medwireNews: A 35-year follow-up study has identified a 27.1% lifetime recurrence rate of axial spondyloarthritis (axSpA) among first-degree relatives of patients with human leukocyte antigen (HLA)-B27-positive ankylosing spondylitis (AS).
“The substantially high lifetime [recurrence rate] of axSpA for [first-degree relatives] of AS probands necessitates greater emphasis on patient education and counselling,” say researcher Sjef van der Linden (University of Bern, Switzerland) and colleagues.
The findings, published in RMD Open, also showed a sex effect, with mothers with HLA-B27-positive AS approximately three times more likely to have at least one child with axSpA than their male counterparts.
“Our findings suggest that female AS probands are genetically ‘enriched’ with disease susceptibility genes,” the team explains.
In 1985, 363 individuals with AS and 806 of their first-degree relatives underwent physical examinations and HLA-B27 typing and completed questionnaires regarding axSpA manifestations.
Among the 358 individuals with AS who could be tissue typed, 86% tested positive for HLA-B27 and these individuals were almost twice as likely to fulfill the modified New York criteria for radiographic sacroiliitis as those testing negative, at 81% versus 44%, indicating that the latter group was significantly more likely to have non-radiographic axSpA.
HLA-B27 positivity was seen in 53.9% of 668 first-degree relatives of HLA-B27-positive patients and 3.3% of HLA-B27-negative patients and radiographic axSpA was present in 4.5% of first-degree relatives (mean age 33.5 years), all of whom were relatives of HLA-B27-positive patients.
In 2019, axSpA was present in 12.5% of 360 available first-degree relatives (mean age 58 years). The majority of these were HLA-B27 positive, at 93.3%, and only 16.7% had confirmed radiographic sacroiliitis in 1985. By contrast, axSpA only occurred in 6.7% of HLA-B27 negative first-degree relatives.
This meant that the lifetime recurrence rate for axSpA among HLA-B27-positive first-degree relatives at follow-up 35 years later was 24.6% (excluding multicase families), increasing to 27.1% when multicase families and relatives who already had AS at baseline were included.
This risk “can be regarded to be complete (lifetime) because it is extremely uncommon to have onset of AS after age 45,” the authors comment.
They also found that, while the sex of the AS patient did not affect the likelihood of their siblings developing axSpA, the risk for their children, both sons and daughters, was sex dependent.
Indeed, the researchers report a significant 3.5-fold increase in the rates of axSpA for children born to mothers with HLA-B27-positive AS compared with fathers, at 31.0% versus 11.4%.
“Since in clinical practice, AS occurs more often in men, the genetic threshold for women to develop AS might be higher […] and that higher genetic load increases the recurrence of disease among both their sons and daughters,” they explain.
Disease severity also affected the sex-specific risk for axSpA being passed from parent to child. A total of 41.4% of children born to mothers with HLA-B27-positive AS and confirmed sacroiliitis developed axSpA, which was a significant 4.9-fold greater than the 12.6% of children born to fathers with HLA-B27-positive AS and confirmed sacroiliitis.
This increased risk for the offspring of mothers applied equally to sons and daughters, van der Linden and co-researchers note. And they highlight that “the risk increases twofold if the child inherits the HLA-B27 allele from the affected parent.”
By comparison, they found that “[i]ndependent of HLA-B27, offspring of patients with [non-radiographic]-axSpA [are] not at increased risk of axSpA.”
The team concludes: “It is important to further investigate this gender effect for uncovering putative additional disease susceptibility factors and for better assessment of lifetime risk for axSpA.”
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