5-aminosalicylic acid suppresses osteoarthritis through the OSCAR-PPARγ axis.

Osteoarthritis (OA) is a progressive and irreversible degenerative joint disease that is characterized by cartilage destruction, osteophyte formation, subchondral bone remodeling, and synovitis. Despite affecting millions of patients, effective and safe disease-modifying osteoarthritis drugs are lacking. Here we reveal an unexpected role for the small molecule 5-aminosalicylic acid (5-ASA), which is used as an anti-inflammatory drug in ulcerative colitis. We show that 5-ASA competes with extracellular-matrix collagen-II to bind to osteoclast-associated receptor (OSCAR) on chondrocytes. Intra-articular 5-ASA injections ameliorate OA generated by surgery-induced medial-meniscus destabilization in male mice. Significantly, this effect is also observed when 5-ASA was administered well after OA onset. Moreover, mice with DMM-induced OA that are treated with 5-ASA at weeks 8-11 and sacrificed at week 12 have thicker cartilage than untreated mice that were sacrificed at week 8. Mechanistically, 5-ASA reverses OSCAR-mediated transcriptional repression of PPARγ in articular chondrocytes, thereby suppressing COX-2-related inflammation. It also improves chondrogenesis, strongly downregulates ECM catabolism, and promotes ECM anabolism. Our results suggest that 5-ASA could serve as a DMOAD.

Comparative risk of incident and recurrent acute anterior uveitis across different biological agents in patients with ankylosing spondylitis.

OBJECTIVE: To evaluate the comparative risk of incident and recurrent acute anterior uveitis (AAU) across different biological disease-modifying anti-rheumatic drugs (bDMARDs) in patients with ankylosing spondylitis (AS). METHODS: A retrospective nationwide cohort study was conducted on 34 621 patients with AS without a previous history of AAU using a national claims database. Patients were followed-up from 2010 to 2021. The comparative risk of incident and recurrent AAU across different bDMARDs was examined using multivariable time-dependent Cox models and counting process (AG) models, respectively. RESULTS: The adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for incident AAU (bDMARDs non-exposure as reference) were: adalimumab 0.674 (0.581-0.891), etanercept 1.760 (1.540-2.012), golimumab 0.771 (0.620-0.959), infliximab 0.891 (0.741-1.071), and secukinumab 1.324 (0.794-2.209). Compared with adalimumab exposure, etanercept (aHR = 2.553 [2.114-3.083]), infliximab (aHR = 1.303 [1.039-1.634]), and secukinumab exposures (aHR = 2.173 [1.273-3.710]) showed a higher risk of incident AAU. The aHRs and 95% CIs for recurrent AAU (bDMARDs non-exposure as reference) were: adalimumab 0.798 (0.659-0.968), etanercept 1.416 (1.185-1.693), golimumab 0.874 (0.645-1.185), infliximab 0.926 (0.729-1.177), and secukinumab 1.257 (0.670-2.359). Compared with adalimumab exposure, etanercept exposure (aHR = 1.793 [1.403-2.292]) was associated with a higher risk of recurrent AAU. CONCLUSION: Our data suggest preference for bDMARDs in the following order: adalimumab/golimumab > infliximab > secukinumab > etanercept (for incident AAU prevention) and adalimumab > golimumab/infliximab/secukinumab > etanercept (for recurrent AAU prevention).

Drug survival and change of disease activity using a second janus kinase inhibitor in patients with difficult-to-treat rheumatoid arthritis who failed to a janus kinase inhibitor and subsequent biologics

