Safety Of Estrogens In Lupus Erythematosus National Assessment Research Articles

Predictors of severe lupus flare: a prospective follow-up study

BackgroundFlare-up of systemic lupus erythematosus (SLE) is a common characteristic that could have deleterious effects on patients’ outcome and survival. The aim of this study was to identify the predictors of severe lupus flare.Methods120 patients with SLE were enrolled and followed-up for 23 months. Demographic, clinical manifestations, laboratory parameters and disease activity were recorded at each visit. In addition, presence of severe lupus flare at each visit was evaluated by using the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLE disease activity index (SLEDAI) flare composite index. Predictors of severe lupus flare were obtained by backward logistic regression analyses. Predictors of SLEDAI were obtained by backward linear regression analyses.ResultsDuring the follow-up period, 47 patients had at least one episode of severe lupus flare. Mean (SD) age of patients with severe flare versus no flare was 31.7 (7.89) and 38.3 (8.24) years, respectively (P = 0.001). Ten (62.5%) out of 16 males and 37 (35.5%) out of 104 females had severe flare (P = 0.04). History of lupus nephritis (LN) was recorded in 76.5% and 44% of patients with severe flare and no severe flare, respectively (P = 0.001). Thirty-five (29.2%) patients with high anti-double-stranded DNA (anti-ds-DNA antibody) and 12 (10%) with negative anti-ds-DNA antibody had severe lupus flare (P = 0.02). By multivariable logistic regression analysis, younger age (OR = 0.87, 95% CI 0.80–0.94, P = 0.0001), history of LN (OR = 4.66, 95% CI 1.55–14.002, P = 0.006) and high SLEDAI at the first visit (OR = 1.19, 95% CI 1.026–1.38) were the main predictors of flare. When severe lupus flare after the first visit was used as the outcome variable, similar findings were observed but, SLEDAI, although left among the final predictors in the model, was not significant. SLEDAIs in future visits were mainly predicted by Anti-ds-DNA antibody, 24-h urine protein and arthritis at the first visit.ConclusionSLE patients with younger age, history of previous LN or high baseline SLEDAI, may need closer monitoring and follow up.

Impact of systemic lupus erythematosus disease activity, hydroxychloroquine and NSAID on the risk of subsequent organ system damage and death: analysis in a single US medical centre

ObjectiveTo assess the impact of mild-moderate systemic lupus erythematosus (SLE) disease activity during a 12-month period on the risk of death or subsequent organ system damage.Methods1168 patients with ≥24 months...

Patterns of fatigue and association with disease activity and clinical manifestations in systemic lupus erythematosus.

The prevalence of fatigue is high in patients with systemic lupus erythematosus (SLE). In this study, we used latent class analysis to reveal patterns of fatigue, anxiety, depression and organ involvement in a large international cohort of SLE patients. We used the Lupus BioBank of the upper Rhein to analyse patterns of fatigue using latent class analysis (LCA). After determining the optimal number of latent classes, patients were assigned according to model generated probabilities, and characteristics of classes were compared. A total of 502 patients were included. Significant fatigue, anxiety and depression were reported by 341 (67.9%), 159 (31.7%) and 52 (10.4%) patients, respectively. LCA revealed a first cluster (67.5% of patients) with low disease activity [median (25th-75th percentile interquartile range) Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI: 2 (0-4)], significant fatigue (55.5%, P < 0.0001), low anxiety (11.8%, P < 0.0001) and depression (0.9%, P < 0.0001). Cluster 2 (25.3%) also comprised patients with low disease activity [SELENA-SLEDAI: 2 (0-6)], but those patients had a very high prevalence of fatigue (100%, P < 0.0001), anxiety (89%, P < 0.0001) and depression (38.6%, P < 0.0001). Cluster 3 (7.2%) comprised patients with high disease activity [SELENA-SLEDAI: 12 (8-17), P < 0.0001] and high fatigue (72.2%, P < 0.0001) with low levels of anxiety (16.7%, P < 0.0001) and no depression (0%, P < 0.0001). LCA revealed three patterns of fatigue with important practical implications. Based on these, it is crucial to distinguish patients with active disease (in whom remission will be achieved) from those with no or mild activity but high levels of fatigue, depression and anxiety, for whom psychological counselling should be prioritized.

