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Stephen Eng, PharmD, BCOP; Grashma Vadakkel, PharmD, BCOP; and Raymond DeMatteo, PharmD, BCOP, are clinical pharmacy specialists at Memorial Sloan Kettering Cancer Center in New York, New York.
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Pharmacy Times
November 2024Volume90 Issue 11
Updates in the Treatment of Moderate to Severe Atopic Dermatitis: A Focus on JAK Inhibitors
Key Takeaways
- Atopic dermatitis affects a significant global population, with varying prevalence across age groups and regions.
- Genetic, environmental, and skin barrier factors contribute to AD risk, necessitating personalized management strategies.
Treatment often involves a combination of preventive measures, topical therapies, and systemic treatments.
Background
Atopic dermatitis (AD), commonly known as eczema, is a chronic and relapsing inflammatory skin condition that affects a significant portion of the global population.1 It is most common in infants and children, although it can persist or develop in adulthood. The prevalence of AD varies across different regions and populations, but it is estimated to affect approximately 15% to 20% of children and 1% to 3% of adults worldwide.2-3 Understanding the background and epidemiology of AD is crucial for effective management.
Image credit: Марина Терехова | stock.adobe.com
Risk Factors
Several risk factors have been identified, including a personal or family history of allergic conditions such as asthma, allergic rhinitis, or other types of eczema.3 Genetic factors and certain gene variations (ie, IL-4, IL-13, and interferon-g) have also been associated with the condition.4 Mutations in filaggrin, an important protein that maintains pH and moisture in the skin, may also lead to an increased risk.1,5
Several environmental risk factors (ie, dust mites, pet dander, pollen, and certain foods) have been proposed, but few are supported by strong epidemiological data. Additional factors such as living in an urban setting, dry climate conditions, and low ultraviolet light exposure have also been associated with an increased risk of AD.2-3 Lastly, infants with a disrupted skin barrier, such as those with a history of early-onset AD or those born prematurely, may be at higher risk.3
Treatment
The treatment approach for AD often involves a combination of preventive measures, topical therapies, and, in some cases, systemic treatments.6 Treatment for AD is highly individualized, taking into account factors such as severity of symptoms, patient age, and medical history. The primary goal is to alleviate symptoms, reduce inflammation, and improve quality of life.7
Topical therapies play a central role, including emollients or moisturizers to hydrate the skin, as well as topical corticosteroids or nonsteroidal creams to reduce inflammation and itching during flare-ups.3,6 Different potencies of topical corticosteroids may be used depending on the severity of symptoms.8 Additionally, topical calcineurin inhibitors (ie, tacrolimus or pimecrolimus) can be prescribed to modulate immune response.6
In cases where symptoms are severe or do not respond to initial therapies, additional treatments that target alternative pathways may be considered.3 These can include oral immunosuppressants or biologic medications that target specific molecules involved in the inflammatory response. Several medications have recently been approved by the FDA for the treatment of moderate to severe AD.9-12
JAK Inhibitors for AD
Janus kinase (JAK) inhibition has emerged as a promising approach for the treatment of AD.12 JAK1 and JAK2 mediate the signaling of various cytokines and growth factors that are responsible for immune function and hematopoiesis. JAK1 mediates IL-4, which stimulates itching by acting on nerve endings, as well as IL-13, IL-31, IL-22, and thymic stromal lymphopoietin. JAK inhibitors work by targeting specific enzymes involved in the signaling pathways that contribute to the inflammatory response. By inhibiting these enzymes, JAK inhibitors can help regulate immune response and reduce the inflammatory processes.
