Expression of CD163 and major histocompatibility complex class I as diagnostic markers for idiopathic inflammatory myopathies.

BACKGROUND: To develop an inflammation-related immunohistochemistry marker-based algorithm that confers higher diagnostic ability for idiopathic inflammatory myopathies (IIMs) than IIM-related histopathologic features. METHODS: Muscle biopsy tissues from 129 IIM patients who met the 2017 EULAR/ACR criteria and 73 control tissues from patients with non-inflammatory myopathies or healthy muscle specimens were evaluated for histological features and immunostaining results of CD3, CD4, CD8, CD20, CD68, CD163, MX1, MHC class I, MHC class II, and HLA-DR. Diagnostic algorithms for IIM were developed based on the results of the classification and regression tree (CART) analysis, which used immunostaining results as predictor variables for classifying patients with IIMs. RESULTS: In the analysis set (IIM, n = 129; control, n = 73), IIM-related histopathologic features had a diagnostic accuracy of 87.6% (sensitivity 80.6%; specificity 100.0%) for IIMs. Notably, muscular expression of CD163 (99.2% vs. 20.8%, p < 0.001) and MHC class I (87.6% vs. 23.1%, p < 0.001) was significantly higher in the IIM group than in controls. Based on the CART analysis results, we developed an algorithm combining CD163 and MHC class I expression that conferred a diagnostic accuracy of 95.5% (sensitivity 96.1%; specificity 94.5%). In addition, our algorithm was able to correctly diagnose IIM in 94.1% (16/17) of patients who did not meet the 2017 EUALR/ACR criteria but were diagnosed as having IIMs by an expert physician. CONCLUSIONS: Combination of CD163 and MHC class I muscular expression may be useful in diagnosing IIMs.

Regional variations of cardiovascular risk in gout patients: a nationwide cohort study in Korea.

Objective: The extent of regional variations in cardiovascular risk and associated risk factors in patients with gout in South Korea remains unclear. Therefore, we aimed to investigate the risk of major cardiovascular events in gout patients in different regions. Methods: This was a nationwide cohort study based on the claims database of the Korean National Health Insurance and the National Health Screening Program. Patients aged 20 to 90 years newly diagnosed with gout after January 2012 were included. After cardiovascular risk profiles before gout diagnosis were adjusted, the relative risks of incident cardiovascular events (myocardial infarction, cerebral infarction, and cerebral hemorrhage) in gout patients in different regions were assessed. Results: In total, 231,668 patients with gout were studied. Regional differences in cardiovascular risk profiles before the diagnosis were observed. Multivariable analysis showed that patients with gout in Jeolla/Gwangju had a significantly high risk of myocardial infarction (adjusted hazard ratio [aHR], 1.27; 95% confidence interval [CI], 1.02~1.56; p=0.03). In addition, patients with gout in Gangwon (aHR, 1.38; 95% CI, 1.09~1.74; p<0.01), Jeolla/Gwangju (aHR, 1.41; 95% CI, 1.19~1.67; p<0.01), and Gyeongsang/Busan/Daegu/Ulsan (aHR, 1.37; 95% CI, 1.19~1.59; p<0.01) had a significantly high risk of cerebral infarction. Conclusion: We found there were regional differences in cardiovascular risk and associated risk factors in gout patients. Physicians should screen gout patients for cardiovascular risk profiles in order to facilitate prompt diagnosis and treatment.

A retrospective observational study of the appropriate starting dose of febuxostat in patients with gout.

