Circulating Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is Associated with Disease Activity and Risk of Incident Cardiovascular Disease in Patients with Systemic Lupus Erythematosus.

To study the relationship of serum PCSK9 and disease activity and major adverse cardiovascular events (MACEs) in systemic lupus erythematosus (SLE). Consecutive patients who fulfilled ≥ 4 ACR criteria for SLE and consented for a biomarker study in 2009-2013 were included. Stored serum samples were assayed for PCSK9. PCSK9 levels were correlated with SLE disease activity scores. Patients were divided into two groups according to the median PCSK9 level and new MACEs over time were evaluated. The effect of PCSK9 level on MACEs and mortality was studied by Cox regression, adjusted for confounders. A total of 539 SLE patients were studied (93% women, age 41.9 ± 14.0 years). The median PCSK9 level at baseline was 220 ng/ml. Patients with higher PCSK9 (≥ 220 ng/ml; n = 269) had significantly higher SLE disease activity index (SLEDAI) than those with lower PCSK9 (< 220 ng/ml; n = 270). PCSK9 levels were significantly higher in patients with active renal than active non-renal SLE, which in turn were significantly higher than those with inactive SLE or healthy controls. PCSK9 level correlated with SLEDAI in the overall population (ρ = 0.30; p < 0.001). Over 91.3 ± 18.6 months, 29 patients developed 31 MACEs and 40 patients succumbed (25% for vascular events). The cumulative incidence of MACEs at 5 years was 4.8% in the higher PCSK9 and 1.1% in the lower PCSK9 group (HR2.51[1.11-5.70]; p = 0.03). Cox regression revealed higher PCSK9 was significantly associated with MACEs (HR1.003[1.000-1.005] per ng/ml; p = 0.02) independent of age, sex, renal function, baseline disease activity score, traditional atherosclerotic risk factors, antiphospholipid antibody and the use of aspirin/warfarin, statins and immunosuppressive drugs. PCSK9 level was also independently associated with all-cause (HR1.002[1.000-1.004] per ng/ml; p = 0.03) and vascular mortality (HR1.004[1.000-1.007]; p = 0.04). We concluded that serum PCSK9 level correlates with SLE disease activity. Higher serum PCSK9 levels are associated with increased risk of cardiovascular events and mortality in SLE.

Relationship between the EULAR/ACR classification criteria and organ damage in systemic lupus erythematosus.

OBJECTIVES: To study the relationship between the 2019 EULAR/ACR classification criteria and organ damage in patients with systemic lupus erythematosus (SLE). METHODS: Patients involved in a cross-sectional validation study of the EULAR/ACR criteria and judged by a panel of rheumatologists to be clinical SLE were studied. Those who fulfilled the EULAR/ACR criteria at their last clinic visit were stratified into 2 groups based on a cutoff score of 20. The last SLE International Collaborating Clinic (SLICC) Organ Damage Index (SDI) was compared between these two groups. Relationship among the domains of the EULAR/ACR criteria and SDI in all patients was studied by using Spearman's rank correlation. RESULTS: A total of 562 SLE patients were studied (93.6% women; age 36.5 ± 14.1 years; follow-up duration 11.6 ± 6.6 years). The mean and median EULAR/ACR criteria scores in those who fulfilled the EULAR/ACR criteria (N = 542) were 24.6 ± 7.3 and 24 (interquartile range 19-30), respectively. A total of 392 patients had EULAR/ACR scores of ≥20 (group 1), and 150 patients had scores of 10-19 (group 2). Group 1 patients had significantly higher prevalence of fever, alopecia, oral ulcers, acute lupus skin lesions, arthritis, serositis, seizure, hemolytic anemia, leukopenia, and renal disease and so were the anti-dsDNA, anti-Sm, antiphospholipid antibodies, and low complement state. Organ damage (SDI score of ≥1) occurred in 232 (42.8%) patients. Patients in group 1 had significantly higher SDI scores in the renal, cardiovascular, dermatological, and gonadal domains than group 2. The renal, neuropsychiatric, and antiphospholipid antibody domain scores of the EULAR/ACR criteria correlated positively with the total SDI. The renal domain of the EULAR/ACR criteria had the strongest correlation with renal damage (Rho 0.30; p < 0.001). Patients who scored 10 points in the renal domain had significantly higher renal damage score than those scored 8 points or 4 points. Gonadal damage score was also significantly more common in the 10-point than in the 8-point group. CONCLUSION: In addition to disease classification, the EULAR/ACR SLE criteria may have value in predicting prognosis.

Prevalence and risk factors of herpes zoster infection in patients with rheumatic diseases not receiving biologic or targeted therapies.