Abstract Background To assess the drug survival and change of disease activity using a second Janus kinase inhibitor (JAKi) after failure to a JAKi and subsequent biologic disease-modifying anti-rheumatic drugs (bDMARDs) in patients with difficult-to-treat rheumatoid arthritis (RA). Methods This retrospective cohort study included 32 patients with difficult-to-treat RA who failed to a JAKi and subsequently to one or more bDMARDs and then switched to a second JAKi. To assess drug survival, electronic medical records of each patient were reviewed. Data on whether the second JAKi was discontinued, and the reasons for discontinuation were collected. The change of disease activity was assessed by analyzing changes in tender joint count (TJC), swollen joint count (SJC), patient's global assessment of disease activity on a visual-analogue scale (VAS), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Disease Activity Score for 28 joints with ESR (DAS28-ESR), and DAS28-CRP from baseline to that at six months from initiation of the second JAKi. Results Overall, discontinuation of the second JAKi occurred in 20 (62.5%) patients. Primary failure, secondary failure, adverse events, and insurance coverage issues were the reasons for discontinuation in 9 (45.0%), 5 (25.0%), 2 (10.0%), and 4 (20.0%) patients, respectively. The estimated 2-year drug survival rate was 39.3%. In terms of change of disease activity, the second JAKi significantly improved TJC (p < 0.001), SJC (p < 0.001), VAS (p < 0.001), CRP (p = 0.026), DAS28-ESR (p < 0.001), and DAS28-CRP (p < 0.001) at 6-month compared with that at the baseline. Conclusions Second JAKi could be a therapeutic option in patients with difficult-to-treat RA who have failed to a JAKi and subsequent bDMARDs.

Higher gamma-glutamyl transferase levels are associated with an increased risk of incident systemic sclerosis: a nationwide population-based study.

Gamma-glutamyl transferase (GGT) is known to promote oxidative stress. As oxidative stress is a key component in the pathogenesis of systemic sclerosis (SSc), we investigated whether GGT levels are associated with the risk of incident SSc. A cohort of individuals without SSc who underwent national health examination in 2009 were extracted from the Korean National Health Insurance Service database. The incidence rate of SSc during the observation period, between 2009 and 2019, was estimated. GGT levels measured in 2009 were categorized into quartiles (Q1 [lowest], Q2, Q3, and Q4 [highest]). Multivariable Cox proportional hazard models were used to estimate the risk of incident SSc according to the quartiles of GGT, using Q1 as the reference. A total of 6,091,788 individuals were included. Incidence rate of SSc was 1.16 per 100,000 person-years over a mean observation period of 9.2 years. After adjusting for age, sex, body mass index, economic income, smoking status, alcohol consumption, physical activity, hypertension, type 2 diabetes, dyslipidemia, and chronic kidney disease, higher quartiles of GGT levels were significantly associated with a higher risk of incident SSc (Q4: adjusted hazard ratio [aHR] 1.807, 95% confidence interval CI 1.446-2.259; Q3: aHR 1.221, 95% CI 0.971-1.536; and Q2: aHR 1.034, 95% CI 0.807-1.324; p for trend < 0.001). Higher GGT levels were associated with a higher risk of incident SSc. These findings could lead to a closer monitoring for high risk individuals and an earlier diagnosis and treatment.

Drug Retention Rate and Factors Associated with Discontinuation of Interleukin-17 Inhibitors in Patients with Axial Spondyloarthritis.

PURPOSE: To assess the drug retention rate of interleukin-17 inhibitors (IL-17is) over long-term observation in patients with axial spondyloarthritis (axSpA) in whom treatment with tumor necrosis factor inhibitors (TNFis) failed and to determine baseline factors associated with discontinuation of IL-17is. MATERIALS AND METHODS: This retrospective cohort study included 68 patients with axSpA started on IL-17is after an inadequate response or intolerance to ≥1 TNFis. Drug retention rates at 1, 2, and 3 years were assessed. Baseline (i.e., at initiation of IL-17is) factors associated with discontinuation of IL-17is were evaluated using multivariable Cox proportional hazard regression analysis. RESULTS: Over 1933.9 person-months of observation in 68 patients, discontinuation of IL-17is occurred in 27 (39.7%) patients. Twenty (29.4%) patients discontinued IL-17is because of ineffectiveness, and 7 (10.3%) patients discontinued IL-17is because of adverse events. The 1-year, 2-year, and 3-year drug retention rates for IL-17is were 71.9%, 66.5%, and 62.0%, respectively. Current smoking was associated with a higher risk of IL-17is discontinuation [adjusted hazard ratio (HR)=2.256, 95% confidence interval (CI)=1.053-4.831, p=0.036], while previous use of ≥3 TNFis (vs. 1) was significantly associated with a lower risk of IL-17is discontinuation (adjusted HR=0.223, 95% CI=0.051-0.969, p=0.045). CONCLUSION: In patients with axSpA in whom TNFis failed, the long-term drug retention rate of IL-17is appears to be acceptable, with a 3-year drug retention rate of approximately 60%. Current smoking was associated with a higher risk of discontinuing IL-17is, whereas previous use of ≥3 TNFis was associated with a lower risk of discontinuing IL-17is.