BACKGROUND/AIMS: The occurrence of gout attacks at the start of uric acid lowering treatment worsens compliance. We aimed to determine the appropriate dose of febuxostat to reduce the occurrence of gout attacks during the initial treatment period. METHODS: We retrospectively analyzed the data of patients diagnosed with gout who underwent treatment at Jeju National University Hospital between May 2018 and May 2020. RESULTS: Two-hundred and twenty-seven patients were included, with a mean age of 53.2 ± 16.4 years, and 219 (96.5%) were male. The patients were divided into two groups according to the starting dose of febuxostat (20 mg vs. 40 mg). There were no significant differences in mean age, disease duration, colchicine, estimated glomerular filtration rate (eGFR), initial uric acid levels, and presence of subcutaneous tophi between the two groups. Gout attacks occurred more frequently in the 20 mg group than in the 40 mg group during the first 3 months of treatment (32.0% vs. 14.3%, p = 0.002), particularly during the first month (21.3% vs. 7.5%, p = 0.005). Multivariate logistic regression analysis was conducted adjusting for the effects of disease duration, the presence of subcutaneous tophi, eGFR, and initial uric acid levels. A febuxostat starting dose of 40 mg (odds ratio, 0.464; 95% confidence interval [CI], 0.246 to 0.862; p = 0.015) and anti-inflammatory prophylaxis (odds ratio, 0.359; 95% CI, 0.158 to 0.813; p = 0.014) were found to be independent factors associated with a gout attack. CONCLUSION: Starting uric acid lowering treatment with febuxostat 40 mg rather than 20 mg may reduce the incidence of gout attacks in the early period of treatment in Korean patients with gout.

Incident and recurrent herpes zoster for first-line bDMARD and tsDMARD users in seropositive rheumatoid arthritis patients: a nationwide cohort study.

BACKGROUND: There is limited information regarding disease-modifying antirheumatic drug (DMARD)-dependent risks of overall, incident, and recurrent herpes zoster (HZ) during first-line biologic DMARD (bDMARD) or targeted synthetic DMARD (tsDMARD) treatment among patients with seropositive rheumatoid arthritis (RA) in terms of HZ risk. METHODS: A total of 11,720 patients with seropositive RA who were prescribed bDMARD or tofacitinib between January 2011 and January 2019 from the Korean Health Insurance Review & Assessment Service database were studied. A multivariate Cox proportional hazards regression model was adopted to evaluate the adjusted hazard ratio (aHR) with 95% confidence interval (CI) for the risk of HZ dependent on the choice of first-line bDMARDs or tsDMARD, including etanercept, infliximab, adalimumab, golimumab, tocilizumab, rituximab, tofacitinib, and abatacept. RESULTS: During the 34,702 person-years of follow-up, 1686 cases (14.4%) of HZ were identified, including 1372 (11.7%) incident and 314 (2.7%) recurrent HZs. Compared with that of the abatacept group, tofacitinib increased the overall risk (aHR, 2.46; 95% CI, 1.61-3.76; P<0.001), incidence (aHR, 1.99; 95% CI, 1.18-3.37; P=0.011), and recurrence (aHR, 3.69; 95% CI, 1.77-7.69; P<0.001) of HZ. Infliximab (aHR, 1.36; 95% CI, 1.06-1.74; P=0.017) and adalimumab (aHR, 1.29; 95% CI, 1.02-1.64; P=0.032) also increased the overall HZ risk. Moreover, a history of HZ was found to be an independent risk factor for HZ (aHR, 1.54; 95% CI, 1.33-1.78; P<0.001). CONCLUSIONS: HZ risk is significantly increased in RA patients with a history of HZ after the initiation of bDMARDs or tsDMARD. The risk of incident and recurrent HZ was higher after tofacitinib treatment in patients with RA than that after treatment with bDMARDs. Individualized characteristics and history of HZ should be considered when selecting bDMARDs or tsDMARD for RA patients considering HZ risks.

Expression of Inflammatory Markers in the Muscles of Patients with Idiopathic Inflammatory Myopathy According to the Presence of Interstitial Lung Disease.

BACKGROUND: Several studies have identified factors associated with the development of interstitial lung disease (ILD) in patients with idiopathic inflammatory myopathies (IIMs). However, few have assessed the association between ILD and muscle biopsy findings, including inflammatory marker expressions analyzed using immunohistochemistry (IHC). METHODS: Muscle biopsies from patients who were newly diagnosed with IIMs between 2000 and 2017 were reviewed. ILD was diagnosed based on chest computed tomography findings at the time of diagnosis of IIMs. IHC staining was performed for CD3, CD4, CD8, CD20, CD68, CD163, MX1, MHC class I, and HLA-DR. The factors associated with the presence of ILD were evaluated by logistic regression analysis. RESULTS: Of the 129 patients with IIM, 49 (38%) had ILD. In the muscle biopsy findings, CD4 expression, MX1 expression on immune cells, and expression of MHC class I and HLA-DR on myofibers were more common in patients with ILD than those without. In the logistic regression analysis, the HLA-DR expression on myofibers was significantly associated with the risk of ILD (OR, 2.39; 95% CI, 1.24-4.90, p = 0.012) after adjusting for pathologic findings, clinical features, and autoantibodies. CONCLUSION: The expression of HLA-DR on myofibers was associated with the presence of ILD in patients with IIM.

