each comparison and clinical heterogeneity amongst the studies. While no serious or total adverse events were elicited explicitly with any of the treatments studied, the reported events were very low. The certainty of the evidence for all comparisons was very low, so no conclusions can be drawn.

Interventions for treating iron deficiency anaemia in inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease affects approximately seven million people globally. Iron deficiency anaemia can occur as a common systemic manifestation, with a prevalence of up to 90%, which can significantly affect quality of life, both during periods of active disease or in remission. It is important that iron deficiency anaemia is treated effectively and not be assumed to be a normal finding of inflammatory bowel disease. The various routes of iron administration, doses and preparations present varying advantages and disadvantages, and a significant proportion of people experience adverse effects with current therapies. Currently, no consensus has been reached amongst physicians as to which treatment path is most beneficial. OBJECTIVES: The primary objective was to evaluate the efficacy and safety of the interventions for the treatment of iron deficiency anaemia in people with inflammatory bowel disease. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and two other databases on 21st November 2019. We also contacted experts in the field and searched references of trials for any additional trials. SELECTION CRITERIA: Randomised controlled trials investigating the effectiveness and safety of iron administration interventions compared to other iron administration interventions or placebo in the treatment of iron deficiency anaemia in inflammatory bowel disease. We considered both adults and children, with studies reporting outcomes of clinical, endoscopic, histologic or surgical remission as defined by study authors. DATA COLLECTION AND ANALYSIS: Two review authors independently conducted data extraction and 'Risk of bias' assessment of included studies. We expressed dichotomous and continuous outcomes as risk ratios and mean differences with 95% confidence intervals. We assessed the certainty of the evidence using the GRADE methodology. MAIN RESULTS: We included 11 studies (1670 randomised participants) that met the inclusion criteria. The studies compared intravenous iron sucrose vs oral iron sulphate (2 studies); oral iron sulphate vs oral iron hydroxide polymaltose complex (1 study); oral iron fumarate vs intravenous iron sucrose (1 study); intravenous ferric carboxymaltose vs intravenous iron sucrose (1 study); erythropoietin injection + intravenous iron sucrose vs intravenous iron sucrose + injection placebo (1 study); oral ferric maltol vs oral placebo (1 study); oral ferric maltol vs intravenous ferric carboxymaltose (1 study); intravenous ferric carboxymaltose vs oral iron sulphate (1 study); intravenous iron isomaltoside vs oral iron sulphate (1 study); erythropoietin injection vs oral placebo (1 study). All studies compared participants with CD and UC together, as well as considering a range of disease activity states. The primary outcome of number of responders, when defined, was stated to be an increase in haemoglobin of 20 g/L in all but two studies in which an increase in 10g/L was used. In one study comparing intravenous ferric carboxymaltose and intravenous iron sucrose, moderate-certainty evidence