Achievement of Optimal Treatment Targets with Oral Janus Kinase Inhibition in Elderly Patients with Atopic Dermatitis: A Real-world, Multicenter, Retrospective Study

J Clin Aesthet Dermatol. 2025;18(2):25–29.

by Diego Ruiz Dasilva, MD; Noelle Desir, BA; Iain Noel Encarnacion, MS; Naiem Issa, MD, PhD; E. James Song, MD; and Nicholas K. Mollanazar, MD, MBA

Drs. Dasilva and Issa are with Forefront Dermatology in Virginia Beach, Virginia. Dr. Encarnacion is with Eastern Virginia Medical School in Norfolk, Virginia. Additionally, Dr. Dasilva is with is with Eastern Virginia Medical School in Norfolk, Virginia. Dr. Desir is with is with Weill Cornell Medical College in New York, New York. Drs. Desir, Encarnacion, and Mollanazar are with the Department of Dermatology at Perelman School of Medicine at the University of Pennsylvania in Philadelphia, Pennsylvania. Additionally, Dr. Issa is with Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery at the University of Miami School of Medicine in Miami, Florida, and the Department of Dermatology at George Washington University School of Medicine and Health Sciences in Washington, District of Columbia. Dr. Song is with Frontier Dermatology in Mill Creek, Washington.

FUNDING: No funding was provided for this article.

DISCLOSURES: Dr. Dasilva is a consultant and/or speaker for AbbVie, Arcutis, Dermavant, Eli Lilly, Galderma, Janssen, LEO pharma, Pfizer, Sanofi & Regeneron, UCB, Verrica. Dr. Issa is a consultant and/or speaker for Abbvie, Bristol Myers Squibb, Castle Biosciences, Dermavant Sciences, DermTech, Galderma, Incyte, Jannsen, Journey, LEO Pharma, Lilly, Ortho Dermatologics, Pfizer, Regeneron, Sanofi, SUN Pharma, Verrica Pharmaceuticals. Dr. Song is a consultant and/or speaker for AbbVie, Arcutis, Alphyn, Amgen, Apogee, Avalo, Bristol Meyers Squibb, Boehringer-Ingelheim, CorEvitas Registry, Dermavant, DermBiont, Eli Lilly, Galderma, Incyte, Janssen, LEO pharma, MoonLake, Novartis, Ortho-dermatologics, Pfizer, Sanofi & Regeneron, SUN pharma, Target Registry, TIMBER, UCB. Dr. Mollanazar is a consultant and/or speaker for AbbVie, Beiersdorf, Boehringer Ingelheim, Janssen, Novartis, Regeneron Pharmaceuticals Inc., Sanofi, Trevi Therapeutics, Menlo Therapeutics Inc, Galderma, Leo Pharma, Pfizer, Sanofi, Regeneron Pharmaceuticals Inc, Genzyme, Novartis, Regeneron Pharmaceuticals Inc., Sanofi, and Janssen. Ms. Desir and Mr. Encarnacion have no conflicts of interest relevant to the content of this article.

ABSTRACT: Objective: Oral Janus kinase inhibitors (JAKi) have demonstrated high levels of efficacy with acceptable safety in patients with atopic dermatitis (AD), yet there remains significant hesitancy among the dermatologic community to use JAKi in elderly populations due to the potential increased risk of serious adverse events in this population. We aimed to perform a retrospective review to describe real-world outcomes for the use of selective JAK-1 inhibitors in patients with AD aged 65 years or older. Methods: We conducted a multicenter retrospective review. AD cases were identified by ICD-10-CM codes L20.8/L20.89/L20.9. Patients aged 65 years or older years treated with a selective JAK-1 inhibitor were included. Body surface area (BSA), Investigator Global Assessment (IGA), and Peak Pruritus Numerical Rating Scale (NRS) were collected and evaluated independently. Results: Thirty-eight AD cases in patients aged 65 years or older treated with a selective JAK-1 inhibitor were identified. Patients were aged 65 to 96 years, and treatment duration ranged from 4 to 28 months. Thirty-six out of 38 patients (94.7%) tolerated treatment well; one was switched to another JAKi due to mood lability and another paused therapy during hospitalization for septic pneumonia. Thirty-five out of 37 (94.6%) patients achieved an IGA of 0/1, 28/30 (93.3%) achieved an NRS of 0/1, and 30/30 (100%) had a peak pruritus response with improvement of ≥4 points on NRS. There were no clinically meaningful laboratory abnormalities throughout the treatment course. No laboratory abnormality resulted in treatment discontinuation. Limitations: Limitations of this retrospective review include selection bias and missing data. Conclusion: We demonstrate the ability to achieve optimal treatment targets and safety of selective JAKi-1 inhibitors in elderly patients with AD.

