Relationship between falls and the use of hypnotics, antidepressants, antipsychotics, and anxiolytics in patients with rheumatoid arthritis: A cross-sectional study.

Objectives This cross-sectional study aimed to determine the relationship between falls and use of psychotropic medications in patients with rheumatoid arthritis. Methods The psychotropic medication group included patients with rheumatoid arthritis prescribed psychotropic medications (hypnotics/sedatives, antidepressants, antipsychotics, and anxiolytic [benzodiazepines] drugs). Poisson regression with robust variance was performed to investigate the relationship between falls and the use of psychotropic medications, with adjustment for age, sex, rheumatoid arthritis disease activity, stroke, dementia, diabetes mellitus, and osteoarthritis. Results Of the 307 patients enrolled, 49 (16.0%) used psychotropic medications, and 70 (22.8%) experienced at least one fall per year. Nineteen of the 49 patients (38.8%) taking psychotropic medications and 51 of 258 (19.8%) not taking psychotropic medications experienced at least one fall per year. Falls were significantly more frequent in the group with psychotropic medications than in the group without psychotropic medications (adjusted incidence rate ratio, 1.63; 95% confidence interval; 1.08-2.48, p = 0.02). No relationship was found between the number of falls and the use of psychotropic medications (adjusted incidence rate ratio, 1.16; 95% confidence interval; 0.39-3.44, p = 0.78). Conclusions There may be a relationship between psychotropic medication use and falls in patients with rheumatoid arthritis.

Mammalian Glycosylation Patterns Protect Citrullinated Chemokine MCP-1/CCL2 from Partial Degradation.

Monocyte chemoattractant protein-1 (MCP-1/CCL2) is a potent chemotactic agent for monocytes, primarily produced by macrophages and endothelial cells. Significantly elevated levels of MCP-1/CCL2 were found in synovial fluids of patients with rheumatoid arthritis (RA), compared to osteoarthritis or other arthritis patients. Several studies suggested an important role for MCP-1 in the massive inflammation at the damaged joint, in part due to its chemotactic and angiogenic effects. It is a known fact that the post-translational modifications (PTMs) of proteins have a significant impact on their properties. In mammals, arginine residues within proteins can be converted into citrulline by peptidylarginine deiminase (PAD) enzymes. Anti-citrullinated protein antibodies (ACPA), recognizing these PTMs, have become a hallmark for rheumatoid arthritis (RA) and other autoimmune diseases and are important in diagnostics and prognosis. In previous studies, we found that citrullination converts the neutrophil attracting chemokine neutrophil-activating peptide 78 (ENA-78) into a potent macrophage chemoattractant. Here we report that both commercially available and recombinant bacterially produced MCP-1/CCL2 are rapidly (partially) degraded upon in vitro citrullination. However, properly glycosylated MCP-1/CCL2 produced by mammalian cells is protected against degradation during efficient citrullination. Site-directed mutagenesis of the potential glycosylation site at the asparagine-14 residue within human MCP-1 revealed lower expression levels in mammalian expression systems. The glycosylation-mediated recombinant chemokine stabilization allows the production of citrullinated MCP-1/CCL2, which can be effectively used to calibrate crucial assays, such as modified ELISAs.

Effectiveness and safety of subcutaneous abatacept in biologic-naïve RA patients at Week 52: A Japanese multicentre investigational study (ORIGAMI study).

