Cytomegalovirus (CMV) can cause life-threatening diseases in immunosuppressed patients. Some of the patients with connective tissue disease develop CMV infection, and approximately half of this group has been reported to have received pulsed-methylprednisolone (p-MPSL) therapy. This study aimed to identify predictors of the onset of CMV infection in patients receiving p-MPSL therapy for connective tissue disease. This was a retrospective, multicenter cohort study. We included patients who received p-MPSL therapy for connective tissue disease and had CMV antigenemia measured between April 2011 and December 2020. Peripheral blood cell data before the start of p-MPSL therapy and at the start of steroid tapering were collected in addition to baseline characteristics, including age, sex, and body mass index. CMV infection was defined as detection of one or more CMV antigen-positive cells (CMV-positive). The study examined and compared the CMV-positive group with the CMV-negative group. Logistic regression analysis was used to explore the factors associated with CMV antigen positivity. Receiver operating characteristic curve analysis was used to identify the cut-off values for the factors associated with CMV antigen sensitivity. Of the 200 patients included, 87 had antigen positivity. Logistic regression analysis showed that age ≥ 65 years [adjusted odds ratio (aOR): 2.75, 95

Objective The incidence of cytomegalovirus (CMV) infection or disease in patients with rheumatic musculoskeletal diseases is reported to be 2%. Over half received pulsed methylprednisolone, and some experienced a fatal outcome. In this study, we aimed to explore predictive and diagnostic biomarkers for CMV infection or disease in such patients and compare them with biomarkers reported for immune reconstitution inflammatory syndrome (IRIS) in people with HIV. Methods In this multicentre prospective cohort study, we collected blood and saliva samples from 38 patients with rheumatic musculoskeletal disease before initiating high-dose glucocorticoid therapy, at the start of glucocorticoid tapering, at the onset of CMV infection, and 4 weeks later. Peripheral blood cell counts, flow cytometry for CD4, CD8, and Tregs, ELISA for cytokine/chemokine panels, and measurements of herpesvirus-derived DNA in saliva were performed. Results Lower white blood cells, CD4(+) cells, IL-6, and interferon-gamma levels and higher interferon-inducible protein (IP)-10 and granulysin levels at baseline could be predictive biomarkers for CMV infection. Furthermore, lower platelet counts and higher IL-10, IP-10, granulysin, TNF-a, IL-1ra, and IL-15 levels at the onset of CMV infection were found as diagnostic biomarkers for CMV infection. EBV, human herpes virus (HHV)-6, and HHV-7 DNA levels in the saliva were significantly increased after high-dose glucocorticoids, regardless of CMV infection. Conclusion We identified predictive and diagnostic biomarkers for CMV infection after high-dose glucocorticoid therapy for rheumatic musculoskeletal diseases. While similarities with IRIS biomarkers in patients living with HIV were observed, complete agreement could not be confirmed.

OBJECTIVES:A disintegrin and metalloproteinase (ADAM)-15 and vascular endothelial (VE)-cadherin are involved in angiogenesis. We investigated the relationship between ADAM-15 and VE-cadherin expressions in rheumatoid arthritis (RA). METHODS:VE-cadherin concentrations in the serum of patients with RA were measured using the enzyme linked immunosorbent assay. We stimulated fibroblast-like synoviocytes (RA-FLS) with VE-cadherin and measured the vascular endothelial growth factor (VEGF) and inflammatory cytokine levels using ELISA. We also examined the correlation between serum VE-cadherin levels and DAS-28ESR, and used the Matrigel assay to examine VE-cadherin involvement in angiogenesis. RESULTS:Serum VE-cadherin levels were significantly higher in patients with RA than in healthy controls. A negative correlation was observed between VE-cadherin and DAS-28ESR. VEGF, chemokine ligand 16, intercellular adhesion molecule-1, and interleukin-8 levels in the supernatant of RA-FLS or human umbilical vein endothelial cells stimulated with VE-cadherin were significantly lower than those in the controls. The number of intercellular bridges formed by endothelial cells using Matrigel significantly decreased in RA synovial fluids from which VE-cadherin had been removed compared to synovial fluids treated with control immunoglobulin G. CONCLUSION:VE-cadherin may have an inhibitory effect on inflammation depending on the phase of RA inflammation.

