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).

Patients with systemic lupus erythematosus who are underweight have distinct disease characteristics.

OBJECTIVE: This study aimed to detail the disease characteristics of systemic lupus erythematosus (SLE) in individuals who are underweight and assess whether underweight status is associated with SLE disease activity. METHODS: This was a retrospective cohort study involving 218 patients newly diagnosed with SLE. Patients were categorized as underweight (body mass index [BMI] <18.5 kg/m2) or not underweight (BMI ≥18.5 kg/m2). We reviewed disease characteristics including the SLE Disease Activity Index 2000 (SLEDAI-2K) at diagnosis. High disease activity was defined as SLEDAI-2K ≥10. Disease characteristics were compared between those who were underweight and not underweight. We used multivariable logistic regression analysis to determine whether underweight status is associated with high disease activity. RESULTS: Out of the 218 patients, 35 (16.1%) were underweight and 183 (83.9%) were not. Underweight patients had less renal involvement (5.7% vs 20.2%, p = .040), lower C-reactive protein levels (1.0 [0.3-2.3] mg/L vs 1.2 [0.8-5.0] mg/L, p = .028), and lower SLEDAI-2K scores (6.7 ± 4.6 vs 9.1 ± 5.7, p = .009), and were less likely to be at high disease activity status (22.9% vs 42.6%, p = .028), compared with those who were not underweight. Following adjustment for multiple covariates, being underweight was inversely associated with high disease activity status (adjusted odds ratio = 0.38, 95% confidence interval = 0.16 to 0.92, p = .031). CONCLUSION: Patients with SLE who were underweight showed less renal involvement and lower SLEDAI-2K scores compared with those who were not underweight. Moreover, those with SLE who were underweight had a 60% lower risk of exhibiting high disease activity.

Risk of atrial fibrillation in patients with systemic sclerosis: a nationwide population-based study.

OBJECTIVE: Atrial fibrillation (AF) is the most common arrhythmia in the general population causing substantial economic burden, morbidity, and mortality. The incidence rate and risk of AF in patients with systemic sclerosis (SSc) are unclear. We aimed to assess the incidence rate of AF in patients with SSc, and the risk of incident AF in patients with SSc compared with the general population. METHODS: The Korean National Health Insurance Service database was used as the data source. Patients with claims data for SSc between 2010 and 2017 were extracted from the database along with 1:5 age- and sex-matched controls. The index date was the earliest date with claims data for SSc between 2010 and 2017. The follow-up duration was from the index date to 2019. Multivariable Cox proportional hazard models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for AF in patients with SSc. RESULTS: Overall, 2,519 patients with SSc and 12,595 age- and sex-matched controls were included. Over a mean follow-up duration of 5.2±2.6 years, the incidence rates of AF were 3.52 and 1.68 per 1,000 person-years for patients with SSc and controls, respectively. Compared with controls, patients with SSc had a significantly higher risk of incident AF (adjusted HR = 2.095, 95% CI = 1.466-2.994). CONCLUSION: Patients with SSc had a two-fold higher risk of incident AF than controls. Given the significant economic burden, morbidity, and mortality that AF poses, close monitoring for incident AF in patients with SSc is warranted.

BASDAI cut-off values corresponding to ASDAS cut-off values.

