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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.

CX3CL1 (fractalkine), a membrane-bound chemokine that induces both the adhesion and the 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 in lung fibroblasts was examined. Normal human fibroblasts were obtained from Promocell (Lonza Walkersville Inc, Md) and were incubated in the presence or absence of various inflammatory stimuli. Culture supernatants were collected, and the soluble CX3CL1 levels were determined with an enzyme-linked immunosorbent assay. The expression of CX3CL1 mRNA transcripts in lung fibroblasts was assessed using quantitative TaqMan real-time polymerase chain reaction. Interleukin (IL)-1β or interferon (IFN)-γ individually 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 a dose- and time-dependent manner. Synergistic up-regulation of cell-associated CX3CL1 protein also was observed after treatment with IL-1β and IFN-γ. The secretion and expression of lung fibroblast-derived CX3CL1 were markedly reduced by specific inhibitors of the STAT-1 transcription factor. These findings suggest that lung fibroblasts are an important cellular source of CX3CL1 and may play a role in pulmonary inflammation and fibrosis.

We report a case of a 67-year-old woman with rheumatoid arthritis with yellow nail syndrome (YNS) that was caused by bucillamine. All three signs (yellow fingernails, lymphatic edema, and bronchiectasis) of YNS manifested, with characteristic timing, first with the nails turning yellow after when bronchiectasis was noticed. We reviewed 10 case reports from Japan and compared the periods until the appearance of yellow nails after starting bucillamine treatment, as well as those until lung disease and leg edema appeared.

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.

Depression in rheumatoid arthritis (RA) patients is more severe than in healthy people. Herein, we report improved depression in RA patients using biologic agents. We examined whether depression was improved by tacrolimus combination therapy when biologic agents were ineffective.The study included 13 RA patients who used biologic agents. The following methods were used before the initiation of tacrolimus combination therapy and at 14 and 30 weeks after treatment initiation: the Zung self-rating depression scale (SDS) to evaluate depression state, disease activity score 28/erythrocyte sedimentation rate (DAS28), tender joint counts, swollen joint counts, a patient global assessment to evaluate RA disease activity, and the modified health assessment questionnaire (mHAQ) to evaluate quality of life.The SDS scores before the initiation of tacrolimus combination therapy and at 14 and 30 weeks after treatment initiation were 45.2 ± 10.6, 44.8 ± 12.8, and 41.6 ± 11.2 (p = 0.047), respectively, indicating significant improvement. The DAS28 was 5.0 ± 1.3 prior to treatment, 3.8 ± 1.3 at 14 weeks, and 3.5 ± 0.9 at 30 weeks, demonstrating significant improvement at both 14 and 30 weeks (p 0.001). The mHAQ score changed from 0.60 ± 0.45 at baseline to 0.54 ± 0.52 and 0.38 ± 0.43 at 14 and 30 weeks, respectively. The mHAQ score was significantly lower at 30 weeks when compared to baseline (p = 0.013).Tacrolimus combination therapy does not directly improve depression in RA patients, but it is possible that the observed improvement in depression accompanies the improvement in the secondary failure of RA.

Michihito Sato, Kumiko Ohtsuka, Ryo Takahashi, Kuninobu Wakabayashi, Tsuyoshi Odai, Takeo Isozaki, Nobuyuki Yajima, Yusuke Miwa, Tsuyoshi KasamaDivision of Rheumatology, Department of Medicine, Showa University School of Medicine, Tokyo, JapanObjective: To examine the relationship between serum chemokine levels and patient responsiveness in rheumatoid arthritis (RA) patients to etanercept (ETN) and the influence of ETN administration on serum chemokine levels.Methods: Serum levels of the chemokines CX3CL1, CXCL8, CXCL10, and CCL3 were quantified prior to (at baseline) and after 14 weeks of treatment with ETN in 20 patients using enzyme-linked immunosorbent assay. Disease status was assessed using the Disease Activity Score (DAS28). The response to ETN was classified according to the European League Against Rheumatism (EULAR) response criteria.Results: By 14 weeks, ETN produced a significant overall reduction in DAS28 among the 20 patients with RA; eight patients achieved a good response, and 10 patients achieved a moderate response based on EULAR response criteria. A significant reduction in CX3CL1 was observed in the responsive group, although ETN treatment had no significant effect on the serum levels of the other three chemokines. In addition, the messenger ribonucleic acid expression of CX3CR1 in peripheral blood mononuclear cells and the cell-surface expression of CX3CR1 protein in peripheral blood CD8+CD3+ T cells were both decreased after ETN treatment.Conclusions: Our results suggest that the CX3CL1 and CX3CR1 in patients with active RA may be sensitive to antitumor necrosis factor-α therapy and confirm that CX3CL1/CX3CR1 axis plays a crucial role in the pathogenesis of RA.Keywords: rheumatoid arthritis, chemokine, CX3CL1, CX3CR1, TNF antagonist, etanercept

