H. Yamanaka

Clinical manifestation and prognostic factor in anti-melanoma differentiation-associated gene 5 antibody-associated interstitial lung disease as a complication of dermatomyositis

OBJECTIVEnThe aim of this study is to evaluate the clinical manifestation and prognostic factors of anti-melanoma differentiation-associated gene 5 (MDA5) antibody-associated interstitial lung disease (ILD) with DM.nnnMETHODSnFourteen patients who presented with anti-MDA5 antibody and 10 patients with anti-aminoacyl-tRNA synthetase (ARS) antibody were enrolled. All patients were diagnosed as having DM with ILD. Clinical manifestations in the patients with anti-MDA5 antibody were compared with those in the patients with anti-ARS antibody.nnnRESULTSnThe frequencies of acute/subacute interstitial pneumonia (A/SIP) and fatal outcome were significantly higher in the subset with anti-MDA5 antibody. The creatine kinase (CK) value was significantly lower and the gamma-glutamyl transpeptidase and ferritin values were significantly higher in the subset with anti-MDA5 antibody. Significant correlations were found between PaO(2)/F(i)O(2) and ferritin (r(s) = -0.59, P = 0.035), alveolar-arterial oxygen difference (A-aDO(2)) and KL-6 (r(s) = 0.73, P = 0.016) and A-aDO(2) and ferritin (r(s) = 0.66, P = 0.013) in the subset with anti-MDA5 antibody. The most significant prognostic factor was ferritin. The cumulative survival rate was significantly lower (P < 0.0001) in the subset with ferritin >or=1600 ng/ml than that in the subset with ferritin <1600 ng/ml in anti-MDA5 antibody-associated ILD.nnnCONCLUSIONnBoth serum ferritin and anti-MDA5 antibody are powerful indicators for the early diagnosis of A/SIP with DM. Ferritin also predicts disease severity and prognosis for patients with anti-MDA5 antibody. Intensive treatment should be administered to cases that have anti-MDA5 antibody-associated ILD with DM showing hyperferritinaemia, especially if the ferritin level is >or=1600 ng/ml.

A role for the aryl hydrocarbon receptor and the dioxin TCDD in rheumatoid arthritis

OBJECTIVEnEnvironmental factors are involved in RA pathogenesis and epidemiological studies have suggested that smoking is an environmental risk factor for RA. The 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is one of the major toxic components in cigarettes. To clarify the biological effects of smoking in RA, we investigated the role of TCDD in RA pathogenesis.nnnMETHODSnHuman synovial tissue was obtained from RA and OA patients and aryl hydrocarbon receptor (AhR) expression in these tissues was evaluated using immunohistochemistry and real-time PCR. Expression of various cytokines was measured by real-time PCR following stimulation of RA synoviocytes with different concentrations of TCDD. To study the role of AhR, we treated RA synoviocytes with alpha-naphthoflavone, a known AhR antagonist. To evaluate which signal transduction pathways were stimulated by the TCDD-AhR interaction, we used inhibitors of nuclear factor-kappaB (NF-kappaB) and extra-cellular stimulus-activated kinase (ERK).nnnRESULTSnHigher AhR mRNA and protein levels were observed in RA synovial tissue than in OA tissue. TCDD up-regulated the expression of IL-1beta, IL-6 and IL-8 through binding to AhR, and this effect was transmitted via the NF-kappaB and ERK signalling cascades. AhR expression in synovial cells was up-regulated by TNF-alpha.nnnCONCLUSIONnTNF-alpha activates AhR expression in RA synovial tissue, and that cigarette smoking and exposure to TCDD enhances RA inflammatory processes. TCDD induces inflammatory cytokines via its association with AhR, resulting in stimulation of the NF-kappaB and ERK signalling cascades. Thus TCDD exposure, such as smoking exacerbates RA pathophysiology.

Decrease in orthopaedic operations, including total joint replacements, in patients with rheumatoid arthritis between 2001 and 2007: data from Japanese outpatients in a single institute-based large observational cohort (IORRA)

Several studies from different countries show that the rate of orthopaedic surgery has decreased for patients with rheumatoid arthritis (RA) in recent years. In Sweden, there was a decrease in RA-related lower limb surgical procedures between 1987 and 2001,1 and in RA-related upper limb surgery between 1998 and 2004.2 Denmark has reported a decrease in the incidence of total hip arthroplasties due to RA,3 and the number of total joint replacement (TJR) operations and synovectomies decreased in the Norwegian population from 1994 to 2004.4 Japan has also reported the declining use of synovectomy surgery for patients with RA.5 These changes may reflect trends in disease severity, management and health outcomes in each country. Meanwhile, Sokka et al reported that the rate of TJR …

Cytokine profiles in polymyositis and dermatomyositis complicated by rapidly progressive or chronic interstitial lung disease