Objectives Pneumocystis pneumonia (PCP) has a poor prognosis in patients with autoimmune diseases. Additionally, the mortality of PCP in autoimmune diseases is higher than that of human immunodeficiency virus-PCP. Therefore, this study aimed to assess the risk factors associated with mortality in patients with autoimmune diseases complicated with PCP. Methods We conducted a retrospective observational study involving 38 patients treated for PCP at Showa University School of Medicine from January 2010 to August 2014. Diagnoses were established based on clinical symptoms, imaging, and laboratory tests, including hypoxemia (partial pressure of oxygen (PaO2) < 70 mmHg), chest computed tomography findings, elevated (1,3)-beta-D-glucan, beta-D-glucan, and positive Pneumocystis jirovecii polymerase chain reaction tests from sputum samples. Data regarding patient demographics, underlying diseases, therapeutic interventions, and laboratory findings were collected. Statistical comparisons between survivors and non-survivors were performed using Fisher's exact probability test and Mann-Whitney U test for independence test with Stata/SE version 17.0 (StataCorp LLC, College Station, TX). Results The median age of the study group was 72.4 years old, with the majority having rheumatoid arthritis. Mortality occurred in 18% (seven out of 38) of cases. Factors associated with increased mortality include males, higher serum creatinine and C-reactive protein levels, lower albumin and immunoglobulin A levels, and lower PaO2/fraction of inspired oxygen (FiO2) ratio. No significant difference was observed in the rate of intratracheal intubation, ICU management, and hospitalization period. Prophylactic administration of trimethoprim-sulfamethoxazole (TMP-SMX) was not performed in any of the cases. Conclusions This study examined the risk of mortality for PCP in patients with autoimmune diseases. The male gender, low IgA and albumin levels, low PaO2/FiO2 ratio, as well as high creatinine and CRP levels, were identified as significant factors for poor prognosis. These factors can help identify patients at high risk for PCP and guide the consideration of prophylactic TMP-SMX administration. They may also provide insights into when to discontinue prophylactic treatment. Future studies should investigate the administration of prophylactic TMP-SMX. Additionally, the risk of mortality for PCP under the administration of new biological agents, such as anifrolumab, belimumab, and rituximab, or immunosuppressants, such as mycophenolate mofetil and voclosporin, should be evaluated. These findings can contribute to improving PCP prevention and treatment strategies in patients with autoimmune diseases, ultimately leading to better patient outcomes.

Eotaxin-1 (CCL11) induces the migration of different leukocyte types by interacting with CCR3. In rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) are pathogenic effectors and a major CCR3-expressing cell. The aim of this study was to investigate the expression and function of CCL11 in RA FLS. The expression of CCL11 and CCR3 was evaluated by ELISA, immunofluorescence and quantitative PCR analysis. The CCL11 levels in serum and synovial fluids (SFs) from RA patients were significantly higher than those in serum from healthy controls and SFs from osteoarthritis patients. CCL11 and CCR3 were expressed in the RA synovial tissue lining layers. The secretion of CCL11 in RA FLS-conditioned medium and the mRNA expression of CCL11 and CCR3 were induced by TNF-α. Furthermore, CCL11 induced the mRNA expression of CCL11 and CCR3. Application of a CCR3 antagonist reduced TNF-α-induced CCL11 secretion from RA FLS. CCL11 induced the migration of RA FLS and monocytes. RA FLS migration was decreased by treatment with CCL11 siRNA. The migration of monocytes to medium conditioned with CCL11 siRNA-transfected and TNF-α-stimulated RA FLS was reduced. These data indicate that the self-amplification of CCL11 via CCR3 may play an important role in cell migration in RA.

Receptor-type protein tyrosine phosphatase ? (RPTP?) is an important positive regulator of SRC kinase activation and a known promoter of cancer growth, fibrosis, and arthritis. The domain structure of RPTPs comprises an extracellular region, a transmembrane helix, and two tandem intracellular catalytic domains referred to as D1 and D2. The D2 domain of RPTPs is believed to mostly play a regulatory function; however, no regulatory model has been established for RPTP?-D2 or other RPTP-D2 domains. Here, we solved the 1.8 ? resolution crystal structure of the cytoplasmic region of RPTP?, encompassing D1 and D2, trapped in a conformation that revealed a possible mechanism through which D2 can allosterically inhibit D1 activity. Using a D2-truncation RPTP? variant and mutational analysis of the D1/D2 interfaces, we show that D2 inhibits RPTP? phosphatase activity and identified a (PFTP408)-P-405 motif in D1 that mediates the inhibitory effect of D2. Expression of the gain-of-function F406A/T407A RPTP? variant in HEK293T cells enhanced SRC activation, supporting the relevance of our proposed D2-mediated regulation mechanism in cell signaling. There is emerging interest in the development of allosteric inhibitors of RPTPs but a scarcity of validated allosteric sites for RPTPs. The results of our study not only shed light on the regulatory role of RPTP-D2 domains, but also provide a potentially useful tool for the discovery of chemical probes targeting RPTP? and other RPTPs.