Increased risk of cardiovascular events and death in the initial phase after discontinuation of febuxostat or allopurinol: another story of the CARES trial.

OBJECTIVES: The Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout (CARES) trial suggested a higher risk of cardiovascular (CV) death from febuxostat than from allopurinol. However, a significant number of patients died after discontinuation of febuxostat or allopurinol. We investigated whether major adverse cardiovascular events (MACE) and CV death were increased because of discontinuation of febuxostat or allopurinol using the CARES trial data. METHODS: We compared the MACE that occurred during administration and after discontinuation in the initial phase after discontinuation, and we compared the CV and non-CV mortality rates in the initial phase after discontinuation to determine the impact of discontinuation of febuxostat or allopurinol. RESULTS: Among 6190 patients, the incidence rate per 100 person-years for MACE was 3.11 during administration and 6.71 after discontinuation. MACE was significantly increased after discontinuation compared with that during administration within 1 month (HR 7.40; 95% CI 5.38 to 10.17) and 6 months (HR 5.22; 95% CI 4.26 to 6.39). In the analysis excluding death induced by adverse events that occurred up to 1 day after the last medication, the CV mortality rate was higher than the non-CV mortality rate within 6 months (45.7% vs 27.9%, p=0.0001). In addition, changes in serum uric acid levels from baseline to the last measurement before discontinuation were significantly associated with higher MACE risk after drug discontinuation (HR 1.14; 95% CI 1.04 to 1.26). CONCLUSIONS: MACE and CV death were increased in the initial stage after discontinuation of febuxostat or allopurinol in patients with gout.

Association of first, second, and third-line bDMARDs and tsDMARD with drug survival among seropositive rheumatoid arthritis patients: Cohort study in A real world setting.

OBJECTIVES: To determine the association of first, second, and third-line biologic disease-modifying antirheumatic drugs (bDMARDs) and tofacitinib with drug survival among seropositive rheumatoid arthritis (RA) patients. METHODS: The study population was composed of 8,018 seropositive RA patients who were prescribed bDMARDs or tofacitinib between January 2014 and January 2019 from the Korean Health Insurance Review and Assessment Service database. First, second, and third-line choice of tumor necrosis factor inhibitors (TNFi) including etanercept, infliximab, adalimumab, and golimumab, as well as non-TNFi including tocilizumab, rituximab, tofacitinib, and abatacept were assessed. Multivariate Cox proportional hazards regression was used to determine the adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for drug failure according to bDMARD or tofacitinib choice starting from the initial prescription date. RESULTS: Compared to first etanercept users, patients with first tocilizumab (aHR 0.56, 95% CI 0.46-0.68), tofacitinib (aHR 0.27, 95% CI 0.18-0.42), or abatacept (aHR 0.83, 95% CI 0.69-0.99) had lower risk of drug failure. Second choice of tocilizumab (aHR 0.38, 95% CI 0.25-0.55), tofacitinib (aHR 0.23, 95% CI 0.15-0.37), or abatacept (aHR 0.54, 95% CI 0.35-0.84) was associated with lower drug failure risk compared to second etanercept users. Finally, third choice of tocilizumab (aHR 0.32, 95% CI 0.16-0.62) or tofacitinib (aHR 0.35, 95% CI 0.19-0.63) was associated with lower drug failure risk compared to third TNFi users. CONCLUSION: First and second-line tocilizumab, tofacitinib, or abatacept may lead to improved drug survival. Third-line use of tocilizumab or tofacitinib may be beneficiary in reducing drug failure risk among seropositive RA patients.

Risk of progression of idiopathic pulmonary fibrosis to connective tissue disease: a long-term observational study in 527 patients.

