Beyond the Gut: A Systematic Review and Meta-analysis of Advanced Therapies for Inflammatory Bowel Disease-associated Extraintestinal Manifestations.

BACKGROUND AND AIMS: Extraintestinal manifestations are frequent in patients with inflammatory bowel disease and have a negative impact on quality of life. Currently, however, there is no evidence available to determine which drug should be recommended for these patients beyond anti-tumour necrosis factor [anti-TNF] treatment. We aimed to analyse the frequency of new extraintestinal manifestations and the behaviour of pre-existing extraintestinal manifestations during advanced therapy. METHODS: We conducted a systematic search on November 15, 2022, and enrolled randomized controlled trials, cohorts, and case series reporting the occurrence and behaviour of extraintestinal manifestations in patients with inflammatory bowel disease receiving advanced therapy [non-TNF inhibitor biologicals and JAK inhibitors]. Proportions of new, recurring, worsening, and improving extraintestinal manifestations were calculated with 95% confidence intervals [CIs]. The risk of bias was assessed with the QUIPS tool. RESULTS: Altogether, 61 studies comprising 13,806 patients reported eligible data on extraintestinal manifestations. The overall proportion of new extraintestinal manifestations was 8% [95% CI, 6-12%] during advanced therapy. There was no significant difference between the frequency of new extraintestinal manifestations during vedolizumab and ustekinumab therapy [11%, 95% CI, 8-15% vs 6%, 95% CI, 3-11%, p = 0.166]. The improvement of pre-existing manifestations was comparable between vedolizumab- and ustekinumab-treated patients, except for joint involvement [42%, 95% CI, 32-53% vs 54%, 95% CI, 42-65%, p = 0.029]. CONCLUSION: The proportion of new extraintestinal manifestations was low during advanced therapy. Furthermore, the improvement of pre-existing manifestations was comparable between advanced therapies, except for pre-existing joint manifestations.

Extended infusion of ß-lactams significantly reduces mortality and enhances microbiological eradication in paediatric patients: a systematic review and meta-analysis.

Background: Paediatric patients are often exposed to subtherapeutic levels or treatment failure of ß-lactams, and prolonged infusion may be beneficial. We aimed to investigate the efficacy and safety of extended infusion (EI; defined as ≥3 h) or continuous infusion vs. short, intermittent infusion (SI; defined as ≤60 min) of ß-lactams in patients <21 years of age. Methods: A systematic review and meta-analysis was conducted to compare EI and continuous infusion with SI of ß-lactams in children. A systematic search was performed in MEDLINE (via PubMed), Embase, CENTRAL, and Scopus databases for randomised controlled trials (RCTs) and observational studies published from database inception up to August 22, 2023. Any comparative study concerned with mortality, clinical efficacy, adverse events, or plasma concentrations of ß-lactams for any infection was eligible. Case reports, case series, and patients aged >21 years were excluded. Odds ratios (OR) and median differences with 95% confidence intervals (CI) were calculated using a random-effects model. Risk of bias (ROB) was assessed using ROB2 and ROBINS-I tools. The protocol was registered with PROSPERO, CRD42022375397. Findings: In total, 19,980 articles were screened, out of which 19 studies (4195 patients) were included in the meta-analysis. EI administration was associated with a significantly lower all-cause mortality in both RCTs and non-RCTs [OR 0.74; CI 0.55-0.99; I2 = 0%; CI 0-58%]. Early microbiological eradication was higher with EI [OR 3.18; CI 2.24-4.51; I2 = 0%; CI 0-90%], but the clinical cure did not differ significantly between the two groups [OR 1.20; CI 0.17-8.71; I2 = 79%; CI 32-93%]. Achieving the optimal plasma level (50-100% fT > MIC) appeared favourable in the EI group compared to the SI. No significant differences were observed in the adverse events. The overall ROB was high because of the small sample sizes and clinically heterogeneous populations. Interpretation: Our findings suggest that extended infusion of ß-lactams was associated with lower mortality and increased microbiological eradication and was considered safe compared to short-term infusion. Funding: None.