OBJECTIVES: The objective was to study the prevalence and risk factors of herpes zoster (HZ) infection in patients with rheumatic diseases. METHODS: Consecutive patients with rheumatic diseases not receiving biologic/targeted DMARDs who attended our rheumatology clinics between March and August 2019 were retrospectively reviewed. Episodes of HZ infection since their first clinic attendance were identified. Laboratory results (total white cell count, neutrophil-to-lymphocyte ratio (NLR), serum albumin, globulin, and creatinine) and use of immunosuppressive medications were compared between those with (preceding infection) and without (preceding last visit) HZ infection. Cox regression analysis was performed to identify factors associated with the first HZ infection in all patients. RESULTS: 1,479 patients were studied (88.3% women, age 45.0 ± 15.8 years). Systemic lupus erythematosus (SLE) (38.7%) and rheumatoid arthritis (28.3%) were the commonest rheumatic diseases. After a follow-up of 14,715 patient-years (9.9 ± 7.0 years), 219 (14.8%) patients developed 258 episodes of HZ infection, giving an overall prevalence of 1.75/100-patient years. The prevalence rates of HZ were highest in SLE and inflammatory myopathies (2.54 and 2.58 per 100 patient-years, respectively). Patients who experienced HZ reactivation were younger, more likely to have SLE, and had significantly lower serum albumin/globulin levels but higher NLR. Significantly more patients with HZ reactivation were using prednisolone and other immunosuppressive drugs in the visits preceding HZ infection. The cumulative risk of having HZ reactivation at 24 and 48 months was 4.9% and 7.6%, respectively. Cox regression analysis revealed that a diagnosis of SLE, increasing age, higher NLR, use of cyclophosphamide, and increasing doses of prednisolone, azathioprine, hydroxychloroquine and leflunomide were independently associated with HZ infection. CONCLUSIONS: Reactivation of HZ is fairly common in patients with rheumatic diseases. Underlying SLE, age, neutrophil/lymphocyte ratio, and immunosuppressive therapies are independent risk factors. Key Points • Herpes zoster (HZ) infection is fairly common in patients with rheumatic diseases undergoing conventional DMARD or immunosuppressive therapies. • Underlying SLE, increasing age, higher neutrophil/lymphocyte ratio and increasing dosages of immunosuppressive drugs are independent risk factors. • Patients with rheumatic diseases, particularly SLE, should be encouraged to receive HZ vaccination.

Validation of the 2019 EULAR/ACR classification criteria for systemic lupus erythematosus in ANA-positive Chinese patients.

Background: The aim of this study was to validate the 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for systemic lupus erythematosus (SLE) in antinuclear antibody (ANA)-positive Chinese patients. Methods: Medical records of all adult patients who attended the rheumatology out-patient clinics between May and September 2019 were reviewed. Patients with ever ANA positive (titre ⩾1:80) were included and evaluated for the fulfilment of the 2019 EULAR/ACR, 2012 Systemic Lupus International Collaborating Clinics (SLICC) and 1997 ACR criteria for SLE classification. The performance of these criteria in predicting a clinical diagnosis of SLE as judged by an independent panel of rheumatologists was studied and compared in different subgroups. Results: A total of 1533 patients (88.2% women; age at first clinic attendance 45.5 ± 15.6 years) were studied and 562 patients were judged to be clinical SLE. The sensitivity and specificity of the EULAR/ACR (⩾10 points), SLICC and ACR criteria for a clinical diagnosis of SLE was 96.1%, 97.9% and 86.1%; and 85.8%, 86.3% and 94.3%, respectively. Applying the attribution rule to the non-SLE controls, the specificity of the three criteria increased to 95.0%, 92.5% and 98.8%, respectively. The specificity of the EULAR/ACR criteria was higher in male patients (97.9%), those aged >50 years (97.0%) and disease duration of ⩽3 years (97.6%). Using a cut-off of 12 points, the specificity of the EULAR/ACR criteria was further increased (96.6%) while a high sensitivity (95.0%) was maintained. Conclusion: In Chinese patients with a positive ANA, the EULAR/ACR criteria for clinical SLE perform equally well to the SLICC criteria. Both the EULAR/ACR and SLICC are more sensitive but less specific than the ACR criteria. The specificity of all the three criteria is enhanced by applying the attribution rule to controls. The specificity of the EULAR/ACR criteria is higher in certain patient subgroups or when the cut-off score is raised.

Estimation of fracture risk by the FRAX tool in patients with systemic lupus erythematosus: a 10-year longitudinal validation study.

