JAK inhibitors for Atopic Dermatitis – STAT!

The future is promising for those with atopic dermatitis (AD). Over the past decade, our understanding of AD pathomechanism has evolved, giving way to numerous potential therapeutic targets. During this time, Janus kinase (JAK) inhibitors—a new class of medications—has also emerged. While the JAK-signal transducer and activator of transcription (JAK-STAT) pathway  did not seem to be an obvious target early on,¹ JAK inhibitors are likely to be the next generation of agents FDA approved for the treatment of moderate to severe AD. Indeed, JAK inhibitors are demonstrating benefit across multiple dermatologic diseases and constitute a promising frontier for dermatologic therapy overall. 

The therapeutic role of JAK inhibitors in AD and other diseases can be explained simply. Cytokine signaling, in which extracellular messages are transmitted to the nucleus, utilizes the JAK-STAT pathway. As in a relay race, cytokines, including interleukins, interferons, and other molecules, dock at the cell surface and pass the baton to JAK enzymes, which in turn pass the baton to STAT proteins, which translocate to the nucleus where they regulate gene transcription (Figure 1). In analogy to the relay race, where hobbling any single runner would interrupt the passing of the baton, cytokine signaling may be interrupted by blocking the cytokines, the JAK enzymes, or the STAT proteins. Therefore, when cytokines are prominent mediators of disease, either an antibody that binds to a specific cytokine (or its receptor) or a JAK inhibitor may effectively disrupt disease pathogenesis, leading to clinical improvement.

Figure 1. The JAK-STAT pathway in cytokine signaling. A cytokine binds to its cell surface receptor (A). JAKs phosphorylate STATs (B). Phosphorylated STATs dimerize and translocate to the nucleus (C). Activation of target gene expression (D). 

There are 4 members of the JAK family of enzymes: JAK1, JAK2, JAK3, and tyrosine kinase 2 (Tyk2). JAK inhibitors are small molecules that target the JAK family of enzymes, with variable selectivity for the different members. Therefore, some JAK inhibitors are more selective, (eg, JAK1 inhibitor or JAK3 inhibitor), and others have broader activity, (eg, JAK1/3 inhibitor). Although many JAK inhibitors are in development for dermatologic and other diseases, 3 JAK inhibitors are currently FDA approved: ruxolitinib (Jakafi), tofacitinib (Xeljanz), and baricitinib (Olumiant). Ruxolitinib is a JAK1/2 inhibitor approved for myelofibrosis and polycythemia vera.² Tofacitinib is a JAK1/3 inhibitor approved for rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis.³ Baricitinib is a JAK1/2 inhibitor recently approved for rheumatoid arthritis.⁴ 

Many of the cytokines that are implicated in the pathogenesis of AD signal directly through the JAK-STAT pathway: IL-4, IL-5, IL-6, IL-12, IL-13, IL-23, and IL-31.^5-7 Dupilumab (Dupixent), FDA approved for moderate to severe AD in 2017,⁸ modulates IL-4 and IL-13 signaling by binding the alpha subunit of the IL-4 receptor (IL-4Rα), thus preventing IL-4 and IL-13 binding (and signaling). Interestingly, IL-4 signals through JAK1/3 and IL-13 through JAK1/Tyk2.^9,10

There may be a role for the JAK-STAT pathway not only in mediating inflammation but also AD-associated pruritus, independent of inflammation. Pruritus is the hallmark symptom of AD and causes significant impairment of quality of life. IL-31, implicated in pruritus associated with AD,^11,12 signals through 3 different pathways, including JAK-STAT (via JAK1/2).¹³ It was recently shown that neuronal IL-4Rα signaling is important for chronic itch; IL-4Rα signals through JAK1.¹⁴ 

The first clinical evidence of effectiveness of JAK inhibitors in AD emerged in 2015, with the report of 6 patients with moderate to severe AD successfully treated with tofacitinib.¹⁵ All 6 patients had previously failed common treatments, including systemic agents. Treatment with tofacitinib led to a 54.8% reduction in the Scoring of AD (SCORAD) Index and 69.9% and 71.2% reductions in pruritus and sleep loss scores, respectively, over 8 to 14 weeks, with stable or further improvement with continued treatment.¹⁵ Since then, we have treated several more patients with moderate to severe AD with tofacitinib with good effect (Figure 2). 

