Background Resveratrol (RSV), a non-toxic polyphenol found in grapes, certain nuts, roots etc., have received increased attention in the last decade due to its anti-inflammatory modulation of a number of pathways, including cyclooxygenase-1/-2, nuclear factor kappa-beta and cytokine production. In vitro, RSV has been shown to reduce production of interleukin 1-beta and tumor necrosis factor alpha in monocytes and inhibit T-cell activation and synoviocyte proliferation. In vivo, intra-articular injections of RSV have demonstrated anti-inflammatory and pannus inhibiting effects in rats with induced arthritis.
Objectives Here, we tested whether the anti-inflammatory effect of RSV in arthritis patients depends on the degree of systemic inflammation and the cellular composition of extracted synovial fluid. Furthermore, we evaluated the anti-inflammatory effect of RSV in combination with methotrexate (MTX) and adalimumab.
Methods Synovial fluid mononuclear cells (SFMCs) from patient with rheumatoid arthritis (n=7) and spondyloarthritis (n=7) were cultured in monoculture for 48 hours (in vivo activated lymphocytes and monocytes) or 21 days (spontaneous generation of osteoclasts). Cultures were either left untreated or treated with RSV (25 μM), methotrexate (0.5 μg/ml), adalimumab (5 μ g/ml) or in combination. Supernatants were analysed for the production of monocyte chemoattractant protein-1 (MCP-1) and matrix metalloproteinase 3 (MMP3). Osteoclast differentiation was analysed with a tartrate resistant acidic phosphatase (TRAP) enzymatic assay.
Results In the SFMC cultures, RSV reduced MCP-1 production by 25% compared with untreated cells (P=0.032). When grouping results by c-reactive protein (CRP), i.e. < median vs. ≥ median, the inhibitory effect of RSV was primarily seen in cultures from patients with CRP <21 mg/l. In this group, RSV reduced MCP-1 production by 63%. Combining MTX and RSV reduced MCP-1 production compared to MTX alone, but only in the group of patients with CRP <21 mg/l (P=0.002). Combining adalimumab and RSV seemed to reduce MCP-1 in the group of patients with CRP <21 mg/l, but increase production in patients with CRP ≥21 mg/l (P=0.03). Similar grouping based on lymphocyte count showed RSV, MTX and adalimumab, alone or in combination, all reduced MCP-1 significantly compared to untreated cells in cultures from patients with ≥62% lymphocytes in the synovial fluid. RSV, MTX and adalimumab did not affect MMP3 production in the SFMC cultures. In the osteoclast cultures, RSV alone did not affect MCP-1 or TRAP. However, the combination of RSV and MTX reduced MCP-1 compared to no treatment (P=0.004). Adalimumab alone or combined with RSV reduced TRAP compared with untreated cultures (P<0.027).
Conclusions RSV exhibits an anti-inflammatory effect on SFMCs. Interestingly; our data suggest that this effect is most pronounced in patients with relatively low CRP. Further, RSV produces an additive anti-inflammatory response in combination with MTX in the group of patients with low CRP and a synovial fluid dominated by lymphocytes. Together, this suggests that RSV may possess an additive potential when added to MTX treatment of arthritis patients with low disease activity.
Disclosure of Interest None declared