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Objective: Fibroblast‐like synoviocytes (FLSs) contribute to inflammation and joint damage in rheumatoid arthritis (RA). However, the regulatory mechanisms of FLSs in relapse and remission of RA remain unknown. Identifying FLS heterogeneity and their underlying pathogenic roles may lead to discovering novel disease‐modifying antirheumatic drugs. Methods: Combining single‐cell RNA sequencing (scRNA‐seq) and spatial transcriptomics, we sequenced six matched synovial tissue samples from three patients with relapse RA and three patients in remission. We analyzed the differences in the transcriptomes of the FLS subsets between the relapse and remitted phases. We validated several key signaling pathways using quantitative real‐time PCR (qPCR) and multiplex immunohistochemistry (mIHC). We further targeted the critical signals in vitro and in vivo using the collagen‐induced arthritis (CIA) model in rats. Results: Lining and sublining FLS subsets were identified using scRNA‐seq. Differential analyses indicated that the fibroblast growth factor (FGF) pathway was highly activated in the lining FLSs from patients with relapse RA for which mIHC confirmed the increased expression of FGF10. Although the type I interferon pathway was also activated in the lining FLSs, in vitro stimulation experiment suggested that it was independent of the FGF10 pathway. FGF10 knockdown by small interfering RNA in FLSs significantly reduced the expression of receptor activator of NF‐κB ligand. Moreover, recombinant FGF10 protein enhanced bone erosion in the primary human‐derived pannus cell culture, whereas the FGF receptor (FGFR) 1 inhibitor attenuated this process. Finally, administering an FGFR1 inhibitor displayed a therapeutic effect in a CIA rat model. Conclusion: The FGF pathway is a critical signaling pathway in relapse RA. Targeted tissue‐specific inhibition of FGF10/FGFR1 may provide new opportunities to treat patients with relapse RA. [ABSTRACT FROM AUTHOR]

Objective: To investigate the role of interleukin‐23 (IL‐23) in pathologic bone remodeling in inflammatory arthritis. Methods: In this study we investigated the role of IL‐23 in osteoclast differentiation and activation using in vivo gene transfer techniques in wild‐type and myeloid DNAX‐activation protein 12–associating lectin‐1 (MDL‐1)–deficient mice, and by performing in vitro and in vivo osteoclastogenesis assays using spectral flow cytometry, micro–computed tomography analysis, Western blotting, and immunoprecipitation. Results: Herein, we show that IL‐23 induces the expansion of a myeloid osteoclast precursor population and supports osteoclastogenesis and bone resorption in inflammatory arthritis. Genetic ablation of C‐type lectin domain family member 5A, also known as MDL‐1, prevents the induction of osteoclast precursors by IL‐23 that is associated with bone destruction, as commonly observed in inflammatory arthritis. Moreover, osteoclasts derived from the bone marrow of MDL‐1–deficient mice showed impaired osteoclastogenesis, and MDL‐1−/− mice had increased bone mineral density. Conclusion: Our data show that IL‐23 signaling regulates the availability of osteoclast precursors in inflammatory arthritis that could be effectively targeted for the treatment of inflammatory bone loss in inflammatory arthritis. [ABSTRACT FROM AUTHOR]

Objective: The predominant mechanism driving hyperuricemia in gout is renal uric acid underexcretion; however, the standard urate‐lowering therapy (ULT) recommendation is first‐line xanthine oxidase inhibitor (XOI), irrespective of the cause of hyperuricemia. This comparative effectiveness clinical trial was undertaken to compare first‐line nontitrated low‐dose benzbromarone (LDBen) uricosuric therapy to XOI ULT with low‐dose febuxostat (LDFeb) in gout patients with renal uric acid underexcretion. Methods: We conducted a prospective, randomized, single‐center, open‐label trial in men with gout and renal uric acid underexcretion (defined as fractional excretion of urate <5.5% and uric acid excretion ≤600 mg/day/1.73 m2). A total of 196 participants were randomly assigned to receive LDBen 25 mg daily or LDFeb 20 mg daily for 12 weeks. All participants received daily urine alkalization with oral sodium bicarbonate. The primary end point was the rate of achieving the serum urate target of <6 mg/dl. Results: More participants in the LDBen group achieved the serum urate target than those in the LDFeb group (61% compared to 32%, P < 0.001). Rates of adverse events, including gout flares and urolithiasis, did not differ between groups, with the exception of greater transaminase elevation in the LDFeb group (4% for LDBen compared to 15% for LDFeb, P = 0.008). Conclusion: Compared to LDFeb, LDBen has superior urate‐lowering efficacy and similar safety in treating relatively young and healthy patients with renal uric acid underexcretion–type gout. [ABSTRACT FROM AUTHOR]

