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To investigate the clinical features and prognosis of nocardiosis complicated by connective tissue diseases (CTDs).We examined patients with CTDs who were diagnosed with nocardiosis from October 2004 to 2019. We retrospectively investigated patient characteristics and therapeutic outcomes. We then performed a comparison between survivors and non-survivors.Fourteen patients were examined. Underlying CTDs were systemic lupus erythematosus (28.6%), vasculitis syndrome (28.6%), rheumatoid arthritis (21.4%), adult Still disease (14.3%) and dermatomyositis (7.1%). Infected organs were lung (85.7%), brain (42.9%), skin/cutaneous lesions (28.6%) and muscle (7.1%). Disseminated infections were seen in nine patients (64.3%). At the onset of nocardiosis, all patients were given prednisolone (23.2 ± 11.9 mg/day). Only two patients (14.3%) were given TMP-SMX for prophylaxis of pneumocystis pneumonia. Relapse occurred in one patient (7.1%) and four patients (28.6%) died from nocardiosis for a cumulative survival rate at 52 weeks of 76.9%. In a comparison of survivors (71.4%) and non-survivors (28.6%), cutaneous lesions were significantly more frequent in the latter (10 vs 75%,Cutaneous lesions as a result of dissemination might be a risk factor for nocardiosis mortality in patients with CTDs.

Thrombotic microangiopathy (TMA) is a rare but life-threatening complication of systemic lupus erythematosus (SLE) and is associated with adverse pregnancy outcomes. We herein report a 30-year-old pregnant woman with SLE complicated by TMA. Because her condition was unresponsive to initial corticosteroid and fresh-frozen plasma infusion treatment, we attempted plasma exchange (PE). Although thrombocytopenia and microangiopathic hemolytic anemia gradually improved, fetal death was confirmed at 23 weeks of gestation. This case suggests that PE is an effective therapeutic option but might be insufficient to maintain pregnancy in patients with SLE complicated by TMA.

Aortic arch aneurysm (AAA) is a rare involvement in Behçet disease (BD). It is often life-threatening, yet few reports related to the treatment of AAA have been published. We herein report a 27-year-old woman with AAA caused by vascular BD. She was initially treated with prednisolone 1 mg/kg/d. However, the inflammation had not subsided after three weeks, so infliximab (IFX) was added for relief. After IFX administration, the C-reactive protein level normalized, and computed tomography at three months after therapeutic intervention revealed that the aneurysm had disappeared. This case suggests that early induction of IFX might be effective for aortic aneurysm in BD.

Cogan's syndrome (CS), a rare vasculitis characterized by non-syphilitic, interstitial keratitis and Meniere-like attacks, is classified into "typical" and "atypical" forms, while Takayasu arteritis (TAK) is a rare large-vessel vasculitis associated with human leukocyte antigen (HLA)-B*52. Very few cases meet both the CS and TAK classification criteria. We herein report a 53-year-old woman diagnosed with atypical CS and aortitis similar to TAK. Her 25-year-old daughter manifested TAK without symptoms of CS, and both are HLA-B*52 positive. Our case highlights the difficulties of distinguishing aortitis with atypical CS from aortitis with TAK.

Objectives: To determine the protein expression level, expressing cell types, and pathogenic roles of chemokine (C-C motif) ligand 18 (CCL18) and its receptor chemokine (C-C motif) receptor 8 (CCR8...

IgG4-related disease (IgG4-RD) is characterized by lympho-plasmacytic infiltration and fibrosis in multiple organs, accompanied by high serum IgG4 levels. Although both IgG4-RD and Sjögren's syndrome (SS) frequently affect salivary and lacrimal glands, the clinical and pathological features of these two conditions are different. In an attempt to delineate the pathomechanisms of IgG4-RD, we compared the gene expression patterns of various molecules in labial salivary glands (LSGs) between IgG4-RD and SS. First, using quantitative PCR, we demonstrated significantly higher mRNA expression levels of activation-induced cytidine deaminase (AID), IL-10, and TGFβ in LSGs of IgG4-RD than SS and healthy controls (HCs). We propose that the combination of AID and IL-10 contributes to IgG4-specific immunoglobulin class switch recombination, and that TGFβ induces LSGs fibrosis in IgG4-RD. Second, DNA microarray identified 2641 differentially expressed genes (DEGs) in LSGs; with 1321 up-regulated and 1320 down-regulated genes in IgG4-RD, relative to SS. Among the up-regulated DEGs in IgG4-RD, quantitative PCR confirmed significantly higher expression levels of chemokine (C-C motif) ligand 18 (CCL18) and lactotransferrin in LSGs of IgG4-RD than SS and HCs. The former has chemotactic activity on various types of lymphocytes and enhances collagen production from fibroblasts, while lactotransferrin is an iron-binding protein abundantly present in milk and has a wide range of functions, including fibroblast proliferation and maturation of dendritic cells (DCs). Third, immunofluorescence staining confirmed specific upregulation of CCL18 in macrophages, CD11c + and B cells, and plasmacytes of LSGs-IgG4-RD. These pathological findings could help in the identification of disease-specific biomarkers as well as development of novel therapeutic strategies.

ObjectiveAn increased proportion of circulating follicular helper T (Tfh) cells was reported in rheumatoid arthritis (RA), but it remains uncertain how Tfh cells affect antibody hyposialylation. We investigated the regulation of autoantibody hyposialylation by Tfh cells in RA using murine model.MethodsBehaviours of Tfh cells and their function on B cell promotion were analysed. Change of arthritogenicity and sialylation of autoantibodies during the course of arthritis was examined by mass spectrometry. Tfh-mediated regulation of hyposialylation was investigated, and the responsible cell surface molecule was specified both in vitro and in vivo. The relation between circulating Tfh cells and hyposialylation was analysed in patients with RA.ResultsAn increase in Tfh, particularly interleukin-17 producing Tfh (Tfh17) cells, at the onset of arthritis and their enhancement of autoantibody production were found. Autoantibodies at the onset phase demonstrated stronger inflammatory properties than those at the resolution phase, and mass spectrometric analysis revealed their difference in sialylation. In vitro coculture showed enhanced hyposialylation by the Tfh cells via OX40, which was highly expressed in the Tfh and Tfh17 cells. Blockade of OX40 prevented the development of arthritis with reduction in Tfh17 cells and recovery of autoantibody sialylation. Analysis of patients with RA showed abundance of OX40-overexpressing Tfh17 cells, and their proportion correlated negatively with the expression of α2,6-sialyltransferase 1, an enzyme responsible for sialylation.ConclusionsOX40 expressed on Tfh cells can regulate autoantibody sialylation and play a crucial role in the development of autoimmune arthritis.

