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Objectives: HCQ and AZA are used to control disease activity and reduce risk of flare during pregnancy in patients with SLE. The aim of this study was to determine the outcomes of children born to mothers with SLE exposed to HCQ or AZA during pregnancy and breast-feeding., Methods: Women attending UK specialist lupus clinics with children ≤17 years old, born after SLE diagnosis, were recruited to this retrospective study. Data were collected using questionnaires and from clinical record review. Factors associated with the outcomes of low birth weight and childhood infection were determined using multivariable mixed-effects logistic regression models., Results: We analysed 284 live births of 199 mothers from 10 UK centres. The first pregnancies of 73.9% of mothers (147/199) were captured in the study; (60.4%) (150/248) and 31.1% (87/280) children were exposed to HCQ and AZA, respectively. There were no significant differences in the frequency of congenital malformations or intrauterine growth restriction between children exposed or not to HCQ or AZA. AZA use was increased in women with a history of hypertension or renal disease. Although AZA was associated with low birth weight in univariate models, there was no significant association in multivariable models. In adjusted models, exposure to AZA was associated with increased reports of childhood infection requiring hospital management [odds ratio 2.283 (1.003, 5.198), P = 0.049]., Conclusions: There were no significant negative outcomes in children exposed to HCQ in pregnancy. AZA use was associated with increased reporting of childhood infection, which warrants further study., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: To determine whether BILAG-2004 index is associated with the development of damage in a cohort of SLE patients. Mortality and development of damage were examined., Methods: This was a multicentre longitudinal study. Patients were recruited within 12 months of achieving fourth ACR classification criterion for SLE. Data were collected on disease activity, damage, SLE-specific drug exposure, cardiovascular risk factors, antiphospholipid syndrome status and death at every visit. This study ran from 1 January 2005 to 31 December 2017. Descriptive statistics were used to analyse mortality and development of new damage. Poisson regression was used to examine potential explanatory variables for development of new damage., Results: A total of 273 SLE patients were recruited with total follow-up of 1767 patient-years (median 73.4 months). There were 6348 assessments with disease activity scores available for analysis. During follow-up, 13 deaths and 114 new damage items (in 83 patients) occurred. The incidence rate for development of damage was higher in the first 3 years before stabilizing at a lower rate. Overall rate for damage accrual was 61.1 per 1000 person-years (95% CI: 50.6, 73.8). Analysis showed that active disease scores according to BILAG-2004 index (systems scores of A or B, counts of systems with A and BILAG-2004 numerical score) were associated with development of new damage. Low disease activity (LDA) states [BILAG-2004 LDA and BILAG Systems Tally (BST) persistent LDA] were inversely associated with development of damage., Conclusions: BILAG-2004 index is associated with new damage. BILAG-2004 LDA and BST persistent LDA can be considered as treatment targets., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To compare the responsiveness of the British Isles Lupus Assessment Group 2004 index (BILAG-2004) and the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) disease activity indices and to determine whether there was any added value in combining BILAG-2004, BILAG-2004 system tally (BST), or simplified BST (sBST) with SLEDAI-2K., Methods: This was a multicenter longitudinal study of SLE patients. Data were collected on BILAG-2004, SLEDAI-2K, and therapy on consecutive assessments in routine practice. The external responsiveness of the indices was assessed by determining the relationship between change in disease activity and change in therapy between 2 consecutive visits. Comparison of indices and their derivatives was performed by assessing the main effects of the indices using logistic regression. Receiver operating characteristic curves analysis was used to describe the performance of these indices individually and in various combinations, and comparisons of area under the curve were performed., Results: There were 1,414 observations from 347 patients. Both BILAG-2004 and SLEDAI-2K maintained an independent relationship with change in therapy when compared. There was some improvement in responsiveness when continuous SLEDAI-2K variables (change in score and score of previous visit) were combined with BILAG-2004 system scores. Dichotomization of BILAG-2004 or SLEDAI-2K resulted in poorer performance. BST and sBST had similar responsiveness as the combination of SLEDAI-2K variables and BILAG-2004 system scores. There was little benefit in combining SLEDAI-2K with BST or sBST., Conclusion: The BILAG-2004 index had comparable responsiveness to SLEDAI-2K. There was some benefit in combining both indices. Dichotomization of BILAG-2004 and SLEDAI-2K leads to suboptimal performance. BST and sBST performed well on their own; sBST is recommended for its simplicity and clinical meaningfulness., (© 2021 American College of Rheumatology.)

