A new systematic review and meta-analysis have shed light on how prior exposure to tumor necrosis factor (TNF) antagonists influences the efficacy of advanced therapies for ulcerative colitis.
In the study, published in Clinical Gastroenterology and Hepatology, investigators examined remission outcomes in patients treated with different drug classes—lymphocyte trafficking inhibitors, interleukin (IL)-12/23 and IL-23 antagonists, and Janus kinase (JAK) inhibitors—stratified by whether patients were TNF antagonist–naive or TNF antagonist–exposed.
“We sought to ascertain how prior exposure to tumor necrosis factor antagonists impacts treatment response with various classes of advanced therapies in patients with ulcerative colitis,” according to lead author Han Hee Lee, MD, of the University of California San Diego and Catholic University of Korea.
Study Design and Methods
The investigators conducted a comprehensive search of MEDLINE, EMBASE, and the Cochrane databases through the end of June 2024, supplemented by clinical trial registries, abstracts from major gastroenterology meetings, and consultation with experts in the field. Only phase II and III randomized controlled trials with adult patients (≥18 years of age) were eligible, and each study had to report outcomes separately for TNF antagonist–naive versus –exposed populations.
Patients were required to have moderately to severely active ulcerative colitis, defined by a Mayo Clinic score of 6 to 12 with an endoscopic subscore of 2 or 3. The primary outcome was induction of clinical remission within 6 to 14 weeks, with endoscopic improvement (Mayo endoscopic subscore 0 or 1) evaluated as a secondary endpoint. All analyses were performed on an intention-to-treat basis, with dropouts assessed as treatment failures.
From more than 5,000 screened studies, 17 randomized controlled trials met inclusion criteria. These included five trials of lymphocyte trafficking inhibitors (two of vedolizumab, three of S1P receptor modulators), six trials of IL antagonists (one of IL-12/23 antagonist, five for selective IL-23 antagonists), and six trials of JAK inhibitors (two of tofacitinib, four of JAK1 inhibitors). Overall, 48% of patients had prior biologic exposure, most commonly to TNF antagonists.
Key Findings by Drug Class
Five randomized controlled trials of lymphocyte trafficking inhibitors (2,046 patients) demonstrated that this class was significantly more effective in TNF antagonist–naive patients (odds ratio = 3.20; 95% confidence interval [CI] = 2.23–4.60) compared with those previously exposed (odds ratio = 1.68; 95% CI = 1.02–2.76, P = .04), with an 88% higher chance of remission in antagonist-naive patients.
These findings persisted across both anti-integrin therapy (vedolizumab) and sphingosine-1-phosphate (S1P) modulators such as ozanimod and etrasimod. As the authors noted, “Exposure to TNF antagonists significantly reduces the efficacy of lymphocyte trafficking inhibitors in inducing remission, including both vedolizumab and S1P receptor modulators, by approximately 50%.”
Six randomized controlled trials of anti-ILs (3,810 patients) observed similar drug efficacy regardless of TNF exposure, with remission odds ratios of 2.98 (95% CI = 2.13-4.18) in antagonist-naive patients and 3.23 (95% CI = 2.15-4.84) in antagonist-exposed patients. In the UNIFI trial of ustekinumab, however, TNF-exposed patients appeared to derive greater benefit, which may suggest a mechanistic distinction between IL-12/23 blockade and selective IL-23 inhibition.
Six randomized controlled trials of JAK inhibitors (3,015 patients) revealed greater benefit among TNF antagonist–exposed patients (OR = 8.53; 95% CI = 3.49–20.83) than in those with no prior exposure (OR = 3.56; 95% CI = 1.92-6.58), suggesting a 53% lower chance of remission in TNF-naive patients, with a borderline level of statistical significance. “These findings reassure positioning of Janus kinase inhibitors after exposure to tumor necrosis factor antagonists in patients with ulcerative colitis,” the authors noted.
Mechanistic Considerations
The authors advanced several hypotheses for these divergent results. TNF blockade may leave a lasting “immunologic scar,” reprogramming immune pathways and altering responsiveness to subsequent therapies. This phenomenon has parallels in infectious disease, where acute infections can permanently recalibrate immune networks, and in lifestyle behaviors such as smoking, which induces enduring changes in adaptive immunity that persist well beyond smoking cessation.
Diminished leukocyte trafficking after TNF inhibition may blunt responses to therapies that rely on trafficking modulation, such as vedolizumab and S1P receptor modulators. Conversely, enhanced activity of the IL-6/JAK/STAT axis following TNF blockade could create a biologic environment in which JAK inhibitors are more effective. Additionally, TNF blockade may alter the balance between type 1 and type 17 immune responses, potentially explaining why IL-12/23 antagonists appear more effective in TNF-exposed patients, while selective IL-23 antagonists do not.
These findings underscore the importance of tailoring therapy sequencing to patient history, noted study authors. Lymphocyte trafficking inhibitors may be most effective in biologic-naive patients, while JAK inhibitors could represent a strong option among patients for whom advanced therapies have failed.
“We observed that there is significant heterogeneity of treatment efficacy for induction of remission with different advanced therapies in patients with moderate-severe ulcerative colitis based on prior exposure to TNF antagonists. Prior exposure to TNF antagonists appears to potentiate the efficacy of JAK inhibitors and IL-12/23 antagonists but may attenuate responsiveness to lymphocyte trafficking inhibitors. Future studies on the mechanistic insight for these intriguing observations are warranted,” the study authors concluded.
Conflict of interest statements are available in the published article below.
