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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., (© 2023 American College of Rheumatology.)

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., (© 2020 American College of Rheumatology.)

Objective: To assess cancer risk factors in incident systemic lupus erythematosus (SLE)., Methods: Clinical variables and cancer outcomes were assessed annually among incident SLE patients. Multivariate hazard regression models (overall risk and most common cancers) included demographic characteristics and time-dependent medications (corticosteroids, antimalarial drugs, immunosuppressants), smoking, and the adjusted mean Systemic Lupus Erythematosus Disease Activity Index 2000 score., Results: Among 1,668 patients (average 9 years follow-up), 65 cancers occurred: 15 breast, 10 nonmelanoma skin, 7 lung, 6 hematologic, 6 prostate, 5 melanoma, 3 cervical, 3 renal, 2 each gastric, head and neck, and thyroid, and 1 each rectal, sarcoma, thymoma, and uterine cancers. Half of the cancers (including all lung cancers) occurred in past/current smokers, versus one-third of patients without cancer. Multivariate analyses indicated that overall cancer risk was related primarily to male sex and older age at SLE diagnosis. In addition, smoking was associated with lung cancer. For breast cancer risk, age was positively associated and antimalarial drugs were negatively associated. Antimalarial drugs and higher disease activity were also negatively associated with nonmelanoma skin cancer risk, whereas age and cyclophosphamide were positively associated. Disease activity was associated positively with hematologic and negatively with nonmelanoma skin cancer risk., Conclusion: Smoking is a key modifiable risk factor, especially for lung cancer, in SLE. Immunosuppressive medications were not clearly associated with higher risk except for cyclophosphamide and nonmelanoma skin cancer. Antimalarials were negatively associated with breast cancer and nonmelanoma skin cancer risk. SLE activity was associated positively with hematologic cancer and negatively with nonmelanoma skin cancer. Since the absolute number of cancers was small, additional follow-up will help consolidate these findings., (© 2020, American College of Rheumatology.)

Objective: The Systemic Lupus International Collaborating Clinics (SLICC) 2012 systemic lupus erythematosus (SLE) classification criteria and the revised American College of Rheumatology (ACR) 1997 criteria are list based, counting each SLE manifestation equally. We derived a classification rule based on giving variable weights to the SLICC criteria and compared its performance to the revised ACR 1997, the unweighted SLICC 2012, and the newly reported European Alliance of Associations for Rheumatology (EULAR)/ACR 2019 criteria sets., Methods: The physician-rated patient scenarios used to develop the SLICC 2012 classification criteria were reemployed to devise a new weighted classification rule using multiple linear regression. The performance of the rule was evaluated on an independent set of expert-diagnosed patient scenarios and compared to the performance of the previously reported classification rules., Results: The weighted SLICC criteria and the EULAR/ACR 2019 criteria had less sensitivity but better specificity compared to the list-based revised ACR 1997 and SLICC 2012 classification criteria. There were no statistically significant differences between any pair of rules with respect to overall agreement with the physician diagnosis., Conclusion: The 2 new weighted classification rules did not perform better than the existing list-based rules in terms of overall agreement on a data set originally generated to assess the SLICC criteria. Given the added complexity of summing weights, researchers may prefer the unweighted SLICC criteria. However, the performance of a classification rule will always depend on the populations from which the cases and non-cases are derived and whether the goal is to prioritize sensitivity or specificity., (© 2020, American College of Rheumatology.)

