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

Abstract

Primary Sjögren's syndrome (pSS) is an auto immune disorder characterized by exocrine dysfunction as a result of chronic inflammation of the glands. Part of the patients also develops inflammation in other organs. In a complex interplay of different cell types such as T-cells, B-cells, dendritic cells, monocytes/macrophages and NK cells and their effector molecules, all contribute to one of the ultimate hallmarks of pSS: B-cell hyperactivity, subsequent autoantibody production and eventually formation of germinal center-like structures in the salivary gland. Effective treatment options for this disease are currently lacking. Biological DMARDs (bDMARDs) including those targeting B-cells or B-cell activation (directly or indirectly) have been studied, so far with limited efficacy. Besides that, their high costs provide a major drawback for implementation. Relatively inexpensive conventional DMARDs (cDMARDs) with well-known safety profiles have been shown efficacious in numerous clinical studies in multiple (rheumatic) diseases. cDMARDs target several pathways that are crucial in pSS immunopathology and some have proven to effectively inhibit B-cell hyperactivity and immune activation when given to patients. However, strong conclusions about potential efficacy are hampered by lack of standardization of inclusion criteria and outcome measures, dosing and validated biomarkers for patient selection. Proper implementation of these could help to optimize the use of cDMARDs in pSS treatment. In analogy with effective treatment strategies in for example rheumatoid arthritis, combination of two cDMARDs targeting different dysregulated pathwaysmight result in additive or synergistic inhibition of immune activation. In view of this and the unique and potent mechanisms of action to target immunopathology in pSS, optimizing cDMARDs for treatment of pSS is worthwhile.