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

Takeo Isozaki, Michihito Sato, Ryo Takahashi, Kuninobu Wakabayashi, Nobuyuki Yajima, Yusuke Miwa, Masao Negishi, Hirotsugu Ide, Tsuyoshi KasamaDivision of Rheumatology, Department of Medicine, Showa University School of Medicine, Tokyo, JapanAbstract: The aim of the present clinical trial was to determine the efficacy and safety of low-dose administration of tacrolimus in combination with methotrexate (MTX) in rheumatoid arthritis (RA) patients with an insufficient clinical response to MTX alone. Eleven patients with active RA, despite treatment with MTX, were enrolled and given tacrolimus in combination with MTX for 24 weeks. The primary endpoint was the assessment of clinical improvement using the European League against Rheumatism criteria. Administration of ­tacrolimus to RA patients with an insufficient response to MTX produced significant improvement in the Disease Activity Score 28 after 8–24 weeks. In addition, after 24 weeks, 50% and 25% of patients had achieved moderate and good responses, respectively, and there were ­significant reductions in the Modified Health Assessment Questionnaire, the rheumatoid ­factor and serum matrix metalloproteinase-3 levels. The present preliminary study suggests that low-dose tacrolimus in combination with MTX is well tolerated and provides both clinical and economic benefits.Keywords: rheumatoid arthritis, methotrexate, tacrolimus, DAS28, mHAQ

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.

Hirohito Kanemitsu, Mizuho Matsunawa, Kuninobu Wakabayashi, Michihito Sato, Ryo Takahashi, Tsuyoshi Odai, Takeo Isozaki, Nobuyuki Yajima, Yusuke Miwa, Tsuyoshi KasamaDivision of Rheumatology, Department of Medicine, Showa University School of Medicine, Tokyo, JapanObjective: To test the hypothesis that macrophage migration inhibitory factor (MIF) is involved in the disease activity of systemic vasculitis.Methods: Patients with systemic vasculitis were divided into three groups based on the size of the affected vessels. Microscopic polyangiitis (MPA) was considered as small vessel vasculitis (SVV), polyarteritis nodosa as medium-sized vessel vasculitis (MVV), and giant cell arteritis and Takayasu arteritis as large vessel vasculitis (LVV). Sera from patients with systemic vasculitis and healthy individuals were collected, and MIF levels were measured using an enzyme-linked immunosorbent assay. Disease activity of vasculitis was assessed using the Birmingham Vasculitis Activity Score (BVAS).Results: Serum MIF levels were significantly higher in the vasculitis patients than in healthy individuals. Among the vasculitis patients, MIF levels were significantly higher in patients in the SVV group (median; 4161.7 pg/ml) than in the other groups (MVV; 1443.2 pg/ml and LVV; 1576.7 pg/ml). In patients with MPA, a positive correlation was observed between serum MIF levels and CRP levels and disease activity (BVAS). Notably, serum MIF levels were significantly diminished after clinical improvement.Conclusions: Our findings suggest that MIF may have an important role in small vessel vasculopathy and serve as a useful serologic marker of MPA disease activity.Keywords: macrophage migration inhibitory factor, systemic vasculitis, microscopic polyangiitis, cytokine