Predictors of fatigue and severe fatigue in a large international cohort of patients with systemic lupus erythematosus and a systematic review of the literature.

Fatigue is reported in up to 90% of patients with SLE. This study was conducted to identify the determinants associated with fatigue in a large cohort of patients with SLE, as well as to provide a systematic review of the literature. Patients from the Lupus BioBank of the upper Rhein, a large German-French cohort of SLE patients, were included in the FATILUP study if they fulfilled the 1997 ACR criteria for SLE and had Fatigue Scale for Motor and Cognitive Functions scores collected. Multivariate logistic regression analyses were performed to assess the determinants of fatigue and severe fatigue. A total of 570 patients were included (89.1% female). The median age was 42 years (interquartile range 25-75: 34-52). The median value of the SAfety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI was 2 (0-4). Fatigue was reported by 386 patients (67.7%) and severe fatigue by 209 (36.7%). In multivariate analyses, fatigue was associated with depression [odds ratio (OR): 4.72 (95% CI: 1.39-16.05), P = 0.01], anxiety [OR: 4.49 (95% CI: 2.60-7.77), P < 0.0001], glucocorticoid treatment [OR: 1.59 (95% CI 1.05-2.41), P = 0.04], SELENA-SLEDAI scores [OR: 1.05 (95% CI: 1.00-1.12) per 1 point increase, P = 0.043] and age at sampling [OR: 1.01 (95% CI: 1.00-1.03) per 1 year increase, P = 0.03]. Severe fatigue was independently associated with anxiety (P < 0.0001), depression (P < 0.0001), glucocorticoid treatment (P = 0.047) and age at sampling (P = 0.03). Both fatigue and severe fatigue are common symptoms in SLE, and are strongly associated with depression and anxiety. Disease activity and the use of glucocorticoids were also independently associated with fatigue, although more weakly.

Cross-cultural validation of Lupus Impact Tracker in five European clinical practice settings.

The aim was to evaluate the cross-cultural validity of the Lupus Impact Tracker (LIT) in five European countries and to assess its acceptability and feasibility from the patient and physician perspectives. A prospective, observational, cross-sectional and multicentre validation study was conducted in clinical settings. Before the visit, patients completed LIT, Short Form 36 (SF-36) and care satisfaction questionnaires. During the visit, physicians assessed disease activity [Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI], organ damage [SLICC/ACR damage index (SDI)] and flare occurrence. Cross-cultural validity was assessed using the Differential Item Functioning method. Five hundred and sixty-nine SLE patients were included by 25 specialists; 91.7% were outpatients and 89.9% female, with mean age 43.5 (13.0) years. Disease profile was as follows: 18.3% experienced flares; mean SELENA-SLEDAI score 3.4 (4.5); mean SDI score 0.8 (1.4); and SF-36 mean physical and mental component summary scores: physical component summary 42.8 (10.8) and mental component summary 43.0 (12.3). Mean LIT score was 34.2 (22.3) (median: 32.5), indicating that lupus moderately impacted patients' daily life. A cultural Differential Item Functioning of negligible magnitude was detected across countries (pseudo- R 2 difference of 0.01-0.04). Differences were observed between LIT scores and Physician Global Assessment, SELENA-SLEDAI, SDI scores = 0 (P < 0.035) and absence of flares (P = 0.004). The LIT showed a strong association with SF-36 physical and social role functioning, vitality, bodily pain and mental health (P < 0.001). The LIT was well accepted by patients and physicians. It was reliable, with Cronbach α coefficients ranging from 0.89 to 0.92 among countries. The LIT is validated in the five participating European countries. The results show its reliability and cultural invariability across countries. They suggest that LIT can be used in routine clinical practice to evaluate and follow patient-reported outcomes in order to improve patient-physician interaction.

