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Beyond the Plaque: Rethinking Psoriasis Heterogeneity
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Beyond the Plaque: Rethinking Psoriasis Heterogeneity

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Disclaimer: This article has been automatically aggregated from

The expert quoted below, Kenneth Gordon, MD, was not compensated for his participation in this article, but has previously served as a paid consultant to and received research funding from Takeda.

The Clinical Variability of Psoriasis

People living with psoriasis often experience different disease trajectories, symptom burdens, flare patterns, comorbidities, and responses to treatment, regardless of how their disease may appear clinically.1-3 Even within the same individual, disease progression and treatment response may change over time.4 Together, these observations highlight an important characteristic of psoriasis: diverse clinical heterogeneity that is not always apparent from what’s visible on the surface.5-6

Psoriasis is now recognized as a chronic, systemic, immune-mediated inflammatory disease with impacts beyond the skin.7 Although advances in psoriasis research have transformed disease management, it continues to impose a considerable physical and psychosocial burden on patients and is associated with various comorbidities.1-3

The biological basis of this heterogeneity is not yet fully understood. Increasing evidence suggests that variations in immune and molecular pathways may contribute to the diverse ways psoriasis develops, progresses, and responds to treatment, shifting attention beyond visible clinical features to include the immune networks that drive disease activity.8-9

An Evolving Understanding of Psoriasis Pathogenesis

Decades of research have transformed the scientific view of psoriasis. Once considered primarily a keratinocyte-driven skin disorder, it is increasingly recognized as a complex, systemic, immune-mediated inflammatory disease.7 Recognition of the interleukin (IL) IL-23/IL-17 axis fundamentally advances current models of psoriasis pathogenesis and remains central to the scientific understanding of the disease.8,10 However, this framework may not fully account for the wide range of clinical presentations encountered in real-world practice. More and more, psoriasis is understood as the result of interactions among immune dysregulation, genetic susceptibility, environmental triggers, and signaling between the innate and adaptive immune systems.11

Hidden Biological Differences May Contribute to Clinical Heterogeneity

Psoriasis can be viewed as a result of overactive, interconnected inflammatory pathways with differences in relative activity and contributions from T helper 17 (Th17)-driven inflammation, type I interferon signaling, and neutrophilic inflammation across patients and throughout the disease course.3,7,12 These differences in immune-signaling activity, or biological heterogeneity, may help explain the clinical variability observed in lesion distribution, disease severity, flare frequency, progression, and treatment response.3,4

“As dermatologists, we understand that no two patients with psoriasis are the same, and even within the same patient, disease presentation and response to therapy can evolve over time,” says Kenneth Gordon, MD, Professor of Dermatology, Medical College of Wisconsin. “Advances in our understanding of psoriasis biology continue to reveal that the dominant inflammatory drivers of disease may not be apparent through clinical examination alone, underscoring the complexity of psoriasis beyond its visible manifestations.”

Interconnected Immune Pathways in Psoriasis

The IL-23/IL-17 axis remains central to the field’s understanding of psoriasis pathogenesis and has fundamentally shaped both disease models and therapeutic development.7,10 Rather than functioning independently, these pathways interact with other immune components to influence disease initiation, amplification, and persistence.11

Type I interferon signaling has been implicated in early inflammatory events that may shape subsequent immune responses, including IL-23 and IL-17 signaling.13 Together, these interactions reinforce the concept that psoriasis arises from a network of interconnected immune pathways rather than a single inflammatory axis.

