Clinical Considerations in Treatment Selection for Atopic Dermatitis

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­­­­­­­­­AJMC®: What has your experience been in treating atopic dermatitis and participating in clinical trials?

SILVERBERG: As a board-certified dermatologist in an academic referral center, I encounter a substantial caseload of patients with atopic dermatitis and other chronic inflammatory skin conditions. Often, these cases are complex, having been referred after assessment by other dermatologists in private practice. Through my academic setting, I’ve had the privilege of witnessing the evolution of innovative therapies in this field. Regarding clinical trials, my involvement spans over a decade, beginning with the original phase 1 trials of dupilumab for atopic dermatitis. Since then, I’ve participated in numerous clinical trials for emerging therapies including those currently in late-stage development. This period has been marked by significant advancements in our understanding and treatment of atopic dermatitis, making it an incredibly exciting time for clinical research in the field.

AJMC: Which other diseases have a similar pathophysiology as atopic dermatitis, and what are the roles of the key mediators of type 2 inflammation?

SILVERBERG: Atopic dermatitis is a complex and heterogeneous disease involving the activation of various immune pathways. Key mediators such as interleukin (IL)-13 and -4 along with the broader Th2 pathway play pivotal roles. Additionally, cytokines like IL-31 and possibly IL-22 may contribute, although further research is needed for the latter. In terms of overlapping pathophysiology, several diseases share similarities with atopic dermatitis, particularly those mediated by type 2 inflammation. These include asthma, hay fever, food allergies, and eosinophilic esophagitis. Recent discussions also highlight the potential involvement of IL-31 in conditions like prurigo nodularis with emerging considerations for disorders such as scleroderma and urticaria. Thymic stromal lymphopoietin, implicated in atopic dermatitis, also plays a significant role in asthma. While some overlaps are practical, like the manifestation of prurigo nodules in some patients with atopic dermatitis, others remain theoretical. Understanding these overlaps is crucial for improved management and targeted treatment approaches.

AJMC: How has the treatment landscape for atopic dermatitis changed over the past 20 years?

SILVERBERG: The treatment landscape for atopic dermatitis has undergone remarkable evolution over the past 2 decades. Initially overshadowed by psoriasis in terms of drug development, atopic dermatitis has seen a surge in therapeutic innovation. In the topical space, significant strides have been made with the approval of various agents. Crisaborole, a phosphodiesterase inhibitor, was a pivotal addition for mild to moderate atopic dermatitis in 2016. Subsequently, topical ruxolitinib (a JAK inhibitor) and topical roflumilast (a PDE4 inhibitor) have further expanded our options with ongoing developments in early-stage modalities. However, the most revolutionary advancements have occurred in the biologic realm. Pre-2017, atopic dermatitis lacked clean biologics until the approval of dupilumab (a monoclonal antibody targeting IL-4 and -13 signals) for moderate to severe disease. Following this, tralokinumab and lebrikizumab (both targeting IL-13) gained approval, with nemolizumab (which targets the IL-31Rα subunit) soon to follow. These biologics offer targeted relief particularly in managing itch and related conditions like prurigo nodularis. Moreover, the oral realm, previously limited to off-label use of medications like methotrexate or cyclosporine, now boasts 2 approved oral JAK inhibitors—upadacitinib and abrocitinib—for moderate to severe atopic dermatitis. While highly effective, these medications can present with challenges regarding safety. This broadening toolbox encompasses oral agents, injectables, and innovative topical agents catering to diverse patient needs and preferences. With options for long-term management and effective itch relief, the current landscape signifies an exciting era in atopic dermatitis treatment.

AJMC: When do you consider switching therapies from topical steroids or adding another therapy in your patients with atopic dermatitis?

