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Macrophage migration inhibitory factor (MIF) is recognized to be an important mediator in several inflammatory disorders, including rheumatoid arthritis (RA) and vasculitis. To evaluate the role of MIF in rheumatoid vasculitis (RV), we determined serum levels of MIF by enzyme-linked immunosorbent assay in RA patients with and without vasculitis and assessed their relationship to disease activity. Serum was obtained from 95 RA patients during active disease states [49 without vasculitis, 35 with extra-articular manifestations without histologically proven vasculitis, and 11 with histologically proven vasculitis] and from 22 healthy individuals. Vasculitis disease activity was assessed using the Birmingham Vasculitis Activity Score (BVAS). MIF levels were significantly higher in RA patients than in controls. Moreover, MIF levels were significantly higher in RA patients with vasculitis than in those without vasculitic complications. In all RA patients, a statistically significant positive correlation was observed between serum MIF levels and each of the following: serum levels of C-reactive protein, rheumatoid factor, and thrombomodulin; and the erythrocyte sedimentation rate. In the RV group, the elevation of MIF levels correlated with the BVAS. Our findings suggest that MIF may serve as an additional serologic inflammatory marker of disease activity in RV, and it may be implicated in the pathogenesis of RV.

Macrophage migration inhibitory factor (MIF) was originally identified in the culture medium of activated T lymphocytes as a soluble factor that inhibited the random migration of macrophages. MIF is now recognized to be a multipotent cytokine involved in the regulation of immune and inflammatory responses. Moreover, the pivotal nature of its involvement highlights the importance of MIF to the pathogenesis of various inflammatory disorders and suggests that blocking MIF may be a useful therapeutic strategy for treating these diseases. This paper discusses the function and expressional regulation of MIF in several rheumatic diseases and related conditions.

The clinical presentation of systemic vasculitis can vary widely and include skin disorders, neuropathy, eye symptoms, and systemic inflammation. The precise molecular mechanisms underlying this syndrome are not fully understood, but the importance of a chronic imbalance of the cytokines and chemokines involved in orchestrating inflammatory responses is now recognized. In similar fashion, atherosclerosis is now recognized to be a chronic inflammatory disease in which chemokines play important roles. In the current review, we discuss the involvement of CX3CL1, which is a unique member of the chemokine family, and its receptor, CX3CR1, in the pathogenesis of these vasculopathies.

Objectives We examined the factors that led to health assessment questionnaire (HAQ) remission after beginning biologics treatment in patients with rheumatoid arthritis (RA) Methods A total of 107 RA patients were assessed prior to treatment and 30 weeks after therapy initiation. The subjects were treated as follows: infliximab, 47 patients; etanercept, 17 patients; adalimumab, 25 patients; and tocilizumab, 18 patients. The age, gender, steroid dosage, methotrexate (MTX) dosage, disease activity (DAS28) score, health-related quality of life (HRQoL) questionnaire scores (modified health assessment questionnaire (mHAQ) and Short Form (SF)-36) and depression scale scores (Japanese version of the structured interview guide for the Hamilton Depression rating scale (HAM-D) and the Self-rating Depression Scale (SDS)) were assessed before initiating biologics treatment. HAQ remission was defined as a score less than 0.5 point after 30 weeks without evaluating clinical and structural remission. Results The HAQ remission group was characterized by younger age (57.8±14.8 vs. 66.8±13.2 years, p=0.005), lower steroid dosages (3.3±3.3 vs. 5.1±3.2 mg per day, p=0.011), higher MTX dosages (8.3±4.0 vs. 6.7±3.7 mg per week, p=0.028) and lower DAS28 scores (4.7±1.3 vs. 5.3±1.4) compared with the no-HAQ-remission group before treatment. In addition, the group had lower HAQ scores (0.32±0.36 vs. 1.1±0.36, p Conclusions Younger age, lower steroid dosages, higher QOL scores and lower depression scores are the important factors for HAQ remission with RA patients who undergo biologics treatment. Disclosure of Interest None Declared

Background Chemokines are key mediators of the pathogenesis of rheumatoid arthritis (RA). Because tocilizumab,a humanized monoclonal antibody that is specific for the IL-6 receptor,induces rapid clinical improvement in RA patients, the clinical and serum factors that are correlated with the responsiveness to tocilizumab should be determined. Objectives To examine the relationship between serum chemokine levels and clinical responsiveness to tocilizumab in patients with RA and to investigate the impact of tocilizumab administration on serum chemokine levels Methods The disease status of 21 RA patientswas assessed at baseline and after 12 weeks of tocilizumab administration (8 mg/kg) using the clinical disease activity index (CDAI) and the disease activity score 28 (DAS28). The minor, moderate and major responses to tocilizumabwere defined as an improvement of greater than 50%, 70% and 85%, respectively, from the baseline CDAI, which is consistent with the improvement criteria proposed by Aletaha and Smolen et al. 1 Serum levels of the following chemokines at baseline and after 12 weeks were quantified using double ligand enzyme-linked immunosorbent assays: CCL2, CCL3, CXCL8, CXCL10, CX3CL1 and macrophage migration inhibitory factor (MIF). Results At the initiation of therapy, the mean age of the patients was 56.1 yrs, the mean disease duration was 11.8 yrs, and the mean baseline CDAI was 22.4. After 12 weeks of tocilizumab administration, 14 patients achieved a greater than 50% improvement (referred to as the responder group), but there were no significant responses in the other 7 patients (the nonresponder group). No significant differences were found for disease activity (CDAI and DAS28), serum C-reactive protein levels, prior use of TNF antagonists between the groups. Although serum baseline levels of CCL2 and CXCL8 were higher in the responder group than in the nonresponder group, there were no significant changes in these chemokine levels after tocilizumab administration. In addition, the serum MIF levels at baseline were higher in the responder group than in the nonresponder group, although this difference was not statistically significant. Furthermore, the serum MIF levels in the responsive group, but not in the nonresponder group, were significantly decreased after tocilizumab administration (2225.8±1527.0 to 1038.7±981.4 pg/ml at week 12, p Conclusions In this study, we found that tocilizumab had no significant effect on serum chemokine levels, excluding MIF levels, which were affected by TNF antagonists 2 . These results may support the hypothesis that the production of proinflammatory cytokines, and chemokines depends on TNF-α stimulation; however, only MIF may be dominantly regulated by the IL-6/IL-6 receptor system and may have a crucial role in the pathogenesis of RA. References Aletaha D, et al. Arthritis Rheum 2011;63:S2226. Kasama T, et al. J Clin Rheumatol Musculoskel Med 2010;1:19. Disclosure of Interest None Declared

