Sakiko Isojima

Comparative Study of Infliximab Therapy and Methotrexate Monotherapy to Improve the Clinical Effect in Rheumatoid Arthritis Patients.

Objective We examined whether infliximab (IFX) therapy was more effective than methotrexate (MTX) monotherapy to achieve an improvement in depressive states in Rheumatoid Arthritis (RA) patients. Methods We examined 152 RA patients (72 IFX patients and 80 MTX patients). We conducted an open-label cohort study to evaluate the disease activity of RA (Simplified Disease Activity Index; SDAI), depressive states (Hamilton Rating Scale for Depression; HAM-D), Activity of Daily Living (ADL) (modified Health Assessment Questionnaire; mHAQ) and Quality of Life (QOL) [Short Form (SF)-36] in patients before and 6 months after receiving therapy. The HAM-D, SDAI, mHAQ and SF-36 scores after 6 months of therapy were measured as the outcomes. Results We analyzed 60 IFX patients and 53 MTX patients. The HAM-D scores significantly improved in both groups (p<0.001), but there was no significant difference in the effectiveness between the IFX and MTX therapies (p=0.792). The SDAI scores significantly improved in both groups after therapy (p<0.001), and IFX therapy was more effective than MTX therapy (p=0.004). The mHAQ and HAM-D scores also improved significantly in both groups after therapy (p<0.001), but no significant difference in the effectiveness between the IFX and MTX therapies was observed (p=0.272, 0.792). The scores of all 8 items of the SF-36 improved in both groups after therapy, but IFX therapy was more effective than MTX therapy in only 4 of the 8 items (p<0.05). Conclusion Both IFX and MTX therapy improved the clinical efficacy, ADL, QOL and depressive states. However, no significant differences regarding an improvement in the depressive states and ADL were observed between IFX therapy and MTX monotherapy.

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.

Clinical Significance of Cytokines and Chemokines in Neuropsychiatric Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a complex multisystem autoimmune disease with a relapsing and remitting course, and neuropsychiatric complications of SLE (NPSLE) are associated with increased morbidity and mortality. In general, the diagnosis of NPSLE is difficult because no single laboratory marker or imaging modality serves as a gold standard, and the diagnosis is primarily clinical. However, recent studies have provided evidence that many cytokines and chemokines, as well as autoantibodies, may be involved in the neuropsychiatric manifestations of SLE. This is supported by the finding that several repertoires of cytokines/chemokines are detectable in the central nervous systems of NPSLE patients during active disease. In addition, we have recently shown elevated levels of the soluble form of CX3CL1, amembrane- bound CX3C chemokine, in the cerebrospinal fluid of patients with active NPSLE. This review will discuss the involvement of cytokines and chemokines in the pathogenesis of NPSLE and evaluate their significance as a useful laboratory parameter of active neuropsychiatric disease.

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

SAT0085 Study of Prognostic Factors Associated with Death from Pneumocystis Pneumonia Complicated by Collagen Diseases

Background Corticosteroids and immunosuppressant are now widely used as a treatment for collagen diseases, and complications of pneumocystis pneumonia (PCP) have become a problem. Objectives We study prognostic factors associated with death from PCP complicated by collagen diseases. Methods We conducted a retrospective analysis on the basis of the medical records of 38 patients with PCP complicated by collagen diseases. For background factors, age, gender, baseline diseases, medications at the time of hospital admission (dose of steroids, immunosuppressant), the presence of complications (respiratory diseases, diabetes, chronic kidney disease), smoking history, trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis were studied. For laboratory data, CBC (including lymphocyte count), serum LDH, albumin, creatinine, CRP, KL-6, SP-D, IgG level, IgA, IgM, (1,3)-β-D-glucan, arterial blood gas, and sputum PCP-DNA (tested by PCR) at the time of hospital admission were investigated. The eGFR was calculated using creatinine value, age, and gender. We also studied treatment methods after hospitalization (TMP-SMX use, change from TMP-SMX to pentamidine, pulsed-steroid therapy, intratracheal intubation, managing in ICU) and hospitalization period. Results In laboratory data, the group of non-survivors had a higher creatinine (0.88±0.38 mg/dl vs. 1.16±0.38, p=0.045), a lower albumin (3.13±0.50 g/dl vs. 2.71±0.38, p=0.031), a higher CRP (7.8±7.0 mg/dl vs. 18.9±8.8, p=0.014), a lower IgA (274±108 mg/dl vs. 174±54, p=0.013), a higher serum SP-D (173±106 vs. 285±285, p=0.047), and a lower PaO2/FiO2 (P/F) ratio (268±99 mmHg vs. 147±98, p=0.025). For sputum PCP (by PCR), all patients were positive in the group of non-survivors, but only 18 out of 31 survivors (58%) were positive. All patients in the group of non-survivors underwent pulsed-steroid therapy, but it was assumed that the therapy was performed in order to treat severe respiratory failure because the patients who resulted in death had a low P/F ratio and severely poor respiratory status. On the other hand, as background factors, there was no significant difference. Conclusions We newly identified prognostic factors associated with death from PCP, which are a low serum albumin and cholinesterase at the time of PCP diagnosis, decreased pulmonary diffusing capacity, and significantly high rate of intratracheal intubation and managing in ICU; in this study, male, older age, a high serum creatinine, a high CRP, a low IgA, a high SP-D, a low P/F ratio, and sputum PCP positive (by PCR) were newly identified as the poor prognostic factors. Disclosure of Interest None declared

