Shinichiro Tsunoda

Protective effect of the HLA-DRB1*13:02 allele in Japanese rheumatoid arthritis patients.

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease. Certain HLA-DRB1 “shared-epitope” alleles are reported to be positively associated with increased RA susceptibility, whereas some of the other alleles may be negatively associated. However, studies on the latter are rare. Here, we focus on the protective effects of DRB1 alleles in Japanese RA patients in an association study. Relative predispositional effects (RPE) were analyzed by sequential elimination of carriers of each allele with the strongest association. The protective effects of DRB1 alleles were investigated in patients stratified according to whether they possessed anti-citrullinated peptide antibodies (ACPA). The DRB1*13:02 allele was found to be negatively associated with RA (P = 4.59×10−10, corrected P (Pc) = 1.42×10−8, odds ratio [OR] 0.42, 95% CI 0.32–0.55, P [RPE] = 1.27×10−6); the genotypes DRB1*04:05/*13:02 and *09:01/*13:02 were also negatively associated with RA. The protective effect of *13:02 was also present in ACPA-positive patients (P = 3.95×10−8, Pc = 1.22×10−6, OR 0.42, 95%CI 0.31–0.58) whereas *15:02 was negatively associated only with ACPA-negative RA (P = 8.87×10−5, Pc = 0.0026, OR 0.26, 95%CI 0.12–0.56). Thus, this study identified a negative association of DRB1*13:02 with Japanese RA; our findings support the protective role of DRB1*13:02 in the pathogenesis of ACPA-positive RA.

Cytokine profile in adult-onset Still's disease: Comparison with systemic juvenile idiopathic arthritis

To compare pro-inflammatory cytokine profiles and kinetics in patients with adult-onset Stills disease (AOSD) to those in patients with systemic juvenile idiopathic arthritis (s-JIA), we analyzed serum cytokine concentrations in 33 patients with AOSD and 77 patients with s-JIA and compared them with clinical features. Patients with AOSD and s-JIA shared a common cytokine profile pattern of a significant increase in IL-18. Patients with AOSD were classified into two subgroups based on serum IL-6 and IL-18 levels. The number of patients with arthritis was significantly higher in the IL-6-dominant subgroup. The cytokine patterns associated with s-JIA and AOSD share common features, such as a significant and predominant increase in IL-18. Distinct IL-6- and IL-18-based cytokine profiles might be responsible for distinct clinical manifestations. The presence of two distinct subgroups in patients with both diseases further supports the view that s-JIA and AOSD share a disease category.

Association of human leukocyte antigen alleles with chronic lung diseases in rheumatoid arthritis

OBJECTIVES Chronic lung diseases including interstitial lung disease and airway disease (AD) occur in RA patients. Interstitial lung disease and AD in RA are extra-articular manifestations that influence the prognosis quoad vitam of RA. Studies on associations of HLA alleles with RA have been carried out, and shared epitopes of several alleles are reported to be associated with RA susceptibility. Few association studies in RA subpopulations with chronic lung diseases have been conducted. The aim of the study was to identify HLA alleles predisposing to RA phenotypes including the presence of AD. METHODS Associations of HLA-DRB1 and DQB1 alleles with chronic lung diseases in RA were analysed. RESULTS A positive association was found between the DR4 serological group and resistance to usual interstitial pneumonia [P = 0.0250, odds ratio (OR) 0.62, 95% CI: 0.41, 0.93]. The DR2 serological group was associated with susceptibility to usual interstitial pneumonia (P = 0.0036, OR = 1.86, 95% CI: 1.23, 2.81). An association was found for shared epitopes alleles with bronchiolitic AD (P = 0.0040, OR = 2.06, 95% CI: 1.24, 3.41). DQB1*03:01 was associated with bronchiectatic AD (P = 0.0021, corrected P-value (Pc) = 0.0315, OR = 1.99, 95% CI: 1.30, 3.06), as well as with emphysema (P = 0.0007, Pc = 0.0104, OR = 2.43, 95% CI: 1.49, 3.95). In combined analysis, a predisposing association of DQB1*03:01 (P = 1.94 ×10(-5), Pc = 0.0003, OR = 2.16, 95% CI: 1.53, 3.06) and a negative association of DQB1*03:02 (P = 0.0008, Pc = 0.0117, OR = 0.33, 95% CI: 0.17, 0.67) with bronchiectatic AD or emphysema were observed in RA. CONCLUSION The present study identified an association of HLA-DQB1*03:01 with predisposition to, and DQB1*03:02 with resistance to, bronchiectatic AD or emphysema in RA.