Fibroblast-like synoviocytes (FLS) are joint-lining cells that promote rheumatoid arthritis (RA) pathology. Current disease-modifying antirheumatic agents (DMARDs) operate through systemic immunosuppression. FLS-targeted approaches could potentially be combined with DMARDs to improve control of RA without increasing immunosuppression. Here, we assessed the potential of immunoglobulin-like domains 1 and 2 (Ig1&2), a decoy protein that activates the receptor tyrosine phosphatase sigma (PTPRS) on FLS, for RA therapy. We report that PTPRS expression is enriched in synovial lining RA FLS and that Ig1&2 reduces migration of RA but not osteoarthritis FLS. Administration of an Fc-fusion Ig1&2 attenuated arthritis in mice without affecting innate or adaptive immunity. Furthermore, PTPRS was down-regulated in FLS by tumor necrosis factor (TNF) via a phosphatidylinositol 3-kinase-mediated pathway, and TNF inhibition enhanced PTPRS expression in arthritic joints. Combination of ineffective doses of TNF inhibitor and Fc-Ig1&2 reversed arthritis in mice, providing an example of synergy between FLS-targeted and immunosuppressive DMARD therapies.

The original version of this article, unfortunately, contained errors. Figure citation, caption, image and updated sentence in the Result section are now presented correctly in this article.

A disintegrin and metalloprotease 15 (ADAM15) is involved in several malignancies. In this study, we investigated the role of ADAM15 in rheumatoid arthritis (RA) angiogenesis. Soluble ADAM15 (s-ADAM15) in serum from RA and normal (NL) subjects was measured using ELISA. To determine membrane-anchored ADAM15 (ADAM15) expression in RA synovial tissues, immunohistochemistry was performed. To examine the role of ADAM15 in angiogenesis, we performed in vitro Matrigel assays and monocyte adhesion assays using human umbilical vein endothelial cells (HUVECs) transfected with ADAM15 siRNA. Finally, to investigate whether angiogenic mediators were affected by ADAM15, cytokines in ADAM15 siRNA-transfected HUVEC-conditioned medium were measured. ADAM15 was significantly higher in RA serum than in NL serum. ADAM15 was also expressed on RAST endothelial cells. ADAM15 siRNA-treated HUVECs had decreased EC tube formation in response to RA synovial fluids compared with non-treated HUVECs. The adhesion index of ADAM15 siRNA-transfected HUVECs was significantly lower than the adhesion index of control siRNA-transfected HUVECs. ENA-78/CXCL5 and ICAM-1 were decreased in tumor necrosis factor (TNF)-α-stimulated ADAM15 siRNA-transfected HUVEC-conditioned medium compared with TNF-α-stimulated control siRNA-transfected HUVEC-conditioned medium. These data show that ADAM15 plays a role in RA angiogenesis, suggesting that ADAM15 might be a potential target in inflammatory diseases such as RA.

Background Biologic agents are highly effective for rheumatoid arthritis (RA); however, not all cases achieve HAQ remission. Although previous studies have reported the prognostic factors, there is no report on predictive factors for HAQ remission. Objectives To study predictive factors for HAQ remission, which is one of the treatment goals in RA, after using biologic agents for 6 months. Methods The subjects were 333 RA patients treated with biologic agents for 6 months. The following patient9s characteristics were investigated: age, gender, the number of previous drugs, disease duration, the type of biologic agents, baseline steroid dosage, MTX dosage, serum RF, MMP-3, ACPA, TNF-α, and IL-6. For evaluation we used SDAI for RA disease activity, HAQ for ADL, Short Form (SF)-36 for QOL, and Hamilton Depression Rating Scale (HAM-D) or Self-rating depression scale (SDS) for depression status. HAQ remission was defined by HAQ0.5 after 6 months of treatment. The subjects were divided into two groups: patients with HAQ0.5 and patients with HAQ u003e0.5 at 6 months, and a retrospective study was conducted. 101 patients were excluded from the study due to loss to 6-month follow-up, and a total of 232 patients were analyzed. Results Compared with a group of RA patients without HAQ remission (n=68), a group of patients with HAQ remission (n=164) had younger age (54.8±15.2 vs. 61.8±13.3, p=0.0011), lower baseline steroid dosage (3.4±3.7mg vs. 4.5±3.5mg, p=0.037), lower serum MMP-3 (196±234 ng/ml vs. 321±551, p=0.047), lower SDAI (22.5±13.4 vs. 32.1±12.9, p Conclusions It was suggested that RA patients with lower disease activity, lower dosage of steroid, younger age, lower serum MMP-3, higher ADL and QOL, and lower depression scores at baseline are more likely to achieve HAQ remission with biologic treatment. Disclosure of Interest Y. Miwa Grant/research support from: Astellas Pharm Inc., Mitsubishi Tanabe Pharma Corporation, AbbVie CK, Pfizer Japan Inc., Chugai Pharmaceutical Co., Ltd., and Eizai Co., Ltd., R. Takahashi: None declared, N. Yajima: None declared, K. Wakabayashi: None declared, T. Tokunaga: None declared, S. Ishii: None declared, A. Nishimi: None declared, T. Kasama: None declared, K. Oh: None declared, Y. Toyoshima: None declared, K. Inagaki: None declared