For decades, topical steroids have been the go-to treatment for inflammatory skin conditions like atopic dermatitis (AD), psoriasis, and contact dermatitis. Steroids are familiar, effective in the short term, and widely used, even with well-known long-term toxicity.1–4 So, when a new dermatology therapy emerges — such as JAK inhibitors for AD — how does it establish its place in such a competitive and well-entrenched treatment landscape? And when the science is relatively new, inconclusive, or controversial: how should questions about positioning and safety be addressed?
JAK Inhibitors in the treatment landscape
For any new therapy to gain acceptance, it must be clearly positioned within the broader treatment landscape. AD is a complex, multifactorial disease driven by intricate immune cell interactions. As mechanisms of disease become increasingly understood, a repertoire of promising new therapies with diverse targets has emerged.5
However, given the complexity of AD, blocking one or two cytokines or pathways may not be sufficient for all patients. This is where JAK inhibitors (JAKinibs) may present a compelling alternative. The JAK-STAT pathway regulates multiple cytokine families, making JAK inhibition a broader immunomodulatory strategy.
This breadth is reflected in the adoption of JAKinibs across multiple disease indications. Initially developed for oncology, JAKinibs have since been approved for various autoimmune and inflammatory conditions, including rheumatoid and psoriatic arthritis, ulcerative colitis, systemic lupus erythematosus, vitiligo, and, more recently, AD.5 Oral JAK inhibitors—baricitinib, abrocitinib, and upadacitinib—have demonstrated efficacy in AD, meeting primary and secondary endpoints across multiple clinical trials.4
Yet when it comes to clinical decision-making and positioning, breadth of action can be double-edged sword.
Weighing the promise and risks
Systemic JAK inhibition brings risks as well as benefits. While trials of pan-JAKinibs overall reported only mild-to-moderate adverse events, increased risk of infections, anaemia, cardiac events, thrombosis and malignancy remain a concern.5 Indeed, the FDA has placed a Boxed Warning label on all JAKinibs due to a study in rheumatoid arthritis with an oral pan-JAK inhibitor.5
This concern has driven the development of second-generation JAKinibs that selectively inhibit JAK1 and/or JAK2 only.6 However, outcomes for selective inhibitors have been mixed, with multiple trials being dropped.6 The outlook for selective vs. pan-JAK inhibitors is currently unclear.
The use of topical JAK inhibitors, where appropriate, may diminish safety concerns and benefit those with localised dermatological conditions including chronic hand eczema (CHE). One question has been whether such treatments would sufficiently penetrate the skin to reach target inflammatory cells within the dermis.5 However, a meta-analysis by Li et al found that topical JAKinibs were generally more effective than systemic ones.7 Communicating the nuances of these trade-offs is critical in helping HCPs and patients make informed choices.
A need for consensus
Where this leaves JAKinibs—and the overall treatment landscape for AD—remains a matter of some debate.
Two topical JAKinibs, ruxolitinib and delgocitinib, have gained approval following successful trials in AD and moderate-to-severe CHE respectively.8,9 Both are positioned as second-line treatments, however the 2023 AAAAI/ACAAI* guidelines suggested against adding topical ruxolitinib in mild-moderate AD, citing in particular the FDA Black Box warning and questions around systemic absorption.5
In a recent guide, the International Eczema Council described the generalization of safety concerns across the entire field of JAKinibs as “unfortunate”. The guide highlighted that “real-world data will be critical in establishing the long-term safety of JAKi as monotherapy or in combination with other systemic treatments.”10
A path forward
In AD, such uncertainty means that JAKinibs are unlikely to take the place of steroids as a first-line option any time soon. However, emerging evidence and the evolving treatment landscape presents an important opportunity: To clarify the risk-benefit profile of JAKinibs in relation to steroids/non-steroidal therapies and enable HCPs to make better informed clinical decisions.
As we have seen, this will require a broad perspective on new data, considering the evidence and expert views from other dermatological diseases and immunology as a whole. It will also require clear and continuous dialogue between industry and the dermatologist community. This is where medical communications will be essential to delivering on the promise of JAKinibs and transforming AD treatment.
*American Academy of Allergy, Asthma and Immunology/American College of Allergy, Asthma and Immunology
By Nicola Joseph
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