Hydroxychloroquine Serum Concentrations and Flares of Systemic Lupus Erythematosus: A Longitudinal Cohort Analysis.

To study the relationship between serum hydroxychloroquine (HCQ) concentrations and flares of systemic lupus erythematosus (SLE) in a longitudinal cohort of patients. Patients who fulfilled ≥4 American College of Rheumatology classification criteria for SLE and had been treated with HCQ for >6 months were studied. Blood was assayed for HCQ levels by tandem mass spectrometry. Patients were serially assessed for disease activity, using the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and flares (SELENA flares instrument). Comparison of the mean summated SLEDAI scores over time and rates of flares in groups with different HCQ levels was performed by the Kruskal-Wallis test. A total of 276 SLE patients were studied (93% women, mean ± SD age 41.0 ± 13.8 years). The proportion of patients with HCQ levels <10 (total noncompliance), 10-500 (subtherapeutic), and >500 ng/ml (therapeutic) was 11%, 77%, and 12%, respectively. HCQ levels correlated significantly with the prescribed dose but not with body weight or renal function. The prescribed HCQ dose also correlated significantly with baseline SLEDAI scores, indicating that higher doses were used for more active manifestations. After a mean ± SD observation period of 32.5 ± 5.5 months, the mean summated SLEDAI score and the incidence of SLE flares was not statistically different among patients with different baseline HCQ levels. In a subgroup of 73 patients with serologic and clinical remission and having therapeutic HCQ levels, a trend of lower disease activity and fewer incidences of flares was observed. Noncompliance and subtherapeutic serum HCQ levels were seen frequently in these SLE patients, which was partly due to the low prescribed dose. In patients in remission, higher HCQ concentrations were associated with a trend showing fewer flares over time.

Prospective Validation of the Lupus Impact Tracker: A Patient-Completed Tool for Clinical Practice to Evaluate the Impact of Systemic Lupus Erythematosus.

To evaluate the reliability, validity, responsiveness, and utility of the Lupus Impact Tracker (LIT). This was a prospective longitudinal study with 20 North American sites participating. Consenting patients completed the LIT, Medical Outcomes Study Short Form 36 (version 2), Patient Health Questionnaire 9 (PHQ-9), LupusQoL, and patient LIT feedback questionnaire. Rheumatologists completed the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, and physician LIT feedback questionnaire. The reliability, convergent validity, construct validity, and responsiveness of the LIT were evaluated. Of the 325 SLE patients enrolled, 90% were female, 53% were white, and 33% were African American. Their mean age was 42 years. The mean ± SD baseline physician's global assessment and total SELENA-SLEDAI scores were 1.04 ± 0.8 and 4.28 ± 3.8, respectively, while 3-month scores were 0.94 ± 0.73 and 4.09 ± 3.79, respectively. Internal consistency reliability was high (>0.9) at both visits. LIT scores correlated highly with other measures of patient-reported outcomes, and construct validity was established against clinical measures. The LIT was highly responsive to patient-reported changes in SLE health status; however, LIT scores were not as responsive to changes in the SELENA-SLEDAI score. The majority of patients and physicians found LIT to be acceptable and feasible to administer in a clinical setting. The LIT is a reliable and valid instrument for assessing the impact of SLE on patients and captures unique and important information not included in physician assessments of disease. It may be useful in clinical practice to facilitate communication between the physician and the patient and enable efficient incorporation of the patient's perspective in disease management.

Definition and initial validation of a Lupus Low Disease Activity State (LLDAS)

AimsTreating to low disease activity is routine in rheumatoid arthritis, but no comparable goal has been defined for systemic lupus erythematosus (SLE). We sought to define and validate a Lupus...

Preliminary test of the LFA rapid evaluation of activity in lupus (LFA-REAL): an efficient outcome measure correlates with validated instruments

ObjectiveCurrent disease activity measures for systemic lupus erythematosus (SLE) are difficult to score or interpret and problematic for use in clinical practice. Lupus Foundation of America (LFA)-Rapid Evaluation of Activity...

