Airi Nishimi

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.

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 patients 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 metalloproteinase (ADAM)-10 as a predictive factor for tocilizumab effectiveness in rheumatoid arthritis

Abstract 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.

Sex Differences in the Effects of a Biological Drug for Rheumatoid Arthritis on Depressive State

Objective : Sex-specific medicine has attracted attention in recent years, but no report on rheumatoid arthritis (RA) has examined sex differences in the effectiveness of biologics on activities of daily living (ADL), quality of life (QOL), or depressive state. Methods : The study subjects were 161 RA patients (female: 138; male: 23) attending regular doctor visits at our hospital. We compared the changes in disease activity, which was evaluated using the simplified disease activity index (SDAI), ADL (using the modified health assessment questionnaire; mHAQ), QOL (using short form-36; SF-36), and the Hamilton Depression Rating Scale (HAM-D) for RA patients between each sex over a six-month observation period while administering biologic treatment. Results : The female patients reported significant improvements in the following metrics: SDAI: from 22.1 ± 11.9 to 8.9 ± 7.8 (p < 0.001); mHAQ: from 0.46 ± 0.50 to 0.32 ± 0.45 (p < 0.001); and HAM-D: from 6.2 ± 4.8 to 3.8 ± 4.1 (p < 0.001). Moreover, all eight items of the SF-36 were significantly improved (p < 0.01). In contrast, the male patients improved on the SDAI (from 27.9 ± 11.7 to 12.7 ± 8.6 (p < 0.001)), but we did not observe significant improvements in the mHAQ or HAM-D scores or in any items on the SF-36. Conclusion : Both male and female patients with RA improved when using a biological drug. Sex differences in the improvement of depressive state were observed.

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.

THU0064 ADAM-10 as a tocilizumab treatment predictive factor in rheumatoid arthritis

Background A disintegrin and metalloproteinases (ADAMs) are a family of transmembrane and secreted proteins. ADAM-10 has been reported to be the enzyme responsible for the release of a number of chemokines and cytokine receptors. We have shown that ADAM-10 is overexpressed on rheumatoid arthritis (RA) synovial tissue endothelial cells (ECs) and lining cells compared with osteoarthritis and normal tissues. We also demonstrated that ADAM-10 mediates EC migration and tube formed. Objectives In order to demonstrate for ADAM-10 in clinical side, we focused on ADAM-10 as predictive factor for treatment with biologics in RA. Methods The serum was collected from patients before the initial treatment with biological therapies. Fifteen patients were treated with adalimumab (ADA), and 20 patents were treated with tocilizumab (TCZ). ADAM-10 and fractalkine/CX3CL1 were measured by enzyme-linked immunosorbent assay at 0, 12, 24 and 54 weeks. Clinical disease activity was evaluated by clinical disease activity index (CDAI). Following biological therapies, we defined biologic-responders as patients whose DAS28 scores decreased by more than 1.2 at 24 weeks. ADAM-10 baseline was also compared between responders and nonresponders at 24 weeks. Results There were no significant differences were observed in the mean age, gender ratio, dosages of predonisolone and methotraxate between ADA and TCZ groups. In ADA group, baseline DAS28 for the 15 patients was 4.8±0.3 (2.5–7.2). On the other hands, baseline DAS28 for the 20 patients was 4.8±0.3 (2.5–6.8) in TCZ group. There were no differences between ADA and TCZ groups. RA patients with an insufficient response to ADA or TCZ showed highly significant improvement of DAS28 after 12 weeks (2.9±0.3 and 2.2±0.4, respectively), and 24 weeks (2.5±0.4 to 2.2±0.2, respectively). ADAM-10 highly correlates with CDAI, and fractalkine/CX3CL1. Serum ADAM-10 levels were no remarkable change after treatment with ADA despite decrease of disease activity of RA. On the other hand, serum ADAM-10 levels in patients who were treated with TCZ were significantly diminished following successful treatment and clinical improvement (baseline 408±88 pg/ml and 54 weeks 138±51 pg/ml, p<0.05). Univariate logistic regression analysis, baseline of DAS28 (ESR), baseline of CDAI, and ADAM-10 were selected as significant variables for improvement of DAS28 (ESR) at 24 weeks. Multiple regression analysis showed that ADAM-10 was only identified as independent predictive variable for improvement of DAS28 (ESR) at 24 weeks. ADAM-10 baseline in TCZ responder was significantly higher than TCZ nonresponders at 24 weeks (620±134 pg/ml and 109±25 pg/ml, respectively, p<0.05). Conclusions This study indicates that ADAM-10 is correlated with RA disease activity, and is higher in TCZ responders. These results suggest that ADAM-10 may be a predictor of treatment effectiveness for RA with TCZ. Disclosure of Interest None declared

AB0296 Clinical Characteristics of Rheumatoid Arthritis Patients Achieving No Depression with 6 Months of Biologic Treatment

