Janus kinase inhibitors (JAKis) have transformed the landscape of dermatological therapy over the last 2 years, with six United States Food and Drug Administration approvals and further clinical trials in progress.1 JAKis have proven highly efficacious in dermatological diseases, by blocking the JAK-signal transducer and activator of transcription (STAT) signalling pathway involved in numerous inflammatory or immune-mediated diseases.2 JAKis are small molecules, which absorb quickly and do not have to be metabolized, allowing for rapid responses to treatment.3 Although the approval of the first-generation JAKi tofacitinib for rheumatoid arthritis (RA) in 2012 was a ground-breaking step forward in immunotherapy, tofacitinib was associated with certain adverse events (AEs) and subject to additional study over the ensuing decade. Following the completion of the ORAL Surveillance (ORALSURV) post-marketing safety study, tofacitinib, along with other JAKis, received a class-wide boxed warning from the US Food and Drug Administration (FDA) outlining potential risk for major adverse cardiovascular events, malignancy, infection, thromboembolic events and death.4,5 However, recent approvals of ruxolitinib cream (atopic dermatitis, vitiligo), abrocitinib (atopic dermatitis), upadacitinib (atopic dermatitis), deucravacitinib (psoriasis), baricitinib (alopecia areata) and ritlecitinib (alopecia areata) have provided much needed options in the dermatologist’s armamentarium for the treatment of chronic inflammatory disease.1,6 Clinical findings for each of these medications has demonstrated high efficacy and favourable safety, with current research efforts centred on generation of long-term safety.3 Further research into the utility of JAKis in rare diseases, where limited treatment options are available, is necessary to provide a potential option for patients who are often overlooked.9
In this expert interview, we spoke with Expert Faculty member Dr Raj Chovatiya to discuss the impact JAKis have already had on the treatment landscape for dermatology, the controversies surrounding the small-molecule therapy, when they should be prescribed and management of known adverse effects, such as ‘jacne’. We also discuss the approval of topical ruxolitinib and the other topical JAKis under investigation, including key clinical trial data. Finally, Dr Chovatiya provides some insight into the possibilities of JAKis for rare diseases in the future.
What JAKis are already approved in the dermatology setting and how have they impacted the treatment landscape?
We have had a huge revolution in JAKis over the last handful of years and there are a number available to us as part of our therapeutic armamentarium for inflammatory diseases. For many years, tofacitinib was used off label for many dermatologic conditions, but never progressed to the point of approval. However, this was the first foray many dermatologists had into JAK inhibition. At present, oral medications that we have at our disposal include those that are approved for atopic dermatitis (abrocitinib, upadacitinib and barcitinib outside of the USA), alopecia areata (baricitinib, ritlecitinib), and psoriasis (deucravacitnib, which is subject to some debate in classification as a JAKi). In a topical format, as of right now, we have ruxolitinib cream, which is approved for both atopic dermatitis and vitiligo, and delgocitinib ointment, which is approved in Japan for atopic dermatitis. JAKis have given us a bevy of topical and oral options for diseases that otherwise had limited to no options, and this has had a major impact on the treatment landscape.
What controversies surround JAKis and when should they be prescribed?
Most of the controversy for JAK inhibition is based on safety, and a lot of this comes from boxed warnings (or ‘special warnings’) that JAKis have received. Based on long-term data that largely comes from studies of tofacitinib (our first JAKi), patients with RA who were older and had cardiovascular comorbidities appeared to have increased risk of major adverse cardiovascular events and malignancy and increased incidence of opportunistic infections, thromboembolic issues, and death compared with patients treated with tumour necrosis factor alpha blockers. By association, regardless of the individual data seen with subsequent JAKi in clinical trials for other indications, these risks have been attached to all JAKi for inflammatory disease. In the real world, there are nuances to prescribing these medications, in that it is critical to understand the baseline health of your patient before making any treatment decisions. JAKi fill such an important need for our patients, and the actual studies for dermatologic indications have borne out very favourable safety results balanced by good efficacy. I tend to be less worried about the class-wide warning for most patients, but I do not dismiss them. I think it is important for us to educate ourselves, so we can appropriately understand context, and individualize our discussions to best figure out which patients are the best candidates.
What clinical data surrounds topical JAKis and in which indications are they being investigated?
Ruxolitinib cream, was first approved for atopic dermatitis and is also now approved for vitiligo. The vitiligo approval was particularly remarkable given the lack of any approved, well-studied therapies for repigmentation in this disease. The clinical data for atopic dermatitis is remarkable, as topical ruxolitinib works rapidly on itch (minutes to hours). It additionally has potency that rivals many strong, broadly acting topical corticosteroids, making it very easy to avoid the need for steroids altogether. In the case of vitiligo, continuous use is associated with clinically significant repigmentation. From the data that we have thus far, it appears that long-term continuous treatment is the key to driving maximal repigmentation. Ruxolitinib cream is currently under investigation for several other inflammatory ermatoses. In addition, delgocitinib cream is currently being evaluated for chronic hand eczema, while an ointment formulation is approved for atopic dermatitis in Japan.10,11
What impact has topical ruxolitinib had on the treatment paradigm for atopic dermatitis and nonsegmental vitiligo since approval in 2021?
Ruxolitinib has really been game changing for both indications, particularly for vitiligo. On the atopic dermatitis side, it has given us a topical, non-steroidal treatment that can be chronically and safely in patients with mild-to-moderate atopic dermatitis – especially in sensitive or tough-to-treat areas where we were historically limited with topical corticosteroids.
In the case of vitiligo, we can think of treatment existing in pre- and post-ruxolitinib periods. Our previous options were non-targeted, slowly acting and limited in efficacy. Due to the approval of ruxolitinib cream, I am able to offer my patients a well-studied, targeted therapy that selectively and predictably treats their disease.
What is the link between JAKis and acne as an AE, and how should ‘jacne’ be managed?
We don’t have an exact answer so far. It does appear that both with oral or topical JAKis, we do see different rates of acne and folliculitis, based on the drug in question. There is some thought that this is related to JAK/STAT signalling pathways in the follicular unit, but we have not really come to a conclusive answer or predictive algorithm as to who is going to be affected.
In general, many cases of acne or folliculitis resolved without treatment in clinical trials. For those that did require therapy, many acne therapies used for mild disease were effective, including topical antimicrobials or topical antibiotics. Most subjects did not require much step-up in acne therapy – and this has mirrored my real-world experience.
In addition, I have found that in my practice, the trade-off of controlling burdensome inflammatory disease versus mild acne is generally always in favour of controlling the primary disease process. Most of my patients who have experienced ‘jacne’ have just not been particularly bothered by it.
What potential utility do JAKis hold in the future for rare diseases?
In dermatology, we spend many years training to see diseases that are fairly uncommon. Despite their rarity, many share core mechanisms of immune dysregulation that feed into a highly conserved pathway like JAK/STAT. It stands to reason that JAKis hold great potential for many different dermatologic conditions – and early studies suggest that this is true. Beyond atopic dermatitis, psoriasis, alopecia areata and vitiligo, I’m extremely excited for the promise that JAKis hold for hidradenitis suppurativa, lichenoid disorders, granulomatous disorders and connective tissue disease – all of which are challenging to manage given the lack of approved therapies.