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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.

Background: It is well known that the use of corticosteroids (CS) results in increased viral replication and elevated alanine aminotransferase in hepatitis B virus (HBV) patients. However, only a few studies have investigated the effect of low-dose CS on HBV reactivation. In addition, there are few studies on the effects of synthetic disease-modifying anti-rheumatic drugs on HBV reactivation. Objective: We investigated the reactivation of HBV in rheumatoid arthritis (RA) patients treated with long-term low-dose corticosteroids. In addition, we analyzed factors affecting HBV reactivation, including disease-modifying anti-rheumatic drugs. Methods: We retrospectively reviewed medical records and analyzed the incidence of HBV reactivation in RA patients who were hepatitis B surface antigen (HBsAg) positive and who were receiving ≤10 mg of prednisolone over 4 weeks. Logistic regression analysis was performed to investigate the factors that increase the risk of HBV reactivation. Results: A total of 141 patients were included in the study, out of which 24 (17.0%) patients had HBV reactivation. The administration of low-dose corticosteroids did not affect HBV reactivation in HBsAg-positive RA patients (odds ratio: 0.807, 95% confidence interval: 0.143–4.546, p = 0.808), nor did the duration of corticosteroid administration, average daily corticosteroid dose, and cumulative corticosteroid dose. Administration of leflunomide was found to significantly increase the risk of HBV reactivation (odds ratio: 3.851, 95% confidence interval: 1.026–14.459, p = 0.046). Conclusion: The administration of low-dose corticosteroids did not affect the rate of HBV reactivation, suggesting that it can be used safely. Leflunomide may increase the risk of HBV reactivation; therefore, HBV patients should be carefully monitored when receiving this drug.

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.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.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; p0.0001).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.

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.

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.

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 and reverse transcription-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 neutralizing 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 increasedinvasiveness of FLS. Our data suggest that Cyr61 might be a potential target to prevent the progression of joint damage in RA.

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.

Background:Since tofacitnib is a tsDMARD with a different mechanism of action compared to bDMARDs, along with the fact that recent releases of bDMARDs or tsDMARDs have led to numerous possible switching patterns, there is a need for comparative studies of bDMARDs and tofacitinib with subsequent drug survival among RA patients.Objectives:To determine the association of first, second, and third-line biologic disease- modifying antirheumatic drugs (bDMARDs) and tofacitinib with drug survival among 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 choices of tocilizumab or tofacitinib may be beneficiary in reducing drug failure risk among RA patients.References:[1].Neovius M, Arkema EV, Olsson H, et al. Drug survival on TNF inhibitors in patients with rheumatoid arthritis comparison of adalimumab, etanercept and infliximab. Ann Rheum Dis 2015;74(2):354-60.Table 1.Risk of drug failure on rheumatoid arthritis patients according to first, second, and third choice of bDMARD or tofacitinib.EventsPerson-yearsIncidenceaHR95% CIFirst-line choice (n=8,018) Etanercept2902,3961211.00reference Infliximab2361,4171671.361.14-1.62 Adalimumab4492,7181651.281.10-1.48 Golimumab2581,9551321.060.90-1.26 Tocilizumab1712,623650.560.46-0.68 Rituximab129340.290.04-2.08 Tofacatinib24502480.270.18-0.42 Abatacept2162,207980.830.69-0.99Second-line choice (n=1,645) Etanercept411512721.00reference Infliximab16513141.040.58-1.88 Adalimumab852753091.070.72-1.60 Golimumab412042010.790.51-1.23 Tocilizumab85918930.380.25-0.55 Rituximab4311290.520.18-1.46 Tofacatinib35484720.230.15-0.37 Abatacept462991540.540.35-0.84Third-line choice (n=353) Etanercept3191581.00reference Infliximab5105001.270.27-5.91 Adalimumab5172940.990.22-4.38 Golimumab13225912.230.60-8.25 Tocilizumab171271340.470.13-1.68 Rituximab3221360.600.12-3.09 Tofacatinib231621420.500.14-1.77 Abatacept17592881.110.31-3.96Adjusted hazard ratios calculated by multivariate Cox proportional hazards regression after adjustments for age, sex, hospital type, number of csDMARDs, first bDMARDs or tofacitinib for second and third-line choice analysis, Charlson comorbidity index, and enrollment year.Incidence calculated as the number of events per 1,000 person-years.Acronyms: aHR, adjusted hazard ratio; CI, confidence interval.Disclosure of Interests:Byeongzu Ghang: None declared, Seulggie Choi: None declared, Eun Young Lee Grant/research support from: This work was supported by grants from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health and Welfare, Republic of Korea [HI14C1277] and Britol-Myers Squibb [IM101-735].

