Real-world effectiveness of a single conventional disease-modifying anti-rheumatic drug (cDMARD) plus an anti-TNF agent versus multiple cDMARDs in rheumatoid arthritis: a prospective observational study.

Objective: The objective of this prospective, observational multicenter study (NCT03264703) was to compare the effectiveness of single conventional disease-modifying anti-rheumatic drug (cDMARD) plus anti-tumor necrosis factor (TNF) therapy versus multiple cDMARD treatments in patients with moderate-to-severe rheumatoid arthritis (RA) following cDMARD failure in the real-world setting in South Korea. Methods: At the treating physicians' discretion, patients received single cDMARD plus anti-TNF therapy or multiple cDMARDs. Changes from baseline in disease activity score 28-joint count with erythrocyte sedimentation rate (DAS28-ESR), corticosteroid use, and Korean Health Assessment Questionnaire (KHAQ-20) scores were evaluated at 3, 6, and 12 months. Results: Of 207 enrollees, the final analysis included 45 of 73 cDMARD plus anti-TNF and 91 of 134 multiple-cDMARD recipients. There were no significant between-group differences (BGDs) in ANCOVA-adjusted changes from baseline in DAS28-ESR at 3, 6 (primary endpoint), and 12 months (BGDs -0.18, -0.38, and -0.03, respectively). More cDMARD plus anti-TNF than multiple-cDMARD recipients achieved a >50% reduction from baseline in corticosteroid dosage at 12 months (35.7% vs 14.6%; p=0.007). Changes from baseline in KHAQ-20 scores at 3, 6, and 12 months were significantly better with cDMARD plus anti-TNF therapy than with multiple cDMARDs (BGD -0.18, -0.19, and -0.19 points, respectively; all p≤0.024). Conclusion: In the real-world setting, relative to multiple cDMARDs, single cDMARD plus anti-TNF therapy significantly improved quality-of-life scores and reduced corticosteroid use, with no significant BGD in disease activity, in RA patients in whom previous cDMARD therapy had failed.

Risk of cardiovascular disease with high-dose versus low-dose use of non-steroidal anti-inflammatory drugs in ankylosing spondylitis.

OBJECTIVE: To investigate the risk of cardiovascular disease (CVD) associated with increasing dose of a non-steroidal anti-inflammatory drug (NSAID) in patients with ankylosing spondylitis (AS). METHODS: Using the Korean National Health Insurance database, patients newly diagnosed with AS without prior CVD between 2010 and 2018 were included in this nationwide cohort study. The primary outcome was CVD, a composite outcome of ischaemic heart disease, stroke or congestive heart failure. Exposure to NSAIDs was evaluated using a time-varying approach. The dose of NSAIDs was considered in each exposure period. Cox proportional hazard regression was used to investigate the risk of CVD associated with NSAID use. RESULTS: Of the 19 775 patients (mean age, 36 years; 75% were male), 19 706 received NSAID treatment. During follow-up period of 98 290 person-years, 1663 cases of CVD occurred including 1157 cases of ischaemic heart disease, 301 cases of stroke and 613 cases of congestive heart failure. Increasing dose of NSAIDs was associated with incident CVD after adjusting for confounders (adjusted HR (aHR) 1.10; 95% CI 1.08 to 1.13). Specifically, increasing dose of NSAIDs was associated with incident ischaemic heart disease (aHR 1.08; 95% CI 1.05 to 1.11), stroke (aHR 1.09; 95% CI 1.04 to 1.15) and congestive heart failure (aHR 1.12; 95% CI 1.08 to 1.16). The association between NSAID dose and higher CVD risk was consistent in different subgroups. CONCLUSION: In a real-world AS cohort, higher dose of NSAID treatment was associated with a higher risk of CVD, including ischaemic heart disease, stroke and congestive heart failure.

Risk of cardiovascular disease associated with long-term use of non-steroidal anti-inflammatory drugs in ankylosing spondylitis.

