Precision Medicine for Lupus Continues to Progress

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CHICAGO—The promise of precision medicine—the tailoring of treatment to a given patient based on genetics and other factors—has probably been best illustrated in oncology, with therapies targeted specifically to markers expressed on tumors. But rheumatology is in the thick of precision medicine as well, said Judith James, MD, PhD, chair of the arthritis and clinical immunology program at the Oklahoma Medical Research Foundation in Oklahoma City.

Compared with other specialties, rheumatology has historically had the highest number of biomarker tests approved by the U.S. Food & Drug Administration, mainly because so many autoantibody tests are used. At the ACR State-of-the-Art Clinical Symposium in April, Dr. James showed how new lupus research is attempting to fuse genetics and other data into practical information that can be used patient-by-patient in the clinic.

Lupus Subsets

This will benefit patients across the rheumatology sphere, but especially in systemic lupus erythematosus (SLE), which manifests in many ways. In the same waiting room, Dr. James said, one patient could mainly suffer from fatigue that makes daily errands difficult, while another’s kidneys have shut down, forcing them onto dialysis.

“The big challenge in lupus is that we have a lot of heterogeneity,” she said. “We hope we can start taking lupus patients and finding different subsets.”

In one of the largest genetic lupus studies published last year, 50,000 unique parts of the genome were interrogated in 27,000 people, including patients and controls.¹ Genetic associations, such as tumor necrosis factor, alpha-induced protein 3 (TNFAIP3), signal transducer and activator of transcription 4 (STAT4) and tyrosine kinase 2 (TYK2), were identified. And Dr. James said researchers are also beginning to see novel associations in African-Americans and Hispanics that haven’t been seen before.

“We have identified genetic associations that may account for more than 50% of the heritable risk of lupus among patients of European-American descent based upon these studies and the other published data,” she said.

But genetics tell only part of the story, she said.

“Genetics are usually what we think of with precision medicine,” she said. “I think that what we’re learning from the genetics in our diseases is that genetics alone are probably not going to be all we need to be able to inform us about how to treat our patients.”

In studies based on the Dallas Pediatric SLE Cohort, clinical and blood transcriptional profiles were collected from 158 pediatric patients and 48 healthy controls over time for up to four years, with SLE Disease Activity Index components and medication use recorded for every visit.² (The Dallas group has modules available that allow clinicians from elsewhere to enter data from their own patients to see their risk of flare.)

‘We have identified genetic associations that may account for more than 50% of the heritable risk of lupus among patients of European-American descent.’ —Dr. James

They found the interferon gene signature was present in 85% of the pediatric lupus patient samples, but in only 15% of samples from healthy children. They also identified 486 transcripts that were most correlated with disease activity, as well as a neutrophil gene signature strongly linked with lupus nephritis.

At Dr. James’ center, researchers have been looking at adult lupus, attempting to use clinical features, gene expression profiling, soluble mediators, autoantibodies and immunophenotyping to try to split patients into subgroups that will characterize them more specifically compared to the general lupus population. Among their findings, patients who were early to flare had elevated CD11b(high) monocytes and elevated CD86(high) B cells, and one group featured more kidney disease than other groups.

Dr. James said some of the same clinical features were seen in different molecular subgroups. “That may suggest that patients get to the same clinical phenotype but through different molecular pathways, which may be important [because] we’re trying to select the right medication for the right patient,” she said.

Despite the progress in trying to treat at the individual patient level, some improvements are needed in rheumatology to take the next steps. “We need more systems biology … approaches to take all of this collective information and distill it into things we can use practically for an individual patient on a given day,” she said.

More effective collaborations are needed as well, Dr. James continued. “And we’re going to need different types of interaction with different kinds of health professionals who we haven’t historically used in rheumatology, like molecular pathologists, who are really focused on the genetic information.”

She mentioned many “huge” precision medicine programs are underway—e.g., the National Institutes of Medicine All of Us Precision Medicine Initiative and the Million Veteran Program—that plan to enroll a million Americans for whole genome sequencing.

“You will see more and more patients [with] the sequencing data.”

Thomas R. Collins is a freelance writer living in South Florida.

References

1. Langefeld CD, Ainsworth HC, Cunninghame Graham DS, et al. Transancestral mapping and genetic load in systemic lupus erythematosus. Nat Commun. 2017 Jul 17;8:16021.
2. Banchereau R, Hong S, Cantarel B, et al. Personalized immunomonitoring uncovers molecular networks that stratify lupus patients. Cell. 2016 Apr 21;165(3):551–565.