Serum proteomics analysis of biomarkers for evaluating clinical response to MTX/IGU therapy in early rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by inflammation of joints, and could further involve extra-articular and systemic manifestations such as interstitial lung disease or cardiovascular disease. If not treated sufficiently, the chronic and progressive inflammation of RA can lead to irreversible disability and increase mortality (Smolen et al., 2016, Listing et al., 2015). The existing statistical analysis and interpretation of data suggest that RA is a public health concern (Radu and Bungau, 2021). Hence, early diagnosis and timely intervention are of great value to remission in RA. According to the recommendations from European League Against Rheumatism (EULAR), disease modifying anti-rheumatic drugs (DMARDs) are the primary treatment for RA, including conventional synthetic DMARDs (csDMARDs) and biological DMARDs (bDMARDs) (Smolen et al., 2020).

Methotrexate, a representative drug of csDMARDs, is the standard therapy for RA. For patients with insufficient response to MTX, other csDMARDs or bDMARDs are required (Smolen et al., 2020). Recently, a novel synthetic DMARD, iguratimod (IGU), has been approved for RA treatment in China and Japan (Xie et al., 2020). Clinical trials showed that IGU was superior over salazosulfapyridine (SAAP) and non-inferior to MTX, and had fewer side effects (Hara et al., 2007, Lu et al., 2009). Besides, combination of IGU with MTX has been confirmed to have good efficacy and tolerability in several studies (Duan et al., 2015, Ishiguro et al., 2013). Nevertheless, the efficacy of the combined MTX/IGU therapy is variable, and approximately 30 % of RA patients showed poor response to the therapy (Hara et al., 2014).

Currently, the underlying mechanism and actual targets of IGU remain unclear (Xie et al., 2020, Li et al., 2019). Besides, disease activity score of 28 joints for erythrocyte sedimentation rate (DAS28-ESR) is the main measure to assessment the disease activity and clinical response. It is monitored every 1–3 months and the therapy will not be adjusted until there is no improvement after 3–6 months of treatment, which is time-consuming and may result in delaying treatment. Thus, it is essential to identify new biomarkers for clarifying its mechanism, and improving the evaluation system to timely and accurately assess the efficacy and disease activity in the early stage of treatment.

Recent researches have illustrated that mass spectrometry-based quantitative proteomics is a promising tool for discovering disease-related biomarkers and studying the mechanisms of drugs based on body liquid (Zhou et al., 2017, Gao et al., 2018). To our knowledge, no studies have applied this approach to explore the influence of MTX/IGU therapy on human serum proteins. In this work, we conducted a study of the serum proteome difference between RA patients with good and poor response to MTX/IGU therapy using mass spectrometry-based label-free quantitative proteomic approach. This work primarily focused on identifying potential dysregulated proteins to determine mechanisms of MTX/IGU therapy, and exploring candidate biomarkers to evaluate the response.

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