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.