TYK2 as a Mediator Across Immune Pathways

As the understanding of psoriasis pathogenesis has evolved, scientific interest has increasingly shifted toward immune mediators that coordinate signaling across multiple inflammatory pathways. Tyrosine kinase 2 (TYK2) is an intracellular enzyme within the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway that transmits signals initiated by several immune cytokine receptors.14

TYK2 plays a central role in signaling associated with IL-23, IL-12, and type I interferons, placing it at the intersection of several pathways implicated in psoriasis and other immune-mediated inflammatory diseases.15-16 Through IL-23 signaling, TYK2 contributes to regulation of the IL-23/IL-17 axis, while TYK2’s role in type I interferon signaling links it to early inflammatory events associated with acute disease initiation and amplification.13,15-16

“We often think about psoriasis in terms of individual inflammatory pathways, but TYK2 is interesting because it connects several pathways already familiar to clinicians,” says Gordon. “When you start looking at where those pathways intersect, you begin to appreciate just how interconnected psoriasis biology really is. Studying those intersections may provide additional insight into why patients with a seemingly similar disease can have different clinical experiences and responses to therapy.”

Through its role in multiple psoriasis-relevant signaling pathways, TYK2 highlights how complex, interdependent immune networks may contribute to psoriasis heterogeneity. Continued investigation reflects broader efforts to understand how interconnected immune pathways contribute to variable disease expression.

TYK2 Is Distinct Within the JAK Family

Although TYK2 belongs to the JAK family of intracellular signaling enzymes, it differs functionally from JAK1, JAK2, and JAK3.17 While all four proteins participate in cytokine signaling, JAK1, JAK2, and JAK3 regulate a broader range of biological processes, including metabolic and hematopoietic pathways.17 By contrast, TYK2 is more specifically associated with immune-mediated cytokine signaling, including pathways involving IL-23, IL-12, and type I interferons.17 Together, these differences distinguish TYK2 within the JAK family and underscore its role in specific immune pathways that contribute to psoriasis pathogenesis.

Toward a More Nuanced Understanding of Psoriasis Biology

Advances in psoriasis research continue to refine the field’s view of the disease as biologically and immunologically complex. While the IL-23/IL-17 axis remains central to current models of pathogenesis, evidence suggests that psoriasis arises from dynamic interactions among multiple immune pathways whose relative activity and contribution may differ across patients and throughout the disease course.11

Within this broader framework, TYK2 acts as a shared mediator across multiple immune signaling pathways implicated in psoriasis pathogenesis.14 As the field’s view of psoriasis continues to evolve, so too does recognition that no single inflammatory pathway is likely to account for every patient’s disease.18 This evolving view of psoriasis suggests that understanding the diversity of inflammatory pathways remains an area of ongoing research and underscores the importance of continuing to align management strategies with the underlying biology of each patient’s disease.18,19

References

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  2. Armstrong AW, Mburu S, Gondo GC, et al. Patient experiences with psoriatic disease in the USA: results from the psoriasis and beyond global study. Drugs Real World Outcomes. 2025;12(4):525-539.
  3. Ma J, Li H, Yang X, et al. Psoriasis as a systemic inflammatory disease: an immune set-point framework for comorbidities and relapse. Front Immunol. 2026;17:1830099.
  4. Geifman N, Azadbakht N, Zeng J, et al. Defining trajectories of response in patients with psoriasis treated with biologic therapies. Br J Dermatol. 2021;185(4):825-835.
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  15. Andrzejczak K, Sternak A, Witkowski W, et al. From convenience to clinical efficacy: selective TYK2 inhibition in psoriasis and the evolving role of next-generation oral targeted therapies. Pharmaceutics. 2026;18(3):347.
  16. García-Domínguez M. The role of IL-23 in the development of inflammatory diseases. Biology (Basel). 2025;14(4):347.
  17. Kircik L, Aldredge LM, DiRuggiero D. Selective tyrosine kinase 2 (TYK2) inhibition in plaque psoriasis. J Drugs Dermatol. 2024;23(8):645-652.
  18. Diotallevi F, Paolinelli M, Radi G, et al. Latest combination therapies in psoriasis: narrative review of the literature. Dermatol Ther. 2022;35(10):e15759.
  19. Miao M, Yan J, Sun Y, et al. Psoriasis: unraveling disease mechanisms and advancing pharmacological and nanotechnological treatments. J Inflamm Res. 2025;18:2045-2072.

C-ANPROM/INT/PsO/0048 / US-NON-13110v1.0 | September 2026

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