Minimal clinically important differences of disease activity indices in childhood‐onset systemic lupus erythematosus

Objective

To determine the minimal clinically important differences (MCIDs) of validated measures of systemic lupus erythematosus (SLE) disease activity in childhood‐onset SLE.

Methods

Childhood‐onset SLE patients (n = 98) were followed every 3 months for up to 7 visits (n = 623 total visits). Disease activity measures (European Consensus Lupus Activity Measure, Systemic Lupus Erythematosus Disease Activity Index, Systemic Lupus Activity Measure, British Isles Lupus Assessment Group, and Responder Index for Lupus Erythematosus [RIFLE]) were completed at the time of each visit. Physician‐rated changes in the disease course (clinically relevant improvement, no change, clinically relevant worsening) between visits served as the criterion standard.

Results

MCIDs defined by mean change scores with improvement and worsening, or those based on the standard error of measurement with stable disease, were both small and did not discriminate well between disease courses (detection rates for improvement or worsening were all <55%). MCIDs based on discriminant and classification analyses yielded similar results. Alternative MCIDs, defined by a 70% predicted probability of improvement or worsening as per the discrimination analysis, were larger but underestimated the proportion of patients with change. The RIFLE only correctly identified 26% and 8% of episodes of clinically important worsening and improvement of childhood‐onset SLE, respectively.

Conclusion

The MCIDs of childhood‐onset SLE disease activity measures are often small but similar to those reported for adults with SLE. Therefore, even small changes in disease activity scores can be clinically relevant. Low correct detection rates of these MCID thresholds for changes in disease course support the notion that worsening and improvement with childhood‐onset SLE, or its response to therapy, is unlikely to be captured adequately by validated measures of disease activity alone.     

European Consensus Lupus Activity Measurement is sensitive to change in disease activity in childhood‐onset systemic lupus erythematosus

Objectives To evaluate the European Consensus Lupus Activity Measurement (ECLAM) for responsiveness to change in disease activity when used in childhood‐onset systemic lupus erythematosus (cSLE). To confirm the construct validity and to characterize the measurement properties of the ECLAM by assessing its ability to predict damage and steroid requirements.

Methods

The disease courses of 66 newly diagnosed cSLE patients were reviewed. The ECLAM and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) were scored for all clinic visits and hospitalizations. Damage was assessed at the end of the followup period using the Systemic Lupus International Collaboration Clinics/American College of Rheumatology Damage Index. Disease activity at the time of diagnosis, 6 months after diagnosis, at the time of first flare, and 6 months after first flare was used to estimate responsiveness of the measures. Responsiveness was measured by the effect size, the effect size index, the standardized response mean, and the relative efficiency index (REI). The measurement properties of the ECLAM and SLEDAI over time were examined by comparing the ability of both measures to predict damage and oral steroid requirement.

Results

The ECLAM and SLEDAI are both responsive to change in disease activity irrespective of the statistic used. The ECLAM is more sensitive than the SLEDAI using the REI (all >1.9). Cumulative disease activity as measured by the SLEDAI or the ECLAM are important predictors of damage. There are no statistically important differences between the 2 measures with regard to their ability to predict steroid requirements.

Conclusions

The ECLAM has construct validity in cSLE and, like the SLEDAI, is highly sensitive to clinically important change in disease activity. The ECLAM may be more responsive. The quantitative properties of the 2 measures are very similar. The SLEDAI likely remains the preferable disease activity measure for cSLE given its overall measurement properties and ease of use.

