Precision medicine in rheumatology: Enormous opportunity exists

The findings led to a “cumulative hit hypothesis” for autoimmune disease, and help to clarify genetic architecture and ethnic disparities in SLE, they concluded.

“So we now have over a hundred genetic regions that have been associated with lupus, compared to healthy controls,” Dr. James said.

A frustration with genetic data such as these, however, is the challenge of “getting it into the clinic,” she noted.

“I think that looking at individual [single nuclear polymorphisms] is probably not what we’re going to be doing, but we’re seeing a lot of interest in the idea of genetic load,” she said, explaining that it may soon be possible to use genetic load information to evaluate patient risk.

A recent study at her institution looked at lupus risk from another angle: She and her colleagues recontacted family members from Oklahoma Lupus Genetics studies to look more closely at which blood relatives of SLE patients transitioned to SLE, and what factors were associated with that transition when compared with relatives who remained unaffected (Arthritis Rheumatol. 2017;69[3]:630-42).

Among the findings was a higher risk of transitioning among family members with both a positive antinuclear antibody test and a baseline Connective Tissue Disease Screening Questionnaire score indicative of connective tissue disease.

“We also found, of course, biomarkers, or blood markers, that helped us identify the individuals who were at the highest risk of transitioning, so we think a blood test might really be helpful,” she said.

That study also suggested that there may be ways to intervene in SLE patients’ relatives at increased risk for also developing lupus. For example, those who transitioned had increased levels of soluble tumor necrosis factor receptors and the interferon-driven chemokine MCP-3; a prevention trial is now underway, she noted.
 

Beyond genetics

Genetics are just one piece of the precision medicine puzzle, and other areas of investigation that may help to divide patients into subgroups for more precise treatment include genomics, soluble mediators, and immunophenotyping, Dr. James said.

“It may be that we need different pieces of all of these things to help guide our treatment in lupus patients,” she said.

Longitudinal clinical and blood transcriptional profiling of patients in the Dallas Pediatric SLE cohort, for example, identified a molecular classification system for SLE patients. The analysis of 972 samples from 158 SLE patients and 48 healthy controls, which were collected for up to 4 years, showed that an interferon response signature was present in 784 of the samples.

The investigators found that a plasmablast signature, which is found more in African-American patients than in other populations, best correlates with disease activity and that a neutrophil-related signature is associated with progression to active lupus nephritis (Cell. 2016;165[3]:551-65).

“This is something that will potentially be helpful [in the clinic], and we need to test this in the adult population,” Dr. James said.

The investigators also were able to stratify patients, based on individual immunoprofiling, into seven major groups based on molecular correlates. They concluded that such stratification could help improve the outcomes of clinical trials in SLE.

In another study, researchers looked at longitudinal gene expression in SLE patients by stratifying each of two independent sets of patients (a pediatric cohort and an adult cohort) into three clinically differentiated disease clusters defined by mechanisms of disease progression (Arthritis Rheumatol. Dec 2018;70[12]:2025-35).

The clusters included one showing a correlation between the percentage of neutrophils and disease activity progression, one showing a correlation between the percentage of lymphocytes and disease activity progression, and a third for which the percentage of neutrophils correlated to a lesser degree with disease activity but was functionally more heterogeneous. Patients in the two neutrophil‐driven clusters had an increased risk of developing proliferative nephritis.

The results have implications for treatment, trial design, and understanding of disease etiology, the investigators concluded.

“This may help us in the future as we think about which medicine to start patients on, and which medicines to start patients on first,” Dr. James said.

It is clear that precision medicine will play an increasingly important role in rheumatology, Dr. James said, when considering the context of other findings in recent years, such as those from studies looking at soluble mediators of inflammation associated with disease flare, as well as those that involved extensive immunophenotyping and showed widely divergent transcriptional patterns based on ancestral backgrounds. Other research, such as the BOLD (Biomarkers of Lupus Disease) study, looked at various mechanisms of disease flare.

Numerous types of personalized therapies are being considered in rheumatology, ranging from expanded regulatory T cells to chimeric antigen receptor T cell therapy to risk profiling for disease prevention, just to name a few. Going forward it will be important to perform more systems biology analyses to assemble precision medicine–related data that can inform clinical diagnosis, prognosis, and therapy selection and optimization, she said.

The future of personalized therapies in rheumatology will require more input from rheumatologists on large-scale precision medicine projects such as the National Institutes of Health’s All of Us Research Project and the Million Veteran Program, as well as other similar programs of major health systems, she noted, adding that different types of training and interaction with molecular pathologists, genetic counselors, health coaches, and other key players also are needed.

Dr. James reported having no relevant disclosures.

sworcester@mdedge.com