Keywords: General dermatology, medical dermatology, Janus kinase inhibitor, elderly, atopic dermatitis, biologics

Introduction

Atopic dermatitis (AD) is a chronic inflammatory skin disease that most commonly presents in childhood with itch, papulosquamous lesions, and a chronic relapsing and remitting course. Adult-onset AD has been increasingly recognized and has been linked to environmental factors, though it is unclear if its prevalence is truly increasing or if there is simply increased recognition and more inclusive diagnostic criteria. Elderly-onset AD is a subgroup of these patients who develop new-onset disease over 65 years of age or who had mild disease earlier in life and now have moderate to severe disease. This entity has been linked to aging populations and immunosenescence, as there is a marked TH2 shift in the elderly.¹ In these patients, it is important to achieve optimal disease targets in line with the minimal disease activity described in international expert consensus-based recommendations.²

Topical treatments (eg, emollients, corticosteroids, calcineurin inhibitors, phosphodiesterase-4 [PDE-4] inhibitors, JAKi) are first-line for AD. If non-responsive to topical medications, immunosuppressants not currently approved for AD by the United States (US) Food and Drug Administration (FDA), such as methotrexate, mycophenolate, cyclosporine, and/or azathioprine, were used. There are now five FDA-approved advanced systemic treatments for AD, including biologics (dupilumab, tralokinumab, lebrikizumab) and oral JAKi (upadacitinib, abrocitinib). These are the only treatments given a strong recommendation by the AAD AD 2023 updated guidelines.³ In addition, these guidelines offer a conditional recommendation for immunosuppressants and a recommendation against the use of systemic corticosteroids (SCS). Given their excellent safety profile, biologics remain the preferred first-line systemic agent for AD in elderly patients. While the drug labels for the FDA-approved JAKi for AD expressly indicate use in the setting of “refractory, moderate to severe atopic dermatitis whose disease is not adequately controlled with other systemic drug products, including biologics,” the use of JAKi in elderly patients remains low due to perceived risk given the mandated boxed warning of increased risk of mortality, major adverse cardiovascular events (MACE), venous thromboembolism (VTE), serious infection, and malignancy. However, this boxed warning is extrapolated from an FDA-mandated post-marketing safety study⁴ of oral tofacitinib, a pan-JAKi, in an enriched high-risk rheumatoid arthritis population treated in combination with other immunosuppressants versus TNF-α inhibitors and may not be generalizable to patients with AD. The use of JAKi in elderly patients is further complicated by a post-hoc analysis of the same study, wherein it was demonstrated that only patients over the age of 65 or who were a current or former smoker had an appreciably higher risk with JAKi versus TNF-α inhibitor use.⁵ Several large studies have demonstrated no increased risk for mortality, MACE, VTE, or malignancy with JAKi in the setting of treating dermatologic conditions.⁵ Nonetheless, there is still hesitancy, due to the natural increase in comorbidities with age, and lower representation of elderly patients in Phase III clinical trials (n=145/3128 for abrocitinib; n=116/2683 for upadacitinib).^7,8 While biologics are highly safe and efficacious medications, there are patients who do not respond adequately, develop side effects, cannot tolerate injections, or have comorbidities that may also be treated with JAKi. These selective JAKi have reported low rates of safety events linked to the boxed warnings.^9,10 It is crucial that our elderly patients are not undertreated and are provided with access to the most current and effective treatments. Herein, we describe the use of upadacitinib or abrocitinib in 38 elderly patients with AD who failed systemic therapy, to demonstrate the efficacy, safety, and utility of these treatments for this population in the largest real-world cohort to date.

Methods

We conducted a retrospective review of patients from three private practice dermatology clinics in Virginia and Washington, DC, and patients from a single provider at one large academic dermatology department in Pennsylvania. AD cases were identified by ICD-10-CM codes L20.8/L20.89/L20.9. Patients ages 65 years or older treated with JAK-1 inhibitors, upadacitinib or abrocitinib, were included.  Demographics, comorbidities, treatment duration, and prior treatments were collected. Effectiveness outcomes included body surface area (BSA), Investigator Global Assessment (IGA), and Peak Pruritus Numerical Rating Scale (NRS), all of which were collected and evaluated independently. Laboratory-related and treatment-related adverse events (AEs) were collected to assess safety.

Results

In this multicenter review, 38 cases of AD treated with a JAK-1 inhibitor in patients aged 65 years or older were identified. Patients ranged in age from 65 to 96 years old, and treatment duration with JAK-1 inhibitors ranged from 4 to 28 months (Table 1). Twenty out of 38 (52.6%) patients were bio-experienced with prior dupilumab or tralokinumab treatment, and switched to JAK-1 inhibitor therapy to achieve adequate control of their AD (Table 1). One patient started upadacitinib and dupilumab at the same time for a severe case of chronic atopic dermatitis and acute bullous pemphigoid overlap (Table 1). Eighteen out of 38 (47.4%) patients were bio-naive, failed systemic treatments (prednisone, immunosuppressives), refused injectable biologics and chose oral JAKi as the next line of treatment (Table 1).

