Abstract
OBJECTIVES: To assess to what extent leflunomide (LEF) and hydroxychloroquine (HCQ) therapy in patients with primary Sjögren's syndrome (RepurpSS-I) targets type I IFN-associated responses and to study the potential of several interferon associated RNA-based and protein-based biomarkers to predict and monitor treatment. METHODS: In 21 patients treated with LEF/HCQ and 8 patients treated with placebo, blood was drawn at baseline, 8, 16 and 24 weeks. IFN-signatures based on RNA expression of five IFN-associated genes were quantified in circulating mononuclear cells and in whole blood. MxA protein levels were measured in whole blood, and protein levels of CXCL10 and Galectin-9 were quantified in serum. Differences between responders and non-responders were assessed and receiver operating characteristic analysis was used to determine the capacity of baseline expression and early changes (after 8 weeks of treatment) in biomarkers to predict treatment response at the clinical endpoint. RESULTS: IFN-signatures in peripheral blood mononuclear cell and whole blood decreased after 24 weeks of LEF/HCQ treatment, however, changes in IFN signatures only poorly correlated with changes in disease activity. In contrast to baseline IFN signatures, baseline protein concentrations of galectin-9 and decreases in circulating MxA and Galectin-9 were robustly associated with clinical response. Early changes in serum Galectin-9 best predicted clinical response at 24 weeks (area under the curve 0.90). CONCLUSIONS: LEF/HCQ combination therapy targets type-I IFN-associated proteins that are associated with strongly decreased B cell hyperactivity and disease activity. IFN-associated Galectin-9 is a promising biomarker for treatment prediction and monitoring in pSS patients treated with LEF/HCQ.
Original language | English |
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Article number | e002979 |
Journal | RMD Open |
Volume | 9 |
Issue number | 3 |
DOIs | |
Publication status | Published - 2 Aug 2023 |
Bibliographical note
Funding Information:For this study, funding was received from ZonMW and ReumaNederland (Translational round 2, projectnummer: 446002502). This project (JvR) also received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement number 806975 (Necessity). JU receives support from the European Union's Horizon 2020 research and innovation program and EFPIA.
Funding Information:
For this study, funding was received from ZonMW and ReumaNederland (Translational round 2, projectnummer: 446002502). This project (JvR) also received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement number 806975 (Necessity). JU receives support from the European Union’s Horizon 2020 research and innovation program and EFPIA.
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