Objective: There is a paucity of data regarding health care costs associated with damage accrual in systemic lupus erythematosus. The present study was undertaken to describe costs associated with damage states across the disease course using multistate modeling., Methods: Patients from 33 centers in 11 countries were enrolled in the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort within 15 months of diagnosis. Annual data on demographics, disease activity, damage (SLICC/American College of Rheumatology Damage Index [SDI]), hospitalizations, medications, dialysis, and selected procedures were collected. Ten-year cumulative costs (Canadian dollars) were estimated by multiplying annual costs associated with each SDI state by the expected state duration using a multistate model., Results: A total of 1,687 patients participated; 88.7% were female, 49.0% were white, mean ± SD age at diagnosis was 34.6 ± 13.3 years, and mean time to follow-up was 8.9 years (range 0.6-18.5 years). Mean annual costs were higher for those with higher SDI scores as follows: $22,006 (Canadian) (95% confidence interval [95% CI] $16,662, $27,350) for SDI scores ≥5 versus $1,833 (95% CI $1,134, $2,532) for SDI scores of 0. Similarly, 10-year cumulative costs were higher for those with higher SDI scores at the beginning of the 10-year interval as follows: $189,073 (Canadian) (95% CI $142,318, $235,827) for SDI scores ≥5 versus $21,713 (95% CI $13,639, $29,788) for SDI scores of 0., Conclusion: Patients with the highest SDI scores incur 10-year cumulative costs that are ~9-fold higher than those with the lowest SDI scores. By estimating the damage trajectory and incorporating annual costs, data on damage can be used to estimate future costs, which is critical knowledge for evaluating the cost-effectiveness of novel therapies., (© 2020, American College of Rheumatology.)

Objective: The spectrum of antinuclear antibodies (ANAs) is changing to include both nuclear staining as well as cytoplasmic and mitotic cell patterns (CMPs) and accordingly a change is occurring in terminology to anticellular antibodies. This study examined the prevalence of indirect immunofluorescence (IIF) anticellular antibody staining using the Systemic Lupus International Collaborating Clinics inception cohort., Methods: Anticellular antibodies were detected by IIF on HEp-2000 substrate using the baseline serum. Three serologic subsets were examined: ANA positive (presence of either nuclear or mixed nuclear/CMP staining), anticellular antibody negative (absence of any intracellular staining), and isolated CMP staining. The odds of being anticellular antibody negative versus ANA or isolated CMP positive was assessed by multivariable analysis., Results: A total of 1,137 patients were included; 1,049 (92.3%) were ANA positive, 71 (6.2%) were anticellular antibody negative, and 17 (1.5%) had an isolated CMP. The isolated CMP-positive group did not differ from the ANA-positive or anticellular antibody-negative groups in clinical, demographic, or serologic features. Patients who were older (odds ratio [OR] 1.02 [95% confidence interval (95% CI) 1.00, 1.04]), of white race/ethnicity (OR 3.53 [95% CI 1.77, 7.03]), or receiving high-dose glucocorticoids at or prior to enrollment (OR 2.39 [95% CI 1.39, 4.12]) were more likely to be anticellular antibody negative. Patients on immunosuppressants (OR 0.35 [95% CI 0.19, 0.64]) or with anti-SSA/Ro 60 (OR 0.41 [95% CI 0.23, 0.74]) or anti-U1 RNP (OR 0.43 [95% CI 0.20, 0.93]) were less likely to be anticellular antibody negative., Conclusion: In newly diagnosed systemic lupus erythematosus, 6.2% of patients were anticellular antibody negative, and 1.5% had an isolated CMP. The prevalence of anticellular antibody-negative systemic lupus erythematosus will likely decrease as emerging nomenclature guidelines recommend that non-nuclear patterns should also be reported as a positive ANA., (© 2018, American College of Rheumatology.)

Objective: To determine the frequency, characteristics, and outcomes of cerebrovascular events (CerVEs), as well as clinical and autoantibody associations in a multiethnic/racial inception cohort of patients with systemic lupus erythematosus (SLE)., Methods: A total of 1,826 patients were assessed annually for 19 neuropsychiatric (NP) events, including 5 types of CerVEs: 1) stroke, 2) transient ischemia, 3) chronic multifocal ischemia, 4) subarachnoid/intracranial hemorrhage, and 5) sinus thrombosis. Global disease activity (Systemic Lupus Erythematosus Disease [SLE] Activity Index 2000), damage scores (SLE International Collaborating Clinics/American College of Rheumatology Damage Index), and Short Form 36 (SF-36) scores were collected. Time to event, linear and logistic regressions, and multistate models were used as appropriate., Results: CerVEs were the fourth most frequent NP event: 82 of 1,826 patients had 109 events; of these events, 103 were attributed to SLE, and 44 were identified at the time of enrollment. The predominant events were stroke (60 of 109 patients) and transient ischemia (28 of 109 patients). CerVEs were associated with other NP events attributed to SLE, non-SLE-attributed NP events, African ancestry (at US SLICC sites), and increased organ damage scores. Lupus anticoagulant increased the risk of first stroke and sinus thrombosis and transient ischemic attack. Physician assessment indicated resolution or improvement in the majority of patients, but patients reported sustained reduction in SF-36 summary and subscale scores following a CerVE., Conclusion: CerVEs, the fourth most frequent NP event in SLE, are usually attributable to lupus. In contrast to good physician-reported outcomes, patients reported a sustained reduction in health-related quality of life following a CerVE., (© 2018, American College of Rheumatology.)

