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.
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.”
The sex-related immune profiles were independent of HLA-B27 status, clinical disease activity or treatment.
Inflammatory Signature Differences
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.