SILVERBERG: Determining when to switch therapies or add additional treatments for patients with atopic dermatitis is not a one-size-fits-all decision. Several important considerations come into play. Shared decision-making is a key approach I advocate for. This involves discussing treatment options with patients, understanding their goals and perspectives, and aligning the right medication with their individual needs and preferences. This process is essential after recognizing that the current therapy may not be effective for the patient. To effectively identify patients with inadequate responses, structured approaches in clinical practice are beneficial. Routinely tracking parameters such as body surface area and severity of lesions along with assessing symptoms like itch, sleep disturbances, and skin pain provides valuable insight. Utilizing tools like numeric rating scales for itch helps to capture the full spectrum of the disease’s symptomatology. If patients exhibit moderate or severe symptoms despite current therapy, it’s time to consider stepping up treatment. This prompts the initiation of shared decision-making discussions to explore alternative options tailored to the patient’s specific needs and treatment goals.

AJMC: Why was it necessary to update the American Association of Dermatology (AAD) guidelines for patients who don’t respond to topical therapies for atopic dermatitis?

SILVERBERG: The last update to the AAD guidelines occurred before significant advancements occurred in the field about a decade ago. This outdated version did not reflect the emergence of therapies like dupilumab and crisaborole, the first of many innovations in atopic dermatitis treatment. With the introduction of multiple biologics, topical agents, and oral medications, the guidelines needed urgent revision to align with current practices. The necessity for updating the guidelines stemmed from their inability to address these new treatment modalities. For instance, reliance on older guidelines would suggest using cyclosporine—which was backed by weak evidence— as a primary treatment approach. Therefore, updating the guidelines was imperative to provide clinicians with accurate and up-to-date recommendations. The revised guidelines encompass 4 key areas: comorbidities, topical therapies, systemic treatments, and biologics. Each component reflects the evolving landscape of atopic dermatitis management. Furthermore, a forthcoming update will specifically address pediatric atopic dermatitis, recognizing the unique considerations in this patient population.

AJMC: What were the key recommendations for patients who do not respond to topical therapy?

SILVERBERG: The updated guidelines offer flexible recommendations for patients who don’t respond to topical therapies and allow clinicians to make informed clinical decisions based on individual patient needs. When topical treatments prove ineffective, the guidelines suggest considering biologics such as dupilumab or tralokinumab for moderate to severe atopic dermatitis as supported by high-grade evidence. Additionally, oral medications like abrocitinib and upadacitinib are recommended for similar cases. While these recommendations align with FDA labeling, the guidelines do not favor 1 treatment over another, leaving the choice to clinical discretion based on patient-specific factors.

AJMC: Why is it important to have real-world data in addition to what was studied in the clinical trials?

SILVERBERG: Real-world data play a vital role complementing findings from clinical trials for several reasons. First, clinical trials maintain strict inclusion and exclusion criteria to minimize confounding factors, but this can limit the representation of patients encountered in everyday clinical practice. Real-world data provide insights into how treatments perform in broader patient populations, ensuring the generalizability of trial results and confirming efficacy. Moreover, real-world studies are crucial for long-term pharmacovigilance, particularly in identifying rare safety signals that may not surface in smaller clinical trials. While regulatory requirements mandate large safety pools, real-world data offer a more extensive and prolonged observation period and enhance postmarketing surveillance. Additionally, real-world data shed light on treatment outcomes in specific patient subsets or off-label scenarios not typically addressed in clinical trials. For instance, assessing the effectiveness of a medication in patients with overlapping conditions like atopic dermatitis and urticaria provides valuable insights that may not be captured in trial settings. In summary, real-world data serve to validate and enhance the understanding of treatment efficacy and safety beyond what clinical trials alone can provide, making them indispensable for informed decision-making in clinical practice.

AJMC: What are the important real-world studies with dupilumab in terms of treatment adherence and other outcomes such as disease severity and quality of life?