Objective Biological disease-modifying anti-rheumatic drugs (bDMARDs) represent an important advance in alleviating rheumatoid arthritis (RA), but their effect on rheumatic airway disease (AD) and interstitial lung disease (ILD) is still unclear. This study was performed to evaluate the association of the use of different bDMARDs with new-onset or worsening of RA-AD/ILD. Methods We performed a retrospective cohort study of RA patients who received bDMARDs and assessed their AD/ILD before and after drug initiation in our hospital over the past 10 years. We evaluated the serial changes in computed tomography (CT), classified patients according to AD/ILD progression, and analyzed associations between clinical characteristics and outcomes. Results We enrolled 49 patients. Thirty patients received tumor necrosis factor inhibitors (TNFis), 12 received abatacept (ABT), and the remaining 7 received tocilizumab (TCZ). Seventeen patients had ILD, 10 had AD, and 6 had both AD and ILD before the initiation of bDMARDs. New emergence or exacerbation of AD/ILD was observed in 18 patients after drug initiation, while the remaining 31 remained stable or improved. Multiple logistic regression analyses revealed that pre-existing AD was an independent risk factor against the emergence or exacerbation of RA-AD/ILD, and ABT use was a protective factor against it. Conclusion Our study showed that pre-existing RA-AD is associated with future worsening of RA-AD/ILD, and ABT over other bDMARDs was associated with a better prognosis. Future studies to confirm our results are needed.

Background: Although anti-cyclic citrullinated peptide antibody (anti-CCP Ab) is reported to be found in 5–20% of patients with psoriatic arthritis (PsA), its clinical significance has not been elu...

Objective: To explore the relevance of citrullinated proteins and anti-citrullinated protein antibodies (ACPA) via protein arginine deiminase (PAD) inhibition in peptide glucose-6-phosphate isomerase-induced arthritis (pGIA).Methods: Cl-amidine, a PAD inhibitor, was injected into pGIA. Clinical scores and histopathological findings of ankle joints were assessed. Serum ACPA titers were analyzed using ELISA. Citrullinated protein expression in joints and sera were examined with immunohistochemistry and Western blot analysis, respectively. Serum levels of IL-6, TNFα, and IL-1β were measured with cytometric bead array (CBA). Gene expression levels of IL-6 and TNFα in joints, lymph nodes, and spleens were analyzed with quantitative PCR. GPI-specific productions of IFNγ and IL-17 from T cells in lymph nodes were evaluated.Results: Cl-amidine treatment significantly reduced arthritis severity while ACPA titers tended to be lower, but not significantly different compared to the control. Citrullinated proteins in joints and sera from treated mice were clearly decreased. With Cl-amidine treatment, serum IL-6 levels were significantly decreased, and IL-6 and TNFα gene expression were significantly reduced in joints. IL-17 production from GPI-specific T cells tended to be lower in Cl-amidine-treated mice, but not significantly different.Conclusion: Our results suggested that PAD-mediated citrullinated protein was involved in the pathogenesis of arthritis via IL-6.

Background Our previous studies reveal that CCL18-CCR8 chemokine axis is upregulated in patients of immunoglobulin G4-related disease (IgG4-RD), suggesting that the CCL18–CCR8 axis is implicated in the etiology of IgG4-RD, although whether this axis has a potential as a therapeutic target remains unclear. Our purpose was to clarify the pathogenic roles and therapeutic potential of the murine CCL8 (analog of human CCL18)–CCR8 axis by using an animal model of IgG4-RD (LAT Y136F knockin mice; LAT mice). Methods We compared the infiltration of inflammatory cells and the fibrosis of the salivary glands of 6-week-old LAT mice and littermate mice. The expressions of Ccl8 and Ccr8 were also compared. Next, we investigated the therapeutic effects of intravenous administration of anti-CCL8 neutralizing antibody in LAT mice against inflammation and fibrosis of the salivary glands. We also investigated the effects of stimulation with recombinant mouse CCL8 on the collagen production in a mouse fibroblast cell line (NIH/3 T3) in vitro. Results When compared with the littermates, the LAT mice showed apparent infiltration of inflammatory cells and fibrosis in the salivary glands. The focus and fibrosis score in the salivary glands were significantly higher in the LAT mice than in the littermates. The expression levels of Ccl8 in the spleen and of Ccr8 in the salivary glands were significantly higher in the LAT mice than in the littermates. Anti-CCL8 antibody significantly improved the focus and fibrosis score in the salivary glands of the LAT mice. In vitro, stimulation with recombinant mouse CCL8 significantly increased the expression of collagen and ERK1/2 phosphorylation in NIH/3 T3. Conclusion We clarified the overexpression and therapeutic potential of the mouse CCL8–CCR8 axis in LAT mice, which could play a crucial role in fibrosis via ERK1/2 phosphorylation, as well as the chemotaxis of inflammatory cells. The human CCL18–CCR8 axis might be a novel therapeutic target for IgG4-RD.

Objectives The primary objective is to reveal the effect of hydroxychloroquine (HCQ) treatment on corrected QT (QTc) interval in patients with systemic lupus erythematosus (SLE). The secondary objective is to investigate factors that affect QTc prolongation. Methods SLE patients who had electrocardiograms between 2015 and 2020 were recruited and assigned to two groups based on whether they were treated with HCQ (HCQ group) or not (control group). Change of QTc before and after HCQ administration in the HCQ group was measured and compared with the control group. Patients treated with HCQ were further divided into two groups based on presence or absence of QTc prolongation and the characteristics were compared. Results In total, 126 patients were recruited, of whom 42 were treated with HCQ. In the HCQ group, the mean QTc significantly increased (p Conclusion HCQ could induce QTc prolongation in SLE patients. It might be better that the possibility of QTc prolongation was taken into consideration when HCQ was administered in the patients with longer disease duration of SLE and coincidence of hypertension.

Objectives We compared large vessel vasculitis (LVV) clinical features between age groups. Methods We retrospectively examined clinical features and therapies in 41 LVV patients at our hospital from January 2010 to March 2020. We compared two patient groups, elderly (≥50 years) and young ( Results Of all patients, 29 were elderly and 12 were young. In the younger group, upper extremity symptoms (p Conclusion LVV clinical features differed between elderly- and young-age-onset groups.