Effect of raloxifene on disease activity and vascular biomarkers in patients with systemic lupus erythematosus: Subgroup analysis of a double-blind randomized controlled trial

The purpose of this study was to identify the effect of raloxifene on disease activity and vascular biomarkers in patients with systemic lupus erythematosus (SLE). Subgroup data were analyzed for postmenopausal female SLE patients who participated in a randomized controlled trial of raloxifene on glucocorticoid-induced osteoporosis. Patients who were receiving a stable daily dose of prednisolone (≤10 mg) for ≥6 months were assigned to receive raloxifene (60 mg/day) or placebo on top of calcium and vitamin D. Disease activity was assessed by the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA), SLE disease activity index (SLEDAI) and physicians' global assessment (PGA) every three months. Lupus flares were assessed by the SELENA flare instrument. Serial serum levels of homocysteine, high-sensitivity C-reactive protein (hsCRP) and soluble thrombomodulin (sTM) were measured. A total of 62 patients (30 raloxifene, 32 placebo) were studied (age 52.5 ± 6.7 years; SLE duration 9.3 ± 7.6 years; menopause duration 7.2 ± 6.6 years). The SLEDAI at entry was 1.8 ± 2.3 (SLEDAI ≥ 6 in 8%). After 12 months, a significant gain in bone mineral density (BMD) of the lumbar spine (1.6%, p = 0.02), and reduction in bone resorption and formation markers was observed in the raloxifene but not in the placebo treated patients. The SELENA-SLEDAI and PGA scores area under the curve over 12 months were not significantly different between the two groups. There were three episodes of mild/moderate lupus flares (33% musculoskeletal, 33% dermatological) in the raloxifene group, compared to nine episodes of mild/moderate flares (27% musculoskeletal, 45% dermatological) in the placebo group (p = 0.11). The low density lipoprotein (LDL) cholesterol level increased significantly in the placebo but not raloxifene treated patients. No significant changes in homocysteine, hsCRP and sTM levels were observed in either group of patients. Raloxifene significantly improves lumbar spine BMD in SLE patients but does not cause an increase in lupus activity or flares.

Vitamin D in Systemic Lupus Erythematosus: Modest Association With Disease Activity and the Urine Protein‐to‐Creatinine Ratio

To investigate whether an increase in vitamin D levels in patients with systemic lupus erythematosus (SLE) was associated with improvement in disease activity. A total of 1,006 SLE patients were monitored over 128 weeks. SLE patients with low levels of 25-hydroxyvitamin D (25[OH]D; <40 ng/ml) were given supplements of 50,000 units of vitamin D2 weekly plus 200 units of calcium/vitamin D3 twice daily. Longitudinal regression models were used to estimate the association between levels of 25(OH)D and various measures of disease activity. The SLE patients had the following characteristics: 91% were female, their mean age was 49.6 years, and their ethnicity was 54% Caucasian, 37% African American, and 8% other. For those with levels of 25(OH)D <40 ng/ml, a 20-unit increase in the 25(OH)D level was associated with a mean decrease of 0.22 (95% confidence interval [95% CI] -0.41, -0.02) (P = 0.032) in the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). This corresponded to a 21% decrease in the odds of having a SELENA-SLEDAI ≥5 (95% CI 1, 37). The mean urine protein-to-creatinine ratio decreased by 2% (95% CI -0.03, -0.01) (P = 0.0001), corresponding to a 15% decrease in the odds of having a ratio >0.5 (95% CI 2, 27). We found that a 20-ng/ml increase in the 25(OH)D level was associated with a 21% decrease in the odds of having a high disease activity score and a 15% decrease in the odds of having clinically important proteinuria. Although these associations were statistically significant, the clinical importance is relatively modest. There was no evidence of additional benefit of 25(OH)D beyond a level of 40 ng/ml.

