WASHINGTON, D.C.—Experts at the 2016 ACR/ARHP Annual Meeting session, Systemic Lupus Erythematosus—Clinical Aspects and Treatment IV: Biomarkers, reported on a number of recent studies showing advancement in our understanding of the disease mechanisms underlying systemic lupus erythematosus (SLE) that place these patients at risk for cardiovascular disease (CVD) and other comorbidities.
Mechanisms of CVD Risk in SLE Patients
Among the presentations on mechanisms of CVD risk in SLE patients was one by Monica Purmalek, a first-year medical student in the Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Md., who reported on the results of a cross-sectional study that tested the hypothesis that aberrant neutrophil subsets contribute significantly to vascular damage and unstable plaque development in patients with SLE.
The study was done to more comprehensively characterize CVD in SLE patients given that CVD is a leading cause of mortality in CVD, said Ms. Purmalek. Specifically, investigators were interested in “identifying whether immune dysregulation and innate immune responses associated with aberrant neutrophils play a key role in driving vascular damage,” she said.
To test this hypothesis, investigators collected clinical and demographic characteristics, Framingham Risk scores, metabolic parameters and lupus medications on a cohort of 54 SLE patients and 32 healthy controls matched by age and gender. In this cohort, they assessed the vascular function of various arterial territories, aortic inflammation by positron emission tomography (PET), with fluorodeoxyglucose (FDG), and computed tomography (CT), and anatomical assessment of plaque by coronary CT angiogram. Flow cytometry was used to quantify circulating low-density granulocytes.
The study found that, compared with the healthy controls, SLE patients had significant impairments in endothelial function and enhanced arterial stiffness suggestive of widespread inflammation and damage across both micro- and macrovascular territories.
“Our results support the hypothesis that aberrant neutrophil subsets significantly contribute to vascular damage and unstable plaque development in patients with SLE,” said Ms. Purmalek. “Our findings suggest that neutrophils, through neutrophil extracellular trap formation, may disrupt [high-density lipoprotein] HDL function and further promote atherogenesis.”
Biomarkers for Cardiovascular Disease in SLE
In another presentation that looked at biomarkers for cardiovascular disease in SLE patients, Ashira Blazer, MD, a rheumatologist at The New York University School of Medicine, N.Y., reported the results of a study that focused on genetic variants in African Americans that place SLE patients at increased risk of developing CVD. These genetic variants are two apolipoprotein L1 (APOL1) risk variants, G1 and G2, located on chromosome 22q12.3 that show a link to excess renal risk in African Americans.
In the retrospective cohort study, Dr. Blazer and colleagues evaluated the prevalence of CVD across APOL1 genotypes in 100 SLE patients to test the hypothesis that the APOL1 phenotype for CVD is more penetrant in patients with SLE.
After completing polymerase chain reaction (PCR) sequencing, patients were stratified by genotype (ancestral, G0/G0; heterozygotes, RV/G0; and RV homozygotes, RV/RV) and clinical CVD endpoints were assessed by chart review.
The study found that APOL1 polymorphisms were associated with prevalent atherosclerotic disease in this cohort of SLE patients, with the risk of CVD increasing in patients who carried one or more APOL1 risk variants. The risk of CVD was 21.2% in patients with a G0/G0 genotype, 41.7% in those with RV/G0 genotype, and 63.6% in those with the RV/RV genotype.
After adjusting for other CVD risk factors (e.g., smoking, obesity, hypertension and early-stage renal disease), patients who carried one or more RV had a 3.1-fold increased risk of CVD (P=0.03) with the strongest association with total atherosclerotic disease (odds ratio [OR] of 6.9) and symptomatic disease (OR of 4.8).
When taken together, these results show the APOL1 risk variant is associated with prevalent CVD in this cohort of African Americans with SLE, said Dr. Blazer. “This suggests that SLE may be an important second hit in the relationship between APOL1 RV and CVD,” she said.
Simple Test for SLE Disease Activity Status
Chaim Putterman, MD, a clinical rheumatologist at the Albert Einstein College of Medicine, The Bronx, N.Y., described a simple test for assessing and monitoring SLE disease activity. The need for such a test, he said, is highlighted by the less-than-optimal tests currently used to assess disease activity. These tests make it challenging to predict and promptly identify and treat disease flares to reduce SLE-related morbidity and mortality. “Therefore, sensitive and specific diagnosis of disease activity remains an important unmet clinical need,” he said.
The simple test Dr. Putterman described employs immunosignature technology (IST) developed by the San Ramon, Calif., biotechnology company HealthTell Inc. The test uses assays to measure serum antibodies bound to a microarray of about 126,000 unique peptides to provide a broad sample. Statistical analysis of this sample is done to identify peptide features with binding intensities that are significantly different in persons with active vs. inactive SLE.
To evaluate the utility of the test, Dr. Putterman—who is a research collaborator and consultant at HealthTell—and his colleagues undertook a study to test the hypotheses on two points: that 1) the antibody profile of a patient with SLE identified with IST would reflect disease activity better than individual biomarkers, and 2) it may be possible to use changes in antibody profiles to monitor changes in disease activity.3
Testing these hypotheses in a sample of 183 SLE patients with varying disease activity, the investigators found that the measurements obtained by the IST were able to distinguish between patients with active disease and those in remission. In addition, the study found that changes in IST measurements between clinical visits successfully modeled changes in disease activity as measured by the SLE Disease Activity Index (SLEDAI), said Dr. Putterman.
Dr. Putterman also said that combining IST with traditional biomarkers (e.g., CS/C4, anti-DNA) further improved performance of the test.
“Simultaneously measuring antibody responses against thousands of peptides in SLE is feasible and can provide clinically actionable information,” said Dr. Putterman, highlighting that the IST technology has also shown promise in other autoimmune and autoinflammatory diseases.
“Future studies of the ImmunoSignature technology in SLE and other rheumatic diseases are intended to provide better diagnostic management tools for the rheumatologist,” he said. Upcoming studies also will look at the potential use of this technology to measure response to therapy and in the prediction of adverse drug effects.
Mary Beth Nierengarten is a freelance medical journalist based in Minneapolis.
References
- Purmalek M, Sakhardande S, Temesgen-Oyelakin Y, et al. Neutrophil subsets, arterial inflammation, and vascular stiffness in patients with systemic lupus erythematosus [abstract 3102]. Arthritis Rheumatol. 2016;68(suppl 10).
- Blazer A, Clancy RM, Belmont HM, et al. Apolipoprotein L1 risk variants associate with prevalent cardiovascular disease in African American systemic lupus erythematous patients [abstract 3103]. Arthritis Rheumatol. 2016;68(suppl 10).
- Putterman C, Rowe M, Legutki JB, et al. A simple test for assessing and monitoring SLE disease activity status [abstract 3106]. Arthritis Rheumatol. 2016;68(suppl 10).
