PD1+ innate lymphoid cells 3 predict JAK-dependent inflammation in rheumatoid arthritis

Innate lymphoid cells (ILCs) play a key role in maintaining immune homeostasis and are linked to inflammation and autoimmunity. This study investigates the role of ILCs in the pathogenesis of rheumatoid arthritis (RA) and their response to two targeted therapies - JAK inhibitors (JAKi), which block critical signaling pathways required for their activation, and TNF inhibitors (TNFi), which target a key inflammatory mediator - offering insights into how these interventions shape ILC-driven inflammation.

ILC distribution correlated with RA activity, as indicated by the DAS28 score, and this imbalance was improved significantly within four weeks of JAKi, underscoring its early therapeutic impact on ILC-mediated inflammation. While levels of ILC3-activating cytokines such as IL-1β and IL-23 declined under JAKi therapy, they remained unchanged with TNFi. Although JAKi and TNFi showed similar treatment efficacy, multivariate regression analysis showed that improvement in DAS28 score was strongly associated with increase in CTLA-4⁺ILC3 and reduction in both PD1⁺ILC3 frequency and systemic IL12p40/IL-23 levels only with JAKi. Notably, this two ILC3 subtypes determined the DAS28 score after 50 d of JAKi. In contrast, patients showing limited response to JAKi (ΔDAS28 < 1.2) maintained high systemic IL-18 levels, a cytokine that induces signaling independent of the JAK pathway, suggesting a potential resistance mechanism. These findings highlight that monitoring PD1⁺ILC3s or IL-12p40/IL-23 may serve as an indicator of JAKi responsiveness, while elevated IL-18 may identify patients benefiting from alternative therapies. These results also emphasize the clinical relevance of targeting innate immunity for more personalized, pathway-focused RA therapies.