M3 muscarinic acetylcholine receptor (M3R) is one of the autoantigens associated with Sjögren’s syndrome (SS) and is localized in exocrine glands where disease-specific inflammation occurs. The inflammatory lesion is characterized by infiltration of CD4(+) T cells, including clonally expanded Th17 cells. We undertook this study to identify circulating M3R-specific Th17 cells and to determine functional properties of those cells. Using the enzyme-linked immunospot assay (ELISpot) method, we identified M3R-reactive Th17 cells in the peripheral blood of patients with primary SS (pSS). Among 10 examined pSS patients, 10 healthy subjects (HS), and 5 IgG4-related disease (IgG4-RD) patients, M3R-reactive IL-17 secreting cells were significantly increased in 5 pSS patients specifically. The most common T cell epitope, which was analyzed and confirmed by coculture of isolated CD4(+) T cells with antigen presenting cells plus M3R peptides in vitro, was peptide 83-95 of M3R. Peptide recognition was partly in an HLA-DR–restricted manner, confirmed by blocking assay. M3R-reactive Th17 cells positivity correlated with higher titers of anti-M3R antibodies, whose systemic disease activity score tended to be higher. Our studies highlight the role of tissue-specific autoantigen–derived circulating Th17 cells in pSS, for which further work might lead to antigen-specific targeted therapy.

Autonomic neuropathy has been reported in autoimmune rheumatic diseases (ARD) including Sjögren’s syndrome, systemic sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. However, the pathophysiological mechanism underlying autonomic dysfunction remains unknown to researchers. On the other hand, autoimmune autonomic ganglionopathy (AAG) is an acquired immune-mediated disorder, which causes dysautonomia that is mediated by autoantibodies against ganglionic acetylcholine receptors (gAChRs). The purpose of this review was to describe the characteristics of autonomic disturbance through previous case reports and the functional tests used in these studies and address the importance of anti-gAChR antibodies. We have established luciferase immunoprecipitation systems to detect antibodies against gAChR in the past and determined the prevalence of gAChR antibodies in various autoimmune diseases including AAG and rheumatic diseases. Autonomic dysfunction, which affects lower parasympathetic and higher sympathetic activity, is usually observed in ARD. The anti-gAChR antibodies may play a crucial role in autonomic dysfunction observed in ARD. Further studies are necessary to determine whether anti-gAChR antibody levels are correlated with the severity of autonomic dysfunction in ARD.

Adult Still disease (ASD) is a systemic disorder of unknown etiology characterized by high spiking fever, rash, and arthritis. The purpose of this study was to identify genes specifically associated with the active phase of the disease. In this study, we have reported that placenta specific 8 (PLAC8) was a newly specific gene involved in ASD. DNA microarray and validation analysis using human monocytes revealed that the expression of PLAC8 was significantly higher in active-ASD patients than in inactive-ASD patients and healthy controls. In ASD, PLAC8 expression level correlated with serum levels of CRP, ferritin, IL-1β, and IL-18. Stimulation of monocytes with LPS results in PLAC8 upregulation. LPS or nigericin stimulation of PLAC8-overexpressing human monocytic cell line (THP-1), but not mock THP-1 cells, was associated with a significant decrease in IL-1β and IL-18 production. PLAC8 overexpression in THP-1 cells was associated with enhanced autophagy and suppression of IL-1β and IL-18 production. Therefore, we found that PLAC8 was upregulated in activated monocytes, as was IL-1β and IL-18. The upregulated PLAC8 acts on the synthesis of inactive precursors of IL-1β and IL-18 and seemed to suppress the production of IL-1β and IL-18 by negative feedback through enhanced autophagy, resulting in the suppression of ASD. The results highlight the role of PLAC8 in the pathogenesis of ASD and suggest its potential suitability as an activity marker and therapeutic target in ASD.

Hemophagocytic syndrome (HPS) associated with systemic lupus erythematosus (SLE), dubbed acute lupus hemophagocytic syndrome (ALHS), is an intractable complication of SLE. A 24-year-old man who had been diagnosed with SLE three months previously, presented with fever, rash, hallucination, and pancytopenia accompanied with hyperferritinemia and bone marrow hemophagocytosis. He was diagnosed with ALHS and neuropsychiatric (NP)-SLE. Although 4 courses of methylprednisolone pulse therapy and 1 course of intravenous cyclophosphamide (IVCY) improved his NP-SLE, his ALHS did not respond. However, the addition of cyclosporine A (CsA) led to a rapid remission from ALHS. This suggests the usefulness of CsA in the treatment of intractable, corticosteroid- and IVCY-resistant ALHS.

Patients with clinically amyopathic dermatomyositis (CADM), a subset of dermatomyositis characterized by a lack of muscle involvement, frequently develop rapidly progressive and treatment-resistant interstitial lung disease. We report the case of a 49-year-old man who was diagnosed with CADM. He developed interstitial pneumonia, which did not respond to combination therapy with methylprednisolone pulse therapy, cyclophosphamide, and cyclosporine. We therefore attempted plasma exchange. After 7 courses of therapeutic plasma exchange, the interstitial pneumonia gradually improved. This case suggests that plasma exchange might be an effective therapeutic option for patients with progressive interstitial lung disease in steroid- and immunosuppressive therapy-refractive CADM.

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).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.Underlying CTDs were SLE (N = 41), MCTD (N = 10), RA (N = 15), SS (N = 10), and others (N = 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.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.

Adult-onset Still disease (AOSD) is a systemic inflammatory disease characterized by fever, arthritis and rash. Corticosteroids represent a promising therapeutic option for AOSD; however, some resistant cases require immunosuppressants and biologic agents. We herein report the case of a 29-year-old Japanese man with severe AOSD, accompanied by constrictive pericarditis (CP) and pleuritis. Although 2 courses of steroid pulse and subsequent high-dose of prednisolone and cyclosporine A improved the patient's CP and pleuritis, his fever and inflammatory responses persisted. Tocilizumab (TCZ) was added to his treatment, which resulted in a rapid remission. This case suggests the usefulness of TCZ in the treatment of severe AOSD with CP and pleuritis.