OBJECTIVES: To evaluate the effectiveness and safety of abatacept over 52 weeks in biologic-naïve rheumatoid arthritis (RA) patients with moderate disease activity in the prospective, 5-year, observational study (ORIGAMI study) in Japan. METHODS: Abatacept (125 mg) was administered subcutaneously once a week. Clinical outcomes included Simplified Disease Activity Index (SDAI) remission at Week 52 (primary endpoint), Japanese Health Assessment Questionnaire (J-HAQ), EuroQol 5-Dimension Questionnaire (EQ-5D), treatment retention, and safety. The results were compared with those of conventional synthetic disease-modifying antirheumatic drug (csDMARD) controls from the ongoing Institute of Rheumatology, Rheumatoid Arthritis (IORRA) registry. RESULTS: Overall, 325 patients were enrolled, with a mean age of 66.9 ± 12.7 years. The proportion of patients achieving SDAI remission (≤3.3) at Week 52 was 18.9% (95% CI: 14.3-23.6) and low disease activity (≤11) was 53.3% (95% CI: 47.4-59.1). A significant improvement was observed in J-HAQ and EQ-5D over 52 weeks in both the abatacept and csDMARD groups. The probability of abatacept treatment retention at Week 52 was 69.9% (95% CI: 64.7-75.5). Adverse events and serious adverse events were reported in 50.0% and 12.1% of patients, respectively. CONCLUSIONS: Abatacept significantly improved disease activity, physical disability, and quality of life for up to 52 weeks in RA patients in a real-world setting.

Eotaxin-1/CCL11 is involved in cell migration in rheumatoid arthritis.

Eotaxin-1 (CCL11) induces the migration of different leukocyte types by interacting with CCR3. In rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) are pathogenic effectors and a major CCR3-expressing cell. The aim of this study was to investigate the expression and function of CCL11 in RA FLS. The expression of CCL11 and CCR3 was evaluated by ELISA, immunofluorescence and quantitative PCR analysis. The CCL11 levels in serum and synovial fluids (SFs) from RA patients were significantly higher than those in serum from healthy controls and SFs from osteoarthritis patients. CCL11 and CCR3 were expressed in the RA synovial tissue lining layers. The secretion of CCL11 in RA FLS-conditioned medium and the mRNA expression of CCL11 and CCR3 were induced by TNF-α. Furthermore, CCL11 induced the mRNA expression of CCL11 and CCR3. Application of a CCR3 antagonist reduced TNF-α-induced CCL11 secretion from RA FLS. CCL11 induced the migration of RA FLS and monocytes. RA FLS migration was decreased by treatment with CCL11 siRNA. The migration of monocytes to medium conditioned with CCL11 siRNA-transfected and TNF-α-stimulated RA FLS was reduced. These data indicate that the self-amplification of CCL11 via CCR3 may play an important role in cell migration in RA.

Inhibition of hepatocyte growth factor/c-Met signalling abrogates joint destruction by suppressing monocyte migration in rheumatoid arthritis.

OBJECTIVES: To determine the expression of hepatocyte growth factor (HGF) in RA biological fluids, the role of HGF in monocyte migration and the therapeutic effect of the c-Met inhibitor savolitinib in an arthritis model mice. METHODS: HGF/c-Met expression in serum, SF and synovial tissues (STs) obtained from RA patients and controls, as well as RA fibroblast-like synoviocytes (FLSs), was evaluated by ELISA and immunostaining. To determine the function of HGF in RA SF, we preincubated RA SF with a neutralizing anti-HGF antibody and measured the chemotactic ability of a human acute monocytic leukaemia cell line (THP-1). Additionally, examinations were conducted of SKG mice treated with savolitinib for 4 weeks. RESULTS: HGF levels in serum from RA patients were significantly higher than those in the controls and were decreased by drug treatment for 24 weeks. Additionally, the HGF level in SF from RA patients was higher than that in SF from OA patients. HGF and c-Met expression was also noted in RA STs. Stimulation of RA FLSs with TNF-α increased HGF/c-Met expression in a concentration-dependent manner, and c-Met signal inhibition suppressed production of fractalkine/CX3CL1 and macrophage inflammatory protein-1α/CCL3. When HGF was removed by immunoprecipitation, migration of THP-1 in RA SF was suppressed. In SKG mice, savolitinib significantly suppressed ankle bone destruction on µCT, with an associated reduction in the number of tartrate-resistant acid phosphatase-positive osteoclasts. CONCLUSION: HGF produced by inflammation in synovium of RA patients activates monocyte migration to synovium and promotes bone destruction via a chemotactic effect and enhanced chemokine production.

