Nao Oguro

Clinical Features of Neuropsychiatric Syndromes in Systemic Lupus Erythematosus and Other Connective Tissue Diseases

Systemic lupus erythematosus (SLE) and related disorders are chronic inflammatory diseases characterized by abnormalities and, in some cases, even complete failure of immune responses as the underlying pathology. Although almost all connective tissue diseases and related disorders can be complicated by various neuropsychiatric syndromes, SLE is a typical connective tissue disease that can cause neurological and psychiatric syndromes. In this review, neuropsychiatric syndromes complicating connective tissue diseases, especially SLE are outlined, and pathological and other conditions that should be considered in the differential diagnosis are also discussed.

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.

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.

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

AB0493 Tacrolimus Therapy for Systemic Lupus Erythematosus with or without Renal Involvement during the Maintenance Phase

Background In Japan, a placebo-controlled clinical trial was undertaken to investigate the efficacy and safety of tacrolimus (TAC) for lupus nephritis. To our knowledge, there has been no previous comparison of systemic lupus erythematosus (SLE) with and without renal involvement in the context of TAC treatment. Objectives The aim of this study was to prospectively evaluate the efficacy and safety of TAC combination therapy for SLE with (Group A) or without (Group B) renal involvement during the maintenance phase. Methods From 2009 to 2013, 38 patients were examined in a single-hospital, prospective cohort study over a one-year period. If manifestations of mild active SLE, such as arthritis, skin eruptions, or asymptomatic nephritis, worsened and/or decreasing titers of serum complement (C3c) were observed, TAC combination therapy (from 1 mg to 5 mg once daily) was administered (e.g., TAC was added to the patients existing treatment regimen, and the dosage of prednisolone (PSL) was decreased). Scores on the SLE disease activity index (SLEDAI); PSL dosage; and serum levels of creatinine, C3c, anti-dsDNA titers, and proteinuria were measured. Evidence of renal involvement was detected by laboratory tests: proteinuria was defined as >0.5 g/day, and cellular debris were detected on urinalysis or pathological findings of lupus nephritis by renal biopsy. The main outcome was the efficacy of SLE treatment”. In this study, Welchs t-test, Fishers exact probability test and repeated measures ANOVA were used for statistical analysis. Results The dosage of PSL was reduced, the serum concentration of C3c increased, titers of anti-dsDNA antibodies decreased and SLEDAI scores improved in both groups (p<0.05). In particular, the following symptoms improved by the SLEDAI: headache (from 7 patients to 1 patient), arthritis (from 3 patients to 0 patients), rash (from 6 patients to 2 patients), alopecia (from 5 patients to 0 patients), mucosal ulcers (from 2 patients to 0 patients), and fever (from 5 patients to 1 patient). According to an analysis by repeated measures ANOVA, serum C3c levels improved from 66.9±16.7 to 83.5±14.2 mg/dl (p=0.021) in Group A, and proteinuria improved from 0.09±0.25 to 0.0±0.0 g/g Cr in Group B. There were no significant differences between Groups A and B in terms of age, sex, disease duration, rate of ACE/ARB use or the rate of statin use before TAC treatment. Two patients discontinued treatment as a result of an adverse effect: muscle cramp or rhabdomyolysis. No patients experienced complications with adverse effects of abnormal urinalysis, and none progressed to renal failure or became candidates for dialysis. Conclusions TAC combination therapy is a useful alternative treatment for SLE despite the presence or absence of renal involvement. Disclosure of Interest K. Otsuka: None declared, Y. Miwa Grant/research support: astellas, N. Oguro: None declared, Y. Miura: None declared, S. Ishii: None declared, S. Seki: None declared, H. Furuya: None declared, R. Yanai: None declared, R. Takahashi: None declared, K. Wakabayashi: None declared, T. Isozaki: None declared, N. Yajima: None declared, T. Kasama Grant/research support: astellas DOI 10.1136/annrheumdis-2014-eular.1627