The objective of this study is to develop clinical practice guideline (CPG) for Sjögren's syndrome (SS) based on recently available clinical and therapeutic evidences.The CPG committee for SS was organized by the Research Team for Autoimmune Diseases, Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW), Japan. The committee completed a systematic review of evidences for several clinical questions and developed CPG for SS 2017 according to the procedure proposed by the Medical Information Network Distribution Service (Minds). The recommendations and their strength were checked by the modified Delphi method. The CPG for SS 2017 has been officially approved by both Japan College of Rheumatology and the Japanese Society for SS.The CPG committee set 38 clinical questions for clinical symptoms, signs, treatment, and management of SS in pediatric, adult and pregnant patients, using the PICO (P: patients, problem, population, I: interventions, C: comparisons, controls, comparators, O: outcomes) format. A summary of evidence, development of recommendation, recommendation, and strength for these 38 clinical questions are presented in the CPG.The CPG for SS 2017 should contribute to improvement and standardization of diagnosis and treatment of SS.

Otitis media with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV) is a new disease entity characterized by progressive sensorineural hearing loss and intractable otitis me...

ObjectivesIdiopathic 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.MethodsWe 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.ResultsWe 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.ConclusionsAs 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.

Summary Tumour necrosis factor alpha (TNF)-α-induced adipose-related protein (TIARP) is a negative regulator of inflammation in arthritis model mice. In humans, six-transmembrane epithelial antigen of prostate 4 (STEAP4) (human counterpart of TIARP) is also expressed in CD14+ monocytes from patients with rheumatoid arthritis (RA). Recently, highly levels of exon 3-spliced variant STEAP4 (v-STEAP4) expression have been observed in porcine lung. The aim of this study is to elucidate the expression and functional role of v-STEAP4, comparing it with that of STEAP4, in the pathogenesis of arthritis. We identified v-STEAP4 in CD14+ cells. The expression of STEAP4 and v-STEAP4 was higher in patients with RA than in healthy participants. We also found that STEAP4 and v-STEAP4 were correlated positively with C-reactive protein and that their expression was decreased after treatment with an interleukin (IL)-6 antagonist in patients with RA. To investigate further the role of STEAP4 and v-STEAP4, we produced STEAP4 and v-STEAP4 over-expressing human monocytic cell lines (THP-1) for functional analysis. In the v-STEAP4 over-expressing cells, the production of IL-6 was suppressed significantly, but TNF-α was increased significantly through lipopolysaccharide (LPS) stimulation. Immunoblot analysis revealed that phosphorylated (p-)nuclear factor kappa B (NF-κB) was increased after LPS stimulation and degradation of nuclear factor kappa B inhibitor alpha (IκBα) was sustained, whereas p-signal transducer and activator of transcription 3 (STAT-3) was decreased with v-STEAP4. We identified specific up-regulation of v-STEAP4 in RA monocytes. V-STEAP4 might play a crucial role in the production of TNF-α and IL-6 through NF-κB and STAT-3 pathways, resulting in the generation of RA.

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.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.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.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.

The effectiveness of an upfront combination therapy of pulmonary arterial vasodilators on pulmonary arterial hypertension (PAH) associated with systemic lupus erythematosus (SLE) has not yet been established. Here we present two cases of SLE-PAH successfully treated by such a regimen. Case 1 was a 42-year-old Chinese female who was diagnosed as SLE based on 1997 American College of Rheumatology (ACR) criteria for arthritis, lymphocytopenia, thrombocytopenia, and positivity for anti-nuclear antibody (ANA) and anti-DNA antibody (ADNA). PAH was diagnosed simultaneously based on increased mean pulmonary arterial pressure (mPAP) (44mmHg) in right heart catheterisation. She was treated with macitentan, tadalaphil, and beraprost sodium, as an upfront triple combination therapy in addition to 45mg/day of prednisolone (PSL). She was successfully treated, resulting in a decrease of right ventricular systolic pressure (RVSP) on echocardiography from 68.4mmHg to 31.4mmHg within 4 months. Case 2 was a 34-year-...

Kikuchi-Fujimoto disease (KFD) is a benign disease of unknown etiology characterized by lymphadenopathy and a fever. For the majority of patients with KFD, the course is self-limited; however, the optimum method of managing recurrent cases has not yet been established. We herein report a case of a 42-year-old Japanese woman with KFD (confirmed by a lymph node biopsy). Although high-dose prednisolone (PSL) rapidly induced remission, she experienced four recurrences on treatment tapering. Concomitant use of hydroxychloroquine (HCQ) with low-dose PSL induced continuous remission. This is the first case to suggest the effectiveness of HCQ for recurrent KFD in a Japanese patient.

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease of the joints, mediated primarily by proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin-6 (I...

IgG4-related disease (IgG4-RD) is a fibro-inflammatory condition characterized by increased serum IgG4 level, infiltration of lymphocytes and IgG4-positive (IgG4+) plasma cells and fibrosis. It can occur in almost all organs, commonly affecting the pancreas, biliary tract, salivary and lacrimal glands and kidneys. However, reports of IgG4-RD accompanied by pathologically confirmed, IgG4-related pleural disease are scarce. Here, we present a case of a 64-year-old man with suspected malignant pleural mesothelioma based on imaging findings but finally diagnosed with IgG4-RD (including pleuritis, periaortitis and bilateral submandibular gland enlargement) based on a high serum IgG4 level and pleural histopathological findings such as lymphoplasmacytic infiltration including IgG4+ plasma cells and fibrosis. Systemic corticosteroid therapy was effective at reducing serum IgG4, improving bilateral submandibular gland enlargement, and regressing pleural thickening and periaortic soft tissue. We also discuss clinical characteristics and pleural pathological features of previously reported cases with IgG4-related pleural disease based on a comprehensive literature review. Our case of IgG4-RD with pleura, aorta and submandibular gland involvement, pathologically confirmed by pleural specimen might be unique and very rare.

Rheumatoid arthritis (RA) is an inflammatory disorder characterized by synovial inflammation in multiple joints. Autoantibodies (Abs) are the hallmark of RA, and as disease-specific and diagnostic markers, rheumatoid factor and anti-citrullinated protein antibody (ACPA) are produced pre-clinically, but their pathogenic roles in RA remain elusive. In this review, we focus on one of the candidate autoantigens in RA; glucose-6-phosphate isomerase (GPI). The arthritogenic role of GPI has been confirmed in two different mouse models: the K/BxN- and GPI-induced arthritis models. Both anti-GPI Abs and citrullinated-GPI peptide Abs have been detected in human RA. Studies conducted in these rodent models have confirmed that the pathogenesis of arthritis involves the localization of autoantigens not only in the joints but also in the circulation. In this review, we revisit and summarize the arthritogenic relevance of GPI in animal RA models and in human RA, and extend the discussion to joint-specific inflammation.