Ultrasonography predicts achievement of Boolean remission after DAS28-based clinical remission of rheumatoid arthritis

Abstract Objectives. To determine whether ultrasonography (US) predicts Boolean remission in rheumatoid arthritis (RA) patients who had achieved disease activity score in 28 joints (DAS28)-based remission criteria. Methods. Thirty-one RA patients in DAS28-based clinical remission were recruited. US semiquantitatively determined Gray scale (GS) and power Doppler (PD) signal scores in the bilateral wrists and all metacarpophalangeals and proximal interphalangeals. Total GS score and total PD score were calculated as the sum of individual scores for each joint. Results. Among 22 RA patients, who maintained DAS28 remission for 2 years, 16 met Boolean remission criteria at the end of study. Both total GS and total PD scores at baseline were significantly lower in Boolean remission group than non-remission group. There was no significant difference in other baseline parameters, including duration of disease, duration of remission, mTSS, and disease activity composite parameters between the two groups. Among the factors for Boolean remission criteria at 2 years, patient global assessment score was associated with total GS score at the entry, while swollen joint count was related to total PD score. Conclusions. Null or low grade of GS and PD findings in US are associated with achieving Boolean remission. Thus, US is essential for assessment and prediction of “deeper remission” of RA.

Predicting joint destruction in rheumatoid arthritis with power Doppler, anti-citrullinated peptide antibody, and joint swelling

Objective. To determine combined evaluation of musculoskeletal ultrasonography (MSUS) and power Doppler (PD) signals, anti-citrullinated peptide antibody (ACPA), and other clinical findings improve the prediction of joint destruction in rheumatoid arthritis (RA). Methods. We performed a retrospective study of 331 RA patients (female n = 280 and male n = 51, mean age: 57.9 ± 13.2 years) who underwent MSUS from 2002 to 2012. Correlations with progression of joint destructions in 1,308 2nd and 3rd metacarpophalangeal (MCP) joints and various factors including PD signals of the same joints, clinical findings, age, disease duration at the study entry, gender, observation period, radiographic bone scores according to modified Sharp–van der Heijde methods, ACPA, and rheumatoid factor (RF) were analyzed in patient- and joint-based fashions, using univariate and multivariate logistic regression analyses and generalized linear mixed model. Results. Patients’ characteristics were as follows: mean disease duration: 5.7 ± 7.5 years, observation period: 4.6 ± 2.6 years, RF positivity: 79.9%, and ACPA positivity: 77.5%. PD-positive 2nd and 3rd joints showed higher rate of joint destruction, especially in ACPA-positive patients. Moreover, PD-positive joints in ACPA-positive patients showed joint destruction even in joints without swelling. Multivariate analysis determined PD, swollen joint (SJ), observation period, basal radiographic bone scores, and ACPA as independent risks for joint destruction. Conclusion. PD, SJ, basal radiographic bone scores, and ACPA are independent predictors for the joint destruction of 2nd and 3rd MCPs in RA; thus, considering these factors would be useful in daily practice.

