By Wayne Kuznar
Washington, DC—Although biomarker progress is easily discernible in cardiology and oncology, researchers are only at the beginning of the long, winding road of biomarker discovery in lupus, said Mary K. Crow, MD, Physician-in-Chief, and Chair, Division of Rheumatology, and Director of the Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York City, at the 2012 meeting of the American College of Rheumatology.
“We are really just beginning to apply and test candidate biomarkers on the appropriate testing populations,” said Dr Crow.
Challenges in Lupus Biomarkers
One of the pertinent questions today regarding lupus biomarkers is whether one can predict the future development of systemic lupus erythematosus (SLE) in a healthy individual.
“I think that is a dream. Perhaps the more pressing question is can we predict the future development of a lupus flare?” Dr Crow asked.
Predicting the development of a lupus flare has significance in terms of patient management and drug development, she added.
“There is a dynamic between biomarker development, candidate biomarker identification, and the elucidation of pathogenic mechanisms that makes this endeavor very valuable, at least in lupus,” Dr Crow explained. “Lupus is a most complex disease. In trying to tackle the identification of candidate biomarkers, we have to keep the whole disease in mind.”
Her presentation highlighted the significant practical challenges that limit the optimal management and outcomes in patients with SLE:
- Recognizing the pathogenic basis of disease heterogeneity to enable the creation and the application of appropriately targeted therapies
- Recognizing the biomarkers of disease activity and the response to therapy that would allow for the monitoring of efficacy in clinical trials and for consistent patient management
- Determining the future flare predictors that would enhance patient enrollment in clinical trials and permit the timely initiation of flare prevention treatment in practice.
“In studying lupus, we are fortunate that the blood really does represent a window into the disease,” Dr Crow said.
Phenotyping cells has proved to be beneficial, as has proteomic analysis, which has yet to be fully explored. Additional value can be extracted from gene expression analysis, microRNA, and genome methylation.
Candidate biomarkers in SLE fall into several categories, including cell analysis, proteomics, genetic polymorphisms and mutations, epigenetic modifications, gene expression, and microRNA.
Cell analysis candidate biomarkers include T follicular helper cells (ie, CXCR5, ICOS, PD-1), cell-bound complement activation products, and mitochondrial hyperpolarization. The proteomics category includes cytokines and the von Willebrand factor. Epigenetic modifications include differentially methylated loci. MicroRNA involves expression and circulating.
In one study involving a group of patients with lupus, researchers in Pittsburgh analyzed anti–double-stranded DNA (anti-dsDNA) levels. Although anti-dsDNA is specific, according to Dr Crow it does not hold as much utility as researchers would like. In the study, an SLE diagnostic index was identified that was somewhat more helpful than anti-dsDNA in terms of identifying patients with lupus.
“It is important to remember that clinical judgment and assessment are at the core of diagnosing lupus. Biomarkers have much less to add than they do in terms of predicting disease flare and measuring or confirming disease activity,” she said.
Much of Dr Crow’s current research is focused on gene expression. “Gene expression analysis distinguishes patients with SLE from healthy controls, but shows apparent heterogeneity among patients,” she noted. “The goal of our research is to use longitudinal biologic data from patients with SLE analyzed in the context of clinical data to characterize disease heterogeneity, correlates of disease activity, and biologic precursors of a flare.”
Dr Crow and her colleagues are now investigating the role of neutrophils in generating lupus flare. For future study, she plans to test the hypothesis that neutrophils are directly related to the development of anti-DNA autoantibodies and that both neutrophils and anti-DNA antibodies are primary mediators of lupus flare.
“What was satisfying, based on our growing burden of data suggesting that neutrophils are important in lupus flares, was the fact that the top-ranked differentially expressed transcripts were virtually all related to neutrophil granulocyte signature,” she said.
So what is a predictor of a future lupus flare? The use of a 4-gene score helps to predict a future flare, said Dr Crow. Patients with a low 4-gene score at nonflaring visits are less likely to develop flares than those who had a high 4-gene score, according to her study findings.
In research designed to identify predictors of future flare, patients with SLE were subdivided into 2 groups based on the annual rate of mild-to-moderate and severe flares. There were 11 patients with >1 flare annually who were designated as high flaring; 11 patients with <1 flare annually were designated as low flaring. In a summary of biologic precursors of flare, a 4-gene score (ie, interferon-induced protein with tetratricopeptide repeats 3; killer cell lectin-like receptor subfamily B, member 1; cluster of differentiation 38; and matrix metalloproteinase-8) was significantly higher at nonflaring visits in high-flaring versus low-flaring patients with SLE. Comparison of high-flaring and low-flaring patients with SLE at the time of nonflaring visits identifies the novel pathways and gene transcripts associated with subsequent flares.
Overall, Dr Crow said that the identification of predictors of future flares and predictors of future development of disease will require more statistical tools and analysis. Promising candidates for further study include cell-bound complement activation products, cell phenotypes associated with disease activity, gene expression scores, plasma von Willebrand factors, and the novel transcripts identified in future-flaring patients with SLE.