Objective: Amyopathic dermatomyositis (ADM) is a heterogeneous and life‐threatening autoimmune disease with a high mortality rate. In particular, anti–melanoma differentiation–associated protein 5 antibody–positive patients are at a high risk of developing rapidly progressive interstitial lung disease (RPILD). This study was undertaken to identify immunologic signatures among patients who have ADM with ILD (ADM‐ILD) and to discover the biomarkers predicting prognosis. Methods: The landscape of 42 immune cell phenotypes in the peripheral blood of 82 ADM‐ILD patients and 82 age‐ and sex‐matched healthy donors was assessed by multicolor flow cytometry. Patients were stratified using an unsupervised machine learning method (hierarchical clustering analysis) by immune cell subsets. Multiple Wilcoxon's signed rank tests and supervised machine learning methods were performed to identify important immune cell subsets. Kaplan‐Meier survival analysis with log rank tests was used to create survival curves. Results: We identified 2 distinct clusters correlating with different disease activities and clinical outcomes in ADM‐ILD. Cluster 1 was enriched in the activated CD45RA+HLA–DR+CD8+ T cells with decreased CD56dim natural killer cell proportions and showed a higher prevalence of RPILD and higher mortality. In contrast, the other subgroup, cluster 2 (the nonactivated T cell–dominant cluster), displayed favorable clinical outcomes with high survival rates. Our data also revealed that immunophenotype was an independent risk factor associated with 1‐year survival. Conclusion: Peripheral immunologic features may have the potential to stratify patients with ADM‐ILD according to different disease severity and clinical outcomes, which may have implications for outcome prediction, pathogenesis study, and therapy selection. [ABSTRACT FROM AUTHOR]

Objective: Coagulopathy is one of the characteristics observed in critically ill patients with coronavirus disease 2019 (COVID‐19). Antiphospholipid antibodies (aPLs) contribute to coagulopathy, though their role in COVID‐19 remains unclear. This study was undertaken to determine the prevalence and characteristics of aPLs in patients with COVID‐19. Methods: Sera collected from 66 COVID‐19 patients who were critically ill and 13 COVID‐19 patients who were not critically ill were tested by chemiluminescence immunoassay for anticardiolipin antibodies (aCLs), anti–β2‐glycoprotein I (anti‐β2GPI) (IgG, IgM, and IgA), and IgG anti‐β2GPI–domain 1 (anti‐β2GPI–D1) and IgM and IgG anti–phosphatidylserine/prothrombin (anti‐PS/PT) antibodies were detected in the serum by enzyme‐linked immunosorbent assay. Results: Of the 66 COVID‐19 patients in critical condition, aPLs were detected in 31 (47%). Antiphospholipid antibodies were not present among COVID‐19 patients who were not in critical condition. The IgA anti‐β2GPI antibody was the most commonly observed aPL in patients with COVID‐19 and was present in 28.8% (19 of 66) of the critically ill patients, followed by IgA aCLs (17 of 66, or 25.8%) and IgG anti‐β2GPI (12 of 66, or 18.2%). For multiple aPLs, IgA anti‐β2GPI + IgA aCLs was the most common antibody profile observed (15 of 66, or 22.7%), followed by IgA anti‐β2GPI + IgA aCL + IgG anti‐β2GPI (10 of 66, or 15.2%). Antiphospholipid antibodies emerge ~35–39 days after disease onset. A dynamic analysis of aPLs revealed 4 patterns based on the persistence or transient appearance of the aPLs. Patients with multiple aPLs had a significantly higher incidence of cerebral infarction compared to patients who were negative for aPLs (P = 0.023). Conclusion: Antiphospholipid antibodies were common in critically ill patients with COVID‐19. Repeated testing demonstrating medium to high titers of aPLs and the number of aPL types a patient is positive for may help in identifying patients who are at risk of developing cerebral infarction. Antiphospholipid antibodies may be transient and disappear within a few weeks, but in genetically predisposed patients, COVID‐19 may trigger the development of an autoimmune condition similar to the antiphospholipid syndrome (APS), referred to as "COVID‐19–induced APS‐like syndrome." Long‐term follow‐up of COVID‐19 patients who are positive for aPLs would be of great importance in understanding the pathogenesis of this novel coronavirus. [ABSTRACT FROM AUTHOR]

