Breaking the Itch-Scratch Cycle

Current treatment strategies for atopic dermatitis (AD) primarily involve topical corticosteroids and other topical agents, as well as oral immunosuppressive drugs for more severe cases.¹ However, these treatments can be associated with a range of side effects and are often insufficient in managing symptoms.² Additionally, there is a significant unmet need for effective and safe treatments for patients with moderate-to-severe AD, highlighting the urgent need for continued research and innovation in this area.

One promising therapy for AD is upadacitinib (RINVOQ®), a selective, reversible oral Janus kinase 1 (JAK1) inhibitor.³ A new study, shared at the 5th Annual Revolutionizing Atopic Dermatitis (RAD) Congress, has presented findings on the long-term safety (over a period of up to 4 years) of upadacitinib for patients with moderate-to-severe AD.⁴

The analysis evaluated the safety and efficacy of upadacitinib 15mg and upadacitinib 30mg in adolescents and adults with moderate-to-severe AD using data from three global ongoing pivotal Phase 3 studies: Measure Up 1 (ClinicalTrials.gov Identifier: NCT03569293), Measure Up 2 (ClinicalTrials.gov Identifier: NCT03607422), and AD Up (ClinicalTrials.gov Identifier: NCT03568318). These multicenter studies included patients who were randomly assigned 1:1:1 to receive once-daily oral upadacitinib 15mg, upadacitinib 30mg, or placebo, either alone (Measure Up 1 and 2) or with concomitant topical corticosteroids (AD Up). At week 16, patients receiving upadacitinib 15mg or 30mg continued their assigned treatment in the blinded extension period, while patients receiving placebo were re-randomized 1:1 to receive either upadacitinib 15mg or 30mg (upadacitinib treatment for up to 260 weeks).

The integrated analysis included 2693 adolescents and adults who received at least one dose of upadacitinib (15mg, 1340; 30mg, 1353). The treatment-emergent adverse events of special interest (AESI) were evaluated as exposure-adjusted rates per 100 patient-years (PY) for the entire treatment period to account for differences in follow-up duration. The results showed that upadacitinib (15mg/30mg) was well tolerated in both age groups. The AESI rates were similar at both the 1-year and up to 4-year analyses for serious infections (2.3 and 2.2/2.8 and 2.8), opportunistic infections (1.6 and 1.8/1.9 and 2.4), active tuberculosis (<0.1/<0.1), herpes zoster (3.5 and 3.1/5.2 and 5.8), nonmelanoma skin cancer (NMSC; 0.3 and 0.4/0.4 and 0.3), malignancy excluding NMSC (0.1 and 0.4/0.5 and 0.3), and adverse events leading to death (0 and 0/<0.1 and <0.1). Adjudicated major adverse cardiovascular events (MACE) rates were low at 0.1 and <0.1/<0.1 and <0.1 for both doses at the 1-year analysis and up to 4-year analysis. Venous thromboembolic event (VTE) rates were also low at <0.1 for both doses at both timepoints. Gastrointestinal perforation rates were 0 for both doses at both timepoints. Rates of serious infections remained below 3.0E/100 PY.

We reached out to study author Christopher G. Bunick, MD, PhD, to delve into the difficulties encountered by patients with moderate-to-severe AD, the existing treatment options, and the advancements in therapies and methods that are being pursued to tackle this multifaceted condition. Dr. Bunick is an Associate Professor of Dermatology at Yale School of Medicine and a specialist in general medical dermatology and dermatologic surgery.

Can you tell us about some of the current treatment challenges for individuals with moderate-to-severe AD?

Overall, patients with AD are in a much better place today regarding available treatments than ever before, with multiple biologics and advanced systemic therapies approved for use. A decade ago, the challenge was “can we find a treatment that helps the patient’s skin at all?” Today, the challenges faced by patients with moderate-to-severe AD relate more to how fast a response a patient can achieve for both rash and itch, as well as how complete a response and the duration that response lasts. We’ve moved from “how to treat” to “can we eradicate appearance and symptoms of” AD. This is why we are likely to see increased efficacy standards of therapeutics for future AD approvals—the new standards are EASI-90, not 75, and NRS 0/1. The focus goes beyond skin appearance and includes quality-of-life measures such as itch, sleep, and school or work performance. Unfortunately, patients continue to face challenges with access to our cutting-edge AD therapies due to insurance regulation. We’ve seen recently backward steps in some states where biologic therapies are being repositioned behind traditional immunosuppressives, which I disagree with.

How do these results impact your current practice when treating patients with moderate-to-severe AD? Can you speak to the efficacy of upadacitinib in providing rapid itch relief and skin clearance?