BACKGROUND: The fracture risk assessment tool has been widely used to stratify the 10-year fracture risk to guide therapy. Using the actual fracture data of a 10-year longitudinal cohort of older patients with systemic lupus erythematosus, we reported an underestimation of the tool in predicting major symptomatic osteoporotic fractures. Treatment of osteoporosis in systemic lupus erythematosus should not be based on fracture risk estimation alone. Relevant time-dependent risk factors should be taken into account for an individualized decision. OBJECTIVE: To compare the observed fracture incidence in a 10-year longitudinal cohort of patients with systemic lupus erythematosus (SLE) with the fracture risk prediction from the fracture risk assessment (FRAX) tool. METHODS: Adult patients (⩾40 years) with SLE who had a first DEXA scan performed in 2005-2009 were studied. The 10-year rates of major osteoporotic and hip fractures were estimated by FRAX using clinical data at DEXA with adjustment for prednisolone dosage. The actual incidence of clinical fractures at 10 years was compared with the estimated rates. Factors associated with new fractures were studied by logistic regression. RESULTS: A total of 229 SLE patients were studied (age: 50.2 ± 6.6 years, 93% women). Glucocorticoid was used in 148 (65%) patients at baseline (mean dose: 7.3 ± 6.9 mg/day; 34% ⩾ 7.5 mg/day). Osteoporosis (bone mineral density T score ⩽ -2.5) at the hip, femoral neck, or spine was present in 61 (27%) patients. The estimated 10-year risk of major osteoporotic and hip fractures by FRAX was 3.4 ± 4.5% and 0.95 ± 2.3%, respectively. After 10 years, three patients developed hip fracture, 6 patients had limb fractures and 20 patients had symptomatic vertebral fractures (major osteoporotic fracture 12.7%, hip fracture 1.3%). The actual major osteoporotic fracture rate was significantly higher than the FRAX estimation (12.7% vs 3.4%; p < 0.001). Logistic regression revealed that osteoporosis (odds ratio (OR): 4.07 [1.51-10.9]), previous fragility fracture (OR: 3.18 [1.02-9.90]), and a parental history of fracture (OR: 4.44 [1.16-17.0]) were independently associated with new clinical fractures at 10 years. CONCLUSION: The FRAX tool underestimates the major clinical fracture risk at 10 years in patients with SLE.

Denosumab versus alendronate in long-term glucocorticoid users: A 12-month randomized controlled trial.

OBJECTIVES: To compare the efficacy of denosumab and alendronate on raising spine bone mineral density (BMD) in long-term glucocorticoid (GC) users. METHODS: Adult patients receiving long-term prednisolone (≥2.5 mg/day for ≥1 year) were recruited and randomized to either subcutaneous denosumab (60 mg/6 months) or oral alendronate (70 mg/week). BMD (lumbar spine, femoral neck, hip) and bone markers (serum P1NP and CTX) were measured at month 0, 6 and 12. The difference in spine BMD (primary outcome) at month 12 was compared between the two groups. RESULTS: 139 subjects were recruited (age 50.0 ± 12.7 years; 96% women): 69 assigned denosumab and 70 assigned alendronate. At entry, 73(53%) patients were osteoporotic and 82(59%) patients were naive to the bisphosphonates. Baseline clinical characteristics and BMD values were similar in the two groups. At month 12, a significant gain in mean BMD at the lumbar spine (+3.5 ± 2.5%; p<0.001), hip (+0.9 ± 2.8%; p=0.01) and femoral neck (+1.04 ± 4.1%; p=0.047); was observed in denosumab-treated patients, whereas the corresponding change was +2.5 ± 2.9% (p<0.001), +1.6 ± 2.7% (p<0.001) and + 1.5 ± 3.9% (p=0.002) in the alendronate group. The spine, but not the hip or femoral neck, BMD at month 12 was significantly higher in the denosumab than alendronate group after adjustment for baseline BMD values, age, sex, osteoporosis risk factors and the cumulative prednisolone doses received in one year. The drop in P1NP and CTX was significantly higher in the denosumab than alendronate group. Frequency of adverse events (AEs), including infections, was similar in the two treatment arms. Seven patients withdrew from the study but not related to AEs. CONCLUSIONS: In patients receiving long-term GCs, denosumab is superior to alendronate in raising the spine BMD after 12 months. Both drugs are well-tolerated.

Trend of Survival of a Cohort of Chinese Patients With Systemic Lupus Erythematosus Over 25 Years.

Objectives: To revisit the trend of survival of systemic lupus erythematosus in a cohort of Chinese patients over 25 years. Methods: Patients who fulfilled the 1997 ACR criteria for SLE and were followed in our hospital since 1995 were included. Patients were stratified into two groups according to the year of diagnosis: (1) 1995-2004 and (2) 2005-2018. Survival of patients was studied by Kaplan-Meier analysis. Organ damage as assessed by the Systemic Lupus International Collaborating Clinics (SLICC) damage index (SDI) and causes of death in the first 10 years of SLE onset was compared between the two groups. Cox regression was used to study factors associated with survival. Results: A total of 1,098 SLE patients were registered in our database. After excluding 157 patients diagnosed outside the time period of 1995-2018, 941 patients were studied (92% women). All were ethnic Chinese. The mean age of SLE onset was 35.1 ± 14.4 years, and the mean duration of observation was 13.1 ± 6.6 years. Seventy-seven (8.2%) patients were lost to follow-up. Groups 1 and 2 consisted of 364 and 577 patients, respectively. The mean SDI score at 10 years of disease onset was significantly higher in group 1 than group 2 patients (1.01 ± 1.43 vs. 0.57 ± 0.94; p < 0.01), particularly in the neuropsychiatric, musculoskeletal, and gonadal domains. Within 10 years of SLE onset, 32 (8.8%) patients in group 1 and 25 (4.3%) patients in group 2 died (p = 0.005). The 5- and 10-year cumulative survival rates were 93.6 and 91.0% in group 1 and 96.5 and 94.2% in group 2 patients, respectively (log-rank test p = 0.048). Infection accounted for more than half of the deaths in both groups. More group 1 than group 2 patients died of vascular events, but the difference was not statistically significant. Cox regression showed that the age of SLE onset and damage score accrued at 10 years, but not the time period in which SLE was diagnosed, were significantly associated with mortality. Conclusions: The improvement in survival of our SLE patients is probably related to the accrual of less organ damage in the past 15 years.