OBJECTIVE: To examine the risk of cardiovascular disease associated with long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) in a large real-world ankylosing spondylitis (AS) cohort. METHODS: This nationwide population-based cohort study used data from the Korean National Health Insurance Database. Patients aged ≥18 years old who were newly diagnosed with AS without prior cardiovascular disease between January 2010 and December 2018 were included in this study. Controls without AS were randomly selected by age, sex, and index year. The primary outcome was cardiovascular disease, a composite outcome of ischemic heart disease, stroke, or congestive heart failure. Long-term use of NSAIDs was defined as use of NSAIDs for >365 cumulative defined daily doses. The association between long-term use of NSAIDs and incident cardiovascular disease was examined in both AS and non-AS populations. RESULTS: Among 19 775 patients with AS and 59 325 matched controls without AS, there were 1,663 and 4,308 incident cases of cardiovascular disease, showing an incidence of 16.9 and 13.8 per 1,000 person-years, respectively. Long-term use of NSAIDs was associated with increased risk of cardiovascular disease in non-AS controls (adjusted hazard ratio [aHR], 1.64; 95% CI, 1.48-1.82). In contrast, long-term use of NSAIDs did not increase the risk of cardiovascular disease in AS patients (aHR, 1.06; 95% CI, 0.94-1.20; adjusted for age, sex, socioeconomic status, body mass index, smoking status, hypertension, diabetes, hyperlipidemia, and tumor necrosis factor inhibitor use). CONCLUSION: Prolonged NSAID treatment in AS patients may not be as harmful as in the general population regarding cardiovascular risk.

Biosimilars in the treatment of rheumatoid arthritis: a pharmacokinetic overview.

INTRODUCTION: As of May 2023, 19 and 18 biosimilars have been approved for the treatment of rheumatoid arthritis (RA) by the European Medicines Agency (EMA) and United States Food and Drug Administration (US FDA) respectively. AREA COVERED: Pharmacokinetic results of phase 1 studies of approved biosimilars were reviewed by systematic literature search. The impact of immunogenicity on the pharmacokinetic data and clinical response was assessed, and the potential benefit of monitoring serum concentrations of biologic drugs is discussed. The advantage of subcutaneous CT-P13 (an infliximab biosimilar) in clinical practice is reviewed. EXPERT OPINION: Biosimilars are approved based on the totality of evidence including comparable physiochemical properties, PK / PD profiles, and clinical efficacy and safety to the originator. To utilize biosimilars more effectively, physicians should be aware of the utility of combination DMARD therapy to reduce immunogenicity and maintain efficacy and PK profile. PK monitoring, however, is not currently recommended in clinical practice. CT-P13 subcutaneous (SC) is the first SC infliximab used for treatment of RA patients. Based on data from clinical studies and the real world, SC-infliximab is an attractive therapeutic option compared to IV formulations of infliximab based on its efficacy, pharmacokinetics, patient-reported outcomes, and safety profile.

The comparable efficacy of denosumab on bone mineral density in rheumatoid arthritis patients with postmenopausal osteoporosis: A retrospective case-control study.

Little is known about differences in the therapeutic efficacy of denosumab in subjects with and without rheumatoid arthritis (RA). This study compares the changes in bone mineral density (BMD) between RA patients and controls without RA who had been treated with denosumab for 2 years for postmenopausal osteoporosis. A total of 82 RA patients and 64 controls were enrolled, who were refractory to selective estrogen receptor modulators (SERMs) or bisphosphonates and completed the treatment of denosumab 60 mg for 2 years. The efficacy of denosumab in RA patients and controls was assessed using areal BMD (aBMD) and T-score of the lumbar spine, femur neck, and total hip. A general linear model with repeated measures analysis of variance was used to determine differences in aBMD and T-score between 2 study groups. No significant differences in percent changes in aBMD and T-scores by denosumab treatment for 2 years at the lumbar spine, femur neck, and total hip were evident between RA patients and controls (P > .05 of all), except T-score of the total hip (P = .034). Denosumab treatment equally increased aBMD at the lumbar spine and T-scores at the lumbar spine and total hip between RA patients and controls without statistical differences, but RA patients showed less improvement in aBMD at the femur neck (ptime*group = 0.032) and T-scores at the femur neck and total hip than controls (ptime*group = 0.004 of both). Changes in aBMD and T-scores after denosumab treatment in RA patients were not affected by previous use of bisphosphonates or SERMs. Differences of T-score at the femur neck among previous bisphosphonate users and aBMD and T-score at the femur neck and T-scores at the total hip were evident. This study revealed that 2 years of denosumab treatment in female RA patients achieved comparable efficacy on BMD to controls at the lumbar spine, but showed somewhat insufficient improvement at the femur neck and total hip.

Comparisons of treatment satisfaction and health-related quality of life in patients with rheumatoid arthritis treated with tofacitinib and adalimumab.