Role of Cytokines in EGPA and the Possibility of Treatment with an Anti-IL-5 Antibody.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a type of systemic vasculitis with eosinophilia in the peripheral blood, which is preceded by bronchial asthma or allergic disease. EGPA is pathologically characterized by microangiopathy granulomatosis vasculitis. Vasculitis can be exacerbated and cause central nervous system and cardiovascular disorders and gastrointestinal perforation. Histological examination reveals eosinophil infiltration and granulomas in lesions in areas such as the lung, nervous system, and skin. Laboratory tests show inflammatory findings such as C-reactive protein (CRP) elevation, increased eosinophils, elevated serum IgE, and elevated myeloperoxidase-anti-neutrophil cytoplasmic antibodies (MPO-ANCA). MPO-ANCA is positive in approximately 40-70% of cases of this disease. EGPA is a necrotizing vasculitis that affects small- and medium-sized blood vessels; however, it differs from other types of ANCA-related vasculitis (such as microscopic polyangiitis and granulomatosis) because it is preceded by bronchial asthma and eosinophilia in the blood and tissues. Treatment with immunosuppressive agents such as steroids or cyclophosphamide depends on the Five Factor Score, which predicts the prognosis and severity of the condition. If the effect of appropriate treatment with steroids is insufficient, the anti-interleukin-5 antibody mepolizumab can be administered. The combination of mepolizumab with standard treatment leads to a significantly longer duration of remission, a higher proportion of patients who achieve sustained remission, and less steroid use than with a placebo.

Peficitinib Inhibits the Chemotactic Activity of Monocytes via Proinflammatory Cytokine Production in Rheumatoid Arthritis Fibroblast-Like Synoviocytes.

Background: This study was performed to examine the effects of the Janus kinase (JAK) inhibitor peficitinib on fibroblast-like synoviocytes (FLS) obtained from patients with rheumatoid arthritis (RA). Methods: To examine the expression of JAK1, JAK2, and JAK3 in RA synovial tissue (ST) and FLS, immunohistochemistry was performed. We investigated the effects of peficitinib on interleukin 6 and IL-6 receptor responses in RA FLS. Phosphorylation of STAT was determined by western blot. To examine the functional analysis of peficitinib, we performed a proliferation and chemotaxis assays with FLS using THP-1 and peripheral blood mononuclear cells (PBMC). The inflammatory mediator expression of FLS was estimated by enzyme-linked immunosorbent assay. Results: JAK1, JAK2, and JAK3 were expressed in RA STs and FLS. Phosphorylation of STAT1, STAT3, and STAT5 in RA FLS was suppressed by peficitinib in a concentration-dependent manner. Peficitinib-treated RA FLS-conditioned medium reduced THP-1 and PBMC migration (p < 0.05) and proliferation of RA FLS (p < 0.05). Peficitinib suppressed the secretion of MCP-1/CCL2 in the RA FLS supernatant (p < 0.05). Conclusion: Peficitinib suppressed the JAK-STAT pathway in RA FLS and also suppressed monocyte chemotaxis and proliferation of FLS through inhibition of inflammatory cytokines.

Citrullinated Inhibitor of DNA Binding 1 Is a Novel Autoantigen in Rheumatoid Arthritis.