Introduction: CX3CL1 (fractalkine), a membrane-bound chemokine that induces both the adhesion and migration of leukocytes, is involved in the recruitment of cells into tissues undergoing inflammatory responses. To explore the regulation of CX3CL1 in pulmonary inflammation and fibrosis, CX3CL1 expression of by lung fibroblast was examined. Methods: Normal human lung fibroblasts were obtained from Promocell were incubated in the presence or absence of various inflammatory stimuli. Culture supernatants were collected, and soluble CX3CL1 levels were determined with an enzyme-linked immunosorbent assay. Expression of CX3CL1 mRNA transcripts in lung fibroblast was examined using quantitative TaqMan real-time polymerase chain reaction. Results: Interleukine (IL)-1β or interferon (IFN)-γ alone induced negligible soluble CX3CL1 secretion by human lung fibroblasts after 24 h. However, the combination of IL-1β and IFN-γ induced dramatic increases in both soluble CX3CL1 protein and mRNA transcripts in dose- and time-dependent manners. The secretion and expression of lung fibroblast-derived CX3CL1 were markedly reduced by specific inhibitors of the STAT-1 transcription factor. Conclusions: These findings suggest that lung fibroblasts are an important cellular source of CX3CL1, and may play roles in pulmonary inflammation and fibrosis like interstitial pneumonia which merges to rheumatoid arthritis and other autoimmune diseases.

Introduction CX3CL1 (fractalkine), a membrane-bound chemokine that induces both the adhesion and migration of leukocytes, is involved in the recruitment of cells to tissues undergoing inflammatory responses. To explore the regulation of CX3CL1 in inflammatory bone diseases, we examined CX3CL1 expression in osteoblasts. Methods Human osteoblasts isolated from the femora of rheumatoid arthritis patients were incubated in the presence or absence of various inflammatory stimuli. Culture supernatants were collected, and soluble CX3CL1 levels were determined with an enzyme-linked immunosorbent assay (ELISA). The expression of CX3CL1 mRNA transcripts in osteoblasts was examined using the quantitative TaqMan real-time polymerase chain reaction. Results The combination of tumor necrosis factor (TNF)-α and interferon (IFN)-γ induced dramatic increases in levels of both soluble CX3CL1 protein and mRNA transcripts. CX3CL1 expression in osteoblasts was decreased by the addition of interleukin(IL)-4 or IL-17 but was increased when stimulation by IFN-γ and IL-17 was supplemented with IL-1β In addition, expression was decreased when TNF-α was added. Conclusions Multiple cytokines, including IL-17, are able to either increase or decrease the expression of CX3CL1 by human osteoblasts.

Objective: To better understand the effects of simvastatin (SS) on the expression and secretion of two chemokines, CXCL10 and CX3CL1, by osteoblasts, and to test whether inhibition of isoprenoid intermediates of cholesterol biosynthesis were involved in the effects of SS. Methods: Human osteoblasts were incubated in the presence or absence of the inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ), with and without SS (0.1–100 µM). Culture supernatants were then collected, and expression of CXCL10 and CX3CL1 mRNA in osteoblasts was examined using quantitative TaqMan real-time polymerase chain reaction. The levels of CXCL10 and CX3CL1 were measured using enzyme-linked immunosorbent assays. Results: At a high concentration (100 µM), SS inhibited expression and secretion of the chemokines and showed cytotoxity, whereas at lower concentrations (0.1–1 µM) SS stimulated the expression and secretion of the chemokines. Expression and secretion of CXCL10 or CX3CL1 from osteoblasts were induced by stimulation with TNF-α and IFN-γ. In addition, SS exerted a biphasic effect on the evoked induction of CXCL10 and CX3CL1. Chemokine expression and secretion was also assayed in the presence of mevalonate (MEV), geranylgeranyl pyrophosphate (GGPP) or farnesyl pyrophosphate (FPP). MEV abolished both the inhibitory effect of high-dose SS and the stimulatory effect of low-dose SS. On the other hand, GGPP abolished only the inhibitory effects of high-dose SS, and FPP had no effect at all. Conclusions: These findings suggest that osteoblasts are an important cellular source of CXCL10 and CX3CL1, and that statins such as SS may modulate the inflammatory process in bone tissues to inhibit bone resorption and stimulate bone formation through biphasic modulation chemokine synthesis.