RESEARCH ARTICLE Cytokine production from stimulated whole blood cultures in rheumatoid arthritis patients treated with various TNF blocking agents Calin Popa 1,2 , Pilar Barrera 2 , Leo A.B. Joosten 1,2,3 , Piet L.C.M. van Riel 2 , Bart-Jan Kullberg 1,3 , Jos W.M. van der Meer 1,3 , Mihai G. Netea 1,3 1 Department of General Internal Medicine 2 Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands 3 Nijmegen Institute for Infection, Inflammation, and Immunity (N4i), Radboud University Nijmegen, Nijmegen, The Netherlands Correspondence: C. Popa, Radboud University Nijmegen Medical Centre, Department of Rheumatology (470), P.O.Box 9101 6500 HB Nijmegen, The Netherlands <c.popa@reuma.umcn.nl> Accepted for publication April 10, 2009 ABSTRACT. Infectious complications are not rare in rheumatoid arthritis (RA), and the susceptibility to infec- tions is increased during treatment with TNF blocking agents. As a possible mechanism contributing to that, we assessed the modulation of cytokine production induced by TNF neutralization. Methods. Whole blood cultures from six healthy volunteers and 13 RA patients starting therapy with either adalimumab (n = 7) or etanercept (n = 6) were stimulated with heat-killed Salmonella typhimurium, Staphylococcus aureus or with S. typhimurium lipopolysaccharide (LPS). The production of interleukin (IL)-1β, IL-6, IL10, IL-17, TNF, IL-8 and IFN-γ was measured by specific immunoassays. Results. Stimulation with Salmonella LPS resulted in a significantly lower production of IL-1β, TNF and a trend towards lower IL-6 and IFN-γ production in RA patients compared to healthy volunteers. Therapy with either of the agents did not significantly alter cytokine production capacity, with the exception of a lower IFN-γ and IL-8 production in patients treated with adalimumab and stimulated with heat-killed S. aureus. Conclusion. The results of our study suggest that the detrimental effects of anti-TNF agents on the immune response can vary quite widely, from very serious to limited effects, as reported here for etanercept and adalimumab. Because anti-TNF therapy can affect the cellular integrity of tuberculous granu- loma, recruitment of new cells at the granuloma site becomes crucial. In line with this, an impaired chemokine production induced by anti-TNF agents may ultimately result in the reactivation of tuberculosis, as previously reported. Therefore, caution should be constantly exercised in order to prevent the development of severe infec- tions and reactivation of tuberculosis whenever therapy with anti-TNF is initiated. Keywords: anti-TNF therapy, rheumatoid arthritis, infections, immune response Treatment strategies that modulate pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin-1 (IL-1)-β constitute a breakthrough in the treatment of rheumatoid arthritis (RA) and other inflam- matory diseases including juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, and Crohn’ s disease. Agents including anakinra, adalimumab, etaner- cept, and infliximab yield substantial improvement in symptoms, disability, and quality of life and prevent joint damage in early and long-standing RA. However, safety issues of increased susceptibility to infections in individuals receiving these treatments, particularly with intracellular pathogens such as Mycobacterium species [1], represent a serious concern. Interestingly, the rate of severe infections is lower in patients treated with the soluble receptor etanercept than in those treated with monoclonal anti-TNF agents, such as adalimumab and infliximab [2-5]. This may be due to differences in the capacity of these drugs to interact with soluble and membrane-bound TNF, to activate comple- ment and to induce cytolysis [6, 7], but the exact mechan- isms are not completely understood. Cellular recognition of pathogens involves binding to pattern recognition receptors (PRRs), including toll-like receptors (TLR), which ultimately leads to the release of proinflammatory cytokines, such as TNF, IL-1β and IFN-γ, and activation of host defense. Salmonella typhi- murium and Staphylococcus aureus are two microorgan- isms that have been previously reported to be able to cause severe infections in RA patients receiving anti- TNF drugs [8-11]. TNF neutralisation in RA results in a marked decrease of circulating, acute phase reactants, IL-6, IL-8 and soluble adhesion molecules, but does not affect white blood cells (WBC) counts and differentiation 88 Eur. Cytokine Netw., Vol. 20 n° 2, June 2009, 88-93 doi: 10.1684/ecn.2009.0150 Copyright © 2017 John Libbey Eurotext. Téléchargé par un robot venant de 54.191.40.80 le 10/07/2017.