Objective: To determine the level of agreement of disease flare severity (distinguishing severe, moderate, and mild flare and persistent disease activity) in a large paper-patient exercise involving 988 individual cases of systemic lupus erythematosus., Methods: A total of 988 individual lupus case histories were assessed by 3 individual physicians. Complete agreement about the degree of flare (or persistent disease activity) was obtained in 451 cases (46%), and these provided the reference standard for the second part of the study. This component used 3 flare activity instruments (the British Isles Lupus Assessment Group [BILAG] 2004, Safety of Estrogens in Lupus Erythematosus National Assessment [SELENA] flare index [SFI] and the revised SELENA flare index [rSFI]). The 451 patient case histories were distributed to 18 pairs of physicians, carefully randomized in a manner designed to ensure a fair case mix and equal distribution of flare according to severity., Results: The 3-physician assessment of flare matched the level of flare using the 3 indices, with 67% for BILAG 2004, 72% for SFI, and 70% for rSFI. The corresponding weighted kappa coefficients for each instrument were 0.82, 0.59, and 0.74, respectively. We undertook a detailed analysis of the discrepant cases and several factors emerged, including a tendency to score moderate flares as severe and persistent activity as flare, especially when the SFI and rSFI instruments were used. Overscoring was also driven by scoring treatment change as flare, even if there were no new or worsening clinical features., Conclusion: Given the complexity of assessing lupus flare, we were encouraged by the overall results reported. However, the problem of capturing lupus flare accurately is not completely solved., (© 2017, The Authors. Arthritis Care & Research published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Objective: To estimate the early prevalence of various electrocardiographic (EKG) abnormalities in patients with systemic lupus erythematosus (SLE) and to evaluate possible associations between repolarization changes (increased corrected QT [QTc] and QT dispersion [QTd]) and clinical and laboratory variables, including the anti-Ro/SSA level and specificity (52 or 60 kd)., Methods: We studied adult SLE patients from 19 centers participating in the Systemic Lupus International Collaborating Clinics (SLICC) Inception Registry. Demographics, disease activity (Systemic Lupus Erythematosus Disease Activity Index 2000 [SLEDAI-2K]), disease damage (SLICC/American College of Rheumatology Damage Index [SDI]), and laboratory data from the baseline or first followup visit were assessed. Multivariate logistic and linear regression models were used to asses for any cross-sectional associations between anti-Ro/SSA and EKG repolarization abnormalities., Results: For the 779 patients included, mean ± SD age was 35.2 ± 13.8 years, 88.4% were women, and mean ± SD disease duration was 10.5 ± 14.5 months. Mean ± SD SLEDAI-2K score was 5.4 ± 5.6 and mean ± SD SDI score was 0.5 ± 1.0. EKG abnormalities were frequent and included nonspecific ST-T changes (30.9%), possible left ventricular hypertrophy (5.4%), and supraventricular arrhythmias (1.3%). A QTc ≥440 msec was found in 15.3%, while a QTc ≥460 msec was found in 5.3%. Mean ± SD QTd was 34.2 ± 14.7 msec and QTd ≥40 msec was frequent (38.1%). Neither the specificity nor the level of anti-Ro/SSA was associated with QTc duration or QTd, although confidence intervals were wide. Total SDI was significantly associated with a QTc interval exceeding 440 msec (odds ratio 1.38 [95% confidence interval 1.06, 1.79])., Conclusion: A substantial proportion of patients with recent-onset SLE exhibited repolarization abnormalities, although severe abnormalities were rare., (Copyright © 2015 by the American College of Rheumatology.)