Korean treatment recommendations for patients with axial spondyloarthritis.

We aimed to develop evidence-based recommendations for treating axial spondylarthritis (axSpA) in Korea. The development committee was constructed, key clinical questions were determined, and the evidence was searched through online databases including MEDLINE, Embase, Cochrane, KoreaMed, and KMbase. Systematic literature reviews were conducted, quality of evidence was determined, and draft recommendations were formulated according to the Grading of Recommendations Assessment, Development, and Evaluations methodology. Recommendations that reached 80% consensus among a voting panel were finalized. Three principles and 21 recommendations were determined. Recommendations 1 and 2 pertain to treatment strategies, regular disease status assessment, and rheumatologist-steered multidisciplinary management. Recommendations 3 and 4 strongly recommend patient education, exercise, and smoking cessation. Recommendations 5~12 address pharmacological treatment of active disease using nonsteroidal anti-inflammatory drugs, glucocorticoids, sulfasalazine, biologics, and Janus kinase inhibitors. Recommendations 13~16 address treatment in stable disease. We suggest against spa and acupuncture as therapies (Recommendation 17). Recommendations 18 and 19 pertain to total hip arthroplasty and spinal surgery. Monitoring of comorbidities and drug toxicities are recommended (Recommendations 20 and 21). Recommendations for axSpA treatment in a Korean context were developed based on comprehensive clinical questions and evidence. These are intended to guide best practice in the treatment of axSpA.

Korean treatment recommendations for patients with axial spondyloarthritis.

We aimed to develop evidence-based recommendations for treating axial spondylarthritis (axSpA) in Korea. The development committee was constructed, key clinical questions were determined, and the evidence was searched through online databases including MEDLINE, Embase, Cochrane, KoreaMed, and Kmbase. Systematic literature reviews were conducted, quality of evidence was determined, and draft recommendations were formulated according to the Grading of Recommendations Assessment, Development, and Evaluations methodology. Recommendations that reached 80% consensus among a voting panel were finalized. Three principles and 21 recommendations were determined. Recommendations 1 and 2 pertain to treatment strategies, regular disease status assessment, and rheumatologist-steered multidisciplinary management. Recommendations 3 and 4 strongly recommend patient education, exercise, and smoking cessation. Recommendations 5-12 address pharmacological treatment of active disease using nonsteroidal anti-inflammatory drugs, glucocorticoids, sulfasalazine, biologics, and Janus kinase inhibitors. Recommendations 13-16 address treatment in stable disease. We suggest against spa and acupuncture as therapies (Recommendation 17). Recommendations 18 and 19 pertain to total hip arthroplasty and spinal surgery. Monitoring of comorbidities and drug toxicities are recommended (Recommendations 20 and 21). Recommendations for axSpA treatment in a Korean context were developed based on comprehensive clinical questions and evidence. These are intended to guide best practice in the treatment of axSpA.

Risk of all-cause and cause-specific mortality associated with immune-mediated inflammatory diseases in Korea.

Objective: Immune-mediated inflammatory disease (IMID) is associated with an increased risk of mortality. It is unclear whether the higher mortality is attributable to the IMIDs themselves or to the higher prevalence of comorbidities in IMIDs. We aimed to investigate whether IMIDs per se confer a higher risk of mortality. Methods: From the Korean National Health Insurance Service-National Sample Cohort database, this population-based cohort study included 25,736 patients newly diagnosed with IMIDs between January 2007 and December 2017, and 128,680 individuals without IMIDs who were matched for age, sex, income, hypertension, type 2 diabetes, dyslipidemia, and the Charlson comorbidity index. All individuals were retrospectively observed through December 31, 2019. The outcomes included all-cause and cause-specific mortalities. Adjustments for age, sex, and comorbidities were performed using multivariable Cox proportional hazard regression analyses, and adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) for the outcomes were estimated. Results: The adjusted risk of all-cause mortality was significantly lower in patients with IMIDs than that in those without (aHR, 0.890; 95% CI, 0.841-0.942). Regarding cause-specific mortality, cancer-specific (aHR, 0.788; 95% CI, 0.712-0.872) and cardiovascular disease-specific (aHR, 0.798; 95% CI, 0.701-0.908) mortalities were the two causes of death that showed significantly lower risks in patients with IMIDs. A similar trend was observed when organ based IMIDs were analyzed separately (i.e., gut, joint, and skin IMIDs). Conclusion: After adjusting for comorbidities, IMIDs were associated with a lower risk of all-cause mortality compared to those without IMIDs. This was attributable to the lower risks of cancer-and cardiovascular disease-specific mortalities.

