Improving the Assessment of SLE Disease Activity
Improving the Assessment of SLE Disease Activity
Physicians' assessment of disease activity in SLE is fundamental but challenging. The
 Systemic Lupus Erythematosus Disease Activity Index (SLEDAI-2K) is one of the most commonly
 used disease activity indices. Clinical trials experience suggested that the disease activity
 instruments did not function well on their own, and composite measures were developed to
 address this issue. This approach has been adopted after learning from clinical trials that
 the absence of a robust sensitive index is a major flaw when designing a trial. Another issue
 with clinical trials is the confounding effect of corticosteroids, which to date have been
 the most effective treatment for the management of lupus. However, unregulated use of
 corticosteroids in drug trials decrease the investigator's ability to differentiate between
 the tested drugs and placebo as they appear to enhance response among the placebo arm and
 thus mask the effect of the tested drug.

 In this study, the aim is to develop and validate a new index, SLEDAI-2K Glucocorticosteroid
 Index (SLEDAI-2KG). It is very challenging to evaluate improvement in drug trials in the
 context of the standard of care treatment which includes corticosteroids. This novel index,
 SLEDAI-2KG, will help to overcome the confounding effect of corticosteroids and to allow for
 more accurate description of disease improvement and thus facilitate accurate investigations
 of new therapeutic agents.
Objectives:

 1. To describe the development and initial validation of the SLEDAI-2KG using the Toronto
 Lupus Cohort (TLC) database.

 2. To conduct further validation of SLEDAI-2KG using BLISS trial data.

 3. To assess concurrent construct validity of SLEDAI-2KG prospectively in the University of
 Toronto Lupus Clinic.

 Study design:

 1. Objective one is a single center study aiming to derive a new index, SLEDAI-2KG, based
 on SLEDAI-2K. Scoring of SLEDAI-2KG will be determined in this study.

 2. Objective two is a retrospective analysis conducted on prospectively collected data from
 two clinical trials, BLISS-52 and BLISS-76.

 3. Objective three is a single centre prospective study.

 Study Population and Sampling Methods:

 Objective I patient selection: Patients with active disease, SLEDAI-2K ≥0, will be identified
 in the TLC database. All patients must have follow up visits at 3 and 6 months.

 Objective II: Data from BLISS-52 and BLISS-76 trials will be used. Objective III patient
 selection: Patients followed at the Toronto Lupus Clinic from May 2017 to December 2017.
 Patients will be identified based on active disease with a flare (increase in SLEDAI-2K by at
 least 4 requiring an increase in the dose of prednisone to ≥ 15 mg/day or initiation of
 prednisone at ≥ 15 mg/day).

 Objective III patient selection: Patients followed at the Toronto Lupus Clinic from May 2017
 to December 2017. The investigator will identify patients with active disease with a flare
 (increase in SLEDAI-2K by at least 4 requiring an increase in the dose of prednisone to ≥ 15
 mg/day or initiation of prednisone at ≥ 15 mg/day).

 Data Sources:

 The University of Toronto Lupus Cohort dataset and GSK BLISS-52 and BLISS-76 trial data The
 Toronto Lupus Cohort (TLC) is the largest lupus cohort in Canada, and more than 1600 patients
 have been enrolled in this cohort. Patients in the TLC are seen at regular intervals (2-6
 months apart) and data, including laboratory and clinical parameters important to lupus, is
 collected using a well-defined protocol.

 Data Analysis Methods:

 In objective I - Phase 1 will focus on the identification of scenarios of real patients to
 derive weight scores for Glucocorticosteroid (GCS). Phase 2 will focus on the development of
 SLEDAI-2KG (derivation of an equation to explain the link between SLEDAI-2K and GCS doses)
 and phase 3 focused on SLEDAI-2KG validation.

 The analysis of the initial validation of SLEDAI-2KG will be conducted on the selected
 patients from the TLC. Improved patients (responders) will be identified based on SLEDAI-2K
 definition of improvement and further will be studied by calculating the SLEDAI-2KG using the
 above described models. The mean change of SLEDAI-2K scores and the mean change of SLEDAI-2KG
 scores in the responders will be studied. Using the SLEDAI-2K responders as "Gold Standard",
 it will be determined if SLEDAI-2KG responders are true responders and not false responders.

 Concurrent construct validity: A clinician (external construct) who does not know the
 patients and will evaluate each patient's record (electronic record and medical chart) and
 assign a clinical activity score for each assessment according to the following scale:
 improved, same, and worse, using standardized predefined definitions. The correlation between
 the external construct and the change in SLEDAI-2K and SLEDAI-2KG scores will be studied.
 Using the clinician scoring of disease activity-Improved as "Gold Standard", the results of
 SLEDAI-2K and SLEDAI-2KG responders will be analyzed by constructing two 2x2 tables.

 Sample Size for 3 objectives:

 Sample Size 1: The sample size calculation of needed scenarios was based on the assumption of
 reliability (Intra-class Correlation Coefficient (ICC)) ≥ 0.80 with a standard error of 0.05
 and 3 raters. The required minimum was 46 scenarios.

 Sample Size 2: For objective two all data available from the BLISS-52 and BLISS-76 trials
 will be used.

 Sample Size 3: For objective three the investigator's target sample size is 100 patients and
 to achieve this number at least 18 months will be required and subsequently a 6 months period
 for follow-up for each patients. Based on the COSMIN recommendations, a sample size ≥100 is
 recommended in this step
Inclusion Criteria:

 Objective I:

 -  ≥4 American College of Rheumatology (ACR) criteria or 3 ACR criteria plus a typical
 histological lesion of SLE on renal or skin biopsy

 -  Clinician's diagnosis based on his/her assessment

 -  Patients from the Toronto Lupus Clinic with regular follow-up, defined as having
 follow up visits at 3 and 6 months from the baseline visit (1st study visit).

 Objective II:

 • Participant in the BLISS-52 and BLISS-76 trials

 Objective III:

 -  ≥4 American College of Rheumatology (ACR) criteria or 3 ACR criteria plus a typical
 histological lesion of SLE on renal or skin biopsy

 -  Increase in SLEDAI-2K ≥4

 -  Clinician's diagnosis based on his/her assessment

 Exclusion Criteria:

 Objective I and III:

 -  Patients with missing follow up visits at 3 and 6 months from the baseline visit (1st
 study visit).

 -  Patients with missing data in the charts for all visits.

 Objective II:

 • Participants who did not complete the trial and therefore have missing data points for
 primary endpoint measures