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ObjectivesLittle is known about the immunology underlying variable treatment response in rheumatoid arthritis (RA). We performed large scale transcriptome analyses of peripheral blood immune cell subsets to identify immune cells that predict treatment resistance.MethodsWe isolated 18 peripheral blood immune cell subsets of 55 pre-treatment RA patients and 39 healthy controls, and performed RNA sequencing. Transcriptome changes in RA and treatment effects were systematically characterized. Association between immune cell gene modules and treatment resistance was evaluated. We validated predictive value of identified parameters for treatment resistance using quantitative polymerase chain reaction (qPCR) and mass cytometric analysis cohorts. We also characterized the identified population by synovial single cell RNA-seq analysis.ResultsImmune cells of RA patients were characterized by enhanced interferon and IL6-JAK-STAT3 signaling that demonstrate partial normalization after treatment. A gene expression module of plasmacytoid dendritic cells (pDC) reflecting the expansion of pre-dendritic cells (pre-DC) exhibited strongest association with treatment resistance. Type I interferon signaling was negatively correlated to pre-DC gene expression. qPCR and mass cytometric analysis in independent cohorts validated that the pre-DC associated gene expression and the proportion of pre-DC were significantly higher before treatment in treatment-resistant patients. A cluster of synovial DCs showed both features of pre-DC and proinflammatory conventional DC2s.ConclusionsAn increase in pre-DC in peripheral blood predicted RA treatment resistance. Pre-DC could have pathophysiological relevance to RA treatment response.Key messagesWhat is already known about this subject?Limited information is available about the immune cells that are associated with RA treatment resistance.What does this study add?RA treatment resistance can be predicted by an increase in pre-DC in peripheral blood prior to treatment.The expression of genes reflecting an increase in pre-DC is negatively correlated to the type I interferon signature, which is associated with good therapeutic response.Synovial pre-DC-like cells are proinflammatory cDC2s.How might this impact on clinical practice or future developments?Stratified treatment of RA is possible using pre-DC as a biomarker, and it might be possible to develop new therapies for treatment-resistant RA by targeting pre-DC.

There have been hundreds of reports on mutations in the NLRP3 gene related to NLRP3-associated autoinflammatory disease, but few of these mutations have occurred as both germline and somatic mosaic mutations. In this case-based review, we report a 68-year-old man with an NLRP3-associated autoinflammatory disease. He developed secondary amyloidosis, including a renal and colorectal presentation in his 50 s. Sequencing of the NLRP3 gene revealed an I574F somatic mosaic mutation, which has up to now only been reported in germline mutations. The patient was treated with canakinumab, which had great efficacy not only on the NLRP3-mediated inflammation, but also on the chronic renal failure and proteinuria provoked by secondary renal amyloidosis. To evaluate the effectiveness of canakinumab, we conducted a literature research on renal amyloidosis related to NLRP3-associated autoinflammatory disease treated with canakinumab. Although our patient had a relatively long medical history and greater amounts of proteinuria than other reported cases, canakinumab had great efficacy on renal impairment, in similar to other reported cases. Along with the first report of a late-onset I574F somatic mosaic mutation in NLRP3-associated autoinflammatory disease, this report demonstrates the effectiveness of canakinumab on renal amyloidosis, probably through the way that IL-1β blockade minimizes podocyte injury.

Objectives PsA is one of the most serious comorbidities associated with psoriasis. While the early intervention in PsA is demanded, risk factors of PsA development are not well-known. This is the first prospective study to evaluate the clinical significance of nailfold capillary (NFC) changes in patients with psoriasis. Methods We conducted a prospective cohort study in a population of 449 psoriasis patients who had not been treated with systemic therapy or topical finger therapy. NFCs were observed by dermoscopy and capillaroscopy, and the correlation of NFC abnormalities, including nailfold bleeding (NFB) and enlarged capillaries, with the prevalence of PsA, incidence of new PsA, and serum levels of TNF-a, IL-17A and IL-23 were analysed. Results Detailed examination at the time of inclusion revealed that of 449 patients, 236 had Psoriasis vulgaris (PsV) and 213 had PsA. Both NFB and enlarged capillaries were significantly more frequent in patients with PsA (34.7% vs 84.5%, P Conclusions NFC abnormalities were suggested to be a predictor of PsA in psoriasis patients, and at the same time, its degree could be an indicator of disease severity.

