# Comparative Safety of Advanced Therapies for Crohn Disease

## TL;DR

A study of 12,245 Crohn disease patients found no major safety differences between advanced therapies like TNF antagonists, vedolizumab, and others over 27 months.

## Contribution

This study provides the first large-scale comparative safety analysis of multiple advanced therapies for Crohn disease using real-world data.

## Key findings

- No significant differences in serious infection risks across therapies like TNF antagonists, vedolizumab, and ustekinumab.
- Low and comparable rates of venous thromboembolism and cardiovascular events across all treatment groups.
- Safety outcomes suggest treatment decisions should prioritize effectiveness over safety concerns.

## Abstract

What is the comparative safety of different advanced therapies in patients with Crohn disease (CD)?

In this comparative effectiveness research study of 12 245 patients with CD, treated with tumor necrosis factor-α antagonists, vedolizumab, ustekinumab, risankizumab, or upadacitinib and followed up over a mean 27 months, no clinically meaningful differences in the risk of key safety events, including serious infections, venous thromboembolism, and major adverse cardiovascular events, were found. The incidence of venous thromboembolism and major adverse cardiovascular events was low across all therapies.

The findings of this study suggest that the safety of different advanced therapies in patients with CD was comparable and should not be the primary driver of treatment positioning in most instances.

This comparative effectiveness research study examines the risk of key safety events associated with different advanced therapies in patients with Crohn disease.

With the availability of multiple classes of advanced therapies for the treatment of Crohn disease (CD), understanding the comparative safety of different therapies can inform treatment positioning.

To compare the risk of serious infections, venous thromboembolism (VTE), and major adverse cardiovascular events (MACE) with different advanced therapies in patients with CD.

This retrospective comparative effectiveness research study was conducted between January 1, 2016, and December 31, 2022, with a mean (SD) follow-up of 26.9 (2.4) months until July 1, 2024. Using an administrative claims database (OptumLabs Data Warehouse), commercially insured patients with CD, who initiated treatment with tumor necrosis factor-α (TNF) antagonists, anti-integrin agents (vedolizumab), interleukin (IL)-12/23p40 antagonists (ustekinumab), IL-23p19 antagonists (primarily risankizumab), or Janus kinase inhibitors (upadacitinib) between 2016 and 2022 and had follow-up for at least 1 year before and after treatment initiation, were included.

TNF antagonists vs anti-integrin agents (vedolizumab) vs IL-12/23p40 antagonists (ustekinumab) vs IL-23p19 antagonists (risankizumab) vs Janus kinase inhibitors (upadacitinib).

The risk of serious infections, VTE, and MACE was compared with various advanced therapies through multinomial propensity score-based inverse probability treatment weighting, with propensity scores estimated through generalized boosted models, accounting for disease characteristics, health care utilization, comorbidities, and prior and concomitant medications, and through competing risk of mortality. Cause-specific hazard ratios (HRs) and 95% CIs for multiple treatment comparisons were calculated.

This study included 12 245 patients with CD (mean [SD] age, 46.5 [17.5] years; 6642 females [54.2%]), who were treated with TNF antagonists (n = 5274), vedolizumab (n = 2716), ustekinumab (n = 3544), risankizumab (n = 559), or upadacitinib (n = 152). Serious infection incidence rates ranged from 5.46 (95% CI, 4.86-6.07) to 9.02 (95% CI, 6.38-11.89) per 100 person-years across therapies. After adjusting for confounding variables, there were no statistically significant differences in the risk of serious infections across different agents, including between risankizumab and ustekinumab (HR, 1.14 [95% CI, 0.78-1.67]), risankizumab and TNF antagonists (HR, 1.00 [95% CI, 0.68-1.47]), or ustekinumab and TNF antagonists (HR, 0.88 [95% CI, 0.74-1.04]). The incidence of VTE (incidence rate, 0.90 [95% CI, 0.71-1.10] to 2.33 [95% CI, 1.06-3.82] per 100 person-years) and MACE (0.68 [95% CI, 0.51-0.85] to 1.49 [95% CI, 0.43-2.76] per 100 person-years) was low, without any significant differences across agents.

In this comparative effectiveness research study of patients with CD, no significant differences in the risks of serious infections, VTE, or MACE across various advanced therapies were found. These findings support clinical decision-making on choice of advanced therapies for most individual patients with CD to be driven primarily by comparative treatment effectiveness rather than driven by concerns of serious adverse events.