The British Isles for the Assessment of Lupus Group (BILAG) began to meet regularly in 1984 and in 1988 developed for the first time an index to measure disease activity in patients with SLE.4 This index was developed based on the physicians intention to treat and evaluates specific manifestations requiring treatment in a total of 8 organs or systems: general, mucocutaneous, neurological, musculoskeletal, cardiorespiratory, vasculitis, renal and hematology. Unlike other indices which provide a global assessment of the disease, BILAG provides an assessment by organ system.

Subsequently, certain minor modifications of this index were conducted and assessed for both their reliability and validity. A study of Hay et al.,5 evaluated the BILAG version 3, which includes a glossary with explanations and recommendations for ease of use. BILAG showed good intraobserver reliability, with kappa ranging from 0.79 to 0.97, depending on the target system. To assess the criterion validity of the BILAG, it was compared to a gold standard defined as starting or increasing treatment with either prednisone or other immunosuppressive therapy. BILAG sensitivity for grade A in any organ or system was 87% and specificity of 99%. BILAG's Cronbach coefficient α calculated to assess the internal consistency and, therefore, the association between its components, is 0.35, lower than what is recommended for reliable comparisons. The BILAG showed moderate correlation with the physician global assessment (ρ=0.43) and patient assessment (ρ=0.50).6

The BILAG was also used to evaluate the occurrence of relapses in patients with lupus. The presence of a severe flare is defined as a score of A, new appearance, and a moderate flare is defined with a rating of B, if it was previously in D or E. A study published in 2003 by Gordon et al. assessed the degree of agreement between the definition of flare by BILAG and the real attitude about treatment by rheumatologists in routine clinical practice.7 92% of patients with a severe flare (A) received intensive treatment by their doctor and only 41% received it in case of a moderate flare (B). Not only BILAG is useful for evaluating the presence of a lupus flare. In a study by Isenberg et al., 3 methods to assess flares were compared; BILAG 2004 index flair index generated for the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) called the SELENA. SLEDAI, the Flare Index (SFI) and the VGM8: The BILAG 2004 had the highest ICC (0.54 [95% CI: 0.32–0.78]) compared to the SFI (0.21 [95% CI: 0.08–0.48]) and VGM (0.18 [95% CI: 0.06–0.45]).

The validity of the BILAG has been evaluated in numerous studies. In a 2010 study9 construct validity was assessed with the hypothesis that patients with higher scores on the BILAG presented higher levels of erythrocyte sedimentation rate (ESR), anti-dsDNA titers and SLEDAI scores, and conversely, presented lower levels of complement. The association between these variables was expected, with an OR=2.6 (1.2–4.3) for ESR>60mm/h, OR=2.5 (1.4–3, 6) for anti-dsDNA greater than 5 times the normal value, OR=4.8 (1.4–15.1) for C3 below half the normal value, OR=4.1 (2.3–5.8) for a C4 below half the normal value and OR=215.6 (99.8–387.6) for a value of SLEDAI above 6.

Only one study has been specifically designed to evaluate the sensitivity to change of BILAG.10 It was a longitudinal multicenter study where the relationship between the change in BILAG 2004 and the change in treatment between 2 consecutive visits was evaluated. BILAG increase was associated with an increase in treatment (coefficient multinomial logistic regression: 1.35, 95% CI: 1.01–1.70). In the opposite direction, this association was also found.

The BILAG can be manually calculated, but there is a computer software known as the British Lupus Integrated Prospective System (Blips) incorporating demographic variables and clinical information necessary to calculate not only the BILAG, but other composite indices such as SLAM, SLEDAI, and SDI the SF-36.11

An updated version was published in BILAG 2005 by Isenberg et al. in an attempt to improve the characteristics of the index.12 In this study, where the BILAG 2004 is described, its viability or ability to be applied by 2 exercises with real patients who were examined by 8 doctors belonging to the BILAG group was evaluated. The ICC was calculated for the total BILAG (0.48, 95% CI: 0.23–0.81) and for each of the 9 systems. The system that showed a higher ICC was the kidney (0.98, 95% CI: 0.96–0.99) and the one that showed a lower ICC was musculoskeletal (0.17, 95% CI: 0.01–0.56). Another measure used in this study to assess feasibility was the ratio between the standard deviation attributable to the physician and the same measure attributable to the patient, showing a high agreement in the mucocutaneous, nervous, renal, ophthalmic and hematological systems. In both exercises, the musculoskeletal system showed low reliability in terms of ICC and level of agreement among physicians.

