‘Revisiting Xeljanz safety concerns based on accumulated long-term data’

Domestic cohort analysis shows no difference in adverse reactions compared to TNF inhibitors

Rapid onset of action highlighted as a strength… “Plays a key role for patients in urgent need of symptom relief”

Eun-mi Song, Professor of Gastroenterology and Hepatology, Ewha Womans University Seoul Hospital

As treatment strategies for ulcerative colitis shift toward maintaining long-term remission, the criteria for selecting treatment options are also changing.

In particular, as Janus kinase (JAK) inhibitors establish themselves as key treatment options alongside biologics, safety concerns surrounding Pfizer’s ‘Xeljanz (tofacitinib),’ including major adverse cardiovascular events (MACE) and thrombosis, have been consistently raised.

Amid this context, as results from domestic cohort studies involving Korean patients accumulate, there is a growing movement to reassess its safety in real-world clinical settings.

Professor Eun-mi Song of the Department of Gastroenterology at Ewha Womans University Seoul Hospital, who led this study, recently told Daily Pharm, “Initially, there were significant concerns about side effects due to the mechanistic characteristics of JAK inhibitors. Looking at actual clinical data, contrary to expectations, the safety profile is comparable to that of existing biologics.”

Ulcerative colitis is a disease characterized by chronic inflammation of the colon's mucosa, with recurring symptoms including diarrhea, bloody stools, and abdominal pain. Unlike acute colitis, it is a chronic condition with no clear cause that involves repeated cycles of remission and relapse, requiring many patients to continue treatment for the rest of their lives.

The number of patients in Korea is also rapidly increasing. Due to Westernized dietary habits and environmental changes, prevalence is rising, particularly among younger patients aged 20–40. As the number of patients in this age group increases, which is highly active in society, the need for long-term disease management also grows.

At the same time, the treatment landscape is evolving. While a step-up strategy, gradually increasing treatment intensity, was previously the norm, an ‘accelerated step-up’ strategy, which adjusts treatment intensity more quickly based on the patient’s condition, is now being applied in clinical practice. Treatment goals are also evolving beyond simple symptom relief toward the fundamental suppression of inflammation, such as achieving endoscopic remission.

The problem lies in the high recurrence rate. Since more than 80% of patients experience recurrence and some progress to severe disease, the continuity of treatment, which maintains stable suppression of inflammation even after initial remission, is identified as a key factor determining long-term prognosis.

Accordingly, efforts are ongoing to establish strategies for maintaining long-term remission while also validating drug safety in real-world clinical settings.

In particular, JAK inhibitors have faced persistent safety concerns since their introduction, including risks of MACE, thrombosis, infections, and malignancies.

However, it has been pointed out that these risks were primarily derived from data on rheumatoid arthritis, which involves a large proportion of elderly patients, and that there are limitations to applying them directly to the ulcerative colitis patient population, which has a relatively high proportion of younger patients.

Furthermore, in actual clinical practice, the patterns of adverse reactions may vary depending on patient comorbidities, age, and concomitant therapies, reinforcing the need for the collection of real-world data from domestic patient populations.

Against this backdrop, a large-scale population-based cohort analysis was conducted in Korea. Using data from the National Health Insurance Service (NHIS), the study compared the risk of serious adverse events (SAEs) between the Xeljanz group (521 patients) and the TNF inhibitor group (1,295 patients) in patients with moderate-to-severe ulcerative colitis from May 2019 to April 2022.

Analysis revealed that the overall incidence rate of SAEs was 4.41 per 100 person-years in the Xeljanz group and 5.33 in the TNF inhibitor group, showing no statistically significant difference between the two treatment groups. In particular, no differences were observed between the groups in the risk of thromboembolism, opportunistic infections such as herpes zoster and tuberculosis, or malignancies.

Professor Song stated, “The occurrence of complications is influenced more by individual risk factors, such as the patient’s age or underlying conditions, than by the drug itself. If treatment and monitoring are conducted in conjunction with consideration of each patient’s risk level, Xeljanz is a viable long-term treatment option.”

Q. Given the reimbursement criteria, the top-down approach seems ideal, but the step-up approach still predominates in real life.

In Korea, ulcerative colitis treatment is moving toward an ‘accelerated step-up’ approach, which is a practical compromise between top-down and traditional step-up strategies. This involves closely monitoring patient response and rapidly escalating to more potent therapies when initial treatments are insufficient, enabling early remission.

In the past, treatment typically began with 5-aminosalicylic acid (5-ASA) agents, followed by sequential use of immunomodulators in a stepwise approach; however, in recent practice, steroids or immunomodulators are used from the outset in patients with severe symptoms. In particular, if the disease continues to worsen despite this initial intervention, biologics or small-molecule agents (JAK inhibitors) such as Xeljanz are introduced early on, in accordance with domestic health insurance reimbursement criteria.