was found that intravenous ferric carboxymaltose was probably superior to intravenous iron sucrose, although there were responders in both groups (150/244 versus 118/239, RR 1.25, 95% CI 1.06 to 1.46, number needed to treat for an additional beneficial outcome (NNTB) = 9). In one study comparing oral ferric maltol to placebo, there was low-certainty evidence of superiority of the iron (36/64 versus 0/64, RR 73.00, 95% CI 4.58 to 1164.36). There were no other direct comparisons that found any difference in the primary outcomes, although certainty was low and very low for all outcomes, due to imprecision from sparse data and risk of bias varying between moderate and high risk. The reporting of secondary outcomes was inconsistent. The most common was the occurrence of serious adverse events or those requiring withdrawal of therapy. In no comparisons was there a difference seen between any of the intervention agents being studied, although the certainty was very low for all comparisons made, due to risk of bias and significant imprecision due to the low numbers of events. Time to remission, histological and biochemical outcomes were sparsely reported in the studies. None of the other secondary outcomes were reported in any of the studies. An analysis of all intravenous iron preparations to all oral iron preparations showed that intravenous administration may lead to more responders (368/554 versus 205/373, RR 1.17, 95% CI 1.05 to 1.31, NNTB = 11, low-certainty due to risk of bias and inconsistency). Withdrawals due to adverse events may be greater in oral iron preparations vs intravenous (15/554 versus 31/373, RR 0.39, 95% CI 0.20 to 0.74, low-certainty due to risk of bias, inconsistency and imprecision). AUTHORS' CONCLUSIONS: Intravenous ferric carboxymaltose probably leads to more people having resolution of IDA (iron deficiency anaemia) than intravenous iron sucrose. Oral ferric maltol may lead to more people having resolution of IDA than placebo. We are unable to draw conclusions on which of the other treatments is most effective in IDA with IBD (inflammatory bowel disease) due to low numbers of studies in each comparison area and clinical heterogeneity within the studies. Therefore, there are no other conclusions regarding the treatments that can be made and certainty of all findings are low or very low. Overall, intravenous iron delivery probably leads to greater response in patients compared with oral iron, with a NNTB (number needed to treat) of 11. Whilst no serious adverse events were specifically elicited with any of the treatments studied, the numbers of reported events were low and the certainty of these findings very low for all comparisons, so no conclusions can be drawn. There may be more withdrawals due to such events when oral is compared with intravenous iron delivery. Other outcomes were poorly reported and once again no conclusions can be made as to the impact of IDA on any of these outcomes. Given the widespread use of many of these treatments in practice and the only guideline that exists recommending the use of intravenous iron in favour of oral iron, research to investigate this key issue is clearly needed. Considering the current ongoing trials identified in this review, these are more focussed on the impact in specific patient groups (young people) or on other symptoms (such as fatigue). Therefore, there is a need for studies to be performed to fill this evidence gap.

