Anti-KIF20B autoantibodies are associated with cranial neuropathy in systemic lupus erythematosus.

BACKGROUND: Cranial neuropathies (CN) are a rare neuropsychiatric SLE (NPSLE) manifestation. Previous studies reported that antibodies to the kinesin family member 20B (KIF20B) (anti-KIF20B) protein were associated with idiopathic ataxia and CN. We assessed anti-KIF20B as a potential biomarker for NPSLE in an international SLE inception cohort. METHODS: Individuals fulfilling the revised 1997 American College of Rheumatology (ACR) SLE classification criteria were enrolled from 31 centres from 1999 to 2011 and followed annually in the Systemic Lupus Erythematosus International Collaborating Clinics inception cohort. Anti-KIF20B testing was performed on baseline (within 15 months of diagnosis or first annual visit) samples using an addressable laser bead immunoassay. Logistic regression (penalised maximum likelihood and adjusting for confounding variables) examined the association between anti-KIF20B and NPSLE manifestations (1999 ACR case definitions), including CN, occurring over the first 5 years of follow-up. RESULTS: Of the 1827 enrolled cohort members, baseline serum and 5 years of follow-up data were available on 795 patients who were included in this study: 29.8% were anti-KIF20B-positive, 88.7% female, and 52.1% White. The frequency of anti-KIF20B positivity differed only for those with CN (n=10) versus without CN (n=785) (70.0% vs 29.3%; OR 5.2, 95% CI 1.4, 18.5). Compared with patients without CN, patients with CN were more likely to fulfil the ACR haematological (90.0% vs 66.1%; difference 23.9%, 95% CI 5.0%, 42.8%) and ANA (100% vs 95.7%; difference 4.3%, 95% CI 2.9%, 5.8%) criteria. In the multivariate analysis adjusting for age at baseline, female, White race and ethnicity, and ACR haematological and ANA criteria, anti-KIF20B positivity remained associated with CN (OR 5.2, 95% CI 1.4, 19.1). CONCLUSION: Anti-KIF20B is a potential biomarker for SLE-related CN. Further studies are needed to examine how autoantibodies against KIF20B, which is variably expressed in a variety of neurological cells, contribute to disease pathogenesis.

Association Between Severe Nonadherence to Hydroxychloroquine and Systemic Lupus Erythematosus Flares, Damage, and Mortality in 660 Patients From the SLICC Inception Cohort.

OBJECTIVE: The goals of this study were to assess the associations of severe nonadherence to hydroxychloroquine (HCQ), objectively assessed by HCQ serum levels, and risks of systemic lupus erythematosus (SLE) flares, damage, and mortality rates over five years of follow-up. METHODS: The Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort is an international multicenter initiative (33 centers throughout 11 countries). The serum of patients prescribed HCQ for at least three months at enrollment were analyzed. Severe nonadherence was defined by a serum HCQ level <106 ng/mL or <53 ng/mL for HCQ doses of 400 or 200 mg/day, respectively. Associations with the risk of a flare (defined as a Systemic Lupus Erythematosus Disease Activity Index 2000 increase ≥4 points, initiation of prednisone or immunosuppressive drugs, or new renal involvement) were studied with logistic regression, and associations with damage (first SLICC/American College of Rheumatology Damage Index [SDI] increase ≥1 point) and mortality with separate Cox proportional hazard models. RESULTS: Of the 1,849 cohort participants, 660 patients (88% women) were included. Median (interquartile range) serum HCQ was 388 ng/mL (244-566); 48 patients (7.3%) had severe HCQ nonadherence. No covariates were clearly associated with severe nonadherence, which was, however, independently associated with both flare (odds ratio 3.38; 95% confidence interval [CI] 1.80-6.42) and an increase in the SDI within each of the first three years (hazard ratio [HR] 1.92 at three years; 95% CI 1.05-3.50). Eleven patients died within five years, including 3 with severe nonadherence (crude HR 5.41; 95% CI 1.43-20.39). CONCLUSION: Severe nonadherence was independently associated with the risks of an SLE flare in the following year, early damage, and five-year mortality.