Objective: SLE is characterized by relapses and remissions. We aimed to describe the frequency, type and time to flare in a cohort of SLE patients., Methods: SLE patients with one or more 'A' or 'B' BILAG-2004 systems meeting flare criteria ('new' or 'worse' items) and requiring an increase in immunosuppression were recruited from nine UK centres and assessed at baseline and monthly for 9 months. Subsequent flares were defined as: severe (any 'A' irrespective of number of 'B' flares), moderate (two or more 'B' without any 'A' flares) and mild (one 'B')., Results: Of the 100 patients, 94% were female, 61% White Caucasians, mean age (s.d.) was 40.7 years (12.7) and mean disease duration (s.d.) was 9.3 years (8.1). A total of 195 flares re-occurred in 76 patients over 781 monthly assessments (flare rate of 0.25/patient-month). There were 37 severe flares, 32 moderate flares and 126 mild flares. By 1 month, 22% had a mild/moderate/severe flare and 22% had a severe flare by 7 months. The median time to any 'A' or 'B' flare was 4 months. Severe/moderate flares tended to be in the system(s) affected at baseline, whereas mild flares could affect any system., Conclusion: . In a population with active SLE we observed an ongoing rate of flares from early in the follow-up period with moderate-severe flares being due to an inability to fully control the disease. This real-world population study demonstrates the limitations of current treatments and provides a useful reference population from which to inform future clinical trial design., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

We describe a man presenting with unusual neurological manifestations of systemic lupus erythematosus (SLE) including pachymeningitis, aseptic meningitis and encephalitis with grossly elevated cerebrospinal fluid protein, responding to immunosuppression. Initially he had intermittent dysarthria, dysphasia and unilateral upper limb weakness. One month later he experienced dysphasia, right-sided hemiparesis and confusion. Cerebrospinal fluid (CSF) analysis showed a white cell count of 70 x 106/litre and an unusually elevated protein level of 5.39 g/litre. An MRI brain showed dural and leptomeningeal enhancement compatible with a meningitic process. He improved with cefotaxime and aciclovir. On day seven of antimicrobials he developed left-sided weakness, sensory inattention and a left homonymous hemianopia. He responded well to intravenous methylprednisolone. On switching to oral prednisolone he developed expressive dysphasia, a right inferior quadrantanopia and seizures. His bloods were suggestive of macrophage activation syndrome. The patient improved with methylprednisolone and intravenous immunoglobulins, and the improvement was sustained on switching back to oral prednisolone. The prevalence of neuropsychiatric manifestations of SLE varies between 14 and 80% and according to the American College of Rheumatology includes 19 conditions. This case is unique because although some features were in keeping with aseptic meningitis the MRI appearances were also suggestive of pachymeningitis.

