Advances in Crohn’s disease therapies show similar safety
Large claims analysis finds no significant differences in serious infections, VTE, or MACE across biologics and JAK inhibitors.
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02/17/2026
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by Doug Brunk
A large real-world analysis of more than 12,000 patients with Crohn’s disease found similar safety profiles across biologics and a JAK inhibitor, with no significant differences in serious infections, venous thromboembolism (VTE), or major cardiovascular events over a mean follow-up of 26.9 months.
For the study, published in JAMA Network Open, corresponding author Siddharth Singh, MD, of the Division of Gastroenterology and Hepatology in the Department of Medicine at Mayo Clinic in Arizona, Scottsdale, and colleagues used the OptumLabs Data Warehouse claims database to conduct a new-user, active-comparator cohort study of commercially insured adults aged 18 to 65 years who initiated advanced CD therapy between January 1, 2016, and December 31, 2022. Exposure groups included 5,274 treated with TNF antagonists, 2,716 treated with vedolizumab, 3,544 treated with ustekinumab, 559 treated with risankizumab, and 152 treated with upadacitinib. Patients were required to have 12 months of continuous enrollment before and after treatment initiation.
To address confounding, the researchers applied multinomial propensity score–based inverse probability weighting using generalized boosted models. Covariates included demographics, comorbidities, health care utilization, prior serious infections or VTE, corticosteroid and immunomodulator exposure, and prior biologic use. Cause-specific Cox proportional hazards models accounted for competing risk of mortality.
The incidence rates of serious infections per 100 person-years were 5.52 for TNF antagonists, 6.65 for vedolizumab, 5.46 for ustekinumab, 9.02 for risankizumab, and 8.81 for upadacitinib.
After adjustment, no significant differences were observed compared with TNF antagonists. Hazard ratios were 0.96 for vedolizumab, 0.88 for ustekinumab, 1.00 for risankizumab, and 0.98 for upadacitinib. The researchers observed no significant differences between risankizumab and ustekinumab. Results were consistent after excluding patients with comorbid immune-mediated inflammatory diseases.
When stratified by infection type, IL-12/23p40 antagonists were associated with a lower risk of gastrointestinal serious infections compared with vedolizumab (HR 0.72). No significant differences were observed for extraintestinal serious infections. The most common gastrointestinal infections were perianal abscess and Clostridioides difficile infection; extraintestinal infections included sepsis, pneumonia, and urinary tract infection.
Venous thromboembolism
Incidence rates of VTE per 100 person-years were 0.90 for TNF antagonists, 1.19 for vedolizumab, 1.14 for ustekinumab, 2.33 for risankizumab, and 1.04 for upadacitinib.
Adjusted analyses showed no significant differences versus TNF antagonists. Hazard ratios were 1.03 for vedolizumab, 1.03 for ustekinumab, 1.25 for risankizumab, and 0.39 for upadacitinib.
In a sensitivity analysis restricted to inpatient or emergency department VTE events, JAK inhibitors were associated with lower VTE risk compared with other agents, although event counts were small.
Major adverse cardiovascular events
MACE incidence per 100 person-years was 0.68 for TNF antagonists, 1.08 for vedolizumab, 0.74 for ustekinumab, 1.49 for risankizumab, and no events for upadacitinib.
Adjusted comparisons versus TNF antagonists showed no significant differences. Hazard ratios were 1.13 for vedolizumab, 0.92 for ustekinumab, and 1.38 for risankizumab.
The researchers acknowledged certain limitations of their analysis, including reliance on administrative claims without clinical disease activity measures or endoscopic data, potential residual confounding, relatively low event rates for VTE and MACE, shorter follow-up compared with long-term safety trials, and small sample sizes for upadacitinib and risankizumab.
“The study’s findings of a broadly comparable safety profile among current treatment options support individualized therapy selection based on clinical and patient-centered factors, with a greater emphasis on effectiveness,” the researchers concluded.
This study was supported by the Crohn’s and Colitis Foundation and by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Singh reported receiving research grants from Pfizer. Other coauthors reported receiving consulting fees, speaking fees, advisory board fees, and/or research support from several pharmaceutical companies.
Source: JAMA Network Open
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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.