OBJECTIVE: To explore the intrinsic role of inhibitor of DNA binding 1 (ID-1) in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) and to investigate whether ID-1 is citrullinated and autoantigenic in RA. METHODS: RA patient serum ID-1 levels were measured before and after infliximab treatment. RA FLS were transfected with a clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 construct targeting ID-1 to examine the effects of ID-1 deletion. RA synovial fluid (SF) and homogenized synovial tissue (ST) were immunoprecipitated for ID-1 and measured for citrullinated residues using an enzyme-linked immunosorbent assay and Western blotting. Liquid chromatography tandem mass spectrometry (LC-MS/MS) was performed on in vitro-citrullinated recombinant human ID-1 (cit-ID-1) to localize the sites of citrullination. Normal and RA sera and SF were analyzed by immunodot blotting for anti-citrullinated protein antibodies (ACPAs) to cit-ID-1. RESULTS: RA patient serum ID-1 levels positively correlated with several disease parameters and were reduced after infliximab treatment. RA FLS displayed reduced growth and a robust increase in interleukin-6 (IL-6) and IL-8 production upon deletion of ID-1. ID-1 immunodepletion significantly reduced the levels of citrullinated residues in RA SF, and citrullinated ID-1 was detected in homogenized RA ST (n = 5 samples; P < 0.05). Immunodot blot analyses revealed ACPAs to cit-ID-1 but not to native ID-1, in RA peripheral blood (PB) sera (n = 30 samples; P < 0.001) and SF (n = 18 samples; P < 0.05) but not in normal PB sera. Following analyses of LC-MS/MS results for citrullination sites and corresponding reactivity in immunodot assays, we determined the critical arginines in ID-1 for autoantigenicity: R33, R52, and R121. CONCLUSION: Novel roles of ID-1 in RA include regulation of FLS proliferation and cytokine secretion as well as autoantigenicity following citrullination.

A Disintegrin and Metalloprotease 15 is Expressed on Rheumatoid Arthritis Synovial Tissue Endothelial Cells and may Mediate Angiogenesis.

A disintegrin and metalloprotease 15 (ADAM15) is involved in several malignancies. In this study, we investigated the role of ADAM15 in rheumatoid arthritis (RA) angiogenesis. Soluble ADAM15 (s-ADAM15) in serum from RA and normal (NL) subjects was measured using ELISA. To determine membrane-anchored ADAM15 (ADAM15) expression in RA synovial tissues, immunohistochemistry was performed. To examine the role of ADAM15 in angiogenesis, we performed in vitro Matrigel assays and monocyte adhesion assays using human umbilical vein endothelial cells (HUVECs) transfected with ADAM15 siRNA. Finally, to investigate whether angiogenic mediators were affected by ADAM15, cytokines in ADAM15 siRNA-transfected HUVEC-conditioned medium were measured. ADAM15 was significantly higher in RA serum than in NL serum. ADAM15 was also expressed on RAST endothelial cells. ADAM15 siRNA-treated HUVECs had decreased EC tube formation in response to RA synovial fluids compared with non-treated HUVECs. The adhesion index of ADAM15 siRNA-transfected HUVECs was significantly lower than the adhesion index of control siRNA-transfected HUVECs. ENA-78/CXCL5 and ICAM-1 were decreased in tumor necrosis factor (TNF)-α-stimulated ADAM15 siRNA-transfected HUVEC-conditioned medium compared with TNF-α-stimulated control siRNA-transfected HUVEC-conditioned medium. These data show that ADAM15 plays a role in RA angiogenesis, suggesting that ADAM15 might be a potential target in inflammatory diseases such as RA.

ADAM-17 is expressed on rheumatoid arthritis fibroblast-like synoviocytes and regulates proinflammatory mediator expression and monocyte adhesion.