Prevalence and risk factors of herpes zoster infection in patients with biopsy proven lupus nephritis undergoing immunosuppressive therapies.

OBJECTIVES: To study the prevalence of herpes zoster infection in patients with biopsy-confirmed lupus nephritis undergoing immunosuppressive therapies. METHODS: Patients who had histologically active lupus nephritis between 2004 and 2018 were retrospectively reviewed. Clinical and laboratory data at baseline and six months post-therapy were collected. The incidence of herpes zoster reactivation within two years of lupus nephritis treatment was calculated. Risk factors for herpes zoster reactivation were studied by logistic regression. RESULTS: Patients (N = 251) with 311 episodes of lupus nephritis were studied (92% women; age 34.2 ± 14.2 years; histological classes III/IV ± V (69%)). Within two years of therapy, 55 (18%) episodes of lupus nephritis were complicated by herpes zoster infection (incidence 8.84/100 patient-years). Fourteen episodes (25%) of herpes zoster were treated by intravenous anti-viral drugs in hospital but disseminated disease or mortality was not reported. Significant post-herpetic neuralgia developed in 9% of the episodes. Patients with herpes zoster reactivation, compared with those without, were more likely to have first-time renal disease and a shorter systemic lupus erythematosus duration at lupus nephritis than those without. Disease activity, treatment response and other clinical/laboratory parameters were not significantly different between patients with and without herpes zoster reactivation. Herpes zoster-infected patients had been treated with a significantly higher dose of prednisolone as induction therapy. Logistic regression revealed that first-time renal disease, peak daily mycophenolate mofetil dose and cumulative cyclophosphamide dose during induction therapy were significantly associated with herpes zoster reactivation. CONCLUSIONS: Herpes zoster reactivation is common in lupus nephritis patients but unpredictable from clinical parameters. Although adverse outcomes of herpes zoster infection are uncommon, using the minimally effective doses of mycophenolate mofetil and cyclophosphamide during induction therapy may help reduce the risk of herpes zoster infection.

Long-term outcome of a randomised controlled trial comparing tacrolimus with mycophenolate mofetil as induction therapy for active lupus nephritis.

OBJECTIVES: To report the 10-year outcome of lupus nephritis (LN) treated with mycophenolate mofetil (MMF) or tacrolimus (TAC) induction in a randomised controlled trial. METHODS: Patients with active LN were treated with MMF or TAC combined with high-dose prednisolone. Responders were switched to azathioprine (AZA) at month 6. Clinical outcomes at 10 years (renal flares, renal function decline and mortality) were assessed. Factors affecting prognosis were studied by Cox regression. Urine protein-to-creatinine ratio (uPCr) and estimated glomerular filtration rate (eGFR) at different time points were evaluated for their prediction of a poor prognosis by receiver operating characteristic (ROC) analysis. RESULTS: 150 patients were studied (age 35.5±12.8 years). Complete renal response rate was similar between MMF (59%) and TAC-treated patients (62%; p=0.71). AZA maintenance was given to 79% patients. After 118.2±42 months, proteinuric and nephritic renal flares occurred in 34% and 37% of the MMF, and 53% and 30% of the TAC groups of patients, respectively (p=0.49). The cumulative incidence of a composite outcome of ↓eGFR ≥30%, chronic kidney disease stage 4/5 or death at 10 years was 33% in both groups (p=0.90). Factors independently associated with a poor renal prognosis were first-time LN (HR 0.12 (0.031 to 0.39); p=0.01), eGFR (HR 0.98 (0.96 to 0.99); p=0.008) and no response at month 6 (HR 5.18 (1.40 to 19.1); p=0.01). ROC analysis revealed an uPCr >0.75 and eGFR of <80 mL/min at month 18 best predicted a poor renal prognosis. CONCLUSIONS: Long-term data confirmed non-inferiority of TAC to MMF as induction therapy of LN. An uPCr≤0.75 and eGFR of ≥80 mL/min at month 18 best predicted a favourable 10-year outcome and may be suitable targets for induction/consolidation therapy. TRIAL REGISTRATION NUMBER: NCT00371319.

Safety and immune response of a live-attenuated herpes zoster vaccine in patients with systemic lupus erythematosus: a randomised placebo-controlled trial.