Objectives: Interstitial lung disease sometimes occurs in rheumatoid arthritis patients. Although the underlying immunological mechanisms responsible for interstitial lung disease associated with rheumatoid arthritis have not yet been clarified, some reports have suggested possible roles of B cells. To examine the role of B-cell subsets in interstitial lung disease in rheumatoid arthritis patients, we analyzed peripheral blood B-cell subsets.Methods: We analyzed the frequencies of the peripheral blood B-cell subsets by flow cytometry in rheumatoid arthritis patients with and without interstitial lung disease (n = 16 and 81, respectively) and in healthy donors (n = 110) by high-resolution computed tomography.Results: Compared with healthy donors, rheumatoid arthritis patients showed statistically higher frequencies of naive B cells and lower frequencies of memory B cells. Moreover, the frequencies of memory B cells were lower in rheumatoid arthritis patients with interstitial lung disease than in those without. Multivariate analysis showed that the frequency of memory B cells, particularly switched memory B cells, was significantly decreased in rheumatoid arthritis patients with interstitial lung disease, even after adjusting for prednisolone dose.Conclusions: We suspect memory B cells play important roles in interstitial lung disease associated with rheumatoid arthritis.

Objectives: Glucocorticoids (GCs) are effective treatments for rheumatoid arthritis (RA) but long-term use has adverse effects. This study aimed to elucidate whether GCs can be discontinued by intr...

Overlap syndrome refers to a group of conditions that have clinical features of more than one well-characterised rheumatic disease and meet the respective classification criteria. There are no typical renal histological findings in overlap syndrome. When patients with overlap syndrome develop renal dysfunction, various potential causes, including lupus nephritis (LN), renal crisis by systemic sclerosis, interstitial nephritis, and so on, need to be distinguished. Here, we report a 44-year-old woman with overlap syndrome involving systemic lupus erythematosus (SLE), diffuse cutaneous systemic scleroderma, and Sjogren’s syndrome, who was also positive for anti-mitochondrial M2 antibody. She developed glomerular haematuria, proteinuria, and increase in creatinine appeared gradually. Suspecting LN, renal biopsy was performed. However, in the interstitium, mild infiltration of lymphocytes and plasma cells and very partial fibrosis were observed. Immunofluorescence microscopy revealed predominant mesangial immunoglobulin M, C3, and λ light chain staining. Overall, LN was not diagnosed based on these findings. Renal dysfunction was normalised by glucocorticoid treatment for 3 months. This case suggests the importance of a renal diagnosis based on renal pathological findings, especially in a case of overlap syndrome including SLE.

We analyzed the transcriptome of detailed CD4+ T cell subsets including them after abatacept treatment, and examined the difference among CD4+ T cell subsets and identified gene sets that are closely associated disease activity and abatacept treatment. Seven CD4+ T cell subsets (naive, Th1, Th17, Th1/17, nonTh1/17, Tfh and Treg) were sorted from PBMCs taken from 10 RA patients and 10 healthy controls, and three RA patients donated samples before and 6 months after abatacept treatment. Paired-end RNA sequencing was performed using HiSeq 2500. A total of 149 samples except for 12 outliers were analyzed. Overview of expression pattern of RA revealed that administration of abatacept exerts a large shift toward the expression pattern of HC. Most of differentially expressed gene (DEG) upregulated in RA (n = 1776) were downregulated with abatacept treatment (n = 1349). Inversely, most of DEG downregulated in RA (n = 1860) were upregulated with abatacept treatment (n = 1294). This DEG-based analysis revealed shared pathway changes in RA CD4+ T cell subsets. Knowledge-based pathway analysis revealed the upregulation of activation-related pathways in RA that was substantially ameliorated by abatacept. Weighted gene co-expression network analysis (WGCNA) evaluated CD4+ T cells collectively and identified a gene module that consisted of 227 genes and was correlated with DAS28-CRP (Spearman's rho = 0.46, p = 4 × 10−9) and abatacept administration (Spearman's rho = −0.91, p = 5 × 10−57). The most highly connected 30 genes of this module included ZAP70 and JAK3, and pathway analysis of this module revealed dysregulation of the TCR signaling pathway network, which was ameliorated by abatacept.

Objective.Shared epitope (SE) alleles are the most significant genetic susceptibility locus in rheumatoid arthritis (RA); however, their target populations in CD4+ T cells are not well elucidated. We analyzed the association between SE alleles and the T cell receptor (TCR) repertoire diversity of naive and memory CD4+ T cells using next-generation sequencing (NGS).Methods.The TCR beta chains in naive and memory CD4+ T cells from the peripheral blood of 22 patients with RA and 18 age- and sex-matched healthy donors (HD) were analyzed by NGS. The Renyi entropy was used to evaluate TCR repertoire diversity and its correlations with SE alleles and other variables were examined. Serum cytokine levels were measured by multiplex ELISA.Results.The TCR repertoire diversity in memory CD4+ T cells was reduced in SE allele-positive patients with RA compared with HD, and showed a significant negative correlation with the SE allele dosage in RA. The TCR repertoire diversity of naive and memory T cells was also negatively correlated with disease activity, and the SE allele dosage and disease activity were independently associated with reduced TCR repertoire diversity. TCR repertoire diversity showed a significant positive correlation with the serum interleukin 2 levels.Conclusion.SE alleles and disease activity were negatively correlated with the TCR repertoire diversity of CD4+ T cells in RA. Considering the pivotal role of CD4+ T cells in RA, restoring the altered TCR repertoire diversity will provide a potential RA therapeutic target.