Objectives: To describe the baseline characteristics of SLE patients requiring biologic therapy in the UK and to explore short term efficacy and infection rates associated with rituximab (RTX) use., Methods: Patients commencing biologic therapy for refractory SLE and who consented to join BILAG-BR were analysed. Baseline characteristics, disease activity (BILAG 2004/SLEDAI-2K) and rates of infection over follow-up were analysed. Response was defined as loss of all A and B BILAG scores to ⩽ 1 B score with no new A/B scores in other organ systems at 6 months., Results: Two hundred and seventy SLE patients commenced biologic therapy from September 2010 to September 2015, most commonly RTX (n = 261). Two hundred and fifty (93%) patients were taking glucocorticoids at baseline at a median [interquartile range (IQR)] oral dose of 10 mg (5-20 mg) daily. Response rates at 6 months were available for 68% of patients. The median (IQR) BILAG score was 15 (10-23) at baseline and 3 (2-12) at 6 months (P < 0.0001). The median (IQR) SLEDAI-2K reduced from 8 (5-12) to 4 (0-7) (P < 0.001). Response was achieved in 49% of patients. There was also a reduction in glucocorticoid use to a median (IQR) dose of 7.5 mg (5-12 mg) at 6 months (P < 0.001). Serious infections occurred in 26 (10%) patients, being more frequent in the first 3 months post-RTX therapy. A higher proportion of early infections were non-respiratory (odds ratio = 1.98, 95% CI: 0.99, 3.9; P = 0.049)., Conclusion: RTX is safe and is associated with improvement in disease activity in refractory SLE patients with concomitant reductions in glucocorticoid use. Early vigilance for infection post-infusion is important to further improve treatment risks and benefits., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Objective: As a health-related quality of life (HRQOL) measure, the LupusQoL is a reliable and valid measure for adults with systemic lupus erythematosus (SLE). This study evaluates the responsiveness and minimal important differences (MIDs) for the 8 LupusQoL domains., Methods: Patients experiencing a flare were recruited from 9 UK centers. At each of the 10 monthly visits, HRQOL (LupusQoL, Short Form 36 health survey [SF-36]), global rating of change (GRC), and disease activity using the British Isles Lupus Assessment Group 2004 index were assessed. The responsiveness of the LupusQoL and the SF-36 was evaluated primarily when patients reported an improvement or deterioration on the GRC scale and additionally with changes in physician-reported disease activity. MIDs were estimated as mean changes when minimal change was reported on the GRC scale., Results: A total of 101 patients were recruited. For all LupusQoL domains, mean HRQOL worsened when patients reported deterioration and improved when patients reported an improvement in GRC; SF-36 domains showed comparable responsiveness. Improvement in some domains of the LupusQoL/SF-36 was observed with a decrease in disease activity, but when disease activity worsened, there was no significant change. LupusQoL MID estimates for deterioration ranged from -2.4 to -8.7, and for improvement from 3.5 to 7.3; for the SF-36, the same MID estimates were -2.0 to -11.1 and 2.8 to 10.9, respectively., Conclusion: All LupusQoL domains are sensitive to change with patient-reported deterioration or improvement in health status. For disease activity, some LupusQoL domains showed responsiveness when there was improvement but none for deterioration. LupusQoL items were derived from SLE patients and provide the advantage of disease-specific domains, important to the patients, not captured by the SF-36., (© 2016, The Authors. Arthritis Care & Research published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.)

Objective: This was an exploratory analysis to develop a new way of representing BILAG-2004 system scores longitudinally that would be clinically meaningful and easier to analyse in comparison with multiple categorical variables., Methods: Data from a multicentre longitudinal study of SLE patients (the BILAG-2004 index and therapy collected at every visit) were used. External responsiveness analysis of the index suggested the possibility of using counts of systems with specified transitions in scores as a basis to analyse the system scores. Exploratory analyses with multinomial logistic regression were used to examine the appropriateness of this new method of analysing BILAG-2004 system scores. Receiver operating characteristic (ROC) curve analysis was used to assess the performance of this approach., Results: There were 1414 observations from 347 patients. A novel method was devised based on counts of systems with defined transitions in score (BILAG-2004 systems tally, BST). It has six components (systems with major deterioration, systems with minor deterioration, systems with persistent significant activity, systems with major improvement, systems with minor improvement and systems with persistent minimal or no activity). This was further simplified (simplified BST, sBST) into three components (systems with active/worsening disease, systems with improving disease and systems with persistent minimal or no activity). Both versions had expected associations with change in therapy. ROC curve analyses demonstrated that both versions had similar good performance characteristics (areas under the curve >0.80) in predicting increase in therapy., Conclusion: The BST and sBST provide alternative approaches to representing BILAG-2004 disease activity longitudinally. Further validation of their use is required.

Objective: To assess the inter-rater reliability of the BILAG2004-Pregnancy index for assessment of SLE disease activity in pregnancy., Methods: Pregnant SLE patients were recruited from four centres and assessed separately by two raters/physicians in routine clinical practice. Disease activity was determined using the BILAG2004-Pregnancy index. Reliability was assessed using level of agreement, κ-statistics and analysis of disagreement. Major disagreement was defined as a score difference of A and C/D/E or B and D/E between the two raters, and minor disagreement was a score difference of A and B or B and C between raters., Results: A total of 30 patients (63.3% Caucasian, 13.3% Afro-Caribbean, 16.7% South Asian) were recruited. The majority of patients had low-level disease activity according to the local rater's assessment, and there was no grade A activity, with grade B activity present in the following systems: mucocutaneous (nine patients), musculoskeletal (two patients), cardiorespiratory (one patient) and renal (one patient). The distribution of disease activity was similar to the external rater's assessment. Good levels of agreement (>70%) were achieved in all systems. κ-statistics were not appropriate for use in the gastrointestinal, ophthalmic, constitutional and neuropsychiatric systems, as there was minimal variation between patients but good levels of agreement otherwise. There were three major disagreements (0.1 per patient, all differences between B and D/E) and five minor disagreements (0.17 per patient)., Conclusion: The BILAG2004-Pregnancy index is reliable for assessment of disease activity in pregnant SLE patients.

