Diffusion-weighted magnetic resonance imaging of parotid glands before and after abatacept therapy in patients with Sjögren’s syndrome associated with rheumatoid arthritis: Utility to evaluate and predict response to treatment

<p><b>Objective:</b> To compare parotid diffusion-weighted images (DWIs) taken before and after abatacept therapy in patients with Sjögren’s syndrome (SS) associated with rheumatoid arthritis (RA) and to examine the utility in evaluation and prediction of response to therapy.</p> <p><b>Methods:</b> DWIs of the parotid glands taken at baseline and 52 weeks after initiation of abatacept were analyzed in nine SS patients with RA using relative standard deviation (RSD) of the entire glands and signal intensity ratio (SIR) within the residual parenchyma. The correlation between changes in RSD and SIR and changes in salivary secretion based on Saxon’s test was examined. Furthermore, baseline characteristics were compared in patients with increased and decreased salivary secretion after treatment. The predictive power of the parameter at baseline was examined using receiver operating characteristic (ROC) analysis.</p> <p><b>Results:</b> Abatacept improved salivary secretion from 2076 ± 1535 at baseline to 2857 ± 1431 mg/2 min at 52 weeks (<i>n</i> = 9, <i>p</i> = .05). Increase of salivary secretion was significantly higher in patients with decreased RSD (<i>n</i> = 6) than increased RSD (<i>n</i> = 3) (1241 ± 713, –137 ± 142 mg/2 min, <i>p</i> = .02). The increase and decrease in RSD completely accorded with those of salivary secretion. Furthermore, SIR was the only parameter that was significantly different between patients with posttreatment increase and decrease in salivary secretion (<i>p</i> = .04). ROC analysis showed the sensitivity and specificity of SIR at baseline of ≥13.0 × 10⁻² for the prediction of the response to abatacept were 75.0% and 83.3%, respectively.</p> <p><b>Conclusions:</b> Parotid DWI seems to be useful for evaluating and predicting the response in salivary secretion to abatacept in SS patients with RA.</p

Evaluation of changes in magnetic resonance images following 24 and 52 weeks of treatment of rheumatoid arthritis with infliximab, tocilizumab, or abatacept

<div><p><i>Objectives.</i> To compare MRI findings in rheumatoid arthritis (RA) patients treated with biologic disease-modifying anti-rheumatic drugs (DMARDs).</p><p><i>Methods.</i> The study subjects were 43 RA patients treated with biologic DMARDs (13 with infliximab, 15 with tocilizumab, and 15 with abatacept). They were evaluated using Simplified Disease Activity Index (SDAI) and low-field extremity MRI at baseline, and at 24 weeks and 52 weeks of treatment.</p><p><i>Results.</i> Synovitis scores were significantly lower by 24 weeks in all groups, compared with baseline (<i>P</i> < 0.05). Significant improvement in bone marrow edema (BME) scores were noted from baseline to 24 weeks in infliximab and abatacept groups (<i>P</i> < 0.05), but from 24 weeks to 52 weeks in tocilizumab group (<i>P</i> < 0.01). No significant change was found in erosion score. The synovitis score at baseline correlated significantly with SDAI at 24 weeks (<i>P</i> < 0.05), and the score at 24 weeks correlated significantly with SDAI at 52 weeks (<i>P</i> < 0.05).</p><p><i>Conclusions.</i> The results suggest that the inflammatory improvement by infliximab and abatacept may express earlier than those by tocilizumab, despite similar improvement in SDAI. MRI-detected synovitis could be a useful predictor of SDAI at 24 weeks of treatment. The MRI remains the best tool to detect and assess the effects of biologic DMARDs in RA.</p></div

Cross-reactive neutralizing antibody responses to enterovirus 71 infections in young children

[[abstract]]Recently, enterovirus 71 (EV71) has caused life-threatening outbreaks involving neurological and cardiopulmonary complications in Asian children with unknown mechanism. EV71 has one single serotype but can be phylogenetically classified into 3 main genogroups (A, B and C) and 11 genotypes (A, B1~B5 and C1~C5). In Taiwan, nationwide EV71 epidemics with different predominant genotypes occurred in 1998 (C2), 2000-2001 (B4), 2004-2005 (C4), and 2008 (B5). In this study, sera were collected to measure cross-reactive neutralizing antibody titers against different genotypes. We collected historical sera from children who developed an EV71 infection in 1998, 2000, 2005, 2008, or 2010 and measured cross-reactive neutralizing antibody titers against all 11 EV71 genotypes. In addition, we aligned and compared the amino acid sequences of P1 proteins of the tested viruses. Serology data showed that children infected with genogroups B and C consistently have lower neutralizing antibody titers against genogroup A (>4-fold difference). The sequence comparisons revealed that five amino acid signatures (N143D in VP2; K18R, H116Y, D167E, and S275A in VP1) are specific for genogroup A and may be related to the observed antigenic variations. In conclusion, this study documented antigenic variations among different EV71 genogroups and identified potential immunodominant amino acid positions. Enterovirus surveillance and vaccine development should monitor these positions