The BILAG 2004 has been developed from the original index, and includes 9 systems: general, mucocutaneous, nervous, musculoskeletal, cardiovascular/respiratory, gastrointestinal, renal, ophthalmic and hematological system. It consists of several items or questions that are assessed on a scale of 0–4, where 0 represents “not present”, 1 means “improving”, 2 is “similar”, 3 is “worse” and 4 is “new event.” Responses were combined into 5 states of system activity: A, the patient is very active and, therefore, would require treatment with immunosuppressants, corticosteroids at medium or high doses (>20mg prednisolone or equivalent) or anticoagulation at a high dose; B, certain activity and, therefore, need for treatment with moderate dose corticosteroid (<20mg prednisolone), antimalarial, anti-depressants, or NSAIDs; C, little activity and need only for symptomatic treatment; D, no activity at the time, although present previously, and E, has never presented activity in this system.

Other attempts to validate the BILAG 2004 were conducted by Yee et al. in 2007. Criterion validity using as a gold standard changes in treatment and the construct validity of trying to corroborate the hypothesis that patients with higher values in the BILAG 2004 would have higher ESR, anti-dsDNA titers and lower values of complement was evaluated.13 BILAG 2004 values indicating high or moderate disease activity (A and B) were significantly associated with an increase in medication (OR=19.3, p<0.01). In addition, the BILAG 2004 had a sensitivity of 81%, a specificity of 91.9%, a positive predictive value of 56.8% and a negative predictive value of 93.6% compared to the change in treatment. Top BILASG 2004 scores were associated with increased ESR of 60mm/h (OR=2.9), a rise in anti-dsDNA titers (OR=2.7), an elevation in the SLEDAI above 4 (OR=20) and halving of C3 (OR=5) and C4 (OR=4.2).

Although the BILAG is an ordinal scale that provides a general assessment of the disease, some authors have proposed its transformation into a numerical scale to facilitate statistical analysis. Initially, the following scheme was proposed: A=9 points, B=3 points, C=1 point and both D and E were equivalent to 0 points, with a range of 0–72.14 In 2009, Cresswell et al. presented a study aimed to validate a numerical score for the BILAG.15 They described three different scoring methods using logistic regression models and later the ROC curves were compared. The transformation finally selected was A=12, B=5, C=1 and D/E=0.

The BILAG is the only validated instrument that gives an idea of lupus activity in each organ at a glance instead of merging the information into an overall score.16 The clinician should be familiar with the glossary where each item is defined, and follow the guidelines and recommendations established by the BILAG group, especially the specific recommendations for use in RCTs and multicenter studies.5,17

The ECLAM was described by the European working group consensus for measuring activity in SLE in 1992.18 It is an index designed to measure disease activity in the last month in patients with lupus.

This index was developed from a cohort that included a significant number of real patients. In an initial analysis, the index was developed and its feasibility and validity were assessed, both apparent and in the content.18 To do so, those clinical and laboratory variables that best correlate with PGA as the gold standard, both on a quantitative scale (0–10) and a qualitative scale (inactive to active) were selected. By univariate analysis, a total of 15 variables able to predict disease activity were selected. Subsequently, a multivariate analysis the weight of each of these variables, which were assigned a specific score, was defined. The ECLAM not only allows to properly classify patients according to their level of disease activity, it is also easy to calculate. In a second study, construct validity was assessed, with the gold standard being the PGA and criterion validity, comparing ECLAM with other composite indices.19 The ECLAM correlation with SLAM, BILAG and SLEDAI was greater than 0.72. These four levels are correlated similarly to the PGA.

The ECLAM includes evaluation of 10 organs and/or systems and 2 laboratory values that are ESR and complement levels. It consists of a total of 33 items that are evaluated from 0.5 to 2, depending on the type of involvement, and a combined global score ranging from 0 to 17.5.

The ECLAM is a simple index that can be used in retrospective studies, since there is a good correlation between the ECLAM calculated immediately and that calculated with data collected on clinical history (rho=0.871).20 Furthermore, it can be calculated by a computerized system with very similar results to the manual calculation (r=0.90–0.92).21

This index measures the degree of activity globally in the last month. The first publication in which it was described appeared in 1986.22 Two years later, it was revised by the residents of Harvard University, who modified the section on cardiovascular events and “others” to improve clarity and reproducibility, resulting in a new version, the SLAM-R. In 2001, Bae et al. presented a study of 30 patients to evaluate the feasibility and construct validity of this new version.23 Reliability was estimated by analysis of variance, with 0.78 interobserver reliability and 0.61 intraobserver reliability. Regarding construct validity, Pearson correlations were calculated SLAM-R with PGA (0.87), levels of anti-dsDNA (0.51), C3 (−0.60) and C4 (−0.29).