BACKGROUND: As significant advances in the field of treatment for rheumatoid arthritis (RA), there is a great need to identify the healthcare outcomes such as treatment satisfaction and health-related quality of life (HRQoL) of patients with various treatment options. This study aims to identify the difference in the treatment satisfaction and HRQoL of patients with RA using different treatment options, by comparing the treatment satisfaction and HRQoL in patients with RA treated with tofacitinib and adalimumab in real-world settings in Korea, using propensity score methods. METHODS: In this non-interventional, multicenter, cross-sectional study (NCT03703817), a total of 410 patients with RA diagnosis were recruited in 21 university-based hospitals throughout Korea. The treatment satisfaction and HRQoL were assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM) and EQ-5D questionnaires self-reported by the patients. This study compared outcomes between two drug groups in unweighted, greedy matching, and stabilized inverse probability of treatment weight (IPTW) samples using propensity score. RESULTS: In all three samples, tofacitinib group showed higher convenience domain of TSQM than that in the adalimumab group, but not effectiveness, side effects, and global satisfaction domains. Multivariable analysis using the covariates of demographic and clinical characteristics of the participants also showed consistent results in TSQM. No statistical difference in EQ-5D-based HRQoL was identified between two drug groups in all three samples. CONCLUSIONS: This study identified that tofacitinib shows higher treatment satisfaction in the convenience domain of TSQM rather than adalimumab, suggesting that various factors such as drug formulation, route or frequency of administration, and storage can have an impact on the treatment satisfaction, especially the convenience domain. These findings may be useful to patients and physicians when determining treatment options. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03703817.

HMG-CoA Reductase Inhibitors Suppress Monosodium Urate-Induced NLRP3 Inflammasome Activation through Peroxisome Proliferator-Activated Receptor-γ Activation in THP-1 Cells.

Peroxisome proliferator-activated receptor γ (PPAR-γ) is thought to negatively regulate NLRP3 inflammasome activation. The aim of this study was to identify the inhibitory effect of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) on monosodium urate (MSU) crystal-induced NLRP3 inflammasome activation through the regulation of PPAR-γ in THP-1 cells. The expression of PPAR-γ, NLRP3, caspase-1, and interleukin-1ß (IL-1ß) in human monocytic THP-1 cells transfected with PPAR-γ siRNA or not and stimulated with MSU crystals was assessed using quantitative a real time-polymerase chain reaction and Western blotting. The expression of those markers in THP-1 cells pretreated with statins (atorvastatin, simvastatin, and mevastatin) was also evaluated. Intracellular reactive oxygen species (ROS) were measured using H2DCF-DA and flow cytometry analyses. THP-1 cells treated with MSU crystals (0.3 mg/mL) inhibited PARR-γ and increased NLRP3, caspase-1, and IL-1ß mRNA and protein expression, and all those changes were significantly reversed by treatment with atorvastatin, simvastatin, or mevastatin. PPAR-γ activity revealed that MSU crystals suppressed PPAR-γ activity, which was markedly augmented by atorvastatin, simvastatin, and mevastatin. Transfecting cells with PPAR-γ siRNA attenuated the inhibitory effect of statins on MSU crystal-mediated NLRP3 inflammasome activation. Statins also significantly reduced the intracellular ROS generation caused by stimulation with MSU crystals. The inhibitory effects of atorvastatin and simvastatin on intracellular ROS generation were reduced in THP-1 cells transfected with PPAR-γ siRNA. This study demonstrates that PPAR-γ is responsible for suppressing MSU-mediated NLRP3 inflammasome activation. The inhibitory effect of statins on MSU-induced NLRP3 inflammasome activation depends on PPAR-γ activity and production and the inhibition of ROS generation.

Histone Deacetylase 6 Inhibitor CKD-WID Suppressed Monosodium Urate-Induced Osteoclast Formation by Blocking Calcineurin-NFAT Pathway in RAW 264.7 Cells.

