A number of TYK2 allosteric JAK inhibitors are in development, with deucravacitinib being the first to have a US Food and Drug Administration (FDA) indication for psoriasis. TYK2 inhibition has the potential to meaningfully broaden the therapeutic spectrum in dermatology, as discussed at the recent 2023 Fall Clinical Dermatology Conference.

Following these proceedings, featured expert Bruce E. Strober, MD, PhD, was interviewed by Conference Reporter Medical Writer Rick Davis. Dr Strober’s clinical perspectives on this topic are presented here.

In their sessions at the 2023 Fall Clinical Dermatology Conference, Raj Chovatiya, MD, PhD, and Mona Shahriari, MD, FAAD, highlighted how JAK inhibitors have the potential to meaningfully broaden the therapeutic spectrum in dermatology. JAK inhibitors have been part of the unofficial treatment armamentarium for patients with psoriasis for years. There are 4 members of the JAK family—JAK1, JAK2, JAK3, and TYK2—and JAK inhibitors can block 1 or many in combination. Deucravacitinib is currently the only allosteric JAK inhibitor with an FDA indication for psoriasis. It is unique from other JAK inhibitors because it selectively inhibits TYK2 and does not meaningfully inhibit JAK1, JAK2, or JAK3 when administered at its FDA-approved dose.

The other JAK inhibitors, which I refer to as the traditional, or active site, JAK inhibitors, are more nonspecific in their binding because they target conserved portions of the catalytic domain shared by all JAKs. Examples include tofacitinib, upadacitinib, abrocitinib, and baricitinib. None of these has FDA approval for the treatment of psoriasis, although both upadacitinib and tofacitinib are approved for the treatment of psoriatic arthritis. However, they are sometimes considered as later-line therapies, such as in patients with refractory palmoplantar psoriasis or scalp psoriasis who do not seem to respond to biologics or small molecules that are commonly prescribed for psoriasis.

I observe in my patients that traditional JAK inhibitors often help rescue those who are resistant to FDA-approved therapies, and this is perhaps because they effectively and more broadly target the pathophysiology of psoriasis. These drugs also have a lower molecular weight than biologics and therefore might “enjoy” better tissue penetration. However, traditional JAK inhibitors need more monitoring and rigorous patient selection, as they rarely can cause serious adverse events. These might include serious infection, major adverse cardiovascular event (MACE), deep vein thrombosis, myocardial infarction, and death, although the relevance of these potential adverse events might be overstated, as they were primarily detected in patients with rheumatoid arthritis who had cardiac risk factors and were taking tofacitinib in combination with methotrexate. In addition, traditional JAK inhibitors have also been associated with a higher risk of herpes zoster. We do believe that deep vein thrombosis and pulmonary embolism thrombotic events probably are much more likely in patients who take traditional JAK inhibitors, as is herpes zoster. There is no doubt that herpes zoster tracks with dosing of JAK inhibition.

Also, since traditional JAK inhibitors can cause abnormalities in lipid profiles, blood cell counts, and liver and renal function tests in some patients, they require blood tests at baseline and ongoing monitoring. Those abnormalities do not commonly occur with deucravacitinib, so such testing might not have the same role in regard to deucravacitinib.