The SLAM evaluates specific manifestations in 9 organs and includes 7 laboratory measurements. Some items are scored from 0 to 3, depending on the degree of severity, and others are evaluated only 0–1. The maximum score is 84, being part of the laboratory parameters a maximum 21 points. A score of 7 or more is considered relevant, since the patient will require a change in treatment in 50% of cases.

The SLAM is considered by some experts the less appropriate index because it includes subjective measures, such as fatigue and joint pain; however, these variables must be scored by the doctor if considered to be due to lupus activity.8 Training is required, since it is necessary to reach a consensus to assess the subjective aspects, especially in multicenter studies.17

The SLEDAI is a global index that was developed by an expert group of Toronto in 1986 and described in detail by Bombardier et al.24 It was amended by the SELENA group for a study to evaluate the use of estrogen and progesterone in women with SLE25 and later was updated by Gladman et al.26 In addition, a version developed by Mexican researchers, to reduce the costs of using this index, excluded some laboratory values.27

Therefore, there are currently 4 versions of this index: SLEDAI, SELENA-SLEDAI, SLEDAI 2000 and MEX-SLEDAI.

To develop the first version of SLEDAI, 24 variables that might be important factors for evaluating disease activity in SLE patients were identified. With these variables, 574 profiles were generated for potential patients and this information was provided to 14 rheumatologists considered to be SLE experts to assess the extent of disease on a scale of 0–10. Multiple regression models were used to estimate the relative importance of each of these 24 clinical variables as assessed by the experts and thus the overall index24 was generated.

The SLEDAI, therefore, is a global index that evaluates the activity of the disease in the last 10 days and consists of 24 items that include specific manifestations in 9 organ systems with a maximum score of 105.

In a 1992 study by Guzman et al. various aspects of the validation of MEX-SLEDAI with the original SLEDAI27 were compared. The correlation between 2 reviewers calculating these indices ranged between 0.87 and 0.89. The agreement on the assessment of the disease among physicians was moderate, with a kappa of 0.43 (p=0.17). Construct validity was assessed using the PGA comparator (on a scale of 0–10), with an almost identical correlation of 0.68 for both versions; the correlation between the two versions was 0.77.

SLEDAI can be used in research and clinical practice. It has proven to be a tool sensitive to change.28 To assess the sensitivity to change of SLEDAI compared with SLAM-R, Chang et al. conducted a secondary analysis of data from a Canadian multicentric RCT where the effectiveness of methotrexate in patients with SLE were evaluated.29 Changes were compared in these 2 indices with respect to changes in the physician and patient global evaluations. Regarding the assessment of physician, the average standardized control response (C-SRM) for the SLAM-R and SLEDAI was −0.47 vs −0.42 for improvement and 0.65 vs 0.66 for worsening. Regarding the assessment by the patient, the C-SRM for the SLAM-R and SLEDAI was −0.31 vs −0.18 for improvement and 0.48 vs 0.05 for worsening. Only SLAM-R maintained 0 out of the 95% CI to detect improvement or deterioration. Both indices exhibit significant sensitivity to change for the physicians but only SLAM-R exhibits a sensitivity to change relevant for patients, possibly by the inclusion of more subjective variables assessed by the patient.

In 2002 a revised and updated version of the SLEDAI, SLEDAI 2000 (SLEDAI-2K), which scored rash, alopecia, ulcers or persistent proteinuria, not only recently introduced but also of new appearance, as occurred in the previous version.26 The SLEDAI-2K was validated against the original SLEDAI with an evaluation within 10 days prior to the visit and it was validated with a temporal space of 30 days for use in RCTs.30,31 The SLEDAI-2K and the previous version had a high correlation (r=0.97) and both indices similarly predict mortality.26

The SLEDAI-2K reflects aspects of the disease as present or absent and may not reflect partial improvement, which limits their use in RCT. For this reason, in 2011 Touma et al. developed a response rate of 50% (SRI-50) to document a 50% improvement in SLEDAI.32 This study evaluated the construct validity using assessment of response to treatment by a physician as an external comparator on a Likert scale (LS) that ranged from 7 (significant improvement) to 1 (much worse). A 50% improvement on this scale would be greater than or equal to a change of 6. In patients with an improvement ≥6 in the LS, there was a decrease in the SRI-50 of 4.15±3.01 (P<0.0001).

In 2004, Uribe et al., in an attempt to dig deeper into the validation of available versions of the SLEDAI, presented a study in which the construct validity of the SLAM-R, the MEX-SLEDAI and SLEDAI-2K was analyzed, using the PGA as the external criterion on a visual analog scale (VAS) from 0 to 10.33 Spearman correlations of these indices with the PGA ranged from 0.54 to 0.67 for the MEX-SLEDAI and SLEDAI-2K. In an attempt to assess the criterion validity using as a gold standard the SLEDAI-2K, it was found that the sensitivity of the SLAM-R was 73%, while that of the MEX-SLEDAI was 58%. The specificity was 63% for the SLAM-R and 93% for MEX-SLEDAI.