Comparative effectiveness of JAK inhibitors and biologic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis.

BACKGROUND/AIMS: We aimed to compare the effectiveness and safety of Janus kinase inhibitors (JAKi) vs. biologic disease- modifying antirheumatic drugs (bDMARD) in Korean patients with rheumatoid arthritis (RA) who had an inadequate response to conventional synthetic DMARDs. METHODS: A quasi-experimental, multi-center, prospective, non-randomized study was conducted to compare response rates between JAKi and bDMARDs in patients with RA naïve to targeted therapy. An interim analysis was performed to estimate the proportion of patients achieving low disease activity (LDA) based on disease activity score (DAS)-28- erythroid sedimentation rate (ESR) (DAS28-ESR) at 24 weeks after treatment initiation and to evaluate the development of adverse events (AEs). RESULTS: Among 506 patients enrolled from 17 institutions between April 2020 and August 2022, 346 (196 JAKi group and 150 bDMARD group) were included in the analysis. After 24 weeks of treatment, 49.0% of JAKi users and 48.7% of bDMARD users achieved LDA (p = 0.954). DAS28-ESR remission rates were also comparable between JAKi and bDMARD users (30.1% and 31.3%, respectively; p = 0.806). The frequency of AEs reported in the JAKi group was numerically higher than that in the bDMARDs group, but the frequencies of serious and severe AEs were comparable between the groups. CONCLUSION: Our interim findings reveal JAKi have comparable effectiveness and safety to bDMARDs at 24 weeks after treatment initiation.

Disease course of non-radiographic axial spondyloarthritis: Data from a long-term retrospective observational cohort.

BACKGROUND: Disease course of non-radiographic axial spondyloarthritis (axSpA) has been extensively studied in non-Asian population; however, there are limited data in Asian population. This study aimed to evaluate the long-term disease course of non-radiographic axSpA in Asian patients and identify factors associated with progression to radiographic axSpA. METHODS: In this retrospective observational cohort study, 56 Korean patients newly diagnosed with non-radiographic axSpA between 2006 and 2015 were included. All patients fulfilled the Assessment of SpondyloArthritis international Society classification criteria for axSpA, and did not fulfil the radiological criterion of the 1984 modified New York criteria. Disease course was assessed by the rate of progression to radiographic axSpA. Factors associated with the risk of progression to radiographic axSpA were assessed using multivariable Cox proportional hazard regression analysis. RESULTS: The mean age at baseline was 31.4±13.3 years, and 37 (66.1%) patients were men. Over a mean observation period of 8.4±3.7 years, 28 (50.0%) patients progressed to radiographic axSpA. In multivariable Cox proportional hazard regression analysis, the presence of syndesmophytes at diagnosis (adjusted hazard ratio [HR]: 4.50, 95% confidence interval [CI]: 1.54-13.15, p = 0.006) and active sacroiliitis on magnetic resonance imaging (MRI) at diagnosis (adjusted HR: 5.88, 95% CI: 2.05-16.82, p = 0.001) were significantly associated with a higher risk of progression to radiographic axSpA, whereas longer exposure to tumor necrosis factor inhibitors (TNFis) was significantly associated with a lower risk of progression to radiographic axSpA (adjusted HR: 0.89, 95% CI: 0.80-0.98, p = 0.022). CONCLUSION: During long-term follow-up, a substantial proportion of Asian patients with non-radiographic axSpA progressed to radiographic axSpA. The presence of syndesmophytes and active sacroiliitis on MRI at the time of non-radiographic axSpA diagnosis were associated with a higher risk of progression to radiographic axSpA, while longer exposure to TNFis was associated with a lower risk of progression to radiographic axSpA.

Interleukin-32 as a biomarker in rheumatic diseases: A narrative review.

