ATOPIC DERMATITIS HIDE AND SEEK: THE IMPENDING ROLE OF OX40 INHIBITION
By Warren R. Heymann, MD, FAAD
Sept. 11, 2024
Vol. 6, No. 37
Treating AD has improved dramatically over the past decade as we have many topical options (corticosteroids, calcineurin inhibitors, PDE4 inhibitors, a topical JAK inhibitor [ruxolitinib], and other agents likely soon to be released [roflumilast, tapinarof]), phototherapy, oral JAK inhibitors (upadacitinib, abrocitinib), and the biologics (dupilumab, tralokinumab). This commentary will focus on the emergence of OX40 inhibitors for AD.
Buhl and Werfel succinctly note that "the pathophysiology of AD is based on a complex interplay of impaired skin barrier function, alterations in the skin microbiome, and type 2 skin inflammation with neuronal involvement." (4) The defective skin barrier in AD is related to filaggrin dysfunction, allowing susceptibility to xerosis and environmental irritants and allergens that lead to inflammation manifested by pruritus and the clinical findings of AD. The inflammation is due to an overactive Th2 response (with increased IL-4 and IL-5 cytokines) in acute lesions and Th1 response (with IFN-gamma and IL-12) in chronic lesions. Other inflammatory cytokines such as TNF-alpha, IL-1, and IL-6 may be at play. Decreased epidermal anti-microbial peptides (human beta-defensins, cathelicidins) contribute to Staphylococcus aureus colonization seen in more than 90% of patients with AD, which may drive its inflammatory process. (1)
Four antibodies against OX40 (rocatinlimab, telazorlimab, and IMG 007) or OX40L (amlitelimab) are currently in clinical development for treating moderate-to-severe AD. Early-phase clinical studies of these antibodies have shown auspicious results based on the Investigator Global Assessment (IGA) 5-point scale or the Eczema Area Severity Index (EASI). (6) An example is the phase 2b randomized trial of telazorlimab for patients with moderate-to-severe AD who were not previously controlled with topical agents, systemic immunosuppressants, or biologic agents. Telazorimab induced significant and progressive clinical improvement of AD. The most common adverse effects occurring in > 5% of subjects were nasopharyngitis, upper respiratory infections, and headache. Two patients discontinued the drug because of paresthesias and pernicious anemia/neutropenia/thrombocytosis, respectively. (7)
What are the potential advantages of OX40/OX40L inhibition? According to Guttman-Yassky et al., "Targeting the OX40L/OX40 signalling axis, an upstream regulator of T-cell proliferation and cytokine release that has been specifically implicated in AD, may allow early intervention at the initiation of chronic inflammation. Furthermore, immune homeostasis restoration may be possible through OX40L/OX40 blockade, controlling effector and memory T-cell proliferation while maintaining regulatory T cells. Rebalancing the T-cell-mediated immune response may prevent escalation of inflammation and future disease flares." (8)
The therapeutic advances in AD have been dramatic, but more needs to be done. Patients deserve an improvement in QoL and to come out of hiding due to loneliness. We must continue to seek new treatment. In the children's hide and seek game, players can safely come out of hiding by declaring "Olly olly oxen free!" Perhaps OX40 inhibition can free our long-suffering AD patients.
Point to Remember: The OX40/OX40 ligand signaling pathway is involved in the pathogenesis of atopic dermatitis. Current trials using OX40/OX40 ligand inhibitors are underway, which are promising.
Our expert's viewpoint
Emma Guttman-Yassky, MD, PhD, FAAD
Waldman Professor and System-Wide Chair
Department of Dermatology
Icahn School of Medicine at Mount Sinai, New York
While our patients are treated now with effective medications for atopic dermatitis, we as treating dermatologists and our patients aspire for treatments with long lasting responses, that can be given less often and may even entertain the idea of real disease modification. Ideally, this would allow stopping treatment after clearance occurs without recurrence.
As our recent reviews (6,8) show, it appears that the OX40/OX40L pathway is increased in patients with atopic dermatitis and is part of the pathogenesis of AD. It is involved in T-cell differentiation and creation of memory T-cells that are taking part in the body's memory leading to again populate lesions in the same area once treatment is stopped. This may be the reason why in early studies we saw a hint of long-lasting responses with targeting OX40/OX40L in atopic dermatitis. Both the anti-OX40 and anti-OX40L studies with rocatinlimab and amlitelimab, respectively, showed that upon treatment cessation, in the majority of patients on higher doses, that disease did not come back for a long follow up period. (9) A similar hint was also shown with the OX40L targeting by Weidinger et al. (10)
Nevertheless, these phase 2 studies were small, and in order to prove long-term disease remission and sustainability of responses, we need large studies that will show that when the drug is discontinued, the disease does not recur for several months and perhaps in the entire follow-up period.
The phase 3 studies that are ongoing will be able to prove if indeed long-lasting responses and perhaps disease modification may be attainable with the new OX40/OX40L treatments that are on the horizon.
Skin Care Physicians of Costa Rica
Clinica Victoria en San Pedro: 4000-1054
Momentum Escazu: 2101-9574
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posted by dermatica at
September 19, 2024
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Marketing claims are used to encourage consumers to purchase products. Terms such as "paraben-free," "hypoallergenic," clinically tested/proven," and "sodium lauryl sulfate–/sulfate-free" represent some of these claims. The authors of this study looking at allergens in baby wash products found these four marketing claims to be the most common. There are many other claims, such as "dermatology-tested" and "clean." The authors reviewed the marketing claims of popular baby wash products that were on common websites and were the most-reviewed products. They then compared the ingredients in these products with allergens identified by the 2020 American Contact Dermatitis Society Core Allergen Series. They found that the mean number of ingredients per product was 18.3, and the mean number of potential allergens per product was 2.5. Overall, 86% of the products contained at least one potential allergen. When looking at specific marketing claims, 88% of the products labeled "hypoallergenic" contained at least one allergen, and, of those labeled as "clinically tested/proven" 85% contained at least one allergen. The most common potential allergens identified were sodium benzoate, decyl glucoside, and cocamidopropyl betaine. This article reminds us that marketing claims do not mean that the products do not contain potential allergens or have the potential to cause allergic reactions. Furthermore, having a potential allergen present in a product does not mean it will become problematic for all, but patch testing helps identify the particular allergen for a specific individual who is having a cutaneous problem. If dermatitis and allergic contact dermatitis are suspected, patch testing should be pursued to help identify allergens.