Background It is known that rheumatoid arthritis (RA) is comorbid with various diseases and especially concomitant depression is common with a high prevalence of approximately 20%. Even if RA disease activity is controlled, patients with persistent depression result in decreased activity of daily life (ADL) and quality of life (QOL). Objectives To study predictive factors for no depression status after using biologic agents for 6 months. Methods The study was 333 RA patients treated with biologic agents. The following patients characteristics were investigated: age, gender, the number of previous drugs, disease duration, the type of biologic agents, baseline steroid dosage, MTX dosage, serum rheumatoid factor (RF), serum matrix metalloproteinase-3 (MMP-3), anti-cyclic citrullinated peptide antibody (anti-CCP antibody), tumor necrosis factor (TNF)-α, and interleukin (IL)-6. For evaluation we used Simplified Disease Activity Index (SDAI) for RA disease activity, Health Assessment Questionnaire (HAQ) for ADL, Short Form (SF)-36 for QOL, and Hamilton Depression Rating Scale (HAM-D) or Self-rating depression scale (SDS) for depression status. No depression was defined by HAM-D≦7 or SDS≦39 after 6 months of treatment. The subjects were divided into two groups according to the presence or absence of depression, and a retrospective study was performed. We excluded 101 patients due to loss to 6-month follow-up and 39 patients due to incomplete data; therefore, we included 193 patients in the analysis. Results Compared with a group of RA patients with depression (n=130), a group of patients without depression (n=63) had younger age (52.7± 14.8 vs. 59.8±14.3, p=0.002), more males (p=0.046), lower baseline steroid dosage (3.2±3.1mg vs. 5.0±4.4mg, p=0.002), lower SDAI (22.9±12.8 vs. 29.5±15.2, p=0.002), lower HAQ (0.43 ±0.47 vs. 0.75±0.62, p<0.001), higher SF-36 (p<0.05 in all categories), lower SDS (38.2±8.5 vs. 46.7±9.6, p<0.001), and lower HAM-D (5.0±4.0 vs. 9.3±6.0, p<0.001) were detected based on univariate analysis. On the other hand, younger age (p=0.0352), more males (p=0.0048), lower baseline steroid dosage (p=0.0459), lower titer of serum RF (p=0.0114), lower HAQ (p=0.0485) and lower “pain (p=0.0222)”, “general health perception (p=0.0364)” and “social functioning (p=0.0078)” item of the SF-36 were detected based on logistic regression analysis. Conclusions It was suggested that RA patients with more male, lower disease activity, lower dosage of steroid, younger age, and higher ADL and QOL at baseline are more likely to achieve no depression status with biologic treatment. Disclosure of Interest Y. Miwa Grant/research support from: Tanabemitsubishi, Chugai, phizer, Ono, M. Hatano: None declared, A. Nishimi: None declared, S. Nishimi: None declared, T. Hayashi: None declared, R. Yanai: None declared, H. Furuya: None declared, M. Umemura: None declared, T. Kasama: None declared, M. Hosaka: None declared, K. Sanada: None declared

AB0329 A Study on Characteristics of Rheumatoid Arthritis Patients Achieving HAQ Remission with 6 Months of Biologic Treatment

Background Biologic agents are highly effective for rheumatoid arthritis (RA); however, not all cases achieve HAQ remission. Although previous studies have reported the prognostic factors, there is no report on predictive factors for HAQ remission. Objectives To study predictive factors for HAQ remission, which is one of the treatment goals in RA, after using biologic agents for 6 months. Methods The subjects were 333 RA patients treated with biologic agents for 6 months. The following patients characteristics were investigated: age, gender, the number of previous drugs, disease duration, the type of biologic agents, baseline steroid dosage, MTX dosage, serum RF, MMP-3, ACPA, TNF-α, and IL-6. For evaluation we used SDAI for RA disease activity, HAQ for ADL, Short Form (SF)-36 for QOL, and Hamilton Depression Rating Scale (HAM-D) or Self-rating depression scale (SDS) for depression status. HAQ remission was defined by HAQ0.5 after 6 months of treatment. The subjects were divided into two groups: patients with HAQ0.5 and patients with HAQ >0.5 at 6 months, and a retrospective study was conducted. 101 patients were excluded from the study due to loss to 6-month follow-up, and a total of 232 patients were analyzed. Results Compared with a group of RA patients without HAQ remission (n=68), a group of patients with HAQ remission (n=164) had younger age (54.8±15.2 vs. 61.8±13.3, p=0.0011), lower baseline steroid dosage (3.4±3.7mg vs. 4.5±3.5mg, p=0.037), lower serum MMP-3 (196±234 ng/ml vs. 321±551, p=0.047), lower SDAI (22.5±13.4 vs. 32.1±12.9, p<0.001), lower HAQ (0.39±0.51 vs. 1.08±0.54, p<0.001), higher SF-36 (p<0.05 in all categories), lower SDS (40.4±9.9 vs. 43.5±9.2, p=0.033), and lower HAM-D (5.0±4.3 vs. 8.4±5.0, p<0.001). On the other hand, there was no significant difference on the types of biologic agents, the order of drugs used in the treatment, gender, MTX dosage, disease duration, serum RF, ACPA, TNF-α, and IL-6. Conclusions It was suggested that RA patients with lower disease activity, lower dosage of steroid, younger age, lower serum MMP-3, higher ADL and QOL, and lower depression scores at baseline are more likely to achieve HAQ remission with biologic treatment. Disclosure of Interest Y. Miwa Grant/research support from: Astellas Pharm Inc., Mitsubishi Tanabe Pharma Corporation, AbbVie CK, Pfizer Japan Inc., Chugai Pharmaceutical Co., Ltd., and Eizai Co., Ltd., R. Takahashi: None declared, N. Yajima: None declared, K. Wakabayashi: None declared, T. Tokunaga: None declared, S. Ishii: None declared, A. Nishimi: None declared, T. Kasama: None declared, K. Oh: None declared, Y. Toyoshima: None declared, K. Inagaki: None declared