A Comparison of the Efficacy and Safety of Ustekinumab and Upadacitinib in Biologically Experienced Ulcerative Colitis Patients

<b>Background/Objectives:</b> Ustekinumab (UST) and upadacitinib (UPA) are molecules that have been used in patients with ulcerative colitis (UC) since 2019 and 2022, respectively. Both agents are generally preferred for biologically experienced UC patients. However, the number of head-to-head studies comparing the efficacy and adverse events of UST and UPA in this patient group is limited. <b>Methods:</b> This was a retrospective cohort study evaluating the efficacy and safety of UST (<i>n</i> = 57) and UPA (<i>n</i> = 32) in biologically experienced UC patients during the induction and 24-week maintenance treatment periods. Most patients in both groups had received prior anti-TNF treatment (98.2% and 96.9%, respectively). Clinical response and remission rates were determined based on the partial Mayo score (PMS). Additionally, patients' pre-treatment laboratory parameters were compared with their results at week 24. <b>Results:</b> During the induction phase, clinical response and remission were achieved in 84.2% and 43.9% of the UST group and 93.8% and 50% of the UPA group, respectively (OR [95% CI] = 2.81 [0.57-6.87] and 1.28 [0.54-3.05]). At week 24, the clinical response and remission rates in the UST and UPA groups were similar (77.1% vs. 80% and 58.3% vs. 63.3%, respectively). No statistically significant difference was found between the groups (<i>p</i> > 0.05). Both UST and UPA provided a marked reduction in fecal calprotectin and CRP levels. Regarding safety, UPA treatment led to increased total, LDL, and HDL cholesterol levels, whereas UST did not. In both groups, glucose; HbA1c; and thyroid, renal, and liver functions remained stable. No serious adverse events were observed in either group. At week 24, treatment continuation rates were 68.4% (<i>n</i> = 39) for UST and 78.2% (<i>n</i> = 25) for UPA (OR = 0.61 [0.22-1.66]). <b>Conclusions:</b> In biologically experienced ulcerative colitis, both UST and UPA are effective and safe treatment options. This study did not statistically demonstrate the superiority of UPA over UST. Given the preliminary nature and limited patient numbers of this investigation, our findings require confirmation through future multicenter, large-scale, and long-term prospective studies.