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Use of JAK inhibitors was not associated with a higher risk of all-cause mortality, major adverse cardiovascular events (MACE), and venous thromboembolism (VTE) compared to other agents in patients with inflammatory skin diseases.

JAK inhibitors have a well-documented record of effectiveness against dermatological conditions, such as psoriasis, atopic dermatitis, alopecia areata, and vitiligo. In 2021, the FDA issued a boxed after findings that showed an increased risk of MACE, VTE, serious infection, malignant neoplasm, and death.

However, researchers of a systematic review and meta-analysis, published recently in , observed that the boxed warning was precipitated by results of the , which only included patients with rheumatoid arthritis. The same associations, researchers noted, may not be present in people with dermatologic conditions.

The analysis ultimately included 35 phase 3 randomized clinical trials, collectively encompassing 20,651 patients (mean [SD] age, 38.5 [10.1] years; male 54%) with a mean follow-up time of 4.9 (2.68) months. Findings did not show a significant difference between JAK inhibitors and placebo/active comparator in composite MACE and all-cause mortality (OR 0.83; 95% CI 0.44-1.57) or VTE (OR 0.52; 95% CI 0.26-1.04).

Co-author Michael Garshick, MD, is an assistant professor of medicine at New York University Grossman School of Medicine and a cardiologist and cardio-rheumatologist with NYU Langone Health. Garshick's discussion of key study findings with the Reading Room has been edited for length and clarity.

How would you set the context for the investigation? What was the impetus for this analysis and what were your key objectives?

Garshick: As many people are aware, there's been concern over the years of an increase in VTE with JAK inhibitors. This ultimately prompted the FDA to conduct the longitudinal follow-up ORAL Surveillance study. That study again showed a signal of concern for VTE events in the rheumatoid arthritis patient population. This led to the FDA warning not just for VTE, but also for arterial thrombotic events.

In our study, we wanted to look at JAKs in just the dermatology patient population.

There's always been some thought that, for a variety of reasons, dermatology patients don't have an inherently higher cardiovascular risk to begin with -- predominantly because they're younger and are often the ones getting these JAK inhibitors. But it may be that these dermatologic conditions are different from the rheumatologic conditions.

What were your key findings?

Garshick: We can't really see a signal to harm in the analysis. And this is important because for a lot of the dermatologic conditions, JAK inhibitors are sometimes the only treatment option. For example, there are many treatments for alopecia areata -- but JAK inhibitors work quite well.

Dermatologists are keenly interested in JAK safety because they want to be able to use these medications and they want to understand what the risk is.

I want to point out that many derm conditions increase cardiovascular risk. So I think we're not really seeing the JAK inhibitor signal.

Part of me wonders whether these dermatology patients were younger to begin with, had fewer cardiovascular risk factors, etc. So it may just be that we're studying a healthier cohort.

What would you like to call out to dermatologists about your results?

Garshick: Despite our findings, I still think it's important to have this conversation with dermatology patients before starting a JAK inhibitor, and show them what studies have shown. It's also important to say, but look... we have a study that was just limited to dermatology patients and we did not necessarily see this harm. So that's an important thing to consider.

When you give a JAK inhibitor, you need to monitor cholesterol, because JAK inhibitors can raise cholesterol levels. Patients need a heads up that this could be a problem down the road. However, we may not be seeing the harm signal in the dermatology patient population, and this is a treatment that can be quite effective.

Is there anything on the horizon that jumps out at you as a particular avenue of need in the research area?

Garshick: A better understanding of the mechanism behind this harm signal is really, really important.

In my lab, we are studying how JAKs may be impacting platelets. This really has not been explored.

Another question: are all JAK inhibitors created equal? We use it as a generic term, but these agents all target different specific JAK molecules. This is also an unmet need, that we are trying to investigate.