Histone deacetylase (HDAC) has been found to play a crucial role in the regulation of osteoclast differentiation and formation. This study was designed to identify the effect of the HDAC6 inhibitor CKD-WID on the receptor for the activation of nuclear factor-κB ligand (RANKL)-mediated osteoclast formation in the presence of monosodium urate (MSU) in RAW 264.7 murine macrophage cells. The expression of osteoclast-specific target genes, calcineurin, and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) was evaluated in RAW 264.7 murine macrophages treated with MSU, RANKL, or CKD-WID by real-time quantitative polymerase chain reaction and Western blot assay. The effect of CKD-WID on osteoclast formation was measured by tartrate-resistant acid phosphatase (TRAP) staining, F-actin ring formation staining, and assays for bone resorption activity. RANKL in the presence of MSU significantly induced HDAC6 gene and protein expression in RAW 264.7 cells. CKD-WID markedly suppressed the expression of osteoclast-related markers such as c-Fos, TRAP, cathepsin K, and carbonic anhydrase II induced by co-stimulation with RANKL and MSU in RAW 264.7 cells. Transcription factor NFATc1 mRNA expression and nuclear NFATc1 protein expression induced by co-stimulation with RANKL and MSU were significantly inhibited by CKD-WID treatment. CKD-WID also decreased the number of TRAP-positive multinuclear cells and F-actin ring-positive cells and attenuated bone resorption activity. Co-stimulation with RANKL and MSU increased calcineurin gene and protein expression, which was significantly blocked by CKD-WID treatment. The HDAC6 inhibitor CKD-WID suppressed MSU-induced osteoclast formation through blocking the calcineurin-NFAT pathway in RAW 264.7 cells. This suggests that HDAC6 is considered a therapeutic target in uric acid-mediated osteoclastogenesis.

CXCL12 and CXCR4 as Novel Biomarkers in Uric Acid-Induced Inflammation and Patients with Gouty Arthritis.

The aim of this study was to evaluate the expression of chemokine receptor CXCR4 and its ligand CXCL12 in patients with gout and uric acid-induced inflammation. A total of 40 patients with intercritical gout and 27 controls were consecutively enrolled. The serum levels of interleukin-1ß (IL-1ß), IL-18, CXCL12, and CXCR4 were assessed using an enzyme-linked immunosorbent assay. The gene and protein expressions for these target molecules were measured in human U937 cells incubated with monosodium urate (MSU) crystals using a real-time reverse transcription polymerase chain reaction and Western blot analysis. Patients with intercritical gout showed higher serum IL-1ß, IL-18, and CXCL12 levels, but not the serum CXCR4 level, than in the controls.The serum CXCR4 level in gout patients was associated with the serum IL-18 level, uric acid level, and uric acid/creatinine ratio (r = 0.331, p = 0.037; r = 0.346, p = 0.028; and r = 0.361, p = 0.022, respectively). U937 cells treated with MSU crystals significantly induced the CXCL12 and CXCR4 mRNA and protein expression in addition to IL-1ß and IL-18. In cells transfected with IL-1ß siRNA or IL-18 siRNA, the CXCL12 and CXCR4 expression was downregulated compared with the non-transfected cells in MSU crystal-induced inflammation. In this study, we revealed that CXCL12 and CXCR4 were involved in the pathogenesis of uric acid-induced inflammation and gouty arthritis.

A non-interventional, post-marketing surveillance study evaluating the safety and effectiveness of biosimilar rituximab (CT-P10) during routine clinical practice in the Republic of Korea.

BACKGROUND: CT-P10 was the first licensed rituximab biosimilar. This Korean post-marketing surveillance study evaluated CT-P10 safety and effectiveness in approved indications. RESEARCH DESIGN AND METHODS: This prospective, open-label, observational, phase 4 study collected routine clinical practice data across 27 centers in the Republic of Korea. Patients received their first CT-P10 treatment, per prescribing information, for non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA), or microscopic polyangiitis (MPA) during the surveillance period (16 November 2016-15 November 2020). Safety (including adverse events [AEs] and adverse drug reactions [ADRs]) and disease-specific clinical response (by best overall response [NHL/CLL], Disease Activity Score in 28-joints [RA], or Birmingham Vasculitis Activity Score for Wegener's Granulomatosis [GPA/MPA]) were assessed for ≤1 year (NHL/CLL) or ≤24 weeks (RA/GPA/MPA). RESULTS: The safety population comprised 677 patients (604 NHL, 16 CLL, 42 RA, 7 GPA, 8 MPA). AEs/ADRs were reported for 68.4%/27.7% (NHL/CLL), 31.0%/14.3% (RA), and 86.7%/13.3% (GPA/MPA) of patients. Serious AEs and unexpected ADRs did not raise new safety signals. Pneumonia was the most frequent serious ADR overall. Positive effectiveness outcomes were observed. CONCLUSIONS: Findings were consistent with the known CT-P10/reference rituximab safety profile, with high effectiveness observed in NHL/CLL and RA.

Association between Novel Hematological Indices and Measures of Disease Activity in Patients with Rheumatoid Arthritis.