Of the total cohort, 35 of 37 (94.6%) patients achieved an IGA of 0/1, 28 of 30 (93.3%) achieved an NRS of 0/1, and 30 of 30 (100%) had a peak pruritus response with improvement of at least four points on NRS (Table 1). Of note, the denominators differ due to incomplete data, as some patients did not have a documented IGA or NRS. Zero out of 38 (0%) patients had any clinically meaningful laboratory abnormalities throughout the treatment course (Table 1). Seven out of 38 (18.4%) patients had mild elevation in lipids that did not alter treatment. Two out of 38 (5.3%) patients had mild creatinine elevations that resolved upon re-check. Three out of 38 patients (7.9%) had mild stable anemia. One out of 38 patients (2.6%) had pre-existing mildly elevated ALT that remained stable and one of 38 patients (2.6%) had leukopenia that improved on treatment (Table 2). Notably, there were no cases of herpes zoster.

Of those who chose JAKi over biologic therapy as first-line advanced systemic treatment, the most common reasons were a desire for oral treatment, rapid improvement, and background presence of comorbid inflammatory diseases that could respond to JAKi. The most common medical comorbidities at baseline were hypertension (n=25/38, 65.8%), type II diabetes mellitus (n=12/38, 36.8%), coronary artery disease (n=9/38, 23.7%) and nonmelanoma skin cancer (n=8/38, 21.1%, Table 1). Seventeen out of 38 (44.7%) were current or former tobacco smokers (Table 1).

Discussion

To our knowledge, this review is the largest of its kind, and pools together patients from several distinct populations who are elderly and considered to be “high-risk” for JAKi therapy; it adds to the body of real-world evidence that JAKi can be used safely in patients over 65. Biologics and JAKi have markedly different mechanisms of action. AD biologics are human monoclonal antibodies that inhibit interleukin (IL)-4 and/or IL-13 function while JAK-1 inhibitors prevent the transduction of signals via the JAK/STAT pathway which includes IL-4 and 13 but also IL-31, IL-22, interferon gamma (IFNy), and thymic stromal lymphopoietin, which are highly relevant cytokines for certain subgroups with atopic dermatitis.

Due to their unique mechanism and mode of administration, there are many reasons an elderly patient might choose JAKis over  biologics. This includes speed of response, depth of response, preference for oral medication, and failure or intolerance of a biologic. Regarding traditional systemic immunosuppressants, a comparison study noted equal or higher incidence of malignancy, VTE, and MACE per 100 patient-years among patients prescribed methotrexate, cyclosporine, or prednisone compared to oral JAKi.¹¹ Subgroup analyses of the upadacitinib and abrocitinib clinical trials have revealed that the risk of the AEs of special interest is higher in the elderly population compared to patients under the age of 65.^12,13 Yet, this was also true in an AD Danish cohort who did not receive an oral JAKi,¹⁴ which underscores the importance of age and disease-severity-matched comparator groups. To better contextualize these risks, we reviewed the incidence rates of these events in an AD cohort of elderly patients in the Kaiser health system which shows a malignancy incidence per 100 patient-years of 1 to 2, MACE of 0.7 to 2.1, and VTE of 0.7 to 1.1 in JAKi-treated patients versus malignancy incidence of 0.3 to 5.7, MACE of 10.6 to 18.6, and VTE of 1.8 to 6 in the untreated background population.^15,16 This mirrors the differences seen in the younger patients, which shows that these AEs occur at rates that are not appreciably different in the untreated versus the treated groups. We acknowledge there are significant limitations to these types of analyses, including the inability to control for various biases, heterogeneity in the patient population, and the retrospective nature of the study that is not designed to show causality (or the lack thereof). Still, real-world data such as ours is useful in that it allows us to observe patients who may not have qualified for a clinical trial due to strict inclusion and exclusion criteria. We hope that our findings provide clinicians with an additional set of data points to help in counseling patients on the usage of oral JAKi in their elderly patients with AD.  While this data is encouraging, we would still like to emphasize the importance of modifying all variable risk factors for any patient considering an oral JAKi.

Conclusion

As treatment of AD is becoming highly personalized, safe and effective treatments should not be withheld from elderly patients and instead shared decision-making should be performed. This dialogue is particularly important with recent data showing that JAKi is more likely to achieve minimal disease activity. The current research should encourage future trials that include a larger number of elderly patients, as this remains a population with an unmet need for high-quality data.¹⁷

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