TYK2, IL-23 Pathway Treatments Assessed in Psoriasis for Lesions, Depressive Symptoms

Tyrosine kinase 2 (TYK2) inhibitor and interleukin (IL)-23 pathway biologic medication use is linked with comparable alleviation of psoriasis lesions and comorbid depressive symptoms, new data suggest.1

These findings were drawn from a recently-published analysis authored by such investigators as Lanmei Lin, MD, from Huashan Hospital of Fudan University in Shanghai. In their study background, Lin and coauthors highlighted TYK2 as a key regulatory molecule and novel therapeutic target for psoriasis, given its role in IL-23/Th17 signal transduction.2

“Clinically, TYK2 inhibitors significantly alleviated both the cutaneous manifestations and depressive symptoms in our cohort of psoriasis patients,” the investigative team wrote.1 “These findings provide clinical evidence supporting further investigation into the mechanisms by which TYK2 inhibitors ameliorate comorbid depression in psoriasis.”

Study Design Details

Lin and colleagues conducted their study using 2 distinct phases, with the first being a cross-sectional evaluation of patients with psoriasis involving the collection of Hospital Anxiety and Depression Scale (HADS) questionnaire data. These data were gathered from 298 individuals living with psoriasis. In the second phase, the study used a retrospective longitudinal evaluation of 107 individuals evaluated by the investigators prior to and after receiving 3 months of TYK2 inhibitor therapy.

A clinically confirmed diagnosis of psoriasis was required by the investigative team for inclusion. Patients would not be involved if their disease was treatment-induced or if they had any comorbid systemic conditions linked with substantial immune compromise. Such conditions included infectious, hematologic, hepatic, neurologic, renal, or pulmonary disorders. The team would provide HADS questionnaires to participants over the course of their routine outpatient clinic interactions.

Within this cross-sectional cohort of 298 subjects, stratification into 3 treatment categories took place:

• Those on TYK2 inhibitors
• Those treated with JAK inhibitors
• A non-JAK comparison group

Within the non-JAK pool, participants were given IL-23 biologics, IL-17 biologics, or other medications. This classification was chosen to minimize overlap in JAK pathway inhibition across cohorts. Any associations between treatment arms and HADS outcomes were assessed through the use of generalized linear models (GENMOD). The analyses accounted for several potential confounders, including sex, Psoriasis Area and Severity Index (PASI), age, involvement of body surface area (BSA), utilization of systemic or biologic drugs within the preceding 12 months, duration of psoriasis, and history of phototherapy use.

Findings in Patients with Psoriasis

When depressive symptoms were assessed through the use of HADS-D scores, individuals given treatment with TYK2 inhibitors were shown to have significantly lower scores as opposed to participants in the non-JAK arm, with a β coefficient of 1.23 (95% CI, 0.37 - 2.10).1 In contrast, Lin et al found no statistically significant distinctions between those included in the TYK2 inhibitor cohort and those given IL-23 biologics (β = 0.67; 95% CI, −0.76 to 2.10) or given JAK inhibitors (β = 0.84; 95% CI, −1.54 to 3.21).

In their exploratory molecular analyses, the investigative team highlighted additional mechanistic insights. In particular, they noted transcriptomic profiling of peripheral blood samples suggested a marked downregulation of genes involved in long-term depression–related pathways, IL-6 receptor signaling, and Th17 cell differentiation, alongside the upregulation of pathways connected to neuronal activity.

In complementary analyses, Lin et al’s data suggested the presence of reduced levels of kynurenic acid, a metabolite known to be linked with pro-inflammatory signaling as well as depressive symptoms. They also suggested the presence of increased concentrations of 1H-indole-3-propanoic acid, known to have anti-inflammatory and neuroprotective properties. These omics-based conclusions were interpreted by the investigative team cautiously, as false discovery rate (FDR) correction was applied to account for multiple testing.

In all, Lin and coauthors’ findings point to the value of a proposed mechanism whereby TYK2 inhibition may work to interrupt a sustained cycle connecting peripheral inflammation and central depressive processes. This, they note, could potentially be done via the modulation of the IL-23/Th17 pathway and the IL-6–tryptophan metabolic axis in such patients. The team then noted the significance of these conclusions.

“These findings offer new therapeutic possibilities for psoriasis—a prototypical psychodermatological condition—and underscore the importance of multidimensional targeting along the neuro–immune–cutaneous axis as a pivotal strategy for managing psoriasis–depression comorbidity,” Lin et al wrote.1

References

1. Lin L, Dong C, Du J, et al. TYK2 and IL-23 Pathway Therapies in Psoriasis: Associations With IL-6, Tryptophan Metabolism, and Depressive Symptoms. Int J Dermatol. 2026 Jan 12. doi: 10.1111/ijd.70230. Epub ahead of print. PMID: 41524454.

2. Armstrong AW, Read C. Pathophysiology, Clinical Presentation, and Treatment of Psoriasis: A Review. JAMA. 2020 May 19;323(19):1945-1960. doi: 10.1001/jama.2020.4006. PMID: 32427307.