MCAM+CD161- Th17 Subset Expressing CD83 Enhances Tc17 Response in Psoriasis.

Recent studies have highlighted the pathogenic roles of IL-17-producing CD8+ T cells (T-cytotoxic 17 [Tc17]) in psoriasis. However, the underlying mechanisms of Tc17 induction remain unclear. In this study, we focused on the pathogenic subsets of Th17 and their mechanism of promotion of Tc17 responses. We determined that the pathogenic Th17-enriched fraction expressed melanoma cell adhesion molecule (MCAM) and CCR6, but not CD161, because this subset produced IL-17A abundantly and the presence of these cells in the peripheral blood of patients has been correlated with the severity of psoriasis. Intriguingly, the serial analysis of gene expression revealed that CCR6+MCAM+CD161-CD4+ T cells displayed the gene profile for adaptive immune responses, including CD83, which is an activator for CD8+ T cells. Coculture assay with or without intercellular contact between CD4+ and CD8+ T cells showed that CCR6+MCAM+CD161-CD4+ T cells induced the proliferation of CD8+ T cells in a CD83-dependent manner. However, the production of IL-17A by CD8+ T cells required exogenous IL-17A, suggesting that intercellular contact via CD83 and the production of IL-17A from activated CD4+ T cells elicit Tc17 responses. Intriguingly, the CD83 expression was enhanced in the presence of IL-15, and CD83+ cells stimulated with IL-1ß, IL-23, IL-15, and IL-15Rα did not express FOXP3. Furthermore, CCR6+MCAM+CD161-CD4+ T cells expressing CD83 were increased in the peripheral blood of patients, and the CD83+ Th17-type cells accumulated in the lesional skin of psoriasis. In conclusion, pathogenic MCAM+CD161- Th17 cells may be involved in the Tc17 responses via IL-17A and CD83 in psoriasis.

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.

Synoviocyte-targeted therapy synergizes with TNF inhibition in arthritis reversal.

Fibroblast-like synoviocytes (FLS) are joint-lining cells that promote rheumatoid arthritis (RA) pathology. Current disease-modifying antirheumatic agents (DMARDs) operate through systemic immunosuppression. FLS-targeted approaches could potentially be combined with DMARDs to improve control of RA without increasing immunosuppression. Here, we assessed the potential of immunoglobulin-like domains 1 and 2 (Ig1&2), a decoy protein that activates the receptor tyrosine phosphatase sigma (PTPRS) on FLS, for RA therapy. We report that PTPRS expression is enriched in synovial lining RA FLS and that Ig1&2 reduces migration of RA but not osteoarthritis FLS. Administration of an Fc-fusion Ig1&2 attenuated arthritis in mice without affecting innate or adaptive immunity. Furthermore, PTPRS was down-regulated in FLS by tumor necrosis factor (TNF) via a phosphatidylinositol 3-kinase-mediated pathway, and TNF inhibition enhanced PTPRS expression in arthritic joints. Combination of ineffective doses of TNF inhibitor and Fc-Ig1&2 reversed arthritis in mice, providing an example of synergy between FLS-targeted and immunosuppressive DMARD therapies.

Seven-day services in surgery and the "weekend effect" at a Japanese teaching hospital: a retrospective cohort study.

BACKGROUND: Hospitals deliver 24-h, 7-day care on a 5-day workweek model, as fewer resources are available on weekends. In prior studies, poorer outcomes have been observed with weekend admission or surgery. The purpose of this study was to investigate the effect of 7-day service at a hospital, including outpatient consultations, diagnostic examinations and elective surgeries, on the likelihood of the "weekend effect" in surgery. METHODS: This was a retrospective cohort study of patients who underwent surgery between April 2014 and October 2016 at an academic medical centre in Tokyo, Japan. The main outcome measure was 30-day in-hospital mortality from the index surgery. The characteristics of the participants were compared using the Mann-Whitney U test or the chi-squared test as appropriate. Logistic regression was used to test for differences in the mortality rate between the two groups, and propensity score adjustments were made. RESULTS: A total of 7442 surgeries were identified, of which, 1386 (19%) took place on the weekend. Of the 947 emergency surgeries, 25% (235) were performed on the weekend. The mortality following emergency weekday surgery was 21‰ (15/712), compared with 55‰ (13/235) following weekend surgery. Of the 6495 elective surgeries, 18% (1151) were performed on the weekend. The mortality following elective weekday surgery was 2.3‰ (12/5344), compared with 0.87‰ (1/1151) following weekend surgery. After adjustment, weekend surgeries were associated with an increased risk of death, especially in the emergency setting (emergency odds ratio: 2.7, 95% confidence interval: 1.2-6.5 vs. elective odds ratio: 0.4, 95% confidence interval: 0.05-3.2). CONCLUSIONS: Patients undergoing emergency surgery on the weekend had higher 30-day mortality, but showed no difference in elective surgery mortality. These findings have potential implications for health administrators and policy makers who may try to restructure the hospital workweek or consider weekend elective surgery.