Background/aims Acute transverse myelitis (ATM) is a severe complication of systemic lupus erythematosus (SLE). This study evaluated the clinical factors related to outcome in patients with SLE-associated ATM. Methods The medical records of patients diagnosed with SLE-associated ATM between January 1995 and January 2015 were reviewed. The patients were divided into two groups based on improvement of neurological deficits after treatment: favorable response group and unfavorable response group. During follow-up, the recurrence of ATM was also analyzed. Results ATM was identified in 16 patients with SLE. All of the patients were treated with high doses of methylprednisolone (≥ 1 mg/kg daily). Although 12 patients (75%) recovered (favorable response group), four (25%) had persistent neurologic deficits (unfavorable response group) after the treatment. Compared to the favorable response group, significantly higher Systemic Lupus Erythematosus Disease Activity Index-2000, lower complement levels and initial severe neurologic deficits were found in the unfavorable response group. Among the 12 favorable response patients, five (41.7%) experienced recurrence of ATM during the followup. Patients (n = 5) who experienced relapse had a shorter duration of high-dose corticosteroid treatment (13.2 days vs. 32.9 days, p = 0.01) compared to patients who did not relapse. The mean duration of tapering-off the corticosteroid until 10 mg per day was significantly longer in non-relapse group (151.3 ± 60.8 days) than in relapse group (63.6 ± 39.4 days, p = 0.013). Conclusion Higher disease activity in SLE and initial severe neurologic deficits might be associated with the poor outcome of ATM. Corticosteroid slowly tapering-off therapy might be helpful in preventing the recurrence of ATM.

Objective The purpose of this study was to investigate the risk of myopathy when statins are coadministered with colchicine in patients with gout. Methods In gout patients who received colchicine with or without statin, clinical data collected included medications and history of hypertension, chronic kidney disease, and liver cirrhosis. Myopathy was defined as the presence of muscle symptoms with elevated creatine kinase or myoglobin. Multivariate analysis was performed to identify risk factors for myopathy. Inverse probability of treatment weighting (IPTW)-adjusted analysis was used to evaluate the influence of concomitant colchicine and statin use on myopathy. Results Of 674 patients, 486 received colchicine alone and 188 also received statin. The incidence of myopathy was not significantly higher in those on both drugs than in those on colchicine alone (2.7% vs 1.4%, P = .330). On multivariate analysis, chronic kidney disease (hazard ratio [HR] 29.056; 95% confidence interval [CI], 4.387-192.450; P P = .029), higher colchicine dose (HR 20.960; 95% CI, 1.835-239.481; P = .014), and concomitant CYP3A4 inhibitor (HR 12.027; 95% CI, 2.743-52.725; P = .001) were associated with increased risk of myopathy. Concomitant use of statins, however, was not, even after adjusting for confounders (HR 1.123; 95% CI, 0.262-4.814; P = .875; IPTW-adjusted HR 0.321; 95% CI, 0.077-1.345; P = .120). Conclusion Concomitant use of statin and colchicine was not associated with increased risk of myopathy. Thus, concomitant use of statin with colchicine seems to be safe from myotoxicity in gout patients.