Background and Objectives: Hematological indices have been known to be available markers used for evaluating disease activity in rheumatoid arthritis (RA). This study serves to verify the association between four different hematological indices and disease activity measures in patients with RA. Materials and Methods: The study included 257 female RA patients and 71 age-matched female controls. Four hematological indices, namely systemic immune-inflammation index (SII), neutrophil-to-hemoglobin and lymphocyte (NHL) score, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR), were evaluated. Composite measures of RA included Disease Activity Score 28 joints (DAS28), the simplified disease activity index (SDAI), and the clinical disease activity index (CDAI). Results: Patients with RA showed statistically higher SII, NHL score, NLR, and PLR compared with controls. SII and NHL score were significantly associated with DAS28 erythrocyte sedimentation rate (DAS28-ESR), DAS28 C-reactive protein (DAS28-CRP), CDAI, and SDAI, whereas NLR was related to DAS28-CRP, CDAI, and SDAI. SII, NHL score, and NLR tended to increase as disease activity based on DAS28-ESR, DAS28-CRP, and CDAI worsened. In the analysis using receiver operating characteristic curve of hematological indices for diagnostic accuracy, the area under the curve was 0.703 (95% confidence interval, CI 0.637−0.769, p < 0.001) for SII and 0.705 (95% CI 0.639−0.770, p < 0.001) for NHL score, which showed acceptable potential for the diagnosis of RA. Four hematological indices showed weak potential for the detection of remission. Conclusions: The present study results showed that SII and NHL scores might be useful markers that adequately reflect disease activity and lead to more accurate diagnosis in RA.

Lung function trajectory of rheumatoid arthritis-associated interstitial lung disease.

OBJECTIVES: To explore the course of lung function and RA disease activity and predictive factors for deteriorating lung function in patients with RA-interstitial lung disease (ILD). METHODS: The Korean Rheumatoid Arthritis-Interstitial Lung Disease cohort is a multicentre, prospective observational cohort. Patients with RA-ILD were enrolled and followed up annually for 3 years for RA disease activity and ILD status assessment. Group-based modelling was used to cluster a similar predicted percentage of forced vital capacity (FVC%) patterns into trajectories. RESULTS: This study included 140 patients who underwent at least two pulmonary function tests. Four distinctive trajectories for predicted FVC% were 'improving' [n = 11 (7.9%)], 'stable' [n = 68 (38.4%)], 'slowly declining' [n = 54 (48.6%)] and 'rapidly declining' [n = 7 (5.0%)]. Most (77.7%) patients maintained or improved to low RA disease activity. The lung function trajectory was not comparable to the RA disease activity trajectory. Age ≥70 years [relative risk (RR) 10.8 (95% CI 1.30, 89.71)] and early RA diagnosed within the preceding 2 years [RR 10.1 (95% CI 1.22, 84.2)] were associated with increased risk for rapidly declining predicted FVC%. The risk for deterioration or mortality increased in patients with a simultaneous diagnosis of RA and ILD within 24 weeks [RR 9.18 (95% CI 2.05, 41.0)] and the extent of lung involvement [RR 3.28 (95% CI 1.12, 9.60)]. CONCLUSION: Most patients with RA-ILD experienced stable or slowly declining lung function. In 5% of patients, predicted FVC% deteriorated rapidly, especially in older adults with early RA. The lung function trajectory was not comparable to the RA disease activity trajectory.

Methotrexate, leflunomide and tacrolimus use and the progression of rheumatoid arthritis-associated interstitial lung disease.

OBJECTIVE: To examine the association between MTX, LEF and tacrolimus use and the progression of RA-associated interstitial lung disease (ILD). METHODS: The Korean RA-ILD cohort prospectively enrolled patients with RA-associated ILD at multiple centres from 2015 to 2018 and followed up with them for 3 years. ILD progression was defined by any of the followings: a decrease of ≥10% in forced vital capacity, a decrease of ≥15% in the diffusing capacity of the lung for carbon monoxide, or death from respiratory failure. RESULTS: Of 143 patients, 64 patients experienced ILD progression during a median follow-up period of 33 months. The use of MTX [adjusted hazard ratio (aHR), 1.06; 95% CI, 0.59, 1.89], LEF (aHR, 1.75; 95% CI, 0.88, 3.46) and tacrolimus (aHR, 0.94; 95% CI, 0.52, 1.72) did not increase the risk of ILD progression. However, the association between LEF use and the risk of ILD progression was significant in subgroups with poor lung function (aHR, 8.42; 95% CI, 2.61, 27.15). Older age, male sex, a shorter RA duration, higher RA disease activity and extensive disease at baseline were independently associated with ILD progression. CONCLUSION: None of the three treatments increased the risk of RA-associated ILD progression, except for LEF, which increased the risk of ILD progression in patients with severe ILD. The appropriate use of conventional synthetic disease-modifying antirheumatic drugs considering RA disease activity and ILD severity would be important for the management of RA-associated ILD.