Topical Ruxolitinib
Ruxolitinib cream (Opzelura; Incyte Corporation) was approved by the FDA in September 2021 for patients 12 years or older with mild to moderate AD who have not responded to initial therapies.11 Ruxolitinib inhibits both the JAK1 and JAK2 pathways. The efficacy and safety of topical ruxolitinib were evaluated in 2 randomized, parallel, double-blinded, placebo-controlled, and vehicle-controlled phase 3 trials: TRuEAD1 (NCT03745638) and TruE-AD2 (NCT03745651).13 Enrolled patients were 12 years and older with AD for 2 or more years, had an Investigator Global Assessment (IGA) score of 2 (mild) or 3 (moderate), and had between 3% and 20% affected body surface area (BSA). Treatment was randomized 2:2:1 to 0.75% ruxolitinib cream, 1.5% ruxolitinib cream, or placebo cream for 8 continuous weeks. The primary end point was the proportion of patients achieving an IGA score of 0 (clear) or 1 (mostly clear), with 2 points or better improvement from baseline.13
The results demonstrated significant efficacy for topical ruxolitinib compared with placebo. In both TRuE-AD1 and TRuE-AD2, a significantly higher proportion of patients treated with 0.75% ruxolitinib cream (50%/39%) and 1.5% ruxolitinib cream (54%/51%) achieved the primary end point of clear or almost clear skin with a reduction in disease severity compared with the placebo group (15%/8%; P < .0001). Topical ruxolitinib also showed a rapid onset of action, with improvements observed as early as 2 weeks. Additionally, patients treated with topical ruxolitinib experienced significant reductions in itch severity, Eczema Area and Severity Index (EASI) scores, and enhancements in quality of life.13
The most common adverse events (AEs) were mild to moderate application site reactions (< 1.0%); these were generally transient and resolved without intervention. TRuE-AD1 and TRuE-AD2 demonstrated the superiority of topical ruxolitinib vs placebo in patients with AD.13
Abrocitinib
Abrocitinib (Cibinqo; Pfizer Inc), an oral JAK1 inhibitor, received FDA approval in January 2022 for the treatment of moderate to severe refractory AD.9 The JADE MONO-1 trial (NCT03349060) was a multicenter, double-blind, randomized, phase 3 trial that evaluated patients with moderate to severe AD who had an IGA score of 3 or greater, an EASI score of 16 or more, and an affected BSA of 10% or more.14 Treatment was randomized 2:2:1 to oral abrocitinib 100 mg, abrocitinib 200 mg, or placebo once daily for 12 weeks.
The coprimary end points were the percentage of patients achieving an IGA response (score of 0/1 with ≥ 2-grade improvement from baseline) and the proportion of patients achieving 75% improvement or better in EASI score from baseline. By the end of the efficacy period, a significantly higher proportion of patients treated with abrocitinib 100 mg or 200 mg met the primary end point compared with those treated with placebo, with respect to IGA response and EASI response.14
Treatment-related AEs were reported in 69% of patients treated with abrocitinib 100 mg and 78% of patients treated with abrocitinib 200 mg, most commonly being nausea and nasopharyngitis. The efficacy and safety of abrocitinib were further confirmed in the JADE MONO-2 trial (NCT03575871).15
Upadacitinib
Upadacitinib (Rinvoq; AbbVie Inc) is an oral JAK1, JAK2, JAK3, and tyrosine kinase 2 inhibitor, with greater inhibitory potency for JAK1.9 Upadacitinib received FDA approval for patients with moderate to severe AD in January 2022, following the results of the Measure Up 1 (NCT03569293) and Measure Up 2 (NCT03607422) trials.16 These were both multicenter, randomized, double-blind, placebo-controlled phase 3 trials. Patients enrolled were 12 years or older, had moderate to severe AD that affects 10% or more BSA, had an EASI score of 16 or higher, a validated IGA score of 3 or more, and a Peak Pruritus Numerical Rating Scale score of 4 or more. Treatment was randomized 1:1:1 with upadacitinib 15 mg once daily, 30 mg once daily, or placebo for up to 16 weeks.16
The coprimary end points were the percentage of patients achieving an IGA response (score of 0/1 with ≥ 2-grade improvement from baseline) and the proportion of patients achieving 75% or more improvement in EASI score from baseline after a 16-week treatment period. At week 16, the coprimary end points were met in both studies (all P < .0001), with a significantly higher proportion of patients in the upadacitinib groups achieving an EASI 75% score reduction and IGA response compared with placebo.16
The most frequently reported AEs of any grade (≥ 5%) in patients treated with upadacitinib were acne, upper respiratory tract infection, nasopharyngitis, headache, and elevation in plasma creatine phosphokinase (Measure Up 1). Elevations in creatinine phosphokinase were asymptomatic and primarily related to exercise. Treatment discontinuation due to AEs occurred infrequently in both groups.13
Conclusion
AD can present with a wide variety of signs and symptoms. It is important for individuals with AD to work closely with health care professionals to develop a personalized management plan that suits their specific needs. Recently, the FDA has approved several agents that inhibit the JAK-STAT pathway (ie, topical ruxolitinib, abrocitinib, and upadacitinib) for patients with moderate to severe AD.