Genetics of longitudinal kidney function in children and adults with systemic lupus erythematosus.

OBJECTIVES: Genome-wide association studies (GWAS) have identified loci associated with estimated glomerular filtration rate (eGFR). Few LN risk loci have been identified to date. We tested the association of SLE and eGFR polygenic risk scores (PRS) with repeated eGFR measures from children and adults with SLE. METHODS: Patients from two tertiary care lupus clinics that met ≥4 ACR and/or SLICC criteria for SLE were genotyped on the Illumina MEGA or Omni1-Quad arrays. PRSs were calculated for SLE and eGFR, using published weighted GWA-significant alleles. eGFR was calculated using the CKD-EPI and Schwartz equations. We tested the effect of eGFR- and SLE-PRSs on eGFR mean and variance, adjusting for age at diagnosis, sex, ancestry, follow-up time, and clinical event flags. RESULTS: We included 1158 SLE patients (37% biopsy-confirmed LN) with 36 733 eGFR measures over a median of 7.6 years (IQR: 3.9-15.3). LN was associated with lower within-person mean eGFR [LN: 93.8 (s.d. 26.4) vs non-LN: 101.6 (s.d. 17.7) mL/min per 1.73 m2; P < 0.0001] and higher variance [LN median: 157.0 (IQR: 89.5, 268.9) vs non-LN median: 84.9 (IQR: 46.9, 138.2) (mL/min per 1.73 m2)2; P < 0.0001]. Increasing SLE-PRSs were associated with lower mean eGFR and greater variance, while increasing eGFR-PRS was associated with increased eGFR mean and variance. CONCLUSION: We observed significant associations between SLE and eGFR PRSs and repeated eGFR measurements, in a large cohort of children and adults with SLE. Longitudinal eGFR may serve as a powerful alternative outcome to LN categories for discovery of LN risk loci.

Assessing the Costs of Neuropsychiatric Disease in the Systemic Lupus International Collaborating Clinics Cohort Using Multistate Modeling.

OBJECTIVE: To estimate direct and indirect costs associated with neuropsychiatric (NP) events in the Systemic Lupus International Collaborating Clinics inception cohort. METHODS: NP events were documented annually using American College of Rheumatology definitions for NP events and attributed to systemic lupus erythematosus (SLE) or non-SLE causes. Patients were stratified into 1 of 3 NP states (no, resolved, or new/ongoing NP event). Change in NP status was characterized by interstate transition rates using multistate modeling. Annual direct costs and indirect costs were based on health care use and impaired productivity over the preceding year. Annual costs associated with NP states and NP events were calculated by averaging all observations in each state and adjusted through random-effects regressions. Five- and 10-year costs for NP states were predicted by multiplying adjusted annual costs per state by expected state duration, forecasted using multistate modeling. RESULTS: A total of 1,697 patients (49% White race/ethnicity) were followed for a mean of 9.6 years. NP events (n = 1,971) occurred in 956 patients, 32% attributed to SLE. For SLE and non-SLE NP events, predicted annual, 5-, and 10-year direct costs and indirect costs were higher in new/ongoing versus no events. Direct costs were 1.5-fold higher and indirect costs 1.3-fold higher in new/ongoing versus no events. Indirect costs exceeded direct costs 3.0 to 5.2 fold. Among frequent SLE NP events, new/ongoing seizure disorder and cerebrovascular disease accounted for the largest increases in annual direct costs. For non-SLE NP events, new/ongoing polyneuropathy accounted for the largest increase in annual direct costs, and new/ongoing headache and mood disorder for the largest increases in indirect costs. CONCLUSION: Patients with new/ongoing SLE or non-SLE NP events incurred higher direct and indirect costs.

Evaluating the Threshold Score for Classification of Systemic Lupus Erythematosus Using the EULAR/ACR Criteria.

