Goh Tsuji

Impact of smoking as a risk factor for developing rheumatoid arthritis: A meta-analysis of observational studies

Objectives: To assess whether smoking is a risk factor for developing rheumatoid arthritis (RA). Design: Meta-analysis. Method: Data sources were observational studies that examined the association between smoking history and the risk of developing RA identified through Medline and EMBASE (from 1966 to December 2006), relevant books and a reference search. Two authors independently extracted the following: authors’ names, publication year, sample size, participant characteristics, odds ratios (OR) or relative risks, adjustment factors, study design and area where the study was conducted. Data syntheses were based upon random effects model. Summarised syntheses effects were expressed by OR. Results: Sixteen studies were selected from among 433 articles. For men, summary OR for ever, current and past smokers were 1.89 (95% CI 1.56 to 2.28), 1.87 (1.49 to 2.34) and 1.76 (1.33 to 2.31), respectively. For rheumatoid factor-positive (RF+) RA, summary OR for ever, current and past smokers were 3.02 (2.35 to 3.88), 3.91 (2.78 to 5.50) and 2.46 (1.74 to 3.47), respectively. Summary OR for 20 or more pack-years of smoking was 2.31 (1.55 to 3.41). For women, summary OR for ever, current and past smokers were 1.27 (1.12 to 1.44), 1.31 (1.12 to 1.54) and 1.22 (1.06 to 1.40), respectively. For RF+ RA, summary OR for ever, current and past smokers were 1.34 (0.99 to 1.80), 1.29 (0.94 to 1.77) and 1.21 (0.83 to 1.77). Summary OR for 20 or more pack-years of smoking was 1.75 (1.52 to 2.02). Conclusion: Smoking is a risk factor for RA, especially RF+ RA men and heavy smokers.

(-)-Epigallocatechin-3-Gallate Suppresses Osteoclast Differentiation and Ameliorates Experimental Arthritis in Mice

OBJECTIVE To verify the effects of (-)-epigallocatechin-3-gallate (EGCG) on osteoclast differentiation and on experimental arthritis in mice. METHODS Human osteoclasts were differentiated from peripheral blood monocytes. The effects of EGCG were examined by tartrate-resistant acid phosphatase (TRAP) staining, bone resorption assay, Western blotting, and quantitative real-time polymerase chain reaction. Arthritis was induced in mice by injecting a cocktail of monoclonal antibodies against collagen. EGCG (20 microg/gm body weight) was administered intraperitoneally every day from day 0 through the end of the experiments (day 15). The effects of EGCG were determined by assessments of joint swelling, histologic changes, and TRAP staining on day 15. RESULTS EGCG reduced the generation of TRAP-positive multinucleated cells, bone resorption activity, and osteoclast-specific gene expression without affecting cell viability. EGCG down-regulated expression of nuclear factor of activated T cells c1 (NF-ATc1), but not of NF-kappaB, c-Fos, and c-Jun, suggesting that down-regulation of NF-ATc1 is one of the molecular bases of EGCG action. Additionally, EGCG treatment ameliorated clinical symptoms and reduced histologic scores in arthritic mice (P < 0.05). The in vivo effect of EGCG on osteoclast differentiation was not clear in this model, probably because EGCG suppressed the inflammation itself. CONCLUSION EGCG suppressed osteoclast differentiation and ameliorated experimental arthritis in mice over the short term. It remains to be established whether EGCG is useful for the prevention and treatment of osteoporosis and rheumatoid arthritis.

IgG4-related skin manifestations in patients with IgG4-related disease

We describe two cases of IgG4-related disease associated with skin manifestations with IgG4-positive plasma cells. The first patient was a 52-year-old woman with a 3-year history of IgG4-related sialadenitis who presented with pruritic, indurated erythematous lesions on the auricle, postauricular and submandibular regions and neck. A skin biopsy showed infiltration of IgG4-positive plasma cells in the subcutaneous tissue. The second patient was a 53-year-old woman with IgG4-related lesions in the ocular adnexal tissues and nasal cavity who presented with pruritic, indurated erythema on the cheek and submandibular region. Histopathological examination of a skin biopsy revealed a dense, patchy infiltrate comprised of lymphocytes, IgG4-positive plasma cells and eosinophils around blood vessels and sweat glands in the entire dermis and subcutis. The skin lesions in these cases were considered to be skin manifestations of IgG4-related disease. The findings of these two cases together with the three reported cases of IgG4-related disease with skin manifestations in the literature suggest that IgG4-related skin lesions may appear on the scalp, face, neck, auricle and postauricular regions during the course of IgG4-related disease.

