ANTI- TUMOR NECROSIS FACTOR ALPHA KEEPS DENDRITIC CELLS TO PRODUCE INTERFERON-ALPHA FOSTERING THE APPEARANCE OF ANTINUCLEAR ANTIBODIES IN RHEUMATOID ARTHRITIS PATIENTS

Background: Tumor necrosis factor alpha (TNF) blockers are highly effective in the treatment of refractory rheumatoid arthritis (RA) and ankylosing spondylitis. But up to 40% of patients treated by TNF blockers develop lupus-like phenomenon, most often limited to antinuclear auto-antibodies (ANA) and occasionally associated with clinical manifestations. Recently, interferon-alpha (IFN) has been shown to play a key role in systemic lupus erythematosus (SLE) pathogenesis, through its ability to activate dendritic cells (DCs) as well as the B cell compartment. Indeed, this cytokine produced by plasmacytoid dendritic cells (pDCs), induces the myeloid dendritic cells (mDCs) activation, and the differentiation of B-cells into antibody-secreting plasmocytes. Upon viral stimulation, pDCs are induced to secrete IFN, and other cytokines including TNF, which induces the pDCs maturation through an autocrine loop, making them much less potent to secrete large amount of IFN. So based on these observations, we hypothesize that TNF blockers could sustain pDCs IFN secretion by blocking their maturation, and therefore may induce lupus-like states.Objectives: To analyse the different sub-types of DC that are engaged in SLE and RA. To correlate the level of DC with the ANA generation. To analyse the relationship between the serum IFN levels and the presence of auto-antibodies in patients treated by anti-TNF or RA, and to evaluate the implication of the TNF system in the secretion of IFN and its relation to the DC system.Methods: Quantification of circulating mDC and pDC (dendritic cells kit, BD Biosciences, Pont de Claix, France) in patients with SLE or RA and comparison with disease activity and ANA generation. For RA patients treated by TNF blockers, the evaluations were performed at baseline and at the moment of each infliximab infusion (W2, W6, W14 and all the 8 weeks). Each in vivo result is confirmed by in vitro experience.Results: In SLE (n=30), disease activity correlated with the pDC level and not to the number of mDC (p<0.01) whereas in RA (n=60), disease activity (DAS 28) correlated with mDC level and not with pDC levels (p<0.01). In sub-groups of RA patients treated by anti-TNF agents and developing ANA among all the biological markers tested, the decrease of pDC level was the best marker which correlated with ANA generation (r=0.175, p=0.01). Two groups of patients treated by anti-TNF were individualized: group 1: patients with positive antinuclear antibodies (ANApos) (n=28) and group 2 patients with negative ANA (ANAneg) (n=30). ANApos patients were characterized by a significant increase of serum IFN levels when compared to ANAneg patients (mean value: 218 vs 36 pg/ml respectively, p<0.01). In vitro studies revealed that TNF blockers keep pDCs in an IFN secreting state upon viral stimulation, likely via the inhibition of pDCs maturation. Furthermore, PBMC cultured in vitro with virus and TNF blockers, allowed for the generation of ANA secreting plasmablasts (CD19+CD20-CD38+), a population which was found significantly increased in ANApos RA patient.Conclusion: The effect of TNF blockers on pDCs maturation may play a key role in the development of ANA in RA patients. Moreover, these results support the hypothesis of autoimmune diseases primarily depending on lymphoid DCs (ie SLE) in opposition to autoimmune diseases depending on myeloid DCs (such as RA).Citation: Ann Rheum Dis, volume 64, supplement III, year 2005, page 77Session: Advances in cellular autoimmunity