OBJECTIVE: To evaluate whether a change in the European Alliance of Associations for Rheumatology (EULAR)/American College of Rheumatology (ACR) systemic lupus erythematosus (SLE) classification criteria threshold score affects accurate classification of SLE cases compared to disease-based control subjects. We evaluated a range of threshold scores to determine the score that maximizes the accurate classification of early SLE. METHODS: We conducted a cross-sectional study comparing SLE cases and control patients. A EULAR/ACR criteria score was calculated using baseline information. Sensitivity, specificity, positive likelihood ratios (+LRs), and negative likelihood ratios (-LRs) with 95% CIs were used to evaluate operating characteristics. Threshold scores of 6 to 12 were evaluated in subjects with early disease (ie, disease duration of ≤ 5 years). +LRs > 10 and -LRs < 0.1 provide evidence to rule in or rule out SLE. RESULTS: A total of 2764 patients were included: 1980 SLE cases who fulfilled either the ACR or Systemic Lupus International Collaborating Clinics criteria and 784 control subjects. The EULAR/ACR SLE criteria had a sensitivity of 98% (95% CI 97-98), a specificity of 99% (95% CI 98-100), a +LR of 95.5 (95% CI 48.0-190), and a -LR 0.03 (95% CI 0.02-0.03). The criteria operated well in those with early disease, in women, in men, and in White, Black, Chinese, and Filipino people. A score of 10 maximized the accurate classification of patients with early disease (+LR 174.4, 95% CI 43.8-694.6; -LR 0.03, 95% CI 0.02-0.04). An increase in the threshold score from 10 to 11 resulted in significant worsening in the -LR (threshold score 10: -LR 0.03, 95% CI 0.02-0.03 vs threshold score 11: -LR 0.05, 95% CI 0.04-0.06). CONCLUSION: The EULAR/ACR SLE classification criteria threshold score of 10 performs well, particularly among those with early disease and across sexes and ethnicities.

Health information use by patients with systemic lupus erythematosus (SLE) pre and during the COVID-19 pandemic.

OBJECTIVE: We conducted an international survey of patients with SLE to assess their access, preference and trust in various health information sources pre-COVID-19 and during the COVID-19 pandemic. METHODS: Patients with SLE were recruited from 18 observational cohorts, and patients self-reporting SLE were recruited through five advocacy organisations. Respondents completed an online survey from June 2020 to December 2021 regarding the sources of health information they accessed in the 12 months preceding (pre-11 March 2020) and during (post-11 March 2020) the pandemic. Multivariable logistic regressions assessed factors associated with accessing news and social media post-11 March 2020, and self-reporting negative impacts from health information accessed through these sources. RESULTS: Surveys were completed by 2111 respondents; 92.8% were female, 76.6% had postsecondary education, mean (SD) age was 48.8 (14.0) years. Lupus specialists and family physicians were the most preferred sources pre-11 March 2020 and post-11 March 2020, yet were accessed less frequently (specialists: 78.5% pre vs 70.2% post, difference -8.3%, 95% CI -10.2% to -6.5%; family physicians: 57.1% pre vs 50.0% post, difference -7.1%, 95% CI -9.2% to -5.0%), while news (53.2% pre vs 62.1% post, difference 8.9%, 95% CI 6.7% to 11.0%) and social media (38.2% pre vs 40.6% post, difference 2.4%, 95% CI 0.7% to 4.2%) were accessed more frequently post-11 March 2020 vs pre-11 March 2020. 17.2% of respondents reported negative impacts from information accessed through news/social media. Those outside Canada, older respondents or with postsecondary education were more likely to access news media. Those in Asia, Latin America or younger respondents were more likely to access social media. Those in Asia, older respondents, males or with postsecondary education in Canada, Asia or the USA were less likely to be negatively impacted. CONCLUSIONS: Physicians, the most preferred and trusted sources, were accessed less frequently, while news and social media, less trusted sources, were accessed more frequently post-11 March 2020 vs pre-11 March 2020. Increasing accessibility to physicians, in person and virtually, may help reduce the consequences of accessing misinformation/disinformation.