Systemic lupus erythematosus (SLE) is an autoimmune disease that involves multiple immune cell subsets. We analyzed immune cell subsets in human peripheral blood mononuclear cells (PBMC) in order to identify the cells that are significantly associated with SLE disease activity and treatment. The frequencies of various subsets of CD4+ T cells, B cells, monocytes and NK cells in PBMC were assessed in 30 healthy controls (HC), 30 rheumatoid arthritis (RA) patients and 26 SLE patients using flow cytometry. The correlations between subset frequencies in SLE and clinical traits including Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) were examined. Changes in subset frequencies after the treatment in SLE patients were investigated. We focused on CD25+LAG3+ T cells and investigated their characteristics, including cytokine secretion, mRNA expression and suppression capacity. We assessed correlations between CD25+LAG3+ T cells and SLEDAI by Spearman's rank correlation coefficient. CD25+LAG3+ T cells were significantly increased in SLE whereas there were few in RA and HC groups. CD25+LAG3+ T cell frequencies were significantly correlated with SLEDAI and were increased in patients with a high SLEDAI score (> 10). CD25+LAG3+ T cells produced both IL-17 and FOXP3, expressed mRNA of both FOXP3 and RORC and lacked suppressive capacity. CD25+LAG3+ T cells were associated with disease activity of SLE. CD25+LAG3+ T cells had features of both CD25+FOXP3+ regulatory T cells (CD25+ Treg) and Th17. CD25+LAG3+ T cells could be associated with the inflammatory pathophysiology of SLE.

Objective Biologic disease-modifying antirheumatic drugs (bDMARDs) used for rheumatoid arthritis (RA) treatment have several mechanisms of action. Interleukin-6 inhibitors (IL-6i) block the production of acute-phase reactants (APRs), which are some of the composite measures of disease activity. We undertook this study to examine the agreement between the European League Against Rheumatism (EULAR) response based on the erythrocyte sedimentation rate (ESR) or C-reactive protein level, the Simplified Disease Activity Index 50% response measure (SDAI50), and the Clinical Disease Activity Index 50% response measure (CDAI50) in patients treated with IL-6i and other bDMARDs. Methods We enrolled 306 patients with RA who started or switched bDMARDs. Treatment response at 6 months was analyzed. Kappa statistics were used to evaluate the agreement between different response measures. The contribution of APRs to improvement in disease activity scores was examined. The change of Health Assessment Questionnaire (HAQ) score was analyzed in IL-6i-treated patients. Results Good agreement was achieved between response measures, with κ >0.6 in patients treated with tumor necrosis factor inhibitors or cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin fusion protein. In IL-6i-treated patients, the agreement was low between the EULAR response (ESR) and the SDAI50 or the CDAI50 (κ = 0.43 and 0.37, respectively). Under IL-6i treatment, APR improvement accounted for 56.0% of total improvement of the Disease Activity Score in 28 joints (DAS28) using the ESR. When discordance was found between the CDAI50 and EULAR response in IL-6i-treated patients, all patients were classified as EULAR-only responders; there was no HAQ improvement in EULAR-only responders. Conclusion EULAR response criteria overestimate the response under IL-6i treatment because the APR improvement largely contributes to the DAS28 improvement.