Serum anti-Müllerian hormone levels in women with rheumatoid arthritis during tumor necrosis factor-α inhibitor treatment: Exploratory research.

BACKGROUND: We evaluated serum anti-Müllerian hormone in women with rheumatoid arthritis newly introduced to tumor necrosis factor-α inhibitor treatment for 54 weeks to investigate the treatment's effect on ovarian reserve. METHODS: A total of 12 premenopausal women with rheumatoid arthritis aged 20-50 years were recruited at our division, who had been newly treated with tumor necrosis factor-α inhibitor (infliximab or etanercept) from 1 April 2008 to 31 March 2014. Serial serum anti-Müllerian hormone levels and disease activity scores (DAS28-CRP) were examined at defined periods: start of treatment and 14, 30, and 54 weeks after start of treatment. RESULTS: DAS28-CRP scores in 12 women were significantly decreased from a mean of 4.6 (±SD: 0.4) to 2.3 (±0.4) after 54 weeks of treatment (p < 0.001). Serum anti-Müllerian hormone levels and its z scores did not change significantly. CONCLUSION: Treatment with a tumor necrosis factor-α inhibitor did not affect serum anti-Müllerian hormone levels in 12 women with rheumatoid arthritis during 54-week treatment.

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.

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.

Is the serum oxytocin level altered by treatment in rheumatoid arthritis patients complicated with depression?

OBJECTIVE: The objective of this study was to investigate the factors associated with depression, including serum oxytocin (OXT) levels, disease activity, activities of daily living (ADL), and quality of life (QOL), and their effects on rheumatoid arthritis (RA). METHODS: This study included 42 RA patients who received treatment with a biological agent. We measured the following variables before and after 6 months of treatment: baseline characteristics, including age, sex, disease duration, smoking, and body mass index (BMI); prednisolone and methotrexate dose; serum level of matrix metalloproteinase-3 (MMP-3); erythrocyte sedimentation rate (ESR); and C-reactive protein (CRP) level. The disease activity of RA was assessed using the Simplified Disease Activity Index (SDAI); depression was assessed using the Hamilton Depression Rating Scale (HAM-D); ADL was assessed using the Health Assessment Questionnaire; and QOL was assessed using the Short Form (SF)-36. Serum OXT levels were determined using enzyme-linked immunosorbent assay. RESULTS: The HAM-D score significantly correlated with the SDAI, and the mental component summary (MCS) score of SF-36. However, the serum OXT levels did not correlate with the HAM-D score. Regression analysis using the HAM-D score as the objective variable identified female sex, smoking, BMI, and all the three component scores of SF-36, but not serum OXT levels, as significant factors. Comparisons between before and after treatment showed that the HAM-D score improved from 5 to 1.5; however, the serum OXT levels did not change. CONCLUSION: The variables of female sex, smoking, BMI, and QOL correlated with depression complicated with RA. However, serum OXT levels did not correlate directly.

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.

The Relationship between the Serum Oxytocin Levels, Disease Activity, the ADLs and the QOL in Patients with Rheumatoid Arthritis.

