The Case for JAK Inhibitors to Treat AD

E. James Song, MD, FAAD, made a compelling case for both the safety and efficacy of JAK inhibitors in treating atopic dermatitis at the 2024 American Academy of Dermatology (AAD) Innovation Academy.

“The efficacy of JAK inhibitors in atopic dermatitis is truly unrivaled,” Dr. Song told Practical Dermatology, “especially when it comes to deeper levels of response in itch reduction and skin clearance. We also have compelling data that patients who achieve more stringent endpoints, such as an EASI 90 and NRS 0/1, have a significantly better quality of life when compared to patients who achieve an EASI 75 or NRS >2. Given the known negative downstream effects of uncontrolled atopic dermatitis, it is our duty as clinicians to strive for these more stringent measures while balancing safety, but therein lies the problem.”

Dr. Song, the Director of Clinical Research and Co-Chief Medical Officer for Frontier Dermatology, presented “JAK Inhibitors in Atopic Dermatitis” at the Innovation Academy. He started his presentation by summarizing the systemic therapy recommendations made by Dr. Dawn M.R. Davis et al in their February 2024 Journal of the American Academy of Dermatology article, “Guidelines of care for the management of atopic dermatitis in adults with phototherapy and systemic therapies.”¹ The authors’ strongest recommendations were dupilumab, tralokinumab, upadacitinib, abrocitinib, and baricitinib. Conditional recommendations were made for immunosuppressants methotrexate, azathioprine, cyclosporine, and mycophenolate mofetil, and the authors conditionally recommended against using systemic corticosteroids.

Dr. Song subsequently recommended that efficacy of therapies be judged based on eczema area and severity index (EASI) 90, as opposed to EASI 75, and he asserted that skin clearance alone is not enough, citing data from multiple studies indicating a 40% or greater difference in patient-reported outcome measure response rates at Week 16 among EASI 90-100 achievers with Worst Pruritis Numeric Rating Scale (WP-NRS) 0-1 vs WP-NRS 2-3.

After presenting various data points on the aforementioned strongly recommended therapies, Dr. Song brought up the topic of concomitant psoriasis and atopic dermatitis, including PsEma, eczematized psoriasis, and psoriasiform eczema. One of the recommended treatments for atopic dermatitis, dupilumab, may lead to the development of psoriasis in some cases, he noted, citing a Journal of the American Academy of Dermatology article by Dr. Caitlin M Brumfiel et al.²

After showing photographs from cases in which JAK inhibitors resolved issues, Dr. Song compared abrocitinib and upadacitinib, noting, among other differences, that abrocitinib has been associated with increased incidences of nausea and headaches and decreased platelets, while upadacitinib has been associated with increased acne. Abrocitinib cannot be used in cases of severe renal impairment, and the 50- or 100-mg doses are recommended with moderate renal impairment; upadacitinib requires no adjustment for mild-to-moderate impairment, and the 15-mg dose can be used for severe impairment.

Dr. Song also covered the boxed warning for JAK inhibitors and noted that it originated from an ORAL Surveillance study with a different type of JAK inhibitor (PAN vs selective) and different disease state (rheumatoid arthritis).³

“Efficacy doesn’t exist in a vacuum—it has to be balanced with safety, tolerability, and access,” Dr. Song told Practical Dermatology. “In my opinion, the safety of JAK inhibitors is largely misunderstood. Much of our perception of safety has come from a post-marketing, safety study, looking at an enriched, high-risk rheumatoid arthritis population with a PAN-JAK inhibitor that was compared to a TNF alpha inhibitor. While the study did not meet the primary endpoint for non-inferiority, the absolute risk for both medications was still exceedingly low—1% to 4%—in a ‘worst-case scenario.’ Furthermore, because there was no placebo group in this study, we cannot conclude whether the incidence rates for these particular adverse events of special interest (AESI) are any higher than the background rate for rheumatoid arthritis patients, which we know is already increased. Lastly, our atopic dermatitis patients are generally younger, healthier, and being treated with selective JAK1 inhibitors, which potentially have a better safety profile than our first-generation JAK inhibitors.”