BACKGROUND: To examine the expression of ADAM-17 in rheumatoid arthritis (RA) biological fluids and the role it plays in monocyte adhesion to RA fibroblast-like synoviocytes (FLSs). METHODS: ADAM-17 expression was measured by enzyme-linked immunosorbent assays (ELISAs) in serum from normal (NL) subjects, osteoarthritis (OA) patients, and RA patients. We also analyzed the correlation between ADAM-17 and disease activity score 28 (DAS28) in RA. To determine expression of ADAM-17 in RA synovial tissues (STs) and RA FLS, we performed immunofluorescence analyses. To determine the role of ADAM-17 in RA, we transfected RA FLSs with small interfering RNA (siRNA) against ADAM-17. THP-1 adhesion to ADAM-17 siRNA-transfected RA FLSs was measured. Finally, adhesion molecules on ADAM-17 siRNA-transfected RA FLSs were measured using cell surface ELISAs. RESULTS: ADAM-17 in RA serum was significantly higher than that in NL and OA serum and correlated with DAS28. ADAM-17 in RA synovial fluids was higher than that in OA synovial fluids. ADAM-17 was expressed on RA cells lining STs and RA FLSs. THP-1 adhesion to ADAM-17 siRNA-transfected RA FLSs was decreased compared with that to control siRNA-transfected RA FLSs. ICAM-1 on TNF-α-stimulated ADAM-17 siRNA-transfected RA FLSs was significantly decreased compared with that on control siRNA-transfected RA FLSs. CONCLUSIONS: These data indicate that ADAM-17 is expressed on RA STs and plays a role in RA inflammation by regulating monocyte adhesion to RA FLSs. ADAM-17 might be an important inflammatory mediator in inflammatory diseases such as RA.

Correction to: ADAM-17 is expressed in the inflammatory myopathy and is involved with interstitial lung disease.

The original version of this article, unfortunately, contained errors. Figure citation, caption, image and updated sentence in the Result section are now presented correctly in this article.

A unique role for galectin-9 in angiogenesis and inflammatory arthritis.

BACKGROUND: Galectin-9 (Gal-9) is a mammalian lectin secreted by endothelial cells that is highly expressed in rheumatoid arthritis synovial tissues and synovial fluid. Roles have been proposed for galectins in the regulation of inflammation and angiogenesis. Therefore, we examined the contribution of Gal-9 to angiogenesis and inflammation in arthritis. METHODS: To determine the role of Gal-9 in angiogenesis, we performed human dermal microvascular endothelial cell (HMVEC) chemotaxis, Matrigel tube formation, and mouse Matrigel plug angiogenesis assays. We also examined the role of signaling molecules in Gal-9-induced angiogenesis by using signaling inhibitors and small interfering RNA (siRNA). We performed monocyte (MN) migration assays in a modified Boyden chamber and assessed the arthritogenicity of Gal-9 by injecting Gal-9 into mouse knees. RESULTS: Gal-9 significantly increased HMVEC migration, which was decreased by inhibitors of extracellular signal-regulating kinases 1/2 (Erk1/2), p38, Janus kinase (Jnk), and phosphatidylinositol 3-kinase. Gal-9 HMVEC-induced tube formation was reduced by Erk1/2, p38, and Jnk inhibitors, and this was confirmed by siRNA knockdown. In mouse Matrigel plug assays, plugs containing Gal-9 induced significantly higher angiogenesis, which was attenuated by a Jnk inhibitor. Gal-9 also induced MN migration, and there was a marked increase in MN ingress when C57BL/6 mouse knees were injected with Gal-9 compared with the control, pointing to a proinflammatory role for Gal-9. CONCLUSIONS: Gal-9 mediates angiogenesis, increases MN migration in vitro, and induces acute inflammatory arthritis in mice, suggesting a novel role for Gal-9 in angiogenesis, joint inflammation, and possibly other inflammatory diseases.

ADAM-17 is expressed in the inflammatory myopathy and is involved with interstitial lung disease.