Objectives: To examine SLEDAI-2000 cut-off scores for definition of active SLE and to determine the sensitivity to change of SLEDAI-2000 for the assessment of SLE disease activity and minimal clinically meaningful changes in score., Methods: Data from two multi-centre studies were used in the analysis: in a cross-sectional and a longitudinal fashion. At every assessment, data were collected on SLEDAI-2000 and treatment. The cross-sectional analysis with receiver operating characteristic (ROC) curves was used to examine the appropriate SLEDAI-2000 score to define active disease and increase in therapy was the reference standard. In the longitudinal analysis, sensitivity to change of SLEDAI-2000 was assessed with multinomial logistic regression. ROC curves analysis was used to examine possible cut-points in score changes associated with change in therapy, and mean changes were estimated., Results: In the cross-sectional analysis, the most appropriate cut-off scores for active disease were 3 or 4. In the longitudinal analysis, the best model for predicting treatment increase was with the change in SLEDAI-2000 score and the score from the previous visit as continuous variables. The use of cut-points was less predictive of treatment change than the use of continuous score. The mean difference in the change in SLEDAI-2000 scores, adjusted for prior score, between patients with treatment increase and those without was 2.64 (95% CI 2.16, 3.14)., Conclusions: An appropriate SLEDAI-2000 score to define active disease is 3 or 4. SLEDAI-2000 index is sensitive to change. The use of SLEDAI-2000 as a continuous outcome is recommended for comparative purposes.

Objective: Having developed and validated a disease-specific health-related quality of life (HRQOL) measure for patients with systemic lupus erythematosus (SLE), the LupusQoL, we determined its relationship to demographic and clinical measurements in a group of patients with SLE., Methods: A group of 322 outpatients completed the LupusQoL. Demographic (age, sex, marital status, ethnicity) and clinical variables (disease duration, disease activity, damage) were recorded. Associations between the 8 LupusQoL domains and age, disease duration, disease activity, and damage were explored using Spearman's correlation coefficients. Differences in LupusQoL scores were examined for sex and marital status using the Mann-Whitney U test. Ethnic groups were compared using ANOVA., Results: All domains of LupusQoL were impaired, with fatigue (56.3) being the worst affected and body image (80.0) the least. The correlations between the LupusQoL domain scores and age (r = -0.01 to -0.22) and disease duration (r = 0 to 0.16) were absent or weak. Similarly, there were no significant differences in the LupusQoL scores regarding sex, marital status, or the 3 main ethnic groups (Black-Caribbean, Asian, White). Although there were statistically significant correlations between the scores of the LupusQoL domains and some scores of the British Isles Lupus Assessment Group index (r = -0.22 to 0.09) and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (r = -0.29 to 0.21), these were weak., Conclusion: HRQOL was impaired in this cohort of outpatients with SLE as assessed by the validated lupus-specific LupusQoL. There were no clinically important associations between the 8 domains of the LupusQoL and clinical or demographic variables in this group of patients. Thus, the LupusQoL is a relatively independent outcome measure in patients with SLE.

Objective: To develop an additive numerical scoring scheme for the BILAG-2004 index., Methods: SLE patients were recruited into this multi-centre cross-sectional study. At every assessment, data were collected on disease activity and therapy. Logistic regression was used to model an increase in therapy, as an indicator of active disease, by the BILAG-2004 index score in the nine systems. As both indicate inactivity, scores of D and E were set to 0 and used as the baseline in the fitted model. The models were used to determine the numerical values for Grades A-C. Different scoring schemes were compared., Results: There were 1510 assessments from 369 SLE patients. The coding schemes suggested for the Classic BILAG index (A = 12, B = 5, C = 1, D/E = 0 and A = 9, B = 3, C = 1, D/E = 0) did not fit the data well. A coding scheme (A = 12, B = 8, C = 1 and D/E = 0) was recommended, based on analysis results and consistency with the numerical coding scheme of the Classic BILAG index., Conclusion: A reasonable additive numerical scoring scheme based on treatment decision for the BILAG-2004 index is A = 12, B = 8, C = 1, D = 0 and E = 0.