A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus

To assess the efficacy/safety of the B lymphocyte stimulator inhibitor belimumab plus standard therapy compared with placebo plus standard therapy in active systemic lupus erythematosus (SLE). In a phase III, multicenter, randomized, placebo-controlled trial, 819 antinuclear antibody-positive or anti-double-stranded DNA-positive SLE patients with scores ≥6 on the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) version of the SLE Disease Activity Index (SLEDAI) were randomized in a 1:1:1 ratio to receive 1 mg/kg belimumab, 10 mg/kg belimumab, or placebo intravenously on days 0, 14, and 28 and then every 28 days for 72 weeks. The primary efficacy end point was the SLE Responder Index (SRI) response rate at week 52 (an SRI response was defined as a ≥4-point reduction in SELENA-SLEDAI score, no new British Isles Lupus Assessment Group [BILAG] A organ domain score and no more than 1 new BILAG B score, and no worsening in physician's global assessment score versus baseline). Belimumab at 10 mg/kg plus standard therapy met the primary efficacy end point, generating a significantly greater SRI response at week 52 compared with placebo (43.2% versus 33.5%; P = 0.017). The rate with 1 mg/kg belimumab was 40.6% (P = 0.089). Response rates at week 76 were 32.4%, 39.1%, and 38.5% with placebo, 1 mg/kg belimumab, and 10 mg/kg belimumab, respectively. In post hoc sensitivity analyses evaluating higher SELENA-SLEDAI score thresholds, 10 mg/kg belimumab achieved better discrimination at weeks 52 and 76. Risk of severe flares over 76 weeks (based on the modified SLE Flare Index) was reduced with 1 mg/kg belimumab (34%) (P = 0.023) and 10 mg/kg belimumab (23%) (P = 0.13). Serious and severe adverse events, including infections, laboratory abnormalities, malignancies, and deaths, were comparable across groups. Belimumab plus standard therapy significantly improved SRI response rate, reduced SLE disease activity and severe flares, and was generally well tolerated in SLE.

Measures of adult systemic lupus erythematosus: Updated Version of British Isles Lupus Assessment Group (BILAG 2004), European Consensus Lupus Activity Measurements (ECLAM), Systemic Lupus Activity Measure, Revised (SLAM‐R), Systemic Lupus Activity Questionnaire for Population Studies (SLAQ), Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI‐2K), and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI)

Measurement of disease activity in systemic lupus erythematosus (SLE) is central to evaluating outcomes, differences among SLE patient groups, responses to a new drug proposed, and also for assessing disease longitudinally for observational and clinical trials. Several validated and updated instruments have been available since the early 1980s, but more recent studies gauging reliability and validity for classifying and monitoring groups of patients in the research setting are now available. Two cardinal features of SLE have challenged investigators refining these tools: first, the complex multisystem nature of this disease with fluctuating levels of disease activity, which may vary between patients and within the same patient over time; second, the absence of a “gold standard” for determining the psychometric properties of each proposed scale limits comparisons to expert opinion using a physician’s visual analog scale or by comparing one scale against other to assess performance across proposed instruments. However, these strategies do not eliminate bias based on personal experience, nor do they differentiate between different opinions on the relative importance of disease manifestations in different systems. Therefore, an experience-based evaluation may be subject to greater interrater variability than the use of the disease activity instrument itself. Furthermore, psychometric properties should be influenced by the length of the scale (number of items and scoring scale), number of patients included, or disease severity of patients under study. Two main types of activity measures in SLE have been developed: global score systems (for example, the European Consensus Lupus Activity Measurements, Systemic Lupus Activity Measure [SLAM], and Systemic Lupus Erythematosus Disease Activity Index [SLEDAI]), which provide an overall measure of activity, and individual organ/system assessment scales that assess disease activity in single organs (such as the British Isles Lupus Assessment Group Index [BILAG]). The Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index score is a measure for chronic damage; it has been included due to its prognostic value in clinical and research basis. The SLEDAI, SLAM, and BILAG have performed in effective and reliable manners in studies; furthermore, they correlate with one another (1-3). The SLEDAI, Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)–SLEDAI, SLEDAI 2000 (4-7), and BILAG (8-10) have been successfully used in observational trials and case studies, although baseline disease activity index (DAI) scores were not always predictors of subsequent damage or other outcomes (11,12). These DAIs were validated in the context of long-term observational trials studies and not in randomized clinical trials (RCTs) (1,9,10,13-15). The few RCTs conducted have shown that improvement in DAI scores correlates with response rates, disease remission, and flare prevention; however, a threshold of clinically meaningful change has not been established (1,13,16,17). Current work has focused on developing a responder index developed in collaboration with the Food and Drug Administration–defined response as improvement and/or no deterioration in patient- and physician-reported outcomes. The SLE responder index, which utilizes the SELENA–SLEDAI score to determine global improvement, BILAG domain scores to ensure no significant worsening in heretofore unaffected organ systems, and physician’s global assessment to ensure that improvements in disease activity are not achieved at the expense of the patient’s overall condition, which may have been missed by either DAI, is one example used in a recent clinical trial (18). Ongoing work to refine or develop responder indices will enhance our ability to measure meaningful outcomes in future RCTs. For purpose of this review, we selected those indices that have shown the strongest evidence of validity when used by investigators from different countries in large studies of patients with SLE. The exact choice of instrument should be governed by the purpose for which it is required in clinicalpractice or research.