Figure 2. Atopic dermatitis. Fifteen-year-old girl with atopic dermatitis. Before and after 12 weeks of tofacitinib 5 mg twice daily.

Subsequently, in 2016, the results of a randomized, double-blind, vehicle-controlled study using tofacitinib 2% ointment showed an 81.7% reduction in Eczema Area and Severity Index (EASI) scores compared with only 29.9% in the control group over the 4-week study period.¹⁶ In the treatment group, approximately 80%, 60%, and 40% of patients achieved EASI 50, EASI 75, and EASI 90 (≥ 50%, 75% and 90% reduction in EASI score relative to baseline), respectively. A rapid decrease in pruritus with topical tofacitinib was also observed.

Presently, there are several large clinical trials evaluating both oral and topical JAK inhibitors in the treatment of AD (Table). Baricitinib, PF-04965842, and upadacitinib are currently in phase 3 trials. The latter 2, PF-04965842¹⁷ and upadacitinib,¹⁸ have been granted Breakthrough Therapy designation by the FDA for AD. 

In a phase 2 trial of oral baricitinib, a JAK1/2 inhibitor,¹⁹ 124 patients with moderate to severe AD were treated with baricitinib 2 mg, 4 mg, or placebo once daily for 16 weeks, topical corticosteroids were permitted during the study. More patients in the baricitinib 4-mg group  achieved ≥50% reduction in the EASI score compared with placebo (61% vs 37%) at 16 weeks; significant separation between the baricitinib 2 mg and 4 mg groups and the placebo group was evident at week 4. Improvement in pruritus was evident at 1 week.

The results of a phase 2 study of PF-04965842, a selective JAK1 inhibitor, in moderate to severe AD have not yet been published but data presented at the 2017 European Academy of Dermatology and Venereology meeting seem promising.²⁰ Similarly, results of a phase 2b study of upadacitinib, another selective JAK1 inhibitor, have not yet been published but data presented at the 2018 American Academy of Dermatology Annual Meeting suggest benefit of upadacitinib.²¹ 

The results of a phase 2 trial evaluating topical JTE-052 ointment (0.25%, 0.5%, 1%, and 3%), a JAK 1/2 inhibitor, with mild activity in JAK3 and Tyk2, in 327 adults with moderate to severe AD demonstrated change from baseline in the modified EASI score of –72·9% for the 3% ointment compared with –12.2% for the vehicle over 4 weeks.²² Notably, the pruritus scores, measured with the numerical rating scale, showed improvement the first day of application of JTE-052. 

The results of a phase 2 trial evaluating topical ruxolitinib (cream 0.15%, 0.5%, and 1.5%), a JAK1/2 inhibitor, compared with vehicle and triamcinolone 0.1% cream in 307 adults with AD have not yet been published but data presented at the 2018 European Academy of Dermatology and Venereology meeting seem promising.²³

Regarding safety, the immunomodulatory effects of JAK inhibition must be considered. Most data regarding safety comes from large clinic trials of tofacitinib or baricitinib in the treatment of rheumatoid arthritis.^24-27 In these trials, patients were always taking concomitant methotrexate, with or without nonsteroidal anti-inflammatory drugs and glucocorticoids. Overall, while these medicines have a black box warning for malignancy and serious infection, the collective data suggests these medicines have a safety profile comparable to most of the biologics.^28,29 

JAK inhibitors appear to be effective for the treatment of AD, and this class of medications is certain to influence the current paradigm of AD management. Not only do JAK inhibitors offer the promise of reliably effective oral therapy for moderate to severe AD, they also offer the possibility of reliably effective topical therapy.  The future is bright for our patients with AD, many of whom have suffered for years without effective treatment for their disease. Together with our patients, we eagerly await the future. 

Dr Wambier is an associate professor of dermatology at the State University of Ponta Grossa in Ponta Grossa, Parana, Brazil, and a clinical research affiliate in the department of dermatology at the Yale University School of Medicine in New Haven, CT. 

Dr King is an associate professor of dermatology at the Yale University School of Medicine in New Haven, CT. 

Disclosure: Dr King has served on advisory boards or is a consultant for Aclaris Therapeutics Inc, Concert Pharmaceuticals Inc, Dermavant Sciences Inc, Eli Lilly and Company, and Pfizer Inc. He is on the speakers bureau for Dupixent for Regeneron Pharmaceuticals and Sanofi Genzyme. 

Dr Wambier has no financial relationships.