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Experts on Results of Long-Term Safety Study of Upadacitinib for AD


Christopher Bunick, MD, PhD, presents the results of the long-term four-year safety study of upadacitinib as treatment for atopic dermatitis (AD).

Ruth Ann Vleugels, MD, MPH, MBA: Chris, can you fill us in on the key takeaways from this? What do you think about the longer-term safety profile for upadacitinib in particular, in atopic dermatitis?

Christopher Bunick, MD, PhD: What’s fascinating about the safety is that upadacitinib demonstrated consistently low rates of adverse events across years 1 to 4, meaning it’s very reassuring that it’s safe for long-term use in patients with moderate to severe eczema. One of the most important figures in this particular safety analysis looks at the patient safety baseline characteristics. Why is this so important? There’s often talk that the data are cherry-picked or the patients in a clinical trial are cherry-picked for a certain outcome. If we look at the actual baseline characteristics of the patients in the upadacitinib studies, we’re seeing that they represent an average human being in today’s society. What do I mean by that? If we look at this figure in the upper right, we can see that upadacitinib is divided between 15 mg and 30 mg. Between 55% and 58% of all patients in this trial have at least 1 cardiovascular risk factor. About 30% are tobacco users, 10% have hypertension, and 5% had a history of a prior cardiovascular event. If we look at those who are over 50 years old with 1 or more cardiovascular risk factors, they were around 15% of the patients, and 20% of the group had a BMI [body mass index] higher than 30.

A lot of individuals bring up the risk of women using oral contraceptives and being on upadacitinib, and that’s very important. In this population, about 20% of the women in this study were on oral contraceptives. Not 1 of them developed any type of venous thromboembolism [VTE]. That speaks loudly for the safety of upadacitinib in that patient population.

If we look at the overall safety events, if we look at any of any adverse events measured across the entire 4 years, it comes to around 230 events per 100 patient-years. But of all those events, only 4 per 100 patient years led to any discontinuation of study drugs, which I find very reassuring. Lastly, if you look at any adverse events leading to death, it’s 0 for the upadacitinib 15 mg group, and it’s less than 0.1 events per 100 patient-years for the 30 mg group. The caveat in this cohort of patients, which involves around 2700 patients, is that only 3 deaths were observed. All 3 of those deaths were in patients who had cardiovascular risk factors and COVID-19 infection. To me, that’s incredibly reassuring about the safety of upadacitinib.

If we dive a little deeper into the safety events, you have the 1-year data in the center, and on the right, the 4-year data. If we look at overall serious infections, it’s around 2 to 2.8 events per 100 patient-years, regardless of whether it’s year 1 or 4, the opportunistic infections stay low—below 2 events, except for the upadacitinib 30 mg dosing at 4 years, which goes up to 2.4. The key point is that these events of opportunistic and serious infections remain stable and low.

If we look at herpes zoster, this is the adverse event that had the highest rates, 3 to 5 events per 100 patient-years. There’s an important caveat that you may not be aware of: less than 5% of the patients in this trial had a shingles vaccine. I’ll hypothesize that if all these patients had the shingles vaccine, the event rate for herpes zoster would be much lower. That’s a consideration that you should have for your patients with atopic dermatitis: use the shingles vaccine because it can significantly reduce that zoster rate.

Ruth Ann Vleugels, MD, MPH, MBA: That’s an excellent point about vaccination against shingles. This is important because in many of the global trials, the percentage of patients who’ve had vaccination against shingles is very low. In the United States, we’re very fortunate because we have accessibility to an inactivated shingles vaccine for the vast majority of our patients. As an important reminder for our audience, a couple of years ago the CDC [Centers for Disease Control and Prevention] approved an inactivated shingles vaccine, or Shingrix, for anyone 18 years or older who’s on any immunosuppressant. That’s really important, because not only can those patients get it, but their insurance will pay for it. Our standard of care is that we don’t make patients get certain vaccinations, but we strongly encourage an inactivated shingles vaccine prior to JAK inhibition, because we know this is a potential risk factor of these medicines based on their mechanism, so we want to avoid it when we can. That’s an important point, but it’s also interesting to see that the numbers are fairly reasonable even in a population where the vast majority of patients haven’t had the vaccination.

Christopher Bunick, MD, PhD: I couldn’t agree more. That’s very well said. If we look at the adverse events of special interests—malignancy; major adverse cardiovascular events [MACEs]; and thromboembolic events, in particular VTE; and nonmelanoma skin cancer—what happened there? What we can see first is that nonmelanoma skin cancer rates range from 0.3 to 0.4 events per 100 patient-years. This was stable across 1 to 4 years of therapy. If we look at malignancy rates, excluding nonmelanoma skin cancer, we’re seeing that from years 1 to 4, the rate stayed at 0.1 to 0.5 events per 100 patient-years—stable and low over 4 years. There were 0 events of gastrointestinal perforations. If we look at MACE and VTE events, what’s important to understand is that they’re less than 0.1 events per 100 patient-years. We’re going to talk a little more about the context of that. But first I want to emphasize the point that if we look across 2, 3, and 4 years of serious infections—herpes zoster, opportunistic infections, or nonmelanoma skin cancers—that trend is stable and low. That’s the key point. When you look at these events of special interest, MACEs, malignancy, and VTE were low and stable over 4 years. This is what’s reassuring about the safety of upadacitinib.


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