Disease activity in systemic lupus erythematosus: report of the Consensus Study Group of the European Workshop for Rheumatology Research. I. A descriptive analysis of 704 European lupus patients. European Consensus Study Group for Disease Activity in SLE.

Using a detailed questionnaire, the cumulative historical and current demographic, clinical and serological data on 704 SLE patients from 29 European centres and 14 countries have been assessed. Ninety-three percent of the patients were Caucasian and the female/male ratio was 10:1. Analysis of the cumulative incidence showed that arthralgia/arthritis (94%), rash (69%), Raynaud's phenomenon (49%), serositis (44%) and renal disease (38%) were the most frequent clinical manifestations. Virtually all the patients (98%) were antinuclear antibody positive, while anti-ds-DNA antibodies (76%), hypocomplementaemia (71%) and anti-Ro(SSA) antibodies (35%) were frequent serological abnormalities. Whilst much of this data is in line with previous reports, it is notable that renal, lung, and central nervous system involvement and the frequency of rheumatoid factor, anti-Sm and anti-RNP antibodies were much lower than in most comparable series in the United States. We assume that ethnic differences and the greater present awareness of lupus could explain this variations. Low dose corticosteroids, non-steroidal anti-inflammatory drugs and anti-malarials were used to treat over half of the patients, 75% of whom were between 15 and 55 years of age. This report offers a useful overview of lupus both clinically and serologically in Europe in the 1990's.     

Disease activity in systemic lupus erythematosus: report of the Consensus Study Group of the European Workshop for Rheumatology Research. II. Identification of the variables indicative of disease activity and their use in the development of an activity score. The European Consensus Study Group for Disease Activity in SLE.

A European Consensus Group study, involving 29 centres from 14 countries, was performed in order to reach agreement on the definition of disease activity in systemic lupus erythematosus (SLE) and to construct a new disease index. Data on 704 lupus patients were collected and analysed, using univariate and multivariate statistical procedures, to select those clinical and laboratory features of the disorder which best correlate with the global assessment of disease activity assigned to the patients by the physician of each participating centre. A combination of 15 clinical and laboratory variables was shown to be the best predictor of disease activity in SLE. A European Consensus Lupus Activity Measurement (ECLAM) was then formulated. This index included the 15 selected variables, weighted (with some adjustments) according to their respective regression coefficients in the multivariate model. ECLAM appears to be an effective instrument for scoring patients with different degrees of disease activity. This is the first SLE disease activity index based on data from a very large number of lupus patients followed at a large number of lupus centres in different countries. It might therefore very well serve as a standardised measure for future European clinical studies. Final assessment of the validity, reliability and sensitivity of this index is now underway.     

Disease activity in rheumatoid arthritis: preliminary report of the Consensus Study Group of the European Workshop for Rheumatology Research.

The most suitable measures to assess the disease activity of rheumatoid arthritis patients treated with slow-acting anti-rheumatic drugs were considered in a prospective study. This was organised across Europe in 12 specialised centres and 282 patients were studied. The patients were all considered to be in need of therapy with a slow-acting anti-rheumatic drug and were studied at the initiation of therapy, and after 3 and 6 months of treatment. There were 215 patients who remained on treatment for 6 months. The most useful measures to assess disease activity were: the number of swollen joints, the number of tender joints, pain, the patients' assessment of response, and ESR. These should form a minimum data set when assessing the activity of rheumatoid arthritis. Some measures such as grip strength, hemoglobin, and the C-reactive protein level showed too much variation between centres and will require considerable standardisation before they can be used across Europe. There were problems in collecting functional data and further work is needed to develop a functional questionnaire available in all European languages with culturally suitable questions.     

Preliminary report on cytokine determination in human synovial fluids: a consensus study of the European Workshop for Rheumatology Research. The Cytokine Consensus Study Group of the European Workshop for Rheumatology Research.