Distinctive Microbial Signatures and Gut-Brain Crosstalk in Pediatric Patients with Coeliac Disease and Type 1 Diabetes Mellitus.

Coeliac disease (CD) and Type 1 diabetes mellitus (T1DM) are immune-mediated diseases. Emerging evidence suggests that dysbiosis in the gut microbiome plays a role in the pathogenesis of both diseases and may also be associated with the development of neuropathy. The primary goal in this cross-sectional pilot study was to identify whether there are distinct gut microbiota alterations in children with CD (n = 19), T1DM (n = 18) and both CD and T1DM (n = 9) compared to healthy controls (n = 12). Our second goal was to explore the relationship between neuropathy (corneal nerve fiber damage) and the gut microbiome composition. Microbiota composition was determined by 16S rRNA gene sequencing. Corneal confocal microscopy was used to determine nerve fiber damage. There was a significant difference in the overall microbial diversity between the four groups with healthy controls having a greater microbial diversity as compared to the patients. The abundance of pathogenic proteobacteria Shigella and E. coli were significantly higher in CD patients. Differential abundance analysis showed that several bacterial amplicon sequence variants (ASVs) distinguished CD from T1DM. The tissue transglutaminase antibody correlated significantly with a decrease in gut microbial diversity. Furthermore, the Bacteroidetes phylum, specifically the genus Parabacteroides was significantly correlated with corneal nerve fiber loss in the subjects with neuropathic damage belonging to the diseased groups. We conclude that disease-specific gut microbial features traceable down to the ASV level distinguish children with CD from T1DM and specific gut microbial signatures may be associated with small fiber neuropathy. Further research on the mechanisms linking altered microbial diversity with neuropathy are warranted.

Role of the gut microbiota in the pathogenesis of coeliac disease and potential therapeutic implications.