OBJECTIVES: To study the safety and immunogenicity of a live-attenuated herpes zoster (HZ) vaccine in patients with systemic lupus erythematosus (SLE). METHODS: Adult SLE patients having a SLEDAI <6 and stable immunosuppressive treatment for ≥6 months were recruited. Participants were randomly assigned to receive HZ vaccine (Zostavax) or placebo injection. Anti-varicella zoster virus (VZV) IgG reactivity (baseline and week 6) was measured by an enzyme-linked fluorescence assay. Cell-mediated response was assessed by a VZV-stimulated interferon-gamma (IFN-γ) enzyme-linked ELISPOT assay. Adverse events and immune responses of the two groups were compared. RESULTS: 90 SLE patients were recruited (age 45.6±14.1 years; 93% women) and assigned to Zostavax or placebo (in 1:1 ratio). Baseline clinical parameters were similar between the two groups. The change in anti-VZV IgG from week 0 to 6 was +59.8% in the vaccine and -2.1% in the placebo group. Week 6 anti-VZV IgG was significantly higher in vaccinated than placebo-treated patients, after adjustment for baseline (4.16±1.26 vs 3.32±1.01; p<0.001). The number of IFN-γ secreting T-cell spots decreased in the placebo-treated patients (-17%) but increased in vaccinated patients (+42%). The T-cell spots number at week 6 was significantly higher in vaccine-than placebo-treated patients after adjustment for baseline (38.1±78.2 vs 23.1±47.9; p=0.02). Significantly more vaccinated patients reported self-limiting injection site reaction than controls (31% vs 7%; p<0.01). Two vaccinated patients (4.4%) and one (2.2%) placebo-treated patient had mild/moderate SLE flares but no patients developed HZ eruption within 6 weeks postvaccination. CONCLUSIONS: In patients with stable SLE not receiving intensive immunosuppression, Zostavax was well-tolerated and provoked an immune response. TRIAL REGISTRATION NUMBER: US ClinicalTrials.gov registry (NCT02477150).

Serum 25-hydroxyvitamin D3 levels and flares of systemic lupus erythematosus: a longitudinal cohort analysis.

The aim of this study is to evaluate the relationship between baseline serum 25-hydroxyvitamin D3 levels and SLE activity/flares over time. This is a longitudinal study of 276 patients who fulfilled ≥ 4 ACR criteria for SLE and recruited in the year 2011. Serum samples were collected at baseline and assayed for 25-hydroxyvitamin D3 at the end of a mean follow-up of 32.5 months. Participants were stratified into three groups according to baseline 25-hydroxyvitamin D3 levels: group I (< 15 ng/ml, deficiency), group II (15-30 ng/ml, insufficiency), and group III (> 30 ng/ml, adequate). Baseline and summated SLE disease activity index (SLEDAI) score over time and the annual incidence of lupus flares were compared among these groups. 25-hydroxyvitamin D3 levels of < 15, 15-30, and > 30 ng/ml were present in 26, 54, and 20% of the recruited patients, respectively. Group I had significantly higher baseline SLEDAI scores. After a follow-up of 32.5 ± 5.5 months, 153 mild/moderate and 91 severe flares developed. The mean summated SLEDAI was 3.2 ± 2.0 in group I, 2.4 ± 1.9 in group II and 2.7 ± 2.1 in group III patients (P = 0.02). The annual incidence of mild/moderate and severe flares was 0.26 ± 0.39 and 0.20 ± 0.45 (group I); 0.20 ± 0.33 and 0.09 ± 0.22 (group II); and 0.20 ± 0.32 and 0.14 ± 0.46 (group III), respectively (P > 0.05). In a subgroup of 73 patients who were clinically and serologically quiescent at baseline, a similar trend of more flares was observed in group I patients. Vitamin D deficiency was frequent in Chinese SLE patients and was associated with more active disease at baseline and over time, as well as a trend of more severe lupus flares.

Urinary angiostatin, CXCL4 and VCAM-1 as biomarkers of lupus nephritis.