The "A disintegrin and metalloprotease" (ADAM) family is thought to play an important role in tissue destruction and inflammatory reactions. ADAM-17 was first described as the protease responsible for tumor necrosis factor (TNF)-α shedding. Here, we have shown the expression of ADAM-17 in inflammatory myopathy and demonstrated the role of inflammation in interstitial lung diseases (ILD). ADAM-17 in inflammatory myopathy serum [polymyositis (n = 26), dermatomyositis (n = 34), and clinically amyopathic dermatomyositis (n = 10)] and healthy control (n = 19) was measured using enzyme-linked immunosorbent assay. The relationship between ADAM-17 and clinical data was examined. Finally, we performed immunohistological analysis to investigate the expression of ADAM-17 on the muscles of the inflammatory myopathy patients. ADAM-17 in inflammatory myopathy was significantly higher than that in healthy control (mean ± SEM, 1048 ± 312 and 36 ± 18 pg/ml, respectively; p < 0.05). ADAM-17 in post-treatment with corticosteroid and/or immunosuppressant serum was significantly decreased compared with that in pre-treatment serum (1465 ± 562 and 1059 ± 503 pg/ml, respectively; p < 0.01). ADAM-17 was significantly positively correlated with fractalkine/CX3CL1 and CXCL16. In addition, ADAM-17 in inflammatory myopathy with ILD patients (n = 46) was significantly higher than that in non-ILD patients (n = 24) (1379 ± 454 and 413 ± 226 pg/ml, respectively; p < 0.05). We found the expression of ADAM-17 on muscle biopsy tissue. ADAM-17 is expressed in inflammatory myopathies especially ILD, suggesting that ADAM-17 plays a role in lung fibrosis. ADAM-17 may be a potential target in inflammatory myopathies with ILD.

A disintegrin and metalloproteinase (ADAM)-10 as a predictive factor for tocilizumab effectiveness in rheumatoid arthritis.

OBJECTIVES: A disintegrin and metalloproteinase (ADAM)-10 is expressed in rheumatoid arthritis (RA). In this study, we focused on ADAM-10 as a predictive factor for the treatment with biologics in RA. METHODS: The levels of ADAM-10 and fractalkine/CX3CL1 in RA and healthy controls serum were measured using enzyme-linked immunosorbent assays. Fifteen patients were treated with adalimumab (ADA), and 20 patients were treated with tocilizumab (TCZ). RESULTS: ADAM-10 positively correlated with fractalkine/CX3CL1 in the sera of RA patients and was presented at a significantly higher level compared to that in normal serum (487 ± 80 pg/ml and 85 ± 33 pg/ml, respectively, p < 0.05). ADAM-10 highly correlates with fractalkine/CX3CL1 in the sera of RA patients. The level of ADAM-10 decreased after the treatment with TCZ but not with ADA. In addition, we found that the level of ADAM-10 in TCZ responders was significantly higher than that of the TCZ nonresponders at 24 weeks (619 ± 134 pg/ml and 109 ± 25 pg/ml, respectively). Multiple regression analysis showed that ADAM-10 was only identified as independent predictive variable for the improvement of DAS28 (ESR) at 24 weeks. CONCLUSIONS: ADAM-10 may be a predictor of the effectiveness of TCZ in treating RA.

Inflammatory properties of inhibitor of DNA binding 1 secreted by synovial fibroblasts in rheumatoid arthritis.

BACKGROUND: Inhibitor of DNA binding 1 (Id1) is a nuclear protein containing a basic helix-loop-helix (bHLH) domain that regulates cell growth by selective binding and prevention of gene transcription. Sources of Id1 production in rheumatoid arthritis synovial tissue (RA ST) and its range of functional effects in RA remain to be clarified. METHODS: We analyzed Id1 produced from synovial fibroblasts and endothelial cells (ECs) with histology and real-time polymerase chain reaction (RT-PCR). Fibroblast supernatants subjected to differential centrifugation to isolate and purify exosomes were measured for Id1 by enzyme-linked immunosorbent assay (ELISA). Western blotting of Id1-stimulated ECs was performed to determine the kinetics of intracellular protein phosphorylation. EC intracellular signaling pathways induced by Id1 were subsequently targeted with silencing RNA (siRNA) for angiogenesis inhibition. RESULTS: By PCR and histologic analysis, we found that the primary source of Id1 in STs is from activated fibroblasts that correlate with inflammatory scores in human RA ST and in joints from K/BxN serum-induced mice. Normal (NL) and RA synovial fibroblasts increase Id1 production with stimulation by transforming growth factor beta (TGF-ß). Most of the Id1 released by RA synovial fibroblasts is contained within exosomes. Endothelial progenitor cells (EPCs) and human dermal microvascular ECs (HMVECs) activate the Jnk signaling pathway in response to Id1, and Jnk siRNA reverses Id1-induced HMVEC vessel formation in Matrigel plugs in vivo. CONCLUSIONS: Id1 is a pleotropic molecule affecting angiogenesis, vasculogenesis, and fibrosis. Our data shows that Id1 is not only an important nuclear protein, but also can be released from fibroblasts via exosomes. The ability of extracellular Id1 to activate signaling pathways expands the role of Id1 in the orchestration of tissue inflammation.