Plasma Platelet-derived Microparticles in Patients with Connective Tissue Diseases

Objective. To clarify the role of platelet-derived microparticles (PDMP), which are small vesicles with thrombotic and immunological properties, in systemic lupus erythematosus (SLE), systemic sclerosis (SSc), dermatomyositis/polymyositis (PM/DM), and mixed connective tissue disease (MCTD). Methods. Plasma levels of PDMP were measured by ELISA, and compared among patients with one of the 4 diseases. Association of PDMP levels with clinical characteristics and medication of the patients was also examined. Results. PDMP levels were higher in patients with MCTD and SSc than in controls. Multiple linear regression analysis revealed that patients with Raynaud’s phenomenon (RP) showed higher PDMP levels than those without. PDMP levels in individual patients did not fluctuate significantly over several months. Conclusion. PDMP level is associated with MCTD, SSc, and RP, and could be a novel marker for RP.

Role of imaging studies in the diagnosis and evaluation of giant cell arteritis in Japanese: report of eight cases

The objective of this study is to clarify the characteristics and imaging results of Japanese patients with giant cell arteritis (GCA). Eight patients with biopsy-proven GCA were enrolled. Their clinical data and imaging results were retrospectively examined from their medical records. All the patients met the criteria for the classification of GCA by the American College of Rheumatology. Although the clinical manifestations are similar to those previously reported, none of the eight patients presented ocular symptoms, and half of them presented jaw claudication. Ultrasonography (US) of temporal artery showed the halo sign in all the patients. Fluorodeoxyglucose positron emission tomography (FDG-PET) was performed in four patients and indicated the presence of aortitis of the patients. US is a quick and noninvasive test to detect inflammation of temporal artery, and FDG-PET is very helpful for early diagnosis of aortitis in GCA. Awareness of the disease and appropriate imaging tests will result in diagnosis of GCA.

Epidural spinal tumor and periaortitis as rare complications of Wegener’s granulomatosis

This case report describes findings in a 61-year-old woman who manifested scleritis, small pulmonary nodules, otitis media, periaortitis, and progressive epidural spinal tumor, associated with elevated serum myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) levels. She was clinically diagnosed with Wegener’s granulomatosis, although vasculitis was not diagnosed due to the lack of typical histological findings. We discuss the differential diagnosis in this patient, and the association of MPO-ANCA with periaortitis or epidural spinal tumor.

Modification of Cytokine Milieu by A2A Adenosine Receptor Signaling–Possible Application for Inflammatory Diseases

Pro‐inflammatory cytokine TNF‐alpha (TNF) production from in vitro lipopolysaccharide (LPS)‐stimulated human peripheral blood CD14+ cells (PB‐CD14) was inhibited by A2A adenosine receptor (AdoR) (A2AR) or ß2 adrenergic receptor (ADR) (ß2R) signaling in a concentration‐dependent manner. These inhibitory effects were presumably mediated by the increase in intracellular cAMP. Furthermore A2AR agonist and ß2R agonist synergistically inhibited the TNF production of LPS‐stimulated PB‐CD14 cells. These results suggest that the anti‐inflammatory effect of extracellular adenosine is, at least in part, due to the modification of the cytokine milieu via A2A signaling, and that the targeting of both A2AR and ß2R may have strong therapeutic potential for the inflammatory diseases.

Analysis of gastrointestinal virus infection in immunocompromised hosts by multiplex virus PCR assay

Regarding viral infection of intestinal mucosa, there have been only a few studies on limited diseases, targeting a few herpes family viruses. In this study, we analyzed 12 kinds of DNA viruses including 8 species of herpes family viruses in the gastrointestinal mucosa of patients with hematologic malignancies, inflammatory bowel diseases, collagen diseases, or other miscellaneous forms of gastroenteritis using the multiplex virus PCR assay, which we recently developed. The virus PCR assay yielded positive results in 63 of 102 patients; Epstein-Barr virus (EBV) was the most frequently detected, followed by cytomegalovirus (CMV), human herpes virus 6 (HHV-6), HHV-7, parvovirus B19, and herpes simplex virus type 1. The frequencies of viral detection in the 4 diseases were similar involving these 6 viruses. Regarding CMV colitis, the multiplex virus PCR assay was superior to the immunohistopathologic method in detecting CMV. All viruses were more efficiently detected in the mucosa than in the blood in individual patients. These results suggest that CMV, EBV, and HHV-6 were commonly detected in the gastrointestinal mucosa of patients with these 4 diseases, and our multiplex virus PCR assay was useful for the early diagnosis of gastrointestinal virus infection, especially CMV colitis.