The new EULAR/ACR 2019 SLE classification criteria: A predictor of long-term outcomes.

OBJECTIVES: To determine the ability of a EULAR/ACR SLE criteria score ≥20 to predict damage accrual and mortality. METHODS: Inception SLE patients from the Toronto Lupus Clinic recruited in the first 12 months after diagnosis were included. A EULAR/ACR criteria score was calculated based on the baseline clinical and laboratory information. A EULAR/ACR score of 20 was used as a threshold to compare outcomes between groups (EULAR/ACR score <20 vs ≥20), based on receiver operating characteristic analysis. RESULTS: 867 SLE patients were included. The group of patients with the higher score accrued more damage compared to the group with the lower score in the first 10 years after diagnosis (210 [46%] vs 167 [40%] for patients with a score ≥20 vs < 20 respectively p = 0.02). This was corroborated by multivariable regression analysis (HR 1.34, p = 0.007). Patients with a score of ≥20 had a higher risk of death (HR 2.34, p = 0.001). When excluding patients who had kidney involvement at baseline, the group with the higher score continued to be at a higher risk of damage accrued (HR 1.46, p = 0.006), although there was no difference in mortality between groups (p = 0.54). CONCLUSION: A EULAR/ACR criteria score ≥20 at baseline is an indicator of long-term outcomes, especially damage accrual.

Outcomes following antimalarial withdrawal in patients with quiescent systemic lupus erythematosus.

OBJECTIVE: Antimalarial medications (AMs) are central to the management of SLE. We investigated the rate of flare in lupus patients who withdrew AM after achieving clinical remission for at least one year, compared to those who continued therapy and compared flare rates in cases who tapered AM versus abruptly withdrew. METHODS: Cases achieved clinical remission for at least one year then ceased their AM. Index date was defined as the date of complete AM cessation. Controls achieved clinical remission for at least one year and continued AM. Controls were matched according to the duration of AM before remission and the duration of therapy from remission date to case index date. All patients had ≥ 2 years of follow up. RESULTS: Of 1573 patients on AM, 165 achieved a one-year remission and then ceased their AM. 96 had adequate follow-up, 88 were successfully matched to one control and 85 to 2 controls for a total of 173 controls. Flare occurred in 61.4% of cases and 45.1% of controls (p = 0.002). 52.3% patients who withdrew AM later restarted it due to disease flare. 88% recaptured control or improved, while 12% did not. Patients who tapered had significantly fewer flares (45.9% vs. 72.6%; p = 0.01). CONCLUSION: AMs aid in preventing disease flare even in patients who have achieved prolonged clinical remission. Tapering AM results in lower flare rates. Hence, except in the setting of toxicity, cessation of antimalarial therapy in patients with prolonged disease quiescence is feasible using a slow taper.

Impact of Belimumab on Organ Damage in Systemic Lupus Erythematosus.

Organ damage is a key determinant of poor long-term prognosis and early death in patients with systemic lupus erythematosus (SLE). Prevention of damage is a key treatment goal of the 2019 update of the European Alliance of Associations for Rheumatology (EULAR) recommendations for SLE management. Belimumab is a monoclonal antibody that inhibits B lymphocyte stimulator (BLyS) and is the only therapy approved for both SLE and lupus nephritis. Here, we review the clinical trial and real-world data on the effects of belimumab on organ damage in adult patients with SLE. Across 4 phase III studies, belimumab in combination with background SLE therapy demonstrated consistent reductions in key drivers of organ damage including disease activity, risk of new severe flares, and glucocorticoid exposure compared to background therapy alone. Long-term belimumab use in SLE also reduced organ damage progression measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, as reported in open-label extension studies, and propensity score-matched comparative analyses to background therapy alone. Results from a clinical trial showed that in patients with active lupus nephritis, belimumab treatment improved renal response, reduced the risk of renal-related events, and impacted features related to kidney damage progression compared to background therapy alone. The decrease of organ damage accumulation observed with belimumab treatment in SLE, including lupus nephritis, suggest a disease-modifying effect.

