Masayu Umemura

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.

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

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

SAT0141 Correlation of Serum Macrophage Migration Inhibitory Factor Levels With Response to Tocilizumab Therapy in Patients with Rheumatoid Arthritis

Background Cytokines, including chemokines are key mediators of the pathogenesis of rheumatoid arthritis (RA). Because tocilizumab, a humanized monoclonal antibody that is specific for the IL-6 receptor, induces rapid clinical improvement in RA patients, it is important to investigate whether tocilizumab administration has any effect(s) on serum cytokine profiles and whether such changes correlated with the clinical improvement of RA disease activity. Objectives To examine the relationship between serum cytokine levels and clinical responsiveness to tocilizumab in patients with RA and to investigate the impact of tocilizumab administration on serum cytokine levels. Methods The disease status of 26 RA patients was assessed at baseline and after 12 weeks of tocilizumab administration (8 mg/kg) using the clinical disease activity index (CDAI) and the disease activity score 28 (DAS28). The minor and major responses to tocilizumab were defined as an improvement of as an improvement of ≥6.7 and 14, respectively, from the baseline CDAI1. Serum levels of the following cytokines at baseline and after 12 weeks were quantified using double ligand enzyme-linked immunosorbent assays: TNF alpha, IL-6, CCL2, CCL3, CXCL8, CXCL10, CX3CL1 and macrophage migration inhibitory factor (MIF). Results After 12 weeks of tocilizumab administration, 19 patients achieved minor and major responses (referred to as the responder group), but there were no significant responses in the other 7 patients (the non-responder group). Although no significant differences at baseline were found for disease activity (CDAI and DAS28), clinical parameters, and baseline serum cytokine levels measured between the groups, only serum MIF levels at baseline were higher in the responder group (2501.5±2325.8 pg/ml, p<0.05) than in the non-responder group (905.9±873.3 pg/ml). Furthermore, MIF levels in the responder group, but not in the non-responder group, were significantly decreased after tocilizumab administration. When RA patients were divided into two groups based on their basal MIF levels, a comparison of patients with lower (<1347 pg/ml; median of MIF levels) and higher basal MIF levels revealed no significant differences in clinical parameters. However, the rate of clinical responses to tocilizumab appeared to be significantly higher (p<0.05) in the higher MIF group (responder, 12 cases vs. non-responder, 1 case) than the lower MIF group (responder, 7 cases vs. non-responder, 6 cases). Finally, in response to tocilizumab, serum MIF levels significantly decreased in patients with higher basal MIF levels (3470.6±2270.9 to 1252.3±1117.7, p<0.01) but not in those with lower basal levels. Conclusions We demonstrated that the MIF levels declined in patients who showed a clinical response to tocilizumab therapy, whereas the serum levels of other cytokines which were affected by TNF antagonists2 were not significantly affected by tocilizumab treatment. Further, our results suggest that the MIF regulation in patients with active RA may be sensitive to anti-IL-6 therapy. References Saevarsdottir S, et al. Ann Rheum Dis 2011;70:469. Kasama T, et al. J Clin Rheumatol Musculoskel Med 2010;1:19. Disclosure of Interest None Declared

THU0441 Potential Fatality Predictors Caused by Pneumocystis Pneumonia (PCP) in Rheumatic Disease

Background Complications of pneumocystis pneumonia (PCP) are one of the predictors of fatality in rheumatic disease. Although clinical characteristics and risk factors for PCP in rheumatic diseases have been studied, there have been no reports of poor prognosis factor of the PCP. Objectives We examined the poor prognosis factors caused by PCP in rheumatic disease at admission. Methods From 2010 to 2012, 28 patients with rheumatic diseases and coexisting PCP were examined retrospectively (rheumatoid arthritis, 19 patients; systemic lupus erythematosus, 2 patients; systemic sclerosis, 2 patients; microscopic polyangiitis, 2 patients; relapsing polychondritis, 1 patient; pseudogout, 1 patient; autoimmune hepatitis, 1 patient). We divided the patients into two groups: surviving patients (group A; n=23) and deceased patients (group B; n=5). Age, sex, smoking history, past history of pulmonary disease, hospitalization and prednisolone dosage were examined. The following were also recorded at admission: white blood cell count, lymphocyte count, arterial blood gas PaO2/FIO2 ratio, serum creatinine level with estimated glomerular filtration rate (eGFR), and the levels of hemoglobin, lactase dehydrogenase(LDH), albumin, C-reactive protein (CRP), β-D-glucan, Krebs von den Lungen-6 (KL-6), pulmonary surfactant-D (SP-D), IgG, and IgA. Results The results were as follows: Conclusions Either higher age, high serum creatinine levels and CRP or low serum albumin levels, IgA and PaO2/FIO2 ratio are potential fatality predictors following admission caused by PCP in patients with rheumatic disease. Disclosure of Interest None Declared