Takahisa Gono

Initial predictors of poor survival in myositis-associated interstitial lung disease: a multicentre cohort of 497 patients

ObjectivenTo identify initial predictors of poor survival in patients with PM/DM-associated interstitial lung disease (ILD).nnnMethodsnWe established a multicentre retrospective cohort of incident cases of PM/DM-associated ILD from 44 institutions across Japan (Multicentre Retrospective Cohort of Japanese Patients with Myositis-associated ILD, JAMI). Inclusion criteria were an onset age ⩾16 years; PM/DM or clinically amyopathic DM according to the published criteria; imaging evidence of ILD; and availability of serum samples for assays of autoantibodies such as anti-melanoma differentiation-associated gene 5 and anti-aminoacyl tRNA synthetase. We collected demographic data and clinical characteristics recorded at the time of diagnosis, as well as follow-up survival data. Predictors of ILD-related mortality were identified by univariate and multivariate analyses.nnnResultsnJAMI enrolled a cohort of 497 patients with PM (15%), classic DM (32%) and clinically amyopathic DM (53%). During the observation period (median 20 months), 76 died of respiratory insufficiency directly related to ILD. Univariate analysis revealed several initial parameters associated with ILD mortality, including demographic, clinical, laboratory, imaging and autoantibody variables. We used multivariate analysis with a stepwise selection of parameters to generate an appropriate predictive model, and identified the following independent risk factors for ILD mortality: age at onset ⩾60 years [hazard ratio (HR) = 4.3, 95% CI: 2.4, 7.5], CRP ⩾1 mg/dl (HR = 2.6, 95% CI: 1.5, 4.8), peripheral capillary oxygen saturation <95% (HR = 2.0, 95% CI: 1.2, 3.4) and anti-melanoma differentiation-associated gene 5 antibody (HR = 7.5, 95% CI: 2.8, 20.2).nnnConclusionnWe established a large cohort of incident cases of PM/DM-associated ILD, and successfully identified independent predictors of short-term ILD mortality.

Rheumatoid factor is correlated with disease activity and inflammatory markers in antineutrophil cytoplasmic antibody-associated vasculitis

BackgroundSome patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) also have positivity of rheumatoid factor (RF). However, the clinical significance of this occurrence remains unknown in AAV patients. The aim of this study was to clarify an association between the presence of RF and clinical features in patients with AAV.ResultsForty-seven patients diagnosed with AAV who were not complicated with RA were enrolled in this study. We compared clinical manifestations of AAV between an RF-positive subset (nu2009=u200929) and an RF-negative subset (nu2009=u200918). The Birmingham Vasculitis Activity Score (BVAS) was higher (Pu2009=u20090.026) in the RF-positive subset than in the RF-negative subset. The levels of CRP and ESR were higher in the RF-positive patients (Pu2009=u20090.020 and Pu2009=u20090.007, respectively) compared to the RF-negative subset. IgM-RF titers were significantly correlated with the BVAS (ru2009=u20090.50, Pu2009=u20090.0004). In addition, the IgM-RF titers had significant correlations with the levels of CRP (ru2009=u20090.41, Pu2009=u20090.004), ESR (ru2009=u20090.39, Pu2009=u20090.016), IgM (ru2009=u20090.36, Pu2009=u20090.016) and IgG (ru2009=u20090.37, Pu2009=u20090.015). The frequency of commencement of dialysis therapy, usage of mechanical ventilation and mortality were higher in the RF-positive subset than in the RF-negative subset.ConclusionsIn patients with AAV, RF titers were significantly correlated with disease activity and the levels of inflammatory markers. The presence of RF could be a poor prognostic factor in patients with AAV.

Comprehensive Understanding of Interstitial Lung Disease in Rheumatoid Arthritis

Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is complicated in approximately 10% of RA patients. High titers of rheumatoid factor or anti-citrullinated protein antibodies (ACPAs), smoking, male gender, older age, longer disease duration, and higher articular disease activity are factors associated with the development of RA-ILD. Genetic factors such as human leukocyte antigen and peptidyl-arginine deiminase (PADI) and environmental factors such as smoking and periodontal disease could be associated with the activation of autoimmunity against citrullinated proteins, the synthesis of ACPAs, and the development of RA or RA-ILD. Metalloproteinase 7 and interferon-r-inducible protein 10 are serum novel biomarkers for the identification of RA-ILD, although surfactant protein A (SP-A), SP-D, and KL-6 are useful conventional biomarkers for the evaluation of RA-ILD. Novel antibodies against the PADI enzyme isoforms 3 and 4 or citrullinated heat shock protein (Hsp) 90a and Hsp90b are associated with RA-ILD and could be useful for predicting the development of RA-ILD. ILD is one of the main causes of mortality in RA. Therefore, prompt management of ILD in RA is necessary. To provide a better prognosis for RA-ILD patients, more efforts need to be made to determine the pathophysiology and the biomarkers for RA-ILD and the causal relationship between the development of ILD and DMARDs.