Background Some prognostic factors for lupus nephritis (LN) have been mentioned such as nephrotic syndrome, class 4 and chronicity on histology. In a previous single-centre study, we reported a potentially poorer renal response to induction therapy in LN that developed later after SLE onset (delayed, D-LN) compared with LN manifesting at SLE onset (early, E-LN) 1). However, our study was limited by a small sample size and lack of long-term observation. Objectives This multicenter study aimed to validate whether D-LN was a useful predictor of a poor response to induction therapy with more detailed clinical and pathological parameters. Furthermore, we investigated whether D-LN was also a predictor of flares and long-term renal outcomes in addition to the established prognostic factors. Methods We retrospectively examined 215 biopsy-proven LN patients (136 E-LN, 79 D-LN) who attended 3 hospitals above between 1997 and 2014 and who were observed for 3–20 (median: 10.8) years from LN onset. We compared baseline clinical, pathological features and treatment options at LN onset between E-LN and D-LN. Then we compared the cumulative complete response (CR) rates, renal/extra-renal relapse rates, and the rates of renal insufficiency between the two groups. Renal insufficiency was defined as follows:1 serum creatinine (SCr) doubling or ESRD for severe insufficiency, and2 SCr increasing by 1.5 times and also >1.0 (female) or >1.2 mg/dl (male) for mild insufficiency. Moreover, we evaluated predictors of the response, flares and long-term renal outcomes with multivariate analysis. Results Anti-Sm/RNP antibodies and mixed proliferative and membranous nephritis (class 3+5 or 4+5) were significantly more prevalent in D-LN than E-LN (48.1 vs. 32.4%, 68.8 vs. 40.4%, 40.5 vs. 18.4%, respectively). Log-rank test showed that significantly lower cumulative CR rates over 3 years (65.8 vs. 83.1% at 12 months, 83.5 vs. 92.6% at 36 months, p Conclusions D-LN might be a novel predictor of a poorer treatment response, renal flares and long-term renal outcomes independent of the established prognostic factors. The distinct differences in the autoantibody profiles between E-LN and D-LN groups suggest that D-LN patients might reflect a refractory SLE subset with a specific immunological profile. Reference [1] Nakano M, et al. Different responses to induction therapy in two onset categories of lupus nephritis.EULAR2017THU 0251. Acknowledgements None Disclosure of Interest None declared

The characteristics of lymphoproliferative disorders (LPD) in patients with rheumatoid arthritis (RA) remain unclear. Therefore, we retrospectively analyzed the clinical characteristics of these patients in our department.Twenty RA patients who developed LPD between April 2003 and August 2016 in our department were analyzed.All of the RA patients who developed LPD had been treated with methotrexate (MTX). The median weekly and total dosages of MTX were 6.8 mg/week and 2530 mg, respectively. The median duration of MTX administration was eight years. Nineteen patients (95%) achieved complete remission (CR) and 15 (75%) achieved CR with MTX cessation alone. Based on the pathological findings, we divided MTX-associated LPD patients into two groups (n = 16); polymorphic LPD (31%) and other groups. CR with MTX cessation alone was achieved in 5 (100%) and 6 (54.5%) patients in the polymorphic LPD and other groups, respectively (p = .12). Moreover, the duration from the cessation of MTX to CR was significantly shorter in the polymorphic LPD group than in the other group (5.3 months vs 12.6 months, p = .01, respectively).Polymorphic LPD, which was the most frequent pathological diagnosis in this cohort, was associated with a higher incidence of CR and a significantly shorter duration to CR.

We analyzed the transcriptome of detailed CD4

Background Regulatory T cells (Tregs) play a role in the suppression of inflammation in autoimmune diseases, and lymphocyte activation gene 3 (LAG3) was reported as a marker of interleukin (IL)-10-producing Tregs. We aimed to clarify the function of human IL-10-producing CD4+CD25−LAG3+ T cells (LAG3+ Tregs) and their association with rheumatoid arthritis (RA). Methods LAG3+ Tregs of human peripheral blood mononuclear cells (PBMCs) were cultured with B cells and follicular helper T cells to examine antibody suppression effects. The frequency of LAG3+ Tregs was evaluated in peripheral blood samples from 101 healthy donors and 85 patients with RA. In patients treated with abatacept, PBMC samples were analyzed before and after treatment. Naive CD4+ T cells were sorted and cultured in the presence of abatacept, followed by flow cytometric analysis and function assays. Results LAG3+ Tregs produced high amounts of IL-10 and interferon-γ, and they suppressed B-cell antibody production more strongly than CD25+ Tregs. Cell-to-cell contact was required for the suppressive function of LAG3+ Tregs. The frequency of LAG3+ Tregs was lower in patients with RA, especially those with higher Clinical Disease Activity Index scores. LAG3+ Tregs significantly increased after 6 months of abatacept treatment, whereas CD25+ Tregs generally decreased. Abatacept treatment in vitro conferred LAG3 and EGR2 expression on naive CD4+ T cells, and abatacept-treated CD4+ T cells exhibited suppressive activity. Conclusions IL-10-producing LAG3+ Tregs are associated with the immunopathology and therapeutic response in RA. LAG3+ Tregs may participate in a mechanism for the anti-inflammatory and immune-modulating effects of targeted therapy for costimulation. Electronic supplementary material The online version of this article (doi:10.1186/s13075-017-1309-x) contains supplementary material, which is available to authorized users.