AB0328 A Study on Characteristics of Rheumatoid Arthritis Patients Achieving Clinical Remission After 6 Months of Treatment with Biologic Agents

Background Biologic agents are highly effective for rheumatoid arthritis (RA); however, not all cases achieve clinical remission. It is difficult to predict the effectiveness before starting the treatment. Objectives To study predictive factors for clinical 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. The following patients characteristics were investigated: age, gender, the type of biologic agents, the number of previous drugs, disease duration, 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, respectively. Clinical remission was defined by SDAI3.3 after 6 months of treatment. The subjects were divided into two groups: patients with SDAI3.3 and patients with SDAI >3.3 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 clinical remission (n=167), a group of patients with clinical remission (n=65) had younger age (50.0±15.5 vs. 59.6±14.1, p<0.001), lower steroid dosage (1.9±2.4 mg/day vs. 4.3±3.8, p<0.001), lower serum MMP-3 (151±197 ng/ml vs. 239±244, p<0.05), lower serum TNF-α (28.4±57.7 pg/ml vs. 76.0±193.8, p=0.028), and lower serum IL-6 (12.5±22.8 pg/ml vs. 60.6±180.8, p=0.017) at baseline. In addition, those who achieved remission showed lower SDAI (17.9±11.7 vs. 28.0±13.7, p<0.001), lower HAQ (0.26±0.38 vs. 0.71±0.63, p<0.001), higher SF-36 (p<0.05 in all categories), lower SDS (38.0±9.5 vs. 42.5±9.7, p=0.0061), and lower HAM-D (4.7±3.6 vs. 6.4±5.2, p<0.05) at baseline. On the other hand, there was no significant difference on gender, the types of biologic agents, the order of drugs used in the treatment, MTX dosage, disease duration, serum RF, and ACPA. Conclusions It was suggested that RA patients with lower disease activity, lower dosage of steroid, younger age, higher ADL and QOL, lower depression scores, and lower serum TNF-α and IL-6 at baseline are more likely to achieve clinical 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, S. Isojima: None declared, T. Isozaki: None declared, M. Saito: None declared, N. Oguro: None declared, S. 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

SAT0145 Plasma Levels of Fibrin/Fibrinogen Degradation Products are a Useful Indicator of Disease Activity and Nephritis Complications in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

Background Plasma levels of fibrin/fibrinogen degradation products (FDPs) are fibrinolytic marker and rises after any thrombotic event. Objectives To study whether plasma levels of FDPs could be an indicator of disease status and nephritis complications in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Methods Patients with microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) and eosinophilic granulomatosis with polyangiitis (EGPA) who were admitted to Showa University Hospital for induction therapy and had their plasma FDP levels checked in the active state from October 2005 to May 2012 were retrospectively included. Plasma FDP levels were compared between the active and inactive states of AAV. Among patients in the active state, plasma FDP levels were evaluated for differences in each disease and were compared between patients with and without nephritis complications. Laboratory markers of AAV and nephritis activity were examined to determine their correlations with plasma FDP levels. Vasculitis disease clinical activity was assessed using Birmingham Vasculitis Activity Scores (BVAS), and the relationship between plasma FDP levels and BVAS is discussed. Results Thirty-six MPA, 10 GPA, and 4 EGPA patients (34 females and 16 males, aged 73±13) were included. Thirty-two patients were checked plasma FDP levels in both the active and inactive states; fatal cases were not checked in both states. Plasma FDP levels were high in the active state and decreased significantly after therapy (p<0.001). Among patients in the active state, plasma FDP levels were significantly higher in patients with MPA than in patients with GPA (p<0.01); levels were also higher in patients with EGPA, though the difference was not significant. Plasma FDP levels were significantly higher in patients with nephritis than in patients without nephritis (p<0.05). Plasma FDP levels significantly correlated with serum C-reactive protein levels (rs=0.42, p<0.01), peripheral blood neutrophil counts (rs=0.57, p<0.001), BVAS (rs=0.33, p<0.05), plasma D-dimer levels (rs=0.81, p<0.001), serum creatinine levels (rs=0.31, p<0.05), estimated glomerular filtration rates(rs=-0.39, p<0.01), and urinary N-acetyl-beta-D-glucosaminidase (rs=0.33, p<0.05). No significant correlation was observed between plasma FDP levels and serum antineutrophil cytoplasmic antibody levels. Plasma FDP levels were significantly higher in the patients with proteinuria (p<0.01) and hematuria (p<0.05). Conclusions Plasma FDP levels are a useful indicator of disease activity and nephritis complications in patients with AAV. Disclosure of Interest None Declared