Assessing Safety of Advanced Therapies for Crohn’s Disease

Recent findings shed light on the safety of various advanced therapies for patients with Crohn’s disease, a chronic inflammatory condition of the digestive tract. With several new treatment options available, patients and healthcare providers must understand how these therapies stack up against each other when it comes to potential risks.

Why it matters

The safety of Crohn’s disease treatments is paramount since many patients rely on multiple therapies over time, often juggling complex regimens. As healthcare providers continue to expand their treatment options, understanding which therapies carry similar risks of serious side effects, like infections or cardiovascular events, can help clinicians make informed choices. Recent research compares the risk of serious infections, venous thromboembolism (VTE), and major adverse cardiovascular events (MACE) with different advanced therapies in patients with Crohn’s disease. Furthermore, these insights may guide future treatment guidelines and patient counseling, ensuring better management of this challenging condition.

Comparative Observational Studies and Real-World Evidence (RWE)

While randomized controlled trials (RCTs) are the industry gold standard, they are often not adequately powered for rare events like MACE, and they typically run for a short period of time, not providing enough information for follow-up. As a result, comparative observational studies may be the answer to provide health care providers and patients alike with additional safety information on tried and true treatment options. The use of real-world data (RWD) turned into real-world evidence (RWE) assists in the informed decision-making process.

A retrospective comparative effectiveness research study was conducted between January 1, 2016, and December 31, 2022, with a mean follow-up of 26.9 months until July 1, 2024. This study included 12, 245 patients with Crohn’s disease (mean age, 46.5 years; 6,642 females) who were treated with factor-α (TNF) antagonists, vedolizumab, ustekinumab, risankizumab, or upadacitinib.

• TNF antagonists: neutralize tumor necrosis factor (TNF)-alpha, an immune system protein
• Vedolizumab: an anti-integrin agent that works by stopping certain immune molecules (integrins) from binding to other cells in the intestinal lining
• Ustekinumab: an interleukin (IL)-12/23p40 antagonist that blocks the action of the interleukin, a protein involved in inflammation
• Risankizumab: an interleukin (IL)-23p19 antagonist that blocks the action of another interleukin, reducing inflammation
• Upadacitinib: a Janus kinase inhibitor that helps reduce inflammation by targeting parts of the immune system that cause inflammation in the intestines

Researchers used an administrative claims database (OptumLabs Data Warehouse) to identify commercially insured patients with Crohn’s disease who initiated treatment with tumor necrosis TNF antagonists (n = 5,274), anti-integrin agents (vedolizumab, n = 2,716), interleukin (IL)-12/23p40 antagonists (ustekinumab, n = 3,544), IL-23p19 antagonists (risankizumab, n = 559), or Janus kinase inhibitors (upadacitinib, n = 152) between 2016 and 2022 and had follow-up for at least 1 year before and after treatment initiation.

Main Outcomes

The main outcomes and measures of this study included the risk of serious infections, VTE, and MACE 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. Additionally, cause-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for multiple treatment comparisons were calculated.

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.

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

Who it affects

Patients diagnosed with Crohn’s disease are directly impacted by these findings, particularly those facing persistent symptoms despite previous treatments. Clinicians managing their care need to weigh the benefits of effectiveness against potential hazards. Additionally, healthcare systems can use this information to approach policy decisions regarding funding and access to the latest therapies.

What is Crohn’s Disease?

According to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) under the National Institutes of Health (NIH), Crohn’s disease is a type of inflammatory bowel disease (IBD). It is a chronic disease in which abnormal reactions of the immune system cause inflammation in the digestive tract. Ulcerative colitis and microscopic colitis are other common types of IBD. Most commonly, Crohn’s disease affects the small intestine and the beginning of the large intestine. However, the disease may affect any part of the digestive tract, from a person’s mouth to their anus. It affects all layers of the intestinal walls, moving outward and causing the walls of the intestines to be inflamed and thicken over time. This thickening makes the affected areas crack, forming tunnels or passageways in the intestinal walls and causing patches of damage that can reach the outer lining.