Objective To investigate the factors associated with depression, including the serum oxytocin (OXT) levels, disease activity, activities of daily living (ADLs) and quality of life (QOL), and their effects on rheumatoid arthritis (RA). Methods This study included 42-RA-patients. We measured the following variables before and after 6 months of treatment with biological disease-modifying antirheumatic drugs (bDMARDs): the baseline characteristics (including age, sex, disease duration, smoking, and body mass index), the doses of prednisolone and methotrexate, the serum level of matrix metalloprotease-3, the erythrocyte sedimentation rate and the C-reactive protein level. The disease activity of RA was assessed using the Simplified Disease Activity Index (SDAI), depression was assessed using the Hamilton Depression Rating Scale (HAM-D), the ADLs were assessed using the Health Assessment Questionnaire disability index and the QOL was assessed using the Short Form (SF)-36. The serum OXT levels were determined using an enzyme-linked immunosorbent assay. Results The HAM-D score was significantly correlated with the SDAI, and the mental component summary score of the SF-36. However, the serum OXT levels were not correlated with the HAM-D score. The serum OXT levels before and after bDMARDs treatment did not differ to a statistically significant extent, regardless of the presence of depression. Although the differences in the serum levels of OXT were observed prior to the initiation of treatment, there was no gender difference after treatment. Conclusion Although RA complicated by depression may be related to the following high disease activity, a poor QOL and poor ADLs, the serum OXT levels were not directly correlated.

Clinical Characteristics of Rheumatoid Arthritis Patients Achieving Functional Remission after Six Months of Non-tumor Necrosis Factor Biological Disease-Modifying Antirheumatic Drugs (DMARDs) Treatment.

Objectives We aimed to identify the factors that predict the likelihood of remission based on a health assessment questionnaire (HAQ) in rheumatoid arthritis (RA) patients who received non-tumor necrosis factor (TNF) biologics for six months before they commenced definitive treatment. Methods The subjects consisted of 97 RA patients treated with tocilizumab or abatacept for 6 months. The following characteristics were investigated: age, gender, body mass index, steroid and methotrexate dosage, serum matrix metalloproteinase-3 levels, simplified disease activity index (SDAI) score, HAQ score (for assessing the activities of daily living [ADL]) and the short form (SF)-36 score (for assessing the quality of life [QOL]). Remission based on the HAQ score is defined as HAQ ≤0.5 after 6 months of treatment. The subjects were divided into two groups: patients with HAQ score ≤0.5 and HAQ score >0.5, and a retrospective study was conducted. Results The group of RA patients who entered remission based on the HAQ (53 patients) had a lower SDAI than the patients who did not enter remission (44 patients), and the RA patients had a lower tender joint count (TJC) and HAQ scores and a lower physician's global assessment (PGA) than those who did not enter remission. The physical component summary score (PCS) and role/social component summary score (RCS) of the SF-36 summary score were higher in the remission patients than in those without. Before the start of the treatment, the HAQ score, patients' global assessment (PtGA) and PCS and mental component summary score (MCS) of the SF-36 were determined based on a logistic regression analysis. Conclusion Our findings suggest that RA patients with lower HAQ scores and PtGA and higher PCS and MCS of the SF-36 at baseline are more likely to achieve HAQ remission with non-TNF biologic treatment than others.

Clinical Characteristics of Rheumatoid Arthritis Patients Achieving Functional Remission with Six Months of Biological DMARDs Treatment.

Objective Although previous studies have reported the prognostic factors for functional remission, no reports have cited the predictive factors. Our aim was to study the predictive factors for functional remission, which is a treatment goal in rheumatoid arthritis (RA), after receiving biological disease-modifying antirheumatic drugs (bDMARDs) treatment for six months. Methods The study consisted of 333 RA patients treated with bDMARDs for six months. The following patient characteristics were investigated: age, gender, disease duration, type of bDMARDs, baseline steroid and methotrexate dosage, and levels of serum rheumatoid factor, matrix metalloprotease, anti-cyclic citrullinated peptides antibody, tumor necrosis factor-α, and interleukin-6. In our evaluation, we used the Simplified Disease Activity Index (SDAI) for RA disease activity, health assessment questionnaire disability index (HAQ-DI) for activity of daily living, Short Form (SF)-36 for quality of life, and Hamilton Depression Rating Scale (HAM-D) or Self-rating Depression Scale (SDS) to determine the patients' depression status. The subjects were divided into two groups: patients with HAQ-DI≤0.5 and HAQ-DI>0.5 at 6 months. Results A univariate analysis comparing a group of RA patients without functional remission (n=68) showed that the patients with functional remission (n=164) had the following in common compared with those without remission: younger age, shorter disease duration, lower baseline steroid dosage, lower SDAI, lower HAQ-DI, higher SF-36, and lower HAM-D. Only lower HAQ-DI scores and "mental health" score on the SF-36 were detected using a logistic regression analysis. Conclusion These findings suggested that RA patients with lower HAQ-DI and lower depression scores at baseline were more likely to achieve functional remission using bDMARDs treatment than those without these variables.

