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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.We conducted a prospective, randomized, single-center, open-label trial in men with gout and renal uric acid underexcretion (defined as fractional excretion of urate5.5% and uric acid excretion ≤600 mg/day/1.73 mMore 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).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.

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-s2 -glycoprotein I (anti-s2 GPI) (IgG, IgM, and IgA), and IgG anti-s2 GPI-domain 1 (anti-s2 GPI-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-s2 GPI 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-s2 GPI (12 of 66, or 18.2%). For multiple aPLs, IgA anti-s2 GPI + IgA aCLs was the most common antibody profile observed (15 of 66, or 22.7%), followed by IgA anti-s2 GPI + IgA aCL + IgG anti-s2 GPI (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.

Objective Peroxiredoxin 6 plays important and complex roles in the process of inflammation, but its role in the development of rheumatoid arthritis (RA) remains unclear. We undertook this study to investigate the roles and mechanisms of peroxiredoxin 6 in the development of collagen antibody-induced arthritis (CAIA) and antigen-induced arthritis (AIA) in peroxiredoxin 6-overexpressing transgenic mice, in peroxiredoxin 6-transfected RAW 264.7 cells, in macrophages isolated from peroxiredoxin 6-overexpressing transgenic mice, and in synoviocytes from arthritis patients. Methods CAIA and AIA were induced using standard methods. Peroxiredoxin 6-transfected RAW 264.7 cells, macrophages isolated from peroxiredoxin 6-overexpressing transgenic mice, and synoviocytes from arthritis patients were used to study proinflammatory responses and mechanisms. Clinical scores and histopathologic changes were determined in peroxiredoxin 6-overexpressing transgenic mice and wild-type (WT) mice with CAIA or AIA. Generation of nitric oxide (NO), expression of inducible NO synthase and cyclooxygenase 2, and activity of NF-κB and activator protein 1 (AP-1) were determined in cultured macrophages and synoviocytes as well as in joint tissue from mice by Western blotting, electrophoretic mobility shift assay, and immunohistochemical analysis. Results Development of CAIA and AIA and proinflammatory responses were more exacerbated in peroxiredoxin 6-overexpressing transgenic mice than in WT mice. Overexpression of peroxiredoxin 6 increased lipopolysaccharide-induced inflammatory responses in RAW 264.7 cells, in macrophages isolated from peroxiredoxin 6-overexpressing transgenic mice, and in synoviocytes from arthritis patients, and this was accompanied by up-regulation of the JNK pathway. Moreover, a JNK inhibitor completely blocked RA development and proinflammatory responses. Conclusion Our findings suggest that overexpression of peroxiredoxin 6 might promote development of RA through NF-κB and AP-1 activity via the JNK pathway.

Objective. Myositis-specific autoantibodies(MSAs) are useful tools for identifying clinical subsets of patients with idiopathic inflammatory myopathies(IIMs). There have been few reports on antibodies to some DNA mismatch repair enzymes (MMREs) inpatients with IIMs. This study was undertaken to determine the frequencies and clinical associations of antibodies to 7 types of MMREs (MLH1, MLH3, MSH2,MSH3, MSH6, PMS1, and PMS2) in patients with IIMs and other systemic autoimmune diseases.Methods. Clinical data and serum samples were collected from 239 Japanese patients with IIMs (147 with adult dermatomyositis, 13 with juvenile dermatomyositis,57 with polymyositis, and 22 with myositis overlap syndrome). One hundred patients with other diseases, including 40 with systemic lupus erythematosus(SLE), were assessed as disease controls. The presence of anti-MMRE antibodies in serum was examined by immunoprecipitation, enzyme-linked immunosorbenassay, and immunoprecipitation/Western blotting.Results. Anti-MMRE antibodies were found in 1 patients with IIMs and 3 patients with SLE. They were restricted to MLH1, PMS1, MSH2, and PMS2, with simultaneous positivity for more than one of these antibodies occurring in some patients. Nine IIM patients with anti-MMREs also had other MSAs and their associated clinical features. All patients with anti-MMREs were still living at the time of the present analysis.Conclusion. Anti-MMRE antibodies, which often co exist with other MSAs, may be serologic markers forgood prognosis in IIMs.

Objective Glucocorticoids remain a mainstay in the treatment of rheumatoid arthritis (RA). Dose-dependent adverse effects highlight the need for therapies that regulate glucocorticoid sensitivity to enable dosage reduction. Macrophage migration inhibitory factor (MIF) is a proinflammatory protein that has been implicated in the pathogenesis of RA; it impairs glucocorticoid sensitivity via MAPK phosphatase 1 (MKP-1) inhibition. The intracellular protein glucocorticoid-induced leucine zipper (GILZ) mimics the effects of glucocorticoids in models of RA, but whether it represents a target for the modulation of glucocorticoid sensitivity remains unknown. We undertook this study to investigate whether GILZ is involved in the regulation of glucocorticoid sensitivity by MIF. Methods GILZ expression was studied in the presence and absence of MIF, and the role of GILZ in the MIF-dependent regulation of the glucocorticoid sensitivity mediator MKP-1 was studied at the level of expression and function. Results GILZ expression was significantly inhibited by endogenous MIF, both basally and during responses to glucocorticoid treatment. The effects of MIF on GILZ were dependent on the expression and Akt-induced nuclear translocation of the transcription factor FoxO3A. GILZ was shown to regulate the expression of MKP-1 and consequent MAPK phosphorylation and cytokine release. Conclusion MIF exerts its effects on MKP-1 expression and MAPK activity through inhibitory effects on GILZ. These findings suggest a previously unsuspected interaction between MIF and GILZ and identify GILZ as a potential target for the therapeutic regulation of glucocorticoid sensitivity.

Objective. Spondyloarthritides (SpA) occur in 1% of the population and include ankylosing spondylitis (AS) and arthropathy of inflammatory bowel disease (IBD), with characteristic spondylitis, arthritis, enthesitis, and IBD. Genetic studies implicate interleukin-23 (IL-23) receptor signaling in the development of SpA and IBD, and IL-23 overexpression in mice is sufficient for enthesitis, driven by entheseal-resident T cells. However, in genetically prone individuals, it is not clear where IL-23 is produced and how it drives the SpA syndrome, including IBD or subclinical gut inflammation of AS. Moreover, it is unclear why specific tissue involvement varies between patients with SpA. We undertook this study to determine the location of IL-23 production and its role in SpA pathogenesis in BALB/c ZAP-70(W163C)-mutant (SKG) mice injected intraperitoneally with beta-1,3-glucan (curdlan).

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