An assessment of disease flare in patients with systemic lupus erythematosus: a comparison of BILAG 2004 and the flare version of SELENA

AimsTo compare the British Isles Lupus Assessment Group (BILAG) 2004, the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) flare index (SFI) and physician's global assessment (PGA) in assessing...

Safety and efficacy of rituximab in systemic lupus erythematosus: Results from 136 patients from the French autoimmunity and rituximab registry

A number of open-label studies have suggested the potential benefit of rituximab (RTX) in systemic lupus erythematosus (SLE). However, in 2 recent randomized controlled trials (RCTs) of RTX, the primary end points were not met. We undertook this study to evaluate the safety and efficacy of RTX in off-trial patients with SLE seen in regular clinical practice. We analyzed prospective data from the French AutoImmunity and Rituximab (AIR) registry, which includes data on patients with autoimmune disorders treated with RTX. One hundred thirty-six patients received treatment for SLE. The mean +/- SD score on the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the SLE Disease Activity Index (SLEDAI) was 11.3 +/- 8.9 at baseline. Severe infections were noted in 12 patients (9%), corresponding to a rate of 6.6/100 patient-years. Most severe infections occurred within the first 3 months after the last RTX infusion. Five patients died, due to severe infection (n = 3) or refractory autoimmune disease (n = 2). Overall response was observed in 80 of 113 patients (71%) by the SELENA-SLEDAI assessment. Efficacy did not differ significantly between patients receiving RTX monotherapy and those receiving concomitant immunosuppressive agents (who had higher baseline disease activity). Articular, cutaneous, renal, and hematologic improvements were noted in 72%, 70%, 74%, and 88% of patients, respectively. Among responders, 41% experienced a relapse of disease, with a response in 91% after retreatment with RTX. Data from the AIR registry show a satisfactory tolerance profile and clinical efficacy of RTX in patients with SLE. The contrasting results with those from recent RCTs leave open the question of the therapeutic use of RTX in SLE. Additional controlled studies with new designs are needed to define the place of RTX in the therapeutic arsenal for SLE.

Erythrocyte C3d and C4d for monitoring disease activity in systemic lupus erythematosus

