JAK Inhibitors Versus Monoclonal Antibodies: Which to Choose?

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In this talk presented at the Fall Clinical Dermatology conference, Dr. James Del Rosso and Dr. Alexandra Golant debate the benefits of JAK inhibitors and monoclonal antibodies.

A debate was held at the 2023 Fall Clinical Dermatology Conference in Las Vegas, during which James Del Rosso, DO, and Alexandra K. Golant, MD, discussed the benefits and drawbacks of monoclonal antibodies versus JAK inhibitors for eczema.

Del Rosso is known for his work as a dermatologist and the research director of JDR Dermatology Research in Las Vegas. Golant is known for her work as medical director of the Dermatology Faculty Practice and program director of the Dermatology Residency Program at Mount Sinai.

Golant began the debate with a discussion of monoclonal antibodies, specifically with regard to atopic dermatitis (AD).

“When we think of the mechanism of action of our monoclonal antibodies in general, I always say ‘Think of where your drug is working,’” Golant said. “Monoclonal antibodies, in general, are targeting cytokine or cytokine receptors, and they have a more specific target because they're working extracellularly. In the case of atopic dermatitis, they are inhibiting the action of 1 or 2 key cytokines involved in the pathogenesis of this disease.”

Golant explained that monoclonal antibodies are extracellular, with a specific target. She compared them to JAK inhibitors which she noted are intracellular, working inside the cell.

“Dupilumab is rock solid, and you see long term extensions showing really excellent efficacy maintained,” Golant said. “So we see consistent efficacy and this will also translate into consistent safety profiles. You might wonder how dupilumab compares to our JAK inhibitors, and this has been studied. There were head to head trials and I'm looking upadacitinib and abrocitinib. This slide is showing you that we have a significant 30 milligram dose, so it is the higher of the 2 doses of upadacitinib.”

She noted on her slideshow that most endpoints showed initial superiority but the closer that it progressed to week 16, or particularly for EASI-75, some catching up of the dupilumab 30 milligram group was observed.

Golant noted some other examples, later adding that the future of dermatology may involve discussion about disease modification. Del Rosso then spoke on JAK inhibitor data.

“I think this is one of the challenges in atopic dermatitis,” Del Rosso said. “There is absolutely no doubt that monoclonal antibodies, especially dupilumab, have certainly changed the lives of our patients…But we’re stuck in a bind, because we know there are differences in the profiles of these patients and what’s going on genetically with these patients.”
Del Rosso explained that clinicians generally treat such patients the same, without being able to differentiate their conditions and acknowledge the heterogeneity of the clinical phenotype of AD.

“So we have ruxolitinib here, we don't want to leave that out,” Del Rosso said. “Approved for atopic dermatitis and vitiligo in adolescents and adults. Unfortunately, it’s carrying a black box warning that it did not deserve based on the clinical data, but we live with them. But it’s very effective rapidly for itch and unlike anything else we have within a matter of days, topically.”

Del Rosso also looked at the emphasis on AD with JAK inhibitors, noting the differences on the spectrum of clinically-relevant cytokine inhibition. He added that there are ways to predict whether patients will respond to dupilumab.

“Certainly, Type 2 inflammation is predominant in many of the patients, and it's IL-4 and IL-13, but that's not the only player,” Del Rosso said. “In some patients…you can have interferon-gamma, which starts to play a role, which is Type 1. You can have IL-17 and IL-22, which for immune response, when they become operative, dupilumab and the other monoclonal antibodies are not active against those. You have to start thinking about going another direction because of the patients not having a complete response.”

Del Rosso explained that monoclonal antibodies are known to target specific cytokines, which is where they are valuable. He added, however, that when attempting to affect multiple cytokines, this is where the JAK inhibitors can come into play.

“It really depends on the quality and the information that is put in there, but essentially all (meta-analyses) have shown that upadacitinib 30 milligram, not the 15 milligram, tends to work the best in terms of what you see when you're looking at week 12 and week 16,” he said. “You see the hierarchy of response, if all these patients were put in a very similar type of study. That doesn't mean that one that’s higher is always going to be better for an individual patient, but it does show you the relative differences in efficacy.”

Del Rosso noted the benefits of putting patients on upadacitinib, given that dupilumab does not always work well for patients, although it can catch up somewhat.

As far as the safety data on JAK inhibitors, Del Rosso noted that the risks are far less in the general population than those in older patients.

Golant responded in agreement with regard to Del Rosso’s view on individualized treatment for different patients.

“I agree with you, and I think these are decisions you make for your individual patient,” Golant said. “Your example of what we do agree on is that these are both agents that you should all be using, both of them. Medications for different patients in different circumstances.”

The quotes contained here were edited for the purposes of clarity.