Takahiro Tokunaga

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.

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.

Serum anticyclic citrullinated protein antibody titers are correlated with the response to biological agents in patients with rheumatoid arthritis

Anticyclic citrullinated protein antibody (ACPA) is known as an important indicator for diagnosis of rheumatoid arthritis (RA). Our aim was to examine the relationship between the serum ACPA titer at baseline and responsiveness to biological agents (antagonists of either tumor necrosis factor or interleukin 6) in patients with RA. ACPA was measured using second-generation chemiluminescent enzyme immunoassay. Disease activity was assessed using disease activity scores 28. Fifty-seven RA patients with biological agents were enrolled, and the median ACPA titer at baseline was 110.0 U/mL. The median ACPA titer was 23.3 U/mL and 183.0 U/mL in the good and moderate response groups, respectively, which were significantly lower than in the no response group (404.0 U/mL). In addition, 69.2% and 26.9% of patients with low (<100 U/mL) and moderate (100–499 U/mL) basal ACPA titers showed a moderate to good response. Of the patients with higher (≥500 U/mL) basal ACPA titers, only 14.0% and 42.5% showed a good or moderate response, respectively. The remission rate was 77.8% in the ACPA-negative, which was significantly higher than the rate of 25% in the ACPA-positive patients. The results suggest that the ACPA titers are correlated with the efficacy of the biological agents used in patients with RA.

AB0377 Efficacy of tacrolimus combination therapy during the maintenance phase of systemic lupus erythematosus

Background In Japan, a placebo-controlled clinical trial of tacrolimus for lupus nephritis was performed to investigate the efficacy and safety of this agent. Based on the results obtained, administration of tacrolimus at an oral dose of 3 mg/day was approved for the treatment of lupus nephritis. Objectives The aim of this study was to prospectively evaluate the efficacy and safety of tacrolimus (TAC) combination therapy during the maintenance phase of systemic lupus erythematosus (SLE). TAC was added to the existing therapy if the clinical symptoms worsened and/or if there was a decrease in the serum complements titer because it allowed for a decrease in the dose of prednisolone (PSL). Methods From 2009 to 2012, 38 patients were included in the study period for 1 year. TAC combination therapy (dosage range: 1 mg to 5 mg once daily) was given if there was worsening of any mild manifestations of active SLE, such as arthritis, skin eruptions, or asymptomatic nephritis, and/or if there was a decrease in the serum complement titer (C3c). This study reviewed the SLE Disease Activity Index (SLEDAI) score, the dosage of PSL, the serum levels of C3c, the anti-dsDNA titers and proteinuria. Results Twenty-eight patients were treated with TAC combination therapy and showed symptom improvement with the following results: 1) the dosage of PSL was reduced from 11.7 ± 5.6 to 8.2 ± 4.2 (mg/day) (P<0.001), 2) the serum C3c concentration increased from 74.7 ± 21.9 to 86.4 ± 17.8 (mg/dl) (P=0.006), 3) the anti-dsDNA titer decreased from 39.6 ± 68.0 to 24.8 ± 49.1 (U/ml) (P<0.001) and 4) the SLEDAI score improved from 6.2 ± 3.7 to 2.6 ± 2.3 (P<0.001). Of note, the components of the SLEDAI with the greatest levels of improvement included headache (decreased from 7 patients to 1 patient), arthritis (from 3 patients to no patients), rash (from 6 patients to 2 patients), alopecia (from 5 patients to no patients), mucosal ulcer (from 2 patients to no patients) and fever (from 5 patients to 1 patient). Although the occurrence of proteinuria decreased from 46.0 ± 95.7 to 30.7 ± 74.2 (mg/dl) upon administration of TAC combination therapy, the difference was not significant (P=0.23). However, 8 patients treated with TAC combination therapy did not show disease improvement nor had worsening SLE. In addition, 2 patients discontinued therapy due to an adverse effect: muscle cramp or rhabdomyolysis. No patients presented abnormal urinalysis, progression to renal failure, or became a candidate for dialysis therapy. Conclusions TAC combination therapy was clinically useful in the maintenance phase of SLE. Disclosure of Interest None Declared

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

Abstract 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.

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

FRI0153 Relationship between Serum Oxytocin Levels and Disease Activity, Depressive State, ADL, and QOL in Patients with Rheumatoid Arthritis