     

Comparison of the validity and sensitivity to change of 5 activity indices in systemic lupus erythematosus

OBJECTIVE: To compare the construct validity and sensitivity to change of the Systemic Lupus Activity Measure (SLAM), Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), Lupus Activity Index (LAI), British Isles Lupus Assessment Group index (BILAG), and the European Consensus Lupus Activity Measure (ECLAM). METHODS: Twenty-three patients with systemic lupus erythematosus (SLE) were examined prospectively every 2 weeks for up to 40 weeks. Nineteen patients completed all 20 assessments. At each assessment, each of the 5 activity indices was scored, along with physicians' and patients' global assessments of SLE activity. Construct validity was determined by the strength of correlations between changes over time in each activity index and changes in physician and patient global assessments. Sensitivity to change was determined by the magnitude of change in each index over the 2 week interval of greatest change in the physician or patient global assessments, and calculated as standardized response means (SRM; mean change/standard deviation of change). Thirteen patients were also examined monthly by a second physician who was blinded to previous scores on the activity indices and to the patient global assessments. RESULTS: Patients had substantial changes in SLE activity during the study. Changes in each activity index were correlated with changes in the physician global assessment (SLAM r = 0.54; SLEDAI r = 0.52; LAI r = 0.75; BILAG r = 0.61; ECLAM r = 0.65; all p < 0.0001). Correlations were somewhat lower with the blinded physician assessment (SLAM r = 0.42; SLEDAI r = 0.12; LAI r = 0.30; BILAG r = 0.28; ECLAM r = 0.32). The SLAM was the only index that was positively correlated with changes in the patient global assessment (r = 0.22; p < 0.0001). Sensitivity to change was greatest for the LAI (SRM = 0.74) and the ECLAM (SRM = 0.75) and smallest for the SLEDAI (SRM = 0.48) when the physician global assessment was used as the standard. Sensitivity to change was greatest for the SLAM (SRM = 0.61) and the BILAG (SRM = 0.57) and smallest for the SLEDAI (SRM = -0.01) when the patient global assessment was used as the standard. CONCLUSION: Each index is a valid measure of SLE activity. The SLAM captures patients' assessments better than the other indices, perhaps because it assesses the patients' subjective complaints to a greater extent. Estimates of sensitivity to change varied with the standard used, but the SLEDAI was least sensitive to change. Larger studies are indicated to further compare the sensitivity to change of these indices.     

Psychological distress and changes in the activity of systemic lupus erythematosus

OBJECTIVE: To determine if changes in depressive symptoms or anxiety lead to changes in the activity of systemic lupus erythematosus (SLE). METHODS: Twenty-three patients with SLE were examined prospectively every 2 weeks for up to 40 weeks. At each assessment, patients completed the Centers for Epidemiologic Studies--Depression scale (CES-D), the State subscale of the State-Trait Anxiety Inventory and a global assessment of the activity of their SLE by visual analogue scale. SLE activity was also assessed at each visit by physician global assessment, the Systemic Lupus Activity Measure (SLAM), the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and the European Consensus Lupus Activity Measure (ECLAM). RESULTS: Changes in depression and anxiety were positively correlated with simultaneous changes in the patient global assessment of SLE activity and in the SLAM, but not with changes in the physician global assessment, SLEDAI or ECLAM. Depression and anxiety scores were also correlated with patient global assessments and SLAM scores 2 weeks later, but lagged scores were not significantly associated with the patient global assessment or SLAM after controlling for current depression and anxiety scores. The associations between depression and anxiety scores and the SLAM were not present when SLAM scores were modified to exclude ratings of depression and fatigue. No measure of SLE activity increased in the 2 weeks immediately after a large increase in CES-D or State Anxiety scores. CONCLUSIONS: Depression and anxiety scores parallel changes in patients' assessments of the activity of their SLE. We found no evidence to support the hypothesis that psychological distress causes increased SLE activity.     

Assessment of patients with systemic lupus erythematosus and the use of lupus disease activity indices

The assessment of disease activity in systemic lupus erythematosus (SLE) is a task faced by clinicians in every day care, but it is also required for clinical research and in randomised controlled trials. It is crucial to distinguish disease activity from infection, chronic damage and co-morbid disease. Over the past 20 years, many indices have been developed to objectively measure lupus disease activity and several of these have been validated. The most widely used indices are the British Isles Lupus Assessment Group (BILAG) index, the European Consensus Lupus Activity Measurement (ECLAM), the Systemic Lupus Activity Measure (SLAM), the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and the Lupus Activity Index (LAI). All these indices have been validated and have excellent reliability, validity and responsiveness to change. In addition to the assessment of disease activity, the evaluation of damage using the validated SLICC/ACR damage index and health-related quality of life is advised for clinical research.     

