Janus Kinase Inhibitors in the Treatment of Atopic Dermatitis: Military Considerations

The atopic dermatitis (AD) therapeutic landscape is changing considerably with the advent of Janus kinase (JAK) inhibitors. Several JAK inhibitors recently have been approved by the US Food and Drug Administration, building off years of foundational research aimed at elucidating the downstream effects of the JAK–signal transducer and activator of transcription (STAT) pathway and its role in AD pathogenesis. Agents within this promising new class of drugs have performed well vs placebo in phase 2 and 3 clinical trials. This article reviews relevant trial efficacy and safety data of several JAK inhibitors as well as the implications of the use of these medications in AD patients, with specific considerations unique to active-duty military personnel.

Background on JAK Inhibitors

The hematopoietin superfamily of cytokine receptors encompasses a broad group that includes receptors for immune (eg, IL-2, IL-4, IFN-γ), hematopoietic (eg, erythropoietin, thrombopoietin, granulocyte-macrophage colony-stimulating factor), and nonimmune (eg, prolactin, leptin, growth hormone) cytokines. These cytokines signal via the JAK-STAT pathway. The hematopoietin family of cytokine receptors lacks intrinsic enzymatic activity, and as a result, they rely on JAK enzymes to transmit their signals intracellularly after cytokine binding to the receptor.¹ Janus, of Roman mythology, was the god of doorways and archways and was commonly depicted with 2 heads. Janus kinases were named for their 2 “faces,” the kinase domain with its adjacent regulatory kinaselike domains.² The binding of a cytokine to its receptor triggers engagement of the receptor by JAKs, leading to phosphorylation of both the JAKs and the receptor. Subsequent recruitment and phosphorylation of STAT proteins occurs. Following STAT phosphorylation, the STAT proteins dissociate, dimerize, and translocate to the nucleus, where they enact changes in cell behavior through transcriptional effects.¹

Humans possess only 4 JAKs. Janus kinase 1, JAK2, and tyrosine kinase 2 are widely expressed, whereas JAK3 expression is largely limited to immune cells. Thus, there is notable overlap in the use of the 4 JAKs among the relatively larger number of various cytokines that utilize them to propagate intracellular signaling.¹ Janus kinase 1 is important for signaling of receptors activated by a variety of interleukins, as well as IFN-α, IFN-β, and IFN-γ. Janus kinase 2 is important for signaling for the hormonelike cytokines erythropoietin, thrombopoietin, growth hormone, granulocyte-macrophage colony-stimulating factor, IL-3, and IL-5. Janus kinase 3 is important for hematopoietic cell proliferation and function.¹

JAK Inhibitors and Atopic Dermatitis

Topical treatments, including corticosteroids and calcineurin inhibitors, are considered the standard-of-care therapy for most patients with AD; however, their clinical benefit often is limited by their anatomic use restrictions and local adverse events, including skin atrophy, striae, and application-site reactions such as stinging and burning.³ As a result, long-term application of these drugs, particularly in sensitive areas, is not recommended owing to safety/tolerability issues.³ Systemic immunomodulatory medications are indicated for patients with AD who do not achieve adequate disease control with topical treatments and/or phototherapy or for patients with severely impaired quality of life.⁴

Janus kinase inhibitors have several key benefits over biologics: oral and topical bioavailability, predictable pharmacokinetics, nonimmunogenicity, and dosing flexibility.⁴ Janus kinase 1 is central to the cell signaling of many cytokines involved in the pathogenesis of AD that comprise the T-helper lymphocytes type 2 axis: IL-4, IL-13, and thymic stromal lymphopoietin. Janus kinase signaling also may mediate itch responses by acting directly on sensory nerve fibers. Consequently, the substantial reduction in pruritus seen in many studies of JAK inhibitors is thought to be in part due to the effects on sensory nerve fibers in the skin and the blockade of early itch signaling in response to IL-4, IL-13, and IL-31.⁵

Abrocitinib is a JAK1 inhibitor with a similar side effect profile to upadacitinib. Both agents were approved by the FDA for the treatment of refractory moderate to severe AD on January 14, 2022.⁶ These are second-generation (also referred to as selective) oral JAK inhibitors with much greater inhibitory potency for JAK1 than for JAK2, JAK3, or tyrosine kinase 2, thereby reducing the risk for hematopoietic effects associated with JAK2 inhibition. The approval of abrocitinib stemmed from the phase 3 clinical trial JAK1 Atopic Dermatitis Efficacy and Safety (JADE)-MONO-1 (N=387),⁷ its replicate trial JADE-MONO-2 (N=391),⁸ and the JADE COMPARE trial.⁹ The JADE-MONO trials were multicenter, double-blind, placebo-controlled studies that enrolled patients 12 years and older with moderate to severe AD.^7,8 Treatment groups consisted of 100-mg and 200-mg doses and were evaluated with the placebo group for their ability to achieve an investigator global assessment (IGA) score of 0 or 1 and eczema area and severity index 75 (EASI-75) at 12 weeks.^7,8 Sixty-three percent of patients in the 200-mg group, 40% in the 100-mg group, and 12% in the placebo group reached the EASI-75 end point, and the differences in these response rates were statistically significant vs placebo (100 mg: 27.9% [95% CI, 17.4-38.3], P<.0001; 200 mg: 51.0% [95% CI, 40.5-61.5], P<.0001). Notably, 44% of patients using the 200-mg dose achieved almost complete or complete resolution of AD (IGA responders, improvement of ≥2 and IGA score of 0 or 1 at 12 weeks).⁷ In JADE-MONO-2, EASI-75 also was achieved significantly more frequently in the treatment groups compared with the placebo group at 12 weeks (200 mg: 61.0%; 100 mg: 44.5%; placebo: 10.4%; P<.001 vs placebo).⁸ Adjunctive therapy with topical corticosteroids was prohibited in both studies. A dose-dependent decrease in platelets was seen in both trials, as in the phase 2 trial that preceded them.¹⁰

The primary end point of the JADE COMPARE trial was to evaluate the efficacy of abrocitinib as compared with placebo at 12 weeks in adult patients with moderate to severe AD and in the setting of concomitant topical corticosteroid therapy.⁹ One of several secondary end points of this study compared the ability of dupilumab vs abrocitinib and placebo treatment groups to achieve itch reduction at 2 weeks, defined as 4-point improvement or more from baseline in the score on the Peak Pruritus Numerical Rating Scale (NRS), a well‐defined, reliable, sensitive, and valid scale for evaluating worst itch intensity in adults with moderate to severe AD.^9,11 The primary end point was the same as in the other phase 3 studies and was met in the JADE COMPARE trial by all treatment arms. An EASI-75 was seen in 70.3% of patients treated with 200 mg of abrocitinib, 58.7% in the 100-mg abrocitinib group, 58.1% in the dupilumab group, and 27.1% in the placebo group (P<.001 for both abrocitinib doses vs placebo). Only the 200-mg dose of abrocitinib demonstrated superior itch response at week 2 compared with dupilumab (22.1% response rate difference [95% CI, 13.5-30.7; P<.001]). Both abrocitinib groups failed to demonstrate significant differences compared with dupilumab with respect to other secondary end points to include IGA response and EASI-75 at week 16.⁹