OBJECTIVE: To determine cut-off values of BASDAI that can discriminate the four disease activity states (inactive disease, moderate disease activity, high disease activity and very high disease activity), separated by the validated Ankylosing Spondylitis Disease Activity Score (ASDAS) cut-off values (1.3, 2.1 and 3.5). METHODS: We included 333 patients with axial SpA whose data on BASDAI and ASDAS-CRP were available. Receiver operating characteristic curve analysis was performed to determine the BASDAI cut-off values that best corresponded to ASDAS-CRP cut-off values. The degree of agreement between disease activity states based on the BASDAI and ASDAS-CRP cut-off values was assessed using weighted kappa. RESULTS: Of the total 333 patients, 52 (15.6%), 190 (57.1%), 76 (22.8%) and 15 (4.5%) patients had inactive disease, moderate disease activity, high disease activity and very high disease activity, respectively, according to the ASDAS-CRP. Receiver operating characteristic analyses revealed that the BASDAI values 1.9 [area under the curve (AUC) 0.948; 95% CI 0.922, 0.974], 3.5 (AUC 0.926; 95% CI 0.887, 0.966) and 4.9 (AUC 0.917; 95% CI 0.837, 0.996) best corresponded to the ASDAS-CRP values 1.3, 2.1 and 3.5, respectively. The degree of agreement between disease activity states based on the BASDAI and ASDAS-CRP cut-off values was good (weighted kappa: 0.724, P <0.001). CONCLUSION: The BASDAI values 1.9, 3.5 and 4.9 corresponded to the ASDAS-CRP values 1.3, 2.1 and 3.5, respectively. These cut-off values could be useful in clinical studies and real-world practice for determining disease activity status when ASDAS-CRP is unavailable.

Effect of statins on the prevention of recurrent thrombosis in thrombotic antiphospholipid syndrome.

OBJECTIVE: To assess the effect of statins on the prevention of recurrent thrombosis in patients with thrombotic APS. METHODS: This retrospective cohort study included 184 patients with thrombotic APS. The effect of statins on recurrent thrombosis was investigated in the total study population and in an inverse probability of treatment weighting (IPTW)-adjusted population. Multivariable and IPTW-adjusted Cox proportional hazard regression analyses were performed on the total study population and the IPTW-adjusted population, respectively, to estimate the hazard ratios (HRs) with 95% CIs for recurrent thrombosis, according to the use of statins. RESULTS: Of the 184 patients, 103 (56.0%) received statins, while the other 81 (44.0%) did not. Recurrent thrombosis occurred in 22 (12.0%) patients during the mean observation period of 48.5 (34.9) months. In the multivariable Cox regression analyses, the use of statins was associated with a lower risk of recurrent thrombosis: (i) model 1 adjusted for risk factors of arterial and venous thrombosis, HR 0.24, 95% CI: 0.09, 0.63, P = 0.004; (ii) model 2 adjusted for the use of anticoagulants, antiplatelets and HCQ, HR 0.28, 95% CI: 0.10, 0.76, P = 0.012; and (iii) model 3 adjusted for the antiphospholipid autoantibody profile, HR 0.26, 95% CI: 0.10, 0.67, P = 0.005. The IPTW-adjusted Cox regression analysis also showed a lower risk of recurrent thrombosis with the use of statins (HR 0.28, 95% CI: 0.12, 0.65, P = 0.003). CONCLUSION: Our data suggest that statins could be effective in reducing the risk of recurrent thrombosis in patients with thrombotic APS.

Seroconversion to antinuclear antibody negativity and its association with disease flare in patients with systemic lupus erythematosus.

