ObjectivesTo investigate the possibility of discontinuing adalimumab (ADA) for 1 year without flaring (DAS28-erythrocyte sedimentation rate (ESR) ≥3.2), and to identify factors enabling established patients with rheumatoid arthritis (RA) to remain ADA-free.MethodsOf 197 RA patients treated with ADA+methotrexate (MTX), 75 patients who met the ADA-free criteria (steroid-free and sustained DAS28-ESR remission for 6 months with stable MTX doses) were studied for 1 year.ResultsThe mean disease duration and DAS28-ESR score in 75 patients was 7.5 years and 5.1 at baseline, respectively. The proportion of patients who sustained DAS28-ESR <2.6 (48%) and DAS28-ESR <3.2 (62%) for 1 year were significantly lower in the ADA discontinuation group than in the ADA continuation group; however, in patients with deep remission (DAS28-ESR ≤1.98) identified by receiver operating characteristics analysis following logistic analysis, these rates increased to 68% and 79%, respectively, with no significant difference between both groups. Remarkably, ADA readministration to patients with flare was effective in returning DAS28-ESR to <3.2 within 6 months in 90% and 9 months in 100% patients; among the patients who sustained DAS28-ESR <3.2 during ADA discontinuation, 100% remained in structural remission and 94% in functional remission.ConclusionsThe possibility of remaining ADA-free for 1 year was demonstrated in established patients with RA with outcomes that ADA can be discontinued without flaring in 79% patients with deep remission, with similar rates in the ADA continuation group, and showed no functional or structural damage in patients with DAS28-ESR <3.2. ADA readministration to patients with flare during ADA discontinuation was effective.

A major neurotransmitter dopamine transmits signals via five different seven-transmembrane G protein-coupled receptors termed D1–D5. Several studies have shown that dopamine not only mediates interactions into the nervous system, but can contribute to the modulation of immunity via receptors expressed on immune cells. We have previously shown an autocrine/paracrine release of dopamine by dendritic cells (DCs) during Ag presentation to naive CD4+ T cells and found efficacious results of a D1-like receptor antagonist SCH-23390 in the experimental autoimmune encephalomyelitis mouse model of multiple sclerosis and in the NOD mouse model of type I diabetes, with inhibition of Th17 response. This study aimed to assess the role of dopaminergic signaling in Th17-mediated immune responses and in the pathogenesis of rheumatoid arthritis (RA). In human naive CD4+ T cells, dopamine increased IL-6–dependent IL-17 production via D1-like receptors, in response to anti-CD3 plus anti-CD28 mAb. Furthermore, dopamine was localized with DCs in the synovial tissue of RA patients and significantly increased in RA synovial fluid. In the RA synovial/SCID mouse chimera model, although a selective D2-like receptor antagonist haloperidol significantly induced accumulation of IL-6+ and IL-17+ T cells with exacerbated cartilage destruction, SCH-23390 strongly suppressed these responses. Taken together, these findings indicate that dopamine released by DCs induces IL-6–Th17 axis and causes aggravation of synovial inflammation of RA, which is the first time, to our knowledge, that actual evidence has shown the pathological relevance of dopaminergic signaling with RA.

Our study indicates that patients with active SLE can be divided into 3 subgroups based on T cell heterogeneity. Further immunophenotyping studies should help elucidate the pathogenesis of SLE and provide important information for the development of new therapies.

Our results suggest that the phenotypic changes of peripheral B cells result in inhibition of T cell differentiation and activation mediated by B cells and thereby bring about longterm remission of SLE. Activated memory B cells or ICOS-positive CD4-positive memory T cells reappeared in association with relapse, probably reflecting the heterogeneity of SLE.

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