BACKGROUND: The aim was to study urinary angiostatin, CXC chemokine ligand 4 (CXCL4) and vascular cell adhesion molecule-1 (VCAM-1) as biomarkers of renal disease in systemic lupus erythematosus (SLE). METHOD: Patients who fulfilled ≥ 4 American College of Rheumatology (ACR) criteria for SLE with active renal, active non-renal or inactive disease, and a group of healthy controls were studied. Urine samples were assayed for angiostatin, CXCL4 and VCAM-1 by ELISA, and normalized by creatinine. Receiver operating characteristic analysis was performed to obtain the best cutoff values to calculate the performance of these markers in differentiating the different groups of patients as compared to anti-double-stranded DNA (anti-dsDNA) and complement C3. Correlation between these urinary biomarkers and various renal parameters was also tested. RESULTS: Patients with SLE (n = 227; 80 with inactive SLE, 67 with active non-renal disease and 80 with active renal disease; 94% women; age 39.2 ± 13.8 years) and 53 controls (96% women) were studied. All were ethnic Chinese. Urinary angiostatin, CXCL4 and VCAM-1 (normalized for creatinine) were significantly higher in patients with active renal disease than in patients with active non-renal disease, patients with inactive SLE and controls. These markers correlated significantly with total SLE disease activity index (SLEDAI) and renal SLEDAI scores, and with the urinary protein-to-creatinine ratio. Urine angiostatin exhibited higher specificity and sensitivity in differentiating active renal from active non-renal SLE (area under the curve (AUC) 0.87) than serum anti-dsDNA/C3. Urine CXCL4 (AUC 0.64) and VCAM-1 (AUC 0.73), on the other hand, performed similarly to anti-dsDNA/C3. All three markers performed comparably to anti-dsDNA/C3 in distinguishing active from inactive SLE. In a subgroup of 68 patients with paired renal biopsy, the urinary levels of these proteins did not differ significantly between the proliferative and non-proliferative types of lupus nephritis. Urinary CXCL4 and VCAM-1 correlated significantly with the histologic activity score, and urinary angiostatin correlated significantly with proteinuria in this subgroup. CONCLUSIONS: Urinary angiostatin, CXCL4 and VCAM-1 are potential biomarkers for SLE, in particular lupus nephritis. Further longitudinal studies are necessary to delineate the performance of these markers in predicting renal flares and prognosis in SLE patients.

Effect of the metabolic syndrome on organ damage and mortality in patients with systemic lupus erythematosus: a longitudinal analysis.

OBJECTIVES: To study the effect of the metabolic syndrome (MetS) on organ damage and mortality in patients with SLE. METHODS: Consecutive patients who fulfilled ≥4 ACR criteria for SLE were assessed for the MetS in October 2010. The MetS was defined by the updated joint consensus criteria, using the Asian criteria for central obesity. Longitudinal data on organ damage and mortality were retrieved. The association between MetS and new damage and mortality was studied by logistic regression. RESULTS: A total of 577 SLE patients were followed (93% women; age 41.2±13.4 years; SLE duration 9.3±7.2 years) and 85 (14.7%) patients qualified the MetS. After a follow-up of 66.3±1.8 month, new organ damage and vascular events developed in 128(22%) and 23(4.0%) patients, respectively. Thirty-nine (6.8%) patients succumbed. Patients with the MetS, compared to those without, had significantly more SLICC damage score accrual (0.70±1.0 vs 0.26±0.6; p<0.001), new vascular events (11% vs 2.8%; p=0.001), all-cause (14% vs 5.5%; p=0.003) and vascular (7.1% vs 0.2%; p<0.001) mortality. Logistic regression revealed that the MetS was significantly associated with new damage in the renal (OR 5.48[2.06-14.6]; p=0.001) and endocrine system (OR 38.0[4.50-321]; p=0.001), adjusted for age, sex, SLE duration, ever smoking, antiphospholipid antibodies and the new use of glucocorticoids or hydroxychloroquine since recruitment. Moreover, the presence of the MetS also significantly increased the risk of new vascular events (OR 3.38[1.31-8.74];p=0.01) and vascular mortality (OR 28.3[3.24-247]; p=0.002) after adjustment for the same covariates. CONCLUSION: In this longitudinal study, the MetS is significantly associated with new organ damage, vascular events and mortality in patients with SLE.

Prevalence of remission and its effect on damage and quality of life in Chinese patients with systemic lupus erythematosus.

OBJECTIVES: To study the prevalence of remission and its effect on damage and quality of life (QOL) in Chinese patients with systemic lupus erythematosus (SLE). METHODS: Patients who fulfilled ≥4 American College of Rheumatology criteria for SLE were identified. Their remission status at last clinic visits was determined by the European consensus criteria (complete/clinical remission ± immunosuppressive drugs). The increase in SLE damage index (SDI) in the preceding 5 years was compared between patients who were and were not in remission for ≥5 years. QOL of patients as assessed by the validated Chinese version of the Medical Outcomes Study Short-Form-36 (SF36) and the LupusPRO was also compared between the remission and non-remission groups by statistical analysis. RESULTS: 769 SLE patients were studied (92% women; age: 46.4±14.6 years; SLE duration: 12.6±8.1 years). At last visit, clinical remission was present in 259 (33.7%) patients and complete remission was present in 280 (36.4%) patients. Clinical and complete remissions for ≥5 years were achieved in 64 (8.3%) and 129 (16.8%) of the patients, respectively. Patients remitted for ≥5 years were older, and had significantly lower prevalence of renal involvement, leucopenia or thrombocytopaenia. Fifty-three (6.9%) patients in remission ≥5 years were taken off all medications, including hydroxychloroquine (HCQ) (drug-free). Patients who remitted for ≥5 years but off-therapy (except HCQ) had significantly less SDI increment than those who did not remit (0.17±0.53 vs 0.67±1.10; p<0.001). Among 453 patients who had QOL assessment, remission for ≥5 years was associated with significantly higher SF36 and the total health-related scores of the LupusPRO. CONCLUSIONS: Durable remission can be achieved in a quarter of patients with SLE. Patients with remission for ≥5 years have significantly less damage accrual and better QOL. Prolonged remission is an appropriate criterion for outcome assessment in SLE.