Predictor of the Simplified Disease Activity Index 50 (SDAI 50) at Month 3 of bDMARD Treatment in Patients with Long-Established Rheumatoid Arthritis.

OBJECTIVES: The Simplified Disease Activity Index (SDAI) 50 has good agreement with European League Against Rheumatism (EULAR) response measures for early Rheumatoid Arthritis (RA). There have been reports on early RA, but not on long-established RA. In this study, we analysed the relationships between various baseline factors and SDAI 50 after three months of treatment with biological disease-modifying antirheumatic drugs (bDMARDs) to determine the prognostic factors for long-established RA. METHODS: Subjects were 260 RA patients who had been treated with bDMARDs for 3 months. The following characteristics were investigated: Patient backgrounds, the erythrocyte sedimentation rate (ESR), C-reactive protein and serum matrix metalloproteinase-3 levels, SDAI scores, and health assessment questionnaire disability index and short form-36 scores. As a primary outcome index, the SDAI response was defined as a 50% reduction in the SDAI score between baseline and 3 months (SDAI 50). RESULTS: Baseline values of disease duration (odds ratio: 0.942, 95% CI: 0.902-0.984), smoking history (odds ratio: 2.272, 1.064-4.850), 28-tender joint count (odds ratio: 0.899, 0.827-0.977), evaluator's global assessment (odds ratio: 1.029, 1.012-1.047) and ESR (odds ratio: 1.015, 1.001-1.030) were determined to be significant factors based on logistic regression analysis. CONCLUSION: Our study demonstrated that RA patients with shorter disease duration, no smoking, and higher RA disease activity are more likely to achieve SDAI 50 through bDMARD treatment.

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.

Influence of renal complications on the efficacy and adverse events of tacrolimus combination therapy in patients with systemic lupus erythematosus (SLE) during a maintenance phase: a single-centre, prospective study.

OBJECTIVES: The study investigated whether renal complications affected the efficacy and safety of tacrolimus combination therapy in patients with systemic lupus erythematosus (SLE) during a maintenance phase. METHODS: Fifty-seven patients with SLE (A: 30 cases with renal complication, B: 27 cases without renal complications) were included. The presence of renal complications was defined as proteinuria ≥0.5 g/day and lupus nephritis on renal biopsy. Major outcome measures included SLE disease activity index (SLEDAI), steroid dose, serum anti-dsDNA Ab, C3 and creatinine (Cr) levels and estimated glomerular filtration rate (eGFR). The patient's background factors included age, gender, disease duration and ACE-I/angiotensin II receptor blocker and statin therapies. We compared these outcome measures pre treatment and after 1 year of treatment. RESULTS: The SLEDAI and serum C3 levels improved in both groups from pretreatment period to post-treatment period: from 7.2±5.0 to 2.8±2.3 in A and 6.4±3.8 to 2.4±2.2 in B, p<0.001, and from 65.9±24.6 to 77.7±18.2 mg/dL in A and 81.8±23.0 to 90.6±19.4 mg/dL in B, p=0.002, respectively. The anti-dsDNA antibody level was reduced, and the serum Cr and eGFR levels were slightly elevated. No patients developed end-stage renal failure that required artificial dialysis. CONCLUSIONS: Tacrolimus combination therapy had additive beneficial effects on reduced proteinuria and increased serum C3 levels in patients with SLE with renal complications during a maintenance phase.

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 case of Degos disease: demonstration of C5b-9-mediated vascular injury.

A 68-year-old Japanese male presented with atrophic erythematous white lesions with peripheral dark reddish rims on his back. Multiple ulcers were detected from his stomach to his large intestine using endoscopy. Although the patient was given high doses of a steroid, aspirin, dipyridamole, and intravenous immunoglobulin therapy, he died of gastrointestinal hemorrhage, perforation and septic shock. An autopsy examination revealed pauci-inflammatory thrombotic microangiopathy with endothelial cell injury, fibrous occlusive arteriopathy, and vascular C5b-9 deposition in the wall of the gastrointestinal tract from the esophagus to the large intestine as well as in the dermis of the skin.