Interleukin-32 (IL-32) is an important cytokine involved in the innate and adaptive immune responses. The role of IL-32 has been studied in the context of various diseases. A growing body of research has investigated the role of IL-32 in rheumatic diseases including inflammatory arthritides (rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis) and connective tissue diseases (systemic lupus erythematosus, systemic sclerosis, granulomatosis and polyangiitis, and giant cell arteritis). IL-32 has been shown to play different roles according to the type of rheumatic diseases. Hence, the putative role of IL-32 as a biomarker is also different in each rheumatic disease: IL-32 could serve as a biomarker for disease activity in some diseases, whereas in other diseases it could be a biomarker for certain disease manifestations. In this narrative review, we summarize the associations between IL-32 and various rheumatic diseases and discuss the putative role of IL-32 as a biomarker in each disease.

Effects of immune-mediated inflammatory diseases on cardiovascular diseases in patients with type 2 diabetes: a nationwide population-based study.

Both type 2 diabetes and immune-mediated inflammatory diseases (IMIDs), such as Crohn's disease (CD), ulcerative colitis, rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriasis (PsO) are risk factors of cardiovascular disease. Whether presence of IMIDs in patients with type 2 diabetes increases their cardiovascular risk remains unclear. We aimed to investigate the risk of cardiovascular morbidity and mortality in patients with type 2 diabetes and IMIDs. Patients with type 2 diabetes without cardiovascular disease were retrospectively enrolled from nationwide data provided by the Korean National Health Insurance Service. The primary outcome was cardiovascular mortality, and the secondary outcomes were myocardial infarction (MI), stroke, and all-cause mortality. Inverse probability of treatment weighting (IPTW)-adjusted Cox proportional hazard regression analysis was performed to estimate the hazard ratios (HRs) and 95% confidence intervals (95% CIs) for each IMID. Overall 2,263,853 patients with type 2 diabetes were analyzed. CD was associated with a significantly higher risk of stroke (IPTW-adjusted HR: 1.877 [95%CI 1.046, 3.367]). UC was associated with a significantly higher risk of MI (1.462 [1.051, 2.032]). RA was associated with a significantly higher risk of cardiovascular mortality (2.156 [1.769, 2.627]), MI (1.958 [1.683, 2.278]), stroke (1.605 [1.396, 1.845]), and all-cause mortality (2.013 [1.849, 2.192]). AS was associated with a significantly higher risk of MI (1.624 [1.164, 2.266]), stroke (2.266 [1.782, 2.882]), and all-cause mortality (1.344 [1.089, 1.658]). PsO was associated with a significantly higher risk of MI (1.146 [1.055, 1.246]), stroke (1.123 [1.046, 1.205]) and all-cause mortality (1.115 [1.062, 1.171]). In patients with type 2 diabetes, concomitant IMIDs increase the risk of cardiovascular morbidity and mortality. Vigilant surveillance for cardiovascular disease is needed in patients with type 2 diabetes and IMIDs.

Effect of tumor necrosis factor inhibitors on risk of cardiovascular disease in patients with axial spondyloarthritis.

BACKGROUND: Axial spondyloarthritis (axSpA) is associated with an increased risk of cardiovascular disease. We aimed to evaluate the effect of tumor necrosis factor inhibitors (TNFis) on the risk of cardiovascular disease in patients with axSpA. METHODS: This retrospective study included 450 patients with axSpA without pre-existing cardiovascular disease. The outcome was incident cardiovascular disease (myocardial infarction or stroke) after the diagnosis of axSpA. The effect of TNFis on cardiovascular risk was analyzed in the total study population and in an inverse probability of treatment weighting (IPTW)-adjusted population. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (95% CIs) for cardiovascular disease, according to exposure to TNFis. RESULTS: Of the 450 patients, 233 (51.8%) and 217 (48.2%) patients were and were not exposed to TNFis, respectively. Twenty cardiovascular diseases occurred during 2868 person-years of follow-up (incidence rate: 6.97/1000 person-years). In the total study population, exposure to TNFis was associated with a reduced cardiovascular risk when adjusted for traditional cardiovascular risk factors (HR 0.30, 95% CI 0.10-0.85, p = 0.024). However, when time-averaged erythrocyte sedimentation rate and C-reactive protein were additionally adjusted, this association was attenuated and lost statistical significance (HR 0.37, 95% CI 0.12-1.12, p = 0.077). Furthermore, in the IPTW-adjusted population, exposure to TNFis showed no significant reduction in cardiovascular risk (HR 0.60, 95% CI 0.23-1.54, p = 0.287). CONCLUSIONS: Although controlling inflammation through TNFis could be beneficial in cardiovascular risk reduction, our data indicate no TNFi-specific reduction in cardiovascular risk in patients with axSpA.