Evaluation of systemic lupus erythematosus activity during pregnancy

Pregnancy in patients with systemic lupus erythematosus (SLE) is considered a high-risk pregnancy. It is complicated by preeclampsia, premature labour and miscarriage more frequently than in the general population. Improved prognosis depends on low disease activity during conception and on appropriate medical care (SLE activity monitoring, selection of therapy safe for the mother and the developing foetus, advances in neonatology). Because symptoms of physiological pregnancy and SLE exacerbation are similar, their correct interpretation is essential for skin lesions, arthralgias, arterial hypertension or results of laboratory tests: proteinuria, thrombocytopenia or leucopenia observed in the patient. In order to standardise the assessment of SLE activity during pregnancy, scores of this activity are used. In the past, scores validated on non-pregnant populations (including male patients) were used: Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), Systemic Lupus Activity Measure (SLAM), European Consensus Lupus Activity Measurment (ECLAM). Only recently have SLE activity scores been introduced that are specific for pregnant women: Lupus Activity Index In Pregnancy (LAI-P), Systemic Lupus Erythematosus Pregnancy Disease Activity Index (SLEPDAI), modified--Systemic Lupus Activity Measure (m-SLAM) and a visual three-grade score modified--Physician Global Assessment (m-PGA). So far, only scores LAI-P and m-PGA have been validated. According to the LAI-P score, clinical data are divided into 4 groups. Group 1 includes mild clinical symptoms, group 2--symptoms of involvement of internal organs, group 3 pertains to modifications of treatment and group 4 to laboratory parameters. Point values are ascribed to individual parameters depending on their intensity.     

The rating scale preference measure as an evaluative measure in systemic lupus erythematosus

Preference measures may be useful tools to assess patients' overall health-related quality of life. We studied the validity and sensitivity to change of the rating scale preference measure in patients with systemic lupus erythematosus (SLE), and compared its properties with those of the patient global assessment of SLE activity, in a prospective longitudinal observational study of changes in the symptoms and clinical disease activity of 23 patients. Patients were assessed every two weeks for up to 40 weeks. Construct validity was assessed by the strength of correlations between changes over time in the rating scale preference measure and patient global assessment and changes in the physician global assessment, Systemic Lupus Activity Measure (SLAM), European Consensus Lupus Activity Measure (ECLAM), the British Isles Lupus Assessment Group index (BILAG), and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Changes in the rating scale were more highly correlated with changes in each of these standards than were changes in the patient global assessment, demonstrating the construct validity of this measure. Sensitivity to change was measured using the two-week interval of greatest change in either the physician global assessment or the SLE activity measures as standards. The rating scale preference measure was less sensitive to change than the patient global assessment when tested against four different standards. The sensitivity to change of the rating scale was less than one-half that of the patient global assessment when either the SLAM or ECLAM was used as the standard. Although these results support the validity of the rating scale as a measure of health-related quality of life in patients with SLE, its limited sensitivity to change may make it less attractive as an endpoint measure in clinical trials.     

European Consensus Lupus Activity Measurement is sensitive to change in disease activity in childhood-onset systemic lupus erythematosus