Safety and Effectiveness of Etanercept Biosimilar SB4 for Rheumatic Diseases in South Korea: Real-World Post-marketing Surveillance Data.

INTRODUCTION: SB4 is the first approved biosimilar of etanercept, a biologic tumor necrosis factor inhibitor, to treat various autoimmune diseases including axial spondylarthritis (axSpA), rheumatoid arthritis (RA), psoriatic arthritis (PsA), and plaque psoriasis (PsO). This post-marketing surveillance (PMS) study of SB4 investigated safety and effectiveness in routine clinical practice and is part of the drug approval process in Korea. METHODS: This prospective, multi-center, open-label, observational, phase IV PMS study was designed to enroll patients with axSpA, RA, PsA, and PsO in Korea from September 2015 to September 2019. Both etanercept-naïve patients or patients switched from reference etanercept were included. SB4 was administered weekly via subcutaneous injections using pre-filled syringes. Safety was assessed by the incidence of adverse events (AEs), adverse drug reactions (ADRs) and serious adverse events (SAE). Effectiveness was assessed by the change from baseline of investigator-rated Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in patients with ankylosing spondylitis (AS) and disease activity score-28 (DAS28) in patients with RA. RESULTS: Among 316 enrolled patients, 314 were included in the safety analysis (176 with AS and 138 with RA). The overall incidence of AEs, ADRs and serious AEs were 17.8, 9.9, and 1.3%, respectively. Most AEs were mild (66.7%) or moderate (31.1%) and not related to SB4 (58.9%). Most common AEs were injection site pruritus (1.9%) and injection site rash (1.3%). At week 24, mean disease activity scores significantly decreased compared to baseline in naïve patients with AS and RA (BASDAI 2.7 vs. 6.2, p < 0.0001; DAS28 3.8 vs. 5.7, p < 0.0001) and in switched patients with AS and RA (BASDAI 1.0 vs. 1.3, p = 0.0018; DAS28 2.4 vs. 2.9, p = 0.0893). CONCLUSION: This first real-world evidence of SB4 from a phase IV PMS study in Korea shows comparable effectiveness to historical SB4 real-world evidence without any new significant safety signals.

CpG Oligodeoxynucleotides Inhibit RANKL-Induced Osteoclast Formation by Upregulating A20 Deubiquitinase in RAW 264.7 Cells.

Objective: Activation of toll-like receptor 9 (TLR9) has been proposed to play an inhibitory role in RANKL-induced osteoclastogenesis. A20 deubiquitinase has been found to be related to bone loss. This study investigated the role of CpG oligodeoxynucleotides (CpG-ODNs) through regulation of A20 deubiquitinase in RANKL-induced osteoclast formation. Methods: RAW 264.7 cells, a murine monocyte-macrophage cell line, were incubated with or without CpG-ODN in the presence of RANKL. Osteoclast-specific genes and their related signaling molecules were measured by real-time quantitative polymerase chain reaction and Western blot assay. Morphological assessment for osteoclast formation was performed using tartrate-resistant acid phosphatase (TRAP) staining and F-actin ring formation staining. Results: RANKL-induced osteoclast-related genes and proteins, c-Fos, NFATc1, TRAP, cathepsin K, and carbonic anhydrase II were significantly inhibited in RAW 264.7 cells stimulated with CpG-ODN. CpG-ODN attenuated TNF receptor-associated factor 6 (TRAF6), p-IκBα, and p-NF-κB expression in RAW 264 cells mediated by RANKL. CpG-ODN increased A20 gene and proteins in time-dependent manner. A20 expression under costimulation with CpG-ODN and RANKL was more decreased than under stimulation with RANKL alone. Cells transfected with A20 siRNA augmented expression of osteoclast-related genes and proteins. Number of TRAP-positive cells transfected with A20 siRNA was higher than those transfected with NC siRNA. A20 expression in cells transfected with IL-1ß siRNA in the presence of both RANKL and CpG-ODN was more decreased than those with NC siRNA. Conclusion: This study showed that CpG-ODN suppressed RANKL-induced osteoclast formation through regulation of the A20-TRAF6 axis in RAW 264.7 cells.