Background:Connective tissue disease (CTD) may be observed during the course of idiopathic pulmonary fibrosis (IPF). However, clinical factors associated with the development of CTD in patients with IPF have not yet been identified. These factors might be valuable clues for determining the pathogenesis of pulmonary fibrosis in patients with CTD. We hypothesize that some IPF patients have a clinically significant association with autoimmunity, and that autoantibodies are important biomarkers for identifying these patients.Objectives:Based on this hypothesis, we investigated whether the serology criteria (anti-neutrophil cytoplasmic antibody (ANCA) or autoantibodies that met the serology criteria for interstitial pneumonitis with autoimmune features (IPAF)) were associated with the development of CTD during the clinical course of IPF in the patients from our previous study(1), with a particular focus on which antibodies have a significant association with the development of CTD.Methods:We retrospectively reviewed the records of 527 patients with a first diagnosis of IPF between January 2007 and March 2014, and investigated the length of time from first visit to the clinic for IPF diagnosis (baseline) to CTD diagnosis by an expert rheumatologist in patients with IPF. Multivariable Cox proportional-hazards models with backward elimination were used to investigate the risk factors for the development of CTD.Results:CTD developed in 15 patients at a median of 2.1 years (range 1.2 to 4.8) after IPF diagnosis. All these patients had ANCA or autoantibodies that met the serology criteria for IPAF. A significant number of IPF patients with high titers of RF, ACPA or MPO-ANCA tested at first visit to the clinic progressed to CTD(Figure 1). Survival duration for IPF patients with progression to CTD was 5.3 [3.8; 6.7] years, which was significantly longer than for the IPF patients without progression to CTD (2.9 [1.7; 4.8], p = 0.001). Independent risk factors for development of CTD 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).Figure 1.Connective tissue disease development in each autoantibody positive IPF patient. ACPA = anti–citrullinated protein antibody; ANA = antinuclear antibody; CTD = connective tissue disease; MPA = microscopic polyangiitis; PAN = polyarteritis nodosa; RA = rheumatoid arthritis; RF = rheumatoid factor; UCTD = Undifferentiated connective tissue disease; SjS = Sjögren’s syndrome.Conclusion:We observed development of CTD in IPF patients with ANCA or autoantibodies that met the IPAF serology criteria. Among these autoantibodies, RF, ACPA, and MPO-ANCA were significantly associated with the development of CTD in IPF patients. Progression to CTD is uncommon in IPF patients, but a significant number of IPF patients with high titers of RF, ACPA or MPO-ANCA progressed to connective tissue disease. IPF with high titers of RF, ACPA or MPO-ANCA might be the initial clinical manifestation of connective tissue disease. Further studies are needed to investigate the role of RF, ACPA, and MPO-ANCA in development of pulmonary fibrosis.References:[1]Ghang B, Lee J, Chan Kwon O, Ahn SM, Oh JS, Hong S, et al. Clinical significance of autoantibody positivity in idiopathic pulmonary fibrosis. Respir Med. 2019;155:43-8.Disclosure of Interests:None declared

Additional file 1: Fig. S1. Transcription factors not involved in IL-6 induced Cyr61 protein synthesis. RA-FLSs transfected with either small interfering RNA (NR4A1 or ATF3) or siNC (control) (20 pmol/L) stimulated by IL-6 (20 ng/mL) for 2 h. Data are representative of at least three independent experiments. Fig. S2. Expression of IL-6 enhanced by Cyr61 secretion. The mRNA level of IL-6 stimulated by Cyr61 protein (100 ng/mL) for 2 h as determined via real time polymerase chain reaction. Values are means (± standard deviation) of at least three independent experiments. **p

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.