Clinical effects of tocilizumab on cytokines and immunological factors in patients with rheumatoid arthritis.

Interleukin (IL)-6 is one of the crucial proinflammatory cytokines. The dysregulation of IL-6 plays a pivotal role in rheumatoid arthritis (RA) and is involved in several of the common clinical manifestations associated with active RA. Recent therapies targeting IL-6 and tumor necrosis factor (TNF) have resulted in clinical improvements in signs and symptoms, disability and quality of life in patients with early and long-standing RA. Because it has been demonstrated that cytokines and inflammatory/immunological factors appear to be important and sensitive mediators in RA patients treated with tocilizumab and with anti-TNF biologics, it is important to investigate whether tocilizumab administration has any effect(s) on the profiles of cytokines and inflammatory/immunological factors and whether these changes correlate with the clinical improvement in RA disease activity. In this review, we discuss the effects on cytokine regulation and the differentiation of immune cells, especially T cells, after tocilizumab therapy in patients with RA.

Therapeutic Efficacy of Leukocytapheresis in a Pregnant Woman with Refractory Adult-onset Still's Disease.

This is the first report of the efficacy of leukocytapheresis (LCAP) in a patient with refractory adult onset Still's disease (AOSD) during pregnancy. A 32-year-old Chinese pregnant woman with AOSD who had been treated with prednisolone failed to achieve disease stabilization. The patient's disease was successfully controlled with the initiation of LCAP. Subsequently, she gave birth via Caesarean section to a 1,878 g baby boy at 34 weeks of gestation while maintaining remission. We conclude that LCAP is an alternative treatment in pregnant patients with refractory AOSD, particularly in those concerned about potential teratogenic and other adverse effects.

A disintegrin and metalloprotease-10 is correlated with disease activity and mediates monocyte migration and adhesion in rheumatoid arthritis.

A disintegrin and metalloproteases (ADAMs) are a family of proteins that have been reported to be involved in several inflammatory conditions. We examined the secretion of ADAM-10 in biological fluids from patients with rheumatoid arthritis (RA) and the role it plays in monocyte migration. ADAM-10 levels were measured using enzyme-linked immunosorbent assays and immunofluorescence. To examine the role of ADAM-10 in RA synovial fluids (SFs), we studied THP-1 (human acute monocyte leukemia cell line) and monocyte chemotaxis. To determine whether ADAM-10 plays a role in cell proliferation in the RA synovium, we assayed the proliferation of ADAM-10 small interfering RNA (siRNA)-transfected RA fibroblast-like synoviocytes (FLSs). The ADAM-10 level in RA serum was significantly higher than that in normal serum and was correlated with a disease activity score of 28. ADAM-10-depleted RA SFs showed a decrease in THP-1 and monocyte migratory activity compared with that of sham-depleted controls. ADAM-10 siRNA inhibited monocyte adhesion to RA FLSs. Finally, blocking ADAM-10 secretion in RA FLSs resulted in decreased production of fractalkine/CX3CL1 and vascular endothelial cell growth factor. These data indicate that ADAM-10 plays a role in monocyte migration in RA and suggest that targeting ADAM-10 may provide a method of decreasing inflammation and potentially treating other inflammatory diseases.

A key role for Fut1-regulated angiogenesis and ICAM-1 expression in K/BxN arthritis.

