Session Type: ACR Concurrent Abstract Session
Session Time: 2:30PM-4:00PM
Background/Purpose: Registration trials for SLE therapeutics require large numbers of patients with active disease, which in turn necessitates the trials be multinational with many participating centers. While all patients meet ACR classification criteria for SLE, there is a range of disease activity at baseline that may influence response to treatment. To investigate this issue, we used objective molecular and biochemical parameters with high sensitivity (low false positive rate) to characterize patients as “SLE(+)” or “SLE(-)” and examined baseline demographics and disease characteristics to see if SLE(+) patients were distinct from SLE(-) patients.
Methods: Analyses are based on data from two phase 3 trials (n=2262) that evaluated the impact of an anti-BAFF antibody on SLE disease activity (1,2). ANA (≥ 1:80) and SLEDAI ≥ 6 was required at entry. Four dichotomous baseline parameters were used to categorize patients, IFN gene signature (high/normal), anti-dsDNA (+/-), C3 (low/normal) and C4 (low/normal). SLE(+) was defined by any of the following: IFN (high), anti-dsDNA (+), C3 (low) and/or C4 (low). SLE(-) required all of the following: IFN signature (normal), anti-dsDNA (-), C3 (normal) and C4 (normal). IFN gene signature was measured as previously described (3); anti-dsDNA, C3 and C4 were measured at a central lab.
Results: Baseline RNA transcript data were available for 1747 of 2262 patients, with 1318 (75%) of patients meeting the IFN (high) criteria. When IFN (high) was combined with the serology criterion, 1500 (86%) were classified as SLE(+) and 247 (14%) were classified as SLE(-). At baseline, SLE(-) patients had significantly lower mean SLEDAI scores (8.3) compared to SLE(+) (10.7 ; p<0.001). Baseline SLEDAI < 10 was observed in 72% of SLE(-) patients compared to 38% of SLE(+). SLE(-) patients had 83% less hematologic, 51% less renal and 70% less vascular organ system involvement at baseline compared to SLE(+) as measured by SLEDAI. Significantly fewer SLE (-) patients were on background medication at baseline. The proportion on corticosteroids at baseline was 49% in SLE(-) compared to 78% in SLE(+), and the proportion on immunosuppressants at baseline was 31% in SLE(-) compared to 44% in SLE(+). An evaluation of geographic distribution revealed that 22% of US patients were SLE(-) compared to 10% for Latin America, 7% for Europe, and 5% for ROW.
Conclusion: A subset of clinical trial patients was identified using biochemical and molecular markers with high sensitivity for SLE. Seronegative SLE patients with normal IFN gene signature represented 14% of the clinical trial population. These patients had lower disease activity and were taking less background medication at baseline, two factors which have been negatively associated with response to treatment in some previous trials. Further study is required to determine if seronegative/IFN normal patients in SLE trials represent a population of SLE patients that can confound the assessment of treatment benefit in SLE clinical trials.
- Merrill et al., Ann Rheum Dis (2016) 75:332-40.
- Isenberg et al., Ann Rheum Dis (2016) 75:323-31
- Hoffman et al., 2015 ACR Mtg, Abstract 1072
To cite this abstract in AMA style:Petri M, Kalunian KC, Urowitz M, Isenberg DA, Furie R, Morgan-Cox M, Silk M, Dow ER, Higgs R, Watts S, Linnik MD. A Molecular Signature Based on IFN Gene Signature and Serology Defines Two Populations of Patients with Different Baseline Disease Activity in a Large Multinational Phase 3 SLE Trial Population [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/a-molecular-signature-based-on-ifn-gene-signature-and-serology-defines-two-populations-of-patients-with-different-baseline-disease-activity-in-a-large-multinational-phase-3-sle-trial-population/. Accessed May 20, 2019.
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