Conceptual framework for defining disease modification in systemic lupus erythematosus: a call for formal criteria.

Disease modification has become a well-established concept in several therapeutic areas; however, no widely accepted definition of disease modification exists for SLE.We reviewed established definitions of disease modification in other conditions and identified a meaningful effect on 'disease manifestations' (ie, signs, symptoms and patient-reported outcomes) and on 'disease outcomes' (eg, long-term remission or progression of damage) as the key principles of disease modification, indicating a positive effect on the natural course of the disease. Based on these findings and the treatment goals and outcome measures for SLE, including lupus nephritis, we suggest a definition of disease modification based on disease activity indices and organ damage outcomes, with the latter as a key anchor. A set of evaluation criteria is also suggested.Establishing a definition of disease modification in SLE will clarify which treatments can be considered disease modifying, provide an opportunity to harmonise future clinical trial outcomes and enable comparison between therapies, all of which could ultimately help to improve patient outcomes. This publication seeks to catalyse further discussion and provide a framework to develop an accepted definition of disease modification in SLE.

Medium Versus High Initial Prednisone Dose for Remission Induction in Lupus Nephritis: A Propensity Score-Matched Analysis.

OBJECTIVE: The existing guidelines for lupus nephritis (LN) recommend initial prednisone doses of 0.3-1.0 mg/kg/day. However, recent studies reported noninferior outcomes with lower doses. The aim of this study was to compare the complete renal response rates in LN patients treated with prednisone ≤30 mg/day or ≥40 mg/day. METHODS: Patients with new-onset LN and standard immunosuppressive treatment were followed for at least 12 months, divided into medium (≤30 mg/day) and high prednisone groups (≥40 mg/day) and matched (propensity score) based on the baseline differences. Complete renal response was defined as proteinuria <0.5 gm/day and no worsening in renal function. Glucocorticoid-related damage was also assessed. RESULTS: High-dose prednisone patients (n = 103; mean ± SD dose 48.6 ± 12.3 mg/day) achieved better rates of complete response compared to the medium group (n = 103; mean ± SD dose 24.2 ± 4.6 mg/day) (61.8% versus 38.2%; P = 0.024) at 12 months. The difference in response rates was reproduced for several subgroups (concomitant immunosuppressive treatment, proliferative/nonproliferative LN). Complete remission rates were higher at 2 years (67.8% versus 39%; P = 0.002) and 3 years (64.9% versus 49.1%; P = 0.025) after LN diagnosis. Cumulative glucocorticoid dose was comparable at 2 and 3 years. Glucocorticoid-related damage was accelerated in both groups for the same period. CONCLUSION: Higher initial prednisone doses (median 45 mg/day) achieved significantly better rates of complete renal response at 12 months in new-onset LN. Cumulative glucocorticoid dose and damage accrual were not different at 2 and 3 years after LN. Damage was more prominent in the late phases of LN in both groups, underlining the importance of rapid tapering and the need to implement alternative strategies.

Prediction of Hospitalizations in Systemic Lupus Erythematosus Using the Systemic Lupus International Collaborating Clinics Frailty Index.