Objective: To determine whether low-dose ciclosporin was a more effective corticosteroid-sparing agent than AZA in patients with SLE., Methods: Patients with SLE requiring a change or initiation of a corticosteroid-sparing agent and who were taking > or =15 mg of prednisolone/day were randomized to receive either ciclosporin or AZA during this 12-month open-label multi-centre trial. There were strict guidelines for the reduction of prednisolone. The primary outcome was the absolute mean change in prednisolone., Results: Eighty-nine patients were randomized. Using an intention-to-treat analysis, the absolute mean change in prednisolone dose between baseline and 12 months, adjusted for baseline prednisolone dose, was 9.0 mg for ciclosporin (95% CI 7.2, 10.8) and 10.7 mg for AZA (95% CI 8.8, 12.7). The difference in the change between treatment groups was -1.7 mg (95% CI -4.4, 0.9; P = 0.2). No significant differences were detected for the secondary outcomes: change in disease activity [classic British Isles Lupus Assessment Group (BILAG) index], number of flares, development of new damage or change in quality of life. A similar number of patients in each arm stopped the study drugs due to adverse events and ineffectiveness. No patient developed severe hypertension or a persistent rise in creatinine. One patient in the ciclosporin arm developed a significant increase in proteinuria due to disease activity., Conclusions: Both drugs were effective corticosteroid-sparing agents. Ciclosporin was not a more effective corticosteroid-sparing agent. Ciclosporin may be considered in patients who are unable to tolerate AZA. Patients on ciclosporin require close monitoring of blood pressure and creatinine., Trial Registration: Current Controlled Trials, http://www.controlled-trials.com/, ISRCTN35919612.

Objective: Accelerated atherosclerosis and premature coronary heart disease (CHD) are recognized complications of systemic lupus erythematosus (SLE), but the exact etiology remains unclear and is likely to be multifactorial. We hypothesized that SLE patients with CHD have increased exposure to traditional risk factors as well as differing disease phenotype and therapy-related factors compared to SLE patients free of CHD. Our aim was to examine risk factors for development of clinical CHD in SLE in the clinical setting., Methods: In a UK-wide multicenter retrospective case-control study we recruited 53 SLE patients with verified clinical CHD (myocardial infarction or angina pectoris) and 96 SLE patients without clinical CHD. Controls were recruited from the same center as the case and matched by disease duration. Charts were reviewed up to time of event for cases, or the same "dummy-date" in controls., Results: SLE patients with clinical CHD were older at the time of event [mean (SD) 53 (10) vs 42 (10) yrs; p < 0.001], more likely to be male [11 (20%) vs 3 (7%); p < 0.001], and had more exposure to all classic CHD risk factors compared to SLE patients without clinical CHD. They were also more likely to have been treated with corticosteroids (OR 2.46; 95% CI 1.03, 5.88) and azathioprine (OR 2.33; 95% CI 1.16, 4.67) and to have evidence of damage on the pre-event SLICC damage index (SDI) (OR 2.20; 95% CI 1.09, 4.44). There was no difference between groups with regard to clinical organ involvement or autoantibody profile., Conclusion: Our study highlights the need for clinical vigilance to identify modifiable risk factors in the clinical setting and in particular with male patients. The pattern of organ involvement did not differ in SLE patients with CHD events. However, the higher pre-event SDI, azathioprine exposure, and pattern of damage items (disease-related rather than therapy-related) in cases suggests that a persistent active lupus phenotype contributes to CHD risk. In this regard, corticosteroids and azathioprine may not control disease well enough to prevent CHD. Clinical trials are needed to determine whether classic risk factor modification will have a role in primary prevention of CHD in SLE patients and whether new therapies that control disease activity can better reduce CHD risk.

Objective: To develop an additive numerical scoring scheme for the Classic BILAG index., Methods: SLE patients were recruited into this multi-centre cross-sectional study. At every assessment, data were collected on disease activity and therapy. Logistic regression was used to model an increase in therapy, as an indicator of active disease, by the Classic BILAG score in eight systems. As both indicate inactivity, scores of D and E were set to 0 and used as the baseline in the fitted model. The coefficients from the fitted model were used to determine the numerical values for Grades A, B and C. Different scoring schemes were then compared using receiver operating characteristic (ROC) curves. Validation analysis was performed using assessments from a single centre., Results: There were 1510 assessments from 369 SLE patients. The currently used coding scheme (A = 9, B = 3, C = 1 and D/E = 0) did not fit the data well. The regression model suggested three possible numerical scoring schemes: (i) A = 11, B = 6, C = 1 and D/E = 0; (ii) A = 12, B = 6, C = 1 and D/E = 0; and (iii) A = 11, B = 7, C = 1 and D/E = 0. These schemes produced comparable ROC curves. Based on this, A = 12, B = 6, C = 1 and D/E = 0 seemed a reasonable and practical choice. The validation analysis suggested that although the A = 12, B = 6, C = 1 and D/E = 0 coding is still reasonable, a scheme with slightly less weighting for B, such as A = 12, B = 5, C = 1 and D/E = 0, may be more appropriate., Conclusions: A reasonable additive numerical scoring scheme based on treatment decision for the Classic BILAG index is A = 12, B = 5, C = 1, D = 0 and E = 0.