OBJECTIVE: To evaluate the rate of seroconversion to antinuclear-antibody negativity in patients with systemic lupus erythematosus and its association with subsequent systemic lupus erythematosus flare risk. METHODS: Medical records of patients with systemic lupus erythematosus with positive antinuclear antibodies (titer ≥1 : 40) at diagnosis and at least one repeat antinuclear antibody test were reviewed. We determined the frequency of seroconversion to antinuclear antibody negativity among these patients and investigated whether seroconversion to antinuclear antibody negativity was associated with subsequent systemic lupus erythematosus flare risk. The seroconversion to antinuclear antibody negativity was defined as a conversion of positive antinuclear antibodies to a titer below the cut-off of 1 : 40. Systemic lupus erythematosus flare was defined as one new British Isles Lupus Assessment Group A or two new British Isles Lupus Assessment Group B domain scores. To estimate hazard ratios and 95% confidence intervals for systemic lupus erythematosus flare according to seroconversion to antinuclear antibody negativity, Cox regression analysis with adjustment for known systemic lupus erythematosus flare risk factors was performed. Kaplan-Meier analysis was used to compare flare-free survival rates between negative converters and non-converters. RESULTS: Among the total 175 patients, seroconversion to antinuclear antibody negativity was found in 17 (9.7%) patients in a median 53.5 (range: 25.7-84.0) months. After the last antinuclear antibody tests, 53 systemic lupus erythematosus flare cases were identified during 14.3 (range: 8.2-21.7) months of follow-up. Systemic lupus erythematosus flare risk was significantly lower in patients with negatively seroconverted antinuclear antibodies (adjusted hazard ratio 0.13, 95% confidence interval 0.03-0.58, p = 0.007). Kaplan-Meier analysis showed significantly higher flare-free survival in negative converters than in non-converters (p = 0.004). CONCLUSION: Seroconversion to antinuclear antibody negativity occurred in 9.7% of patients over 53.5 months and was associated with a lower future systemic lupus erythematosus flare risk.

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.

MiR-451 suppresses inflammatory responses in ankylosing spondylitis by targeting macrophage migration inhibitory factor.

OBJECTIVES: To investigate the associations of miR-451 and macrophage migration inhibitory factor (MIF) with disease activity, radiographic progression, and cytokine levels of ankylosing spondylitis (AS). METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated and cultured from 43 AS patients, 11 peripheral spondyloarthritis (pSpA) patients, and 31 healthy controls. ASDAS-CRP and mSASSS were assessed at the time of blood sampling. Expression levels of miR-451 and MIF were determined using quantitative real-time PCR, and the supernatant concentrations of MIF and cytokines were measured using ELISA. After transfection of miR-451 synthetic mimic or FAM-labelled negative control mimic to AS PBMCs, MIF and cytokine levels were determined using quantitative real-time PCR or ELISA. RESULTS: Level of miR-451 expression was lower in AS PBMCs than in pSpA and control PBMCs, while MIF expression was significantly increased in AS PBMCs compared with those in pSpA and control PBMCs. MIF, TNF-α, and IL-6 concentrations in cell supernatants of AS PBMCs were significantly higher than those of pSpA and control PBMCs. miR-451 expression level did not show significant correlation with clinical parameters, but MIF expression level was elevated in PBMCs from AS patients with high mSASSS (12 or more). Treatment of AS PBMCs with the miR-451 synthetic miRNA mimic significantly reduced mRNA expression levels and cell supernatant concentrations of MIF, TNF-α, and IL-6. CONCLUSIONS: The MIF level was elevated in AS patients with greater radiographic damage and overexpression of miR-451 suppressed the MIF and inflammatory cytokine levels. These findings suggest miR-451/MIF may be a novel therapeutic target in the treatment of AS.

Positive conversion of interferon-γ release assay in patients with rheumatic diseases treated with biologics.

The objective of this study is to investigate whether the type of biologics (TNFi or others) or type of rheumatic diseases (RA or AS) influence the conversion rate of initially negative tuberculosis (TB) screening test results. A total of 119 patients with RA or AS who had negative baseline interferon-γ release assay (IGRA) results assessed by QuantiFERON-TB Gold in tube (QTF-GIT) were included. All patients received biologic agents, and rescreening with QTF-GIT was performed after a median of 25.9 months from the baseline test. Clinical characteristics and IFN-γ levels were compared between converters and non-converters. Logistic regression analysis was performed to identify factors associated with positive conversion. IGRA conversion was found in 14 of 119 patients (11.8%). The converters were older (53.4 ± 14.2 vs 44.4 ± 15.5 years, p = 0.040), had higher baseline TB-specific IFN-γ responses (0.105 [0.018-0.205] vs 0.010 [0.000-0.035] IU/ml, p = 0.001) and higher incidence of active TB (14.3% vs 0.0%, p = 0.013). The number of patients with RA or AS was 9 (64.3%) or 5 (35.7%) in converters, and 45 (42.9%) or 60 (57.1%) in non-converters. In terms of use of biologics, TNFi of monoclonal antibody form was less commonly used in the converters (p = 0.024). In the logistic regression analysis, type of disease and type of biologics used were not associated with IGRA conversion, whereas baseline TB-specific IFN-γ response was significantly associated with IGRA conversion (OR 1.083, 95% CI 1.019-1.151, p = 0.011). Serial monitoring of LTBI with IGRA retesting is needed during biologic treatment, regardless of the type of rheumatic diseases or type biologics used.