OBJECTIVE: The Systemic Lupus International Collaborating Clinics (SLICC) frailty index (FI) predicts mortality and damage accrual in systemic lupus erythematosus (SLE), but its association with hospitalizations has not been described. Our objective was to estimate the association of baseline SLICC-FI values with future hospitalizations in the SLICC inception cohort. METHODS: Baseline SLICC-FI scores were calculated. The number and duration of inpatient hospitalizations during follow-up were recorded. Negative binomial regression was used to estimate the association between baseline SLICC-FI values and the rate of hospitalizations per patient-year of follow-up. Linear regression was used to estimate the association of baseline SLICC-FI scores with the proportion of follow-up time spent in the hospital. Multivariable models were adjusted for relevant baseline characteristics. RESULTS: The 1,549 patients with SLE eligible for this analysis were mostly female (88.7%), with a mean ± SD age of 35.7 ± 13.3 years and a median disease duration of 1.2 years (interquartile range 0.9-1.5) at baseline. Mean ± SD baseline SLICC-FI was 0.17 ± 0.08. During mean ± SD follow-up of 7.2 ± 3.7 years, 614 patients (39.6%) experienced 1,570 hospitalizations. Higher baseline SLICC-FI values (per 0.05 increment) were associated with more frequent hospitalizations during follow-up, with an incidence rate ratio of 1.21 (95% confidence interval [95% CI] 1.13-1.30) after adjustment for baseline age, sex, glucocorticoid use, immunosuppressive use, ethnicity/location, SLE Disease Activity Index 2000 score, SLICC/American College of Rheumatology Damage Index score, and disease duration. Among patients with ≥1 hospitalization, higher baseline SLICC-FI values predicted a greater proportion of follow-up time spent hospitalized (relative rate 1.09 [95% CI 1.02-1.16]). CONCLUSION: The SLICC-FI predicts future hospitalizations among incident SLE patients, further supporting the SLICC-FI as a valid health measure in SLE.

Gradual Glucocorticosteroid Withdrawal Is Safe in Clinically Quiescent Systemic Lupus Erythematosus.

OBJECTIVES: Patients with systemic lupus erythematosus (SLE) are usually treated with glucocorticosteroids even during periods of clinically quiescent disease. A recent study showed that abrupt glucocorticoid withdrawal was associated with an increased likelihood of flare in the next 12 months. The aim of the present study was to assess clinical flare rates and damage accrual in patients who tapered glucocorticosteroids gradually. METHODS: Patients from the Toronto Lupus Clinic with 2 consecutive years of clinically quiescent disease were retrieved from the database. Individuals who maintained a low prednisone dose (5 mg/day) comprised the maintenance group, whereas patients who gradually tapered prednisone within these two years comprised the withdrawal group. All individuals were followed for 2 years after prednisone discontinuation or the corresponding date for the maintenance group. Propensity score matching was implemented to adjust for certain baseline differences. Outcomes included clinical flares and damage accrual. RESULTS: Of 270 eligible patients, 204 were matched (102 in each group). Flare rate (any increase in clinical SLE Disease Activity Index 2000) was lower in the withdrawal group both at 12 (17.6% versus 29.4%; P = 0.023) and 24 months (33.3% versus 50%; P = 0.01). Moderate to severe flares (requiring systemic treatment escalation) were not different at 12 months (10.8% versus 13.7%; P = 0.467) but were less frequent at 24 months (14.7% versus 27.5%; P = 0.024). Damage accrual was less frequent in the withdrawal group (6.9% versus 17.6%; P = 0.022). No predictors for clinical flares were identified. CONCLUSION: Gradual glucocorticoid withdrawal is safe in clinically quiescent SLE and is associated with fewer clinical flares and less damage accrual at 24 months.

Barriers to medication adherence and degree of nonadherence in a systemic lupus erythematosus (SLE) outpatient population.