Objective: To determine if the BILAG-2004 index is sensitive to change for assessment of SLE disease activity., Methods: This was a prospective multi-centre longitudinal study of SLE patients. At every assessment, data were collected on disease activity (BILAG-2004 index) and treatment. Analyses were performed using overall BILAG-2004 index score (as determined by the highest score achieved by any of the individual systems) and all the systems scores. Sensitivity to change was assessed by determining the relationship between change in disease activity and change in therapy between two consecutive visits. Statistical analyses were performed using multinomial logistic regression., Results: There were 1761 assessments from 347 SLE patients that contributed 1414 observations for analysis. An increase in therapy between visits occurred in 22.7% observations, while 37.3% had a decrease in therapy and in 40.0% therapy was unchanged. Increase in overall BILAG-2004 index score was associated with increase in therapy and inversely associated with decrease in therapy. Decrease in overall BILAG-2004 index score was associated with decrease in therapy and was inversely associated with increase in therapy. Changes in overall BILAG-2004 index score were differentially related to change in therapy, with greater change in score having greater predictive power. Increase in the scores of most systems was independently associated with an increase in treatment and there was no significant association between decreases in the score of any system with an increase in therapy., Conclusions: The BILAG-2004 index is sensitive to change and is suitable for use in longitudinal studies of SLE.

Objective: To assess the reliability of Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)-2000 index in routine practice and its ability to capture disease activity as compared with the British Isles Lupus Assessment Group (BILAG)-2004 index., Methods: Patients with systemic lupus erythematosus from 11 centres were assessed separately by two raters in routine practice. Disease activity was assessed using the BILAG-2004 and SLEDAI-2000 indices. The level of agreement for items was used to assess the reliability of SLEDAI-2000. The ability to detect disease activity was assessed by determining the number of patients with a high activity on BILAG-2004 (overall score A or B) but low SLEDAI-2000 score (<6) and number of patients with low activity on BILAG-2004 (overall score C, D or E) but high SLEDAI-2000 score (>or=6). Treatment of these patients was analysed, and the increase in treatment was used as the gold standard for active disease., Results: 93 patients (90.3% women, 69.9% Caucasian) were studied: mean age was 43.8 years, mean disease duration 10 years. There were 43 patients (46.2%) with a difference in SLEDAI-2000 score between the two raters and this difference was >or=4 in 19 patients (20.4%). Agreement for each of the items in SLEDAI-2000 was between 81.7 and 100%. 35 patients (37.6%) had high activity on BILAG-2004 but a low SLEDAI-2000 score, of which 48.6% had treatment increased. There were only five patients (5.4%) with low activity on BILAG-2004 but a high SLEDAI-2000 score., Conclusions: SLEDAI-2000 is a reliable index to assess systemic lupus erythematosus disease activity but it is less able than the BILAG-2004 index to detect active disease requiring increased treatment.