Factors affecting drug survival of an alternative TNF inhibitor and secukinumab in patients with ankylosing spondylitis switching from the first TNF inhibitor.

BACKGROUND: To investigate factors associated with drug survival of an alternative tumour necrosis factor inhibitor (TNFi) and secukinumab (SEC) after switching from the first TNFi in patients with ankylosing spondylitis (AS). METHODS: We included a total of 78 patients with AS who switched to an alternative TNFi (n = 56) or SEC (n = 22) from the first TNFi. Patient characteristics at the time of switching and drug discontinuation rate were compared between the two groups. Cox regression analyses were performed to evaluate factors associated with the risk of discontinuing the alternative TNFi and SEC. RESULTS: The proportion of patients with syndesmophytes was numerically lower (28.6% versus 45.5%, p = 0.155) and the C-reactive protein (CRP) level was numerically higher [3.8 (1.0-15.4) mg/L versus 1.1 (0.5-3.5) mg/L, p = 0.060] in patients who received an alternative TNFi. The drug discontinuation rate (alternative TNFi: 35.7% versus SEC: 36.4%, p = 0.957) and reasons for discontinuation were similar (primary failure, p = 0.342; secondary failure, p > 0.999; and adverse events, p = 0.670) between the two groups. A higher CRP level at switching was associated with a lower risk (adjusted HR = 0.93, 95% CI = 0.87-0.99, p = 0.022) of discontinuing the alternative TNFi, and primary failure of the first TNFi was associated with a higher risk [adjusted HR (HR) = 5.20, 95% confidence interval (CI) = 1.91-14.11, p = 0.001]. Current smokers (adjusted HR = 5.77, 95% CI = 1.20-27.74, p = 0.029) and the presence of syndesmophytes (adjusted HR = 7.49, 95% CI = 1.39-40.23, p = 0.019) were associated with a higher risk of discontinuing SEC. CONCLUSION: When switching the drug from the first TNFi in patients with AS, an alternative TNFi could be preferable in patients with higher CRP levels or syndesmophytes, or current smokers, whereas SEC could be a better choice in patients who presented primary failure of the first TNFi in terms of drug survival.

Tumour necrosis factor inhibitor tapering in patients with ankylosing spondylitis at low disease activity: factors associated with flare.

BACKGROUND: To investigate factors associated with flare in patients with ankylosing spondylitis (AS) who tapered tumour necrosis factor inhibitors (TNFis) after achievement of low disease activity (LDA) with the standard dose of TNFis. METHODS: This retrospective cohort study included 101 patients with AS who tapered their first TNFis after achievement of LDA. The proportion of reduced versus standard doses of TNFi throughout the follow up in each patient was quantified using the time-averaged dose quotient (DQ). Clinical characteristics were compared between patients who did and did not experience flare after TNFi tapering. Multivariable Cox regression analysis was performed to identify factors associated with flare. Receiver operating characteristic curve analysis was performed to determine the cut-offs of these covariates that best predicted flare. RESULTS: Of the total 101 patients, 45 (44.6%) patients experienced flare after TNFi tapering. Compared with patients who did not experience flare, those who experienced flare had a shorter disease duration (p = 0.006), shorter LDA duration before TNFi tapering (p < 0.001) and lower time-averaged DQ (p < 0.001). In multivariable Cox regression analysis, the LDA duration [adjusted hazard ratio (HR): 0.944, 95% confidence interval (CI): 0.906-0.983, p = 0.006] and time-averaged DQ (adjusted HR: 0.978, 95% CI: 0.959-0.998, p = 0.032) were inversely associated with flare. The cut-off values of the LDA duration and time-averaged DQ that best predicted flares were <5.3 months and <60.6%, respectively. CONCLUSION: Shorter LDA duration (cut-off value: 5.3 months) and lower time-averaged DQ (cut-off value: 60.6%) were associated with a higher risk of flare after tapering TNFi.

Worse Renal Presentation and Prognosis in Initial-Onset Lupus Nephritis than Early-Onset Lupus Nephritis.