REFERENCES
1. Hadi HA, Tarmizi AI, Khalid KA, Gadjács M, Aslam A, Jamshed S. The epidemiology and global burden of atopic dermatitis: a narrative review. Life (Basel).2021;11(9):936. doi:10.3390/life11090936
2. Nutten S. Atopic dermatitis: global epidemiology and risk factors. Ann Nutr Metab. 2015;66(suppl 1):8-16. doi:10.1159/000370220
3. Weidinger S, Beck LA, Bieber T, Kabashima K, Irvine AD. Atopic dermatitis. Nat Rev Dis Primers. 2018;4(1):1. doi:10.1038/s41572-018-0001-z
4. Kantor R, Silverberg JI. Environmental risk factors and their role in the management of atopic dermatitis. Expert Rev Clin Immunol. 2017;13(1):15-26. doi:10.1080/1744666X.2016.1212660
5. Teye K, Numata S, Krol RP, et al. Prevalence of filaggrin gene mutations in patients with atopic dermatitis and ichthyosis vulgaris in Kyushu area of Japan and South Korea. J Dermatol Sci. 2017;86(2):174-177. doi:10.1016/j.jdermsci.2017.01.009
6. Frazier W, Bhardwaj N. Atopic dermatitis: diagnosis and treatment. Am Fam Physician.2020;101(10):590-598.
7. Langan SM, Irvine AD, Weidinger S. Atopic dermatitis. Lancet. 2020;396(10247):345-360. doi:10.1016/S0140-6736(20)31286-1
8. Ference JD, Last AR. Choosing topical corticosteroids. Am Fam Physician.2009;79(2):135-140.
9. Rinvoq. Package insert. Incyte; 2022. Accessed October 21, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/211675s003lbl.pdf
10. Cibinqo. Package insert. Pfizer Inc; 2022. Accessed October 21, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/213871s000lbl.pdf
11. Opzelura. Package insert. AbbVie; 2022. Accessed October 21, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215309s001lbl.pdf
12. Chovatiya R, Paller AS. JAK inhibitors in the treatment of atopic dermatitis. J Allergy Clin Immunol. 2021;148(4):927-940. doi:10.1016/j.jaci.2021.08.009
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. Simpson EL, Sinclair R, Forman S, et al. Efficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (JADE MONO-1): a multicentre, double-blind, randomized, placebo-controlled, phase 3 trial. Lancet. 2020;396(10246):255-266. doi:10.1016/S0140-6736(20)30732-7
15. Silverberg JI, Simpson EL, Thyssen JP, et al. Efficacy and safety of abrocitinib in patients with moderate-to-severe atopic dermatitis: a randomized clinical trial. JAMA Dermatol. 2020;156(8):863-873. doi:10.1001/jamadermatol.2020.1406
16. Guttman-Yassky E, Teixeira HD, Simpson EL, et al. Once-daily Upadacitinib versus placebo in adolescents and adults with moderate-to-severe atopic dermatitis (Measure Up 1 and Measure Up 2): results from two replicate double-blind, randomized controlled phase 3 trials. Lancet. 2021;397(10290):2151-2168. doi:10.1016/S0140-6736(21)00588-2
Clinicians referring a patient to MSK can do so by visiting msk.org/refer, emailing referapatient@mskcc.org, or by calling 833-315-2722.
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