By Kathy Holliman
“It is evident that sex plays a very important role in AS. The symptomatic burden of AS tends to be higher in females than in males. Progression of spinal changes by X-ray, on the other hand, are more accelerated in males than females. Some inflammatory markers in the blood tend to be higher in males than females with AS. Although there is a male predominance of AS, in that subset of patients without X-ray damage in the sacroiliac joints (‘non-radiographic axial spondyloarthritis’) there is a higher representation of females. Finally, in some studies there have been male/female differences in the response to biologic treatments.
“To better understand the biologic basis of these sex differences in AS, our research team has just published a study examining the immune profiles in male AS patients vs female AS patients.”
— Robert D. Inman MD, FRCPC, FACP, FRCP Edin
Senior study author
The following article is reprinted from The Rheumatologist with permission from The American College of Rheumatology and Wiley.
A study that found distinct *sexual dimorphism in the immunologic profiles of patients with ankylosing spondylosis (AS) suggests that sex is an important variable to address in future research and may eventually lead to more effective sex-specific therapy for patients with the disease.
*Sexual dimorphism relates to the distinct physical differences (beyond sexual organs) between males and females of the same species.
The research, published in the March 2016 issue of Arthritis & Rheumatology, demonstrated that men with AS have elevations of IL-17A and Th17 cells, which are key factors in the inflammatory Th17 axis.1 These elevations were not found in women with the disease. Men and women with AS had a number of shared gene expression patterns, but the male patients had additional alterations in gene expression that were not seen in the female patients. The sex-related immune profiles were independent of HLA-B27 status, clinical disease activity or treatment.
Robert Inman, MD, senior author of the study and Professor of Medicine and Immunology at the University of Toronto, says there are several clinical indications that a patient’s sex impacts the expression of AS. AS has long been considered a male-dominated disease, and this assumption often delays the diagnosis in women who may manifest the disease very differently than their male counterparts.
Once the disease declares itself, clinical disease expression severity varies depending on whether the patient is male or female. X-rays of the spine and pelvis identify greater radiographic changes in men with the disease than women, specifically erosive damage, and joint fusion is more advanced in men. Women tend to record higher pain symptoms on self-administered questionnaires, “suggesting there are important differences in perception and processing of pain,” Dr. Inman says.
This dichotomy has given rise to the concept of clinical subsets in the diagnostic classification of axial spondyloarthritis, he explains. “Whereas AS, which involves diagnostic radiographic sacroiliitis, is male dominant, nonradiographic axial spondyloarthritis shows a female predominance in most series,” he explains.
“Fundamentally, it is probably all part of the same spectrum, and the classification differences really hang on radiographic severity. The implication is that erosive radiographic sacroiliitis is more likely to occur earlier and more frequently in males than in females. And then once the disease is established, it looks like the course of radiographic severity and the trajectory of the changes are more accelerated in males than in females,” he says.
Acute phase reactants, such as CRP and ESR, are typically higher in males than in females with the disease, Dr. Inman says. “There is a biological basis for all these differences, including neurobiological differences in processing pain. Large genetic studies have demonstrated that AS is driven by immune-related genes, especially those of the Th17 axis. The question therefore arises if immune profiles, in particular those of the Th17 axis, correlate with sex-related clinical differences in AS patients.”
Dr. Inman and his colleagues’ research, the first to systematically address the issue of sex differences at the immunologic level in patients with AS, has now demonstrated that there are differences in the inflammatory signature between males and females diagnosed with the disease.
Fifty-three male and 41 female patients with diagnosed AS were included in the study, matched for age and sex with 70 healthy controls. Subsets of the cohort were selected for serum analysis, flow cytometric analysis and gene expression analysis.
Analysis of peripheral blood revealed that the male patients with AS had significantly higher levels of IL-17A and TNF than female patients, whereas men and women had comparable serum levels of IFNγ. The male patients had significantly higher levels of Th17 cells compared with the female patients. The investigators say the Th17 axis is unlikely to be the primary inducer of AS, but that it is possible that “a distinct immunologic event, perhaps one that is mediated by CD8+ T cells and orchestrated by class I MHC, such as HLA B27, precipitates the inflammatory cascade leading to AS, while alterations in the Th17 axis modify disease expression and severity.”
In an effort to define a mechanistic basis for the male sex bias in the Th17 axis, the investigators examined the influence of sex hormones and found that levels of estrogen or testosterone were not significantly different between AS patients and those in the control group.
Study investigator Eric Gracey, BSc, a PhD graduate student in Dr. Inman’s lab at the University of Toronto, says the pathogenic role of IL-17 producing cells in patients with the disease remains unclear. “There is a lot of evidence from in vitro studies and from animal studies that IL-17 itself, as well as being an inflammatory molecule, actually promotes arthritic changes by promoting osteoclast and osteoblast function. IL-17 producing cells can be found at the sites of inflammation in spondyloarthritis, mainly where the tendons and ligaments insert into the bone.”
Cells of the Th17 axis, including TH17 cells, also play important protective roles. They promote healthy gut function and help combat fungal and bacterial infections. “They are a double-edged sword, in that they are absolutely necessary but too much can be a bad thing,” Mr. Gracey says.
Gene expression studies that he and his colleagues have conducted with AS patients indicate the sex bias may exceed the Th17 axis. “In future studies we are going to explore the function of genes differentially expressed in male and female patients and how they may impact on the immune response in male patients,” he says.
Sex is an incredibly important variable in research, he adds. “Often, with sex-dominated diseases, it is hard to balance the sexes in your studies, making it difficult to statistically compare the groups. With RA, for example, most of the studies are centered on female patients, but there may be important differences [when compared with male patients] that researchers are missing. Lessons learned from these studies cannot always be applied to both males and females.”
One aspect of this current study points toward a future that will offer more personalized approaches to therapeutics. “The study looking at gene expression profiles of patients begins to usher in a new era of targeted personalized therapeutics that are based directly on the patient’s own immune profile,” Dr. Inman says.
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.”
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