At the ODAC 2025 conference, Dr. Shawn Kwatra, Professor and Chair of Dermatology at the University of Maryland School of Medicine and a leading figure in chronic inflammatory skin diseases, delivered a compelling presentation on atopic dermatitis (AD). Dr. Kwatra provided an overview of current AD treatment options, along with valuable insights into the latest advancements emerging in the field of dermatology.
Atopic Dermatitis Pathogenesis
Atopic dermatitis is a chronic inflammatory skin disease characterized by a complex interplay of skin barrier dysfunction, immune dysregulation, and environmental factors. The disrupted skin barrier, often due to mutations in the filaggrin gene, allows external allergens and irritants to penetrate and trigger an immune response. This response is dominated by a Th2 inflammatory axis, with cytokines such as IL-4 and IL-13 playing central roles in promoting inflammation and exacerbating barrier dysfunction. IL-31 is a key pruritogenic cytokine, contributing significantly to the intense itch associated with AD. Additionally, IL-22 is involved in the development of more severe, thickened lesions by promoting keratinocyte proliferation. Current treatments for AD focus on targeting cytokines, their receptors, and other key molecules involved in the pathogenesis to disrupt the disease process and improve symptoms.
Approved Therapies for Atopic Dermatitis
Dupilumab
Dupilumab is a monoclonal antibody that targets the IL-4Rα subunit, blocking both IL-4 and IL-13 signaling. Approved for children as young as six months with AD, it has been available long enough for comprehensive data to emerge: (1) it reduces overall infection rates in preschool patients with AD compared to placebo; (2) it is associated with a reduced risk of developing comorbidities linked to the ‘atopic march,’ such as asthma and allergic rhinitis; and (3) it decreases serum IgE levels in pediatric patients with food allergies, suggesting its potential to modulate allergic responses beyond skin symptoms. Overall, dupilumab offers a comprehensive approach to managing AD by addressing both cutaneous manifestations and reducing the risk of associated comorbidities.
Lebrikizumab
Lebrikizumab is a monoclonal antibody that targets IL-13 with high affinity and a slow off-rate. Approved for moderate to severe AD in patients aged 12 and older, it is administered subcutaneously every two weeks initially, with the option to extend dosing to every four weeks if a satisfactory response is achieved by week 16. Notably, lebrikizumab provides rapid itch reduction within the first four weeks. While common adverse effects include a slight risk of conjunctivitis and headaches, no laboratory monitoring is required. In comparison to dupilumab, lebrikizumab demonstrates similar efficacy in terms of both Investigator’s Global Assessment and Eczema Area and Severity Index scores.
Dr. Kwatra presented findings from the ADapt trial which highlighted lebrikizumab’s potential for patients who discontinued dupilumab due to adverse events. Among those who switched to lebrikizumab, none reported similar eye-related events or facial dermatitis that originally led to their discontinuation of dupilumab.
Tralokinumab
Tralokinumab is another IL-13-targeting monoclonal antibody, approved for patients aged 12 and older. It is administered every other week. While it takes longer to relieve itch and improve skin compared to other treatments, it eventually achieves similar outcomes. Conjunctivitis risk varies among patients, particularly those with a history of this condition on dupilumab
Nemolizumab
Nemolizumab targets the IL-31 receptor, offering rapid itch reduction. Recent studies suggest it may be particularly beneficial for African American patients with a follicular-based type of AD, which often presents with higher levels of IL-31. Nemolizumab’s efficacy can be maintained with dosing spaced up to eight weeks apart.
JAK inhibitors
JAK 1 inhibitors, such as abrocitinib and upadacitinib, are recognized for their rapid itch reduction in treating AD. They often provide faster relief compared to dupilumab, although both treatments eventually achieve similar outcomes. Notably, studies have shown that switching patients with conjunctivitis and facial dermatitis from dupilumab to a JAK inhibitor can lead to significant symptom improvement and resolution.
Dr. Kwatra emphasized a thoughtful approach when initiating oral JAK inhibitors. He advises patients about potential risks, noting that while lymphoma and other malignancies have been reported in patients with rheumatoid arthritis taking JAK inhibitors, these risks were observed in older patients on additional medications like methotrexate and prednisone. Current studies in AD have not replicated these findings. However, Dr. Kwatra considers age over 65 a significant factor due to increased adverse events and avoids initiating JAK inhibitors in patients with a history of blood clots. Before starting treatment, he also recommends baseline tests including a complete blood count with differential, comprehensive metabolic pattern, tuberculosis screening, liver panel, hepatitis testing, lipid panel, and a pregnancy test. To ensure safe monitoring, some of these tests are repeated at one month and then every three to six months thereafter.
Ruxolitinib is a JAK 1 and 2 inhibitor available as a 1.5% topical cream for AD. Phase 2 studies have shown that it provides faster and greater itch reduction and lesion clearance compared to topical triamcinolone, while minimizing the risk of steroid-related side effects like atrophy and hypopigmentation. Ruxolitinib is particularly effective in skin of color patients with papular-based disease, as it effectively reduces the high levels of Th22 and Th17 cells present in these lesions.
Crisaborole
Crisaborole is a phosphodiesterase 4 (PDE4) inhibitor suitable for patients with mild disease or those seeking to maintain clearance. Data suggests that using crisaborole a few times a week can effectively maintain clearance and prevent flares, making it a good option for sparing patients from topical steroids.
Roflumilast
Roflumilast has a significantly higher affinity for PDE4 compared to crisaborole and apremilast, being 25- to 300-fold more potent in vitro. It modulates inflammatory cytokines and decreases the expression of pro-inflammatory cytokines such as IFN-γ, TNF-α, IL-4, IL-17, and IL-23. Roflumilast is effective for quick itch reduction and achieving clearance, with minimal topical side effects observed.
Tapinarof
Tapinarof is an aryl hydrocarbon receptor agonist that can restore filaggrin expression, as this receptor is expressed in keratinocytes and dendritic cells. It is currently approved for patients with AD aged 2 years and older. While effective for lesion clearance and itch reduction, some patients may experience folliculitis as a side effect.
Next Generation Treatments: OX40 Ligand Inhibitors
OX40 ligand inhibitors represent a promising next generation of treatments in AD. These medications target work “upstream” within the inflammatory cascade of AD. In addition to efficacy patients could require fewer injections than current injectable immunomodulators as it can be administered every 12 weeks. OX40 is a co-stimulatory molecule expressed on activated T cells, involved in clonal expansion, survival, memory formation, and Th2 responses. Amlitelimab, currently under study, binds to OX40 ligands on antigen-presenting cells, preventing interaction with OX40-expressing T cells. By targeting OX40 ligand, amlitelimab aims to block T-cell pathway activation, potentially re-establishing balance between pro-inflammatory and anti-inflammatory responses and inhibiting the persistent immune response driving AD pathophysiology.
In conclusion, the landscape of AD treatment is rapidly evolving, offering patients a range of effective options tailored to their specific needs. From monoclonal antibodies like dupilumab and lebrikizumab, which target key cytokines involved in inflammation, to JAK inhibitors that provide rapid itch relief, the choices are expanding. Additionally, emerging therapies such as OX40 ligand inhibitors promise to further enhance treatment outcomes by targeting upstream pathways in the inflammatory cascade. As research continues to advance, it is crucial for healthcare providers to stay informed about these developments to provide the most personalized and effective care for patients with AD.
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