Disease activity in systemic lupus erythematosus (SLE) is typically monitored by measuring serum C3 and C4. However, these proteins have limited utility as lupus biomarkers, because they are substrates rather than products of complement activation. The aim of this study was to evaluate the utility of measuring the erythrocyte-bound complement activation products, erythrocyte-bound C3d (E-C3d) and E-C4d, compared with that of serum C3 and C4 for monitoring disease activity in patients with SLE. The levels of E-C3d and E-C4d were measured by flow cytometry in 157 patients with SLE, 290 patients with other diseases, and 256 healthy individuals. The patients with SLE were followed up longitudinally. Disease activity was measured at each visit, using the validated Systemic Lupus Activity Measure (SLAM) and the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). At baseline, patients with SLE had higher median levels of E-C3d and E-C4d (P < 0.0001) in addition to higher within-patient and between-patient variability in both E-C3d and E-C4d when compared with the 2 non-SLE groups. In a longitudinal analysis of patients with SLE, E-C3d, E-C4d, serum C3, and anti-double-stranded DNA (anti-dsDNA) antibodies were each significantly associated with the SLAM and SELENA-SLEDAI. In a multivariable analysis, E-C4d remained significantly associated with these SLE activity measures after adjusting for serum C3, C4, and anti-dsDNA antibodies; however, E-C3d was associated with the SLAM but not with the SELENA-SLEDAI. Determining the levels of the erythrocyte-bound complement activation products, especially E-C4d, is an informative measure of SLE disease activity as compared with assessing serum C4 levels and should be considered for monitoring disease activity in patients with SLE.

Novel evidence-based systemic lupus erythematosus responder index.

To describe a new systemic lupus erythematosus (SLE) responder index (SRI) based on a belimumab phase II SLE trial and demonstrate its potential utility in SLE clinical trials. Data from a randomized, double-blind, placebo-controlled study in 449 patients of 3 doses of belimumab (1, 4, 10 mg/kg) or placebo plus standard of care therapy (SOC) over a 56-week period were analyzed. The Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and British Isles Lupus Assessment Group (BILAG) SLE disease activity instruments, the Short Form 36 health survey, and biomarker analyses were used to create a novel SRI. Response to treatment in a subset of 321 serologically active SLE patients (antinuclear antibodies >/=1:80 and/or anti-double-stranded DNA antibodies >/=30 IU/ml) at baseline was retrospectively evaluated using the SRI. SRI response is defined as 1) a >/=4-point reduction in SELENA-SLEDAI score, 2) no new BILAG A or no more than 1 new BILAG B domain score, and 3) no deterioration from baseline in the physician's global assessment by >/=0.3 points. In serologically active patients, the addition of belimumab to SOC resulted in a response in 46% of patients at week 52 compared with 29% of the placebo patients (P = 0.006). SRI responses were independent of baseline autoantibody subtype. This evidence-based evaluation of a large randomized, placebo-controlled trial in SLE resulted in the ability to define a robust responder index based on improvement in disease activity without worsening the overall condition or the development of significant disease activity in new organ systems.

A phase II, randomized, double‐blind, placebo‐controlled, dose‐ranging study of belimumab in patients with active systemic lupus erythematosus

To assess the safety, tolerability, biologic activity, and efficacy of belimumab in combination with standard of care therapy (SOC) in patients with active systemic lupus erythematosus (SLE). Patients with a Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score >/=4 (n = 449) were randomly assigned to belimumab (1, 4, or 10 mg/kg) or placebo in a 52-week study. Coprimary end points were the percent change in the SELENA-SLEDAI score at week 24 and the time to first SLE flare. Significant differences between the treatment and placebo groups were not attained for either primary end point, and no dose response was observed. Reductions in SELENA-SLEDAI scores from baseline were 19.5% in the combined belimumab group versus 17.2% in the placebo group. The median time to first SLE flare was 67 days in the combined belimumab group versus 83 days in the placebo group. However, the median time to first SLE flare during weeks 24-52 was significantly longer with belimumab treatment (154 versus 108 days; P = 0.0361). In the subgroup (71.5%) of serologically active patients (antinuclear antibody titer >/=1:80 and/or anti-double-stranded DNA [anti-dsDNA] >/=30 IU/ml), belimumab treatment resulted in significantly better responses at week 52 than placebo for SELENA-SLEDAI score (-28.8% versus -14.2%; P = 0.0435), physician's global assessment (-32.7% versus -10.7%; P = 0.0011), and Short Form 36 physical component score (+3.0 versus +1.2 points; P = 0.0410). Treatment with belimumab resulted in a 63-71% reduction of naive, activated, and plasmacytoid CD20+ B cells, and a 29.4% reduction in anti-dsDNA titers (P = 0.0017) by week 52. The rates of adverse events and serious adverse events were similar in the belimumab and placebo groups. Belimumab was biologically active and well tolerated. The effect of belimumab on the reduction of SLE disease activity or flares was not significant. However, serologically active SLE patients responded significantly better to belimumab therapy plus SOC than to SOC alone.