To estimate the level of medication adherence and barriers to adherence among systemic lupus erythematosus (SLE) patients. Patients taking antimalarials, immunosuppressives, and/or steroids to treat SLE were included. Adherence was measured using the Medication Adherence Self Report Inventory (MASRI) and adherence rates < 80% were considered nonadherent while rates ≥ 80% sufficiently adherent. Pill counts were conducted in a proportion of participants. Barriers to adherence were identified using the Identification of Medication Adherence Barriers Questionnaire 30 (IMAB-Q 30). Associations between adherence and patient demographics and disease-specific characteristics were explored. A total of 94 patients were studied and 28 pill counts conducted. 10 patients were classified as nonadherent and 84 patients as sufficiently adherent. 46% of patients were taking steroids, 77.7% antimalarials, and 55.3% immunosuppressives. 88% of patients were taking ≥ 1 medication for non-SLE conditions. The mean medication adherence rate for the SLE patients was 90.7%. Important barriers to adherence reported by nonadherent patients were: concern about harmful side effects (50%), being easily distracted (50%), life getting in the way (50%), being unsure or disagreeing that their condition will worsen without medications (50%), and having personal reasons for not taking medications (50%). Non-adherent patients reported significantly more barriers than sufficiently adherent patients (p < 0.001). The adherence rate in our population was higher than expected, reaching 90%. Barriers to medication adherence were identified and should be addressed on a population and individualized basis to improve patient outcomes.

Neuropsychiatric Events in Systemic Lupus Erythematosus: Predictors of Occurrence and Resolution in a Longitudinal Analysis of an International Inception Cohort.

OBJECTIVE: To determine predictors of change in neuropsychiatric (NP) event status in a large, prospective, international inception cohort of patients with systemic lupus erythematosus (SLE). METHODS: Upon enrollment and annually thereafter, NP events attributed to SLE and non-SLE causes and physician-determined resolution were documented. Factors potentially associated with the onset and resolution of NP events were determined by time-to-event analysis using a multistate modeling structure. RESULTS: NP events occurred in 955 (52.3%) of 1,827 patients, and 593 (31.0%) of 1,910 unique events were attributed to SLE. For SLE-associated NP (SLE NP) events, multivariate analysis revealed a positive association with male sex (P = 0.028), concurrent non-SLE NP events excluding headache (P < 0.001), active SLE (P = 0.012), and glucocorticoid use (P = 0.008). There was a negative association with Asian race (P = 0.002), postsecondary education (P = 0.001), and treatment with immunosuppressive drugs (P = 0.019) or antimalarial drugs (P = 0.056). For non-SLE NP events excluding headache, there was a positive association with concurrent SLE NP events (P < 0.001) and a negative association with African race (P = 0.012) and Asian race (P < 0.001). NP events attributed to SLE had a higher resolution rate than non-SLE NP events, with the exception of headache, which had comparable resolution rates. For SLE NP events, multivariate analysis revealed that resolution was more common in patients of Asian race (P = 0.006) and for central/focal NP events (P < 0.001). For non-SLE NP events, resolution was more common in patients of African race (P = 0.017) and less common in patients who were older at SLE diagnosis (P < 0.001). CONCLUSION: In a large and long-term study of the occurrence and resolution of NP events in SLE, we identified subgroups with better and worse prognosis. The course of NP events differs greatly depending on their nature and attribution.

Assessment of cardiovascular risk tools as predictors of cardiovascular disease events in systemic lupus erythematosus.

BACKGROUND: SLE is an independent risk factor for cardiovascular disease (CVD). This study aimed to determine which among QRISK2, QRISK3, Framingham Risk Score (FRS), modified Framingham Risk Score (mFRS) and SLE Cardiovascular Risk Equation (SLECRE) best predicts CVD. METHODS: This is a single-centre analysis on 1887 patients with SLE followed prospectively according to a standard protocol. Tools' scores were evaluated against CVD development at/within 10 years for patients with CVD and without CVD. For patients with CVD, the index date for risk score calculation was chosen as close to 10 years prior to CVD event. For patients without CVD, risk scores were calculated as close to 10 years prior to the most recent clinic appointment. Proportions of low-risk (<10%), intermediate-risk (10%-20%) and high-risk (>20%) patients for developing CVD according to each tool were determined, allowing sensitivity, specificity, positive/negative predictive value and concordance (c) statistics analysis. RESULTS: Among 1887 patients, 232 CVD events occurred. QRISK2 and FRS, and QRISK3 and mFRS, performed similarly. SLECRE classified the highest number of patients as intermediate and high risk. Sensitivities and specificities were 19% and 93% for QRISK2, 22% and 93% for FRS, 46% and 83% for mFRS, 47% and 78% for QRISK3, and 61% and 64% for SLECRE. Tools were similar in negative predictive value, ranging from 89% (QRISK2) to 92% (SLECRE). FRS and mFRS had the greatest c-statistics (0.73), while QRISK3 and SLECRE had the lowest (0. 67). CONCLUSION: mFRS was superior to FRS and was not outperformed by the QRISK tools. SLECRE had the highest sensitivity but the lowest specificity. mFRS is an SLE-adjusted practical tool with a simple, intuitive scoring system reasonably appropriate for ambulatory settings, with more research needed to develop more accurate CVD risk prediction tools in this population.