PURPOSE: Although genetic predisposition and exposure to dietary gluten are considered necessary triggers for the development of coeliac disease, alterations in the gut microbial composition may also contribute towards the pathogenesis of coeliac disease. This review aims to provide an overview of the available data on the potential mechanisms through which the gut microbiota plays a role in the causation of coeliac disease and to discuss the potential therapeutic strategies that could diminish the consequences of microbial dysbiosis. METHOD: A search of the literature was performed using the PubMed, Embase, and JSTOR databases; relevant articles were included. RESULTS: Recent studies in patients with coeliac disease have reported an increase in the relative amounts of gram negative bacterial genera such as Bacteroides, Prevotella, and Escherichia, and reduced amounts of protective anti-inflammatory bacteria such as Bifidobacteria and Lactobacilli. Dysbiotic microbiota may lead to a dysregulated immune response that may contribute to the pathogenesis of coeliac disease. In infancy, antibiotic use and certain infant feeding practices may lead to alterations in the developing gut microbiota to influence the immune maturation process and predispose to coeliac disease. CONCLUSION: The induction of the intestinal immune system and gluten intolerance may be influenced by the relative abundance of certain microbiota. Factors such as infant feeding practices, diet, antibiotics, and infections, may be involved in the development of coeliac disease due to their influence on gut microbial composition. The efficacy of potential modulators of the gut microbiota such as probiotics, prebiotics, and fecal microbial transplant as adjunctive treatments to gluten-free diet in coeliac disease is unproven and requires further investigation.

Probiotics for induction of remission in Crohn's disease.

BACKGROUND: Crohn's disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract, in which the pathogenesis is believed to be partly influenced by the gut microbiome. Probiotics can be used to manipulate the microbiome and have therefore been considered as a potential therapy for CD. There is some evidence that probiotics benefit other gastrointestinal conditions, such as irritable bowel syndrome and ulcerative colitis, but their efficacy in CD is unclear. This is the first update of a Cochrane Review previously published in 2008. OBJECTIVES: To assess the efficacy and safety of probiotics for the induction of remission in CD. SEARCH METHODS: The following electronic databases were searched: MEDLINE (from inception to 6 July 2020), Embase (from inception to 6 July 2020), the Cochrane Central Register of Controlled Trials (CENTRAL), The Cochrane IBD Review Group Specialised Trials Register, World Health Organization (WHO) International Clinical Trials Registry, and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) that compared probiotics with placebo or any other non-probiotic intervention for the induction of remission in CD were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the methodological quality of included studies. The primary outcome was clinical remission. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated for dichotomous outcomes. MAIN RESULTS: There were two studies that met criteria for inclusion. One study from Germany had 11 adult participants with mild-to-moderate CD, who were treated with a one-week course of corticosteroids and antibiotics (ciprofloxacin 500 mg twice daily and metronidazole 250 mg three times a day), followed by randomised assignment to Lactobacillus rhamnosus strain GG (two billion colony-forming units per day) or corn starch placebo. The other study from the United Kingdom (UK) had 35 adult participants with active CD (CDAI score of 150 to 450) randomised to receive a synbiotic treatment (comprised of freeze-dried Bifidobacterium longum and a commercial product) or placebo. The overall risk of bias was low in one study, whereas the other study had unclear risk of bias in relation to random sequence generation, allocation concealment, and blinding. There was no evidence of a difference between the use of probiotics and placebo for the induction of remission in CD (RR 1.06; 95% CI 0.65 to 1.71; 2 studies, 46 participants) after six months. There was no difference in adverse events between probiotics and placebo (RR 2.55; 95% CI 0.11 to 58.60; 2 studies, 46 participants). The evidence for both outcomes was of very low certainty due to risk of bias and imprecision. AUTHORS' CONCLUSIONS: The available evidence is very uncertain about the efficacy or safety of probiotics, when compared with placebo, for induction of remission in Crohn's disease. There is a lack of well-designed RCTs in this area and further research is needed.

Probiotics for maintenance of remission in ulcerative colitis.