OBJECTIVES: To evaluate the European Consensus Lupus Activity Measurement (ECLAM) for responsiveness to change in disease activity when used in childhood-onset systemic lupus erythematosus (cSLE). To confirm the construct validity and to characterize the measurement properties of the ECLAM by assessing its ability to predict damage and steroid requirements.METHODS: The disease courses of 66 newly diagnosed cSLE patients were reviewed. The ECLAM and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) were scored for all clinic visits and hospitalizations. Damage was assessed at the end of the followup period using the Systemic Lupus International Collaboration Clinics/American College of Rheumatology Damage Index. Disease activity at the time of diagnosis, 6 months after diagnosis, at the time of first flare, and 6 months after first flare was used to estimate responsiveness of the measures. Responsiveness was measured by the effect size, the effect size index, the standardized response mean, and the relative efficiency index (REI). The measurement properties of the ECLAM and SLEDAI over time were examined by comparing the ability of both measures to predict damage and oral steroid requirement. RESULTS: The ECLAM and SLEDAI are both responsive to change in disease activity irrespective of the statistic used. The ECLAM is more sensitive than the SLEDAI using the REI (all >1.9). Cumulative disease activity as measured by the SLEDAI or the ECLAM are important predictors of damage. There are no statistically important differences between the 2 measures with regard to their ability to predict steroid requirements. CONCLUSIONS: The ECLAM has construct validity in cSLE and, like the SLEDAI, is highly sensitive to clinically important change in disease activity. The ECLAM may be more responsive. The quantitative properties of the 2 measures are very similar. The SLEDAI likely remains the preferable disease activity measure for cSLE given its overall measurement properties and ease of use.     

Decreases in anti–double‐stranded DNA levels are associated with concurrent flares in patients with systemic lupus erythematosus

Objective

To determine the degree to which changes in anti–double‐stranded DNA (anti‐dsDNA), as determined by Crithidia and enzyme‐linked immunosorbent assays (ELISAs), precede or coincide with changes in systemic lupus erythematosus (SLE) activity, as measured by 5 clinical indices, the physician's global assessment (PGA), modified SLE Disease Activity Index (M‐SLEDAI), modified Lupus Activity Index (M‐LAI), Systemic Lupus Activity Measure (SLAM), and the modified British Isles Lupus Assessment Group (M‐BILAG).

Methods

Disease activity and anti‐dsDNA were measured monthly in 53 SLE patients who were followed up for 1 year. Lupus flare was defined as an increase in PGA of ≥1.0, M‐SLEDAI ≥3, M‐LAI ≥0.1, SLAM ≥3, and M‐BILAG ≥4 within a 1‐month period. Flare rates were calculated for groups, which were defined by “previous” (1 month prior to the flare) or “concurrent” (at the time of the flare) changes in anti‐dsDNA. Logistic regression models were used to determine the significance of the association between recent changes in anti‐dsDNA and flare, controlling for the prednisone dosage.

Results

Flares occurred at 12% of visits, based on the PGA measure of disease activity. Using the other indices, flare rates were 19% (M‐SLEDAI), 25% (M‐LAI), 13% (SLAM), and 12% (M‐BILAG). A concurrent decrease in anti‐dsDNA (ELISA) was associated with significantly higher flare rates based on PGA (18 of 84, 21%; P = 0.0014), M‐SLEDAI (27 of 89, 30%; P = 0.0019), M‐LAI (37 of 89, 42%; P = 0.0001), and M‐BILAG (19 of 89, 21%; P = 0.0264) scores. Flare rates were also significantly higher after a previous increase in anti‐dsDNA (ELISA) based on M‐SLEDAI (26 of 93, 30%; P = 0.0022) and M‐LAI (34 of 93, 37%; P = 0.0117) scores. Flare rates tended to be lowest when there was a concurrent increase in anti‐dsDNA (ELISA). Analysis of specific organ systems showed that a concurrent decrease in anti‐dsDNA (ELISA) was significantly associated with increases in renal disease activity. Similar results were obtained using the Crithidia assay.

Conclusion

A previous increase in anti‐dsDNA levels occurred before SLE flares, as measured by the M‐SLEDAI and M‐LAI only. However, during lupus flares, including the subset of renal flares, anti‐dsDNA levels frequently decreased. We hypothesize that this decrease in anti‐dsDNA represents deposition in tissue at the time of flare.

     

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

Objective

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.

Methods

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).

Results

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.

Conclusion

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.

     

Systemic lupus erythematosus: clinical features in patients with a disease duration of over 10 years, first evaluation.

