With the cost of sequencing a whole genome dropping below even exponential expectation, precision medicine has already made an impact on rheumatology. The two-day ACR CRC: Precision Medicine in Rheumatic Diseases: Hopes & Challenges provided a comprehensive look at past, ongoing, and future research initiatives and the technology currently being implemented in a variety of diseases.
“A lot of the interest in precision medicine has been driven by technologies that have come online to do high-dimensional measurements for our patients. These have been widely employed in the discovery space and now are increasingly being implemented into our clinical workflow,” said session co-chair Soumya Raychaudhuri, MD, PhD, in his opening remarks on Friday.
Many of these technologies have scaled rapidly, making them appealing for precision medicine, Dr. Raychaudhuri said. Next generation sequencing, for example, is becoming a standard tool in clinical practice.
“Flow cytometry has scaled up tremendously, initially from just a handful of markers to north of 20 markers,” he said. “Mass cytometry allows us to look at up to 40 markers per cell at a given time. Single-cell RNA-seq measures the transcriptome of a single cell. Being able to do that on thousands of cells makes this approach useful potentially for clinical care. Now, we are easily able to do up to 100 thousand cells per run.”
Dr. Raychaudhuri said that rheumatology already performs many facets of precision medicine, such as testing TPMT enzyme activity routinely in the TPMT genotype before starting Imuran therapy.
Daniel L. Kastner, MD, PhD, Scientific Director of the Division of Intramural Research of the National Human Genome Research Institute, outlined ongoing work since President Obama’s call for a precision medicine initiative during his 2015 State of the Union address.
Reviewing a variety of studies using new genetic information as a way to inform treatment, Dr. Kastner highlighted the work in his group to identify the gene mutated in familial Mediterranean fever by positional cloning as well as their discovery of the genetic basis for a second recurrent fever syndrome they named TNF receptor-associated periodic syndrome (TRAPS).
One of the most compelling examples was how TNF inhibitors treated the deficiency of adenosine deaminase 2, caused by mutations in the CECR1 gene, a condition causing multiple early onset strokes.
“The results have been absolutely incredible. In 15 patients, they had 55 strokes over 2,000 or so patient months of observation. In those same 15 patients since going on TNF inhibitor, besides having these normalizations of their lab values, they have had, over the course of 583 patient months of observation, zero strokes,” he said.
Presenter Judith A. James, MD, PhD, Member and Program Chair of the Arthritis & Clinical Immunology Research Program at the Oklahoma Medical Research Foundation, said that when it comes to systemic lupus erythematosus (SLE), precision medicine is not as far along.
Despite having a patient population who all have the same diagnosis and who all meet the appropriate classification criteria, there are many failed clinical trials in the lupus space because of significant heterogeneity that is not fully understood.
“If we could find a way to be able to pull out the different patients who share molecular pathways, we could find a directed therapeutic that may individually work for different groups of patients,” said Dr. James, who reviewed a number of studies focusing on genetics, genomics, immunophenotyping, and soluble mediator approaches to tackling SLE.
Peter Nigrovic, MD, Director of the Center for Adults with Pediatric Rheumatic Illness at Brigham & Women’s Hospital, Boston, MA, shared an overview of the precision medicine challenges posed by classification differences between juvenile onset arthritis and adult onset arthritis, which he said should be considered a continuum and studied together.
Other speakers during the two-day session discussed the role of analyzing large data sets in establishing large collaborative networks to further the goals of precision medicine in rheumatology and the complexities and challenges in rheumatic disease optimal interventions.