OBJECTIVES: Angiogenesis contributes to the pathogenesis of rheumatoid arthritis. Fucosyltransferases (Futs) are involved in angiogenesis and tumour growth. Here, we examined the role of Fut1 in angiogenesis and K/BxN serum transfer arthritis. METHODS: We examined Fut1 expression in human dermal microvascular endothelial cells (HMVECs) by quantitative PCR. We performed a number of angiogenesis assays to determine the role of Fut1 using HMVECs, Fut1 null (Fut1(-/-)), and wild type (wt) endothelial cells (ECs) and mice. K/BxN serum transfer arthritis was performed to determine the contribution of Fut1-mediated angiogenesis in Fut1(-/-) and wt mice. A static adhesion assay was implemented with RAW264.7 (mouse macrophage cell line) and mouse ECs. Quantitative PCR, immunofluorescence and flow cytometry were performed with Fut1(-/-) and wt ECs for adhesion molecule expression. RESULTS: Tumour necrosis factor-α induced Fut1 mRNA and protein expression in HMVECs. HMVECs transfected with Fut1 antisense oligodeoxynucleotide and Fut1(-/-) ECs formed significantly fewer tubes on Matrigel. Fut1(-/-) mice had reduced angiogenesis in Matrigel plug and sponge granuloma angiogenesis assays compared with wt mice. Fut1(-/-) mice were resistant to K/BxN serum transfer arthritis and had decreased angiogenesis and leucocyte ingress into inflamed joints. Adhesion of RAW264.7 cells to wt mouse ECs was significantly reduced when Fut1 was lacking. Fut1(-/-) ECs had decreased intercellular adhesion molecule-1 (ICAM-1) expression at mRNA and protein levels compared with wt ECs. ICAM-1 was also decreased in Fut1(-/-) arthritic ankle cryosections compared with wt ankles. CONCLUSIONS: Fut1 plays an important role in regulating angiogenesis and ICAM-1 expression in inflammatory arthritis.

Citrullination of epithelial neutrophil-activating peptide 78/CXCL5 results in conversion from a non-monocyte-recruiting chemokine to a monocyte-recruiting chemokine.

OBJECTIVE: To examine whether the citrullinated chemokines epithelial neutrophil-activating peptide 78 (ENA-78)/CXCL5, macrophage inflammatory protein 1α/CCL3, and monocyte chemotactic protein 1/CCL2 are detected in the biologic fluid of patients with rheumatoid arthritis (RA), and if so, to determine the biologic activities of these chemokines. METHODS: Recombinant human chemokines were citrullinated by peptidylarginine deiminase. Enzyme-linked immunosorbent assays were performed to measure the concentrations of citrullinated chemokines in sera from patients with rheumatoid arthritis (RA) and normal individuals and in synovial fluid from patients with RA, patients with osteoarthritis (OA), and patients with other inflammatory rheumatic diseases. The correlation between the citrullinated chemokine levels and clinical data was analyzed. Monocyte and neutrophil chemotaxis assays were performed, and native (noncitrullinated) or citrullinated ENA-78/CXCL5 was injected into mouse knees to evaluate the biologic activities of these chemokines. RESULTS: The concentration of citrullinated ENA-78/CXCL5 was significantly higher in RA sera and SF than in normal sera and in SF from patients with other rheumatic diseases including OA. In RA SF, a strong correlation between the amount of citrullinated ENA-78/CXCL5 and the C-reactive protein level or the erythrocyte sedimentation rate was observed. Citrullinated ENA-78/CXCL5 induced monocyte chemotaxis via CXCR1 and CXCR2, while noncitrullinated ENA-78/CXCL5 did not. In a mouse model of inflammatory arthritis, citrullinated ENA-78/CXCL5 induced more severe inflammation and recruited more monocytes than did noncitrullinated ENA-78/CXCL5. CONCLUSION: Citrullinated ENA-78/CXCL5 is highly correlated with RA disease activity and, unlike noncitrullinated ENA-78/CXCL5, recruits monocytes. These results indicate that citrullinated ENA-78/CXCL5 may exert previously unrecognized inflammatory properties in RA by recruiting monocytes to inflamed joint tissue.