Background:When serum uric acid rapidly increases or decreases due to such as alcohol consumption or fasting, free urate crystals are formed, which induce an acute joint inflammation referred to as an acute gout attack. In 86.4% of patients with gout, dual energy computed tomography demonstrated the deposition of urate crystals in vasculature, and urate crystals have been observed in coronary arteries and various tissues in 10.9% of patients with a heart transplant. However, whether hyperuricemia and urate crystal directly cause cardiovascular disease is not well known. We previously reanalyzed the CARES trial to calculate the mortality rates based on the median duration of exposure to study drugs and the median follow-up duration. A sharp increase in mortality was observed after allopurinol and febuxostat were discontinued. Even in view of the Sick-Stopper Effect, for about 40-fold increase in mortality following drug discontinuation, we postulated that the sharp increase in mortality may be associated with rapid changes in uric acid level (rebound hyperuricemia), and that withdrawal of hypouricemic agent leads to an acute inflammatory response due to an abrupt increase in serum uric acid level with subsequent free urate crystal formation in the cardiovascular system (cardiovascular gout attack)(1).Objectives:Based on this hypothesis that some cardiovascular events may be cardiovascular gout attacks, we investigated the association between the cardiovascular event and initiation of hypouricemic agent, when is accompanied by acute gout attack and/or fluctuation of uric acid, in gout patients.Methods:Using the Korean National Health Insurance Service (KNHIS) database, which covers the entire Korean population, we conducted a population-based cohort study among gout patients who initiated allopurinol or febuxostat between 2012 and 2018. The initiators were defined as those who had no prior dispensing of any urate-lowering therapy for at least 60 months before the first dispensing date (i.e. index date) of either allopurinol or febuxostat. We excluded patients with a diagnosis of cancer and patients treated with benzbromarone. We investgated a composite cardiovascular event of hospitalized myocardial infarction, ischemic stroke, and cerebral hemorrhage.Results:We identified hospitalizations for cardiovascular event (acute myocardial infarction (n = 3538), cerebral infarction (n = 5127), and cerebral hemorrhage (n = 1593)) that occurred within 2 year before and 2 year after initiation of allopurinol or febuxostat. Of these, 4333 cardiovascular event (0.014 per person-time, 95% confidence interval [CI], 0.014 to 0.015) occurred in 2 years before initiation of allopurinol or febuxostat, 1032 cardiovascular event (0.081 per person-time, 95% confidence interval [CI], 0.076 to 0.086) occurred in 30 days before initiation of allopurinol or febuxostat. And, 83 cardiovascular event (0.030 per person-time, 95% CI, 0.024 to 0.037) occurred in 7 days after initiation of allopurinol or febuxostat. (Figure)Figure 1Conclusion:Initiation of febuxostat and allopurinol was significantly associated with acute myocardial infarction, cerebral infarction, and cerebral hemorrhage. Considering that allopurinol and febuxostat usually are initiated a few weeks after a acute gout attack. Acute gout attack and/or fluctuation of uric acid level might be significantly associated with cardiovascular event. Some of cardiovascular events might be cardiovascular gout attack.References:[1]Ghang B, Ahn SM, Kim J, Kim YG, Lee CK, Yoo B. Discontinuing febuxostat might cause more deaths than continuing febuxostat: the untold story from the CARES trial. Rheumatology (Oxford). 2019.Disclosure of Interests:None declared

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.

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.

Objective. To gain a better understanding of the pathogenesis of autoimmune arthritis-associated interstitial lung disease (ILD), we sought to identify the characteristics of lung-infiltrating cells in SKG mice with ILD. Methods. We injected curdlan in SKG mice at 8 weeks of age, and identified the presence of ILD by PET-MRI at 20 weeks post-injection and histological analysis at 22 weeks post-injection. Lung-infiltrating cells were examined by flow cytometry. Analysis of serum cytokines by the Luminex multiplex cytokine assay was performed at 14 and 22 weeks post-injection, and cytokine profiles before and after the development of ILD were compared. Opal multiplexed immunofluorescent staining of lung tissue was also performed. Results. At 20 weeks post-injection, curdlan-treated SKG mice developed not only arthritis but also lung inflammation combined with fibrosis, which was identified by PET-MRI and histological analysis. The majority of inflammatory cells that accumulated in the lungs of curdlan-treated SKG mice were CD11b+Gr1+ neutrophils, which co-express IL-17A and GM-CSF, rather than TNF-α. Compared with 14 weeks post-injection, serum levels of GM-CSF, MCP1, IL-17A, IL-23, TSLP, and soluble IL-7Rα had increased at 22 weeks post-injection, whereas those of IFN-, IL-22, IL-6, and TNF-α remained unchanged. Furthermore, IL-23, CXCL5, IL-17A, and GM-CSF, but not TNF-α, were observed in immunofluorescent-stained lung tissue. Conclusion. We found that IL-17A+GM-CSF+ neutrophils represented the major inflammatory cells in the lungs of curdlan-treated SKG mice. In addition, GM-CSF and IL-17A appear to play a more important role than TNF-α in ILD development.