Differential expressions of NOD-like receptors and their associations with inflammatory responses in rheumatoid arthritis.

OBJECTIVES: To determine the differential expressions of nucleotide oligomerisation domain (NOD)-like receptors (NLRs) and to investigate their association with inflammatory responses in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS). METHODS: Gene expression and protein levels of various NLRs, including NOD1, NOD2, NLRP1, NLRP3, NLRP12, NLRX1, and NLRC3, were determined in FLS and synovial tissues from patients with RA and patients with osteoarthritis (OA) using quantitative real-time PCR and immunohistochemistry. After transfection of NOD2 RNAi plasmids or a pcDNA3.1-NLRX1 vector, gene expression levels of pro-inflammatory cytokines in RA FLS and the protein levels of these cytokines in culture supernatants were determined using quantitative real-time PCR and enzyme-linked immunosorbent assays. The effects of NLR gene regulation on NF-κB and caspase-1 were evaluated using Western blot analysis. RESULTS: Gene expression levels of NOD1, NLRP1, NLRP3, NLRP12, and NLRC3 were not different between RA and OA samples. NOD2 gene expression and protein levels were significantly increased in RA samples, whereas the levels of NLRX1 were significantly decreased. Downregulation of NOD2 gene expression by transfection with NOD2 RNAi plasmid significantly reduced pro-inflammatory cytokine levels in RA FLS, while transfection with adenoviral vectors encoding NLRX1 had no effect on pro-inflammatory cytokine levels. Downregulation of NOD2 gene expression significantly decreased NF-κB, TRAF6, and IKK levels, but not caspase-1 levels, in RA FLS. CONCLUSIONS: NOD2 is upregulated in RA FLS; moreover, downregulation of NOD2 gene expression reduces pro-inflammatory cytokine and NF-κB levels in RA FLS. These findings provide evidence that NOD2 exerts pro-inflammatory effects in RA.

Maintenance, reduction, or withdrawal of etanercept after treatment with etanercept and methotrexate in patients with moderate rheumatoid arthritis (PRESERVE): a randomised controlled trial.