The baseline interferon signature predicts disease severity over the subsequent 5 years in systemic lupus erythematosus.

OBJECTIVES: Type I interferons (IFNs) play an important role in the pathophysiology of systemic lupus erythematosus (SLE). While cross-sectional data suggest an association between IFN-induced gene expression and SLE disease activity, interest in this as a biomarker of flare has been tempered by a lack of fluctuation with disease activity in the majority of patients. This led us to question whether IFN-induced gene expression might instead be a biomarker of overall disease severity, with patients with high levels spending more time in an active disease state. METHODS: Levels of five interferon-responsive genes were measured in the whole peripheral blood at baseline visit for 137 SLE patients subsequently followed for 5 years. Log transformed values were summed to yield a composite IFN5 score, and the correlation with various disease outcomes examined. Receiver operator characteristic analyses were performed for outcomes of interest. Kaplan-Meier curves were generated to compare the proportion of flare-free patients with high and low IFN5 scores over time. RESULTS: The baseline IFN5 score was positively correlated with the adjusted mean SLE disease activity index-2000, number of flares, adjusted mean prednisone dose, and number of new immunosuppressive medications over the subsequent 5 years. Optimal cut-offs for the IFN5 score were determined using Youden's index and predicted more severe outcomes with 57-67% accuracy. A high baseline IFN5 level was associated with a significantly increased risk of subsequent flare. CONCLUSIONS: Measurement of the type I IFN signature is a useful tool for predicting the subsequent disease activity course.

Effect of Disease Activity on Organ Damage Progression in Systemic Lupus Erythematosus: University of Toronto Lupus Clinic Cohort.

OBJECTIVE: To examine the role of disease activity on organ damage over 5 years in patients with active systemic lupus erythematosus (SLE) despite standard of care. METHODS: This analysis of the University of Toronto Lupus Clinic cohort assessed organ damage [measured by Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI)] in patients with active SLE [SLE Disease Activity Index 2000 (SLEDAI-2K) ≥ 6], using Cox proportional time-independent hazard models. Subgroup analyses were conducted in patients with SLEDAI-2K 6 or 7, 8 or 9, and ≥ 10 at baseline, and in the overall study population by steroid dose at study entry (< 7.5 vs ≥ 7.5 mg/day). RESULTS: Among the overall study population (n = 649), SDI progression was observed in 209 (32.2%) patients over the 5-year follow-up period. Mean SDI change in patients with a score > 0 was generally consistent across all SLEDAI-2K subgroups. Multivariable analyses identified age at study start (HR 1.03, P < 0.0001), steroid dose (HR 2.03, P < 0.0001), immunosuppressants (HR 1.44, P = 0.021), and SLEDAI-2K (subgroup analyses HR 1.64-2.03, P = 0.0017 to < 0.0001) as the greatest risk factors for SDI progression, while a study start date after the year 2000 had a protective effect on SDI progression compared with a start date prior to the year 2000 (HR 0.65, P = 0.0004). CONCLUSION: Patients within the higher SLEDAI-2K subgroups at study entry or receiving high doses of steroids were more likely to have organ damage progression.