Therapeutic functions of astrocytes to treat α-synuclein pathology in Parkinson's disease.

Intraneuronal inclusions of misfolded α-synuclein (α-syn) and prion-like spread of the pathologic α-syn contribute to progressive neuronal death in Parkinson's disease (PD). Despite the pathologic significance, no efficient therapeutic intervention targeting α-synucleinopathy has been developed. In this study, we provide evidence that astrocytes, especially those cultured from the ventral midbrain (VM), show therapeutic potential to alleviate α-syn pathology in multiple in vitro and in vivo α-synucleinopathic models. Regulation of neuronal α-syn proteostasis underlies the therapeutic function of astrocytes. Specifically, VM-derived astrocytes inhibited neuronal α-syn aggregation and transmission in a paracrine manner by correcting not only intraneuronal oxidative and mitochondrial stresses but also extracellular inflammatory environments, in which α-syn proteins are prone to pathologic misfolding. The astrocyte-derived paracrine factors also promoted disassembly of extracellular α-syn aggregates. In addition to the aggregated form of α-syn, VM astrocytes reduced total α-syn protein loads both by actively scavenging extracellular α-syn fibrils and by a paracrine stimulation of neuronal autophagic clearance of α-syn. Transplantation of VM astrocytes into the midbrain of PD model mice alleviated α-syn pathology and protected the midbrain dopamine neurons from neurodegeneration. We further showed that cografting of VM astrocytes could be exploited in stem cell-based therapy for PD, in which host-to-graft transmission of α-syn pathology remains a critical concern for long-term cell therapeutic effects.

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.

LIN28A loss of function is associated with Parkinson's disease pathogenesis.

Parkinson's disease (PD) is neurodegenerative movement disorder characterized by degeneration of midbrain-type dopamine (mDA) neurons in the substantia nigra (SN). The RNA-binding protein Lin28 plays a role in neuronal stem cell development and neuronal differentiation. In this study, we reveal that Lin28 conditional knockout (cKO) mice show degeneration of mDA neurons in the SN, as well as PD-related behavioral deficits. We identify a loss-of-function variant of LIN28A (R192G substitution) in two early-onset PD patients. Using an isogenic human embryonic stem cell (hESC)/human induced pluripotent stem cell (hiPSC)-based disease model, we find that the Lin28 R192G variant leads to developmental defects and PD-related phenotypes in mDA neuronal cells that can be rescued by expression of wild-type Lin28A. Cell transplantation experiments in PD model rats show that correction of the LIN28A variant in the donor patient (pt)-hiPSCs leads to improved behavioral phenotypes. Our data link LIN28A to PD pathogenesis and suggest future personalized medicine targeting this variant in patients.

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.

Factors associated with aggravation of tubulointerstitial damage on repeated biopsies in lupus nephritis patients with treatment failure.

OBJECTIVES: Tubulointerstitial damage in lupus nephritis (LN) is an important predictor of renal prognosis. Here, we investigated the factors associated with aggravation of tubulointerstitial damage in patients with LN. METHODS: Patients with LN, who underwent repeated renal biopsy due to treatment failure at a tertiary referral hospital between 1997 and 2017 were identified. Clinicopathologic and laboratory data were collected. Aggravation of tubulointerstitial damage (tubular atrophy and/or interstitial fibrosis) was defined as progression of severity from none-to-mild to moderate-to-severe. Factors associated with aggravation of tubulointerstitial damage were evaluated using logistic regression analysis. RESULTS: A total of 52 LN patients were included for analysis. Aggravation of tubulointerstitial damage at the second renal biopsy was observed in 19 (36.5%) patients. In multivariable logistic regression analysis, use of hydroxychloroquine (adjusted OR 0.215, 95% CI 0.049-0.941, p=0.041) was inversely associated with aggravation of tubulointerstitial damage, and higher renal component of systemic lupus erythematosus disease activity index (SLEDAI) at first biopsy (adjusted OR 1.331, 95% CI 1.083-1.636, p=0.007) was associated with aggravation of tubulointerstitial damage. In terms of use of HCQ, both length of treatment with HCQ (adjusted OR 0.974, 95% CI 0.951-0.998, p=0.036) and cumulative dose of HCQ (log transferred value) (adjusted OR 0.485, 95% CI 0.262-0.896, p=0.020) were inversely associated with aggravation of tubulointerstitial damage. CONCLUSIONS: Use of hydroxychloroquine was associated with lower risk of aggravation in tubulointerstitial damage, and higher renal component of SLEDAI at first renal biopsy was associated with higher risk of aggravation in tubulointerstitial damage.