Overview: Clinical Significance of Lung Disease Associated with Rheumatoid Arthritis

Rheumatoid arthritis (RA) is an immune-mediated disease that primarily affects joints. In the 2000s, numerous novel antirheumatic agents, called biological disease-modifying antirheumatic drugs (bDMARDs) as well as methotrexate, have becom available worldwide. These developments in treatment have resulted in RA remission or low disease activity in greater than 50% of RA patients. This recent progress has allowed RA patients attain improved physical function and prognosis. However, treatment-related events, such as infections, have occurred and occasionally caused severe or fatal outcomes in RA patients. Thus, clinicians must pay attention to complications during treatment with corticosteroids and/or DMARDs, especially bDMARDs. Approximately 50% of the causes of death in RA patients treated with bDMARDs involve respiratory disease, including pneumonia and interstitial lung disease. Therefore, clinicians should manage these pulmonary complications promptly. In this book, we will describe the current status of knowledge about lung disease in RA and would suggest the best form of management of lung disease in RA patients for clinicians, including general practitioners, rheumatologists, respirologists, radiologists, and pathologists. We hope that this book will prove helpful to all types of medical staff and clinicians who take care of RA patients.

Organizing Pneumonia in Rheumatoid Arthritis

Organizing pneumonia (OP) is one of the extra-articular manifestations in rheumatoid arthritis (RA). OP is noninfectious pneumonia with less responsiveness to antibiotics, occasionally mimicking bacterial pneumonia. RA patients with OP typically experience flu-like symptoms and respiratory symptoms such as nonproductive cough and dyspnea at the onset of OP. However, some RA patients do not reveal any respiratory symptoms. The characteristics of chest imaging include bilateral/multiple consolidations or ground-glass opacities with normal lung volumes. The lung lesions are occasionally unilateral/solitary and are frequently observed in the lower zone of the lungs. In the pathophysiology of OP with RA, Th1-dominant response and pro-inflammatory cytokines are associated with the development of OP with RA.

Progressive destructive bronchiolectasis followed by appearance of multiple pulmonary cystic lesions mimicking honeycombing in a patient with rheumatoid arthritis

Abstract The patient was a 62-year-old man with anticitrullinated protein antibody-positive rheumatoid arthritis (RA) and a history of repeated respiratory tract infections and organizing pneumonia for eight years. Each pulmonary event required antibiotic therapy followed by adjunctive intermediate-dose corticosteroids. His RA activity had been controlled by etanercept and tacrolimus. The sequential changes in this patient’s chest CT findings illustrated the development of progressive bronchiectasis and honeycomb-like lesions over the eight years. A lung biopsy was done by video-assisted thoracic surgery. Histological examination of the specimen revealed that the multiple cystic lesions corresponding to the honeycombing on CT were mainly composed of dilated bronchioles, with abundant inflammatory cells, dense fibrous tissue and loss of elastic lamina in the walls, accompanied by vanishing alveolar structure. These findings suggest that a destructive bronchiolar inflammatory process led to the development of multiple cystic lesions mimicking honeycombing. The pathophysiology of these cystic lesions was different from that of the honeycombing associated with usual interstitial pneumonia/idiopathic pulmonary fibrosis.

Improved quantification of a commercial enzyme-linked immunosorbent assay kit for measuring anti-MDA5 antibody

Abstract Objectives: To compare the quantitative performance for measuring anti-MDA5 antibody titer of two enzyme-linked immunosorbent assay (ELISA) systems: an in-house ELISA and the commercial MESACUPTM anti-MDA5 test. Methods: Anti-MDA5 antibody titer was measured in sera from 70 patients with dermatomyositis using an in-house ELISA and the MESACUPTM anti-MDA5 test side-by-side. For the commercial ELISA kit, serum samples diluted 1:101 were used according to the manufacturer’s protocol, but serial dilutions of sera were also examined to identify the optimal serum dilution for quantification. Results: The anti-MDA5 antibody titers measured by the in-house and commercial ELISAs were positively correlated with each other (ru2009=u20090.53, pu2009=u2009.0001), but the antibody titer measured by the commercial ELISA was less sensitive to change after medical treatment, and 37 (80%) of 46 anti-MDA5-positive sera had antibody titer exceeding the quantification range specified by the manufacturer (≥150 index). Experiments using diluted serum samples revealed that diluting the sera 1:5050 improved the quantitative performance of the MESACUPTM anti-MDA5 test, including a better correlation with the in-house ELISA results and an increased sensitivity to change. Conclusion: We improved the ability of the commercial ELISA kit to quantify anti-MDA5 antibody titer by altering its protocol.