Background Recently, the concept of interstitial pneumonia with autoimmune features (IPAF) was proposed by the American Thoracic Society. 1 The serologic domain of IPAF is composed of antibodies to extractable nuclear antigens, cyclic citrullinated peptide antibody, a high titer of rheumatoid factor, and a high titer of antinuclear antibody. However, the clinical significance of the serologic domain of IPAF has not yet been evaluated in idiopathic pulmonary fibrosis (IPF). Objectives To investigate the clinical significance of autoantibody positivity in IPF. Methods We retrospectively reviewed the records of 528 patients who met the ATS/ERS/JRS/ALAT diagnostic criteria for IPF at a tertiary hospital from January 2007 through March 2014. Patients treated with pirfenidone or nintedanib, an established IPF treatment regimen, were excluded. All patients were divided into the following 3 groups: autoimmune IPF (n=153), patients with autoantibodies that met the criteria for the IPAF serologic domain; incomplete autoimmune IPF (n=68), patients who did not completely meet the criteria for the IPAF serologic domain; lone IPF (n=307), patients without autoantibodies. Multivariate Cox proportional hazards models with backward elimination were used to investigate the risk factors for mortality. Results The 5 year mortality rates were as follows: autoimmune IPF group, 54.9% (n=84, 3.4 years after diagnosis [median; IQR=1.9–5.0]); incomplete autoimmune IPF group, 64.7%; lone IPF group, 58.6% (n=180, 2.9 years after diagnosis [median; IQR=1.6–4.9]). Independent risk factors for mortality on multivariable analysis in the overall IPF patient population included age at diagnosis (adjusted hazard ratio (HR) 1.028, p=0.002), autoimmune IPF (adjusted HR 0.747, p=0.050), baseline SaO 2 in the 6 min walking test (6MWT, adjusted HR 0.973, p=0.012), baseline distance in the 6MWT (adjusted HR 0.998, p=0.001), baseline forced vital capacity (adjusted HR 0.977, p Conclusions Our results suggest that positive autoimmunity might be a favourable factor for 5 year mortality in IPF patients compared to those without autoimmunity, and the use of immunosuppressants could be associated with improved mortality in autoimmune IPF patients. Reference [1] Fischer A, Antoniou KM, Brown KK, Cadranel J, Corte TJ, du Bois RM, et al. An official European Respiratory Society/American Thoracic Society research statement: interstitial pneumonia with autoimmune features. The European respiratory journal2015;46(4):976–87. Disclosure of Interest None declared

Pseudoxanthoma elasticum (PXE)-like disorder with multiple coagulation factor deficiency is a genetic disease characterized by dystrophic mineralization of the connective tissue in multiple organs such as the skin, arteries, and retina. Patients with this disorder have excessive folding and sagging of the skin with loss of recoil, as well as coagulopathy. Crohn’s disease is a chronic inflammatory condition of the gastrointestinal tract, which primary affects the small intestine, often leading to malnutrition. Here, we describe the case of a 25-year-old woman who presented with these diseases. We found that nutrient deficiency due to long-term Crohn’s disease aggravated the coagulopathy associated with PXE-like disorder. (Korean J Med 2015;89:474-477)

A 71-year-old male initially presented with vocal cord palsy and underwent tracheostomy. After thorough examination, urogenital dysfunction, orthostatic hypotension, and Parkinsonism were found, which led to the diagnosis of multiple system atrophy (MSA). After the tracheostomy, bi-level positive airway pressure ventilation was required during the night due to nocturnal hypoxemia. Nighttime hypoxemia is related to central sleep apnea, which is one of the manifestations of MSA. This is the first case of MSA manifested by bilateral vocal cord palsy as an initial sign in Korea. This case supports the notion that MSA should be taken into consideration when vocal cord paralysis is observed.

We report a case of duodenal metastasis from squamous cell carcinoma of the cervix confirmed by histopathological diagnosis. A 48-year-old woman was diagnosed with uterine cervix cancer stage IVB and underwent chemotherapy. During followup after chemotherapy, a mass suspicious of malignancy was found at the 3rd portion of the duodenum on the magnetic resonance imaging of the abdomen. Esophagogastroduodenoscopy with biopsy was done for an ulcerofungating mass at the 3rd portion of the duodenum. Squamous cell carcinoma was confirmed on the biopsy which was same as the histopathological diagnosis confirmed by cervix biopsy and right supraclavicular lymph node biopsy resulting from metastasis of cervix. Since 1981, only ten cases of small bowel metastasis from squamous cell carcinoma of cervix have been reported. It is exceedingly rare to find metastasis to the duodenum from uterine cervix cancer. Korean J Pancreatobiliary 2015;20(2):111-114