OBJECTIVE: Most information available about the disease course of patients with systemic lupus erythematosus (SLE) is restricted to the first 5 yr after disease onset. Data about the disease course 10 yr after disease onset are rare. The aim of this multicentre study was to describe the outcome of SLE patients with a disease duration of >10 yr. METHODS: Outcome parameters were the SLE Disease Activity Index (SLEDAI), the European Consensus Lupus Activity Measure (ECLAM), the Systemic Lupus International Collaborative Clinics/American College of Rheumatology Damage Index (SLICC/ACR), a global damage index (DI) and required treatment. In 10 different European rheumatology centres, all SLE patients who were evaluated in the last 3 months of 1994, and who had been diagnosed with SLE at least 10 yr ago, were included in the study. RESULTS: It should be stressed that our results are confined to a patient cohort, defined by a disease duration of at least 10 yr, and who are still under clinical care at the different centres in Europe. These SLE patients still showed some disease activity, related to symptoms of the skin and musculoskeletal systems, next to the presence of renal involvement. A total of 72% of the patients needed treatment with prednisolone (相似文献   

Comparison of the Sensitivity to Change of the 36‐Item Short Form Health Survey and the Lupus Quality of Life Measure Using Various Definitions of Minimum Clinically Important Differences in Patients With Active Systemic Lupus Erythematosus

Objective

The Medical Outcomes Study Short Form 36 (SF‐36) and Lupus Quality of Life (LupusQoL) are health‐related quality of life questionnaires used in systemic lupus erythematosus (SLE). We first determined the hypothesis‐testing construct validity of the SF‐36 and LupusQoL against disease activity in patients with active SLE and then compared the sensitivity to change of SF‐36 and LupusQoL domains according to different definitions of minimum clinically important differences (MCIDs) for improvement and worsening in the current cohort.

Methods

Seventy‐eight clinically active SLE patients concurrently completed both questionnaires at their baseline and followup visits. Questionnaire domain scores were correlated with the SLE Disease Activity Index 2000 (SLEDAI‐2K) and evaluated for floor/ceiling effects. The sensitivity to change of domains in each questionnaire was analyzed first, according to the various MCID definitions and, second, by clinically meaningful changes in disease activity. The magnitudes of change in each domain score between the baseline and followup visit were evaluated using standardized response means.

Results

In the 78 patients, the mean ± SD SLEDAI‐2K scores were 9.7 ± 4.8 at baseline and 8.8 ± 5.1 at followup. SF‐36/LupusQoL domain scores did not correlate with disease activity. The SF‐36 showed floor effects, and ceiling effects were evident in both questionnaires. All domains of both questionnaires showed sensitivity to change over time. Specific domains that reflected worsening or improvement differed according to differing MCID definitions.

Conclusion

In SLE patients with active disease, both the SF‐36 and LupusQoL are sensitive to change, reflecting both improvement and worsening. More importantly, the LupusQoL SLE‐specific domains (planning, burden to others, body image, and intimate relationships) were largely responsive to change.     

Systemic lupus erythematosus in three ethnic groups. VIII. Predictors of early mortality in the LUMINA cohort

Objective

To determine the features associated with mortality in a multiethnic US cohort of patients with systemic lupus erythematosus (SLE) within 5 years of study onset.

Methods

Socioeconomic and demographic features (age, gender, ethnicity, marital status, education, occupation, poverty, and health‐related behaviors [drinking, smoking, exercising]), clinical and immunologic features (disease duration, disease onset type, disease activity according to the Systemic Lupus Activity Measure [SLAM], disease damage according to the Systemic Lupus International Collaborating Clinics [SLICC] Damage Index [SDI], number of American College of Rheumatology criteria at diagnosis, organ system manifestations, fatigue and pain ratings, and medication usage and autoantibodies), immunogenetic features (HLA class II genotypes), and behavioral and psychosocial features (social support, illness‐related behaviors, and helplessness), as obtained at enrollment into the study, were compared between survivors and deceased patients. Logistic regression analysis was used to determine significant independent risk factors for mortality.

