Getting (Re)acquainted with JAK

In this issue of Healio Psoriatic Disease, we focus on JAK inhibitors.

While they are not approved for psoriasis, two Janus kinase (JAK) inhibitors, tofacitinib and upadacitinib, are approved for psoriatic arthritis. Moreover, JAKs are now approved for atopic dermatitis (upadacitinib and abrocitinib) and alopecia areata (baricitinib). Similar to the explosion of biologics, there is an explosion of JAKs, with at least 14 in some stage of development for dermatological indications.

When treating psoriatic disease, we have many excellent options, and JAK inhibitors are clearly second-line options due to safety concerns. That said, they have impressive efficacy in psoriatic arthritis, rivaling tumor necrosis factor inhibitors, and do have some efficacy for skin psoriasis. In phase 3 trials of upadacitinib for psoriatic arthritis, the PASI 75 was about 62%. In a similarly designed trial, again in patients with psoriatic arthritis, tofacitinib achieved a PASI 75 of about 43%. While these are not head-to-head trials, these results have led me to favor upadacitinib in my patients with psoriasis when I need to use a JAK. I tend to use or recommend JAK inhibitors to my patients who have severe psoriatic arthritis and have failed biologics, in my patients who have psoriatic arthritis but their skin disease tends to be more eczematous, and in my patients with pustular variants of psoriasis, in which I have had some anecdotal success.

In my view, the key to success when using a JAK is patient selection in order to maximize benefit and minimize risk of side effects. First and foremost, the patient must have severe enough disease and have failed alternative safer treatment options (if alternatives exist) before trying oral JAKs. The main safety concerns with JAKs are malignancy, infection (particularly zoster) and thromboembolic events. These risks increase with age and underlying risk factors. The risk of zoster may be mitigated by use of the Shingrix vaccine (GSK) in patients with a history of chicken pox. Patients should be encouraged to be up to date with all recommended vaccines, particularly COVID vaccines, and age-appropriate cancer screening. Risks of JAKs can likely be further mitigated through intermittent use if the disease is well controlled. Such a strategy may be most effective in conditions such as atopic dermatitis in which once the epidermal barrier is repaired, skin-directed therapies may be more effective. It is more unlikely to be successful in psoriatic arthritis or alopecia areata in which recurrence of disease can lead to permanent joint damage in the former or distressing hair loss in the latter. In other words, most of our patients will require long-term treatment with JAKs for years — if not decades — further emphasizing the importance of patient selection and counseling.

In my own practice, I have found JAKs incredibly helpful for my most challenging cases. Going forward, we will need to learn from each other’s experience through real-world studies in order to determine the optimal use of these transformative therapies.

• References:
• Mease P, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1615975.
• McInnes IB, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2022516.
• Shalabi MMK, et al. Skin Therapy Lett. 2022;27(1):4-9