Sinus bradycardia is reported as an adverse effect of high-dose glucocorticoid therapy. We report three cases of systemic lupus erythematosus, wherein intravenous pulse methylprednisolone was administered. The patients' average baseline heart rate was 72 beats/min, which decreased 30% from baseline at 61 h after beginning the therapy. The average minimum heart rate was 38 beats/min, and this rate continued for 169 h on average. No other causes for bradycardia were found, suggesting that the administration of glucocorticoid pulse therapy resulted in decreased heart rate.

Purpose Interleukin-32 (IL-32) is an inflammatory cytokine that is associated with the pathogenesis of several connective tissue diseases. We measured serum IL-32γ concentrations of systemic lupus erythematosus (SLE) patients. Methods Serum samples were obtained from SLE patients ( n = 51), and healthy controls ( n = 15). Serum IL-32 concentrations were measured using ELISA. Clinical information was obtained from medical records. Results Serum IL-32γ was detectable in three cases of SLE patients, whereas it was not detected in any healthy controls. Case 1: a 44-year-old female with lupus nephritis (LN) (Class II) and antiphospholipid antibody syndrome. Serum IL-32γ was 5.1 pg/ml. Case 2: a 30-year-old female with a history of diffuse proliferative LN (Class IV G (A/C)) and pulmonary hemorrhage. Serum IL-32γ was 8.9 pg/ml. Case 3: a 45-year-old female with chronic LN. Serum IL-32γ was 9.1 pg/ml. All three cases of IL-32γ-detectable patients had histories of LN and one had an active disease. In the context of LN, serum IL-32γ was detectable in 18.8% (three of 16) of SLE patients with histories of LN. Conclusion We suppose that IL-32γ could contribute to the pathogenesis of renal diseases in some LN patients.

A 75-year-old woman was admitted to our department because of backache and multiple joint pain. Serum C-reactive protein (CRP) level was 6.8 mg/dL, and serum rheumatoid factor and anti-citrullinated peptide antibody were negative. Magnetic resonance imaging (MRI) showed bone edema and synovitis of the sacroiliac joints. (18)Fluorodeoxyglucose-positron emission tomography ((18)FDG-PET) showed increased uptakes in the bilateral elbow, shoulder, sternoclavicular, hip, and sacroiliac joints. In addition, increased uptakes were also observed in the bilateral cervical and subclavian arteries, and the thoracic aorta. Moreover, inflammation of the vascular walls and an aneurism in the right subclavian artery were observed on MRI. The patient's HLA type was HLA-B48 and B60. According to the Assessment of Spondyloarthritis (ASAS) classification criteria, peripheral spondyloarthropathy (SpA) was also diagnosed. Although the diagnostic criteria of Takayasu aortitis or giant cell aortitis were not fulfilled, we thought that active aortitis was also involved, and high-dose prednisolone was started. The patient's symptoms were diminished immediately, and CRP levels returned to normal. Although the etiology of the aortitis was not certain, this is the first report of late-onset peripheral SpA with aortitis, diagnosed by (18)FDG-PET and MRI. We recommended that it is important to evaluate the aortic involvement in late-onset SpA patients, when elevated systemic inflammation is observed.

IgG4-related disease (IgG4-RD) is associated with the infiltration of IgG4-positive plasma cells into various organs. Nephropathy of IgG4-RD is generally interstitial nephritis and glomerulonephritis is rare. We describe a case of membranous nephropathy (MN) without interstitial nephritis associated with IgG4-RD symptoms including lymphadenopathy and pulmonary and pleural lesions. Treatment with steroids improved these clinical symptoms, but withdrawal of steroids induced the repeated relapse of MN. Finally, flaring of MN was prevented by the combination of steroids and cyclosporine. This is the first report of the successful treatment of MN associated with IgG4-RD by this combination therapy.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that leads to destructive arthritis. Although the HLA class II locus is the strongest genetic risk factor for rheumatoid arthritis, the relationship between HLA class II alleles and lymphocyte activation remains unclear. We performed immunophenotyping of peripheral blood mononuclear cells on 91 HLA-DRB1-genotyped RA patients and 110 healthy donors. The frequency of memory CXCR4+CD4+ T cells and not Th1 and Th17 cells, was significantly associated with disease severity by multiple linear regression analysis. RA patients with one or more susceptible HLA-DR haplotypes (shared epitope: SE) displayed a significantly higher frequency of memory CXCR4+CD4+ T cells. Moreover, the frequency of memory CXCR4+CD4+ T cells significantly correlated with the expression level of HLA-DR on B cells, which was elevated in RA patients with SE. In vitro analysis and transcriptomic pathway analysis suggested that the interaction between HLA-DR and T cell receptors is an important regulator of memory CXCR4+CD4+ T cells. Clinically, a higher frequency of memory CXCR4+CD4+ T cells predicted a better response to CTLA4-Ig. Memory CXCR4+CD4+ T cells may serve as a powerful biomarker for unraveling the linkage between HLA-DRB1 genotype and disease activity in RA.

