BackgroundTumour necrosis factor (TNF) inhibitors enable tight control of disease activity in patients with rheumatoid arthritis (RA). Discontinuation of TNF inhibitors after acquisition of low disease activity (LDA) is important for safety and economic reasons.ObjectiveTo determine whether infliximab might be discontinued after achievement of LDA in patients with RA and to evaluate progression of articular destruction during the discontinuation.Methods114 patients with RA who had received infliximab treatment, and whose Disease Activity Score, including a 28-joint count (DAS28) was <3.2 (LDA) for 24 weeks, were studied.ResultsThe mean disease duration of the 114 patients was 5.9 years, mean DAS28 5.5 and mean modified total Sharp score (mTSS) 63.3. After maintaining LDA for >24 weeks by infliximab treatment, the drug was discontinued and DAS28 in 102 patients was evaluated at year 1. Fifty-six patients (55%) continued to have DAS28<3.2 and 43% reached DAS<2.6 at 1 year after discontinuing infliximab. For 46 patients remission induction by Remicade in RA (RRR) failed: disease in 29 patients flared within 1 year and DAS28 was >3.2 at year 1 in 17 patients. Yearly progression of mTSS (ΔTSS) remained <0.5 in 67% and 44% of the RRR-achieved and RRR-failed groups, respectively. The estimated ΔmTSS was 0.3 and 1.6 and Health Assessment Questionnaire-Disability Index was 0.174 and 0.614 in the RRR-achieved and RRR-failed groups, respectively, 1 year after the discontinuation.ConclusionAfter attaining LDA by infliximab, 56 (55%) of the 102 patients with RA were able to discontinue infliximab for >1 year without progression of radiological articular destruction.

Aim: Neuropsychiatric systemic lupus erythematosus (NPSLE) is a serious treatment-resistant phenotype of systemic lupus erythematosus. A standard treatment for NPSLE is not available. This report describes the clinical and laboratory tests of 10 patients with NPSLE before and after rituximab treatment, including changes in lymphocyte phenotypes. Methods: Rituximab was administered at different doses in 10 patients with refractory NPSLE, despite intensive treatment. Results: Treatment with rituximab resulted in rapid improvement of central nervous system-related manifestations, particularly acute confusional state. Rituximab also improved cognitive dysfunction, psychosis and seizure, and reduced the SLE Disease Activity Index Score at day 28 in all 10 patients. These effects lasted for .1 year in five patients. Flow cytometric analysis showed that rituximab down regulated CD40 and CD80 on B cells and CD40L, CD69 and inducible costimulator on CD4+ T cells. Conclusions: Rituximab rapidly improved refractory NPSLE, as evident by resolution of various clinical signs and symptoms and improvement of radiographic findings. The down regulation of functional molecules on B and T cells suggests that rituximab modulates the interaction of activated B and T cells through costimulatory molecules. These results warrant further analysis of rituximab as treatment for NPSLE.

