Prior TNF antagonist exposure influences efficacy of advanced therapies in ulcerative colitis
"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."
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09/24/2025
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.
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The guidelines emphasize four-hour gastric emptying studies over two-hour testing. How do you see this affecting diagnostic workflows in practice?
Dr. Staller: Moving to a four-hour solid-meal scintigraphy will actually simplify decision-making. The two-hour reads miss a meaningful proportion of delayed emptying; standardizing on four hours reduces false negatives and the “maybe gastroparesis” purgatory that leads to repeat testing. Practically, it means closer coordination with nuclear medicine (longer slots, consistent standardized meal), updating order sets to default to a four-hour protocol, and educating front-line teams so patients arrive appropriately prepped. The payoff is fewer equivocal studies and more confident treatment plans.
Metoclopramide and erythromycin are the only agents conditionally recommended for initial therapy. How does this align with what is being currently prescribed?
Dr. Staller: This largely mirrors real-world practice. Metoclopramide remains the only FDA-approved prokinetic for gastroparesis, and short “pulsed” erythromycin courses are familiar to many of us—recognizing tachyphylaxis limits durability. Our recommendation is “conditional” because the underlying evidence is modest and patient responses are heterogeneous, but it formalizes what many clinicians already do: start with metoclopramide (lowest effective dose, limited duration, counsel on neurologic adverse effects) and reserve erythromycin for targeted use (exacerbations, bridging).
Several agents, including domperidone and prucalopride, received recommendations against first-line use. How will that influence discussions with patients who ask about these therapies?
Dr. Staller: Two points I share with patients: evidence and access/safety. For domperidone, the data quality is mixed, and US access is through an FDA IND mechanism; you’re committing patients to EKG monitoring and a non-trivial administrative lift. For prucalopride, the gastroparesis-specific evidence isn’t strong enough yet to justify first-line use. So, our stance is not “never,” it’s just “not first.” If someone fails or cannot tolerate initial therapy, we can revisit these options through shared decision-making, setting expectations about benefit, monitoring, and off-label use. The guideline language helps clinicians have a transparent, evidence-based conversation at the first visit.
The guidelines suggest reserving procedures like G-POEM and gastric electrical stimulation for refractory cases. In your practice, how do you decide when a patient is “refractory” to medical therapy?
Dr. Staller: I define “refractory” with three anchors.
1. Adequate trials of foundational care: dietary optimization and glycemic control; an antiemetic; and at least one prokinetic at appropriate dose/duration (with intolerance documented if stopped early).
2. Persistent, function-limiting symptoms: ongoing nausea/vomiting, weight loss, dehydration, ER visits/hospitalizations, or malnutrition despite the above—ideally tracked with a validated instrument (e.g., GCSI) plus nutritional metrics.
3. Objective correlation: delayed emptying on a standardized 4-hour solid-meal study that aligns with the clinical picture (and medications that slow emptying addressed).
At that point, referral to a center with procedural expertise for G-POEM or consideration of gastric electrical stimulation becomes appropriate, with multidisciplinary evaluation (GI, nutrition, psychology, and, when needed, surgery).
What role do you see dietary modification and glycemic control playing alongside pharmacologic therapy in light of these recommendations?
Dr. Staller: They’re the bedrock. A small-particle, lower-fat, calorie-dense diet—often leaning on nutrient-rich liquids—can meaningfully reduce symptom burden. Partnering with dietitians early pays dividends. For diabetes, tighter glycemic control can improve gastric emptying and symptoms; I explicitly review medications that can slow emptying (e.g., opioids; consider timing/necessity of GLP-1 receptor agonists) and encourage continuous glucose monitor-informed adjustments. Pharmacotherapy sits on top of those pillars; without them, medications will likely underperform.
The guideline notes “considerable unmet need” in gastroparesis treatment. Where do you think future therapies or research are most urgently needed?
Dr. Staller: I see three major areas.
1. Truly durable prokinetics: agents that improve emptying and symptoms over months, with better safety than legacy options (e.g., next-gen motilin/ghrelin agonists, better-studied 5-HT4 strategies).
2. Endotyping and biomarkers: we need to stop treating all gastroparesis as one disease. Clinical, physiologic, and microbiome/omic signatures that predict who benefits from which therapy (drug vs G-POEM vs GES) would transform care.
3. Patient-centered trials: larger, longer RCTs that prioritize validated symptom and quality-of-life outcomes, include nutritional endpoints, and reflect real-world medication confounders.
Our guideline intentionally highlights these gaps to hopefully catalyze better trials and smarter referral pathways.
Dr. Staller is with the Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston.