JAK Inhibitors for Patients With Refractory Mild to Moderate Atopic Dermatitis

The development of both topical and oral JAK inhibitors has expanded the treatment options available for patients affected by refractory mild to moderate AD, especially for those whom topical calcineurin inhibitors and crisaborole ointment are ineffective or poorly tolerated. Topical JAK inhibitors have been demonstrated to have good safety profiles for long-term use, thereby allowing patients to continue treatment uninterrupted, in contrast to corticosteroids, which can cause damage if used for an extended time.
 
Brett King, MD, PhD, is an associate professor of dermatology at Yale University School of Medicine in New Haven, Connecticut, specializing in inflammatory skin diseases. Dr King pioneered the use of JAK inhibitors in dermatology, and his work has revealed the broad utility of JAK inhibitors for the treatment of AD, alopecia areata, vitiligo, and granulomatous diseases. In this article, Dr King discusses the development of topical and oral JAK inhibitors, the role they can play in treating patients with refractory mild to moderate AD, and what may be yielded from future research on these drugs.

How is refractory mild to moderate AD best defined in clinical practice, and what are some of the most common reasons for treatment failure?

The definition of mild to moderate AD depends on the clinician, but I think of it as AD that involves about 10% or less of the body surface area, which is about the area of an entire arm. Often, this amount of AD can be treated with topical therapies, including topical corticosteroids (TCS), topical calcineurin inhibitors, crisaborole ointment, and — more recently — ruxolitinib cream. It is difficult to address dermatitis with topical agents when greater than 10% of the body surface area is affected.
 
Patients with mild to moderate AD generally respond to topical treatments, but many have refractory disease, meaning that their symptoms flare as soon as they stop applying these therapies. Before ruxolitinib cream, the treatment toolbox for these patients was limited. This was a problem for patients for whom TCS was the only therapy that was effective, as application of TCS to the same area for many weeks is hazardous; it will damage the skin, causing it to atrophy, develop stretch marks, and undergo other changes.

In 2021, ruxolitinib cream became the first US Food and Drug Administration (FDA)-approved topical JAK inhibitor for the treatment of mild to moderate AD in adolescents and adults.¹ How does JAK signaling pathway inhibition work, and what is the current role of topical ruxolitinib cream for treating patients with mild to moderate AD? How does this therapy fit into the treatment landscape with the other available topical treatments for mild to moderate AD?

The development of ruxolitinib cream was a huge treatment advancement because it is not a steroid and it is effective. Clinical trial data showed that it is at least as good at controlling itch as triamcinolone 0.1% cream, a commonly used mid-potency TCS.² Ruxolitinib cream, and other topical JAK inhibitors in development, will not become first-line treatments, largely because of cost, but for patients whose disease cannot be controlled by short-term TCS use or for whom topical calcineurin inhibitors or crisaborole ointment are ineffective or poorly tolerated, ruxolitinib cream is invaluable.
 
JAK inhibitors work by blocking the activity of 1 or more proteins in the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway, which suppresses the activity of many cytokines that drive AD, including interleukins (IL)-4, IL-13, and IL-31. Because JAK inhibitors are small molecules, they can be administered topically, as in ruxolitinib cream, or orally, as with abrocitinib and upadacitinib, which are approved by the FDA for moderate to severe AD.^3-5

What do we know about the long-term safety and durability of topical JAK inhibitors, and are there any data that suggest that these therapies may have better long-term safety than topical steroids, which are the mainstay treatment for mild to moderate AD?

The phase 3 trials of ruxolitinib cream, TRuE AD1 (ClinicalTrials.gov identifier: NCT03745638) and TRuE AD2 (ClinicalTrials.gov identifier: NCT03745651) were designed to have an 8-week randomized, placebo-controlled period followed by a 44-week extension (52 weeks total). The results from the extension period demonstrated a good safety profile and a durable response to ruxolitinib cream twice per day, with most patients maintaining clear or almost-clear skin over 52 weeks.⁶ This is a high bar of achievement.
 
Because of these data and clinical experience, we have very little concern about long-term, regular use of ruxolitinib cream. This is in contrast to TCS — we tell patients they should not use them for more than a 2-week period and to take 1 to 2 weeks off between treatment periods to avoid skin atrophy. Because of these concerns regarding the long-term, regular use of TCS, it is highly unlikely that anyone would design a clinical trial comparing long-term efficacy of TCS vs JAK inhibitors.
 
It is important to note that there is a boxed warning for ruxolitinib cream,⁷ just as with oral JAK inhibitors.^4,5 But I think the extremely low risk for cardiovascular events or blood clots really only comes into play when ruxolitinib cream is used on a large body surface area over long periods of time, in which case it may be more similar to a low-dose oral therapy. I believe that as long as use is limited to smaller areas, we can use ruxolitinib cream relatively freely.

Do you think there could be a role for oral JAK inhibitors, such as abrocitinib or upadacitinib, in the treatment of certain cases of refractory mild to moderate AD, or is it likely that topical JAK inhibitors will be more appropriate for individuals with this level of disease severity? Additionally, are there any long-term safety concerns associated with the use of oral JAK inhibitors in the treatment of refractory mild to moderate AD?

Oral JAK inhibitors definitely have a role in mild to moderate AD, in particular for patients with what I call multifocal and persistent AD, which is dermatitis or itch that affects 5 or 6 or more body sites that change every few days or every week. Topical therapies, including ruxolitinib cream, may be effective in suppressing disease where it is applied, but although the patient gets relief at that site, the disease then moves to a different site, which can be like playing a maddening game of whack-a-mole. For these patients, systemic therapy such as dupilumab, tralokinumab, or an oral JAK inhibitor is appropriate.
 
Before patients begin an oral JAK inhibitor, we take a careful medical and family history and perform screening through blood work. Subsequently, we do regular blood work, usually 2 to 3 times a year. It is also important for patients to undergo age-appropriate cancer screening and get annual skin checks while taking oral JAK inhibitors.

What is the impact of JAK inhibitors on quality-of-life measures, such as itch and sleep disturbance, in patients with refractory mild to moderate AD?

Because JAK inhibitors suppress IL-31 signaling, which is an important mediator of itch, we expect these agents to improve itch, which patients have reported is the most burdensome symptom of AD.^3,8 However, it is amazing how quickly and effectively JAK inhibitors, including ruxolitinib cream as well as the oral agents, suppress itch.^9-11 Some patients notice an improvement within hours of starting these therapies.
 
Sleep disturbance is commonly seen with AD, affecting many if not most adults and children with the disease,¹² but it is also an overlooked aspect of the disease that many of us do not ask about enough. The good news is that we can make it better, and clinical trials show that improvements in sleep are observed in patients receiving ruxolitinib cream.¹³ Everything that people do in a day is more challenging when they are itchy and have not slept well. Therefore, it is not surprising that patients treated with ruxolitinib cream experience quality-of-life improvements, as measured by Skindex-16.¹⁴

AD is more prevalent in pediatric populations than adults, affecting about 20% of children and 10% of adults worldwide.¹⁵ What considerations should be taken into account when prescribing JAK inhibitors to pediatric patients with AD, particularly with respect to dosing and monitoring?

Currently, ruxolitinib cream is approved for patients aged 12 years and older.⁷ Because AD is very often a disease of childhood, including children of all ages, we sometimes use ruxolitinib cream off-label for even younger children who have refractory disease. Everyone is waiting for clinical trials of ruxolitinib cream in younger populations, which will hopefully lead to an FDA approval for it in this age group. Delgocitinib, a topical JAK inhibitor, is well-tolerated and effective in children with AD in Japan, but it is not available in the US.¹⁶
 
The safety considerations when prescribing JAK inhibitors to children are similar to those for adults. Children taking oral inhibitors need regular blood work and monitoring, just as an adult would. It will be important to see the safety data from clinical trials of ruxolitinib cream in younger populations.

JAK inhibitors are a rapidly emerging therapeutic class for the treatment of AD, with at least 10 agents in drug development. What safety and efficacy data from ongoing clinical trials do you think will have the biggest impact on the care of adults and young adults with refractory mild to moderate AD?

As more JAK inhibitors are studied, we will hopefully learn why certain agents work well in some patients but not in others and why patients may experience an adverse event with one agent but not another. In addition, one JAK inhibitor may be more appropriate than another, depending on how AD presents, such as on the hands or face. Efforts to develop different formulations of topical JAK inhibitors — cream, ointment, and foam — are also important because patient preferences vary and different formulations may work better on different body sites. For example, it would be useful to have a foam for AD that involves the scalp, whereas ointment may be desirable for very dry areas of skin.

This Q&A was edited for clarity and length.

Disclosures

Brett King, MD, PhD, reported affiliations with Incyte Corporation; AbbVie, Inc; AltruBio, Inc; Almirall, SA; AnaptysBio; Arena Pharmaceuticals, Inc; Bioniz Therapeutics; Bristol-Myers Squibb Company; Concert Pharmaceuticals, Inc; Equillium; Horizon Therapeutics plc; Eli Lilly and Company; Janssen Pharmaceuticals, Inc; LEO Pharma, Inc; Otsuka Pharmaceutical Co, Ltd; Pfizer, Inc; Regeneron Pharmaceuticals, Inc; Sanofi-Aventis US LLC; Sun Pharmaceutical Industries, Ltd; TWi Biotechnology, Inc; Viela Bio; and Ventyx Biosciences, Inc.

References

1. Incyte announces U.S. FDA approval of Opzelura™ (ruxolitinib) cream, a topical JAK inhibitor, for the treatment of atopic dermatitis (AD). News release. Incyte Corporation. September 21, 2021. Accessed March 29, 2023. https://investor.incyte.com/news-releases/news-release-details/incyte-announces-us-fda-approval-opzeluratm-ruxolitinib-cream
 
2. Kim BS, Howell MD, Sun K, Papp K, Nasir A, Kuligowski ME; INCB 18424-206 Study Investigators. Treatment of atopic dermatitis with ruxolitinib cream (JAK1/JAK2 inhibitor) or triamcinolone cream. J Allergy Clin Immunol. 2020;145(2):572-582. doi:10.1016/j.jaci.2019.08.042
 
3. Schwartz DM, Kanno Y, Villarino A, Ward M, Gadina M, O’Shea JJ. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov. 2017;16(12):843-862. doi:10.1038/nrd.2017.201
 
4. Cibinqo^TM. Prescribing information. Pfizer, Inc; 2022. Accessed March 22, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/213871s000lbl.pdf
 
5. Rinvoq^®. Prescribing information. AbbVie, Inc; 2019. Accessed March 22, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/211675s004lbl.pdf
 
6. Papp K, Szepietowski JC, Kircik L, et al. Long-term safety and disease control with ruxolitinib cream in atopic dermatitis: results from two phase 3 studies. J Am Acad Dermatol. 2022;S0190-9622(22)03136-X. doi:10.1016/j.jaad.2022.09.060
 
7. Opzelura^TM. Prescribing information. Incyte Corporation; 2011; revised 2022. Accessed March 22, 2023. https://www.opzelura.com/prescribing-information.pdf
 
8. Silverberg JI, Gelfand JM, Margolis DJ, et al. Patient burden and quality of life in atopic dermatitis in US adults: a population-based cross-sectional study. Ann Allergy Asthma Immunol. 2018;121(3):340-347.doi:10.1016/j.anai.2018.07.006
 
9. Blauvelt A, Kircik L, Papp KA, et al. Rapid pruritus reduction with ruxolitinib cream treatment in patients with atopic dermatitis. J Eur Acad Dermatol Venereol. 2023;37(1):137-146. doi:10.1111/jdv.18571
 
10. Kim BS, Silverberg JI, Ständer S, et al. Rapid improvement of itch associated with atopic dermatitis with abrocitinib is partially independent of overall disease improvement: results from pooled phase 2b and 3 monotherapy studies. Dermatitis. 2021;32(1S1):S39-S44.doi:10.1097/DER.0000000000000770
 
11. Simpson EL, Papp KA, Blauvelt A, et al. Efficacy and safety of upadacitinib in patients with moderate to severe atopic dermatitis: analysis of follow-up data from the Measure Up 1 and Measure Up 2 randomized clinical trials. JAMA Dermatol. 2022;158(4):404-413. doi:10.1001/jamadermatol.2022.0029
 
12. Bawany F, Northcott CA, Beck LA, Pigeon WR. Sleep disturbances and atopic dermatitis: relationships, methods for assessment, and therapies. J Allergy Clin Immunol Pract. 2021;9(4):1488-1500. doi:10.1016/j.jaip.2020.12.007
 
13. Papp K, Szepietowski JC, Kircik L, et al. Efficacy and safety of ruxolitinib cream for the treatment of atopic dermatitis: results from 2 phase 3, randomized, double-blind studies. J Am Acad Dermatol. 2021;85(4):863-872. doi:10.1016/j.jaad.2021.04.085
 
14. Kim BS, Sun K, Papp K, Venturanza M, Nasir A, Kuligowski ME. Effects of ruxolitinib cream on pruritus and quality of life in atopic dermatitis: results from a phase 2, randomized, dose-ranging, vehicle- and active-controlled study. J Am Acad Dermatol. 2020;82(6):1305-1313. doi:10.1016/j.jaad.2020.02.009
 
15. Sadeghi S, Mohandesi NA. Efficacy and safety of topical JAK inhibitors in the treatment of atopic dermatitis in paediatrics and adults: a systematic review. Exp Dermatol. 2023;00:1-12. doi:10.1111/exd.14753
 
16. Nakagawa H, Nemoto O, Igarashi A, et al. Delgocitinib ointment in pediatric patients with atopic dermatitis: a phase 3, randomized, double-blind, vehicle-controlled study and a subsequent open-label, long-term study. J Am Acad Dermatol. 2021;85(4):854-862. doi:10.1016/j.jaad.2021.06.014

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