Background: RORγt+Foxp3+ regulatory T (Treg) cells, designated as Tr17 is one of the new subset of Treg cells, having the potential to regulate the development of experimental autoimmune encephalomyelitis (EAE) thorough a specific repression of Th17 mediated inflammation (1). The function of Tr17 remain unclear in the development of other autoimmune diseases such as collagen induced arthritis (CIA). Objectives: To clarify the role of RORγt+Foxp3+ (Tr17) cells in the development CIA. Methods: 1) Lymphocytes in draining lymph node (LN) were harvested from C57BL/6 mice on 10 days after immunization of type II collagen (CII) emulsified with complete Freund’s adjuvant. The expression of RORγt in Foxp3+Treg cells was analyzed by flow cytometry and compared them with lymphocytes of non-immunized mice. 2) At 10 days after CII immunization, C-C chemokine receptor type 6 (CCR6), CD25, cytotoxic T-lymphocyte antigen 4 (CTLA-4), and glucocorticoid-induced TNF-receptor (GITR) expression on Tr17, RORγt-Treg cells, and RORγt+non-Treg cells in LN were analyzed by flow cytometry. 3) Lymphocytes were harvested from Foxp3IRES-gfp reporter mice on 10 days after first CII immunization. CD4+GFP+ Treg and CD4+GFP- T cells were isolated and stimulated with anti-CD3 monoclonal antibody (mAb) and anti-CD28 mAb in vitro. The expression of IL-10 and IL-17 in RORγt+GFP+ Tr17 cells was analyzed by flow cytometry and compared with that in RORγt-GFP+ cells or RORγt+GFP- cells. 4) After the induction of CIA, lymphocytes in inflamed ankle joints and LN were harvested from C57BL/6 mice. The expression of RORγt in both Foxp3+Treg cells and Foxp3- non-Treg cells were analyzed by flow cytometry. 5) Foxp3creRORγtfl/fl (conditional knock out; cKO) mice which deficit Tr17 cells were immunized with CII on days 0 and 21. Incidence and severity of CIA were analyzed and compered with Foxp3wtRORγtfl/fl (control) mice. 6) At 10 days post first CII immunization. Lymphocytes from control mice and cKO mice were cultured with or without 100 μg/mL of denatured CII for 72 h. IL-17 and IFNγ levels in supernatants measured by ELISA. Results: 1) Tr17 cells in draining lymph nodes were significantly increased in CII-immunized mice compared with non-immunized mice. 2) CCR6, CD25, CTLA-4, and GITR expression was elevated on Tr17 cells compared with RORγt-Treg cells and Th17 cells. 3) IL-10 producing cells were significantly increased in Tr17 cells compared with RORγt-Treg cells (12.57 +/- 1.135, p Conclusion: Tr17 cells were increased in the course of CIA and infiltrated into inflamed joints. Moreover, Tr17 cells had the potential to regulate the development of CIA thorough the high expression of suppressive molecules such as IL-10 and CTLA-4. Reference [1] Byong-Seok K. et al. Generation of RORγt+ Antigen-Specific T Regulatory 17 Cells from Foxp3+ Precursors in Autoimmunity. Cell Reports. 2017. 21, 195-207 Disclosure of Interests: Kotona Furuyama: None declared, Yuya Kondo: None declared, Masahiro Yokosawa: None declared, Masaru Shimizu: None declared, Hiroto Tsuboi: None declared, Isao Matsumoto: None declared, Takayuki Sumida Grant/research support from: Bristol-Myers Squibb, Speakers bureau: Bristol-Myers Squibb

Background The transcriptional factor T-bet is required for Th-1 differentiation and important for regulating Th-17 differentiation, which plays a critical role in the development of collagen-induced arthritis (CIA). Previous studies reported that overexpression of T-bet suppresses Th-17 differentiation via inhibition of retinoic acid-related orphan receptor (ROR) γt and aryl hydrocarbon receptor (AhR) (1, 2). However, the function of T-bet in the development of CIA remains largely unknown. Objectives To clarify the role of T-bet on the pathogenesis of CIA. Methods 1) T-bet knockout (T-bet-/-) mice (C57BL/6, B6 background) were generated as previously described (3). T-bet-/- mice were immunized with CII with CFA, and the incidence and severity of CIA was assessed. 2) Anti-CII antibodies in the sera from T-bet-/- mice on day 60 after the first immunization were measured. 3) Lymph node cells from B6 or T-bet-/- mice immunized with CII were analyzed by flow cytometry using antibodies specific for CD3, CD4, CD8, CD11b, CD11c, CD19, Gr1 and NK1.1. 4) The lymph node cells described above were cultured in the CII containing medium, then the cytokine production was assayed by ELISA. Results 1) CIA developed in the T-bet-/- mice was more severe than that of B6 wild-type mice and the incidence of arthritis was around 1.5-fold higher. 2) The levels of total IgG, IgG1, IgG2b, IgG3 antibodies against native chicken CII were significantly higher in T-bet-/- mice. However, IgG2a antibody production was significantly lower in T-bet-/- mice compared to B6 mice. 3) The number of CD4+ T (CD3+CD4+), CD8+ T (CD3+CD8+), B (CD19+), dendritic cells (CD11c+), macrophage (CD11c-CD11b+Gr1-), neutrophil (CD11c-CD11b+Gr1+), NK cell (CD3-NK1.1+) in the lymph node was not different but the number of NKT (CD3+NK1.1+) cells was significantly decreased in T-bet-/- mice. 4) The level of IL-17 and IL-22 in the culture supernatant was significantly higher in T-bet-/- mice, whereas that of IFNγ was comparable in the two groups. Conclusion CIA was significantly severe in T-bet-/- mice. The mechanisms of severe arthritis might be mediated through the up-regulation of IL-17 and IL-22 by Th-17 differentiation in the T-bet deficient and IFNγ independent manner or the decrease of NKT cells. References [1] Kondo Y, et al. Overexpression of T-bet gene regulates murine autoimmune arthritis. Arthritis Rheum2012;64:162-72. [2] Yokosawa M, et al. T-bet over-expression regulates aryl hydrocarbon receptor-mediated T helper type 17 differentiation through an interferon g-independent pathway. Clin Exp Immunol2016;188:22–35. [3] Szabo, et al. Distinct effects of T-bet in TH1 lineage commitment and IFNg production in CD4 an CD8 T cells. Science. 2002;295:338-42. Disclosure of Interests Masaru Shimizu: None declared, Yuya Kondo: None declared, Kotona Furuyama: None declared, Masahiro Yokosawa: None declared, Hiroto Tsuboi: None declared, Isao Matsumoto: None declared, Takayuki Sumida Grant/research support from: Bristol-Myers Squibb, Speakers bureau: Bristol-Myers Squibb