CHST3 and CHST13 polymorphisms as predictors of bosentan-induced liver toxicity in Japanese patients with pulmonary arterial hypertension

ABSTRACT Bosentan, an endothelin receptor antagonist, has been widely used as a first‐line drug for the treatment of pulmonary arterial hypertension (PAH). In addition, bosentan is approved for patients with digital ulcers related to systemic sclerosis. Liver dysfunction is a major adverse effect of bosentan and may lead to discontinuation of therapy. The purpose of this study was to identify genomic biomarkers to predict bosentan‐induced liver injury. A total of 69 PAH patients were recruited into the study. An exploratory analysis of 1936 single‐nucleotide polymorphisms (SNPs) in 231 genes involved in absorption, distribution, metabolism, and elimination of multiple medications using Affimetrix DMET™ (Drug Metabolism Enzymes and Transporters) chips was performed. We extracted 16 SNPs (P < 0.05) using the Jonckheere‐Terpstra trend test and multiplex logistic analysis; we identified two SNPs in two genes, CHST3 and CHST13, which are responsible for proteoglycan sulfation and were significantly associated with bosentan‐induced liver injury. We constructed a predictive model for bosentan‐induced liver injury (area under the curve [AUC]: 0.89, sensitivity: 82.61%, specificity: 86.05%) via receiver operating curve (ROC) analysis using 2 SNPs and 2 non‐genetic factors. Two SNPs were identified as potential predictive markers for bosentan‐induced liver injury in Japanese patients with pulmonary arterial hypertension. This is the first pharmacogenomics study linking proteoglycan sulfating genes to drug‐induced liver dysfunction, a frequently observed clinical adverse effect of bosentan therapy. These results may provide a way to personalize PAH medicine as well as provide novel mechanistic insights to drug‐induced liver dysfunction.

SAT0083 The genetic and clinical prediction models for efficacy and hepatotoxicity of methotrexate in patients with rheumatoid arthritis

Background The efficacy and toxicity of methotrexate (MTX) depend on individual patients with rheumatoid arthritis (RA) and are difficult to predict before treatment although MTX is the anchor drug and achieving the treatment target earlier is desirable to prevent progression of structural and functional damage. Our previous studies revealed high predictive accuracy of single nucleotide polymorphisms (SNPs) to predict the efficacy and toxicity of MTX, suggesting the influence of genetic variations in enzymes associated with MTX metabolism and folate metabolic pathway1,2. However, higher accuracy and replicability is demanded for clinical application. Objectives To develop combined genetic and clinical models to predict the efficacy and hepatotoxicity of MTX. Methods Patients with RA under the treatment of MTX according to Japanese guideline for the management of RA with MTX were enrolled. To predict the efficacy and hepatotoxicity, 1971 polymorphisms of 246 enzymes/transporters potentially relevant to pharmacokinetics and pharmacodynamics of MTX were measured by the DMET microarray (Affymetrix Inc.) and direct-sequencing method and clinical variables at baseline were collected. As for efficacy, the EULAR-CRP response criteria was chosen to classify patients with RA as responders (good response) and non-responders (moderate or no response). Hepatotoxicity was defined as either serum AST or ALT levels higher than 1.5 times the upper limit of the normal range. Among SNPs and clinical variables with significant association with outcomes using univariate analyses, stepwise model selection was conducted by Akaike information criterion in logistic regression model and receiver operating characteristic (ROC) analyses were performed. Bootstrapping (n=100,000) was used to assess the robustness of the results. Results A total of 166 patients with RA was included. The median age was 61.5 years with 81.3% of women. For efficacy, genetic prediction model using 7 SNPs showed area under the curve of ROC (AUC) was 0.822 with sensitivity of 74.3% and specificity of 76.8%, while combined clinical and genetic model indicated AUC was 0.844 with sensitivity of 81.5% and specificity of 76.9%. By incorporating clinical variables into the genetic model, overall category-free net reclassification improvement (NRI) was 0.700 (p<0.0001) and overall integrated discrimination improvement (IDI) was 0.089 (p=0.0005). For hepatotoxicity, genetic prediction model using 7 SNPs showed AUC was 0.783 with sensitivity of 70.0% and specificity of 80.0%, while combined clinical and genetic model indicated AUC was 0.906 with sensitivity of 85.1% and specificity of 87.8%. Overall category-free NRI was 1.122 (p<0.0001) and overall IDI was 0.279 (p<0.0001). Conclusions Genetic and clinical models showed higher predictive accuracy for both efficacy and hepatotoxicity of MTX. These models should be validated with a larger scale of prospective study. References [1] Kumagai S. Ann Rhem Dis. 2015;74(suppl2):263. [2] Kumagai S. Ann Rhem Dis. 2014;73(suppl2):119. Acknowledgements None. Disclosure of Interest None declared