OBJECTIVE: Connective tissue disease (CTD) might occur during the course of idiopathic pulmonary fibrosis (IPF). Clinical factors associated with CTD development in IPF patients have still not been identified. We investigated which antibodies have a significant association with the development of CTD during the clinical course of IPF. METHODS: We retrospectively reviewed the records of 527 patients with a first diagnosis of IPF between January 2007 and March 2014 and investigated the time to CTD development after IPF diagnosis in these patients. RESULTS: CTD developed in 15 patients at a median of 2.1 years (range 1.2-4.8) after IPF diagnosis. All patients had anti-neutrophil cytoplasmic antibodies (ANCA) or autoantibodies that met the serology criteria for interstitial pneumonia with autoimmune features (IPAF). Survival duration for IPF patients with progression to CTD was 5.3 (3.8, 6.7) years, which was significantly longer than for IPF patients without progression to CTD [2.9 (1.7, 4.8), p = 0.001]. Independent risk factors for CTD development in IPF patients included female gender [adjusted hazard ratio (HR) 5.319, p = 0.0082], titer of rheumatoid factor (RF; adjusted HR, 1.006; p = 0.022), titer of anti-citrullinated protein antibody (ACPA; adjusted HR, 1.009; p = 0.0011), and titer of myeloperoxidase (MPO)-ANCA (adjusted HR, 1.02; p < 0.0001). CONCLUSION: Progression to CTD is uncommon in IPF patients. However, a significant number of IPF patients with high titers of RF, ACPA, or MPO-ANCA progressed to CTD. RF, ACPA, and MPO-ANCA might be significantly associated with CTD development in IPF patients. Key Points • A significant number of IPF patients with high titers of RF, ACPA, or MPO-ANCA progressed to CTD. • IPF/UIP with high titers of RF, ACPA, or MPO-ANCA might be the initial clinical manifestation of CTD. • RF, ACPA, and MPO-ANCA may be significantly associated with the development of pulmonary fibrosis in patients with CTD.

Recent Hydroxychloroquine Use Is Not Significantly Associated with Positive PCR Results for SARS-CoV-2: A Nationwide Observational Study in South Korea.

BACKGROUND: To evaluate the role of hydroxychloroquine (HCQ) as pre-exposure prophylaxis against coronavirus disease 2019 (COVID-19), we investigated the prevalence of positive test results for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing according to recent HCQ use in patients who had been tested using nationwide health-insurance data of South Korea. METHODS: All adults tested for SARS-CoV-2 from 20 January 2020 to 15 May 2020 were identified. HCQ users were defined as patients who had been pretreated with HCQ for at least 30 days until the date of SARS-CoV-2 testing. The prevalence of positive PCR results for SARS-CoV-2 was compared between HCQ users and nonusers. RESULTS: Of a total of 216,686 individuals who had been tested for SARS-CoV-2, 743 (0.3%) were pretreated with HCQ. The prevalence of positive results was not significantly different between HCQ users (2.2%) and nonusers (2.7%; P = 0.35), with an odds ratio of 0.79 (95% confidence interval (CI), 0.48-1.30). Propensity score-matched-cohort analysis showed similar results in terms of the prevalence of positive results (2.2% in HCQ users vs. 3.1% in nonusers; P = 0.18), with an odds ratio of 0.69 (95% CI, 0.40-1.19). The rate of positive PCR was not significantly different in long-term HCQ users (more than 3 or 6 months) compared with nonusers. CONCLUSIONS: In this population-based study, recent exposure to HCQ was not significantly associated with a lower risk of SARS-CoV-2 infection. Our data do not support the use of HCQ as pre-exposure prophylaxis against COVID-19.

Cyr61 synthesis is induced by interleukin-6 and promotes migration and invasion of fibroblast-like synoviocytes in rheumatoid arthritis.

