Repurposing established drugs for new indications: leflunomide and hydroxychloroquine combination therapy for Sjögren’s syndrome

Autor: Eefje Hanna Martine van der Heijden
Přispěvatelé: Radstake, T.R.D.J., Roon, J.A.G. van, Kruize, A.A., University Utrecht
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Popis: The immunopathology of pSS is characterized by broad immune-activation involving a wide variety of immune cells. Effective therapeutic options are lacking. Considering the complex interplay of involved immune cells, the hypothesis to this thesis is that successful inhibition of pSS immune-activation requires a combination of drugs targeting both overlapping and distinct immunopathological pathways, jointly resulting in broad immune inhibition. The combination of the cDMARDs leflunomide and hydroxychloroquine may hold promise of clinical efficacy. In this thesis, the efficacy and safety of leflunomide/hydroxychloroquine therapy in pSS patients was investigated. An overview of the current knowledge on pSS immunopathology is provided in Chapter 2, and the place of cDMARDs in its treatment is described. Given the upregulation of potential additive pathways in pSS, synergism between the different cell-types involved is likely to occur. Consequently, combining drugs targeting several pathways, for example cDMARDs leflunomide and hydroxychloroquine, seems reasonable. In Chapter 3, we showed in an in vitro system mimicking pSS pathology that at different concentration combinations leflunomide and hydroxychloroquine inhibited several immune hallmark features more potently than each single compound. A placebo-controlled, double-blinded randomized trial investigating leflunomide/hydroxychloroquine therapy in pSS patients was performed (Chapter 4). The study included 29 patients with active disease (EULAR Sjogren’s Syndrome Disease Activity Index, ESSDAI score ≥ 5). 21 patients received leflunomide/hydroxychloroquine therapy, 8 patients were assigned to placebo treatment. Disease activity reflected by ESSDAI, the primary endpoint, significantly decreased upon leflunomide/hydroxychloroquine compared to placebo. Also other clinical parameters such as patient reported outcome ESSPRI-score and saliva output improved. Histological assessment by parotid biopsies supported these positive findings. Leflunomide/hydroxychloroquine combination therapy proved to be safe and well-tolerated. Response to therapy could be predicted with high accuracy by a model comprising ten circulating proteins. In Chapter 5, five different IFN- associated biomarkers (IFN-score in whole blood and PBMCs, MxA in whole blood, CXCL10 and Galectin-9 in serum) in patients treated with either leflunomide/hydroxychloroquine or placebo were assessed and their potential for treatment monitoring was investigated. Patients responding to the therapy showed strong early decreases of MxA and Galectin-9 levels from week 8 onwards. Subsequent ROC analysis revealed good predictive values for early changes in (delta) MxA and Galactin-9 levels after 8 weeks, the latter outperforming the former. In Chapter 6 we focused on Galectin-9 as a biomarker that reflects the IFN signature in patients with SLE, APS and pSS. The findings of this chapter are in line with previous findings showing that Galectin-9 is an easy to measure and accurate biomarker for the IFN signature in SLE and APS patients and correlates with disease activity. Usage of Galectin-9 as a biomarker for the IFN signature needs further confirmation. Data from this thesis indicate that at the least Galectin-9 might play an additional role in monitoring of pSS immunopathology and disease activity. Leflunomide/hydroxychloroquine treatment induced a decline in Galectin-9 levels, parallel with changes in B cell hyperactivity, ESSDAI and ESSPRI, and markers of IFN activity. This warrants further study of Galectin-9 as a biomarker for disease monitoring in pSS.
Databáze: OpenAIRE
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