Association of depressive/anxiety symptoms with quality of life and work ability in patients with systemic lupus erythematosus.

OBJECTIVES: To study the association of depressive/anxiety symptoms with health-related quality of life (HRQoL) and work ability in Chinese patients with systemic lupus erythematosus (SLE). METHODS: Consecutive patients with ≥4 ACR criteria for SLE were recruited. Depressive and anxiety symptoms were assessed by the Hospital Anxiety and Depression scale (HADS). HRQoL was assessed by the Chinese version of MOS-Short Form (SF)-36. Disease activity of SLE was assessed by the SLE disease activity index (SLEDAI) and organ damage was assessed by the ACR/SLICC damage index (SDI). The relationship between HAD scores, work ability and HRQoL was studied. RESULTS: A total of 367 SLE patients were studied (95% women; age 40.2±12.9 years; disease duration 9.3±7.2 years). Fifty-five (15%) patients had HADS-depression score ≥10 and 70 (19%) patients had HADS-anxiety score ≥10. Patients with either score ≥10 had significantly lower SF36 score (physical and mental component) than those with score <10. In separate linear regression models, the mental and physical component scores of SF36 were significantly associated with the HAD-depression and HAD-anxiety score after adjustment for age, sex, SLE duration, years of education, religious belief, marital status, employment status, poverty, SDI and mean SLEDAI score in the preceding year. Among those who were working in the preceding year (n=190), 30(16%) patients either quitted their job (n=22) or reduced working hours (n=8). Patients with work disability had significantly higher HAD-depression score than those without (6.31±5.51 vs 3.93±3.72; p=0.03). CONCLUSIONS: Depressive/anxiety symptoms were fairly common in SLE patients and independently associated with poorer HRQoL. Patients with more depressive symptoms were more likely to experience work disability.

Switching of oral bisphosphonates to denosumab in chronic glucocorticoid users: a 12-month randomized controlled trial.

OBJECTIVES: To evaluate the effect of switching from oral bisphosphonates to denosumab on bone mineral density (BMD) in long-term glucocorticoid users. METHODS: Adult patients who were receiving long-term prednisolone (≥2.5 mg/day for ≥1 year) and oral bisphosphonates (≥2 years) were recruited. Participants were randomized to either continue oral bisphosphonates or switch to denosumab (60 mg subcutaneously every 6 months) for 12 months. Serial BMD (lumbar spine, hip) and bone turnover markers (serum osteocalcin, P1NP, ß-CTX) were measured. RESULTS: 42 women were recruited (age 54.7±12.9 years; 21 shifted to denosumab and 21 continued on bisphosphonates). The duration of prednisolone therapy was 101±66.3 months and the daily dose was 4.4±2.1 mg. Baseline demographic data, osteoporosis risk factors, and BMD at various sites were similar between the two groups of patients. At month 12, BMD of the spine and hip increased by +3.4±0.9% (p=0.002) and +1.4±0.6% (p=0.03), respectively, in the denosumab group; whereas the corresponding change was +1.5±0.4% (p=0.001) and +0.80±0.5% (p=0.12) in the bisphosphonate group. The spinal BMD at month 12 was significantly higher in the denosumab than bisphosphonate group after adjustment for baseline BMD and ß-CTX values, and other confounding factors (p=0.01). Bone turnover markers (ß-CTX and P1NP) were more strongly suppressed by denosumab than the bisphosphonates. Minor infections were more common in denosumab-treated patients while other adverse events occurred at similar frequencies between the two groups. CONCLUSIONS: In patients receiving long-term glucocorticoids, switching from oral bisphosphonates to denosumab resulted in greater gain of the spinal BMD and suppression of bone turnover markers after 12 months of therapy. The results have to be confirmed by a larger clinical trial with fracture as endpoint.

Validation of the LupusPRO in Chinese patients from Hong Kong with systemic lupus erythematosus.

OBJECTIVE: LupusPRO is a disease-targeted, patient-reported outcome (PRO) measure that was developed and validated for assessment of quality of life in US patients with systemic lupus erythematosus (SLE). We present results of adapting the LupusPRO into Chinese and testing its psychometric properties in Chinese patients with SLE. METHODS: LupusPRO was translated into "traditional" Chinese, followed by pretesting among native Cantonese Chinese speakers. The translation version was revised based on the feedback obtained. The Chinese language LupusPRO tool was administered along with a generic PRO tool (the Short Form 36 health survey [SF-36]) to ethnic Chinese SLE patients. At the same time, demographic information, clinical data, disease activity (Safety of Estrogens in Lupus Erythematosus National Assessment [SELENA] version of the Systemic Lupus Erythematosus Disease Activity Index [SLEDAI]), and damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index [SDI]) were obtained. We performed confirmatory factor analysis of the Chinese LupusPRO and evaluated internal consistency reliability, as well as convergent and criterion validity. RESULTS: Among the 463 SLE patients (95% women) with a mean ± SD age of 42.3 ± 13.5 years, the mean ± SD physician global assessment score was 0.48 ± 0.45, the mean ± SD SELENA-SLEDAI score was 2.9 ± 3.0, and the mean ± SD SDI score was 0.7 ± 1.2. Results of factor analysis conformed to the original LupusPRO model with only minor modifications. The reliability of the LupusPRO domains ranged from 0.60-0.94. LupusPRO domains had correlations as expected with the corresponding SF-36 domains. A significant but weak correlation with disease activity was noted for criterion validity as expected. CONCLUSION: The Chinese language LupusPRO has fair psychometric properties and may be used in SLE clinical trials.

