Cadherins, a family of adhesion molecules, may be another way to regulate these pathways, Dr. Agarwal said. Cad-11 plays a role in synovial inflammation, and in scleroderma, recent findings show that cad-11 expression is higher in scleroderma skin relative to controls. In addition, cad-11–deficient mice develop less lung and skin fibrosis than wild type mice in mouse models of tissue fibrosis.
“Cad-11 regulates TGF beta production and the epithelial to mesenchymal transition,” Dr. Agarwal said. “I think, and indeed we’re hoping, it’s another therapeutic target in scleroderma.”
Using Pharmacogenetics to Treat RA
There are no reliable genetic predictors of response to therapy in rheumatoid arthritis (RA), but there are some promising and interesting predictors according to Robert Plenge, MD, PhD, director of genetics and genomics in the division of rheumatology, immunology, and allergy at Brigham and Women’s Hospital in Boston. Dr. Plenge and his team found a statistically significant association between the response to anti–tumor necrosis factor (TNF) therapy and an RA risk allele at the PTPRC gene locus (rs10919563) based on qualitative endpoints of response to treatment using the European League Against Rheumatism (EULAR) response criteria and the Disease Activity Score in 28 joints (delta-DAS28). An opportunity for future research is to define disease activity more quantitatively and to use novel approaches for gathering larger patient samples.
GWAS genotyping is helping researchers make strides in this arena because it allows the sample size to be greatly increased—up to 8 million single-nucleotide polymorphisms (SNPs). The disadvantage is that the sample becomes more heterogeneous. The future likely will include incorporating polygenic models and using electronic medical record (EMR) data to create virtual cohorts, Dr. Plenge said.
“One major limitation [of current research models] is we don’t use the human as a model organism enough,” Dr. Plenge said. “We don’t have integrated clinics that involve investigation across disciplines. We need to think about ways to integrate and bring these silos together. As we begin to do this, we can actually find better biomarker predictors.”
Health System as a Risk Factor in RA and SLE
At hospitals with a clinic specific for vulnerable populations (e.g., with translators, physicians experienced with other cultures), there is less disparity in the outcome of RA, according to Edward Yelin, PhD, professor in residence of medicine and health policy in the division of rheumatology and Institute for Health Policy Studies at the University of California, San Francisco. For the future, Dr. Yelin said, “We need to figure out what it is about clinics devoted to the vulnerable that reduces the disparities in outcomes.”