BACKGROUND: Ulcerative colitis is an inflammatory condition affecting the colon, with an annual incidence of approximately 10 to 20 per 100,000 people. The majority of people with ulcerative colitis can be put into remission, leaving a group who do not respond to first- or second-line therapies. There is a significant proportion of people who experience adverse effects with current therapies. Consequently, new alternatives for the treatment of ulcerative colitis are constantly being sought. Probiotics are live microbial feed supplements that may beneficially affect the host by improving intestinal microbial balance, enhancing gut barrier function and improving local immune response. OBJECTIVES: The primary objective was to determine the efficacy of probiotics compared to placebo, no treatment, or any other intervention for the maintenance of remission in people with ulcerative colitis. The secondary objective was to assess the occurrence of adverse events associated with the use of probiotics. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and two other databases on 31 October 2019. We contacted authors of relevant studies and manufacturers of probiotics regarding ongoing or unpublished trials that may be relevant to the review, and we searched ClinicalTrials.gov. We also searched references of trials for any additional trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) that compared probiotics against placebo or any other intervention, in both adults and children, for the maintenance of remission in ulcerative colitis were eligible for inclusion. Maintenance therapy had to be for a minimum of three months when remission has been established by any clinical, endoscopic,histological or radiological relapse as defined by study authors. DATA COLLECTION AND ANALYSIS: Two review authors independently conducted data extraction and 'Risk of bias' assessment of included studies. We analysed data using Review Manager 5. We expressed dichotomous and continuous outcomes as risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs). We assessed the certainty of the evidence using the GRADE methodology. MAIN RESULTS: In this review, we included 12 studies (1473 randomised participants) that met the inclusion criteria. Participants were mostly adults. The studies compared probiotics to placebo, probiotics to 5-aminosalicylic acid (5-ASA) and a combination of probiotics and 5-ASA to 5-ASA. The studies ranged in length from 12 to 52 weeks. The average age of participants was between 32 and 51, with a range between 18 and 88 years. Seven studies investigated a single bacterial strain, and five studies considered mixed preparations of multiple strains. The risk of bias was high in all except three studies due to selective reporting, incomplete outcome data and lack of blinding. This resulted in low- to very low-certainty of evidence. It is uncertain if there is any difference in occurrence of clinical relapse when probiotics are compared with placebo (RR 0.87, 95% CI 0.63 to 1.18; 4 studies, 361 participants; very low-certainty evidence (downgraded for risk of bias, imbalance in baseline characteristics and imprecision)). It is also uncertain whether probiotics lead to a difference in the number of people who maintain clinical remission compared with placebo (RR 1.16, 95% CI 0.98 to 1.37; 2 studies, 141 participants; very low-certainty evidence (downgraded for risk of bias, imbalance in baseline characteristics and imprecision)). When probiotics are compared with 5-ASA, there may be little or no difference in clinical relapse (RR 1.01, 95% CI 0.84 to 1.22; 2 studies, 452 participants; low-certainty evidence) and maintenance of clinical remission (RR 1.06, 95% CI 0.90 to 1.25; 1 study, 125 participants; low-certainty evidence). It is uncertain if there is any difference in clinical relapse when probiotics, combined with 5-ASA are compared with 5-ASA alone (RR 1.11, 95% CI 0.66 to 1.87; 2 studies, 242 participants; very low-certainty evidence (downgraded due to risk of bias and imprecision)). There may be little or no difference in maintenance of remission when probiotics, combined with 5-ASA, are compared with 5-ASA alone (RR 1.05, 95% CI 0.89 to 1.24; 1 study, 122 participants; low-certainty evidence). Where reported, most of the studies which compared probiotics with placebo recorded no serious adverse events or withdrawals due to adverse events. For the comparison of probiotics and 5-ASA, one trial reported 11/110 withdrawals due to adverse events with probiotics and 11/112 with 5-ASA (RR 1.02, 95% CI 0.46 to 2.25; 222 participants; very low-certainty evidence). Discontinuation of therapy was due to gastrointestinal symptoms. One study (24 participants) comparing probiotics combined with 5-ASA with 5-ASA alone, reported no withdrawals due to adverse events; and two studies reported two withdrawals in the probiotic arm, due to avascular necrosis of bilateral femoral head and pulmonary thromboembolism (RR 5.29, 95% CI 0.26 to 107.63; 127 participants; very low-certainty evidence). Health-related quality of life and need for additional therapy were reported infrequently. AUTHORS' CONCLUSIONS: The effectiveness of probiotics for the maintenance of remission in ulcerative colitis remains unclear. This is due to low- to very low-certainty evidence from poorly conducted studies, which contribute limited amounts of data from a small number of participants. Future trials comparing probiotics with 5-ASA rather than placebo will better reflect conventional care given to people with ulcerative colitis. Appropriately powered studies with a minimum length of 12 months are needed.