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.

Conventional synthetic disease-modifying antirheumatic drugs and bone mineral density in rheumatoid arthritis patients with osteoporosis: possible beneficial effect of leflunomide.

OBJECTIVES: To investigate the effect of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) on bone mineral density (BMD) in rheumatoid arthritis (RA) patients with osteoporosis. METHODS: Patients with RA who were newly diagnosed with osteoporosis (T-score ≤ -2.5) between 2010 and 2017 were included. All patients received background bisphosphonate for treatment of osteoporosis. BMD was measured at baseline and after one year. To identify csDMARDs or other factors associated with significant increase in BMD (≥3%) at lumbar spine and femoral neck at one year, we performed logistic regression analysis. To exclude the possibility of confounding by methotrexate, which was commonly used as a combination therapy with other csDMARDs, we also performed logistic regression analysis in the methotrexate users (subgroup analysis). RESULTS: In total, 153 RA patients with newly diagnosed osteoporosis were included. Leflunomide was the only csDMARD associated with significant increase in lumbar spine BMD (adjusted odds ratio (OR) 3.000, 95% confidence interval (CI) 1.177-7.645, p=0.021). In regard to femoral neck BMD, no csDMARDs were associated with significant increase in BMD. In the subgroup analysis, use of leflunomide was still associated with significant increase in lumbar spine BMD (adjusted OR 2.653, 95% CI 1.030-6.836, p=0.043), whereas no csDMARDs were associated with significant increase in femoral neck BMD. CONCLUSIONS: Among the csDMARDs, leflunomide can be beneficial in lumbar spine BMD in RA patients with osteoporosis.

Clinical features and risk of recurrence of acute calcium pyrophosphate crystal arthritis.

OBJECTIVES: It is unclear whether attack recurrence rates are similar between acute calcium pyrophosphate (CPP) crystal arthritis and gout. This study compared the clinical features and recurrence rates of both conditions. METHODS: In this retrospective study, we reviewed 106 patients with acute CPP crystal arthritis (based on the presence of CPP crystals and/or chondrocalcinosis) and 173 patients with gout (based on the presence of monosodium urate crystals). We analysed clinical variables and compared them between the two conditions. We identified factors associated with the recurrence of acute CPP crystal arthritis. RESULTS: Patients with acute CPP crystal arthritis were older (76.5 vs. 62 years, p<0.001) and female (69.8% vs. 6.9%, p<0.001); they had a lower body mass index (22.3 vs. 23.7, p=0.002), lower renal insufficiency rate (27.4% vs. 41.6%, p=0.016), and higher rate of preceding infection (22.6% vs. 11.0%, p=0.009) than those with acute gout. Recurrence rates were similar between the groups (19.1% vs. 22.9%, p=0.562). Use of proton pump inhibitors (PPIs) [hazard ratio (HR), 5.625; 95% CI, 1.672-18.925; p=0.005] and warfarin (HR, 7.301; 95% CI, 1.930-27.622; p=0.003) or exposure to chemotherapy (HR, 5.663; 95% CI, 1.180-27.169; p=0.03) were associated with acute CPP crystal arthritis recurrence. CONCLUSIONS: Acute CPP crystal arthritis was more common than acute gout in older women with preserved renal function. Physicians should be aware of the association between recurrence and PPI, warfarin, or chemotherapy use in these patients.

Renal flare in class V lupus nephritis: increased risk in patients with tubulointerstitial lesions.

The objective of this study is to investigate the risk factors of renal flare in patients with membranous lupus nephritis (class V lupus nephritis). Biopsy-proven pure membranous lupus nephritis patients diagnosed between January 1997 and September 2017 were studied. We assessed and compared the clinical and pathological parameters between patients who experienced renal flare and those who did not. To identify risk factors of renal flare, multivariable Cox proportional hazard regression analysis was performed. Out of the 53 patients with pure membranous lupus nephritis, 17 patients (32.1%) experienced renal flare during a median follow-up of 121.5 months (range 44.4-196.9). Patients who experienced renal flare had significantly higher proportion of tubulointerstitial inflammation (76.5% vs. 36.1%, p = 0.006) and tubular atrophy/interstitial fibrosis (70.6% vs. 27.8%, p = 0.003) at baseline. In multivariable Cox proportional hazard regression analysis, the presence of tubulointerstitial inflammation [adjusted hazard ratio (HR) 5.532, 95% confidence interval (CI) 1.722-17.776, p = 0.004] and tubular atrophy/interstitial fibrosis (adjusted HR 4.328, 95% CI 1.450-12.916, p = 0.009) at baseline was significantly associated with increased risk of renal flare. The presence of tubulointerstitial inflammation and tubular atrophy/interstitial fibrosis is associated with increased risk of renal flare in patients with membranous lupus nephritis.