CSVd could not infect Nicotiana benthamiana when the plants were pretreated with crude leaf extract of Capsicum chinense ‘Sy-2’. C. chinense leaves were revealed to contain strong RNA-digesting activity. Several studies have identified active antiviral and antiviroid agents in plants. Capsicum plants are known to contain antiviral agents, but the mechanism of their activity has not been determined. We aimed to elucidate the mechanism of Capsicum extract’s antiviroid activity. Chrysanthemum stunt viroid (CSVd) was inoculated into Nicotiana benthamiana plants before or after treating the plants with a leaf extract of Capsicum chinense ‘Sy-2’. CSVd infection was determined using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) 3 weeks after inoculation. When Capsicum extract was sprayed or painted onto N. benthamiana before inoculation, it was effective in preventing infection by CSVd. To evaluate CSVd digestion activity in leaf extracts, CSVd was mixed with leaf extracts of Mirabilis, Phytolacca, Pelargonium and Capsicum. CSVd-digesting activities were examined by quantifying undigested CSVd using qRT-PCR, and RNA gel blotting permitted visualization of the digested CSVd. Only Capsicum leaf extract digested CSVd, and in the Capsicum treatment, small digested CSVd products were detected by RNA gel blot analysis. When the digesting experiment was performed for various cultivars and species of Capsicum, only cultivars of C. chinense showed strong CSVd-digesting activity. Our observations indicated that Capsicum extract contains strong RNA-digesting activity, leading to the conclusion that this activity is the main mechanism for protection from infection by CSVd through spraying or painting before inoculation. To our knowledge, this is the first report of a strong RNA-digesting activity by a plant extract.

To assess the long-term safety and efficacy of tacrolimus (TAC) used in combination with oral methotrexate (MTX) in patients with rheumatoid arthritis (RA) whose disease remains active despite treatment with MTX alone. The clinical courses of 24 RA patients who received TAC added to MTX from a single center were analyzed retrospectively. The disease activity was evaluated by the DAS28-ESR(3) every 12 months after the addition of TAC, and side effects were evaluated for 3 years. At 3 years after starting the treatment, TAC was still being used by 19 patients (79 %). The causes of discontinuation were an inadequate response (3 cases), oral ulcers and elevation of creatinine (1 case), and worsening of interstitial pneumonia (1 case). No death was registered. The DAS28-ESR(3) was decreased from 4.81 to 3.41 after 3 years of treatment. The doses of prednisolone were decreased from 5.1 mg/day to 3.2 mg/day after 3 years. In patients whose active RA persists despite treatment with MTX, TAC in combination with MTX is safe and well tolerated and provided clinical benefit for a long time in this single-center retrospective study. Further studies are required to confirm the safety and efficacy of this combination therapy.

A 69-year-old man with sensorineural hearing loss and iritis was diagnosed with atypical Cogan's syndrome. He had several systematic manifestations: aortitis, meningitis, panniculitis and seronegative arthritis. Remission induced by treatment with high doses of prednisolone was followed by relapse within 1 year. Although his condition was resistant to various immunosuppressive drugs, including methotrexate, cyclosporine, azathioprine and adalimumab, his symptoms, inflammatory response and quality of life measures were successfully improved by tocilizumab, a humanized anti-interleukin-6 receptor antibody.

シタフロキサシン（STFX：グレースビット®錠50 mg，細粒10%）は，第一三共株式会社において創製され，2008年6月に発売されたキノリン骨格の1位にフルオロシクロプロピル基を，7位にスピロ型アミノピロリジン基を有するキノロン系抗菌薬である．本剤は，既存のキノロン系抗菌薬耐性菌を含むグラム陽性菌ならびにグラム陰性菌，さらにはマイコプラズマおよびクラミジアなどの非定型菌に対して，既存キノロン系抗菌薬と比較して最も高い抗菌活性を示した．特に，呼吸器感染症主要原因菌である肺炎球菌および尿路感染症主要原因菌である大腸菌に対し，既存キノロン系抗菌薬と比較してそれぞれ2～32倍および8～16倍強い抗菌力を示した．STFXは細菌の標的酵素であるDNAジャイレースおよびトポイソメラーゼIVのいずれの酵素に対しても強い阻害作用を有し，さらに既存のキノロン系抗菌薬に耐性化した変異酵素の活性も強く阻害するため，他のキノロン系抗菌薬の耐性株に対しても強い抗菌力を発揮できると考えられた．STFXはヒトにおいて経口投与により速やかに吸収された後，良好な組織移行性と約6時間の半減期を示しながら，その大部分（約70%）が未変化体として尿中に排泄された．臨床試験においては，呼吸器感染症，尿路感染症をはじめとする各種感染症において90%以上の高い有効性が認められ，さらに，直前抗菌化学療法無効患者においても93.4%の高い有効性が認められた．細菌学的効果（菌消失率）は，呼吸器感染症で92.0%，尿路感染症で95.8%であり，本剤の強い抗菌力を反映した優れた効果が認められた．臨床試験で認められた主な副作用は下痢（13.0%）であったが，大部分が軽度であり一過性のものであった．これらの基礎試験および臨床試験成績から，STFXは呼吸器感染症，尿路感染症をはじめとする細菌感染症治療の有用な選択肢と考えられる．