It is unclear whether attack recurrence rates are similar between acute calcium pyrophosphate (CPP) crystal arthritis and gout. This study compared the clinical features and recurrence rates of both conditions.In this retrospective study, we reviewed 106 patients with acute CPP crystal arthritis (based on the presence of CPP crystals and/or chondrocalcinosis) and 173 patients with gout (based on the presence of monosodium urate crystals). We analysed clinical variables and compared them between the two conditions. We identified factors associated with the recurrence of acute CPP crystal arthritis.Patients with acute CPP crystal arthritis were older (76.5 vs. 62 years, p0.001) and female (69.8% vs. 6.9%, p0.001); they had a lower body mass index (22.3 vs. 23.7, p=0.002), lower renal insufficiency rate (27.4% vs. 41.6%, p=0.016), and higher rate of preceding infection (22.6% vs. 11.0%, p=0.009) than those with acute gout. Recurrence rates were similar between the groups (19.1% vs. 22.9%, p=0.562). Use of proton pump inhibitors (PPIs) [hazard ratio (HR), 5.625; 95% CI, 1.672-18.925; p=0.005] and warfarin (HR, 7.301; 95% CI, 1.930-27.622; p=0.003) or exposure to chemotherapy (HR, 5.663; 95% CI, 1.180-27.169; p=0.03) were associated with acute CPP crystal arthritis recurrence.Acute CPP crystal arthritis was more common than acute gout in older women with preserved renal function. Physicians should be aware of the association between recurrence and PPI, warfarin, or chemotherapy use in these patients.

To investigate factors predictive of future lupus nephritis development when systemic lupus erythematosus (SLE) is diagnosed.Patients with newly diagnosed SLE without renal manifestations were followed for development of lupus nephritis, comparing findings at baseline between those who did or did not develop nephritis. Albumin-to-globulin ratio (AGR) was calculated as albumin/(total protein-albumin). Cox proportional hazard model was used to identify predictors of lupus nephritis.Of 278 patients, 241 did not and 37 did develop lupus nephritis during follow-up. On univariate analysis, young age, low C3, low C4, high anti-dsDNA titre, anti-Sm antibody, anti-RNP antibody and low AGR were associated with a higher risk of lupus nephritis. On multivariate analysis, factors predictive of nephritis were age [adjusted hazard ratio (aHR) 0.928, 95% confidence interval (CI): 0.895-0.961, p0.001], C3 (aHR 0.977, 95% CI: 0.966-0.989, p0.001), anti-dsDNA titre (aHR 1.004, 95% CI: 1.000-1.007, p = 0.026) and anti-Sm antibody (aHR 2.097, 95% CI: 1.040-4.229, p = 0.038). In particular, a low AGR (aHR 4.972, 95% CI: 2.394-10.326, p0.001) was strongly associated with an increased risk of future lupus nephritis development.Young age, low C3, high anti-dsDNA titre and presence of anti-Sm antibody at diagnosis of SLE were associated with a risk of future lupus nephritis, but the hazard was greatest with a low AGR value, suggesting that a greater proportion of immunoglobulin relative to total protein is associated with the development of nephritis.

It has been suggested that inflammasome-mediated IL-1β production in monocytic cells is responsible for the acute inflammatory response in gouty arthritis. However, phenotypical and functional analyses of monocytes during gouty arthritis have yet to be conducted. Therefore, we investigated the characteristics of monocytes/macrophages in the synovial fluid cells of patients with acute gout. The number and frequency of monocytes/macrophages in the synovial fluid mononuclear cells (SFMCs) of patients was examined. The expression of markers for monocyte recruitment and tissue-resident macrophages, the production of pro-inflammatory and anti-inflammatory cytokines, and phagocytosis were analyzed in the monocytes/macrophages of patients with acute gout attacks. The number and frequency of CD14+CD3-CD19-CD56- monocytes/macrophages was markedly increased in the SFMCs of patients with gout compared to those of patients with rheumatoid arthritis (RA). CD14+ cells showed the phenotypes of infiltrated monocytes rather than tissue-resident macrophages, characterized by a high expression of CCR2, MRP8, and MRP14, but a low expression of MERTK and 25F9. These cells had the capacity to produce pro-inflammatory cytokines such as TNF-α and IL-1β after stimulation with lipopolysaccharides. In addition, anti-inflammatory features, including CD163 expression and IL-10 production from CD14+ cells, were significantly higher in patients with gout than in those with RA. CD14+ cells with phenotype of M2 macrophages had high phagocytic activity for monosodium urate crystals. Thus, our results indicate that monocytes/macrophages from patients with gout have the phenotype of infiltrated monocytes, and these cells consist of different populations characterized by anti-inflammatory activities as well as pro-inflammatory functions.