Results

Within 5 years of study onset, 34 of 288 patients have died. Fourteen deaths could be directly attributed to SLE and 11 to infections. In 1 patient the cause of death could not be determined. In the remaining 8 patients the cause of death was neither infectious nor disease‐related. There were 10 deaths among Hispanics, 18 among African Americans, and 6 among Caucasians (P< 0.05). Variables associated with mortality in the univariable analyses included poverty, less than full‐time employment, difficulty in accessing health care, shorter disease duration, cardiovascular and renal involvement, higher serum creatinine levels and lower hematocrit values, higher SLAM and SDI scores, lower use of antimalarial drugs, and higher use of (some) immunosuppressants. Specific autoantibodies and class II HLA genotypes were not associated with mortality. Poverty and higher baseline SLAM and SDI scores were independently associated with mortality in the multivariable analyses.

Conclusions

Disease activity, disease damage, and poverty appear to be the most important determinants of mortality in this multiethnic US cohort of SLE patients. These results have applicability to the management of patients with SLE, a disease that more severely affects disadvantaged minority population groups.

     

Quantitative clinical assessment of disease activity in systemic lupus erythematosus: progress report and research agenda

Summary No single test allows an adequate measure of disease activity in multisystem diseases such as systemic lupus erythematosus (SLE). In order to evaluate the spectrum of manifestations of disease activity in SLE, investigators have developed numerous ad hoc scales which have not been tested for their validity or reliability. Three instruments have been extensively studied: the British Isles Lupus Activity Group instrument (BILAG), the SLE Disease Activity Index (SLEDAI), and the Systemic Lupus Activity Measure (SLAM). All three have been demonstrated to have convergent and construct validity when compared to the clinician's judgement. The summation of the number of criteria of the American Rheumatism Association (ARA) SLE criteria has been shown to be an inadequate measure of disease activity. Standardized measures of disease activity for SLE should enhance our ability to compare results from different centers in finer distinctions than dead or alive.     

Serum free light chains as biomarkers for systemic lupus erythematosus disease activity

Objective

To evaluate serum free light chains (FLC) as a putative biomarker of systemic lupus erythematosus (SLE) activity.

Methods

Seventy‐five SLE patients and 41 age‐ and sex‐matched rheumatoid arthritis (RA) controls were enrolled. Disease activity was assessed using the Safety of Estrogens in Lupus Erythematosus: National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) definition and physician global assessments for SLE and the Disease Activity Score in 28 joints for RA. Serum FLC levels were compared against other biomarkers (IgG, C3, C4, double‐stranded DNA [dsDNA] antibody). Nonparametric tests were used to compare 1) FLC and IgG in SLE versus RA and healthy controls, 2) FLC and IgG among different levels of activity in SLE, and 3) FLC in active versus nonactive RA. Correlation of FLC, C3, C4, dsDNA antibody, and IgG with the SLEDAI and modified SLEDAI (M‐SLEDAI) were obtained.

Results

FLC was higher in SLE than in RA; both were higher than referent healthy controls. Total FLC was significantly higher in subjects with greater SLE disease activity than lower/no activity. There were no significant differences in IgG, C4, or dsDNA antibody stratified by disease activity. Total FLC and C3 showed moderate to strong correlation with the SLEDAI and M‐SLEDAI. In RA, no differences were seen in FLC levels for different levels of disease activity. Similar results were seen after controlling for renal function, age, and sex. In multiple linear regression, FLC significantly explained 50% variance of the SLEDAI after adjusting for renal function, age, and sex.

Conclusion

Serum FLC levels correlate strongly with disease activity in SLE, but not in RA. Serum FLC may be used as a biomarker of SLE disease activity.     