BACKGROUND: Clinical remission and low disease activity are essential treatment targets in patients with rheumatoid arthritis. Although moderately active rheumatoid arthritis is common, treatment effects in moderate disease have not been well studied. Additionally, optimum use of biologics needs further investigation, including the use of induction, maintenance, and withdrawal treatment strategies. The aim of the PRESERVE trial was to assess whether low disease activity would be sustained with reduced doses or withdrawal of etanercept in patients with moderately active disease. METHODS: In a randomised controlled trial, patients aged between 18 and 70 years with moderately active rheumatoid arthritis (disease activity score in 28 joints [DAS28] >3.2 and ≤5.1) despite treatment with methotrexate were enrolled at 80 centres in Europe, Latin America, Asia, and Australia between March 6, 2008, and Sept 9, 2009. To be eligible, patients had to have been receiving 15-25 mg of methotrexate every week for at least 8 weeks. In an open-label period of 36 weeks, all patients were given 50 mg etanercept plus methotrexate every week. To be eligible for a subsequent double-blind period of 52 weeks, participants had to have achieved sustained low disease activity. These patients were randomly assigned (1:1:1) by an interactive voice-response system to one of three treatment groups: 50 mg etanercept plus methotrexate, 25 mg etanercept plus methotrexate, or placebo plus methotrexate. Patients were stratified in blocks of three by DAS28 response (low disease activity or remission) at week 36. Patients, investigators, data analysts, and study staff were all masked to treatment allocation. The primary endpoint was the proportion of patients with low disease activity at week 88 in the groups given 50 mg etanercept or placebo in the double-blind period. A conditional primary endpoint was the proportion of patients receiving 25 mg etanercept who achieved low disease activity. Modified intention-to-treat populations were used for analyses. This trial is registered with ClinicalTrials.gov, number NCT00565409. FINDINGS: 604 (72.4%) of 834 enrolled patients were eligible for the double-blind period, of whom 202 were assigned to 50 mg etanercept plus methotrexate, 202 to 25 mg etanercept plus methotrexate, and 200 to placebo plus methotrexate. At week 88, 166 (82.6%) of 201 patients who had received at least one dose of 50 mg etanercept and one or more DAS28 evaluations had low disease activity, compared with 84 (42.6%) of 197 who had received placebo (mean difference 40.8%, 95% CI 32.5-49.1%; p<0.0001). Additionally, 159 (79.1%) of 201 patients given 25 mg etanercept had low disease activity at week 88 (mean difference from placebo 35.9%, 27.0-44.8%; p<0.0001). INTERPRETATION: Conventional or reduced doses of etanercept with methotrexate in patients with moderately active rheumatoid arthritis more effectively maintain low disease activity than does methotrexate alone after withdrawal of etanercept. FUNDING: Pfizer.

Secreted frizzled-related protein 5 suppresses inflammatory response in rheumatoid arthritis fibroblast-like synoviocytes through down-regulation of c-Jun N-terminal kinase.

OBJECTIVE: This study was performed to investigate the effect of secreted frizzled-related protein 5 (Sfrp5), a novel anti-inflammatory adipokine that competes with the frizzled proteins for Wnt binding, on inflammatory response and the c-Jun N-terminal kinase (JNK) signalling pathway in RA. METHODS: Expression of Sfrp5 mRNA in peripheral blood mononuclear cells (PBMCs) and fibroblast-like synoviocytes (FLSs) from patients with RA and OA was determined using real-time quantitative PCR (qPCR). Sfrp5 RNA interference (RNAi) plasmids were transfected to abrogate Sfrp5 expression in RA FLSs, and adenovirus containing the Sfrp5 transcript was delivered into RA FLSs to strengthen Sfrp5 expression. Levels of pro-inflammatory genes and their protein products were determined using real-time qPCR and ELISA in RA FLSs. Production of mitogen-activated protein kinase kinase 7 (MKK-7), JNK and c-Jun were assessed by Western blot analysis. RESULTS: Expression of Sfrp5 mRNA was decreased in PMBCs and FLSs from patients with RA compared with patients with OA. Gene expression and production of IL-1ß, IL-6, chemokine ligand 2 (CCL-2), CCL-7, cyclooxygenase 2 and MMP-9 were markedly increased in Sfrp5 RNAi plasmid-transfected RA FLSs, while transfection with adenoviral vectors encoding Sfrp5 induced reductions in those levels. Phosphorylated forms of MKK-7, JNK and c-Jun were increased by Sfrp5 RNAi plasmids and were decreased by adenoviral vectors encoding Sfrp5. CONCLUSION: Sfrp5 suppressed the inflammatory response and down-regulated JNK signalling in RA FLSs. These findings provide evidence for the anti-inflammatory effect of Sfrp5 in RA.

The concomitant use of meloxicam and methotrexate does not clearly increase the risk of silent kidney and liver damages in patients with rheumatoid arthritis.