Background Symptomatic differences between male and female patients with IgG4-related disease (IgG4-RD) have been reported [1]. Associations between IgG4-RD and allergy and malignancy have also been reported, although they are controversial. Objectives We previously analyzed the treatment course of IgG4-RD using a multi-center cohort [2]. In the present study, we investigated the associations between organ symptoms and gender, allergic diseases, and malignancies. Methods Data of 166 patients with a definitive diagnosis of IgG4-RD were retrospectively analyzed. Results The cohort consisted of 108 men (65%) and 58 women (35%). Most frequently, the submandibular gland (52%), pancreas (46%), lachrymal gland (43%), and lymph node (38%) were affected. Furthermore, we assessed the frequencies of female sex, allergy, and malignancy in patients with each affected organ (Table 1). The organs with high frequencies of women included the lachrymal gland (50%), lungs (44%), and submandibular gland (43%). Those with low frequencies of women included the thyroid gland (0%), retroperitoneum (17%), and para-aorta (19%). In addition, allergic diseases were found in 60 patients (36%) (Fig. 1A). The organs with high frequencies of allergy included the thyroid gland (50%), submandibular gland (47%), and lachrymal gland (40%). Those with low frequencies of allergy were the para-aorta (13%), prostate gland (30%), and retroperitoneum (31%). Malignancies were found in 23 (14%) patients (Fig. 1B). Organs with high frequencies of malignancy included the para-aorta (38%), prostate gland (30%), and retroperitoneum (21%). In comparison, those with low frequencies of malignancy included the thyroid gland (0%), lungs (8%), and kidney (8%). Conclusion Craniocervical organ involvement was associated with female sex and presence of allergic diseases, suggesting that allergy may contribute to onset of IgG4-RD in some patients. Abdominal organ involvement was associated with male sex and presence of malignancies, suggesting that malignancy may in part contribute to IgG4-RD. Reference [1] Wang, et al., Rheumatology, 2018. [2] Shirakashi, et al., Sci Rep, 2018. Disclosure of Interests Hajime Yoshifuji: None declared, Mirei Shirakashi: None declared, Yuzo Kodama: None declared, Tsutomu Chiba: None declared, Motohisa Yamamoto: None declared, Hiroki Takahashi: None declared, Kazushige Uchida: None declared, Kazuichi Okazaki: None declared, Tetsuya Ito: None declared, Shigeyuki Kawa: None declared, Kazunori Yamada: None declared, Mitsuhiro Kawano: None declared, Shintaro Hirata Grant/research support from: Eli Lilly, UCB, Consultant for: Bristol-Myers Squibb, Jansen, UCB, Paid instructor for: AbbVie, Eisai, Tanabe-Mitsubishi, Speakers bureau: AbbVie, Astellas, Ayumi, Bristol-Myers Squibb, Chugai, Eisai, Eli Lilly, Jansen, Kissei, Pfizer, Sanofi, Takeda, Tanabe-Mitsubishi, UCB, Yoshiya Tanaka Grant/research support from: Abbvie, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi-Tanabe, MSD, Ono, Taisho-Toyama, Takeda, Speakers bureau: Abbvie, Asahi-kasei, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eli Lilly, Eisai, Glaxo-Smithkline, Janssen, Mitsubishi-Tanabe, Novartis, Pfizer Japan Inc, Sanofi, Takeda, UCB, YL Biologics, Masafumi Moriyama: None declared, Seiji Nakamura: None declared, Terumi Kamisawa: None declared, Shoko Matsui: None declared, Hiroto Tsuboi: None declared, Takayuki Sumida Grant/research support from: Bristol-Myers Squibb, Speakers bureau: Bristol-Myers Squibb, Motoko Shibata: None declared, Hiroshi Goto: None declared, Yasuharu Sato: None declared, Tadashi Yoshino: None declared, Tsuneyo Mimori: None declared

Background: IgG4-related disease (IgG4-RD) is characterized by elevated serum IgG4 and tissue infiltration by IgG4-positive plasma cells. The pathogenesis of this disease is not clear. Transcriptom...

Objective: To clarify the efficacy and safety of abatacept for secondary Sjögren’s syndrome (SS) associated with rheumatoid arthritis (RA)., Methods: The primary endpoint of this open-labeled, prospective, observational multicenter study for secondary SS with RA was the remission rate of Simplified Disease Activity Index (SDAI) at 52 weeks after initiation of abatacept. The secondary endpoints included Saxon’s test and Schirmer’s test. Adverse events and adherence rate during the study period were also analyzed., Results: Thirty-six patients (all females) were enrolled in this study. The mean SDAI decreased significantly from 20.6 ± 11.2 (±SD) at baseline to 10.0 ± 10.5 at 52 weeks (p, Conclusion: Abatacept seems to be effective for both RA and SS related manifestations.

