Why Do Some Psoriasis Patients Respond Differently to Biologics? New Study Offers Clues

A More Complex Picture of Psoriasis

Biologic therapies targeting the IL-23/Th17 pathway have transformed psoriasis care, but not every patient achieves the same response. New research suggests one reason may lie in previously unrecognized immune differences. As Dermatology Times previously reported, advances in understanding the IL-23/IL-17 signaling pathway fundamentally reshaped modern psoriasis management.

Although IL-17 and IL-23 inhibitors have dramatically improved outcomes for many patients with moderate to severe psoriasis, a subset experiences inadequate or waning responses despite treatment. Despite these therapeutic advances, not all patients achieve the same level or durability of response, prompting researchers to investigate whether underlying immune differences could help explain this variability.

In a study published in the Journal of the American Academy of Dermatology, investigators identified a previously unrecognized dual Th17/Type 2 transcriptomic endotype in Taiwanese patients with chronic plaque psoriasis, suggesting distinct immune profiles may contribute to differences in disease severity and biologic response.¹

Unexpected Type 2 Inflammation Emerges

Using bulk RNA sequencing, researchers analyzed lesional and nonlesional skin biopsies from 11 patients with plaque psoriasis and healthy controls, while validating circulating cytokine profiles in an additional cohort of 50 patients. Although investigators confirmed strong activation of the expected IL-23/Th17 pathway—including IL-17A, IL-17C, and IL-23A—they also identified significant upregulation of Type 2 inflammatory markers, including IL-4R, CCL17, and thymic stromal lymphopoietin (TSLP).

The study also demonstrated consistent activation of the IL-36 cytokine family, with IL-36G emerging as one of the most highly upregulated inflammatory mediators, alongside decreased expression of multiple genes involved in epidermal barrier function.¹

Together, these findings suggest that psoriasis may be more immunologically heterogeneous than previously appreciated and could partly help explain why some patients experience variable responses to biologic therapy.

Potential Implications for Precision Medicine

These findings build on the longstanding understanding that the IL-23/Th17 axis is the primary driver of psoriasis pathogenesis. Instead, the authors propose that some patients may possess a more complex immune profile characterized by simultaneous Th17 and Type 2 inflammation, potentially helping explain why responses to currently available biologics vary between individuals.

As the number of targeted therapies continues to expand, understanding the biological drivers of treatment response may become increasingly important for optimizing treatment selection. Dermatology Times recently highlighted advances in IL-17-targeted therapies and the continued evolution of psoriasis management.¹²

Potential Biomarkers Highlight Future Research Directions

In exploratory analyses, investigators identified amphiregulin (AREG), corneodesmosin (CDSN), and IL-36RN as potential biomarkers associated with disease severity, suggesting these biomarkers may warrant further investigation as potential tools for disease stratification and treatment selection. However, the authors emphasized that these findings remain hypothesis-generating and require validation in larger, more diverse populations before they can influence routine clinical practice.²

Study Limitations

The authors cautioned that transcriptomic analyses were performed on a relatively small biopsy cohort and exclusively in Taiwanese patients, limiting the generalizability of the findings. Additionally, the results are observational and hypothesis-generating rather than mechanistic, requiring validation in larger, more diverse populations before they can influence clinical practice.²

What This Means for Clinicians

The findings are particularly relevant as the psoriasis treatment landscape continues to expand, with an increasing number of targeted therapies offering clinicians more options—but also making treatment selection more complex.

Although these findings are unlikely to change clinical practice immediately, they come at a time when dermatologists have more targeted treatment options than ever before, making patient selection increasingly important. As precision medicine continues to evolve, molecular profiling could eventually help dermatologists better understand why some patients respond differently to biologic therapy and support more individualized treatment decisions.

References

1. Chen CH, Lee MS, Chang WY, et al. Uncovering a dual Th17/Type 2 transcriptomic endotype in psoriasis. J Am Acad Dermatol. 2026; S0190-9622(26)03028-8. doi:10.1016/j.jaad.2026.06.131.
2. Hebebrand M. Inside IL-17 inhibitors: Advancing psoriasis care. Dermatology Times. 2025. https://www.dermatologytimes.com/view/inside-il-17-inhibitors-advancing-psoriasis-care