Cell-free DNA may be biomarker for AS activity, treatment response

Relationship between cfDNA and disease activity, therapy response examined

Patricia Inacio PhD avatar

by Patricia Inacio PhD |

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Blood cells are shown flowing through a blood vessel in this illustration.

The levels of circulating cell-free DNA may be a biomarker for assessing disease activity and treatment response in people with ankylosing spondylitis (AS).

The study, “Circulating cell-free DNA correlate to disease activity and treatment response of patients with radiographic axial spondyloarthritis” was published in Scientific Reports.

AS is a type of arthritis that features the inflammation of the sacroiliac joints, where the base of the spine connects with the pelvis.

Biomarkers of disease progression, namely inflammation and disease activity, could identify patients who would benefit from early treatment interventions.

A feature of several inflammatory diseases is the release into circulation of DNA from damaged blood vessels or organs. This circulating cell-free DNA (cfDNA) is used as a biomarker to stratify patients and predict disease progression and treatment response in diseases like systemic lupus erythematosus and rheumatoid arthritis.

Researchers in China examined the relationship between cfDNA levels and disease activity, as well as patients’ response to therapy. They measured the cfDNA in a first group of AS patients — called the discovery group — which was composed of 79 patients (mean age, 34.2; 76% men) and compared it to 42 age-matched healthy participants, who served as controls.

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Significance of cfDNA levels in AS

AS patients had significantly higher cfDNA levels than healthy participants (mean, 227 nanograms/ml vs. 192 ng/ml), and men with AS had significantly higher levels than women. The same was seen among patients with shorter disease duration (up to five years) versus those diagnosed for more than five years.

Higher cfDNA levels correlated with higher levels of neutrophils, the “first responders” of the immune system, and of C-reactive protein (CRP), a marker of inflammation. The AS disease activity score with c-reactive protein (ASDAS-CRP) also had a positive correlation with cfDNA levels.

The amount of cfDNA also correlated with disease activity, as assessed using patients’ and physicians’ global assessments, though it wasn’t associated with the Bath Ankylosing Spondylitis Disease Activity Index.

The researchers then validated the predictive potential of cfDNA levels in a second (validation) group, composed of 60 patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs), either alone or with other therapies.

Patients were evaluated at diagnosis and then again after about three months of follow-up. Those in the validation group also had significantly higher cfDNA levels than healthy participants.

A further analysis of 51 patients showed cfDNA was significantly reduced after three months of treatment, from a mean of 243 ng/ml (diagnosis) to 206 ng/ml. The reduction was only seen in those treated with a combination of NSAIDs and disease-modifying, anti-rheumatic drugs (DMARDs; from 230 to 197 ng/ml) or with NSAIDs and TNF inhibitors (277 vs. 223 ng/ml).

cfDNA levels fell significantly during treatment in responders (from 260 to 211 ng/ml), who are defined as patients with a ASDAS-CRP decline of at least 1.1, after three months of treatment, but not in nonresponders. No changes were seen in either the CRP or erythrocyte sedimentation rate (ESR) groups. ESR is also a measure of inflammation.

While CRP and ESR are commonly used to assess disease activity, biomarkers for response to treatment remain scarce, leading the researchers to analyze treatment response in those with low versus high cfDNA levels at diagnosis.

Participants with high cfDNA levels showed a significantly poorer response to treatment with NSAIDs alone, which was rescued with combo therapy. In contrast, no differences were seen regarding treatment response with NSAIDs alone or combo therapy when stratifying patients according to CRP or ESR levels.

“Patients with high cfDNA levels at diagnosis may need to initiate more aggressive therapy including DMARDs or [TNF inhibitors],” wrote the researchers, who said “cfDNA may serve as a useful biomarker in reflecting disease activity and monitoring treatment response as well as optimizing the drug selection at diagnosis in [AS].”