Natural Bioactive Compounds in Rheumatoid Arthritis: Experimental Evidence from Adjuvant Arthritis Model Supporting Combination Strategies with Methotrexate

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that represents continuous synovial inflammation, oxidative stress, immune dysregulation, and progressive cartilage degradation and bone erosion. Although disease-modifying antirheumatic drugs (DMARDs), including methotrexate (MTX), have improved clinical outcomes, treatment-limiting adverse effects remain a concern. Increasing evidence suggests that natural bioactive compounds may serve as adjunctive approaches by modulating multiple pathogenic pathways. This review summarizes biomarker-based modulation of inflammatory, oxidative, and immune pathways by plant-derived extracts, nutraceuticals, and biologically derived compounds, with particular emphasis on evidence from adjuvant arthritis (AA). AA is a widely used experimental model that reproduces several inflammatory and oxidative features relevant to RA, including cytokine activation, NF-κB/MAPK signaling, Th17/JAK-STAT3 signaling, redox imbalance, and tissue degeneration. Studies in AA indicate that selected natural compounds, alone or in combination with MTX, can reduce inflammatory cytokines (e.g., IL-1β, IL-6, IL-17A), matrix-remodeling markers (e.g., MMP-9), and oxidative-stress markers (e.g., protein carbonyls and lipid peroxidation) while supporting antioxidant defenses (e.g., HO-1 and CAT). Overall, natural bioactive substances may have potential as adjunctive candidates for further investigation in RA, particularly because of their effects on inflammatory and oxidative pathways. Preclinical studies of MTX combinations have reported additional improvements in selected disease-associated outcomes; however, these findings require confirmation in well-designed clinical studies. This review critically evaluates the preclinical evidence for natural bioactive compounds, with a focus on mechanistic studies in AA and the potential for combination strategies with methotrexate.