437. Association of Neostigmine, Clonidine and Ropivacaine 0,75% I.T for Orthopaedic Treatment of Proximal Femoral Fracture in Elderly

Aims Treating to low disease activity is routine in rheumatoid arthritis, but no comparable goal has been defined for systemic lupus erythematosus (SLE). We sought to define and validate a Lupus Low Disease Activity State (LLDAS). Methods A consensus definition of LLDAS was generated using Delphi and nominal group techniques. Criterion validity was determined by measuring the ability of LLDAS attainment, in a single-centre SLE cohort, to predict non-accrual of irreversible organ damage, measured using the Systemic Lupus International Collaborating Clinics Damage Index (SDI). Results Consensus methodology led to the following definition of LLDAS: (1) SLE Disease Activity Index (SLEDAI)-2K ≤4, with no activity in major organ systems (renal, central nervous system (CNS), cardiopulmonary, vasculitis, fever) and no haemolytic anaemia or gastrointestinal activity; (2) no new lupus disease activity compared with the previous assessment; (3) a Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI physician global assessment (scale 0–3) ≤1; (4) a current prednisolone (or equivalent) dose ≤7.5 mg daily; and (5) well tolerated standard maintenance doses of immunosuppressive drugs and approved biological agents. Achievement of LLDAS was determined in 191 patients followed for a mean of 3.9 years. Patients who spent greater than 50% of their observed time in LLDAS had significantly reduced organ damage accrual compared with patients who spent less than 50% of their time in LLDAS (p=0.0007) and were significantly less likely to have an increase in SDI of ≥1 (relative risk 0.47, 95% CI 0.28 to 0.79, p=0.005). Conclusions A definition of LLDAS has been generated, and preliminary validation demonstrates its attainment to be associated with improved outcomes in SLE.

Association of plasma B lymphocyte stimulator levels and disease activity in systemic lupus erythematosus

To determine the association of plasma B lymphocyte stimulator (BLyS) levels, immunosuppressive therapy, and other clinical parameters with disease activity in systemic lupus erythematosus (SLE). Two hundred forty-five SLE patients were evaluated prospectively over a 2-year period at 4 centers. Assessments were performed every 3-6 months. Univariate analysis was used to determine the association among the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, serum anti-double-stranded DNA (anti-dsDNA), and plasma BLyS levels. A multivariate repeated-measures model incorporating immunosuppressive therapy was utilized. Ninety-two percent of the patients were female. Sixty-seven percent were white, 31% African American, and 2% Asian (all of these groups may include Hispanic). Mean values at baseline were as follows: age 41.5 years, disease duration 8.1 years, SELENA-SLEDAI 3.3 (median 2, range 0-18), BLyS 5.57 ng/ml, IgG 1,439 mg/dl, C3 104.4 mg/dl, and C4 21.3 mg/dl; among those positive for anti-dsDNA, the median titer was 1:40 (range 1:10-1:1,280). Univariate analysis showed that plasma BLyS levels were associated with anti-dsDNA titers (P = 0.0465) and SELENA-SLEDAI scores (P = 0.0002). In multivariate analyses, a greater increase in the SELENA-SLEDAI score from the previous visit was associated with higher BLyS levels at the previous visit (P = 0.0042) and with a greater increase in the BLyS level from the previous visit (P = 0.0007). The findings of association between a greater increase in the BLyS level from the previous visit and a greater increase in the SELENA-SLEDAI score at the subsequent visit, and between an elevated BLyS level at the previous visit and a greater SELENA-SLEDAI score at the subsequent visit, demonstrate a relationship between circulating BLyS levels and SLE disease activity. These results lend support to the notion that BLyS is a candidate for therapeutic targeting in SLE.