Objective: To determine the construct and criterion validity of the British Isles Lupus Assessment Group 2004 (BILAG-2004) index for assessing disease activity in systemic lupus erythematosus (SLE)., Methods: Patients with SLE were recruited into a multicenter cross-sectional study. Data on SLE disease activity (scores on the BILAG-2004 index, Classic BILAG index, and Systemic Lupus Erythematosus Disease Activity Index 2000 [SLEDAI-2K]), investigations, and therapy were collected. Overall BILAG-2004 and overall Classic BILAG scores were determined by the highest score achieved in any of the individual systems in the respective index. Erythrocyte sedimentation rates (ESRs), C3 levels, C4 levels, anti-double-stranded DNA (anti-dsDNA) levels, and SLEDAI-2K scores were used in the analysis of construct validity, and increase in therapy was used as the criterion for active disease in the analysis of criterion validity. Statistical analyses were performed using ordinal logistic regression for construct validity and logistic regression for criterion validity. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated., Results: Of the 369 patients with SLE, 92.7% were women, 59.9% were white, 18.4% were Afro-Caribbean and 18.4% were South Asian. Their mean +/- SD age was 41.6 +/- 13.2 years and mean disease duration was 8.8 +/- 7.7 years. More than 1 assessment was obtained on 88.6% of the patients, and a total of 1,510 assessments were obtained. Increasing overall scores on the BILAG-2004 index were associated with increasing ESRs, decreasing C3 levels, decreasing C4 levels, elevated anti-dsDNA levels, and increasing SLEDAI-2K scores (all P < 0.01). Increase in therapy was observed more frequently in patients with overall BILAG-2004 scores reflecting higher disease activity. Scores indicating active disease (overall BILAG-2004 scores of A and B) were significantly associated with increase in therapy (odds ratio [OR] 19.3, P < 0.01). The BILAG-2004 and Classic BILAG indices had comparable sensitivity, specificity, PPV, and NPV., Conclusion: These findings show that the BILAG-2004 index has construct and criterion validity.

Objective: To develop and validate a disease-specific health-related quality of life (HRQOL) instrument for adults with systemic lupus erythematosus (SLE)., Methods: The work consisted of 6 stages. Stage 1 included item generation for questionnaire content from semistructured interviews with SLE patients. In stage 2 item selection for the draft questionnaire was performed by thematic analysis of the patient interview transcripts and expert panel agreement. In stage 3 the content validity of the draft questionnaire was assessed by patients completing the questionnaire and providing critical feedback. In stages 4 and 5 construct validity and internal reliability of the 3 versions of the LupusQoL were evaluated using principal component analysis with varimax rotation and Cronbach's alpha coefficients, respectively. In stage 6 discriminatory validity, concurrent validity, and test-retest reliability were evaluated., Results: Stages 1, 2, and 3 resulted in a preliminary instrument containing 63 items. In stage 4, 8 domains were identified. This factor structure, accounting for 82% of the variance, was confirmed in stage 5. The domains and Cronbach's alpha coefficients were physical health (0.94), emotional health (0.94), body image (0.89), pain (0.92), planning (0.93), fatigue (0.88), intimate relationships (0.96), and burden to others (0.94). Discriminant validity was demonstrated for different levels of disease activity (British Isles Lupus Assessment Group Index) and damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index). High correlations (r = 0.71-0.79) between comparable domains of the Short Form 36 and the LupusQoL assured acceptable concurrent validity. Good test-retest reliability (r = 0.72-0.93) was demonstrated., Conclusion: The LupusQoL is a validated SLE-specific HRQOL instrument with 34 items across 8 domains defined by patients as being important.

Objectives: This is a family-based association study to investigate the genetic contribution of tyrosine kinase 2 (TYK2 ) to disease susceptibility in 380 UK systemic lupus erythematosus (SLE) families, consisting of parents and affected offspring., Methods: Genotyping was performed using the Sequenom platform on DNA from affected individuals and their parents. Haplotypes were constructed using Haploview from the founders, and family-based association was conducted using GENEHUNTER-TDT and Family-Based Association Test., Results: There are two associated haplotypes across TYK2, both carrying alleles with distorted inheritance. One SNP shows individual association to SLE. This is the under-transmitted rare A allele of TYK2 SNP 6 (P = 0.004), which tags the under-transmitted haplotype 2 (P = 0.055). A second SNP shows a trend for association. This is the A allele of TYK2 SNP 13, which is unique to the over-transmitted haplotype 1 (P = 0.014). We defined a 2.8 kb core association region in TYK2, between these two variants, which narrows down the 5.7 kb gap in the study by Sigurdsson et al. (Sigurdsson S, Nordmark G, Goring HH et al. Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. Am J Hum Genet 2005;76:528-37)., Conclusions: We have shown association to SLE from individual SNPs and haplotypes in TYK2. The strongest individual association, which is carried on the associated haplotype, is from TYK2 SNP 6. The variant is located close to an intron/exon boundary, suggesting a role for mis-splicing events in molecular pathogenesis. The associated haplotype also carries a missense mutation at TYK2. Therefore it is likely that the allelic contribution of TYK2 to SLE is complex, our data confirm previous findings and provide additional resolution regarding the causal polymorphisms in this gene.