It has been suggested that inflammasome-mediated IL-1β production in monocytic cells is responsible for the acute inflammatory response in gouty arthritis. However, phenotypical and functional analyses of monocytes during gouty arthritis have yet to be conducted. Therefore, we investigated the characteristics of monocytes/macrophages in the synovial fluid cells of patients with acute gout. The number and frequency of monocytes/macrophages in the synovial fluid mononuclear cells (SFMCs) of patients was examined. The expression of markers for monocyte recruitment and tissue-resident macrophages, the production of pro-inflammatory and anti-inflammatory cytokines, and phagocytosis were analyzed in the monocytes/macrophages of patients with acute gout attacks. The number and frequency of CD14+CD3−CD19−CD56− monocytes/macrophages was markedly increased in the SFMCs of patients with gout compared to those of patients with rheumatoid arthritis (RA). CD14+ cells showed the phenotypes of infiltrated monocytes rather than tissue-resident macrophages, characterized by a high expression of CCR2, MRP8, and MRP14, but a low expression of MERTK and 25F9. These cells had the capacity to produce pro-inflammatory cytokines such as TNF-α and IL-1β after stimulation with lipopolysaccharides. In addition, anti-inflammatory features, including CD163 expression and IL-10 production from CD14+ cells, were significantly higher in patients with gout than in those with RA. CD14+ cells with phenotype of M2 macrophages had high phagocytic activity for monosodium urate crystals. Thus, our results indicate that monocytes/macrophages from patients with gout have the phenotype of infiltrated monocytes, and these cells consist of different populations characterized by anti-inflammatory activities as well as pro-inflammatory functions.

Objective.Takayasu arteritis (TA) involving the renal artery can result in hypertension (HTN), renal dysfunction, and premature death. The aim of this study was to investigate the longterm outcomes and factors that predict outcomes in patients with TA with renal artery stenosis.Methods.The medical records of patients diagnosed with TA between January 1997 and December 2014 were reviewed retrospectively. Renal artery involvement was based on computed tomography and/or angiography findings. Poor outcome was defined as refractory HTN, chronic renal insufficiency, or death.Results.Of the 62 TA patients with renal artery involvement, 11 (17.7%) underwent renal artery revascularization. Younger age, male sex, and more severe stenosis (> 70%) were associated with vascular intervention. After a median followup of 90.6 months, 11 (17.7%) of the 62 patients had refractory HTN and 6 (9.7%) had chronic renal insufficiency. Renal insufficiency [5/15 (33.3%) vs 3/47 (6.4%), p = 0.016] and bilateral involvement [12/15 (80.0%) vs 23/47 (48.9%), p = 0.041] were significantly more frequent in patients with poor than good outcomes. Multivariate Cox analysis revealed that renal insufficiency at presentation (HR 13.778, 95% CI 3.530–53.786, p < 0.001) and bilateral renal artery involvement (HR 5.053, 95% CI 1.179–21.661, p = 0.029) were significant risk factors for poor outcomes at followup, but performance of revascularization procedure was not (HR 0.663, 95% CI 0.176–2.498, p = 0.543).Conclusion.Bilateral lesions and renal functional impairment at presentation, but not implementation of revascularization procedures, were significant factors for outcomes in TA patients with renal artery involvement.