PURPOSE: To compare the clinical characteristics and renal outcomes between patients who initially had lupus nephritis (LN) at the onset of systemic lupus erythematosus (SLE) (initial-onset LN) and those who developed LN within 5 years after SLE onset (early-onset LN). MATERIALS AND METHODS: SLE patients with biopsy-proven LN were retrospectively reviewed. The clinical parameters and renal outcomes were compared between initial-onset and early-onset LN groups. We used Cox regression analysis to estimate risk of worse renal outcomes according to the onset time of LN. RESULTS: Of all 136 LN patients, 92 (67.6%) and 44 (32.4%) patients were classified into the initial-onset and early-onset LN groups, respectively. The initial-onset LN group had higher prevalences of class IV LN (54.3% vs. 34.1%, p=0.027), impaired renal function (34.8% vs. 11.4%, p=0.004), microscopic hematuria (73.9% vs. 54.5%, p=0.024), and higher urine protein/creatinine ratio [4626.1 (2180.0-6788.3) mg/g vs. 2410.0 (1265.0-5168.5) mg/g, p=0.006] at LN diagnosis. Renal relapse (46.3% vs. 25.7%, p=0.039) and progression to chronic kidney disease (CKD) or end-stage renal disease (ESRD) were more common (24.4% vs. 8.3%, p=0.042) in the initial-onset LN group. In Cox regression analysis, the initial-onset LN group had higher risks of renal relapse [adjusted hazard ratio (HR) 3.56, 95% confidence interval (CI) 1.51-8.35, p=0.004] and progression to CKD or ESRD (adjusted HR 4.57, 95% CI 1.03-20.17, p=0.045), compared with the early-onset LN group. CONCLUSION: Patients with LN at SLE onset may have more severe renal presentations and experience worse renal outcomes than those who develop LN within 5 years.

Osteoclast-associated receptor blockade prevents articular cartilage destruction via chondrocyte apoptosis regulation.

Osteoarthritis (OA), primarily characterized by articular cartilage destruction, is the most common form of age-related degenerative whole-joint disease. No disease-modifying treatments for OA are currently available. Although OA is primarily characterized by cartilage destruction, our understanding of the processes controlling OA progression is poor. Here, we report the association of OA with increased levels of osteoclast-associated receptor (OSCAR), an immunoglobulin-like collagen-recognition receptor. In mice, OSCAR deletion abrogates OA manifestations, such as articular cartilage destruction, subchondral bone sclerosis, and hyaline cartilage loss. These effects are a result of decreased chondrocyte apoptosis, which is caused by the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in induced OA. Treatments with human OSCAR-Fc fusion protein attenuates OA pathogenesis caused by experimental OA. Thus, this work highlights the function of OSCAR as a catabolic regulator of OA pathogenesis, indicating that OSCAR blockade is a potential therapy for OA.

Non-histologic factors discriminating proliferative lupus nephritis from membranous lupus nephritis.

BACKGROUND: To investigate non-histologic factors that can discriminate proliferative lupus nephritis (LN) from membranous LN in patients with systemic lupus erythematosus with renal manifestations. METHODS: Patients with biopsy-proven proliferative LN (class III ± V and class IV ± V) and membranous LN (class V) were included. Non-histologic factors were compared between the two groups. A logistic regression analysis was performed to identify the factors associated with proliferative LN. To assess the accuracy of these factors in discriminating between proliferative LN and membranous LN, we performed a receiver-operating characteristic analysis. RESULTS: Of the total 168 patients with biopsy-proven LN, 150 patients (89.3%) had proliferative LN, and 18 patients (10.7%) had membranous LN. In the multivariable logistic regression analysis, positive anti-double-stranded DNA (anti-dsDNA) antibody (adjusted OR = 11.200, 95% CI = 2.202-56.957, p = 0.004) was associated with proliferative LN, while positive anti-U1RNP antibody (adjusted OR = 0.176, 95% CI = 0.040-0.769, p = 0.021) and higher glomerular filtration rate (GFR) (adjusted OR = 0.973, 95% CI = 0.951-0.994, p = 0.013) were inversely associated with proliferative LN. Among these covariates, the anti-dsDNA antibody (area under the curve = 0.806, 95% CI = 0.695-0.916) had the highest accuracy in discriminating between proliferative LN and membranous LN. CONCLUSION: The positivity of anti-dsDNA antibody was associated with proliferative LN, while the positivity of anti-U1RNP antibody and GFR were inversely associated with proliferative LN. The anti-dsDNA antibody had a good accuracy in discriminating proliferative LN from membranous LN.