A consensus study involving several European research groups was conducted in order to assess the reliability and reproducibility of cytokine measurements in biological fluids. Six synovial fluids and one serum--some of them spiked with recombinant human cytokines--were aliquoted and distributed blindly to different laboratories. The samples were tested for tumor necrosis factor alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha) and 1 beta, IL-6, IL-2, interferon gamma (IFN-gamma), and the soluble receptors of IL-2 (IL-2R) and TNF (TNF-sR55 and -sR75), using various immunoassays and, occasionally, bioassays. The same ELISA used in different laboratories yielded comparable results, whereas different ELISAs usually detected the highest levels in the same samples, but yielded different absolute values. This finding highlights the necessity of establishing international standards for all immunoassays. Many other questions arose during this preliminary study, and further investigations are planned to clarify them.     

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.     

Mild presentation of systemic lupus erythematosus in elderly patients assessed by SLEDAI. SLE Disease Activity Index.

OBJECTIVE: Systemic lupus erythematosus (SLE) predominantly affects young patients. SLE starting in later life has a clinical presentation different than in younger patients. We have used the SLE Disease Activity Index (SLEDAI) to explore the relationship between age of onset and disease activity. METHODS: We selected all patients controlled in our hospital at the moment of clinical diagnosis of SLE (100 patients; 85 females and 15 males). They were classified in two groups: those with early onset (>50 y) and those with late onset (>50 y) based on their age at the moment of clinical diagnosis of SLE. RESULTS: In 12 patients the onset of SLE was >50 y (10 females and two males; mean age 59 y). The early onset patients had significantly higher SLEDAI values at the presentation and during the first year of disease with respect to elderly patients. Antibodies to DNA and hypocomplementemia were detected more often in younger patients. CONCLUSION: Our results confirm using SLEDAI, that the lupus of the elderly patients is a distinct clinical subgroup with a milder course of disease.     

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.

     

C-reactive protein and serological indices of disease activity in systemic lupus erythematosus.

The concentration of C-reactive protein (CRP) in sera from 70 patients with systemic lupus erythematosus (SLE) showed no correlation with commonly accepted laboratory indices of disease activity. Most patients had detectable serum CRP, but in some patients CRP was not found despite repeated testing. This absence of a CRP response did not appear to be related to medication. In some patients high levels of CRP were seen in the absence of infection. Measurement of serum CRP in SLE is unlikely to be useful in the laboratory diagnosis of disease activity.     

Workshop report on some new ideas about the treatment of systemic lupus erythematosus

Our increased understanding of the pathogenesis of systemic lupus erythematosus is leading to new ideas about its therapy. In this session of the workshop the use of LJP 394 a B cell toleragen and the use of an anti-CD20 monoclonal antibody were discussed in some detail. Their rationale and early clinical results were reviewed; both have shown encouraging clinical and serological benefit. Definitive double-blind clinical trials are still, however, awaited. In addition, the intriguing notion of using a nasal instillation of a histone peptide was described and early work in an experimental model presented.     

Oral contraceptives in systemic lupus erythematosus: side-effects and influence on the activity of SLE.

The risk of a disease flare-up and the side-effects experienced during the use of oral contraceptives (OCs) were studied in 85 female SLE patients, 18-44 years old, regularly attending two specialist rheumatological clinics. Thirty-one patients had used combined oral contraceptives (cOCs) during or after the onset of SLE. Initial manifestations or exacerbations of SLE were noted in 4 (13%) of these patients during the first six months after starting cOCs and three of these four patients had major renal involvement. The incidence of disease flare-ups was the same as in patients not using cOCs. Two patients developed deep venous thrombosis during cOCs, and they both had antiphospholipid antibodies. Thirty-two patients had used progestagen-only contraceptives (PCs) and they were discontinued in 25 (78%) of the patients because of minor side-effects, mainly reflecting poor gynaecological tolerance. Albeit there is no definitive proof that cOCs actually precipitate or exacerbate SLE some patients may be more likely to have adverse effects while taking cOCs. It appears best to avoid cOCs in SLE patients with high levels of antiphospholipid antibodies and in patients with active nephritis. PCs cause many side-effects in SLE patients, but do not seem to activate the disease.     

