IL-6 and IL-17 Pathway Modulation Following Upadacitinib Treatment for Psoriatic Arthritis

Interleukin (IL)-6 and IL-17 pathway inhibition and beta-defensin 2 (BD2) expression patterns in relationship with clinical outcomes may play different roles in joint and skin symptom improvement in patients with psoriatic arthritis (PsA) treated with upadacitinib, according to study results presented at the European Alliance of Associations for Rheumatology (EULAR) Congress 2022, held from June 1 to 5 in Copenhagen, Denmark.

Researchers evaluated the relationship between IL-6 and IL-17 pathway modulation and clinical outcomes following upadacitinib treatment in patients with PsA who had inadequate response to non-biologic disease-modifying antirheumatic drugs (nbDMARD-IR) and biological disease-modifying antirheumatic drugs (bDMARD-IR).

Patients were randomly selected from the SELECT-PsA1 and SELECT-PsA2 studies. Data for the analyses included serum levels of IL-6, IL-17A, IL-17F, and BD2 at baseline, week 2, and week 12. A repeated measure mixed linear model was used to compare changes in measured parameters between patients receiving upadacitinib vs placebo and between upadacitinib responders and non-responders.

Upadacitinib response was defined as a psoriatic arthritis disease activity score (PASDAS) of 3.6 or lower (minimal disease activity [MDA]), and a 75% decrease in the psoriasis area and severity index (PASI75) at week 12. Pearson correlation was used to assess the relationships between cytokines and upadacitinib response (PASI and DAS28-CRP) at baseline and after treatment.

The profiles of IL-6 and IL-17 pathway inhibition in relationship with clinical outcomes varied between patients treated with nbDMARD-IR vs bDMARD-IR. In patients treated with nbDMARD-IR, baseline IL-17A, IL-17F and BD2 were correlated with PASI, while IL-6 was correlated with DAS28-CRP. In patients treated with bDMARD-IR, IL-17A was elevated but showed no correlation with PASI.

At week 12, IL-6 decreased in patients with nbDMARD-IR, particularly in PASDAS responders and patients with DAS28-CRP improvement. IL-17A and IL-17F were unchanged after upadacitinib treatment. In patients treated with bDMARD-IR, there was no difference in IL-6 decrease between responders and non-responders (PASDAS MDA or PASI75). Significant decreases were seen in IL-17A in PASDAS MDA responders and IL-17F in PASI75 responders. In patients treated with both nbDMARD-IR and bDMARD-IR, a decrease of BD2 correlated with PASI75 improvement.

The study authors concluded, “IL-6 decrease was more pronounced in [patients with nbDMARD-IR PsA] and associated with joint manifestation improvement, while IL-17A and IL-17F decreases were only observed in [patients with bDMARD-IR PsA] and associated with psoriasis improvement. BD2, a biomarker of Th17-associated skin pathology, significantly decreased after [upadacitinib] treatment in both nbDMARD-IR and bDMARD-IR PsA studies, which likely contributed to [upadacitinib] effects on psoriasis improvement in a broad range of [patients with PsA].”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

Reference

Cai F, Sornasse T, Ruzek M, et al. Differentiation between IL-6 and IL-17 pathway inhibition in relationship with clinical outcomes in non-biological DMARD-IR and biological DMARD-IR psoriatic arthritis patients treated with upadacitinib in select-PsA 1 and select-PsA 2 studies. Presented at: EULAR Congress 2022; June 1-4, 2022; Copenhagen, Denmark. Abstract OP0024.