The most likely patients to experience serious adverse events on a JAK inhibitor, Dr. Song said, are those ages 65 or older; those with a history of long-term smoking, cardiovascular disease, and/or history or risk factors for venous thromboembolism (VTE); and those with personal history of malignancies. He said these situations still should not be considered absolute contraindications, but that multi-disciplinary management is necessary to modify variable risk factors.

“Fortunately, our real-world studies have provided reassuring data that the incidence rates for our AESI in AD patients on JAK inhibitors are not appreciably higher than age, matched, controlled patients with atopic dermatitis who are not treated with JAK inhibitors,” Dr. Song told Practical Dermatology. “When these events do happen, they are generally seen in patients who already have baseline risk factors, so it is difficult to ascertain how much of this was due to a medication vs their medical history. Nonetheless, we need to do our best to control the modifiable risk factors, so that we can keep our patients safe and allow them to continue benefitting from these medications.”

After further discussing the safety of upadacitinib and JAK inhibitors in general, Dr. Song summarized a three-step approach to discussing JAK inhibitors with patients: Normalize the boxed warning, contextualize the ORAL surveillance study, and reference real-world study data.

“The reception has been overall very positive,” Dr. Song told Practical Dermatology. “I think normalizing a ‘boxed warning’ really helps put into perspective that this is not unique to JAK inhibitors. I will often make a joke that the non-steroidal anti-inflammatory drug (NSAID) they took for their headache this morning also has a warning about heart attacks, death, kidney failure, etc. As I mentioned, it also helps to point out that these scary events happen primarily in patients who have risk factors. So, if a patient doesn’t have a prior history of heart attacks, strokes, cancer, blood clots, does not smoke, and is not morbidly obese, then the risks are very low. If they do have risk factors, the discussion is going to be more involved, but these are not absolute contraindications.”

Contextualizing the ORAL surveillance study and speaking to real-world data has been the most impactful for his patients, Dr. Song added.

“I will often give examples such as, ‘Yes, a blood clot can happen in one out of 1000 patient-years who took this particular JAK inhibitor. However, when we looked at patients who had the same condition, similar age, and medical history, the incidence rate was also very similar: one in 1,000,’” he told Practical Dermatology. “Perhaps the most important point I make, however, is that we often focus so much on the potential or theoretical risk of a drug, but there are also risks to not treating a disease effectively. If we don’t make any changes to their current treatment regimen, whether it’s with a JAK inhibitor or not, their atopic dermatitis most likely will not get better, and they will continue to suffer from their disease.”

In conclusion, Dr. Song asserted that JAK inhibitors are faster and can achieve deeper levels of itch and skin response; they are effective even in “dupilumab failures;” clinical phenotypes that may respond better to JAK inhibitors include predominant H&N involvement, itch-predominant atopic dermatitis, prurigo-type atopic dermatitis, psoriasis/atopic dermatitis overlap, and concomitant allergic contact dermatitis that is unavoidable; that the ORAL surveillance study showed higher rates of major adverse cardiovascular events, VTEs, and malignancy in a high-risk rheumatoid arthritis population but that even in this worst-case scenario, absolute rates were low; and that randomized controlled trials/letters to the editor and real-world evidence studies have not corroborated the ORAL surveillance data, particularly in dermatology patients.

1. Davis D et al. Guidelines of care for the management of atopic dermatitis in adults with phototherapy and systemic therapies. J Am Acad Dermatol. 2023;90(2):e43-e56. doi.org/10.1016/j.jaad.2023.08.102.
2. Brumfiel CM, Patel MH, Zirwas MJ. Development of psoriasis during treatment with dupilumab: A systematic review. J Am Acad Dermatol. 2022 Mar;86(3):708-709. doi: 10.1016/j.jaad.2021.05.013.
3. Ytterberg SR et al. Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis. N Engl J Med. 2022;386(4):316-326. doi: 10.1056/NEJMoa2109927.