Systemic lupus erythematosus in a multiethnic cohort (LUMINA): XXIX. Elevation of erythrocyte sedimentation rate is associated with disease activity and damage accrual

OBJECTIVE: To determine if different categories of erythrocyte sedimentation rate (ESR) elevation are associated with disease activity and/or damage in systemic lupus erythematosus (SLE). METHODS: We studied 2317 study visits in 553 SLE patients (> or = 4 American College of Rheumatology criteria, < or = 5 years' disease duration at enrollment) from a multiethnic (Hispanic, African American, and Caucasian) longitudinal study of outcome. A study visit was done every 6 months for the first year and annually thereafter. Erythrocyte sedimentation rate (ESR) was measured using the Westergren method; results were expressed in 4 categories: < 25 (normal), 25-50 (mild elevation), 51-75 (moderate elevation), and > 75 (marked elevation) mm/h. Anti-dsDNA antibodies were measured at enrollment with the Crithidia luciliae assay. Disease activity was assessed with the Systemic Lupus Activity Measure (SLAM) and the Physician's Global Assessment (PGA). Because ESR is one of the measures evaluated in the SLAM, it was excluded from the total SLAM score. Disease damage was assessed with the Systemic Lupus International Collaborating Clinics damage index (SDI). The relationship between the SLAM (total and PGA) and SDI scores (at baseline and for all visits) and anti-dsDNA antibodies (at enrollment) with ESR was examined by univariable and generalized estimating equation (GEE) regression analyses. Ethnicity, age, and sex were entered in all regression models. RESULTS: The cohort consisted of 89.7% women with mean age 36.8 (SD 12.6) years and disease duration 4.6 (SD 3.2) years. GEE analyses showed that increasing levels of ESR and anti-dsDNA antibody positivity were independently associated with SLAM and PGA scores, at enrollment and for all visits. Overall, the associations of ESR with SLAM and PGA scores were stronger than for the presence of anti-dsDNA antibodies. At baseline, there was no relationship of ESR elevation or anti-dsDNA positivity with SDI scores. However, when all visits were studied, moderate and marked elevations of ESR were independently associated with SDI scores. CONCLUSION: Mild, moderate, and marked ESR elevations are strongly associated with disease activity in SLE. Moderate and marked ESR elevations are also associated with damage accrual. These associations are stronger than those for the presence of anti-dsDNA antibodies. Our data suggest that ESR could be used to assess disease activity and predict organ/system damage in a relatively rapid and inexpensive manner in SLE.     

Novel evidence‐based systemic lupus erythematosus responder index

Objective

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.

Methods

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.

Results

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.

Conclusion

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.     

Urinary neutrophil gelatinase–associated lipocalin as a biomarker of nephritis in childhood‐onset systemic lupus erythematosus

Objective

Renal involvement in systemic lupus erythematosus (SLE) is associated with poor prognosis. Currently available renal biomarkers are relatively insensitive and nonspecific for diagnosing SLE nephritis. Previous research suggests that neutrophil gelatinase–associated lipocalin (NGAL) is a high‐quality renal biomarker of acute kidney injury, while its usefulness in SLE is unclear. We undertook this study to determine the relationship between urinary NGAL excretion and SLE disease activity or damage, with a focus on nephritis.

Methods

A cohort of 35 patients diagnosed as having SLE prior to age 16 years (childhood‐onset SLE) was assessed for disease activity (using the Systemic Lupus Erythematosus Disease Activity Index 2000 update) and damage (using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology SLE Damage Index) in a double‐blind, cross‐sectional study. Information on current markers of renal function and disease was obtained and compared with NGAL levels (ng/mg of urinary creatinine) measured by enzyme‐linked immunosorbent assay. Eight children with juvenile idiopathic arthritis (JIA) served as controls.

Results

NGAL levels did not differ with the age, weight, height, sex, or race of the patients. Patients with childhood‐onset SLE had significantly higher NGAL levels than did those with JIA (P < 0.0001). NGAL levels were strongly to moderately correlated with renal disease activity and renal damage (Spearman's r ≥ 0.47, P < 0.0001 for both comparisons), but not with extrarenal disease activity or extrarenal damage. NGAL levels of >0.6 ng/mg urinary creatinine were 90% sensitive and 100% specific for identifying childhood‐onset SLE patients with biopsy‐proven nephritis.