Q. When considering switching, what specific criteria are used to make the change?

Disease severity is the primary factor. Physicians assess symptom severity, endoscopic inflammation, and laboratory results to evaluate disease status. The first criterion is selecting the treatment with the highest expected efficacy based on severity, followed by safety considerations.

The criteria for selecting ulcerative colitis treatments have evolved to comprehensively consider not only the patient’s clinical characteristics but also safety in relation to comorbidities, as well as the patient’s individual preferences and lifestyle patterns. While treatment options were limited in the past, the recent introduction of new drugs with diverse administration routes and schedules has made it possible to design sophisticated treatment plans tailored to each patient’s specific situation.

Q. How was the Xeljanz cohort study conducted?

This large-scale, population-based cohort study of Korean ulcerative colitis patients was designed to directly compare Xeljanz with TNF inhibitors, which have been in clinical use for a relatively long period and are considered to have an established safety profile, as the control group.

The study results confirmed that the safety profile of Xeljanz is comparable to that of existing biologics, namely TNF inhibitors. Initially, due to its mechanism of action, it was anticipated that the Xeljanz group would have a relatively higher risk of viral infections or thrombosis, however, actual analysis revealed no statistically significant difference in the incidence of serious adverse events between the two treatment groups.

However, a major limitation of this study is that specific data on initial drug dosing were not obtained during the study, preventing precise analysis of dose-dependent safety and efficacy differences. Previous studies, such as ORAL Surveillance, have already suggested that dosage differences in JAK inhibitors can have a significant impact on safety outcomes, and there remains a possibility that this study could also reveal differences in clinical outcomes based on dosage.

Q. Despite the periodic release of safety data on Xeljanz, concerns regarding risks still persist.

Even among healthcare professionals, there is a vague fear of complications when prescribing JAK inhibitors like Xeljanz. However, clinical data reported domestically and internationally to date show that these concerns do not translate into actual risks. In conclusion, it has been confirmed that effectively controlling the inflammatory state early on with Xeljanz, which has a potent and rapid effect, actually contributes to reducing the risk of disease-related complications and ensuring long-term patient safety.

Furthermore, compared to Western populations, the absolute probability and incidence of thrombosis in Asian patient groups have been observed to be relatively lower. While Western populations exhibit higher thrombosis rates due to factors such as larger body frames and a higher proportion of obese individuals, Asian populations show a similar trend of increased risk compared to the general population, yet the absolute number of cases tends to be lower.

Previous safety warnings regarding JAK inhibitors were primarily based on data from rheumatoid arthritis, which involves a large number of elderly patients in their 50s and 60s. However, since the ulcerative colitis patient population consists mostly of younger individuals, the risks of thrombosis and other complications, which were raised in the rheumatoid arthritis data dominated by elderly patients, were found to be relatively lower.

Q. Do clinical experiences in actual prescribing practice show similar patterns to study findings in terms of efficacy and safety?

Combined results from domestic multicenter studies and real-world clinical experience indicate that the safety concerns raised during the early stages of the introduction of JAK inhibitors, including Xeljanz, do not pose a significant problem in real-world clinical settings. In particular, regarding herpes zoster, which was expected to carry a high risk based on the mechanism of action, no serious safety issues as previously feared emerged, thanks to thorough preemptive vaccination of healthcare providers and close monitoring. On the contrary, the greatest strength of Xeljanz perceived in clinical practice was its very rapid and potent efficacy, providing immediate therapeutic benefits to patients in urgent need of rapid symptom improvement.

Q. What are the limitations of the current treatment environment, including reimbursement?

While Western practice emphasizes top-down strategies for improved long-term outcomes, Korea faces practical constraints regarding the application of early, potent treatment due to the National Health Insurance system and financial limitations.

Thus, greater flexibility in enabling early use of potent therapies, especially for severe patients, is considered essential for improving treatment outcomes. Furthermore, recent accumulated data have demonstrated that switching between different JAK inhibitors yields clinically significant efficacy. Consequently, it is anticipated that switching between different JAK inhibitors, even if a patient shows an inadequate response to a specific JAK inhibitor, may provide meaningful clinical benefits, offering additional options for patients who do not respond adequately to a specific agent.

Q. What is the clinical significance of JAK inhibitors in ulcerative colitis?

Despite their relatively recent introduction, small-molecule therapies have become a core pillar, playing a central role in the treatment of ulcerative colitis. While there was once a vague apprehension regarding these treatments even among clinicians, the experience and data shared by professors who have prescribed drugs such as Xeljanz in actual clinical practice confirmed that the risk of complications, which had been a concern, was lower than expected and manageable.

In particular, for moderate-to-severe patients who struggled with the burden of even daily outings due to recurring cycles of symptom improvement and flare-ups, oral small-molecule agents, which offer high convenience, have become a practical alternative that dramatically improves quality of life. With the recent expansion of available treatment options to 3 or more, led by the introduction of Xeljanz, and ongoing new drug development, it is crucial for patients to maintain hope and work closely with healthcare professionals to establish a treatment strategy optimized for their individual needs in order to maintain long-term remission.