Circulating microRNAs linked to poor response to TNF inhibitors
Researchers: Molecules miR-146a, miR-155 could help tailor treatment choices
High blood levels of two microRNAs, a type of small molecule involved in controlling which genes are turned on and off in cells, may predict a poor response to TNF inhibitors in people with ankylosing spondylitis, according to a study in China.
While those microRNAs, called miR-146a and miR-155, could help tailor treatment choices, “like many other novel biomarkers at their early stages of research, extensive investigations … are required to validate their great potential,” the researchers wrote in “Predictive values of circulating miR-146a and miR-155 for disease activity and clinical response to TNF-α blocking therapy in patients with ankylosing spondylitis,” which was published in the International Journal of Rheumatic Diseases.
TNF inhibitors are medications that block the action of TNF, a protein that promotes inflammation and is abundant in the swollen, tender joints of people with arthritis such as ankylosing spondylitis, which is marked by inflammation in the spine.
Because TNF inhibitors don’t work well for everyone with ankylosing spondylitis, there’s been growing interest in microRNAs, or miRNAs, as a biomarker for predicting how the disease progresses and how patients respond to treatment.
“miRNAs are now commanding much attention in ankylosing spondylitis due to their discovery paving a new avenue for diagnosis and treatment, as well as providing possible answer to the challenges in predicting treatment outcome,” wrote researchers who looked at the levels of two specific miRNAs — miR-146a and miR-155 — in 62 adults with ankylosing spondylitis who were treated with the TNF inhibitor Humira (adalimumab) for six months. Both miR-146a and miR-155 are regulators of immune responses.
The study included 49 men and 13 women, with a mean age of 38.7, who’d been living with ankylosing spondylitis for an average of 6.3 years. Before treatment, they had significantly higher circulating levels of miR-146a and miR-155 than a group of 62 healthy people who served as controls.
MicroRNAs and response to treatment
On average, patients scored 5.6 points on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), a measure of disease activity where a score of 4 or higher suggests the disease is not well under control despite treatment.
The higher the levels of miR-146a or miR-155, the higher the BASDAI score. There also was a positive relationship between miR-146a or miR-155 and levels of TNF in the blood. “These data suggest that high levels of circulating miR-146a and miR-155 may be associated with inflammatory response in ankylosing spondylitis.”
After treatment with Humira, the patients were divided into two groups: 38 were responders, meaning they had an improvement of at least 40% in the ASAS40 score, a measure of disease activity, whereas the remaining 24 were defined as nonresponders.
Responders had significantly lower levels of miR-146a and miR-155 in the blood than nonresponders. They also scored significantly lower on BASDAI (5.3 vs. 6.2 points) and had lower levels of C-reactive protein, a biomarker of inflammation (10 vs. 33 milligrams per liter).
“These data indicate that high levels of circulating miR-146a and miR-155 may be associated with poor treatment response for ankylosing spondylitis,” at least after receiving Humira for six months, the researchers wrote.
Using miR-146a and miR-155, either alone or combined, they could predict the outcome of TNF inhibitor treatment with up to 93.6% accuracy. miR-146a plus miR-155 correctly identified response to treatment in 87.5% of cases, and correctly ruled it out in 97%.
When the researchers looked at other factors, they found the erythrocyte sedimentation rate (ESR) was an independent predictor of how well patients responded to treatment. ESR is a measure of how quickly red blood cells sink to the bottom of a tube; inflammation makes them clump together and sink faster than normal.
Circulating miRNAs were stronger predictors of a response to treatment, however, with people with higher levels of miR-146a being almost 14 times as likely to not respond. The odds were more than five times as high for those with higher levels of miR-155.
The miRNAs could help doctors predict which patients might not benefit as much from TNF inhibitors like Humira, allowing for more tailored and effective treatment. They also provide targets to “develop a novel therapeutic strategy,” the researchers said.