Prevalence of the antiphospholipid syndrome and its effect on survival in 679 Chinese patients with systemic lupus erythematosus: a cohort study.

UNLABELLED: In this work we evaluate the prevalence of the antiphospholipid syndrome (APS) and its impact on survival in Chinese patients with systemic lupus erythematosus (SLE). We studied a prospective cohort of southern Chinese patients who fulfilled ≥4 American College of Rheumatology criteria for SLE. The cumulative rate of survival over time was calculated by the Kaplan-Meier method. APS was defined by the 2006 updated consensus criteria. We evaluated the prevalence and manifestations of APS, and compared the survival of patients with and without APS. We followed 679 patients with SLE (92% women; age of onset, 32.5 ± 14 yr) for 9.7 ± 7.3 years. Sixty-eight (10%) patients died and 33 (4.9%) patients were lost to follow-up. Forty-four (6.5%) patients met the criteria for APS, manifested by the following: ischemic stroke (55%), deep venous thrombosis (32%), obstetric morbidity (14%), cardiovascular events (9%), and peripheral vascular disease (9%). Nine (9/44 [20%]) APS patients died, which was more frequent than the non-APS patients (59/635 [9%]; p = 0.02). The cumulative mortality of patients with APS was 4.6% at 5 years, 7.8% at 10 years, and 22.2% at 15 years, which was not significantly higher than that of non-APS patients (5.4% at 5 years, 9.2% at 10 years, and 11.3% at 15 years; p = 0.14). However, if we considered only patients with APS caused by arterial thrombosis, the presence of APS was significantly associated with mortality (hazard ratio, 2.29; 95% confidence interval, 1.13-4.64; p = 0.02). We conclude that the presence of APS increases the mortality risk of Chinese patients with SLE, which is mainly contributed by arterial thrombotic events. CLINICAL SIGNIFICANCE: 1) APS is infrequent in southern Chinese patients with SLE compared to white patients. 2) Arterial thrombosis is a more common manifestation of APS than venous thrombosis in Chinese SLE patients. 3) APS related to arterial thrombosis is associated with increased mortality in Chinese patients with SLE.

High-sensitivity C-reactive protein, disease activity, and cardiovascular risk factors in systemic lupus erythematosus.

OBJECTIVE: To study the level of high-sensitivity C-reactive protein (hsCRP) and its relationship with disease activity, damage, and cardiovascular risk factors in patients with systemic lupus erythematosus (SLE). METHODS: Consecutive patients who fulfilled ≥4 American College of Rheumatology criteria for SLE who did not have a concurrent infection were recruited. Blood was assayed for hsCRP level, and disease activity, organ damage of SLE, and cardiovascular risk factors were assessed. Linear regression analyses were performed for the relationship between hsCRP levels, SLE activity, damage, and cardiovascular risk factors. RESULTS: In total, 289 patients were studied (94% women, mean ± SD age 39.0 ± 13.1 years, and mean ± SD SLE duration 7.8 ± 6.7 years). The mean ± SD Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score was 4.9 ± 5.6 and clinically active SLE was present in 122 patients (42%). The mean ± SD hsCRP level was 4.87 ± 12.7 mg/liter, and 28 patients with active SLE (23%) had an undetectable hsCRP level (<0.3 mg/liter). The linear regression analyses revealed a significant correlation between hsCRP level and musculoskeletal disease (ß = 0.21), hematologic disease (ß = 0.19), active serositis (ß = 0.46), and clinical SLEDAI score (ß = 0.24) after adjusting for age, sex, body mass index, serum creatinine, and the use of various medications (P < 0.005 for all). hsCRP levels correlated significantly with anti-double-stranded DNA titer (ß = 0.33, P < 0.001) but did not correlate with complement C3 (ß = -0.07, P = 0.26). An hsCRP level >3 mg/liter was significantly associated with male sex, long-term smoking, diabetes mellitus, a higher atherogenic index, and a history of arterial thrombosis. hsCRP levels correlated significantly with pulmonary and endocrine damage scores. CONCLUSION: hsCRP was detectable in 77% of SLE patients with clinically active disease and correlated with SLEDAI scores, particularly in serositis and in the musculoskeletal and hematologic systems. Elevated hsCRP levels in SLE were associated with certain cardiovascular risk factors and a history of arterial thromboembolism.