The research, he explains, has several implications for future research related to therapy. “We are not really thinking of AS as a monolithic single entity anymore. If you factor in genetic diversity, clinical stratifications, and the immune signature of a particular patient, we will more effectively and intelligently be able to develop therapeutic plans that match particular patients. We need to be able to identify the biologic basis of clinical heterogeneity so that we can target that more specifically.”
TNF blockers, he says, have been found to work broadly across a wide range of rheumatologic diseases, including RA, Crohn’s disease and AS. The new generation of biologics includes the IL-17 blockers, such as secukinumab, that are also demonstrating efficacy in patients with AS, Dr. Inman says. “IL-17 seems to be not only a very attractive target in AS but is a target that differentiates chronic inflammation in AS from RA and inflammatory bowel disease,” he says.
According to Mr. Gracey, the study “suggests that males may respond better to IL-17 blocking than females in light of the sex difference in the Th17–IL-17 pathway.”
There may be some attractive therapeutic targets that arise not only in the microarray profiles that this research group has completed but also in combination with the genome-wide association study, Dr. Inman says. “We may find some candidate genes that pop up in both those screens and some that may seem to fit biologically with what we know about the process—that it is a chronic inflammatory disease associated with new bone growth formation at the site of inflammation. For example, there may be some potential candidates that affect osteoblast function or osteoproliferation.”
Additional research is needed into which differentially regulated genes may serve to identify biomarkers in AS. This research has examined functional gene networks rather than the expression of single genes, a method that has shown shifts in basic metabolic processes such as mitochondrial function and protein translation. “The alteration of genes related to basic cell functions in AS patients likely reflects an altered state of these cells under a state of chronic inflammation,” the researchers say.
Further studies “are required to determine whether these changes represent changes in cell activation, differentiation or proliferation,” they add. “The gene expression pathways shared between male and female patients with AS may represent a base disease profile, with additional gene pathways altered in male patients acting as disease modifiers.”
Kathy L. Holliman, MEd, is a medical writer based in Beverly, Mass.
Resources
- Gracey E, Yao Y, Green B, et al. Sexual dimorphism in the Th17 signature of ankylosing spondylitis. Arthritis Rheumatol. 2016 Mar;68(3):679–689.