Background:Sjögren’s syndrome (SS) is an autoimmune disease which is characterized by lymphocytic infiltration including CD4+IL-17 producing helper T (Th17) cells to the lacrimal and salivary glands. We previously detected anti-M3 muscarinic acetylcholine receptor (M3R) antibodies (1) and M3R reactive CD4+IFNγ producing helper T (Th1) cells (2) in SS patients. Moreover, we clarified that M3R reactive Th1 and Th17 cells had pathogenic roles in the development of auto-immune sialadenitis in SS mouse model (3).Objectives:The purpose of this study was to identify circulating M3R reactive Th17 cells among primary SS (pSS) patients, and to determine functional properties of those cells.Methods:1)Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood of 10 pSS patients, age gender matched 10 healthy controls (HC), and 5 IgG4-related disease (IgG4-RD) patients. According to their HLA-DRB1 typing, top 10 ranked 20 mer peptides from the full length of M3R, which were highly predicted to bind to each HLA molecules according to the immune epitope database website, were selected for each subjects. PBMCs were stimulated with these selected M3R peptides mixed for 40 hours, and M3R peptide reactive IL-17 secreting cells were detected by IL-17 enzyme-linked immunospot assay (ELISpot).2)PBMCs from 5 pSS patients who were positive for M3R specific IL-17 secreting cells, were stimulated with selected 12-20 mer M3R peptides separately, to identify the dominant M3R peptides responsible for IL-17 secretion by ELISpot.3)To identify whether detected IL-17 secreting cells were Th17 cells or not, isolated CD4+T cells from 3 pSS patients who were positive for M3R specific IL-17 secreting cells, were co-cultured with auto-monocyte derived dendritic cells (DCs), and stimulated with the dominant IL-17 secreting M3R peptides detected in method 2.4)Anti-M3R antibodies were examined using ELISA method.5)Clinical features were compared between M3R specific Th17 cells positive and negative pSS patients.Results:1)5 of 10 (50%) pSS patients, while none of 10 (0%) HC, and 5 (0%) IgG4-RD patients, showed significantly increased IL-17 positive spots against selected M3R peptides mixed stimulation compared with non-stimulation in ELISpot (Figure 1). M3R specific IL-17 secreting cells were detected significantly more frequently in pSS (5/10, 50%) than in HC (0/10, 0%) (p=0.03).2)All 5 pSS patients, who were positive for M3R specific IL-17 secreting cells, showed significantly increased IL-17 positive spots against M3R AA76-95 peptides.3)Co-culturing CD4+ T cells with DCs, stimulated with identified dominant M3R peptides in method 2, showed significantly increased spots, clarifying that IL-17 secreting cells were peripheral M3R reactive Th17 cells.4)Titers of anti-M3R antibodies were significantly higher among M3R reactive Th17 cells positive pSS patients than negative pSS patients.5)5 pSS patients positive for M3R reactive Th17 cells had significantly higher disease activity score (ESSDAI: 8.0±4.3) than 5 negative pSS patients (2.8±1.7) (P=0.01).Conclusion:We detected circulating M3R reactive Th17 cells in pSS patients using ELISpot, whose T cell epitopes were shown to be included in M3R AA76-95. Moreover, M3R reactive Th17 cells might correlate with higher disease activity and production of anti-M3R antibodies in pSS patients.References:[1]Tsuboi H, et al. New epitopes and function of anti-M3 muscarinic acetylcholine receptor antibodies in patients with Sjögren’s syndrome.Clin Exp Immunol2010;162:53-61[2]Naito Y, et al. Altered peptide ligands regulate muscarinic acetylcholine receptor reactive T cells of patients with Sjögren’s syndrome.Ann Rheum Dis2005;65:269-71[3]Iizuka M, et al. Pathogenic role of immune response to M3 muscarinic acetylcholine receptor in Sjögren’s syndrome-like sialoadenitis.J Autoimmun.2010;35:383-9Disclosure of Interests:None declared

Glucocorticoids (GC) are effective for treating IgG4-related disease (IgG4-RD); however, relapse is often observed. We conducted a retrospective multicentre study to investigate risk factors in GC regimens associated with relapses of IgG4-RD. Data on 166 patients with definitive IgG4-RD diagnosis were collected from 12 institutions. Comprehensive surveillance of clinical backgrounds and GC regimens as well as multivariate analysis of factors associated with treatment responses and relapses was performed. To determine the initial maximal GC dose, the patients were stratified into three groups depending on the initial prednisolone (PSL) dosage: 0.7 mg/kg/day. The multivariate analysis extracted the disease duration and reduction speed of initial GC dose. Patients treated with initial GC 0.7 mg/kg/day of PSL showed higher relapse rates than those treated with 0.4–0.69 mg/kg/day. The relapse rates were significantly higher in patients with fast reduction of the initial dose (>0.4 mg/day) than in patients with slow reduction (

Background Circulating follicular helper T (Tfh) cells were reported to be increased and promote B cell activation and antibody production in rheumatoid arthritis. Recently, IL-23-Th17 cells axis and hyposialylation of antibodies were proved to be linked to the inflammation of experimental and rheumatoid arthritis. However it remains uncertain how Tfh, including IL-17 producing Tfh (Tfh17), is associated to arthritis and whether its function includes promotion of antibody hyposialylation. Objectives The aim of this study is to explore the relation between Tfh and autoantibody hyposialylation in glucose-6-phosphate isomerase (GPI) induced arthritis (GIA), which mouse model was dependent on T cells, B cells and IL-17. Methods Fluctuation of Tfh and its subsets in draining lymph nodes (dLNs) were analysed and expression of co–stimulatory molecules were assessed among these subsets. Their localization were examined by immunofluorescence (IF) staining. In order to explore the counterpart reaction, serial changes of plasmablast and plasma cell population in dLNs were also analysed. To elucidate Tfh function in ex–vivo, naive B cells were co–cultured with Tfh and the ratio of differentiated plasmablast was quantified. Anti–GPI antibody production from plasmablast was measured in the existence of Tfh. The titers of anti–GPI antibodies in GIA sera were measured by ELISA. DCs were stimulated with purified anti–GPI antibodies from day 7 (arthritis onset phase) and day 28 (resolving phase) GIA to examine the pathogenicity change of antibody. MRNA of ST6 beta–galactoside alpha–2,6–sialyltransferase 1 (st6gal1), the responsible protein for antibody sialylation, in plasmablast was quantified by PCR and detection of sialic acid in anti–GPI antibody was performed by lectin blotting. Naive B cells were co–cultured with Tfh and the st6gal1 expression in differentiated plasmablast was measured by flow cytometry. Results Tfh cells were increased in GIA. It peaked at day 7, the onset of arthritis, and Tfh17 was specifically increased at the same time. Moreover, OX40 expression in Tfh17 was higher than other subsets. IF showed that Tfh and Tfh17 were accumulated in germinal centre of dLNs. As counterparts, plasmablasts and plasma cells were most increased at day 7 as well. When co–cultured with Tfh, the frequency of differentiated plasmablast was much higher than other conditions, and anti–GPI antibody production was up–regulated in the existence of Tfh and GPI. Conflicting with the results above, anti–GPI antibody titers in the sera were gradually elevated even after day 7 and this elevation continued while GIA peaked out. DCs produced higher level of TNF–alpha when stimulated with the antibody from day 7 GIA than day 28. St6gal1 expression in plasmablast was significantly decreased at day 7 and recovered at day 28. In addition, the day 7 antibodies were tended to be contain less sialic acid. Decreased expression of st6gal1 was observed in differentiated plasmablast co–cultured with Tfh. Conclusions Tfh, especially Tfh17 were increased in the induction phase of arthritis. Also, Tfh could have a crucial role in the development of arthritis via plasmablast activation and regulation of autoantibody hyposialylation in GIA. Disclosure of Interest None declared

