Extraintestinal Manifestations and Cytomegalovirus Reactivation Are Predictors of Difficult-To-Treat in Ulcerative...

Ulcerative colitis (UC) is a diffuse, nonspecific inflammatory disease of unknown etiology. Although corticosteroids are essential for inducing remission in moderate to severe UC, steroid dependence and refractoriness remain significant clinical obstacles. Predicting which patients will develop steroid dependence or refractoriness remains challenging. Furthermore, difficult-to-treat (D-to-T) cases - those unresponsive to advanced therapies - have emerged as additional therapeutic concerns. This study aimed to identify factors associated with refractory UC, including steroid-dependent, steroid-refractory, and D-to-T presentations.

A total of 216 patients with UC who received treatment at Sapporo Medical University Hospital between April 2017 and December 2023 were retrospectively analyzed. Patients were classified into four groups: steroid-naive (SN), steroid-free (SF), steroid-dependent (SD), and steroid-refractory (SR). D-to-T cases were identified within the SD and SR groups. Patient background characteristics were obtained from electronic medical records. Variables analyzed included sex, age of onset, disease duration, alcohol consumption, smoking status, disease phenotype, extraintestinal manifestations (EIMs), and cytomegalovirus (CMV) and Clostridioides difficile infection status.

Significant differences were observed in the prevalence of EIM and CMV reactivation across the four groups (p < 0.001 for EIM; p < 0.001 for CMV). The prevalence of EIM was significantly higher in the SR group compared with the SN group (45.5% vs. 7.7%, p = 0.002) and the SF group (45.5% vs. 4.5%, p < 0.001). CMV reactivation was more frequent in the SR group than in the SN group (36.4% vs. 1.3%, p < 0.001) and the SF group (36.4% vs. 4.5%, p < 0.004). Multivariable analysis revealed that, in comparison with the SN group, the SD group was independently associated with EIM (odds ratio [OR] = 4.59, 95% confidence interval [CI]: 1.35-15.6) and CMV reactivation (OR = 12.5, 95% CI: 1.31-119). Compared to the SF group, the SD group was associated with EIM (OR = 5.71, 95% CI: 1.44-22.7). The SR group was independently associated with EIM (OR = 12.8, 95% CI: 2.51-64.9) and CMV reactivation (OR = 65.1, 95% CI: 4.39-964) compared to the SN group. Compared to the SF group, the SR group was associated with EIM (OR = 16.4, 95% CI: 2.95-90.8) and CMV reactivation (OR = 17.0, 95% CI: 2.03-142). There are also significant associations between D-to-T status and both EIM (p < 0.01) and CMV reactivation (p = 0.037).

Among patients with UC, the presence of EIM and CMV reactivation was significantly associated with steroid dependence, steroid refractoriness, and resistance to biologic and molecular-targeted therapies.