Study Suggests Predictive Biomarker for Therapeutic Outcomes in Ankylosing Spondylitis

A recent German study published in Arthritis Research & Therapy suggests that CD8+ natural killer (NK) cells are a biomarker that can predict therapeutic outcome for patients with ankylosing spondylitis (AS) who are administered anti—tumor necrosis factor (TNF) agents because they are nonresponsive to conventional treatment.

However, one-third of AS patients treated with TNF blockers show only a poor response that can be partly attributed to the development of anti-drug antibodies, resulting in reduced bioavailability. Thus, finding new biomarkers that would aid clinicians in their decision making to select appropriate therapeutic options is critically needed, but there are no reliable predictive biomarkers for anti-TNF responsiveness in AS.

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Researchers, led by Ursula Schulte-Wrede, PhD, used a high-dimensional, multi-parametric flow integrated cytometric approach and a new unsupervised data clustering approach to identify possible baseline predictors in 31 patients with AS prior to treatment with the TNF blockers adalimumab (16 patients) and etanercept (15 patients) that are qualitatively or quantitatively different in responders and nonresponders.

The 31 patients (22 male, 9 female), of whom 81% were positive for HLA-B27 (an antigen linked with AS), were recruited from a rheumatology outpatient clinic. Ten healthy volunteers (7 male, 3 female) also participated in the study as controls.

All patients with AS were eligible for anti-TNF treatment because of persistently high disease activity (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI] score of greater than 4) despite treatment with conventional drugs. Disease activity was assessed according to the BASDAI index. The mean baseline BASDAI prior to TNF inhibitor therapy was 6.2 (±1.3). Response to treatment was assessed 1 to 6 months after the start of therapy, and defined as a 50% BASDAI reduction relative to baseline BASDAI.

At baseline, anti-TNF responders showed significantly increased frequencies of CD8+ NK cells compared with nonresponders. After 1 to 6 months of treatment, the relative reduction of disease activity assessed by BASDAI was 51.1% (±31.7%) for etanercept-treated patients and 44.3% (±31.6%) for adalimumab-treated patients. According to the BASDAI response criteria, 5 patients in the etanercept group and 7 patients in the adalimumab group failed to respond.

Clinical parameters available at baseline, such as disease duration, baseline BASDAI, C-reactive protein levels, erythrocyte sedimentation rate, as well as the expression of HLA-B27, allowed no discrimination between patients who would respond to anti-TNF drugs and those who would fail.

The researchers believe theirs is the first study to demonstrate that the composition of the NK cell compartment has predictive power concerning the therapeutic outcome for TNF blockers, and they conclude that CD8+ NK cells are “a potential new player in the TNF-alpha-driven chronic inflammatory immune response of AS.”

Although the findings are promising, they say, a further validation of CD8-positive NK cells as a potential biomarker for TNF responsiveness is needed in an independent cohort of AS and other rheumatic and gastrointestinal diseases where anti-TNF blockers are successfully administered.

The FDA has approved biosimilars for both etanercept and adalimumab reference biologics.

Reference

Schulte-Wrede U, Sorensen T, Grun JR, et al. An exploratory study on deep profiling of peripheral leukocytes to identify predictors for responsiveness to anti-tumor necrosis factor alpha therapies in ankylosing spondylitis: natural killer cells in focus. Arthritis Res Ther. 2018;20:191. doi: 0.1186/s13075-018-1692-y.