Paeoniflorin in rheumatoid arthritis: Translational insights and limited clinical evidence

Dear Editor, Rheumatoid arthritis (RA) remains a chronic autoimmune disorder characterized by persistent synovial inflammation, progressive joint damage, and systemic immune dysregulation. Despite advances in disease-modifying antirheumatic drugs (DMARDs) and biologic therapies, a subset of patients fails to achieve sustained remission or experiences treatment-limiting adverse effects. These challenges have prompted interest in adjunctive therapies, including plant-derived compounds with immunomodulatory properties [1]. Paeoniflorin, a bioactive constituent of Paeonia lactiflora, has been widely used in the form of total glucosides of paeony (TGP), a multi-component extract approved in China for inflammatory and autoimmune conditions, including RA. It is important to distinguish between TGP and isolated paeoniflorin: most clinical evidence to date pertains to TGP, whereas mechanistic insights are largely derived from studies of paeoniflorin in experimental systems [2]. From a clinical perspective, several randomized and controlled studies have evaluated TGP as monotherapy or in combination with conventional DMARDs. These studies suggest that TGP may be associated with modest improvements in clinical parameters such as joint symptoms, erythrocyte sedimentation rate, and C-reactive protein, and in some cases, improved the American College of Rheumatology response rates. However, these findings are based on relatively small cohorts, heterogeneous methodologies, and variable study quality, limiting the strength of clinical inference [2,3]. With respect to safety, TGP has generally been reported to be well-tolerated. Some studies have suggested a lower incidence of liver enzyme elevations when used alongside methotrexate; however, robust RA-specific evidence supporting a hepatoprotective effect remains limited and requires confirmation in well-designed clinical trials. Mechanistically, paeoniflorin has been shown in preclinical studies to modulate inflammatory signaling pathways. Experimental data indicate that it may inhibit nuclear factor-kappa B activation and reduce the production of pro-inflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1 beta (IL-1β), and IL-6. However, these findings are predominantly derived from in vitro systems and animal models, and direct validation in human RA synovial tissue is currently lacking [4]. Similarly, immunomodulatory effects involving T-cell subsets have been reported in experimental models. Paeoniflorin has been associated with reduced T helper 17 responses and enhanced regulatory T-cell activity in murine arthritis and other inflammatory conditions. Whether such effects occur in RA patients treated with TGP has not yet been established through detailed immunophenotyping studies [5]. RA pathogenesis also involves multiple immune cell populations, including B cells, macrophages, dendritic cells, and the production of autoantibodies. The influence of paeoniflorin or TGP on these components remains insufficiently characterized, highlighting an important gap in current understanding [4]. At the cellular level, in vitro studies suggest that paeoniflorin can inhibit the proliferation, migration, and matrix metalloproteinase production of fibroblast-like synoviocytes, which are key mediators of joint destruction in RA. While these findings provide mechanistic insight, their translational relevance to human disease progression requires further validation. Although oxidative stress has been implicated in RA pathophysiology, evidence supporting a clinically meaningful antioxidant role of paeoniflorin in RA patients remains limited. Reported antioxidant effects are largely derived from general pharmacological studies rather than RA-specific clinical investigations [6]. Pharmacokinetic limitations, including relatively low oral bioavailability of paeoniflorin, may restrict its therapeutic utility as a single compound. Derivatives such as CP-25 have demonstrated improved pharmacological properties in preclinical studies; however, these agents have not yet undergone clinical evaluation in RA populations [7]. Despite these limitations, TGP represents a standardized herbal formulation; however, variability across manufacturers and the extent to which standardization captures the full spectrum of bioactive constituents remain important considerations for broader clinical translation [1,2]. In summary, paeoniflorin and TGP represent promising candidates for adjunctive therapy in RA, supported by preliminary clinical observations and a growing body of preclinical evidence. However, current data remain insufficient to draw definitive conclusions regarding efficacy, mechanisms in human disease, or long-term safety. Large-scale, well-designed clinical trials and mechanistic studies in patient populations are needed to clarify their role in RA management. Author’s contribution The author is solely responsible for the conception, drafting, and writing of the manuscript. Data availability statement Data will be available upon request. Financial support and sponsorship Not applicable. Conflict of interests No conflict of interests declared.