BACKGROUND: Interleukin-6 (IL-6) is involved in fibroblast-like synoviocyte (FLS) activation and promotes pannus formation and bone and cartilage destruction in rheumatoid arthritis (RA). Cysteine-rich 61 (Cyr61) protein regulates cell proliferation, migration, and differentiation. The aim of this study was to investigate the role of Cyr61 in RA-FLS migration and invasion after IL-6 stimulation. METHODS: Western blotting, immunohistochemistry, reverse transcription-polymerase chain reaction, and real time-polymerase chain reaction were used to examine protein and mRNA levels of Cyr61, matrix metalloproteinases (MMPs), and other signalling proteins. Knockdown of gene expression was performed with siRNA, and RNA sequencing was performed for differential gene analysis. Migration and invasion were assessed by wound healing and Boyden chamber assays. RESULTS: Cyr61 levels were elevated in FLSs from RA patients compared to those in osteoarthritis patients. Control and IL-6-treated FLSs showed differential gene expression. IL-6 stimulated protein synthesis of Cyr61, which was attenuated by the extracellular signal-related kinase 1/2 (ERK 1/2) inhibitor, PD98059, and knockdown of early growth response 3 (EGR3), but not of JUN. IL-6-induced Cyr61 protein synthesis increased expression of MMP2. Cyr61 promoted FLS migration and invasion in an autocrine manner. Knockdown of CYR61 and a neutralising antibody attenuated Cyr61 synthesis and IL-6-induced FLS migration. CONCLUSIONS: By modulating the ERK/EGR3 pathway, IL-6 stimulated Cyr61 production and in turn increased invasiveness of FLS. Our data suggest that Cyr61 might be a potential target to prevent the progression of joint damage in RA.

Clinical significance of autoantibody positivity in idiopathic pulmonary fibrosis.

RATIONALE: The concept of interstitial pneumonia with autoimmune features (IPAF) was recently proposed by the American Thoracic Society. However, the clinical significance of the serologic domain of IPAF has not yet been established in idiopathic pulmonary fibrosis (IPF). OBJECTIVES: We aimed to investigate the clinical significance of autoantibody positivity in IPF. METHODS: We retrospectively reviewed the records of 512 patients diagnosed as IPF from January 2007 through March 2014. The patients were divided into two subgroups: (i) an autoantibody-positive IPF subgroup (n = 138), consisting of patients with anti-neutrophil cytoplasmic antibody (ANCA) or autoantibodies that met the criteria for the IPAF serologic domain; (ii) a lone IPF subgroup (n = 374), consisting of the rest of the IPF patients. MEASUREMENTS AND MAIN RESULTS: Autoantibody-positivity (HR 0.736, p = 0.043) was an independent risk factors for 5-year mortality on multivariable analysis in the overall IPF patients. In the autoantibody-positive IPF patients, use of glucocorticoid (not for management of acute exacerbation, HR 2.121, p = 0.019), use of immunomodulators (HR 0.310, p = 0.002), malignancy (HR 3.359, p = 0.002), baseline forced vital capacity (HR 0.974, p = 0.017), baseline diffusing capacity of the lung for carbon monoxide (HR 0.981, p = 0.041), and baseline 6-min walk test distance (HR 0.996, p = 0.002) were independent risk factors for 5-year mortality. CONCLUSIONS: Presence of ANCA or autoantibodies of the IPAF serologic domain in IPF patients is associated with better survival outcomes, and the use of immunomodulators is associated with superior survival outcomes.

Immunoglobulin Binding Protein 1 as a Potential Urine Biomarker in Patients with Lupus Nephritis.

We evaluated the role of immunoglobulin binding protein 1 (IGBP1), a phosphoprotein associated with the B cell receptor (BCR) complex, as a urine biomarker in lupus nephritis (LN). The IGBP1 concentrations in plasma and urine of patients with LN, systemic lupus erythematosus (SLE) without nephritis and healthy controls were estimated by ELISA. IGBP1 expression in the kidneys of LN patients and transplantation donors was detected by immunohistochemistry. Microarray-based global gene expression profile of HK-2 cells with IGBP1 knock-down and fluorescence-activated cell sorting (FACS) for intracellular IGBP1 expression in human peripheral blood mononuclear cells (PBMCs) was performed. Urine IGBP1 levels were elevated significantly in LN patients, and it correlated with the clinical activity indices (complement 3 (C3) level, anti-dsDNA antibodies titer, SLE Disease Activity Index-2000 (SLEDAI-2K) and histological activity index. IGBP1 expression was increased in LN patients as compared to the donors and was detected mainly in the tubules by histopathology. In microarray analysis, several genes related to SLE pathogenesis (PPME1, ROCK2, VTCN1, IL-17R, NEU1, HLA-DM, and PTX3) responded to siRNA-mediated IGBP1 silencing. In FACS, IGBP1 was expressed mainly in the CD14+ cells. The overall expression of IGBP1 in PBMCs was higher in LN patients as compared with that in SLE patients without nephritis. Conclusively, urinary IGBP1 may be a novel biomarker reflecting the clinical and histological activities in LN.

