All content on this site is intended for healthcare professionals only. By acknowledging this message and accessing the information on this website you are confirming that you are a Healthcare Professional.
In recent years, many promising treatments for systemic lupus erythematosus (SLE) have failed to meet the primary efficacy endpoint in phase III trials, with the exception belimumab in the BLISS-52 and BLISS-76 trials (NCT00424476; NCT00410384).1 It has been suggested that current lupus clinical trial outcome measures do not adequately detect improvement and worsening in symptoms and disease activity.1
A commonly used endpoint in SLE trials is the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), a global disease activity score that may not reflect simultaneous improvement or worsening in disease severity across different organs. Another endpoint, frequently used for organ assessment, is the British Isles Lupus Assessment Group (BILAG); this measure may not have the ability to differentiate between multiple events within one organ.
Due to these difficulties, composite measures have been created which are able to detect improvement (without worsening) in SLE disease activity. These measures are the SLE Responder Index (SRI) and the BILAG-Based Composite Lupus Assessment (BICLA). Here, we discuss the different outcome measures currently used in SLE clinical trials, the results from a study comparing SRI and BICLA against a physician’s judgement of reponse,1 and provide an overview of new outcome measures in development.
Figure 1 summarizes the current outcome measures used in SLE clinical trials.
Figure 1. Definitions of the current outcome measures used in SLE trials*
BICLA, BILAG-Based Composite Lupus Assessment; BILAG, British Isles Lupus Assessment Group; PGA, physician’s global assessment; SLEDAI, Systemic Lupus Erythematosus Disease Activity Index; SRI, Systemic Lupus Erythematosus Responder Index.
*Data from Connelly, et al.2
Patients from the Oklahoma Lupus Cohort study were enrolled if they had SLE according to the 1997 modified American College of Rheumatology classification criteria, had a baseline SLEDAI of ≥6, and had been scored using BILAG, SLEDAI, and physician’s global assessment (PGA) at two study visits. Some PGA values were retrospectively assessed, if PGA had not been measured at the time of study visit, and clinical changes were compared with baseline, assessed as physician-rated improvement (PRI). Changes to medication were also measured from baselines to both study follow-up visits. Patients were assessed between 2009 and 2012.
In total, 91 patients with SLE were included in this analysis. The mean age at baseline was 41 years. As measured by PRI, 68 patients improved, 17 stayed the same, and 6 patients deteriorated. Improvement and deterioration were also measured using PGA, SLEDAI, and BILAG, and compared to PRI. Disease activity as measured by PGA, SLEDAI, and BILAG in patients who were found to have improved by PRI is shown in Figure 2.
Figure 2. Change in disease activity from baseline to follow up in PRI responders*
BILAG, British Isles Lupus Assessment Group; PGA, physician’s global assessment; PRI, physician-rated improvement; SLEDAI, Systemic Lupus Erythematosus Disease Activity Index.
*Data from Thanou, et al.1
Of the 68 patients who were found to have improvements by PRI, 58 met the SRI endpoint (agreement sensitivity with PRI, 85%) and 52 met the BICLA endpoint (agreement sensitivity with PRI, 76%). Of the 23 patients who stayed the same or deteriorated according to PRI, 17 and 23 did not meet the SRI and BICLA endpoints, respectively, with a specificity of SRI for PRI of 74% and BICLA for PRI of 78%.
Ten patients did not meet SRI despite improvements in PRI, of these patients seven met the BICLA endpoint. Further, of the 16 patients who improved in PRI but not BICLA, 13 improved by SRI. This highlights the variable success of endpoints in identifying improvement. It was also found that a BILCA response was less likely when a greater number of organs were active at baseline.
This study demonstrated that BICLA may be less sensitive than SRI in detecting improvement, when compared to PRI. It is important to note that this comparison does not consider all patient populations or background treatments, which may influence the accuracy of these measures in other clinical trials.
Newly developed and novel outcome measures, which can measure changes to response, are needed. Newer approaches in various stages of development include:
There is a need for improved methods of measuring efficacy in SLE clinical trials, with many promising therapies failing to proceed past phase III trials.1 Ideally, future outcomes can be developed to take both physician and patient reported measures into account which are simple and reliable.2 Reliance on PGA and BILAG, which may lack consistency due to the subjective nature of the measurements, is not sufficient to properly define SLE disease activity.2 In addition, SRI and BICLA have been shown to miss improvements or deteriorations in disease, when compared with PRI.1 Finally, outcome measures used for clinical trials should be considered on an individual basis, based on the study design and patient population enrolled.
Editorial theme | LLDAS versus remission as treat-to-target goals
During a meeting of the Lupus Hub Steering Committee, key opinion leaders discussed the topic of LLDAS versus remission as treat-to-target goals.
Editorial theme | Treat-to-target in SLE
The treat-to-target (T2T) strategy is examined, along with a discussion of the advantages and disadvantages of its use when managing patients with SLE, in this first editorial theme article on treatment goals.
Subscribe to get the best content related to lupus delivered to your inbox