What Makes JAK Inhibitors Safe in Dermatology

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Matthew Zirwas, MD, reviews the clinical discrepancies of certain JAK-targeting therapies and their role in dermatology patient outcomes.

The matter of treatment safety with Janus kinase (JAK) inhibitors may be more complex than the level of information a patient is generally receiving from a prescribing clinician, but there are more straightforward ways to reassure any worry.

In the second segment of an interview with the Society of Dermatology Physician Assistants (SDPA) 2024 Summer Meeting, Matthew Zirwas, MD, director of the clinical trials and dermatitis center at Dermatologists of Greater Columbus, provided further guidance on how dermatologists should address the black box warning included in some of the labels for JAK inhibitors indicated to treat chronic skin diseases like atopic dermatitis. While Zirwas previously provided his perspective on the legitimacy of the warning—which states an associated increased risk of major adverse cardiovascular events (MACE), cancer and death with some JAK inhibitors1—he followed up on the topic by explaining how that manifests in a clinician-patient interaction.

“I tell patients the same thing I tell them with any medication—especially any new medication: anything weird happens, call and let me know. But I don't even go over with the patient, 'Hey, if your calf starts to swell, if your calf starts to hurt, if you get short of breath, or get a cough, if you have pressure in your chest...' I don't go over any of that, because I am a firm believer there is no additional risk compared to whatever their baseline risk status would be,” Zirwas said.

Zirwas cited meta-analysis data showing some well-established JAK inhibitors in dermatology are actually associated with reduced risk of MACE and venous thromboembolism compared to other therapies; he also noted there are upward of 50,000 patient-years’ worth of data showing no risk of treatment-associated adverse events linking the JAK inhibitors used in practice to such outcomes.

The matter lost in translation to patients, Zirwas said, is the specific targeted pathway of said JAK inhibitors and the associated risks of said agents. Tofacitinib, Zirwas said, is primarily a JAK-3 inhibitor that has been associated with the adverse event risks listed on black box warnings. The JAK inhibitors commonly used in dermatology, though, target the JAK-1 and JAK-2 pathways. There’s also an issue of uncertainty regarding that associated risk itself, Zirwas said.

“One of the things that a lot of dermatologists don't get is that the oral surveillance trial with (tofacitinib) did not show an increased risk of heart attacks, MACE, VTE, cancer or death, right? What it showed was that if you were on (tofacitinib), the rate of those things happening is higher than if you're on (adalimumab),” Zirwas said. “Well, in the rheumatology literature, they talk about, 'Well, we don't know, was it that (tofacitinib) increased the risk of those things, or that (tofacitinib) had no effect and (adalimumab) decreased the risk?' Because there's certainly lots of belief that (adalimumab) is cardio-protected..but there's not even any proof that (tofacitinib) increases the risk, even in high-risk rheumatoid arthritis patients on methotrexate. It just showed that risk was higher than if you were on HUMIRA. And so that's a crucial thing.”

Of course, the complexities of this safety outcome discourse is not necessarily patient-friendly—and may only exacerbate their fears surrounding a new targeted therapy with a black box warning. As such, Zirwas recommends this explanation: “A much older generation of this type of medication may have shown an increased risk, and that's why you're getting these warnings, but these newer generation medications, there's not been any risk detected.”


Kunzmann K. The JAK Inhibitor Safety Conversation. HCPLive. Published June 10, 2024.