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Upadacitinib Significantly Decreases Biomarker BD2 in Patients with PsA

“The differential contribution of IL-6 and IL-17 pathways to the pathogenesis of psoriatic arthritis is not fully understood,” investigators stated.

Interleukin-6 (IL-6) and IL-17 inhibition of patients with psoriatic arthritis (PsA) receiving the oral janus kinase (JAK) inhibitor upadacitinib (UPA) varied in terms of outcomes in those with inadequate response to non-biologic disease-modifying antirheumatic drugs (nbDMARD-IR) and inadequate response to biologic disease-modifying antirheumatic drugs (bDMARD-IR). In nbDMARD-IR patients, a decrease in IL-6 and joint manifestation improvement was reported, while decreases in IL-17A and IL-17F and improvement in psoriasis symptoms were seen in the bDMARD-IR cohort. However, beta-defensin 2 (BD2), a biomarker of Th17-associated skin pathology, was significantly reduced in both groups after treatment with UPA and positively impacted psoriasis improvement.

“The differential contribution of IL-6 and IL-17 pathways to the pathogenesis of psoriatic arthritis is not fully understood,” investigators stated. “Targeted proteomic analysis suggested that UPA modulates multiple biological pathways in innate and adaptive immune systems via direct and indirect inhibition of key regulators, including IL-6 and IL-17 pathways, with a possible shift from Th1 predominance in nbDMARD-IR PsA to a more Th17 bias in bDMARD-IR PsA.”

Patients were randomly selected from the SELECT-PsA 1 (74 patients received UPA 15mg daily, 74 received placebo) and SELECT-PsA 2 studies (90 patients received UPA 15 mg daily, 81 received placebo). IL-6, IL-17A, IL-17F, and BD2 proteins were measured by validated immunoassays at baseline and then again at week 2 and week 12. A Repeated Measure Mixed Linear Model compared the UPA and placebo cohorts overall as well as between responders and non-responders. Response was defined as a Psoriatic Arthritis Disease Activity Score PASDAS score ≤ 3.6 (Minimal Disease Activity, MDA) and Psoriasis Area and Severity Index 75 (PASI75) at week 12. The Pearson’s correlation evaluated any link between cytokines and clinical outcomes (PASI and Disease Activity Score-28 C-reactive protein [DAS28-CRP]) at baseline and at the end of treatment.

At week 12, patients receiving UPA had significantly decreased IL-6 and BD2. IL-17A, IL-17F, and BD2 levels correlated both with each other and with PASI in nbDMARD-IR patients. However, IL-6 levels were independent from the IL-17 pathway and was associated with DAS28-CRP. An increase in IL-6 was more significant in PASDAS MDA responders and was linked to DAS28-CRP improvement. Reductions in BD2 were more significant in PASI75 responders and associated with PASI improvement. Conversely, IL-17A and IL-17F levels did not change after UPA treatment and were not associated with clinical outcomes at week 12.

IL-17A levels were significantly higher in the bDMARD-IR cohort when compared with nbDMARD-IR patients and showed no correlation with PASI. Reductions in IL-6 were not different between responders and non-responders in terms of PASDAS MDA or PASI75 and did not correlate with DAS28-CRP improvement. BD2 decreases remained significant in patients who achieved PASI75 and PASI improvement. The reduction of IL-17F was linked to PASI improvement at the end of the study period.

The study, “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,” was presented at the Annual European Congress of Rheumatology (EULAR 2022).