The 4-year safety data of upadacitinib are very reassuring that this medication can perform as a first-line therapy in appropriate patients with moderate to severe AD. Much energy over this past year has been focused on the safety of JAK inhibitors given the boxed warning from the FDA. However, as we examine (i) the context of the boxed warning, (ii) the adverse events per 100 patient years compared to baseline AD and general population rates, and (iii) adverse event rates per 100 patient years compared to traditional immunotherapies, we learn that JAK inhibitors are proving much safer than many dermatologists expected given the concerns over the boxed warning label. Couple this with the newly released 4-year safety data of upadacitinib, and these facts definitely impact my clinical practice, largely by providing confidence that I can prescribe JAK inhibitors and expect a high level of safety in the AD population. Furthermore, there now is more safety data to provide accurate context to patients about the risks of selective JAK inhibitors in AD compared to pan-JAK inhibitors—this facilitates the shared decision-making process and reassures the patient in their choice of therapy. With regard to upadacitinib efficacy, the data support this therapy as a difference-maker for patients with AD: It provides rapid and sustained itch relief in a matter of days to weeks and nearly complete skin clearance in weeks to months. Upadacitinib and abrocitinib are redefining the standards of patient response in AD due to their high efficacy, and they make a strong case for EASI-90 and NRS of 0/1 as the new standard-of-care therapeutic milestones for patients with AD. This is much like the evolution in psoriasis patient response, where newer generation biologics have pushed the threshold to PASI-90 (and even potentially PASI-100).

How did rates of AESIs change over time (up to 4 years) for patients who received upadacitinib?

Importantly, the AESI rates at 4 years remained stable and low compared to years 1, 2, and 3. These are exactly the results dermatologists needed to see in order to gain growing confidence in using JAK inhibitors in their practice and using them over long time periods as many AD patients require. In total, at 4 years the trial data encompasses over 3000 patient-years of safety data, and the rates of MACE and VTE are substantially lower than the background MACE and VTE 100–patient-year event rates of the untreated AD population. This data argues that JAK inhibitors provide favorable systemic anti-inflammatory properties to patients with AD, much like biologics do for patients with psoriasis. In addition, the rates of malignancy (excluding NMSC) were on par with background rates both in AD and in the general US population, indicating that at 4 years of upadacitinib use there does not appear to be a significant increase in malignancy risk to what the normal human experiences. The AE with the highest rate at 4 years was herpes zoster; however, in this dataset only about 5% of patients had the shingles vaccine prior to taking upadacitinib. One area of my practice I will pay closer attention to is recommending the shingles vaccine to patients older than age 50 going on a JAK inhibitor. This can proactively help the patient avoid unnecessary zoster flares.

Are there any future directions for research in the treatment of AD that you are particularly excited about?

As a physician-scientist funded by the Dermatology Foundation and NIH for the past 10 years to investigate the molecular functions in AD, I am excited to say that there continues to be a lot of research and innovation in the AD space. Within 5 years, the AD space, both topically and systematically, will be almost as crowded as the psoriasis space. This is good for patients because therapies covering different molecular pathways ensures that all AD patient endotypes will have some form of advanced therapy available to treat them. CBP-201 is an IL-4Rα targeted biologic with an optimized epitope for interfering with IL-4/IL-4Rα interaction. Lebrikizumab targets a different molecular epitope on IL-13 than tralokinumab, and Eblasakimib is a biologic targeting IL-13Rα1, not the IL-13 cytokine. Newer pathways under investigation in AD include OX40L, aryl hydrocarbon receptor, TSLP, and TYK2, and even established pathways like PDE4 inhibition will be making noise in AD. It is certain that AD will be an exciting place of discovery for quite some time.

Disclosure: Dr. Bunick has served as an investigator for Almirall, Timber, and Palvella; and a consultant for AbbVie, Almirall, Apogee, Arcutis, Eli Lilly, EPI Health/Novan, LEO Pharma, Novartis, Ortho Dermatologic, Pfizer, Sanofi-Regeneron, and UCB.

1. Boytsov NN, Gorritz M, Wang X, Malatestinic WN, Wade RL, Goldblum OM. The current treatment landscape in adult atopic dermatitis in the United States: results from a cross-sectional real-world study. J Dermatolog Treat. 2022;33(3):1707-1717. doi: 10.1080/09546634.2021.1898530.

2. Calabrese G, Licata G, Gambardella A, De Rosa A, Alfano R, Argenziano G. Topical and conventional systemic treatments in atopic dermatitis: Have they gone out of fashion? Dermatol Pract Concept. 2022;12(1):e2022155. doi: 10.5826/dpc.1201a155.

3. Rinvoq. Prescribing Information. AbbVie; 2022. Updated April 2023. Accessed May 11, 2023. www.rxabbvie.com/pdf/rinvoq_pi.pdf

4. Silverberg JI, Bunick CG, Lio P, et al. Long-term 4-year ssafety of upadacitinib in moderate-to-severe atopic dermatitis: results of an integrated analysis of phase 3 studies. Abstract presented at: 5th Annual Revolutionizing Atopic Dermatitis (RAD) Congress; April 29 2023, Washington, DC, USA. Abstract 114-1000427.