The objective of this study was to assess both the anti-inflammatory and immunomodulatory effects of low-dosage simvastatin on rheumatoid arthritis (RA). In each patient, simvastatin at 10 mg/day was administered for 12 weeks. The other treatments were unchanged at least 3 months before simvastatin administration to the end of the study. Patients were assessed for the improvement in clinical, laboratory, and immunological parameters of RA and for adverse events. Twenty-four patients with RA were enrolled. Clinical symptoms, including patient's assessment of pain and disease activity on visual analog scale (VAS), the swollen joint and tender joint counts, and handgrip strength significantly improved. Physician's assessment of disease activity on VAS, a period of morning stiffness and modified health assessment questionnaire showed a tendency of improving after administration of low-dosage of simvastatin. Of special interest was that the median levels of erythrocytes sedimentation rate, C-reactive protein, and rheumatoid factor were significantly decreased from 54.0 mm/h to 45.5 mm/h, from 1.50 mg/dl to 0.85 mg/dl, and from 57.0 IU/ml to 28.0 IU/ml, respectively, after administration of simvastatin. ACR20 and ACR50 responses were achieved in 62% and 38%, respectively, of simvastatin-treated patients for 12 weeks. Immunological assessment in peripheral blood revealed that the Th1/Th2 and CD4/CD8 ratios were significantly reduced by simvastatin. No adverse events were reported during simvastatin treatment. Immunomodulation through the alteration of Th1/Th2 and CD4/CD8 ratios may be a pharmacological mechanism in the anti-rheumatic effect of low-dosage simvastatin. Although it is necessary to evaluate the long-term effects of statins, low-dosage statins appear to be good as additional therapeutic agents.

A series of 4-oxo-4H-pyrido[1,2-a]pyrimidine derivatives, derivatized at the 2-position with aromatic substituents, were synthesized by the Suzuki cross-coupling method and evaluated for their ability to potentiate the activity of the fluoroquinolone levofloxacin (LVFX) and the anti-pseudomonas beta-lactam aztreonam (AZT) in Pseudomonas aeruginosa. By incorporating hydrophilic substituents onto the aryl nucleus, we found a morpholine analogue that possessed improved solubility, retained activity in vitro, and displayed potentiation activity in vivo in a rat model of P. aeruginosa pneumonia.

A 58-year-old man concurrently developed polymyositis (PM), interstitial lung disease, and nephrotic-range proteinuria. Renal biopsy revealed focal mesangial proliferative glomerulonephritis (mesPGN) with depositions of immunoglobulin and complements. A combination therapy of corticosteroid, intravenous immunoglobulin, and cyclosporine was found very effective for the patient. Glomerulonephritis associated with PM/dermatomyositis (DM) is rare. In our review of related literature, mesPGN was exclusively observed in polymyositis while membranous nephropathy in DM. The mechanism underlying the association between myositis and glomerulonephritis remains to be elucidated.

A series of 4-oxo-4H-pyrido[1,2-a]pyrimidine derivatives, derivatized at the 2-position with carbon-linked substituents, were synthesized and evaluated for their ability to potentiate the activity of the fluoroquinolone levofloxacin (LVFX) and the anti-pseudomonas beta-lactam aztreonam (AZT) in Pseudomonas aeruginosa. Palladium-catalyzed cross-coupling methods were applied for the incorporation of aliphatic and aromatic substituents.

CD25 + CD4 + regulatory T cells suppress immune responses and are believed to play roles in preventing autoimmune diseases. However, the mechanism(s) underlying the suppression and the regulation of their homeostasis remain to be elucidated. Here we show that these regulatory T cells downregulated CD25 − CD4 + T-cell-mediated production of IL-12 from antigen-presenting cells, which can act as a growth factor for CD25 − CD4 + T cells. We further found that CD25 + CD4 + T cells, despite their well-documented “anergic” nature, proliferate significantly in vitro only when CD25 − CD4 + T cells are present. Notably, this proliferation was strongly dependent on IL-2 and relatively independent of IL-12. Thus, CD25 + CD4 + T cells suppress CD25 − CD4 + T-cell responses, at least in part, by inhibiting IL-12 production while they themselves can undergo proliferation with the mediation of CD25 − CD4 + T cells in vitro. These results offer a novel negative feedback system involving a tripartite interaction among CD25 + CD4 + and CD25 − CD4 + T cells, and APCs that may contribute to the termination of immune responses.