Background Oxytocin, which is also called a happy hormone, has been reported to be related to various conditions including depressive state. However, the positioning of oxytocin in rheumatoid arthritis (RA) remains unclear. Objectives The objective of this study was to investigate the relationship between serum oxytocin levels and disease activity, depressive state, activity of daily life (ADL), and quality of life (QOL) in RA. Methods The study included 20 patients with RA who received treatment with a biological agent. We measured the following items before and at 6 months after the start of treatment. The baseline characteristics included the age, sex, prednisolone dose, methotrexate dose, duration of disease, anti-cyclic citrullinated peptide antibody (anti-CCP antibody), rheumatoid factor (RF), serum matrix metalloproteinase-3 (MMP-3), erythrocyte sedimentation rate, and C-reactive protein (CRP). The disease activity of rheumatoid arthritis was assessed using the Simplified Disease Activity Index (SDAI), depressive state using Hamilton Depression Rating Scale (HAM-D), ADL using the Health Assessment Questionnaire (HAQ), and QOL using the 36-Item Short Form Health Survey (SF-36). Serum oxytocin levels were determined by enzyme-linked immunosorbent assay (ELISA). The correlation between each item and the serum oxytocin levels were examined. Results The serum oxytocin levels before the start of treatment were correlated with RF (r=−0.529), HAQ (r=0.446), HAM-D (r=0.508), and among the 8 categories of the SF-36, physical function (r=−0.676), role function (physical) (r=−0.801), pain (r=−0.506), general health perception (r=−0.787), role function (emotional) (r=−0.844), and mental health (MH) (r=−0.516). On the other hand, the serum oxytocin levels did not correlate with the SDAI (r=−0.078). The serum oxytocin levels after the start of treatment were correlated with the age (r=−0.549), SDAI (r=−0.539), HAQ (r=0.813), HAM-D (r=0.584), and all of the SF-36 categories except for MH (r=0.038) (r>0.4). Other items did not correlate to the serum oxytocin levels. Conclusions The serum oxytocin levels before the start of treatment were correlated with depressive state, ADL, and QOL but not with disease activity. Those after the start of treatment were correlated with the SDAI, depressive state, ADL, and QOL. Disclosure of Interest Y. Miwa Grant/research support from: Tanabemitsubishi, Chugai, phizer, Ono, R. Takahashi: None declared, S. Isojima: None declared, M. Saito: None declared, Y. Miura: None declared, S. Ishii: None declared, Y. Ikari: None declared, T. Tokunaga: None declared, T. Kasama: None declared, Y. Toyoshima: None declared, K. Inagaki: 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

AB0263 Correlation of cx3cl1 levels with adl, hrqol and depression to biologic agent therapy in patients with rheumatoid arthritis

Background The serum levels of the soluble fractalkine (CX3CL1) play crucial roles in the pathogenesis of rheumatoid arthritis (RA) and neuropsychiatric systemic lupus erythematous. The relationship of CX3CL1 and the activities of daily living (ADL), health-related quality of life (HRQoL) and depression in RA patients were not clear. Objectives The objective of this study was to analyze the correlation of the serum levels of CX3CL1 with the ADL, HRQoL, and depression in patients with RA. Methods A total of 161 RA patients were assessed prior to treatment and 30 weeks after initiating the biologic therapy. Infliximab, etanercept, adalimumab, tocilizumab, abatacept, and golimumab were used as the biologic therapies, and the choice of treatment was at the physicians’ discretion. Age, gender, and steroid dosage were recorded for each participant, and the disease activity score (DAS) 28/ESR4, the ADL (modified Health Assessment Questionnaire; mHAQ), the HRQoL questionnaire (Short Form [SF]-36), the depression scale (The Self-rating Depression scale [SDS]) and serum levels of CX3CL1 were evaluated in the patients. The serum level of CX3CL1 was quantified using a commercial ELISA kit according to the manufacturer’s instructions. Results Patients with lower (<1000 pg/ml, Group 1) and higher titer (>1000, Group 2) basal CX3CL1 levels were compared. The DAS28 score (4.3 ± 1.4, mean ± SD) in Group 1 was lower than that in Group 2 (4.9 ± 1.8) (p<0.05), and the mHAQ score (0.37 ± 0.43) in Group 1 was lower than that in Group 2 (0.54 ± 0.50) (p<0.05) at baseline. After 30 weeks of treatment, the mHAQ score was lower in Group 1 (0.14 ± 0.26) than in Group 2 (0.38 ± 0.47) (p<0.005), and the SDS score was lower in Group 1 (35.9 ± 9.1) than in Group 2 (40.3 ± 11.0) (p<0.05). The SDS score at baseline and the DAS28 score were not significantly improved. Although there was a direct correlation between the mHAQ and CX3CL1 (p<0.05) at baseline, no significant improvements in the DAS28 and SDS scores were observed. In addition, the age, gender, and steroid dosage were not significantly different between Groups 1 and 2. Conclusions In this study, a higher titer of CX3CL1 serum levels led to the aggravation of not only the disease activity and ADL at baseline but also the ADL and depression after the biologics treatment. The serum levels of CX3CL1 may be more closely related to ADL in RA patients. Disclosure of Interest Y. Miwa Grant/research support from: Tanabemitsubishi, Wyeth, Abbott, Eizai, Chugai, S. Isojima: None Declared, M. Umemura: None Declared, H. Tsukamoto: None Declared, T. Tokunaga: None Declared, H. Furuya: None Declared, R. Yanai: None Declared, K. Otsuka: None Declared, R. Takahashi: None Declared, K. Wakabayashi: None Declared, N. Yajima: None Declared, T. Kasama: None Declared, M. Hosaka: None Declared