Associations between maternal clinical features and fetal outcomes in pregnancies of mothers with connective tissue diseases

<p><b>Objectives:</b> The purpose of this study is to clarify associations between maternal clinical features and adverse pregnancy outcomes (APOs) in mothers with connective tissue diseases (CTDs).</p> <p><b>Methods:</b> We retrospectively examined maternal clinical features including backgrounds, autoantibodies, CTD flare-ups, and therapies during pregnancies as well as fetal outcomes in 90 pregnancies (66 mothers) at our hospital from January 2006 to September 2016.</p> <p><b>Results:</b> Underlying CTDs were SLE (<i>N</i> = 41), MCTD (<i>N</i> = 10), RA (<i>N</i> = 15), SS (<i>N</i> = 10), and others (<i>N</i> = 14). Anti-SS-A antibody was detected in 60.3%, lupus anticoagulant (LAC) was in 11.4%, and anti-cardiolipin-β2glycoprotein1 antibody was in 18.5%. Flare-ups of CTDs occurred in 20 pregnancies (22.2%). Corticosteroids (CS) was administered in 73 pregnancies, immunosuppressants in four, and biologics in one. Among the 85 pregnancies other than five early abortions within 12 weeks of gestational age, 33 cases had APOs while the remaining 52 cases were normal. Although disease duration, MCTD, high dose of CS, flare-ups of CTDs, and positive LAC significantly correlated with APOs by univariate analysis, only MCTD was a significant independent predictor for APOs by multivariate analysis.</p> <p><b>Conclusion:</b> Disease duration, MCTD, high dose of CS, flare-ups of CTDs, and LAC might be possible predictive risk factors for APOs in pregnancies with CTDs. Of these, MCTD was a significant independent risk factor.</p

Additional file 2: of Identification of novel biomarker as citrullinated inter-alpha-trypsin inhibitor heavy chain 4, specifically increased in sera with experimental and rheumatoid arthritis

Figure S2. (a) Padi4 gene expression levels in articular tissue samples from pGIA and control mice, analyzed by qPCR (n = 6). Data are mean Âą SEM. (TIFF 97 kb

Additional file 4: of Identification of novel biomarker as citrullinated inter-alpha-trypsin inhibitor heavy chain 4, specifically increased in sera with experimental and rheumatoid arthritis

Figure S4. (a) Sera of pGIA and control mice obtained at day 14 were separated by SDS-PAGE and stained with Coomassie brilliant blue (left) or subjected to Western blot analysis using AMC antibodies (right). Citrullinated proteins were detected at ~ 120 kDa in pGIA mice but not in the control mice. G1, 2: pGIA; C1, 2: control mice. (b) The MS spectrum of ITIH4429–438 and modified peptides bearing the citrullinated arginine (R438) in pGIA. Citrullinated residues were identified by the modified y6, y7, and y8 ion confirmed a mass increase of 1.0 Da. (TIFF 217 kb

Additional file 6: of Identification of novel biomarker as citrullinated inter-alpha-trypsin inhibitor heavy chain 4, specifically increased in sera with experimental and rheumatoid arthritis

Figure S6. (a) Sera from patients with RA, HS, patients with OA, patients with SLE, and patients with SS was subjected to Western blot analysis using AMC antibodies. Citrullinated proteins were specifically detected as an ~ 120 kDa band in patients with RA. (TIFF 238 kb

Additional file 1: of Identification of novel biomarker as citrullinated inter-alpha-trypsin inhibitor heavy chain 4, specifically increased in sera with experimental and rheumatoid arthritis

Figure S1. DBA/1 mice were immunized with pGPI. (a) The clinical score (mean ± SEM) of pGIA (n = 11). (b) Sera were obtained once per week between days 0 and 28 from pGIA and control mice. The titers of anti-CCP antibodies were analyzed by ELISA (n = 12–18). Each symbol represents a single mouse, and the horizontal and vertical bars represent the mean and SEM values, respectively. *p < 0.05, **p < 0.01. (TIFF 120 kb