Impact of a pharmaceutical care service for patients with rheumatoid arthritis using a customised mobile device (the PROUD trial): study protocol for a randomised controlled trial.

INTRODUCTION: Rheumatoid arthritis (RA) generally requires lifelong treatment; however, its medication complexity might affect non-adherence. Pharmacist-led telehealth services were as effective as face-to-face services and reduced potential side effects in outpatients with chronic diseases. This study aims to analyse the effect of a telepharmacy service with a customised mobile device in comparison with the usual pharmacist service on the humanistic and clinical outcomes in patients with RA. METHODS AND ANALYSIS: The study is designed as a prospective, randomised, open-label, and controlled trial to compare the humanistic and clinical outcomes of the pharmaceutical care service with monthly telecommunications and a customised mobile application (telepharmacy care group) against the usual service by community pharmacists (usual care group) in 256 patients with RA and prescribed at least one of the disease-modifying antirheumatic drugs. Participants will be recruited from a tertiary hospital in Republic of Korea with written informed consent. The primary outcome will be the changes in health-related quality of life as measured by the Korean version of the EuroQoL's five-dimensional questionnaire at 6 months compared with baseline. The secondary outcomes will be the changes in the following: scores of the Korean version of the Compliance Questionnaire-Rheumatology and medication knowledge at 3 and 6 months compared with baseline; scores of the Korean version of the Pharmacy Service Questionnaire at 6 months compared with baseline; clinical parameters such as erythrocyte sedimentation rate, C reactive protein level, and pain score at 3 and 6 months compared with baseline; frequency of acute care utilisation over 6 months. Analysis will be carried out with intent-to-treat and per-protocol principles. ETHICS AND DISSEMINATION: The study protocol was reviewed and approved by the Institutional Review Board (IRB) of Daegu Catholic University Medical Center (IRB no. CR-21-082-L, 14 July 2021). The study findings will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: KCT0006508.

Biological insights into systemic lupus erythematosus through an immune cell-specific transcriptome-wide association study.

OBJECTIVE: Genome-wide association studies (GWAS) have identified >100 risk loci for systemic lupus erythematosus (SLE), but the disease genes at most loci remain unclear, hampering translation of these genetic discoveries. We aimed to prioritise genes underlying the 110 SLE loci that were identified in the latest East Asian GWAS meta-analysis. METHODS: We built gene expression predictive models in blood B cells, CD4+ and CD8+ T cells, monocytes, natural killer cells and peripheral blood cells of 105 Japanese individuals. We performed a transcriptome-wide association study (TWAS) using data from the latest genome-wide association meta-analysis of 208 370 East Asians and searched for candidate genes using TWAS and three data-driven computational approaches. RESULTS: TWAS identified 171 genes for SLE (p<1.0×10-5); 114 (66.7%) showed significance only in a single cell type; 127 (74.3%) were in SLE GWAS loci. TWAS identified a strong association between CD83 and SLE (p<7.7×10-8). Meta-analysis of genetic associations in the existing 208 370 East Asian and additional 1498 cases and 3330 controls found a novel single-variant association at rs72836542 (OR=1.11, p=4.5×10-9) around CD83. For the 110 SLE loci, we identified 276 gene candidates, including 104 genes at recently-identified SLE novel loci. We demonstrated in vitro that putative causal variant rs61759532 exhibited an allele-specific regulatory effect on ACAP1, and that presence of the SLE risk allele decreased ACAP1 expression. CONCLUSIONS: Cell-level TWAS in six types of immune cells complemented SLE gene discovery and guided the identification of novel genetic associations. The gene findings shed biological insights into SLE genetic associations.

Decline of Lung Function in Knee and Spine Osteoarthritis in the Korean Population: Cross-Sectional Analysis of Data from the Korea National Health and Nutrition Examination Survey.

