Abstract
During rheumatoid arthritis (RA), steroids and biotherapies are used alone and combined. Efficacy has been established in clinical trials but their differential effects at the cellular level are less documented. The aim was to study these cellular effects using an in vitro model with synoviocytes interacting with peripheral blood mononuclear cells (PBMC) to reproduce the interactions in the RA synovium. Activated-PBMC were cocultured with RA synoviocytes during 48 h. A dose-response of methylprednisolone (MP) was tested and different biotherapies (Infliximab, Etanercept, Adalimumab, Tocilizumab, Abatacept, and Rituximab) were added alone or in combination with MP. Cytokine production (IL-17, IL-6, IL-1β, IFN-γ and IL-10) was measured by ELISA. Addition of MP to cocultures inhibited the production of all cytokines. The response to the biotherapies alone was treatment-dependent. IL-17 production was inhibited only by Tocilizumab (p = 0.004), while IL-6 was decreased only by Infliximab (p ≤ 0.002). IL-1β level was affected in all conditions (p ≤ 0.03). IFN-γ production was mainly decreased by Infliximab (p = 0.004) and IL-10 by Infliximab and Tocilizumab (p ≤ 0.004). The combination MP and biotherapies did not induce an additional effect on pro-inflammatory cytokine inhibition. The combination MP and biotherapies induced a higher IL-10 secretion than MP alone, mainly with Rituximab. Steroids inhibited the secretion of all cytokines, and low doses were as potent. The anti-inflammatory effect of biotherapies was dependent on their mechanism of action. MP and biotherapy combination did not enhance the inhibitory effect on pro-inflammatory cytokines but could have a beneficial effect by increasing IL-10 production.
Highlights
Rheumatoid arthritis (RA) is a chronic inflammatory disease leading to joint destruction [1]
In the RA context, synoviocytes from patients were cultured in the presence of activated-peripheral blood mononuclear cells (PBMC)
These cell–cell interactions lead to massive cytokine production, compared to PBMC alone
Summary
Rheumatoid arthritis (RA) is a chronic inflammatory disease leading to joint destruction [1]. Steroids ( named glucocorticoids or corticosteroids) are the oldest and the most classical anti-inflammatory therapy used for many chronic inflammatory diseases other than RA. They act by inhibiting multiple inflammatory genes (encoding cytokines, chemokines, etc.) that are activated during chronic inflammation [2,3,4]. Their use is associated with adverse events mainly infections at high dose. Non-responsiveness or resistance can be observed [5] Another key drug is methotrexate (MTX), the most common treatment of RA. The aim was to study these cellular effects using an in vitro model with synoviocytes interacting with peripheral blood mononuclear cells (PBMC) to reproduce the interactions in the RA synovium
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