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.     

Comparison of three indices for the evaluation of disease activity in systemic lupus erythematosus]

Assessing disease activity in SLE is often difficult due to the multiple organ systems involved. Three recent disease activity indices (SLAM, BILAG, and SLEDAI) are being increasingly used. Retrospective investigations comparing these indices have not been performed. We compared SLAM, BILAG, and SLEDAI in a retrospective study of 52 patients with SLE. SLAM and BILAG were found to correlate well with one another and with clinicians' evaluations of disease activity (as measured by intensity of immunosuppressive treatment). They correlated less well or insignificantly with laboratory parameters (ESR, anti-ds-DNA-antibodies). If practicability is also considered, SLAM, in particular, appears to be suitable for retrospective evaluation of disease activity in SLE.     

Depression, fatigue, and pain in systemic lupus erythematosus (SLE): relationship to the American College of Rheumatology SLE neuropsychological battery

OBJECTIVE: To examine the frequency and reliability of depression, fatigue, and pain self-report measures in patients with systemic lupus erythematosus (SLE) and healthy controls, and to examine the relationship between a cognitive impairment index (CII) derived from the American College of Rheumatology neuropsychology research battery of tests for SLE (ACR-SLE battery) and measures of depression, pain, fatigue, and perceived cognitive dysfunction. METHODS: Thirty-one patients with SLE with a history of overt neuropsychiatric symptoms (neuropsychiatric SLE [NPSLE]), 22 patients with SLE without overt neuropsychiatric symptoms (non-NPSLE), and 25 healthy controls completed the following measures at baseline and 1-month followup: ACR-SLE battery, perceived cognitive difficulties, depression, fatigue, and pain. RESULTS: Patients with SLE (both NPSLE and non-NPSLE) showed higher symptoms of depression, higher levels of fatigue, greater pain, and more perceived cognitive problems. All measures except the Center for Epidemiologic Studies Depression scale (CES-D) demonstrated adequate reliability across the SLE groups at retest. Only patients with NPSLE had significant correlations between CII and depression, fatigue, and pain. Neither the non-NPSLE patients nor the controls had significant relationships with the CII and these behavioral measures. CONCLUSION: Patients with SLE report higher levels of cognitive difficulties, depression, pain, and fatigue compared with controls. Reliability for all measures, except the CES-D, was established in the SLE group. Overall, results suggest that cognitive dysfunction, pain, fatigue, and depression in patients with NPSLE may represent global changes in the central nervous system that require ongoing evaluation and treatment.     

Measurement of disease activity in systemic lupus erythematosus. Prospective validation of 3 clinical indices.

Several clinical indices have been proposed to measure disease activity in patients with systemic lupus erythematosus. Only a few have been subjected to extensive analysis. We report a methodological comparison of reliability, validity, responsiveness, and feasibility of the Lupus Activity Criteria Count, the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and our own simplified modification of the latter (MEX-SLEDAI). They were applied prospectively to 39 patients with diverse degrees of disease activity in 3 consecutive visits. Inter-observer reliability outweighed experts' evaluation (rs = 0.86 to 0.89, p < 0.0001 versus 0.74). Significant association was demonstrated between indices and experts' judgment, managing physician's opinion, changes in treatment and clinical course. Moreover, indices showed good convergent validity (rs = 0.76 to 0.79, p < 0.0001), and responsiveness. MEX-SLEDAI was the least expensive instrument.     

Disease activity during the premenopausal and postmenopausal periods in women with systemic lupus erythematosus.