We investigated whether the concomitant use of meloxicam and methotrexate might induce kidney and liver damages in patients with rheumatoid arthritis (RA). We enrolled 101 RA patients with normal kidney and liver functions taking meloxicam and methotrexate concomitantly for more than 6 months. Blood and urine tests were performed. Estimated glomerular filtration rate (eGFR) and liver stiffness measurement (LSM) were used for evaluating silent kidney and liver damages. Ultrasonography was also performed to exclude structural abnormalities. We adopted 90 mL/min/1.73 mm(2) and 5.3 kPa as the cutoff for an abnormal eGFR and LSM. The mean age (85 women) was 51.9 years. The mean eGFR was 97.0 mL/min/1.73 m(2) and the mean LSM was 4.7 kPa. The mean weekly dose of methotrexate was 13.4 mg. The mean weekly dose of methotrexate did not correlate with eGFR or LSM. Neither the cumulative dose of meloxicam or methotrexate nor the mean weekly dose of methotrexate showed the significant odds ratio or relative risk for abnormal eGFR and LSM values. The use of higher-dose MTX, above 15 mg per week, with meloxicam did not significantly increase the risk for abnormal LSM and eGFR (RR = 2.042, p = 0.185; RR = 0.473, p = 0.218). The concomitant use of meloxicam and MTX did not clearly increase the risk of silent kidney or liver damage in RA patients with normal laboratory results taking MTX and meloxicam concurrently for over 6 months.

Active tuberculosis risk with tumor necrosis factor inhibitors after treating latent tuberculosis.

BACKGROUND: Active tuberculosis (TB) risk increases during anti-tumor necrosis factor (TNF) therapy; therefore, latent TB infection (LTBI) screening is recommended in potential TNF inhibitor users. It is unclear whether anti-TNF therapy increases the risk of active TB infection even after standard LTBI treatment. OBJECTIVE: The objective of this study was to compare the risk of active TB development in LTBI-positive versus LBTI-negative TNF inhibitor users following the current national LTBI treatment guidelines for LTBI. METHODS: We retrospectively studied 949 TNF inhibitor users with immune-mediated inflammatory diseases from 2005 to 2012 at the Yonsei University Health System. We compared the incidence of active TB among LTBI-positive TNF inhibitor users treated according to national guidelines (n = 256) and LTBI-negative TNF inhibitor users (n = 521), using Poisson regression. RESULTS: The active TB incidence was 1107 per 100,000 patient-years in LTBI-positive TNF inhibitor users who received standard LTBI treatment and 490 per 100,000 patient-years in LTBI-negative TNF inhibitor users. Analysis showed that despite this numerical trend active TB risk was not statistically significantly elevated in LTBI-positive versus LTBI-negative TNF inhibitor users (incidence risk ratio, 2.15; P = 0.24; 95% confidence interval, 0.6-7.7). CONCLUSIONS: This study demonstrated no statistically significantly increased risk of active TB in LTBI-positive TNF inhibitor users who received standard LTBI treatment compared with LTBI-negative TNF inhibitor users.

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.

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.

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.

Corrigendum: Korean treatment recommendations for patients with axial spondyloarthritis.

[This corrects the article on p. 151 in vol. 30, PMID: 37476674.].

Activation of liver X receptors suppresses inflammatory gene expressions and transcriptional corepressor clearance in rheumatoid arthritis fibroblast like synoviocytes.