The objectives of this study are to investigate the prevalence of PAD4 and anti-PAD4 antibodies (Abs) in autoimmune diseases and to clarify their association with anticitrullinated protein antibodies (ACPAs) and shared epitope (SE) in patients with rheumatoid arthritis (RA). Levels of human PAD4 and anti-PAD4 Abs in serum or plasma were measured using sandwich ELISA. Samples were obtained from patients with RA (n = 148), SLE (n = 36), or SS (n = 37) and from healthy controls (HCs; n = 40). Antibodies against cyclic citrullinated glucose-6-phosphate isomerase (GPI) (CCG)-2, CCG-7, anti-CEP-1, and anti-CCP Abs were also measured using ELISA. Patients with RA were genotyped for HLA-DRB1. The human PAD4 and anti-PAD4 Ab levels were compared with the ACPA and SE in patients with RA. The PAD4 levels were 111.9 U/ml in the RA, 30.4 U/ml in the SLE, 81.9 U/ml in the SS patients, and 46.6 U/ml in the HCs. The PAD4 levels were significantly higher in the RA than in the SLE patients or the HCs. Anti-PAD4 Abs were detected in 29.7 % of the patients with RA, but not in the patients with SLE or SS, nor in the HCs. In the RA patients, the PAD4 levels in the anti-PAD4 Ab-negative group were significantly higher than those in the anti-PAD4 Ab-positive group. Moreover, anti-CCG-2, CCG-7, CEP-1, and anti-CCP Ab levels were significantly higher in the anti-PAD4 Ab-positive group than in the anti-PAD4 Ab-negative group. In the RA patients, the PAD4 levels were not correlated with ACPAs. Neither PAD4 nor anti-PAD4 Abs were significantly correlated with the presence of SE alleles. The PAD4 levels were higher in RA than in SLE or HC. Anti-PAD4 Abs appeared specifically in patients with RA. Moreover, anti-PAD4 Abs were associated with ACPAs.

A 36-year-old man with a 16-year history of refractory Behçet's disease (BD)-associated uveitis and chronic renal failure requiring hemodialysis suffered from frequent ocular attacks despite treatment with systemic corticosteroids and cyclosporine A. Following infliximab administration, the patient's BD ocular attack score 24 and visual acuity improved. Although he developed mild acute gastroenteritis, he did not experience any other adverse events. In our review of the literature, we identified seven patients on hemodialysis with inflammatory disease successfully treated with infliximab. Infliximab may be effective and safe in cases of BD and other diseases, including in patients under hemodialysis.

To clarify the pathogenic role of transcription factor expression of CD4 + T helper (Th) cell subsets in the development of rheumatoid arthritis (RA).We collected CD4 + T cells from peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) by magnetic cell sorting. The proportion of Th cell subsets were classified from cell surface markers (CD45RA, CXCR5, CXCR3, CCR6) and the expression of their transcription factors (T-bet, GATA3, RORγt) were analyzed by flow cytometry before and at 24 weeks after anti-rheumatic treatment. Chemotaxis assays quantified migratory ability.The expression of CCR6 and RORγt in Th17 cells from PBMC of RA patients was significantly higher than in healthy control volunteers and osteoarthritis patients. The proportion of Th17 cells in SFMCs of RA patients was significantly higher than that in PBMCs. Chemotaxis assays revealed that the migration index of Th17 cells towards CCL20 was remarkably enhanced in RA patients. The expression of CCR6 and RORγt in Th17 cells at 24 weeks post-therapeutic intervention was significantly decreased compared to before treatment.The high expression of RORγt might facilitate the migration of Th17 cells to inflamed joints via the enhanced expression of CCR6 and contribute to the pathology of RA.

Aim Allergy inhibitory receptor-1 (Allergin-1) is a newly identified immune regulatory molecule thought to influence autoantibody production. Autoantibody production, like that observed in Allergin-1-deficient mice, is crucial in the pathogenesis of several autoimmune diseases such as systemic lupus erythematosus. The purpose of this study is to clarify the regulatory role of Allergin-1-mediated autoantibody production using a murine model of thymocytic anaphylaxis. Methods C57BL/6 (WT) and Allergin-1-deficient mice were treated with apoptotic cells from naive thymocytes stimulated by dexamethasone. Antibody titers of total or immunoglobulin G (IgG) subclass of anti-double-stranded DNA (anti-dsDNA) and anti-histone antibody from serum were measured using an enzyme-linked immunosorbent assay. Macrophages from wild-type (WT) or Allergin-1-deficient mice were co-cultured with fluorescence-labeled apoptotic thymocytes or fluorogenic reagent and resultant phagocytic activity was quantified by with flow cytometry. Results After apoptotic cells injection, antibody titers of total and IgG3 anti-dsDNA and total anti-histone from serum were significantly increased in Allergin-1-deficient versus WT mice. Phagocytic activity was significantly lower in macrophages from Allergin-1-deficient mice versus WT mice. Conclusion Allergin-1 might play an inhibitory role in autoantibody production via upregulation of macrophage phagocytosis.

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.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.Abatacept improved salivary secretion from 2076 ± 1535 at baseline to 2857 ± 1431 mg/2 min at 52 weeks (n = 9, p = .05). Increase of salivary secretion was significantly higher in patients with decreased RSD (n = 6) than increased RSD (n = 3) (1241 ± 713, -137 ± 142 mg/2 min, p = .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 (p = .04). ROC analysis showed the sensitivity and specificity of SIR at baseline of ≥13.0 × 10Parotid DWI seems to be useful for evaluating and predicting the response in salivary secretion to abatacept in SS patients with RA.

Objective. To define the clinical features of IgG4-related disease (IgG4-RD) complicated with perivascular lesions. Methods. 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. Results. 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 (n = 1), thoracic aorta (n = 2), abdominal aorta (n = 6), coronary (n = 1), celiac (n = 1), superior mesenteric (n = 1), renal (n = 2), inferior mesenteric (n = 5), and iliac (n = 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). Conclusion. 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.