Probiotics for induction of remission in ulcerative colitis.

BACKGROUND: Ulcerative colitis is an inflammatory condition affecting the colon, with an annual incidence of approximately 10 to 20 per 100,000 people. The majority of people with ulcerative colitis can be put into remission, leaving a group who do not respond to first- or second-line therapies. There is a significant proportion of people who experience adverse effects with current therapies. Consequently, new alternatives for the treatment of ulcerative colitis are constantly being sought. Probiotics are live microbial feed supplements that may beneficially affect the host by improving intestinal microbial balance, enhancing gut barrier function and improving local immune response. OBJECTIVES: To assess the efficacy of probiotics compared with placebo or standard medical treatment (5-aminosalicylates, sulphasalazine or corticosteroids) for the induction of remission in people with active ulcerative colitis. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and two other databases on 31 October 2019. We contacted authors of relevant studies and manufacturers of probiotics regarding ongoing or unpublished trials that may be relevant to the review, and we searched ClinicalTrials.gov. We also searched references of trials for any additional trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) investigating the effectiveness of probiotics compared to standard treatments or placebo in the induction of remission of active ulcerative colitis. We considered both adults and children, with studies reporting outcomes of clinical, endoscopic, histologic or surgical remission as defined by study authors DATA COLLECTION AND ANALYSIS: Two review authors independently conducted data extraction and 'Risk of bias' assessment of included studies. We analysed data using Review Manager 5. We expressed dichotomous and continuous outcomes as risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs). We assessed the certainty of the evidence using the GRADE methodology. MAIN RESULTS: In this review, we included 14 studies (865 randomised participants) that met the inclusion criteria. Twelve of the studies looked at adult participants and two studies looked at paediatric participants with mild to moderate ulcerative colitis, the average age was between 12.5 and 47.7 years. The studies compared probiotics to placebo, probiotics to 5-ASA and a combination of probiotics plus 5-ASA compared to 5-ASA alone. Seven studies used a single probiotic strain and seven used a mixture of strains. The studies ranged from two weeks to 52 weeks. The risk of bias was high for all except two studies due to allocation concealment, blinding of participants, incomplete reports of outcome data and selective reporting. This led to GRADE ratings of the evidence ranging from moderate to very low. Probiotics versus placebo Probiotics may induce clinical remission when compared to placebo (RR 1.73, 95% CI 1.19 to 2.54; 9 studies, 594 participants; low-certainty evidence; downgraded due to imprecision and risk of bias, number needed to treat for an additional beneficial outcome (NNTB) 5). Probiotics may lead to an improvement in clinical disease scores (RR 2.29, 95% CI 1.13 to 4.63; 2 studies, 54 participants; downgraded due to risk of bias and imprecision). There may be little or no difference in minor adverse events, but the evidence is of very low certainty (RR 1.04, 95% CI 0.42 to 2.59; 7 studies, 520 participants). Reported adverse events included abdominal bloating and discomfort. Probiotics did not lead to any serious adverse events in any of the seven studies that reported on it, however five adverse events were reported in the placebo arm of one study (RR 0.09, CI 0.01 to 1.66; 1 study, 526 participants; very low-certainty evidence; downgraded due to high risk of bias and imprecision). Probiotics may make little or no difference to withdrawals due to adverse events (RR 0.85, 95% CI 0.42 to 1.72; 4 studies, 401 participants; low-certainty evidence). Probiotics versus 5-ASA There may be little or no difference in the induction of remission with probiotics when compared to 5-ASA (RR 0.92, 95% CI 0.73 to 1.16; 1 study, 116 participants; low-certainty evidence; downgraded due to risk of bias and imprecision). There may be little or no difference in minor adverse events, but the evidence is of very low certainty (RR 1.33, 95% CI 0.53 to 3.33; 1 study, 116 participants). Reported adverse events included abdominal pain, nausea, headache and mouth ulcers. There were no serious adverse events with probiotics, however perforated sigmoid diverticulum and respiratory failure in a patient with severe emphysema were reported in the 5-ASA arm (RR 0.21, 95% CI 0.01 to 4.22; 1 study, 116 participants; very low-certainty evidence). Probiotics combined with 5-ASA versus 5-ASA alone Low-certainty evidence from a single study shows that when combined with 5-ASA, probiotics may slightly improve the induction of remission (based on the Sunderland disease activity index) compared to 5-ASA alone (RR 1.22 CI 1.01 to 1.47; 1 study, 84 participants; low-certainty evidence; downgraded due to unclear risk of bias and imprecision). No information about adverse events was reported. Time to remission, histological and biochemical outcomes were sparsely reported in the studies. None of the other secondary outcomes (progression to surgery, need for additional therapy, quality of life scores, or steroid withdrawal) were reported in any of the studies. AUTHORS' CONCLUSIONS: Low-certainty evidence suggests that probiotics may induce clinical remission in active ulcerative colitis when compared to placebo. There may be little or no difference in clinical remission with probiotics alone compared to 5-ASA. There is limited evidence from a single study which failed to provide a definition of remission, that probiotics may slightly improve the induction of remission when used in combination with 5-ASA. There was no evidence to assess whether probiotics are effective in people with severe and more extensive disease, or if specific preparations are superior to others. Further targeted and appropriately designed RCTs are needed to address the gaps in the evidence base. In particular, appropriate powering of studies and the use of standardised participant groups and outcome measures in line with the wider field are needed, as well as reporting to minimise risk of bias.

