Yoshie Kusunoki

Exacerbation of adult‐onset Still’s disease, possibly related to elevation of serum tumor necrosis factor‐alpha after etanercept administration

Adult‐onset Still’s disease (AOSD) is a systemic inflammatory disease of unknown etiology. A 44‐year‐old male patient presented with AOSD complicated by macrophage activation syndrome after etanercept therapy. His serum tumor necrosis factor‐α (TNF‐α) level was increased dramatically after etanercept therapy. The clinical course of this case suggests that the increased TNF‐α level by etanercept administration might cause macrophage activation syndrome in this case.

Clinical value of second- and third-generation assays of anti-cyclic citrullinated peptide antibodies in rheumatoid arthritis

Anti-cyclic citrullinated peptide (CCP) antibodies are useful for the diagnosis of rheumatoid arthritis (RA) because of their higher specificity.1 First-generation anti-CCP (CCP1) ELISAs were based on synthetic peptides derived from human filaggrin.2 The second-generation anti-CCP (CCP2) test, which contains epitopes selected from libraries of citrullinated peptides, performs better than anti-CCP1.3 4 Recently, a third-generation anti-CCP (CCP3) test was introduced. We compare the performance of the anti-CCP3 test with that of two anti-CCP2 tests, and assess their value in diagnosing RA. A total of 502 participants were studied: 227 patients fulfilling the American College of Rheumatology criteria for RA,5 173 patients with non-RA autoimmune diseases (details are indicated …

FRI0030 Jak2/stat3 is a major pathway of leptin-induced interleukin-6 production by rheumatoid synovial fibroblasts

Background Since proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6, play major pathophysiological roles in rheumatoid arthritis (RA), their inhibitors have recently been developed as potent biological anti-rheumatic drugs. However, they are not curative and the effects are still partial, with many patients failing to respond. Leptin is the product of the ob gene, and is a peptide hormone synthesized almost exclusively by adipocytes that regulates appetite and energy expenditure. It is also suggested that leptin may contribute to inflammation and autoimmunity. We previously reported that serum leptin level was elevated in patients with RA [1]. Accordingly, we examined the direct effects of leptin on cultured rheumatoid synovial fibroblasts (RSFs) in the present study. Objectives To determine the effects of leptin on the production of proinflammatory cytokines by RSFs. Methods Synovial tissue was obtained at total knee replacement operation from patients with RA who gave consent. RSFs were harvested from the synovial tissues of these patients. Leptin receptor mRNAs were detected by reverse transcription–polymerase chain reaction. Productions of mRNA by RSFs and protein concentrations of TNF-α, IL-1β, and IL-6 in the culture medium were detected by real-time PCR and ELISA kit, respectively. Small interfering RNA (siRNA) was transfected into RSFs to down-regulate the expression of leptin receptor. Effects of inhibitors of janus kinase 2 (JAK2), phosphatidylinositol 3-kinase (PI3K), and mitogen-activated protein kinase (MAPK) on IL-6 production were evaluated. Phosphorylation of signal transducer and activator of transcription 3 (STAT3) in RSFs were determined by Western blot analysis. This study was approved (No. 19021) by Ethics Committee of Toho University School of Medicine. Results We detected leptin receptor mRNAs in RSFs. Expressions of IL-1β and IL-6 mRNAs were enhanced in a concentration-dependent manner by addition of leptin to RSFs. IL-6 secretion by RSFs showed an increase after leptin stimulation, while IL-1β did not increase in the culture media. Leptin-induced production of IL-6 by RSFs was decreased after exposure to siRNA targeting leptin receptor (Ob-Rb). A JAK2 inhibitor, but not PI3K and MAPK inhibitors, decreased leptin-induced IL-6 production. Enhanced phosphorylation of STAT3 was observed in RSFs after stimulation by leptin. Conclusions Leptin possibly acts as a proinflammatory cytokine that up-regulates IL-6 production in RSFs via activation of JAK2/STAT3 in RSFs. Leptin and JAK/STAT pathway may represent a new alternative therapeutic target in the treatment of RA. References Yoshino T, Kusunoki N, Tanaka N, Kaneko K, Kusunoki Y, Endo H, Hasunuma T, Kawai S. Elevated serum levels of resistin, leptin, and adiponectin are associated with C-reactive protein and also other clinical conditions in rheumatoid arthritis. Intern Med. 2011;50:269. Disclosure of Interest None Declared

THU0388 Menatetrenone (Vitamin K2) Partially Restores the Suppression of Bone Formation by Glucocorticoid Therapy in Patients with Systemic Autoimmune Diseases

Background Osteoporosis is a serious complication of systemic glucocorticoid (GC) therapy. Bisphosphonate is recommended, however insufficient result have been reported in some cases. Menatetrenone (vitamin K2;VK) is a stimulator of bone formation in vitro and in vivo. We recently have reported that severity of GC-induced osteoporosis might be determined by serum basal sRANKL levels in patients with systemic autoimmune disease [1]. In the present study, we conducted post-hoc analysis to determine whether VK influenced bone metabolism markers in these patients. Objectives To study the efficacy of VK on serum bone metabolism markers and on bone mineral density (BMD) in patients under GC therapy. Methods This study was approved by the Ethics Committee at Toho University Omori Hospital (No. 21-61). Detailed study design was previously shown elsewhere [1]. Briefly, sixty patients (40 women) with systemic lupus erythematosus (n=21), vasculitis syndrome (n=19), polymyositis/dermatomyositis (n=15), and adult-onset Still’s disease (n=5) who were started to received prednisolone (30-60mg daily) were enrolled. Serum samples were obtained just before and 1 to 4 weeks after the start of GC therapy. All patients received bisphosphonate for our regimen of GC therapy. Twenty patients received VK 45 mg daily from 2 weeks after GC therapy. As bone formation markers, serum levels of osteocalcin (OC), procollagen type I N-terminal peptide (PINP), undercarboxylated OC (ucOC), and bone alkaline phosphatase (BAP) were measured. As bone resorption markers, serum levels of type I collagen cross-linked N-telopeptide (NTx) and tartrate resistant acid phosphatase isoform 5b (TRACP-5b) were measured. The BMD of lumbar spine was measured before and after (at 15 months) GC therapy. Results Serum levels of OC and ucOC were significantly (P<0.01) decreased at 1 to 4 weeks after GC therapy. Serum PINP level was also significantly (P<0.01) decreased after GC therapy, while the serum BAP level was not changed. Serum levels of NTx and TRACP-5b did not change during 4 weeks after GC therapy. Additional use of VK restored serum OC level to the half levels of the baseline. In contrast, serum ucOC level was decreased in patients both with and without administration of VK. The percentage of BMD was not changed from baseline in the VK group, whereas it was decreased in the bisphosphonate monotherapy group. Conclusions Additional use of VK partially restored serum OC level from the suppressed level by GC therapy. In addition, the BMD value in the VK group was not changed after GC therapy. These results suggest that VK may possibly provide some effects on bisphosphonate therapy to prevent from GC-induced osteoporosis. References Kaneko K, et al. Changes of serum soluble receptor activator for nuclear factor-κB ligand after glucocorticoid therapy reflect regulation of its expression by osteoblast. J Clin Endocrinol Metab. 2012; 97:E1909-1917. Disclosure of Interest None Declared