Interleukin-32γ: Possible association with the activity and development of nephritis in patients with systemic lupus erythematosus.

AIM: Growing evidence suggests that interleukin (IL)-32 is a cytokine involved in various autoimmune diseases. We aimed to investigate whether IL-32γ is involved in systemic lupus erythematosus (SLE), particularly in patients with lupus nephritis (LN). METHOD: Sera from SLE patients without LN (n = 47), LN patients (n = 19) and healthy controls (n = 10) were collected. The serum concentrations of inflammatory cytokines, including tumor necrosis factor-α, interferon-γ, IL-6, IL-18, and IL-32γ, were measured using enzyme-linked immunosorbent assay. Clinical parameters at the time of sampling were obtained from medical records, and correlations between IL-32γ and clinical parameters were analyzed by Spearman correlation analysis. Immunohistochemistry evaluating IL-32 expression was performed in renal tissues of LN patients and healthy controls. RESULTS: Among the cytokines measured in sera, the level of IL-32γ was higher in LN patients than in SLE patients without LN and in healthy controls. Among clinical parameters, concentrations of C3/C4 were lower and erythrocyte sedimentation rate, C-reactive protein, anti-double-stranded DNA (anti-dsDNA) antibodies, and SLE Disease Activity Index-2000 (SLEDAI-2K) were higher in LN patients than in SLE patients without LN. IL-32γ level was negatively correlated with C3/C4 and positively correlated with anti-dsDNA antibodies and the renal component of SLEDAI-2K. In LN patients, IL-32γ level was positively correlated with the activity and chronicity indices. IL-32 expression was significantly higher in renal tissues of LN patients than in healthy controls. CONCLUSION: IL-32γ could be associated with the activity and development of LN in SLE.

Surgical Outcomes in Behcet's Disease Patients With Severe Aortic Regurgitation.

BACKGROUND: An optimal treatment for aortic regurgitation in Behcet's disease has not been established. We investigated the effect of operative technique, prosthetic material, and immunomodulation therapy on surgical outcomes. METHODS: In this study, 23 patients with Behcet's disease surgically treated for aortic regurgitation were assessed. Significant postoperative events were defined as death, aortic valve or graft-related problem(s), infective endocarditis, disabling stroke, and aortic valve or root reoperation. Surgical procedures were classified as isolated aortic valve replacement, bioprosthetic root replacement, and mechanical root replacement. Allograft root replacements were included in the bioprosthetic root replacement group. RESULTS: A total of 40 operations, including 39 aortic valve or root surgeries and 1 orthotopic heart transplantation, were performed on patients confirmed with Behcet's disease. However, the study only reviewed 35 of the 40 cases (4 cases with inadequately documented medical records and 1 heart transplantation case were excluded). Significant adverse events occurred in 8 of 11 (73%) isolated aortic valve replacement, 9 of 12 (75%) bioprosthetic root replacement (5 xenografts and 7 allografts), and 4 of 12 (33%) mechanical root replacement cases. Multivariate analysis revealed that the 1-month postdischarge C-reactive protein level and operative age were independent predictive factors for postoperative event-free survival. Mechanical root replacement was identified as the most significant predictive factor leading to positive outcomes (hazard ratio, 0.147; 95% confidence interval, 0.028 to 0.766; p = 0.023). CONCLUSIONS: The findings suggest that mechanical root replacement combined with a low postoperative C-reactive protein level maintained through adjunctive immunomodulation therapy may lead to optimal surgical outcomes in Behcet's disease associated with severe aortic regurgitation.