Azathioprine and 6-mercaptopurine for maintenance of surgically-induced remission in Crohn's disease.

BACKGROUND: Crohn's disease (CD) is a chronic relapsing inflammatory condition and maintenance of remission is a major issue as many patients fail to achieve remission with medical management and require surgical interventions. Purine analogues such as azathioprine (AZA) and 6-mercaptopurine (6-MP) have been used to maintain surgically-induced remission in CD, but the effectiveness, tolerability and safety of these agents remains controversial. OBJECTIVES: To assess the efficacy and safety of purine analogues (AZA and 6-MP) for maintenance of surgically-induced remission in CD. SEARCH METHODS: We searched PubMed, MEDLINE, Embase, CENTRAL, and the Cochrane IBD Group Specialized Register from inception to 26 July 2018 (and from inception to 31 July 2019). In addition, we searched reference lists of all included studies and relevant reviews, conference proceedings and trials registers. SELECTION CRITERIA: Randomised controlled trials (RCTs) with a duration of at least three months that enrolled adults and children with surgically-induced remission of CD and compared AZA or 6-MP to no treatment, placebo or any other active intervention were considered for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial eligibility, extracted data, assessed the risk of bias and assessed the certainty of the evidence using GRADE. The primary outcome was clinical relapse. Secondary outcomes included endoscopic relapse, radiologic and surgical relapse, adverse events (AEs), serious adverse events (SAEs), withdrawal due to AEs and health-related quality of life. MAIN RESULTS: Ten RCTs with a total of 928 participants were included. Study participants were adults recruited from university clinics and gastroenterology hospitals who received interventions post-surgery for a duration between 12 to 36 months. Most study participants were recruited less than three months after surgery in all except one study where participants were recruited between 6 to 24 months post-surgery. One study was rated as low risk of bias, six studies were rated high risk of bias and three were rated unclear risk of bias.There was moderate certainty evidence that purine analogues are more efficient for preventing clinical relapse than placebo. At 12 to 36 months, 51% (109/215) of AZA/6-MP participants relapsed compared to 64% (124/193) of placebo participants (RR 0.79; 95% CI 0.67 to 0.92; 408 participants; 3 studies; I² = 0%; moderate certainty evidence). The certainty of the evidence regarding the efficacy of AZA or 6-MP for maintaining postoperative clinical remission compared to 5-ASA compounds was low. At 12 to 24 months , 64% (113/177) of purine analogue participants relapsed compared to 59% (101/170) of 5-ASA participants (RR 1.05; 95% CI 0.89 to 1.24; 347 participants; 4 studies; I² = 8%; low certainty evidence). The certainty of evidence that purine analogues are inferior for preventing postsurgical clinical relapse compared to tumour necrosis factor alpha agents (anti-TNF-α) was very low. At 12 to 24 months, 43% (29/67) of AZA participants relapsed compared to 14% (10/72) of anti-TNF-α participants (RR 2.89; 95% CI 1.50 to 5.57; 139 participants; 3 studies; I² = 0%; very low certainty evidence).The effect of purine analogues compounds on AEs compared to placebo or any active treatment was uncertain, as the quality of evidence ranged from very low to low. After 12 to 24 months, 14% (12/87) of purine analogue participants experienced an AE compared to 10% (8/81) of placebo participants (RR 1.36; 95% CI 0.57 to 3.27; 168 participants; 2 studies; I² = 0%; low certainty evidence). The effect of purine analogues on AEs compared to 5-ASA agents was uncertain. After 12 to 24 months, 41% (73/176) of purine analogue participants had an AE compared to 47% (81/171) of 5-ASA participants (RR 0.89; 95% CI 0.74 to 1.07; 346 participants; 4 studies; I² = 15%; low certainty evidence). The effect of purine analogues on AEs in comparison to anti TNF-α agents was uncertain. At 12 to 24 months, 57% (32/56) of AZA participants had an AE compared to 51% (31/61) of anti-TNF-α participants (RR 1.13; 95% CI 0.83 to 1.53; 117 participants; 2 studies; I² = 0%; low certainty evidence). Purine analogue participants were more like than 5-ASA participants to have a SAE (RR 3.39, 95% CI 1.26 to 9.13, 311 participants; 3 studies; I² = 9%; very low certainty evidence), or to withdraw due to an AE (RR 2.21, 95% CI 1.28 to 3.81; 425 participants; 5 studies; I² = 0%; low certainty evidence). Commonly reported AEs across all studies included leucopenia, arthralgia, abdominal pain or severe epigastric intolerance, elevated liver enzymes, nausea and vomiting, pancreatitis, anaemia, nasopharyngitis and flatulence. AUTHORS' CONCLUSIONS: Moderate certainty evidence suggests that AZA and 6-MP may be superior to placebo for maintenance of surgically-induced remission in participants with CD. There was no clear difference in the number of clinical relapses when purine analogues were compared with 5-ASA agents, however this is based on low certainty evidence. There was very low certainty evidence that AZA and 6-MP are more likely to result in more serious adverse events (SAEs) and withdrawals due to an AE (low certainty) when compared to 5-ASA agents. Very low certainty evidence suggests that purine analogues may be inferior to anti-TNF-α agents, however, no firm conclusions can be drawn. Further research investigating the efficacy and safety of AZA and 6-MP in comparison to other active medications in surgically-induced remission of CD is warranted.