Clinical features of patients with IgG4-related disease complicated with perivascular lesions

<p><i>Objective.</i> To define the clinical features of IgG4-related disease (IgG4-RD) complicated with perivascular lesions.</p> <p><i>Methods.</i> The clinical features of seven patients with IgG4-RD and perivascular lesions diagnosed at the University of Tsukuba Hospital between October 2008 and October 2013, were analyzed, including clinical background, results of imaging studies, satisfaction of the 2011 comprehensive diagnostic criteria (CDC) for IgG4-RD, laboratory data, distribution of perivascular lesions, involvement of other organs, and response to steroid therapy.</p> <p><i>Results.</i> We studied six men and one woman with a mean age of 66.9 ± 6.7 years (± SD). Six of seven patients were diagnosed as definite IgG4-RD, while the seventh was considered possible IgG4-RD, based on the CDC for IgG4-RD. Serum IgG4 levels at diagnosis were higher than 135 mg/dl in all seven patients (mean, 933 ± 527). Serum C-reactive protein (CRP) levels were elevated in two only (mean, 1.42 ± 3.56 mg/dl). The perivascular lesions were located in the pulmonary artery (<i>n</i> = 1), thoracic aorta (<i>n</i> = 2), abdominal aorta (<i>n</i> = 6), coronary (<i>n</i> = 1), celiac (<i>n</i> = 1), superior mesenteric (<i>n</i> = 1), renal (<i>n</i> = 2), inferior mesenteric (<i>n</i> = 5), and iliac (<i>n</i> = 3) arteries. In addition to perivascular lesions, six patients showed involvement of other organs. All seven patients were treated with prednisolone (0.6 mg/kg/day), which rapidly improved the perivascular and other organ lesions in six patients (the other one patient have not yet been evaluated due to the short follow-up).</p> <p><i>Conclusion.</i> Perivascular lesions show wide distribution in patients with IgG4-RD. Serum CRP levels are not necessarily elevated in these patients. Steroid therapy is effective in IgG4-RD and results in resolution of lesions.</p

Association of Functional Polymorphisms in <i>Interferon Regulatory Factor 2</i> (<i>IRF2</i>) with Susceptibility to Systemic Lupus Erythematosus: A Case-Control Association Study

<div><p>Interferon regulatory factor 2 (IRF2) negatively regulates type I interferon (IFN) responses, while it plays a role in induction of Th1 differentiation. Previous linkage and association studies in European-American populations suggested genetic role of <i>IRF2</i> in systemic lupus erythematosus (SLE); however, this observation has not yet been confirmed. No studies have been reported in the Asian populations. Here we investigated whether <i>IRF2</i> polymorphisms contribute to susceptibility to SLE in a Japanese population. Association study of 46 <i>IRF2</i> tag single nucleotide polymorphisms (SNPs) detected association of an intronic SNP, rs13146124, with SLE. When the association was analyzed in 834 Japanese patients with SLE and 817 healthy controls, rs13146124 T was significantly increased in SLE compared with healthy controls (dominant model, P = 5.4×10⁻⁴, Bonferroni-corrected P [Pc] = 0.026, odds ratio [OR] 1.48, 95% confidence interval [CI] 1.18–1.85). To find causal SNPs, resequencing was performed by next-generation sequencing. Twelve polymorphisms in linkage disequilibrium with rs13146124 (r²: 0.30–1.00) were identified, among which significant association was observed for rs66801661 (allele model, P = 7.7×10⁻⁴, Pc = 0.037, OR 1.53, 95%CI 1.19–1.96) and rs62339994 (dominant model, P = 9.0×10⁻⁴, Pc = 0.043, OR 1.46, 95%CI 1.17–1.82). The haplotype carrying both of the risk alleles (rs66801661A–rs62339994A) was significantly increased in SLE (P = 9.9×10⁻⁴), while the haplotype constituted by both of the non-risk alleles (rs66801661G–rs62339994G) was decreased (P = 0.0020). A reporter assay was carried out to examine the effect of the <i>IRF2</i> haplotypes on the transcriptional activity, and association of the <i>IRF2</i> risk haplotype with higher transcriptional activity was detected in Jurkat T cells under IFNγ stimulation (Tukey's test, P = 1.2×10⁻⁴). In conclusion, our observations supported the association of <i>IRF2</i> with susceptibility to SLE, and the risk haplotype was suggested to be associated with transcriptional activation of <i>IRF2</i>.</p></div