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
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 an...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2023-08-01
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| Series: | RMD Open |
| Online Access: | https://rmdopen.bmj.com/content/9/3/e002979.full |
| _version_ | 1797640363223023616 |
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| author | Cornelis P J Bekker Maarten R Hillen Sofie L M Blokland Aike A Kruize Joel AG van Roon Timothy RDJ Radstake Cornelia G van Helden-Meeuwsen Marjan A Versnel Helen L Leavis Safae Hamkour Ana P Lopes Eefje HM van der Heijden |
| author_facet | Cornelis P J Bekker Maarten R Hillen Sofie L M Blokland Aike A Kruize Joel AG van Roon Timothy RDJ Radstake Cornelia G van Helden-Meeuwsen Marjan A Versnel Helen L Leavis Safae Hamkour Ana P Lopes Eefje HM van der Heijden |
| author_sort | Cornelis P J Bekker |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T13:30:47Z |
| format | Article |
| id | doaj.art-b2355b45dacc41cd96ffe4289a16288d |
| institution | Directory Open Access Journal |
| issn | 2056-5933 |
| language | English |
| last_indexed | 2024-03-11T13:30:47Z |
| publishDate | 2023-08-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | RMD Open |
| spelling | doaj.art-b2355b45dacc41cd96ffe4289a16288d2023-11-02T21:55:08ZengBMJ Publishing GroupRMD Open2056-59332023-08-019310.1136/rmdopen-2023-002979Leflunomide/hydroxychloroquine combination therapy targets type I IFN-associated proteins in patients with Sjögren’s syndrome that show potential to predict and monitor clinical responseCornelis P J Bekker0Maarten R Hillen1Sofie L M Blokland2Aike A Kruize3Joel AG van Roon4Timothy RDJ Radstake5Cornelia G van Helden-Meeuwsen6Marjan A Versnel7Helen L Leavis8Safae Hamkour9Ana P Lopes10Eefje HM van der Heijden11Department of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, UMC, Utrecht, The NetherlandsDepartment of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, UMC, Utrecht, The NetherlandsDepartment of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, UMC, Utrecht, The NetherlandsDepartment of Rheumatology and Clinical Immunology, Utrecht University, Utrecht, The NetherlandsDepartment of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, UMC, Utrecht, The NetherlandsDepartment of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, UMC, Utrecht, The NetherlandsImmunology, Erasmus Medical Center, Rotterdam, The NetherlandsImmunology, Erasmus Medical Center, Rotterdam, The NetherlandsDepartment of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, UMC, Utrecht, The NetherlandsDepartment of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, UMC, Utrecht, The NetherlandsDepartment of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, UMC, Utrecht, The NetherlandsDepartment of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, UMC, Utrecht, The NetherlandsObjectives 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.https://rmdopen.bmj.com/content/9/3/e002979.full |
| spellingShingle | Cornelis P J Bekker Maarten R Hillen Sofie L M Blokland Aike A Kruize Joel AG van Roon Timothy RDJ Radstake Cornelia G van Helden-Meeuwsen Marjan A Versnel Helen L Leavis Safae Hamkour Ana P Lopes Eefje HM van der Heijden 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 RMD Open |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | leflunomide hydroxychloroquine combination therapy targets type i ifn associated proteins in patients with sjogren s syndrome that show potential to predict and monitor clinical response |
| url | https://rmdopen.bmj.com/content/9/3/e002979.full |
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