Non-steroidal anti-inflammatory drugs in patients with stable ankylosing spondylitis receiving tumor necrosis factor inhibitor: continued vs withdrawn.

OBJECTIVE: To investigate the effect of non-steroidal anti-inflammatory drugs (NSAIDs) on disease activity in patients with stable ankylosing spondylitis (AS) receiving tumor necrosis factor inhibitor (TNFi). METHODS: In this retrospective observational study, a total of 189 patients with stable AS receiving TNFi were included. Patients were classified into NSAID withdrawn group (n = 48) and NSAID continued group (n = 141), according to the use of NSAIDs. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were measured every 3 months, and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was measured every 6 months as parameters to evaluate disease activity. ESR, CRP, and BASDAI at each time point, and time-averaged values of each parameter during the observation period of 1 year were compared between the two groups. Repeated-measure ANOVA was performed to compare changes in disease activity parameters during the observation period between the two groups. RESULTS: The level of ESR, CRP, and BASDAI at baseline and during the observation period did not differ between the two groups. The time-averaged values of ESR (p = 0.096), CRP (p = 0.136), and BASDAI (p = 0.421), and changes of ESR (p = 0.101), CRP (p = 0.714), and BASDAI (p = 0.613) during the observation period were not significantly different between the two groups. CONCLUSION: The continued use of NSAIDs in patients with stable AS receiving TNFi had no additional benefit in controlling the disease activity, as compared to patients who withdrew NSAIDs. Considering the risk of toxicity of long-term NSAID use, withdrawal of NSAIDs in stable AS patients receiving TNFi may be preferable. Key points • There is a lack of supportive evidence whether to continue or withdraw non-steroidal anti-inflammatory drugs (NSAIDs) in patients with stable ankylosing spondylitis (AS) receiving tumor necrosis factor inhibitor (TNFi). • Compared with patients who withdrew NSAIDs, continuing NSAIDs in patients with stable AS receiving TNFi had no additional benefit in controlling disease activity. • The results of the present study provide evidence that supports withdrawal of NSAIDs in patients with stable AS receiving TNFi.

Plasma immunoglobulin binding protein 1 as a predictor of development of lupus nephritis.

Objective: Urine levels of immunoglobulin binding protein 1 (IGBP1) are increased in patients with lupus nephritis (LN) compared with systemic lupus erythematosus (SLE) patients without nephritis. However, the clinical significance of IGBP1 level in plasma is unclear. We aimed to evaluate whether the plasma level of IGBP1 can predict future development of LN in SLE patients without nephritis. Methods: Forty-three SLE patients without nephritis were followed for 5 years. Plasma IGBP1 levels were measured using ELISA, and clinical and laboratory data were obtained at study entry. Development of LN was confirmed by renal biopsy. Cox regression analysis was performed to identify factors associated with development of LN, and receiver operating characteristic curve analysis was used to determine the predictive value of each factor. Results: Of the total 43 patients, eight (18.6%) developed LN during the follow-up period. Compared with patients who did not develop LN, those who developed LN had higher levels of plasma IGBP1 (6.3 ng/ml (range 4.3­9.6 ng/mL) vs. 13.3 ng/ml (range 7.2­31.3 ng/ml); p=0.023). In the Cox regression analysis, higher CRP (hazard ratio (HR)=1.325, 95% confidence interval (CI) 1.073­1.637, p=0.009), anti-dsDNA antibody (Ab; HR=1.066, 95% CI 1.012­1.124, p=0.017) and plasma IGBP1 (HR=1.091, 95% CI 1.034­1.152, p=0.002) were associated with future development of LN. Among these factors, anti-dsDNA Ab (area under the curve (AUC)=0.893) had the highest predictive value followed by plasma IGBP1 (AUC=0.761) and CRP (AUC=0.634). A combination of anti-dsDNA Ab and plasma IGBP1 as a composite predictor was highly specific (97%) for predicting the development of LN. Conclusions: Plasma IGBP1 can be used complementarily with anti-dsDNA Ab for detecting SLE patients at a higher risk of developing LN.