AB0154 The il12rb2 gene is a novel candidate susceptible to systemic sclerosis in the japanese population

Background Systemic sclerosis (SSc) is a multisystem disorder of connective tissue characterized by excessive accumulation of extracellular matrix in the skin and various internal organs. Some clinical studies have shown that autoantibodies and genetic polymorphisms could reflect clinical manifestations of SSc. IL12RB2 genetic variants have been associated with multiple autoimmune disorders. In 2012, Bossini-Castillo et al. revealed the association of an IL12RB2 genetic variant with SSc in Caucasian populations. Objectives In this study we explored the association of a single nucleotide polymorphism (SNP) of the IL12RB2 gene with susceptibility to SSc in the Japanese population. Methods Four hundred thirty-five patients with SSc, 46 patients with SLE and 322 healthy controls (HC) were enrolled in this study. Three SNPs (rs1495965, rs924080, and rs3790567) in the IL12RB2 gene were determined by allelic discrimination with the use of each specific TaqMan probe. In patients with SSc, the number of female and male was three hundred eighty-nine and forty-six. The frequencies of the patients with diffuse cutaneous type were 47%, interstitial lung disease were 55%, and anti-topoisomerase I positivity were 33%. Results Only a SNP (rs1495965) was significantly associated with susceptibility to SSc in the Japanese population. At rs1495965, the C allele showed a significantly higher frequency in patients with SScthan that in controls (P = 0.0060; odds ratio, 1.34; 95% confidence interval, 1.1-1.7). In this study, we didn’t support an association of IL12RB2 rs924080 and rs3790567 with SSc, as previously reported in Caucasian populations. In contrast, any significant associations of SLE with the SNPs were observed in the present study. In particular, the clinical subsets of SSc showed a more significant association between the C allele and diffuse cutaneous SSc (dcSSc, P = 0.0015) and the presence of interstitial lung disease (ILD, P = 0.0022), the presence of anti-topoisomerase antibody (Topo, P = 0.00039). We showed the significant association between a SNP in the IL12RB2 gene and susceptibility to SSc in the Japanese population, especially in the presence of dcSSc, ILD, and Topo. However, the SNP we found as a susceptibility gene in the present study was different from the SNP previously reported in the Caucasian population. Conclusions The IL12RB2 gene was one of susceptibility-genes in patients with SSc. Our results strongly suggest that this SNP may be a powerful indicator for the severity of skin and lung involvement in patients with SSc. References Rueda B, Broen J, Simeon C, et al. The STAT4 gene influences the genetic predisposition to systemic sclerosis phenotype. Hum Mol Genet 2009;18:2071-7 Dieude P, Guedj M, Wipff J, et al. Association between the IRF5 re2004640 functional polymorphism and systemic sclerosis: a new perspective for pulmonary fibrosis. Arthritis Rheum 2009;60:225-33 Mizuki N, Meguro A, Ota M, et al. Genome-wide association studies identify IL23R-IL12RB2 and IL-10 as Behcet’s disease susceptibility loci. Nat Genet 2010; 42:703-706 Bossini-Castillo L, Martin JE, Broen J, et al. A GWAS follow-up study reveals the association of the IL12RB2 gene with systemic sclerosis in Caucasian populations. Hum Mol Genet 2012;21:926-933 Disclosure of Interest None Declared

THU0459 Clinical Characteristics in Rheumatoid Arthritis (RA) - Type of Patients with Adult-Onset Still’s Disease

Background Adult-onset Still’s disease (AOSD) is an acute inflammatory disorder of unknown origin that characterized by high spiking fever, polyarthralgia, a salmon-pink skin rash, liver dysfunction and lymphoadenopathy. It is well known that a chronic and erosive arthritis is observed in a number of patients with AOSD, which sometimes may be resistant to a conventional steroid therapy. Objectives In the present study, we aimed to determine clinical features of chronic and erosive arthritis in patients with AOSD, and to establish a biomarker distinguishing them from all of patients with AOSD. Methods Seventy-three patients with AOSD who were treated in Institute of Rheumatology, Tokyo Women’s Medical University enrolled in this study. The patients group consisted of 26 men and 47 women. We classified the patients with AOSD into 2 groups; rheumatoid arthritis (RA)-subtype (n = 16) who met the revised criteria of American College of Rheumatology clinical diagnostic criteria for RA and nonRA-subtype (n = 57) who didn’t met it. Results Our results indicated that serum levels of ferritin and IL-18 were extremely high in patients with AOSD. In particular, serum levels of them were significantly higher in nonRA-subtype than those in RA-subtype, suggesting these biomarkers could be useful for predicting severe arthritis. To define the optimal cut-off point with the highest diagnostic accuracy, we performed ROC for distinct serum ferritin and IL-18 concentrations. The two subtypes were classified by serum ferritin of 1500ng/ml and serum IL-18 of 44 ng/ml. The autoantibodies including ANA, RF and anti-CCP antibody were not detected in most patients with either nonRA-subtype and RA-subtype. Wrist, knee, MCP, MTP joint arthralgia were more frequently observed and cervical spine, hip, DIP joint arthralgia and radiographic findings were more frequently observed than RA. Ankylosing carpal arthritis was observed in 8 patients of RA-subtype. Patients with ankylosing carpal arthritis were accompanied with organized pneumonia, and thrombotic-thrombocytopenic-purpura and two patients in them received the operation of joints. Conclusions Our observations suggest that ferritin and IL-18 may be the useful biomarkers for predicting severe arthritis such like RA. The patterns of arthritis in patients with RA-subtype AOSD are different from those of true RA, and few patients with RA-subtype AOSD have rheumatoid factor or anti-CCP antibody. These findings strongly suppose that the etiology of AOSD with severe arthritis is distinct from true RA. Disclosure of Interest None Declared