Objective: To derive and validate a brief patient-completed instrument, the Lupus Impact Tracker (LIT), to assess and monitor the impact of systemic lupus erythematosus (SLE)., Methods: Items for the LIT were selected from the LupusPRO, a validated patient-reported outcomes measure, using 3 approaches: confirmatory factor analysis (CFA), stepwise regression, and patient focus groups. CFA was conducted to find items from the LupusPRO that fit a unidimensional structure to allow scoring as a single index. Stepwise regression methods identified items with the strongest relationship (convergent validity) with disease activity measures and patient health rating. Focus groups (n = 26 patients) identified the most important items describing SLE impact. Selected items were evaluated for reliability and validity., Results: CFA found 21 items that fit a unidimensional structure. Stepwise regressions identified 15 of 21 items having good convergent validity with clinical measures. Patient focus groups identified 9 of 15 items as best capturing the impact of SLE. Overall, 7 items were selected across all 3 approaches (CFA, stepwise regression, and focus groups). Another 15 items were selected across 2 approaches. Through consensus with rheumatology clinician experts, a final set of 10 items was selected for the LIT. The LIT items showed good internal consistency (0.89) and test-retest reliabilities (0.87). Mean LIT scores differed significantly (P < 0.05) across criterion groups in the hypothesized direction, providing evidence of discriminant validity and responsiveness., Conclusion: The LIT is reliable and valid in SLE patients and offers a practical way for physicians and patients to assess and monitor the impact of SLE., (Copyright © 2014 by the American College of Rheumatology.)

Objective: An association between 25-hydroxyvitamin D (25[OH]D; vitamin D) deficiency and increased cardiovascular (CV) risk factors and CV disease (CVD) has been shown in general population studies. Vitamin D deficiency has been noted in systemic lupus erythematosus (SLE), and CVD is a major cause of morbidity and mortality in SLE. The objectives of this study were to estimate the associations of 25(OH)D levels with CV risk factors and to determine whether low baseline 25(OH)D levels predict future CV events in patients participating in an international inception cohort., Methods: Data were collected on 890 participants, including demographics, SLE activity and damage assessments, CV risk factors and events, medications, laboratory assessments of 25(OH)D levels, and inflammatory markers. Multiple logistic and Cox regressions were used to estimate the associations of baseline 25(OH)D levels with baseline CV risk factors and CVD events. The models were adjusted for age, sex, race, season, and country, with and without body mass index., Results: Patients in the higher quartiles of 25(OH)D were less likely to have hypertension and hyperlipidemia and were more likely to have lower C-reactive protein levels and lower Systemic Lupus Erythematosus Disease Activity Index 2000 scores at baseline when compared with the first quartile. Vitamin D levels were not independently associated with CVD event incidence; however, hazard ratios for CVD event incidence decreased with successively higher quartiles., Conclusion: Lower baseline 25(OH)D levels are associated with higher risk for CV risk factors and more active SLE at baseline. There may be a trend toward a lower likelihood of CVD events in those with higher baseline 25(OH)D levels., (Copyright © 2014 by the American College of Rheumatology.)