To investigate the reliable markers reflecting treatment response better than the traditional inflammatory indices in patients with rheumatoid arthritis (RA) receiving tocilizumab therapy.A total of 58 RA patients treated with tocilizumab for more than six months from January 2013 to December 2014 were initially included. Flares were defined as events that required steroid dose escalation, intra-articular steroid injections, or switching tocilizumab to other biologic agents. The clinical and laboratory data were retrospectively collected from electronic medical records.Of the 52 patients except for six patients who were excluded, 16 experienced flares, and 36 were stable during tocilizumab therapy. The C-reactive protein (CRP) level did not significantly differ between a stable state before flares and at flares. Compared with those at the preflare time point, erythrocyte sedimentation rate (ESR), and neutrophil to lymphocyte ratio (NLR) were significantly higher at flares; however, ESR levels (n = 9) were within the normal limit or decreased (n = 4) at flares. Interestingly, NLR increased at flares in all but one patient in the flare group.NLR is a more reliable marker than ESR or CRP for evaluating the disease activity in patients with RA during tocilizumab therapy.

The aim of this study was to determine whether adult IgA vasculitis patients who developed the disease at an older age differ from early-onset patients in terms of clinical features and outcomes.All consecutive adult patients who were diagnosed with IgA vasculitis between January 1997 and December 2014 were reviewed retrospectively. Patients who developed the disease at an older age (≥60 years; late-onset) were compared with those with an earlier onset of disease (60 years; early-onset). Renal insufficiency was defined as an estimated glomerular filtration rate60 ml/minute.In total, 100 adult patients were diagnosed with IgA vasculitis (mean age, 45.61 ± 17.24 years), of whom 31 (31%) had late-onset disease. Compared to early-onset patients, late-onset patients were less likely to have a preceding upper respiratory tract infection (0/31, 0.0% vs. 14/69, 20.3%; p=0.004), and more likely to have renal involvement at presentation (27/31, 87.1% vs. 43/69, 62.3%; p=0.017). At the last follow-up visit, late-onset patients were more likely to have chronic renal insufficiency, including end-stage renal disease (18/28, 64.3% vs. 7/62, 11.3%; p=0.000). Multivariate Cox analysis revealed that late-onset was a significant risk factor for renal insufficiency at follow-up (hazard ratio, 16.980, 95% confidence intervals, 4.380-65.830; p=0.000).Patients with late-onset IgA vasculitis in adults exhibit distinct clinical features characterized by greater renal involvement and worse renal outcomes. Thus, watchful follow-up might be needed for adult IgA vasculitis patients, in particular those with late-onset disease.

Background Osteocalcin (OC) has been known as one of bone-forming markers and the serum level in rheumatoid arthritis (RA) patients was usually lower than that in healthy control. Serum OC, secreted from osteoblasts, exists in either carboxylated OC (cOC, major form) or undercarboxylated OC (ucOC, minor form). Different to the osteogenic role of cOC, ucOC has been suggested to be involved in energy metabolism. Recent studies have shown that significantly lower concentration of ucOC in the blood was associated with metabolic derangement including insulin resistance. Therefore, we would like to investigate whether level of ucOC in RA patients decreased and it was accompanied by metabolic dysregulation, which has never been studied before. Objectives To determine the association between ucOC and metabolic alteration including insulin resistance in patients with RA Methods Clinical information of patients and healthy volunteers was collected from electronic data base of single center registry. The concentrations of cOC and ucOC were measured in the sera from established RA patients (n=30) and healthy subjects (n=13) by enzyme-linked immunosorbent assay (ELISA). Various metabolic parameters, including insulin concentration, homeostasis model assessment of insulin resistance (HOMA-IR) and body mass index (BMI), were measured and analyzed. Results The concentration of cOC in blood was not significantly different between RA patients (13.49±2.97 ng/mL) and healthy controls (14.45±2.48 ng/mL). However, the concentration of ucOC was significantly lower in the sera of patients with RA (3.29±2.36 ng/mL) than in those of healthy individuals (5.94±2.75 ng/mL, p=0.003). Intriguingly, ucOC levels have been found to be positively associated with parameters of metabolic derangement including insulin levels, HOMA-IR and BMI (Figure 1). These associations were not found in healthy controls. Conclusions The present study show that the concentration of ucOC, but not cOC was significantly lower in patients with RA, and its value was positively correlated with insulin resistance. Therefore, ucOC can be supposed to have a unique role in metabolic dysregulation in RA. Disclosure of Interest None declared