The LAI was initially used in studies of serious infections and renal involvement in patients with SLE.34–36 This is an index with 5 domains that reflect the disease activity in the previous 2 weeks and is completed by the physician in about a minute. As in the rest of the indices, only those manifestations attributable to SLE were evaluated. It includes PGA VAS from 0 to 3, and includes 4 VAS regarding fatigue, rash, joint and serositis, and a part that quantifies the involvement in 4 organs: neurological, renal, pulmonary, and hematologic, with a VAS ranging from 0 to 3. Moreover, this last part assigns different scores according to the need for medication and laboratory values.

In a study by Petri et al.,37 the reliability and construct validity of this index were evaluated using SLEDAI compared to the PGA reference. The PGA had a higher correlation with LAI (r=0.64) than with SLEDAI (r=0.55). As for reliability, LAI showed greater reliability, both intra-and interobserver.

The SLAQ was developed as a measurement tool for the patient to be used in epidemiological studies and large patient cohorts. It was described and validated by Karlson et al.38 It was developed in a clinical cohort of 93 patients and compared with SLAM (excluding laboratory data), showing a good correlation (r=0.62, P<0.001). Each individual item correlation between patients–physicians ranged from 0.06 for the evaluation of lymphadenopathy and vasculitis and 0.7 for evaluation of Raynaud's syndrome.

Subsequently Yazdany et al. evaluated other aspects of validation in a cohort of 982 patients39. The SLAQ showed good internal consistency, with a Cronbach α 0.87. To assess construct validity, we examined the correlation of SLAQ with PGA (r=0.73) and the SF-36 (r=0.66). The index showed a low sensitivity to change with an SRM of 0.12, but when it was compared with the change in other measures, the SLAQ score changed in the right direction.

It was developed in 1996 by an international collaboration (SLICC group) and adopted by the CAR.42 In this first study, the index was developed and its content validity was assessed. A list of variables that could reflect damage in patients with SLE was generated and a consensus was reached on which variables should be included in an index generated to assess irreversible damage. In another study of the same year and by the same authors, interobserver reliability was assessed with 10 patients who rheumatologists from 5 different countries applied this index to.43 The authors concluded in this study that doctors in different countries assess damage in patients with SLE very similarly.

The SDI evaluates irreversible damage in lupus patients regardless of the cause that produces it. It includes 42 items measuring involvement in 12 domains, with a maximum score of 46 points. Each item is scored as present or absent with the possibility of scoring a 2 or 3 in case of recurring events, such as may be the case of a stroke.

The definition of damage in patients with SLE is an irreversible change in an organ or system that has occurred since the onset of SLE and is present for at least the last 6 months. At the time of diagnosis, the score should be 0 by definition.

The SDI is completed by the physician at baseline in order to enter an RCT. It has moderate internal consistency (Cronbach α=0.41). In an attempt to assess construct validity, Stoll et al. compared SDI with BILAG and a patient's medication score, both with very low correlation (0.19 BILAG and 0.33 for the medication index).14

When SDI is completed by another physician to retrospectively review the patient's history, it also shows good interobserver reliability.44 SDI values increase with disease progression similarly in patients from different countries and is also a tool that predicts mortality in patients with SLE.45,46

The LDIQ was described by Costenbader et al. in an attempt to develop a measure of irreversible damage based on the SDI but completed by the patient to be used in clinical practice or epidemiological studies.47 This study is a first step in the development of an index, evaluating the apparent content validity with a group of 37 patients and 7 rheumatologists, with a more elaborate multicentric level validation later. To assess criterion validity, SDI is used as the gold standard, resulting in a sensitivity of 53.3%, a specificity of 94.6% and a degree of agreement between the 2 measures of 93.2%. To assess construct validity, the correlation between LDIQ and SDI (Spearman correlation coefficient=0.48, P<0.001) was calculated.

The LDIQ consists of 56 questions to assess each domain included in the SDI and is designed to be administered as a survey. Versions in Spanish, Portuguese and French have been validated.48

The BILD was described in 2011 by Yazdany et al. as a measure of damage in SLE patients for use in population studies.49 Like LDIQ, it is completed by the patient but is a shorter version that includes only 28 questions. BILD criterion validity was examined through its correlation with other instrument that also measured damage, such as SDI, and can be considered as the gold standard (r=0.64, P<0.001). Construct validity was assessed by comparing the demographic and clinical characteristics of the patients divided into the 4 quartiles of BILD. Patients with higher values for the BILD were older, with longer duration of illness and greater disease activity.