Objective: Interstitial lung disease (ILD) accompanied by anti–melanoma differentiation–associated gene 5 (anti–MDA‐5)–positive dermatomyositis (DM) is often rapidly progressive and associated with poor prognosis. Because there is no established treatment, we undertook this study to prospectively evaluate the efficacy and safety of a combined immunosuppressive regimen for anti–MDA‐5–positive DM patients with ILD. Methods: Adult Japanese patients with new‐onset anti–MDA‐5–positive DM with ILD (n = 29) were enrolled at multiple study centers from 2014 to 2017. They were treated with a regimen of high‐dose glucocorticoids (GCs), tacrolimus, and intravenous cyclophosphamide (IV CYC). Plasmapheresis was used if a patient's condition worsened after the regimen started. The primary end point was 6‐month survival, which was compared between this group of patients and a historical control group (n = 15) consisting of anti–MDA‐5–positive DM patients with ILD who received step‐up treatment (high‐dose GC and stepwise addition of immunosuppressant). Secondary end points were 12‐month survival rate, adverse events, and changes in laboratory data. Results: The combined immunosuppressive regimen group showed significantly higher 6‐month survival rates than the step‐up treatment group (89% versus 33%; P < 0.0001). Over a period of 52 weeks, improvements in anti–MDA‐5 titers, serum ferritin levels, vital capacity, and chest high‐resolution computed tomography scores were observed. The combined immunosuppressive regimen group received IV CYC nearly 20 days earlier with shorter intervals and tended to receive plasmapheresis more often than patients undergoing step‐up treatment. Cytomegalovirus reactivation was frequently observed over 52 weeks. Conclusion: A combined immunosuppressive regimen is effective for anti–MDA‐5–positive DM patients with ILD. Plasmapheresis can be used for additional effect in intractable disease. Patients should be carefully monitored for opportunistic infections during treatment. [ABSTRACT FROM AUTHOR]

Background/Purpose: One and a half million Americans suffer from systemic lupus erythematosus (SLE), with increased death rate in the 15-44 year age group. SLE has a wide range of symptoms and affects multiple organs and tissues. SLE affects each person differently over time. Treatment options are limited with potential serious side effects. There is no cure currently due to the lack of understanding of the mechanism of disease at molecular levels. However, recent developments in the field of molecular imaging provide a tool for noninvasive, target-specific and longitudinal study of multiple disease components at the same time as well as understanding the dynamic change of the disease. We hypothesize genetic differences play a role in development and severity of the disease. In addition, multiple different disease molecules in different organs at one time point make SLE difficult to treat by standard regiments. Methods: We tested our hypothesis in animal models with two different genetic backgrounds and three target-specific molecular imaging agents. Two groups of mice carrying normal or mutant Fas gene with SLE were utilized in the study. Optical imaging agents that specifically target to pro-inflammatory cytokine (IL-11), cytokine from T-cells (CXCR4), or disease stroma (matrix metalloproteinase, MMP) were injected through the tail vein. Mice were imaged immediately after injection and for as long as 48 hours afterward. SAS software was used to analyze data by one-way-ANOVA or the general linear model. Data comparison was presented in notched box-and whisker plots. The significant level was set at 0.05 with two-tailed test. Results: Mice with a normal Fas gene have statistical higher signal intensities for all agents in the joint regions than the Fas mutant mice ( P = 0.0139). Target-specific agents have different organ distributions in Fas mutant mice. The MMP signals are in the kidney (Fig. 1A) and IL-11 signals are in the lung (Fig. 1B). Both agents have statistical low signal intensities in the same organs in the control mice with normal Fas gene (P<0.0002). The animal with normal Fas gene has high IL-11 signal intensity in the knee (Fig. 1C). On contrary, CXCR4 has significantly low signal intensity in the Fas mutant mice. Fas mutant mice also have enlarged spleen and kidney by either size or weight than control mice (P<0.0001). [ABSTRACT FROM AUTHOR]