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

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

Incidence rate of recurrent cardiovascular events in patients with radiographic axial spondyloarthritis and the effect of tumor necrosis factor inhibitors.

BACKGROUND: Patients with radiographic axial spondyloarthritis (r-axSpA) are at increased risk of incident cardiovascular events. Tumor necrosis factor inhibitors (TNFi) have shown a protective effect against incident cardiovacular events. However, the incidence of recurrent cardiovascular events in patients with r-axSpA with a history of cardiovascular events, and the effect of TNFi on recurrent cardiovascular events remain unclear. We aimed to assess the incidence rate of recurrent cardiovascular events in patients with r-axSpA with a history of cardiovascular events and evaluate the effect of TNFi on the risk of recurrent cardiovascular events. METHODS: This nationwide cohort study used data from the Korean National Claims Database. Data of patients with r-axSpA who had a history of cardiovascular events after being diagnosed with r-axSpA were extracted from the database. The outcome of interest was the recurrence of cardiovascular events (myocardial infarction or stroke). Patients were followed from the index date (date of the first cardiovascular event) to the date of cardiovascular event recurrence, the last date with claims data, or December 31, 2021, whichever occured first. The incidence rate of recurrent cardiovascular events was calculated. An inverse probability weighted Cox model was used to assess the effect of TNFi exposure on the risk of recurrent cardiovascular events. RESULTS: This study included 413 patients (TNFi non-exposure, n = 338; TNFi exposure, n = 75). The incidence rate of recurrent cardiovascular events was 32 (95% confidence interval [CI] 22-42) per 1,000 person-years (TNFi non-exposure, 36 [95% CI 24-48] per 1,000 person-years; TNFi exposure, 19 [95% CI 2-35] per 1,000 person-years). In the inverse probability weighted Cox model, TNFi exposure was significantly associated with a lower risk of recurrent cardiovascular events (hazard ratio 0.33, 95% CI 0.12-0.94). CONCLUSIONS: The incidence rate of recurrent cardiovascular events in patients with r-axSpA is substantial. TNFi exposure was associated with a lower risk of recurrent cardiovascular events.

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.

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.

Risk of systemic lupus erythematosus flares according to autoantibody positivity at the time of diagnosis.

To estimate the risk of systemic lupus erythematosus (SLE) flares based on the autoantibody positivity at the time of SLE diagnosis. This retrospective cohort study included 228 patients with newly diagnosed SLE. Clinical characteristics including autoantibody positivity at the time of diagnosis of SLE were reviewed. Flares were defined as a new British Isles Lupus Assessment Group (BILAG) A score or BILAG B score for at least one organ system. Multivariable Cox regression analyses were performed to estimate the risk of flares according to autoantibody positivity. Anti-dsDNA, anti-Sm, anti-U1RNP, anti-Ro, and anti-La antibodies (Abs) were positive in 50.0%, 30.7%, 42.5%, 54.8%, and 22.4% of the patients, respectively. The incidence rate of flares was 28.2/100 person-years. Multivariable Cox regression analysis, adjusted for potential confounders, revealed that anti-dsDNA Ab positivity (adjusted hazard ratio [HR]: 1.46, p = 0.037) and anti-Sm Ab positivity (adjusted HR: 1.81, p = 0.004) at the time of diagnosis of SLE were associated with higher risk of flares. To better delineate the flare risk, patients were categorized as double-negative, single-positive, double-positive for anti-dsDNA and anti-Sm Abs. Compared with double-negativity, double-positivity (adjusted HR: 3.34, p < 0.001) was associated with higher risk of flares, while anti-dsDNA Ab single-positivity (adjusted HR: 1.11, p = 0.620) or anti-Sm Ab single-positivity (adjusted HR: 1.32, p = 0.270) was not associated with higher risk of flares. Patients who are double-positive for anti-dsDNA and anti-Sm Abs at the time of the diagnosis of SLE are at higher risk of flares and may benefit from stringent monitoring and early preventive treatment.