Through genomic research, rheumatologists are discovering new gene mutations that lead to more accurate diagnosis and effective treatment of many diseases. When patients thought to have lupus didn’t respond to standard therapy, for instance, NHGRI researchers used exome sequencing to discover a gene mutation in TNFAIP3 that caused haploinsufficiency of the protein A20. This mutation upregulated the NFκB signaling pathway, activated the NLRP3 inflammasome and triggered overproduction of cytokines. The patients didn’t have lupus, but a disorder similar to Behçet’s disease, suggesting biologics might provide effective therapy, he said.4
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Explore This IssueFebruary 2018
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Precision Medicine in Lupus
How can rheumatologists use precision medicine to understand and manage a complex autoimmune disease such as systemic lupus erythematosus (SLE)? Although we know a great deal about its genetic etiology, “we aren’t as far along in lupus as we are in other complex human diseases like cancer,” said Judith A. James, MD, PhD, Vice President of Clinical Affairs at the Oklahoma Medical Research Foundation in Oklahoma City. “Lupus has had a lot of failed clinical trials. Different patients may have the same diagnosis and meet the classification criteria, but patients may have pathogenic heterogeneity we don’t yet fully understand.”
In lupus, precision medicine may require targeted therapy based on trials of patients who share a molecular pathway, she said. “Lupus is a complicated process. Interrogating just an individual’s DNA or cells or soluble mediators may not [suffice], and we may have to start thinking about putting together different pieces so we can assemble a more cohesive story and identify which patient should be in which group or treated with a specific therapy.”
In the past, lupus patients have been grouped by organ involvement, demographics or certain biomarkers, but personalized medicine research may need to encompass genetics, genomics, immunophenotyping and soluble mediators. More than 100 genetic associations in lupus have been mapped, including a major new study that used Immunochip genotype data from 27,574 individuals of different ethnic backgrounds and revealed novel associations and definition of genetic load in this disease, she said.5 This genetic association study included mostly patients of European descent, so “we need more information on genetic risk factors in African-American, Hispanic and patients from other racial/ethnic backgrounds.” With more comprehensive genome-wide association study (GWAS) data, rheumatologists will learn more about the genetic architecture and genetic load of lupus.
“This information will eventually come into our clinics so we can counsel individuals about their genetic risk and environmental factors, ideally putting this information together to help inform our patients and individuals at risk for autoimmune rheumatic diseases,” she said.