Leflunomide/hydroxychloroquine combination therapy targets type I IFN-associated proteins in patients with Sjögren's syndrome that show potential to predict and monitor clinical response

Safae Hamkour, Eefje Hm van der Heijden, Ana P. Lopes, Sofie L.M. Blokland, Cornelis P.J. Bekker, Cornelia G. Van Helden-Meeuwsen, Marjan A. Versnel, Aike A. Kruize, Timothy Rdj Radstake, Helen L. Leavis, Maarten R. Hillen, Joel Ag van Roon*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)
22 Downloads (Pure)

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 languageEnglish
Article numbere002979
JournalRMD Open
Volume9
Issue number3
DOIs
Publication statusPublished - 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.

Publisher Copyright:
© 2023 BMJ Publishing Group. All rights reserved.

Fingerprint

Dive into the research topics of 'Leflunomide/hydroxychloroquine combination therapy targets type I IFN-associated proteins in patients with Sjögren's syndrome that show potential to predict and monitor clinical response'. Together they form a unique fingerprint.

Cite this