Objective: To test the interrater reliability of the revised British Isles Lupus Assessment Group 2004 (BILAG-2004) index for the assessment of systemic lupus erythematosus (SLE) activity., Methods: Patients with SLE were recruited from 11 centers. Two physician raters separately assessed the patients' disease activity using the BILAG-2004 index in routine clinical practice. Scores ranged from A (for very active disease) to E (for inactivity). Two reliability exercises were performed. Changes were made to the index after the first exercise (E1), and additional training was provided to the raters before the second exercise (E2). E1 and E2 involved 12 and 14 raters, respectively. Interrater reliability was assessed using kappa statistics and intraclass correlation coefficients. Levels of agreement and the extent of major disagreement were also examined. Major disagreement was defined as a score difference between raters of A versus C, D, or E or B versus D or E., Results: For each exercise, 97 patients were recruited. In E1, the mean age of the patients was 42.3 years (range 18.5-82.2 years), 89.7% were women, and 74.2% were white, 8.2% were Afro-Caribbean, and 13.4% were South Asian, and in E2, the mean age was 43.7 years (range 17.7-75 years), 90.7% were women, and 68% were white, 15.5% were Afro-Caribbean, and 11.3% were South Asian. The mean disease duration was 9.4 years (range 0-32.1 years) for patients in E1 and 10 years (range 0-34.8 years) in E2. There was improvement in the interrater reliability and the level of agreement from E1 to E2. Further improvement was achieved after removal of poorly performing items., Conclusion: The BILAG-2004 index is a reliable tool to assess SLE activity. The use of a well-defined glossary and training of raters are essential to ensure the optimal performance of the index.

Objective: To devise a more discriminating version of the British Isles Lupus Assessment Group (BILAG) disease activity index and to show that it is reliable., Methods: A nominal consensus approach was undertaken by members of BILAG to update and improve the BILAG lupus disease activity index. The index has been revised following intense consultations over a 1-yr period. It has been assessed in two real-patient exercises. These involved patients with diverse clinical features of SLE, including gastrointestinal, hepatic and ophthalmic problems, which the earlier versions of the index did not fully take into account. Reliability in terms of the ability to differentiate patients was assessed by calculating intraclass correlation coefficients. The level of agreement between physicians was determined by calculating the ratio of estimates of the standard error (SE) attributable to the physicians to the SE attributable to the patients., Results: Good reliability and high levels of physician agreement were observed in one or both exercises in the constitutional, mucocutaneous, neurological, cardiorespiratory, renal, ophthalmic and haematological systems. In contrast, the musculoskeletal system did not score as well, although providing more clear-cut glossary definitions should greatly improve the situation., Conclusions: Some significant changes in the BILAG disease activity index to assess patients with SLE are proposed. The process of demonstrating validity and reliability has started with these two exercises assessing real patients. Further validation studies are under way. BILAG 2004 is likely to be valuable in clinical trials assessing new therapies for the treatment of SLE, as it provides a more comprehensive system-based disease activity measure than has been available previously.

Case Reports: Three patients are described whose original presentation and immunological profile led to the erroneous diagnosis of systemic lupus erythematosus. The correct diagnosis of gluten sensitivity was made after years of treatment with steroids and other immunosuppressive drugs., Conclusions: The immunological profile of IgA deficiency and/or raised double stranded DNA in the absence of antinuclear factor together with raised inflammatory markers and symptoms suggestive of an immune diathesis should alert the physician to the possibility of gluten sensitivity. The presence of an enteropathy is no longer a prerequisite for the diagnosis of gluten sensitivity, which can solely present with extraintestinal symptoms and signs. Knowledge of the diverse manifestations of gluten sensitivity is essential in avoiding such misdiagnosis.

Defective DNA damage processing has been reported in systemic lupus erythematosus (SLE). Vitamin C may modulate formation/removal of the oxidative DNA lesion 8-oxo-2'-deoxyguanosine (8-oxodG). Baseline levels of 8-oxodG measured in SLE serum, urine and PBMC DNA did not differ significantly from healthy subjects. In contrast to healthy subjects, no significant decrease in PBMC 8-oxodG or increase in urinary 8-oxodG was noted in vitamin C supplemented SLE patients. A significant, although attenuated, increase in serum 8-oxodG was detected in SLE patients, compared to healthy subjects. These data support putative abnormalities in the repair/processing of 8-oxodG in SLE., (Copyright 2000 Academic Press.)