Conclusion

Urinary NGAL is a promising potential biomarker of childhood‐onset SLE nephritis. The results of the current study require validation in a larger cohort to more accurately delineate urinary NGAL excretion in relation to the diverse SLE phenotypes.

     

Incomplete lupus erythematosus: results of a multicentre study under the supervision of the EULAR Standing Committee on International Clinical Studies Including Therapeutic Trials (ESCISIT)

OBJECTIVE: Patients characterized with antinuclear antibodies (ANA) and disease symptoms related to one organ system can be described as having incomplete systemic lupus erythematosus (SLE). The aim of this multicentre study was to describe the outcome of these so-called incomplete SLE patients. Two aspects of the outcome were studied: (i) the disease course, defined by the presence or absence of clinical symptoms; and (ii) the number of patients that eventually developed full SLE. METHODS: Outcome parameters were the ACR criteria, the SLE disease Activity Index (SLEDAI), the European Consensus Lupus Activity Measure (ECLAM) and the requirement for treatment. In 10 European rheumatology centres, patients who had been evaluated in the last 3 months of 1994 and had been diagnosed as having incomplete SLE on clinical grounds for at least 1 yr were included in the study. All 122 patients who were included in the study were evaluated annually during 3 yr of follow-up. RESULTS: Our results are confined to a patient cohort defined by disease duration of at least 1 yr, being under clinical care at the different centres in Europe. These patients showed disease activity that was related mostly to symptoms of the skin and the musculoskeletal system, and leucocytopenia. During the follow-up, low doses of prednisolone were still being prescribed in 43% of the patients. On recruitment to the study, 22 of the 122 incomplete SLE patients already fulfilled the ACR criteria for the diagnosis of SLE. In the 3 yr of follow-up only three patients developed SLE. CONCLUSIONS: A high proportion of patients in our cohort defined on clinical grounds as having incomplete SLE eventually showed disease activity defined by the SLEDAI as well as ECLAM. However, only three cases developed to SLE during the follow-up. This suggests that incomplete SLE forms a subgroup of SLE that has a good prognosis.     

Neutrophil gelatinase–associated lipocalin is a predictor of the course of global and renal childhood‐onset systemic lupus erythematosus disease activity

Objective

To determine whether neutrophil gelatinase–associated lipocalin (NGAL) can predict worsening of global and renal disease activity in childhood‐onset systemic lupus erythematosus (SLE).

Methods

One hundred eleven patients with childhood‐onset SLE were enrolled in a longitudinal, prospective study with quarterly study visits and had at least 3 study visits. At each visit, global disease activity was measured using 3 external standards: the numerically converted British Isles Lupus Assessment Group (BILAG) index, the SLE Disease Activity Index 2000 update score, and the physician's assessment of global disease activity. Renal and extrarenal disease activity were measured by the respective domain scores. The disease course over time was categorized at the most recent visit (persistently active, persistently inactive, improved, or worsening). Plasma and urinary NGAL levels were measured by enzyme‐linked immunosorbent assay, and urinary NGAL levels were standardized to the urinary creatinine concentration. The longitudinal changes in NGAL levels were compared with the changes in SLE disease activity using mixed‐effect models.

Results

Significant increases in standardized urinary NGAL levels of up to 104% were detected up to 3 months before worsening of lupus nephritis (as measured by all 3 external standards). Plasma NGAL levels increased significantly by as much as 26% up to 3 months before worsening of global SLE disease activity as measured by all 3 external standards. Plasma NGAL levels increased significantly by 26% as early as 3 months prior to worsening of lupus nephritis as measured by the BILAG renal score.

Conclusion

Serial measurement of urinary and plasma NGAL levels may be valuable in predicting impending worsening of global and renal childhood‐onset SLE disease activity.