PURPOSE: Cyclophosphamide-induced ovarian failure has been reported to be protective against flares of systemic lupus erythematosus (SLE). We studied whether patients with SLE experience a decrease in disease activity after natural menopause. SUBJECTS AND METHODS: We studied 30 SLE patients with natural menopause who had been observed at least 2 years before and after menopause and who did not receive hormone replacement therapy or danazol. Menopause was defined as the date of the last self-reported menstrual period. Disease activity was assessed retrospectively by medical chart review using standard measures (the SLE disease activity index) during the immediate premenopausal and postmenopausal periods, and 2 (n = 30 patients), 3 (n = 19), and 4 (n = 13) years before and after menopause. We also compared the use of health services and medications. RESULTS: Patients were studied for a mean (+/- SD) of 6.4 +/- 1.7 years (premenopausal, 3.3 +/- 0.9 years; postmenopausal, 3.2 +/- 0.9 years). During the premenopausal periods, the mean disease activity score was 2.3 +/- 2.3 (range, 0 to 9 on a 0 to 105 scale), compared with 2.3 +/- 2.9 (range, 0 to 12; P = 0.37) after menopause. The maximum disease activity score was somewhat greater in the premenopausal period (7.9 +/- 6.0 [range, 0 to 22] vs. 5.8 +/- 5.1 [range, 0 to 22]; P = 0.04). The incidence rates of flares (0.56 per year vs. 0.43 per year, P = 0.20) and severe flares (0.17 per year vs. 0.12 per year, P = 0.33) were similar in the premenopausal and postmenopausal periods. Differences in disease activity scores (mean and maximum) and the number of visits to a rheumatologist's office were only significant when the fourth year before menopause was compared with the fourth year after menopause. CONCLUSIONS: Disease activity is mild during the premenopausal and postmenopausal periods in women with SLE. A modest decrease, especially in the maximum disease activity, is seen after natural menopause.     

Diagnostic criteria for neuropsychiatric systemic lupus erythematosus: the results of a consensus meeting. The Ad Hoc Neuropsychiatric Lupus Workshop Group

Definitions and classifications proposed for the neuropsychiatric complications of systemic lupus erythematosus (NP-SLE) indicate a wide range of approaches taken by different researchers and clinicians. A meeting of investigators was convened to begin a consensus process for standardizing its classification. We found that the level of agreement among raters on the importance of elements to the diagnosis of NP-SLE increased significantly as indicated by an intraclass correlation coefficient of 0.05 before the conference to 0.60 after the conference. The results of such studies can be used to generate and test the utility of diagnostic criteria for NP-SLE in multicenter trials.     

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.     

Reliability and validity of the proposed American College of Rheumatology neuropsychological battery for systemic lupus erythematosus

OBJECTIVE: To examine the reliability and validity of the proposed American College of Rheumatology (ACR) neuropsychological battery for patients with systemic lupus erythematosus (SLE). METHODS: Thirty-one SLE patients with a history of neuropsychiatric symptoms (NPSLE), 22 SLE patients without a history of neuropsychiatric symptoms (non-NPSLE), and 25 healthy controls completed measures of cognition at baseline and after 1 month. The 1-hour proposed ACR-SLE battery was compared with a 4-hour comprehensive battery (CB). RESULTS: Seven of 12 measures from the ACR-SLE battery were lower in SLE patients compared with controls. Overall agreement between impairment on the ACR-SLE battery and the CB was 90%. This was established using previously defined impairment on the CB and 4 of 12 scores impaired on the ACR-SLE battery. Almost perfect agreement between the 2 batteries was found for non-NPSLE patients and healthy controls (95-96%) and moderate agreement was reported for NPSLE patients (81%). Intraclass correlation coefficients for ACR-SLE tests ranged from 0.40 to 0.90, indicating adequate reliability. CONCLUSION: Reliability and validity of the ACR-SLE battery was established in this study. Agreement regarding classification for impairment was almost perfect for non-NPSLE and moderate for the NPSLE patients. The ACR battery is well designed for general classification of cognitive impairment in SLE. However, comprehensive testing may be useful in identifying specific deficits in NPSLE.