OBJECTIVEnPM and DM are often complicated by interstitial lung disease (ILD). In this study we aimed to evaluate various serum cytokines in patients with PM/DM with ILD so as to clarify the differences in pathophysiology between anti-melanoma differentiation-associated gene 5 antibody-associated ILD (anti-MDA5-ILD) and anti-aminoacyl tRNA synthetase antibody-associated ILD (anti-ARS-ILD).nnnMETHODSnWe evaluated the serum cytokine profiles of 38 patients with PM/DM and compared the cytokine profiles of the non-ILD and ILD subsets as well as the anti-MDA5-ILD and anti-ARS-ILD subsets.nnnRESULTSnThe myositis intention-to-treat activity index score, which indicates whole disease activity, significantly correlated with serum IL-6, IL-8, TNF-α and IP-10. These cytokine levels were significantly higher in the ILD subset than the non-ILD subset and were lower in the ILD subset following treatment. By multivariate analysis, TNF-α was the most significant cytokine [P = 0.0006, odds ratio (OR) 1.4, CI 1.1, 2.2] associated with PM/DM with ILD. IL-8 levels were significantly higher in anti-MDA5-ILD than in anti-ARS-ILD, although IL-6, TNF-α and IP-10 levels were high in both subsets. IL-8 was the most significant cytokine (P = 0.0006, OR 1.5, CI 1.1, 3.0) associated with anti-MDA5-ILD by multivariate analysis. Moreover, the ratio of IL-4 to IFN-γ was lower in anti-MDA5-ILD than in anti-ARS-ILD.nnnCONCLUSIONnIL-6, IL-8, TNF-α and IP-10 are associated with global disease activity in PM/DM. These cytokine levels were high, especially in the ILD subset. Serum IL-8 levels and the balance between IL-4 and IFN-γ may contribute to the differences in pathophysiology between anti-ARS-ILD and anti-MDA5-ILD.

Declining use of synovectomy surgery for patients with rheumatoid arthritis in Japan

Several studies from different countries suggest that the rates of orthopaedic surgery have decreased for patients with rheumatoid arthritis (RA) in recent years. From the Rochester Epidemiology Project, there was a reduction in the overall rates for all types of joint-related surgery inpatients.1 The California State Hospitalization Database for 1983–2001 reported a decrease in the rate of total knee arthroplasty for patients with RA.2 From Scandinavian countries, there was a decrease of RA-related surgical procedures to the lower limbs in Swedish patients between 1987 and 2001,3 from Denmark a decrease in the incidence rate of total hip arthroplasties due to RA was reported,4 …

Low disease activity state with corticosteroid may not represent ‘true’ low disease activity state in patients with rheumatoid arthritis

OBJECTIVEnCorticosteroids constitute one of the most common treatments of RA. The purpose of this study is to investigate whether long-term corticosteroid use suppresses the progression of disability in RA patients with low disease activity state.nnnMETHODSnData collected from a large observational cohort of RA patients at our institution were analysed for 214 RA patients whose disease activity score (DAS) 28 and HAQ were available consecutively from October 2000 to October 2004. All 214 patients had average DAS 28 <3.2, meaning only those who had well-controlled RA disease activity were chosen as subjects. The subjects were divided into steroid users who received continuous corticosteroids every month and non-steroid users who did not receive consecutive corticosteroids continuously every month.nnnRESULTSnFifty-five patients (25.7%) were corticosteroid users and 159 (74.3%) were non-users. Average prednisolone for the former group was 4.2 mg/day. No significant differences were observed among baseline variables and RA disease activity variables. However, for steroid users, HAQ progressively worsened with time and for non-steroid users, HAQ progressively improved.nnnCONCLUSIONSnAlthough DAS 28 and other variables may suggest well-controlled RA disease activity, functional capacity of patients on low-dose corticosteroids deteriorated. Thus, low disease activity state with corticosteroid may not represent the true low disease activity state. Along with the achievement of a low disease activity state, long-term efficacy, prognosis, and the quality of remission need to be also considered in the tight control of RA activity.

CTLA-4 CT60 polymorphism is not an independent genetic risk marker of rheumatoid arthritis in a Japanese population

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) molecule belongs to the immunoglobulin superfamily and is a critical down-regulatory molecule expressed on T cells that inhibits T cell activation and maintains peripheral tolerance.1 Previous meta-analyses indicated that exon 1 +49G (rs231775) on CTLA-4 could be a possible genetic risk factor for rheumatoid arthritis (RA).2 3 It causes a non-synonymous substitution in the CTLA-4 protein and has been suggested to influence inhibitory function of CTLA-4 by changing the cell surface expression.4 Recently, CT60 (rs3087243), another polymorphism on 3′ untranslated region, was identified as a disease causal variant for a variety of autoimmune diseases.5 The result was confirmed in a large-scale population of European descent with RA and in a Han Chinese population with RA. …

Lack of association between PADI4 and functional severity in Japanese rheumatoid arthritis patients

Clinical presentation of rheumatoid arthritis (RA) varies from mild deformity of small joints to mutilating severe arthritis causing remarkable functional disorder and restriction of daily life activities. Prediction of disease outcome may allow better targeting of aggressive treatment. Recently, anti-cyclic citrullinated peptide antibody (anti-CCP) has been reported to be associated with disease outcomes.1–5 Peptidylarginine deiminase type 4 ( PADI4 ), encoding citrullinating enzyme, was identified as one of the RA susceptibility genes and was also reported to be associated with the level of anti-CCP in RA patients.6 These findings suggest the hypothesis that PADI4 determines disease severity of RA as well as its susceptibility. Our aim was to investigate the association between …

