Drivers of Response and Non-response for SRI-4 and BICLA in Systemic Lupus Erythematosus (SLE) Clinical Trials
Working Group Chair: Matthew Linnik (Eli Lilly)
The paucity of success in late-stage clinical trials in systemic lupus erythematosus (SLE) remains a persistent and challenging problem with one of the key issues being the primary endpoints, SRI-4 and BILAG. These do not always provide similar answers within a trial. There are many examples from late-stage studies where the SRI-4 and BICLA endpoints provided very different answers, with one arguing the intervention was efficacious and the other suggesting the intervention was ineffective.
There is relatively poor understanding of the factors that drive response for SRI-4 and BICLA. Each of these composite endpoints require more than 120 determinations, and there is incomplete understanding of which measurements contribute to the efficacy signal and which contribute to noise.
To address this problem with SLE trial endpoints, the LIC established a Working Group with two key goals: (1) Create a better understanding of the factors that drive response and nonresponse for SRI-4 and BICLA, and (2) determine the concordance and discordance between SRI-4 and BICLA at the individual patient level. A post-hoc common analysis plan was developed and applied to data from placebo-treated patients from six randomized controlled trials of non-renal SLE. The analysis examined concordance and discordance in the SRI-4 and BICLA outcome measures among placebo recipients, and explored reasons for SRI-4/BICLA nonresponse.
Results were shared at the 2022 meeting of the American College of Rheumatology, and the work continued as a part of the Lupus Accelerating Breakthroughs Consortium Treatment Response Measure for SLE working group.
Dynamic Imaging of Variation in Lupus Nephritis (DIVINE)
PI: Peter Lipsky (AMPEL BioSolutions LLC)
Co-PIs: David Karp (University of Texas Southwestern) and Brad Rovin (Ohio State University)
The goal of this study was to develop a multi-modality imaging approach for the evaluation of pathologic changes in Lupus Nephritis (LN).
The study employed multiple renal imaging modalities, including diffusion weighted imaging (DWI), blood oxygen level dependent (BOLD) imaging, T1rho (T1rho) imaging, and dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) to evaluate intra-renal blood flow, perfusion, cellularity, fibrosis and atrophy within the kidneys of patients with lupus nephritis (LN) and compare these parameters to renal biopsy findings to determine whether DWI, BOLD, T1rho, and DCE- MRI may provide a set of non-invasive tools to assess renal function and pathology in LN.
Initial results of the clinical study (NCT03180021) were presented at the 2019 ACR meeting (Abstract #1919).
Determinants of ANA Expression in Patients with Lupus
PI: David Pisetsky (Duke University)
Co-PIs: Megan Clowse (Duke University), Peter Lipsky (AMPEL BioSolutions LLC), Brad Rovin (Ohio State University)
The goal of this study was to assess the expression of antinuclear antibodies (ANA) in SLE, focusing on the frequency of ANA negativity in patients with established disease.
The study demonstrated that in 103 patients with established SLE the frequency of ANA negativity varied widely from 5% to 23% depending on the assay platform and kit used to measure the antibodies. The findings also showed a difference between the patient samples that tested ANA positive in all assays from those that were discordant across assays. Specifically, the consistently ANA positive samples had higher likelihood of historical anti-dsDNA positivity and a lower level of complement component C3 compared to the ANA discordant samples.
The results of this study were published in the Annals of Rheumatic Diseases and a related letter was published in Arthritis Care & Research.
LIC-OMERACT Partnership to Advance SLE Outcome Measures
Executive Committee: John Esdaile (Arthritis Research Centre of Canada), Matthew Liang (Harvard Medical School), Peter Lipsky (AMPEL BioSolutions LLC), Rosalind-Ramsey-Goldman (Northwestern University), Lee Simon (SDG LLC), Vibeke Strand (Stanford University), Margaret Dowd (LRA)
The long-term objective of the project was to propose and then validate new outcome measure(s) for trials of new treatments in SLE by developing Multi-dimensional Response Indices (MRI) with better ‘responsiveness to change’ than the conventional outcome measures, such as SRI used in recent SLE trials.
Together with OMERACT, the LIC developed a Lupus Multivariable Outcome Score (LuMOS) based on the contrast between outcomes in the Belimumab (BM) 10 mg/kg (n=273) versus Placebo (n=275) subgroups in the BLISS-76 trial (Furie et. al. A&R 2012) and validated using an independent dataset, from the BLISS-52 trial.
The LuMOS development and initial validation was published in Arthritis & Rheumatology. Additional validation of LuMOS was conducted by Astra Zeneca (AZ) using the data from the Phase 2b Anifrolumab lupus trial; the results were presented by AZ at the July 2018 LIC meeting.
Updated June 2025
