Background
Onset of effect of advanced therapies is an important parameter due to symptom load and risk of disease complications in moderate-to-severe ulcerative colitis (UC), but comparative data are lacking. Therefore, we aimed to assess the comparative onset of efficacy of biological therapies and small molecules for this patient population.

Methods
In this systematic review and network meta-analysis, we searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials from inception to 24 August 2022, for randomised controlled trials or open-label studies assessing the efficacy of biologics or small molecule drugs within the first six weeks of treatment in adults with UC. The co-primary outcomes were the induction of clinical response and clinical remission at week 2. Network meta-analyses was conducted under the Bayesian framework. This study is registered with PROSPERO: CRD42021250236.

Findings
The systematic literature search identified 20,406 citations, of which 25 studies comprising 11,074 patients fulfilled the eligibility criteria. Upadacitinib ranked highest for induction of clinical response and clinical remission at week 2 and was significantly superior to all agents but tofacitinib, which ranked second highest. Although the rankings remained consistent, no differences between upadacitinib and biological therapies were demonstrated in the sensitivity analyses of partial Mayo clinic score response or resolution of rectal bleeding at week 2. Tumor necrosis factor-α (TNF) inhibitors were significantly superior to vedolizumab and ustekinumab for patient-reported outcome-2 (PRO-2) remission at week 2 in bio-naïve patients. Filgotinib 100 mg, ustekinumab, and ozanimod ranked lowest across all endpoints.

Interpretation
In this network meta-analysis, we found upadacitinib to be significantly superior to all agents but tofacitinib for the induction of clinical response and clinical remission two weeks after treatment initiation. In contrast, ustekinumab and ozanimod ranked lowest. Our findings help to establish the evidence regarding the onset of efficacy of advanced therapies.