Objective: We describe disease activity, damage, and the accrual of key autoantibodies in an inception systemic lupus erythematosus (SLE) cohort., Methods: The Systemic Lupus International Collaborating Clinics (SLICC) International Research Network, comprising 27 centers from 11 countries, has followed an inception cohort of SLE patients yearly according to a standardized protocol. Of these patients, 298 were followed for a minimum of 5 years and constitute the study population. Disease activity was assessed using the SLE Disease Activity Index 2000 (SLEDAI-2K) and damage was assessed using the SLICC/American College of Rheumatology Damage Index (SDI). Antinuclear antibody (ANA), anti-DNA, and anticardiolipin antibody (aCL) levels and lupus anticoagulant were assessed yearly. Descriptive statistics were generated and repeated-measures general linear models were used to evaluate SLEDAI-2K and SDI over time between whites and nonwhites., Results: Of the 298 patients, 87% were women, 55% were white, 12% were African American, 14% were Asian, 16% were Hispanic, and 2% were categorized as "other." At enrollment, the mean age was 35.3 years, the mean SLEDAI-2K score was 5.9, and the mean disease duration was 5.5 months. Mean SLEDAI-2K scores decreased in the first year and then remained low. SLEDAI-2K scores were significantly lower at each year in whites compared to nonwhites. Mean SDI scores increased progressively over 5 years; there was no significant difference between whites and nonwhites. As expected, ANA positivity was high and anti-DNA positivity was relatively low at enrollment, and both increased over 5 years. Although lupus anticoagulant increased slightly over 5 years, aCL positivity did not., Conclusion: Disease activity in newly diagnosed patients decreases over their first 5 years, while damage increases. Antibody positivity ran variable courses over this period., (Copyright © 2012 by the American College of Rheumatology.)

Objective: Multiple disease-related factors may limit the number of children born to women with systemic lupus erythematosus (SLE). We calculated live births in women with SLE and compared this with general population rates., Methods: We studied women with SLE from a subset of centers participating in the Systemic Lupus International Collaborating Clinics Prospective Inception Cohort Study of SLE. Women diagnosed as having SLE before age 50 years were included. Using age, calendar-period, and country-specific general population birth rates, we calculated the standardized incidence ratio (SIR) of observed to expected live births. We also performed a multivariate analysis with the SIR as the dependent variable to explore potential predictors of live births., Results: A total of 339 women with SLE were studied. The number of live births over the interval (n = 313) was substantially below that which would be expected (n = 479; SIR 0.65, 95% confidence interval [95% CI] 0.58-0.73). In the multivariate analyses, black race/ethnicity (SIR 1.47, 95% CI 1.08-2.00) and being married or living common-law (SIR 2.04, 95% CI 1.52-2.74) were associated with increased live births (relative to what would be expected). There were trends for fewer live births in women exposed to cyclophosphamide (SIR 0.88, 95% CI 0.56-1.38) and in those with high disease activity (mean SLE Disease Activity Index 2000 update score ≥5; SIR 0.82, 95% CI 0.54-1.25)., Conclusion: Overall, we found that women with SLE have fewer live births compared with the general population. Marital status, race/ethnicity, and possibly clinical factors may mediate this effect., (Copyright © 2011 by the American College of Rheumatology.)

Objective: To describe vascular events during an 8-year followup in a multicenter systemic lupus erythematosus (SLE) inception cohort and their attribution to atherosclerosis., Methods: Clinical data, including comorbidities, were recorded yearly. Vascular events were recorded and attributed to atherosclerosis or not. All of the events met standard clinical criteria. Factors associated with atherosclerotic vascular events were analyzed using descriptive statistics, t-tests, and chi-square tests. Stepwise multivariate logistic regression was used to assess the association of factors with vascular events attributed to atherosclerosis., Results: Since 2000, 1,249 patients have been entered into the cohort. There have been 97 vascular events in 72 patients, including: myocardial infarction (n = 13), angina (n = 15), congestive heart failure (n = 24), peripheral vascular disease (n = 8), transient ischemic attack (n = 13), stroke (n = 23), and pacemaker insertion (n = 1). Fifty of the events were attributed to active lupus, 31 events in 22 patients were attributed to atherosclerosis, and 16 events were attributed to other causes. The mean +/- SD time from diagnosis to the first atherosclerotic event was 2.0 +/- 1.5 years. Compared with patients followed for 2 years without atherosclerotic events (n = 615), at enrollment, patients with atherosclerotic vascular events were more frequently white, men, older at diagnosis of SLE, obese, smokers, hypertensive, and had a family history of coronary artery disease. On multivariate analysis, only male sex and older age at diagnosis were associated factors., Conclusion: In an inception cohort with SLE followed for up to 8 years, there were 97 vascular events, but only 31 were attributable to atherosclerosis. Patients with atherosclerotic events were more likely to be men and to be older at diagnosis of SLE.