Recent immunosuppressive treatments for lupus nephritis have improved renal survival rate, however, there still exists lupus nephritis refractory to these treatments. Angiotensin receptor blockers (ARBs) are known not only to decrease blood pressure but also to have an independent renoprotecting effect by interrupting renin-angiotensin system. The aim of this study was to evaluate whether ARBs have an additive effect on refractory lupus nephritis. Enrolled in this trial were twelve patients with lupus nephritis who were diagnosed by renal biopsy and remained proteinuria despite corticosteroids and/or immunosuppressive treatments. ARB, losartan or candesartan, was administered for six months. Various clinical parameters were compared before and after ARB administration. Proteinuria decreased after ARB treatment in 83% of the patients and the median amount of proteinuria significantly decreased from 2530 mg/gCr to 459 mg/gCr (P = 0.03). In addition, serum albumin and cholesterol levels were significantly improved. Systolic blood pressure significantly decreased, but none had symptoms of hypotension. The antiproteinuric effect of ARB did not correlate with the reduction of blood pressure. Interestingly, higher total complement activity levels before ARB treatment were associated with a greater reduction of proteinuria. The addition of ARB would be a safe and effective treatment for lupus nephritis with persistent proteinuria despite corticosteroids and/or immunosuppressive treatments.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a systemic disease with autoimmune characteristics caused by mutations in a single gene called AIRE. Although a defect in negative selection has been emphasized for the pathogenesis of the autoimmune symptoms on the basis of studies of Aire-targeted mice, the function of the gene in the peripheral immune system and the cause of immunodeficiency noted in the disease have not been clarified yet. In this study, we demonstrated using murine Aire transfectants that Aire downregulates IL-1 receptor antagonist (IL-1Ra), which is important for immune suppression, and major histocompatibility complex (MHC) class II molecules, which are critical for acquired immunity. It was surprising to learn that Aire, which has been supposed to positively regulate transcription, downregulates multiple molecules. This downregulation of IL-1Ra and MHC class II molecules seems to be caused by the competition for transcriptional coactivator, CREB-binding protein (CBP), and may explain part of the contradictory (i.e., both autoimmune and immunodeficient) nature of APECED.

We describe a patient with systemic lupus erythematosus (SLE) who developed severe and acute thrombotic thrombocytopenic purpura (TTP). Detection of the fragmentation of peripheral red blood cells (RBC) helped the early diagnosis of TTP and the patient was rescued by extensive plasma exchange started promptly after the diagnosis. Because manifestations of TTP are similar to those in SLE, it is sometimes difficult to make an accurate diagnosis of TTP in SLE patients. We emphasise here the significance of the early diagnosis of TTP by the observation of fragmented RBC and the intensive therapy, including plasma exchange, for this very severe condition.

Influence of various hemodialysis membranes on the plasma (1→3)-β-D-glucan level. Background Recently, invasive fungal infections have increased significantly because of the growing number of immunocompromised hosts. The measurement of plasma (1→3)-β-D-glucan has been proposed as a useful diagnostic tool for deep mycosis. In this study, we analyzed the alteration of the plasma (1→3)-β-D-glucan concentration by using different kinds of hemodialysis (HD) membranes in end-stage renal disease (ESRD) patients and estimated its half-life. Methods Twenty-seven patients with ESRD without known fungal infections (with a median age of 66 years old) were enrolled in this study. Cellulose triacetate (CTA) membrane, cellulose (Cu) membrane, and polymethyl methacrylate (PMMA) membrane were used in three consecutive initiations of HD and plasma (1→3)-β-D-glucan concentration was measured before and after each HD session. Results The level did not change between before and after HD when CTA and PMMA membranes were used. In contrast, the plasma (1→3)-β-D-glucan level increased greatly after HD using the Cu membrane (from 9.4 to 332 pg/mL in median). Hypothesizing that the plasma (1→3)-β-D-glucan level declines exponentially, its median half-life is estimated at 20 hours, which is not affected by hepatic or renal function. Conclusions Because the plasma (1→3)-β-D-glucan level increases dramatically after HD using the Cu membrane, dialyzers with Cu membrane should be avoided for HD in patients with suspected deep mycosis. The measurement of plasma (1→3)-β-D-glucan is also useful for the patients with hepatic or renal failure.