Background: Evidence on the close association between osteoarthritis (OA) and lung diseases is supported by the shared pathogenesis of the two diseases. We assessed the association between knee and spine OA and chronic obstructive pulmonary disease (COPD) in the Korean population. Methods: Using data from the Korea National Health and Nutrition Examination Survey (KNHANES) 2012, a total of 2006 subjects who underwent both plain radiography for assessment of knee and lumbar spine and spirometry analysis for lung function were analyzed. Radiographic severity grade for OA was assessed using the Kellgren−Lawrence (K-L) grading scale. COPD was defined as a ratio of forced expiratory volume in one second (FEV1) to forced vital capacity (FVC) less than 0.7. Results: Subjects with spine OA had higher prevalence of COPD than controls (p < 0.001), but not knee OA (p = 0.990). FVC (L), FEV1 (L), and FVC/FEV1 (%) were significantly decreased in spine OA compared to in controls (p = 0.003, p < 0.001, and p < 0.001, respectively). FVC (L), FVC (%), FEV1 (L), and FEV1 (%) were significantly different between knee OA and controls. Univariate regression analysis showed that spine OA was significantly associated with COPD (OR 1.581, 95% CI 1.204−2.076, p = 0.001), but not knee OA. Multivariate analysis revealed that spine OA lost statistical significance for COPD. Conclusion: This study found that subjects with knee OA and spine OA had a decline of lung function compared to subjects without OA, although OA was not associated with COPD.

Association between Hematological Indicesand Disease Activity in Patients with Rheumatoid Arthritis Treated with Janus Kinase Inhibitors for 24 Weeks.

Background and Objective: Hematological indices have been considered reliable markers for assessment of disease activity in rheumatoid arthritis (RA). This study assessed whether hematological indices reflect changes in disease activity in patients with RA treated with Janus kinase (JAK) inhibitors. Materials and Methods: This study recruited 123 patients with RA who completed a regimen of JAK inhibitors, including baricitinib or tofacitinib, for 24 weeks, and 80 age- and sex-matched healthy control subjects. Hematological indices were systemic immune-inflammation index (SII), neutrophil-to-hemoglobin and lymphocyte (NHL) score, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR). Disease Activity Score 28 joints using erythrocyte sedimentation rate (DAS28-ESR) was evaluated as a measure of RA disease activity. Results: At baseline, patients with RA had a significantly higher SII, NHL score, NLR, and PLR than controls (p < 0.001 for all). SII, NHL score, NLR, and PLR at baseline were associated with DAS28-ESR (p < 0.05 for all). Changes in SII, NHL score, NLR, and PLR were associated with those in DAS28-ESR during treatment with JAK inhibitors. Such treatment markedly decreased SII, NHL score, and NLR values compared to those at baseline (p < 0.001 for all) but did not decrease PLR (p = 0.056). There were no differences in changes in SII, NHL score, NLR, and PLR between baricitinib and tofacitinib treatments. No hematological index showed predictive potential with respect to non-response to JAK inhibitor treatment. Conclusions: This study showed that hematological indices might be useful in monitoring changes in disease activity in patients with RA treated with JAK inhibitors.

Comorbidities and Health-Related Quality of Life in Subjects with Spine Osteoarthritis at 50 Years of Age or Older: Data from the Korea National Health and Nutrition Examination Survey.

Background and Objective: This study assessed comorbidities and health-related quality of life (HRQOL) in subjects with lumbar spine osteoarthritis (OA) in the Korean population. Materials and Methods: We analyzed 3256 subjects who were 50 years or older and underwent plain radiography of the lumbar spine as part of the Korea National Health and Nutrition Examination Survey (KNHANES) 2012. Radiographic assessment was based on Kellgren-Lawrence (K-L) grade ranging from 0 to 2, with K-L grade 2 defined as lumbar spine OA. HRQOL was assessed by EuroQol-5 dimensions (EQ-5D), which include the EQ-5D index and visual analogue scale (EQ-VAS) measurements. Results: Comorbidities such as hypertension, myocardial infarction, angina, cerebral infarction, and diabetes mellitus were more frequent in spine OA than in controls, while dyslipidemia was less common. Subjects with spine OA had higher mean number of comorbid conditions than controls (1.40 (SE 0.05) vs. 1.20 (SE 0.03), p = 0.001). Subjects with spine OA had much lower EQ-5D index than controls (p < 0.001) but not lower EQ-VAS score. Multivariate binary logistic analysis showed that hypertension and colon cancer were associated with spine OA compared to controls (OR 1.219, 95% CI 1.020-1.456, p = 0.030 and OR 0.200, 95% CI 0.079-0.505, p = 0.001, respectively) after adjustment for confounding factors. Lower EQ-5D index was related to spine OA (95% CI 0.256, 95% CI 0.110-0.595, p = 0.002) but not EQ-VAS score. Conclusion: In this study, we found that comorbidities such as hypertension and colon cancer as well as lower HRQOL were associated with spine OA.