FRI0436 CCPA Reverses the Fibrotic Phenotype of Dermal Fibroblasts in Systemic Sclerosis

Background Systemic Sclerosis (SSc) is a connective tissue disease with excessive fibrosis that affects the skin and various internal organs. Skin fibrosis is one of the main manifestations of SSc, however, the therapeutic strategy has not been established merely because the fibrotic mechanisms in the affected skin has not been fully elucidated. An autotaxin (ATX)/lysophosphatidic acid (LPA) axis has emerged as a novel pathogenic factor in various fibrotic disorder including SSc [1]. Cyclic phosphatidic acid (CPA), which is catalyzed by ATX as well as LPA, shows several distinct activities from LPA such as the inhibitory effects of proliferation, invasion and metastasis of cancer cells [2]. In addition, CPA has been reported to inhibit ATX activity and then, LPA production. These findings suggest that CPA may be a potent agent to ameliorate fibrosis. Objectives The aim of our study was to investigate the anti-fibrotic property of metabolically stabilized carba derivatives of CPA (CCPA) in dermal fibroblasts from patients with SSc. Methods Primary human dermal fibroblasts obtained from SSc patients or healthy individuals were incubated with CCPA in the presence or absence of TGF-β1 or LPA. The mRNA levels of COL1A1, COL1A2, CTGF, ACTA2, fibronectin (FN), MMP-1, endothelin-1 (ET-1), IL-6 and TGF-β1 were assessed using quantitative real-time RT-PCR. In addition, the protein levels of type I collagen, CTGF and αSMA in cell lysates were evaluated using Western blotting. To examine the effects of CCPA on the Smad and the MAPK signaling pathway, the expression of total and phosphorylated Smad2/3, p38 and ERK1/2 were detected using Western blotting. Results CCPA significantly decreased the expression of COL1A1, COL1A2, CTGF, ACTA2 and FN mRNA in SSc- and healthy-dermal fibroblasts stimulated by TGF-β1 in a concentration dependent manner, whereas the expression of MMP-1 mRNA was increased. Furthermore, the expression of TGF-β1, ET-1 and IL-6 mRNA was significantly down-regulated at 24h after the treatment with CCPA. The protein levels of type I collagen, CTGF and αSMA were also significantly reduced by CCPA. These effects were shown without the stimulation of LPA. CCPA suppressed the phosphorylation of p38 and ERK1/2, suggesting that the anti-fibrotic effects of CCPA were in part through MAPK signaling pathways. Conclusions We demonstrated for the first time that CCPA reversed the fibrotic phenotype of SSc dermal fibroblasts. Intriguingly, CCPA showed anti-fibrotic effects in SSc dermal fibroblasts without the stimulation of LPA, suggesting that CCPA has pleiotropic effects other than antagonizing the ATX/LPA axis. CCPA would be a novel therapeutic strategy for the treatment of skin fibrosis of SSc. References Castelino F, et al. Arthritis Rheum 2011;63:1405-15. Baker D, et al. J Biol Chem 2006;281:22786-93. Disclosure of Interest None declared

SAT0667 Presepsin and procalcitonin are of diagnostic value for bacterial infection in patients with connective tissue diseases

Background Recently, presepsin (soluble CD14-subtype) and procalcitonin are reported as a good diagnostic markers of bacterial infection, especially sepsis. However, their utility in patients with connective tissue diseases (CTDs) has been unknown. Objectives To assess the diagnostic value of presepsin and procalcitonin in patients with CTDs. Methods We enrolled the consecutive patients with CTDs, who checked the level of procalcitonin and/or presepsin during January to September, 2016, retrospectively. We divided two groups; the infection group and non-infectious group. Infection was diagnosed by symptoms, micro-bacterial methods and the good response to antibiotics. The data analysis were assessed using IBM SPSS statistics 22. Results Eighty-four patients with CTDs were enrolled, including 42 patients with rheumatoid arthritis (RA). The level of procalcitonin was evaluated in all patients, and the level of presepsin was in 48 patients. Thirty-six patients were classified in infection group; 38 patients in the CRP-positive non-infection group; and 10 patients in CRP-negative non-infection group. The level of presepsin was significant higher in infection group than CRP-positive non-infection group (693 +/- 577 pg/mL vs. 250 +/- 101 pg/mL, p<0.01) (Fig. 1). Among the patients with RA, the level of presepsin was significant higher in infection group than non-infection group (809 +/- 637 pg/mL vs. 233 +/- 135 pg/mL, p<0.01). AUCs of procalcitonin (0.823) and presepsin (0.821) showed similar diagnostic value. The cut-off value of presepsin and procalcitonin were 265 pg/mL and 0.16 ng/mL, respectively (sensitivity: 78.3% and 82.6%, specificity: 76.0% and 76.0%). Conclusions Procalcitonin and presepsin may be of diagnostic value for bacterial infection in patients with CTDs, especially may distinguish bactrial infection from active phase in patients with CTDs. Disclosure of Interest None declared