SILVERBERG: Real-world studies provide robust evidence supporting the effectiveness and safety of dupilumab in treating atopic dermatitis and other conditions. These studies consistently reproduce the positive clinical outcomes observed in clinical trials, demonstrating the real-world efficacy and safety of dupilumab. Beyond clinical efficacy, real-world studies explore various end points not extensively studied in trials. For instance, significant improvements in sleep quality and reduction in sleep disturbances were noted with dupilumab treatment. Additionally, dupilumab use was associated with decreased hospitalization rates, comorbidities, and secondary infection rates. Studies on treatment persistence indicate favorable long-term effectiveness and tolerability with patients adhering to the medication over time. Moreover, dupilumab treatment has demonstrated significant enhancements in quality of life across multiple domains, including school and work performance, and was cost-effective. These findings underscore the holistic benefits of dupilumab in improving outcomes for patients with atopic dermatitis.

AJMC: What has real-world evidence demonstrated with tralokinumab in patients with atopic dermatitis?

SILVERBERG: Tralokinumab, a newer therapy when compared with dupilumab, has garnered increasing real-world evidence over the years since its approval that reaffirmed its effectiveness and safety in treating atopic dermatitis. Studies including case reports, case series, and larger investigations have demonstrated real-world effectiveness and safety profiles consistent with clinical trial outcomes without observations of any new safety signals. In addition to replicating clinical trial results, investigators involved in real-world studies have explored various end points such as sleep quality and quality of life outcomes, further supporting the holistic benefits of tralokinumab in atopic dermatitis management. An interesting aspect is the comparison between tralokinumab and dupilumab, with tralokinumab emerging as a potential alternative for patients who may not have responded optimally to dupilumab. Real-world evidence suggests that tralokinumab can be effective even in patients who previously had an inadequate response to dupilumab, providing clinicians with valuable insights into treatment options for a diverse patient population.

AJMC: How do you balance safety and efficacy of JAK inhibitors when considering their use in patients with atopic dermatitis?

SILVERBERG: When considering the safety and efficacy of JAK inhibitors for atopic dermatitis, it’s crucial to prioritize patient safety in clinical decision-making. There are class-wide safety considerations mandated by the FDA, but not all JAK inhibitors share the same safety profile. Therefore, it’s essential to assess how each specific JAK inhibitor performs in atopic dermatitis and how it may affect an individual patient. Overall, data from clinical trials offer reassuring insights into the safety profile of JAK inhibitors in atopic dermatitis. Cases of adverse events were reported in longer-term studies, yet the event rates remain relatively low and comparable to those of placebo arms. Additionally, real-world evidence does not suggest an elevated risk compared to previous observations in other health conditions. However, it’s important to acknowledge that no medication is entirely risk free. Patients should be informed about the potential rare but serious risks associated with JAK inhibitors, although these occurrences are exceedingly rare. This discussion forms an integral part of shared decision-making, in which patients can weigh the benefits of oral medications like JAK inhibitors against their potential risks. Ultimately, the decision to use JAK inhibitors in atopic dermatitis should involve collaboration between clinicians and patients and consider individual clinical characteristics and treatment preferences. Shared decision-making ensures that patients are actively involved in their treatment journey, which leads to the best possible outcome for their needs and circumstances.

AJMC: What are you most excited about for the future of atopic dermatitis management?

SILVERBERG: I’m particularly excited about the imminent advancements in atopic dermatitis management. The upcoming approvals of therapies like lebrikizumab, nemolizumab, and topical tapinarof are on the horizon, promising new options for patients in the near future. These developments are actionable, and their use requires thorough preparation as they approach approval. Additionally, ongoing phase 3 trials, especially those exploring IL-40 and IL-40 ligand inhibitors, showcase the continuous progress in understanding and targeting the underlying biology of atopic dermatitis. Overall, while I’m intrigued by the innovative exploration of novel pathways and technologies in early-stage trials, my current excitement lies in the tangible advancements that we anticipate in the management of atopic dermatitis.

For other articles and videos in this AJMC® Perspectives publication, please visit "Managing Atopic Dermatitis: Clinical Considerations, Payer Perspective, and 2024 Guidelines"