DAY 3: Comparative Studies of Inflammatory Bowel Disease Advanced Therapeutics

In a bonus session, Benjamin J. Click, MD, MS, from the University of Colorado School of Medicine, described “buzzwords” that come to mind when thinking about the safety of the various classes of advanced IBD therapies, including infections, malignancies, cardiometabolic events, and other rare effects related to their distinct mechanisms of action. Looking at controlled and real-world studies, anti-TNFs are associated with some increase in the risk of infections, and JAK inhibitors with Zoster reactivation, but most of the other advanced therapies have been found to be relatively safe. He noted that there is no convincing data linking solid or hematologic tumor risk with IBD therapies, with the exception of thiopurines. Anti-TNFs may have some association with lymphoma and melanoma and JAK inhibitors with lymphoma and non-melanoma skin cancer, but the data are not conclusive. In the area of cardiovascular events, the JAK inhibitor black box warning came from a study of tofacitinib in rheumatoid arthritis that showed greater risk of major adverse cardiovascular events and venous thrombosis (Ytterberg et al, 2022), but no studies in IBD populations have shown this same increase in risk. He emphasized that corticosteroids are the most dangerous therapy options for IBD and increase the risk of infection and mortality. Disease activity is a major driver of the complications seen with IBD treatment. Dr. Click presented a “safety pyramid” of IBD therapies by class, with corticosteroids as the least safe options, followed by anti-TNF plus thiopurine and thiopurine monotherapy, to therapies with “intermediate safety,” such as anti-TNF monotherapy and JAK inhibitors, and the newer therapies that are considered relatively safe, including anti-integrins, anti-IL-12/23, anti-IL23, and S1P receptor modulators. He noted that inadequate treatment should be considered an adverse event and surgery is sometimes the best treatment option. In patients with severely active IBD, Dr. Click prioritizes efficacy over safety, whereas in mild-to-moderately active IBD, he prioritizes safety and pursues shared decision-making with patients in treatment selection.

Rahul S. Dalal, MD, MPH, from Brigham and Women's Hospital and Harvard Medical School, described the results of a 52-week real-world comparative effectiveness of vedolizumab versus upadacitinib and risankizumab in Crohn’s disease (CD). Each therapy has a different mechanism of action, and no head-to-head studies have been performed. They looked at all adults at their center who initiated any of the 3 treatments. Steroid-free clinical remission and treatment discontinuation at 52 weeks were the primary endpoints; the same endpoints were examined at 12 weeks, along with endoscopic/radiologic response. The study analyzed 72 patients who received vedolizumab, 67 who received upadacitinib, and 125 who were taking risankizumab. Oral corticosteroid use was similar between the groups. For all outcomes, risankizumab performed better than vedolizumab at both 12 and 52 weeks, and vedolizumab had a higher incidence of discontinuation. Upadacitinib was more likely than vedolizumab to achieve a clinical response at 12 weeks, but this was not observed at 52 weeks. Adverse events were similar across all 3 therapies.

Mira Sridharan, MD, from Boston Medical Center, shared the outcomes of a real-world study comparing upadacitinib and risankizumab as second-line therapy in patients with CD. The study was a retrospective analysis of data from the US Collaborative Network of 73 health organizations with more that 100 million patients. They identified 436 adults with CD and prior anti-TNF exposure who started upadacitinib and risankizumab between 2003 and 2004 and evaluated a primary composite endpoint of hospitalization requiring IV steroids or surgery within 12 months. They used 1:1 propensity score matching to create two cohorts of 218 patients each. They found no difference between upadacitinib and risankizumab, except that patients on risankizumab were more likely to need IV steroids within the first year of treatment, particularly those with inflammatory disease (rather than fistulizing/structuring disease). There was no difference in CRP or fecal calprotectin (FCP) levels. While upadacitinib was associated with lower risk of hospitalization at 1 year, there was a higher likelihood of therapy change within that cohort. There were low rates of adverse events with both therapies.

Archit Garg, MD, from Saint Peter’s University Hospital, described a systematic review and meta-analysis of tofacitinib, vedolizumab, and ustekinumab outcomes in patients with chronic pouchitis. Pouchitis affects up to 70% of patients with ulcerative colitis (UC) following ileal pouch anal anastomosis, and 15% of these patients can progress to chronic pouchitis. Biologic and small molecule agents have been used to treat chronic pouchitis, but there is no data comparing their efficacy for this use. Garg and colleagues conducted a systematic review and meta-analysis of 23 studies of tofacitinib, vedolizumab, or ustekinumab in patients with chronic pouchitis. Ustekinumab had the highest clinical response rate (73.3%) compared to vedolizumab (54.9%) and tofacitinib (47.7%). Endoscopic response rates were similar for ustekinumab and vedolizumab (58.5%) and were higher than for tofacitinib (51.7%). Endoscopic remission rates were similar across the 3 agents, ranging from 36.4% to 41. 2%. Adverse event rates were 30.9% for tofacitinib, which also had a more frequent discontinuation rate for lack of efficacy (43%). Adverse events were 17% for vedolizumab and 4.6% with ustekinumab. Discontinuation was 30.3% for vedolizumab and 12.5% for ustekinumab. The authors concluded that ustekinumab appeared to be the better choice for treatment of chronic pouchitis compared to either vedolizumab or tofacitinib. (P1034)

Mohamed Eldesouki, MD, from Saint Michael’s Medical Center, New York Medical College, described the results of a retrospective analysis of data from the TriNetX U.S. Collaborative Research Network (2021-2024), comparing the 1-year outcomes of treatment with ustekinumab and the S1P receptor modulator ozanimod in patients with UC and naïve to anti-TNF therapy. Patients were matched for demographics, co-morbid conditions, and laboratory measurements. One-year outcomes were corticosteroid use, surgery, hospitalizations, ED visits, and initiation of anti-TNF. After matching, a total of 306 patients in each treatment arm were included. Analysis showed no significant difference in any of the 1-year endpoints between the two groups, with a trend toward reduced initiation of anti-TNF in the ustekinumab group. (P1078)
Shahryar Khan, MD, from the University of Kansas Medical Center, conducted a network meta-analysis of randomized placebo-controlled trials of all advanced therapies in the treatment of fistulizing CD with at least 6 months of follow-up data reported. They compared the efficacy of treatment for fistula remission (complete closure of all fistulas) and fistula response (≥50% reduction in the number of draining fistulas with no new fistula formation). The analysis included 13 trials that evaluated 14 advanced therapies. Adalimumab plus ciprofloxacin ranked highest among all evaluated treatments for fistula remission; infliximab plus ciprofloxacin ranked the highest for fistula response, followed by upadacitinib. Vedolizumab and the JAK inhibitor filgotinib were not better than placebo for fistula remission or response. Data on newer IL-23 inhibitors was limited and was not included in the analysis. (P3196)

Jeremy A. Klein, MD, from the University of Chicago Medicine’s Inflammatory Bowel Disease Center, shared the results of a retrospective cohort analysis comparing risankizumab and ustekinumab for prevention of post-operative CD recurrence. The study included 112 patients with CD who underwent surgical resection with primary re-anastomosis before starting risankizumab (n=36), ustekinumab (n=33), or an anti-TNF (n=43). The analysis found no significant difference between the 3 treatments for post-operative recurrence-free survival or recurrence. Prior use of 3 or more advanced therapies predicted post-operative recurrence of CD. (P5455)