In these studies, we have identified DNA sequences and specific protein interactions necessary for transcriptional regulation of the human prointerleukin 113 (proIL-i1i) gene. A cell-type-independent lipopolysaccharide (LPS)-responsive enhancer element located between -3757 and -2729 bp upstream from the transcription start site (cap site) consisted of at least six discrete subregions which were essential to the maximal induction by LPS in transfected monocytes. The enhancer also appeared to mediate phorbol myristate acetate induction in monocytes and IL-1 responsiveness in fibroblasts. Deletion and base substitution mutations along with DNA binding studies demonstrated that the enhancer contained a minimum of three functional protein binding sequences, two of which appeared to be important for gene induction. One of the essential proteins which bound to the enhancer was similar or identical to members of the C/EBP family of transcription factors required for both IL-1-and LPS-specific induction of the IL-6 gene (i.e., the NF-IL6 proteins). When ligated to the proIL-1l3 cap site-proximal region (located between -131 to +12), both the proIL-1,3 and the simian virus 40 enhancer elements functioned more efficiently in monocytes than in HeLa cells, which are not normally competent for IL-11 expression. When ligated to the murine c-fos promoter, however, the proIL-1j3 enhancer was inducible in phorbol myristate acetate-stimulated HeLa cells, suggesting the existence of a proIL-1,3 promoter-proximal requirement for tissue specificity.Interleukin 11 (IL-113), a 17-kDa cytokine involved in inflammatory and immunological processes, is produced by activated monocytes/macrophages, fibroblasts, endothelial cells, and other cell types. The IL-1 proteins are translated as larger 31-kDa precursors (proIL-1) which are extracellularly processed into smaller 17-kDa forms (mature IL-1) (4, 20). There are two proIL-1 genes (proIL-lco and proIL-113) coding for distinct proteins which are observed in many different species (7, 18). The two proIL-1 genes are located on human chromosome 2 (11, 30, 48) and show a high conservation of exon/intron structure (7). IL-1 has a variety of biological activities on a wide range of tissues (see reference 13 for a review). For example, IL-1 induces the production of inflammatory mediators, proteolytic enzymes, and other cytokines that are involved in the joint destruction and inflammation of rheumatoid arthritis (29). IL-1 also modifies connective tissue and bone metabolism through the induction and type switch of collagen and the induction of bone resorption (21).The proIL-113 gene is normally not transcribed in competent cells until activated by stimuli such as lipopolysaccharide (LPS) or phorbol 12-myristate acetate (PMA) or by 17-kDa IL-11 protein (9,13,14 with LPS, IL-1P mRNA is rapidly and transiently transcribed in the absence of protein synthesis (15), suggesting the activation of preexisting transcription factors. Our previous studies revealed the importance of promoter sequences immediat...

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.

Objective. Tofacitinib (CP-690,550) is a novel JAK inhibitor that is currently in clinical trials for the treatment of rheumatoid arthritis (RA). The aim of this study was to examine the effects of tofacitinib in vitro and in vivo in RA, in order to elucidate the role of JAK in the disease process.Methods. CD4؉ T cells, CD14؉ monocytes, and synovial fibroblasts (SFs) were purified from the synovium and peripheral blood of patients with RA and were evaluated for the effect of tofacitinib on cytokine production and cell proliferation. For in vivo analysis, synovium and cartilage samples obtained from patients with RA were implanted in immunodeficient mice (SCID-HuRAg mice), and tofacitinib was administered via an osmotic minipump.Results. Tofacitinib treatment of CD4؉ T cells originating from synovium and peripheral blood inhibited the production of interleukin-17 (IL-17) and interferon-␥ (IFN␥) in a dose-dependent manner, affecting both proliferation and transcription, but had no effect on IL-6 and IL-8 production. Tofacitinib did not affect IL-6 and IL-8 production by RASFs and CD14؉ monocytes. However, conditioned medium from CD4؉ T cells cultured with tofacitinib inhibited IL-6 production by RASFs and IL-8 production by CD14؉ monocytes. Treatment of SCID-HuRAg mice with tofacitinib decreased serum levels of human IL-6 and IL-8 and markedly suppressed invasion of synovial tissue into cartilage. Conclusion. Tofacitinib directly suppressed the production of IL-17 and IFN␥ and the proliferation of CD4؉ T cells, resulting in inhibition of IL-6 production by RASFs and IL-8 production by CD14؉ cells and decreased cartilage destruction. In CD4؉ T cells, presumably Th1 and Th17 cells, JAK plays a crucial role in RA synovitis.

A site located between -2782 and -2729 of the human prointerleukin-1o (IL1B) The prointerleukin-1 (proIL-l1,) gene coding for the IL-1,P precursor protein (referred to here by its genomic locus name, IL1B) has been previously reported (10) to be rapidly and transiently transcribed in monocytes by lipopolysaccharide (LPS). The immediate-early transcription of this gene in the absence of protein synthesis (10) strongly supports a mechanism by which one or more preexisting transcription factors is activated. Such immediate activation is inconsistent with the involvement of AP-1 transcription factors, since unstimulated THP-1 monocytes lack the Jun proteins essential for AP-1 activity (38).We recently demonstrated (40)

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 pilot study provides sufficient evidence of excellent tolerability and high efficacy of rituximab therapy in refractory SLE. Rituximab not only reduced B-cell number and IgG levels but down-regulated CD40 and CD80 on B cells, suggesting possible disturbance of T-cell activation through these costimulatory molecules. Reduction of both quantity and quality of B cells suggests that rituximab could improve the disease course in patients with refractory SLE.