Evaluation of the alternative classification criteria of systemic lupus erythematosus established by Systemic Lupus International Collaborating Clinics (SLICC)

Abstract Objective: To evaluate the performance of the 2012 Systemic Lupus International Collaborating Clinics criteria (SLICC-12) on classifying systemic lupus erythematosus (SLE) in an uncontrolled multi-centered study with real-life scenario of the patients in Japan. Methods: This study comprised 495 patients with SLE or non-SLE rheumatic diseases and allied conditions from 12 institutes in Japan. Chart review of each patient was performed by the 27 expert rheumatologists and diagnosis of 487 cases reached to the consensus. Value of the SLICC-12 on SLE classification was analyzed comparing with the 1997 revised American College of Rheumatology SLE classification criteria (ACR-97) employing the expert-consented diagnoses. Results: Compared to the ACR-97, the SLICC-12 had a higher sensitivity (ACR-97 vs. SLICC-12: 0.88 vs. 0.99, p < .01) and comparable specificity (0.85 vs. 0.80). The rate of misclassification (0.14 vs. 0.11) or the area under the receiver operating characteristic curves (0.863 vs. 0.894) was not statistically different. In the cases that diagnoses corresponded in high rates among experts, both criteria showed high accordance of SLE classification over 85% with the expert diagnoses. Conclusion: Although employment of SLICC-12 for the classification for SLE should be carefully considered, the SLICC-12 showed the higher sensitivity on classifying SLE in Japanese population.

Splicing variant of WDFY4 augments MDA5 signalling and the risk of clinically amyopathic dermatomyositis

Objectives Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare autoimmune diseases in which both genetic and environmental factors play important roles. To identify genetic factors of IIM including polymyositis, dermatomyositis (DM) and clinically amyopathic DM (CADM), we performed the first genome-wide association study for IIM in an Asian population. Methods We genotyped and tested 496 819 single nucleotide polymorphism for association using 576 patients with IIM and 6270 control subjects. We also examined the causal mechanism of disease-associated variants by in silico analyses using publicly available data sets as well as by in in vitro analyses using reporter assays and apoptosis assays. Results We identified a variant in WDFY4 that was significantly associated with CADM (rs7919656; OR=3.87; P=1.5×10−8). This variant had a cis-splicing quantitative trait locus (QTL) effect for a truncated WDFY4isoform (tr-WDFY4), with higher expression in the risk allele. Transexpression QTL analysis of this variant showed a positive correlation with the expression of NF-κB associated genes. Furthermore, we demonstrated that both WDFY4 and tr-WDFY4 interacted with pattern recognition receptors such as TLR3, TLR4, TLR9 and MDA5 and augmented the NF-κB activation by these receptors. WDFY4 isoforms also enhanced MDA5-induced apoptosis to a greater extent in the tr-WDFY4-transfected cells. Conclusions As CADM is characterised by the appearance of anti-MDA5 autoantibodies and severe lung inflammation, the WDFY4 variant may play a critical role in the pathogenesis of CADM.

Reliability and clinical utility of Enzyme-linked immunosorbent assay for detection of anti-aminoacyl-tRNA synthetase antibody.

Anti-aminoacyl-tRNA synthetase (ARS) antibody is one of the myositis-specific autoantibodies to make a diagnosis of polymyositis (PM) and dermatomyositis (DM). Recently a new enzyme-linked immunosorbent assay (ELISA) kit of concurrently detected anti-ARS antibodies (anti-Jo-1, anti-PL-7, anti-PL-12, anti-EJ and anti-KS) have become to measure in the clinical setting. To evaluate the reliability of this ELISA kit, we measured anti-ARS antibodies in 75 PM and DM patients using by this ELISA assay and compared them with the results by RNA immunoprecipitation assay. Between the measurements of anti-PL-7, anti-PL-12, anti-EJ and anti-KS autoantibodies by ELISA assay and RNA-IP assay, the concordance rate of reproducibility is 95.1% and the positive agreement rate is 90.9% and negative agreement rate is 96.0% and kappa statistic is 0.841. Between the measurements of existing anti-Jo-1 antibody ELISA kit and anti-ARS antibody ELISA kit, the concordance rate of reproducibility is 96.9%, the positive agreement rate is 100%, negative agreement rate is 96.1% and kappa statistic is 0.909. The lung involvement in patients with PM and DM patients are positive of anti-ARS antibodies and anti-melanoma differentiation associated gene5 (MDA5) antibody at a rate around 70%. Then most life-threatening ILD with anti-MDA5 positive clinically amyopathic dermatomyositis patients could be highly guessed when anti-ARS antibodies are negative.