Crohn’s disease most often begins slowly and may get worse over time. Symptoms can range from mild to severe, and when patients have symptoms, it’s called a flare. In between flares, most people have periods of remission, times when symptoms disappear. Periods of remission can last for weeks or years. The goal of Crohn’s disease treatment is to keep people in remission long-term.

There are an estimated 1 million people in the United States with diagnosed Crohn’s disease. Interestingly, studies show that Crohn’s disease has become more common, not just in the United States but also in other parts of the world. The reason for this uptick in diagnoses is unknown.

While experts aren’t sure what causes Crohn’s disease, there are several different factors that may play a role in its causation, including abnormal immune reaction, environment, genes, and a person’s own microbiome. A patient’s immune system may react poorly and attack bacteria that live in the intestines, causing an inflammatory response in the digestive tract, leading to Crohn’s disease. Or a patient’s environment, like where they live, the conditions that they live in, and factors that surround their everyday life, may play a role in causing Crohn’s disease. For example, research has shown that smoking doubles a patient’s risk of developing Crohn’s disease.

Demographics that are more likely to develop Crohn’s disease include people who

• are between 20 and 29 years old
• have a close family member, like a sibling or parent, with IBD
• are of Jewish descent
• smoke cigarettes

Crohn’s disease may lead to complications that develop over a patient’s lifetime. Complications include anemia, bone problems, problems with growth and development in children, and malnutrition.

• Anemia: Crohn’s disease may lead to more than one type of anemia, including iron-deficiency anemia, anemia of inflammation or chronic disease, or vitamin B12 deficiency anemia
• Bone problems: Crohn’s disease and corticosteroids used to treat the disease may lead to low bone mass – known as osteopenia or osteoporosis
• Problems with growth and development in children include gaining less weight than normal, slowed growth, short stature, or delayed puberty
• Malnutrition: due to poor absorption of adequate vitamins, minerals, and other nutrients

Inflammation due to Crohn’s disease may also lead to serious complications, requiring hospitalization or surgery. Complications include intestinal obstruction, fistulas, abscesses, anal fissures, or ulcers. A subset of patients also has inflammation in parts of the body outside of the digestive tract, including the joints, skin, eyes, liver and bile ducts, kidneys, and lungs.

Treatment of Crohn’s disease includes medications and surgery. Treatment goals for patients are to 1) lower inflammation in the intestines, 2) prevent flares of symptoms, and 3) stay in remission. When it comes to medication therapy, options depend on a patient’s symptoms, where the disease is causing inflammation, as well as additional health and lifestyle factors.

Medication therapies in Crohn’s disease reduce inflammation and keep patients in remission. Options include corticosteroids (used short-term), immunosuppressants, biologics, and new small molecule medications (usually as a last line option for unresponsive patients).

What changes

• Healthcare providers can feel reassured that no specific advanced therapy appears to present higher risks for serious adverse events among the current treatment options.
• Health care teams and patients may also feel less burden regarding supportive care and additional labs for monitoring side effects.
• Patients may gain confidence in discussing a broader range of therapies without heightened anxiety over serious side effects, allowing for more personalized treatment plans.
• Patients may also be more willing to try alternative therapies in the case of initial therapy failure.
• This research also suggests that patients and health care providers should use shared decision-making to make informed decisions based on therapy benefits, effectiveness, and risks.
• Ongoing evaluation of therapies will be essential, as this knowledge informs future drug development and enhances patient safety measures in Crohn disease management.

References

1. https://www.niddk.nih.gov/health-information/digestive-diseases/crohns-disease/definition-facts
2. https://www.niddk.nih.gov/health-information/digestive-diseases/crohns-disease/symptoms-causes
3. https://www.niddk.nih.gov/health-information/digestive-diseases/crohns-disease/treatment
4. https://pubmed.ncbi.nlm.nih.gov/41649814/