Exploring the OX40 Ligand Pathway and Chronic Itch

“We talked about itch and malignancy, how new onset itch within 3 months or a year is slightly more associated with malignancy,” said Shawn Kwatra, MD, in an interview with Dermatology Times at the 2025 Fall Clinical Dermatology Conference in Las Vegas, Nevada.

Kwatra, professor and chair of dermatology at the University of Maryland School of Medicine in Baltimore and a Dermatology Times editorial advisory board member, discussed a range of chronic itch presentations and novel immune-based mechanisms shaping future dermatologic care. His sessions emphasized diagnostic precision in prurigo nodularis (PN) and chronic pruritus of unknown origin, along with the promising therapeutic implications of OX40 ligand inhibition in atopic dermatitis (AD).^1,2

Kwatra first highlighted that PN often presents with diverse morphologies, ranging from nodules and papules to excoriated plaques, and is frequently misdiagnosed as neurotic excoriations. He noted that recognizing the characteristic “itch-driven” phenotype is crucial, as these patients may respond dramatically to biologic therapy.

In discussing chronic pruritus of unknown origin, he described an “immune-stimulated” subset—patients exhibiting elevated IgE or eosinophil levels and systemic pruritus following immune activation, such as post–COVID vaccination or PD-1 inhibitor therapy. These cases, he said, respond well to immunomodulatory interventions, including intramuscular corticosteroids and off-label biologics such as dupilumab.

He also emphasized the importance of considering malignancy in cases of new-onset itch, particularly within the first year, citing a notable association with Hodgkin lymphoma. He further explained the complex overlap between type 2 and type 17 inflammation through a case of erythroderma responsive to targeted immune modulation. For symptom management, he pointed to off-label options such as low-dose naltrexone as adjunctive therapy in chronic itch syndromes.

Transitioning to future therapeutic directions, Kwatra described the OX-40 ligand pathway as “the prequel to inflammation”—a pivotal upstream event that precedes cytokine signaling (IL-4, IL-13, IL-31). As Kwatra discussed, in AD, barrier dysfunction permits antigen entry, leading to OX-40 ligand interaction between antigen-presenting cells and activated T cells. This cascade drives cytokine release, suppresses regulatory T-cell activity, and generates memory T cells that sustain inflammation.

By inhibiting the OX-40 ligand pathway, Kwatra explained, clinicians may achieve deeper and longer-lasting disease remission. Data from the phase 2b STREAM-AD trial (NCT05131477) demonstrated that patients maintained clinical responses even after drug levels decreased, suggesting durable immunologic recalibration.³

Kwatra concluded that OX-40 ligand inhibition represents a distinct shift for a heterogeneous disease such as AD, offering a mechanism that not only controls inflammation but may also extend treatment-free remission periods.

“Since atopic dermatitis is such a heterogeneous disease, we'll be hearing a lot more about OX-40 ligand in the future of dermatology,” Kwatra concluded.

References

1. Kwatra G. What's itching you today? Contact derm? Atopic derm? What else? Presented at: 2025 Fall Clinical Dermatology Conference; October 23-26, 2025; Las Vegas, NV.
2. Kwatra G. Exploring the OX40 ligand signaling pathway in atopic dermatitis. Presented at: 2025 Fall Clinical Dermatology Conference; October 23-26, 2025; Las Vegas, NV.
3. Weidinger S, Blauvelt A, Papp KA, et al. Phase 2b randomized clinical trial of amlitelimab, an anti-OX40 ligand antibody, in patients with moderate-to-severe atopic dermatitis. J Allergy Clin Immunol. 2025;155(4):1264-1275. doi: 10.1016/j.jaci.2024.10.031