Assessment of 2012 EULAR/ACR new classification criteria for polymyalgia rheumatica in Japanese patients diagnosed using Bird's criteria

The 2012 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for polymyalgia rheumatica (PMR) were published in 2012. The present study aimed to assess the 2012 EULAR/ACR classification criteria for PMR in Japanese patients diagnosed with PMR using Birds criteria.

AB0394 Early Effect of Tofacitinib on Osteoclast Regulator in Rheumatoid Arthritis

Background The selective Janus kinase (JAK) inhibitor tofacitinib has demonstrated excellent efficacy for rheumatoid arthritis (RA). These results suggest the possibility that tofacitinib improves osteoclastic bone destruction of RA. However, the detailed mechanism of tofacitinib for osteoclastogenesis in RA is pooly understood. In this study, we investigated the effect of tofacitinib on serum biomarkers related to osteoclast regulation such as soluble receptor activator of NF-kappa B ligand (sRANKL) and osteoprotegerin (OPG) in patients with RA. Objectives To clarify the effect of tofacitinib on osteoclast regulator in RA. Methods Fourteen patients with active RA who inadequate response to disease-modifying antirheumatic drugs (DMARDs) (mean age: 54.6 years, mean disease duration: 4.1 years, mean simplified disease activity index: 26.9, ACPA positive: 86%, oral steroid use: 29%, mean oral steroid dose: 10mg/day, MTX use: 93%, mean MTX dose:10.9mg/week, biologic DMARDs naïve: 57%) were started on treatment with tofacitinib 5mg twice daily (BID). Disease activity was assessed using the 28-joint count disease activity score-C-reactive protein sedimentation rate (DAS28-CRP) and simplified disease activity index (SDAI). Next, circulating levels of sRANKL and OPG were examined by enzyme-linked immunosorbent assay (ELISA) (sRANKL: human RANKL ELISA kit, Biomedica, OPG: human osteoprotegerin ELISA kit, Biomedica respectively) at the baseline, week 2, 4 and 12. Results After treatment of tofacitinib, SDAI score among all fourteen patients decreased significantly from 26.9±12.4 (mean±SD) at the baseline to 14.7±9.9 at week 4 (p<0.0001), to 8.3±6.1 at week 12 (p<0.0001). Baseline levels of sRANKL were significantly correlated with the levels of CRP (Spearman r2=0.488, P=0.0054). Average of sRANKL levels decreased immediately from 0.15±0.11 pmol/L at the baseline to 0.09±0.05 pmol/L at week 2 (p=0.0097), to 0.11±0.10 pmol/L at week 4 (p=0.0311), to 0.08±0.05 pmol/L at week 12 (p=0.0014). On the other hand, statistically significant changes in OPG levels were not observed during 12 weeks. Consequently, average of sRANKL/OPG ratio decreased significantly from 4.81±4.82 at the baseline to 2.62±1.84 at week 2 (p=0.0186), to 3.11±2.81 at week 4 (p=0.0191), to 2.11±1.72 at week 12 (p=0.0052). Interestingly, decreasing effects of sRANKL levels or sRANKL/OPG ratio were greater in patient with high sRANKL level at the baseline. Conclusions Here, we show for the first time that tofacitinib has improved inflammatory bone destruction immediately through the regulation of sRANKL levels and sRANKL/OPG balance in RA. This mechanism might be a control of RANKL induction via JAK pathway inhibition in activated CD4+ T cells and synovial fibroblasts Disclosure of Interest None declared