OBJECTIVES: Liver X receptors (LXR) are nuclear receptors that play important roles in lipid metabolism and transport. LXR also suppress inflammatory responses in macrophages through a unique mechanism of transrepression. This study was performed to investigate whether the synthetic LXR agonist GW3965 can modulate the inflammatory status of fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA) and to identify the mechanism for their effect. METHODS: RA FLS were treated with 0.1 and 1 µM of GW3965, a synthetic LXR agonist. The mRNA expressions of pro-inflammatory mediators were measured using quantitative real-time PCR. Apoptotic cell death of RA FLS was assessed using TUNEL assay and determination of caspase-3 activity by a colorimetric assay. The levels of transcriptional corepressors including NCoR and SMRT were determined using western blot analyses. RESULTS: Treatment of RA FLS with GW3965 induced dose-dependent reductions in mRNA expression of pro-inflammatory mediators (IL-1ß, IL-6, MMP-9, CCL-2, CCL-7, and COX-2). However, treatment with GW3965 at the concentration selected for this study had no effect on apoptosis of RA FLS. Decreased productions of NCoR and SMRT by LPS stimulation was attenuated by GW3965 treatment. CONCLUSIONS: GW3965 treatment suppressed mRNA expressions of pro-inflammatory mediators from RA FLS and inhibited the clearance of transcriptional corepressors. These data suggest that LXR activation can be used as a therapeutic approach to reduce the synovial inflammation in RA.

The role of (18) F-fluorodeoxyglucose-positron emission tomography in the assessment of disease activity in patients with takayasu arteritis.

OBJECTIVE: The assessment of disease activity in Takayasu arteritis (TA) is difficult in clinical situations because clinical symptoms and laboratory parameters do not always reflect the actual inflammation of the arterial wall. We undertook this study to comprehensively investigate the role of (18) F-fluorodeoxyglucose-positron emission tomography (FDG-PET) in the assessment of disease activity in patients with TA. METHODS: We performed a retrospective chart review of 53 FDG-PET scans in 38 patients with TA. We measured (18) F-fluorodeoxyglucose ((18) F-FDG) accumulation in the vascular wall of the large vessel using semiquantitative (visual grade) and quantitative (standard uptake value intensity) analyses. Clinical disease activity was evaluated based on the National Institutes of Health criteria for active TA, and erythrocyte sedimentation rates (ESRs) and C-reactive protein (CRP) levels were measured. RESULTS: At baseline, active vascular (18) F-FDG uptake (visual grade ≥2) was observed in 18 of 24 patients with active disease and in 5 of 14 patients with inactive disease. There was a significant association between clinical disease activity and disease activity judged by FDG-PET (P = 0.008). Visual grade, standard uptake value intensity, and the number of vascular lesions with active (18) F-FDG uptake were significantly higher in patients with active disease and correlated well with the ESR and CRP levels. In 15 followup FDG-PET scans, the changes in visual grade, areas of active vascular (18) F-FDG uptake, and standard uptake value intensity reflected changes in clinical disease activity. CONCLUSION: (18) F-FDG uptake was associated with clinical disease activity and markers of inflammation, and FDG-PET reflected changes in clinical disease activity in patients with TA. FDG-PET may be a useful tool for aiding in the assessment of disease activity in patients with TA.

Adjusted neutropenia is associated with early serious infection in systemic lupus erythematosus.

OBJECTIVES: The susceptibility to infection increases in systemic lupus erythematosus (SLE) patients with neutropenia, but the link between infection risk and the cutoff neutrophil count still remains controversial. In this study, we investigated a valuable parameter associated with early serious infection in SLE patients during the first follow-up year. METHODS: We reviewed the medical records of 160 patients with SLE. The initial levels were defined as the mean of the results of the first two consecutive tests. The adjusted levels were defined as the results of the accumulated area under the curve divided by interval follow-up days. Patients were divided into two groups according to early serious infection and initial and adjusted neutropenia and were then compared. RESULTS: Immunosuppressive-naïve SLE patients with early serious infection more frequently had initial, latest, and adjusted leukopenia and neutropenia (<2,500/mm(3)) and hypocomplementemia than those without. Adjusted neutropenia was the only independent predictive value for early serious infection [odds ratio (OR 11.366)]. Initial neutropenia was the independent predictive value for adjusted neutropenia (OR 6.504). CONCLUSIONS: We suggest that adjusted neutropenia is useful for predicting early serious infection in SLE patients during the first follow-up year.