Background/Purpose: Spondyloarthritis (SpA) is a group of inflammatory diseases that includes axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA). AxSpA patients have irregular neutrophil responses, as indicated clinically by neutrophilia, increased neutrophil to lymphocyte ratios, and aberrant neutrophil activation. However, the role of neutrophils in disease pathogenesis remains unknown. Here we employed an experimental model of SpA (SKG mice) in tandem with SpA patient data to determine the role of neutrophils in SpA.

Methods: Arthritis was induced in SKG mice by intraperitoneal injection of 1.5mg β-glucan (zymosan). Splenic CD4+ T cells were stimulated in vitro with PMA/ionomycin and the Th17 response was quantified by flow cytometry. Neutrophils were depleted in SKG mice with anti-Ly6G (1A8) or isotype control (2A3) beginning 24h prior to zymosan and every 2d for 5d. For mouse studies, three independent experiments were performed (n=5-6 mice/genotype), and data analyzed using non-parametric statistics. SpA patients with axSpA or PsA from the Program to Understand the Long term Outcomes in Spondyloarthritis Registry (Pulsar) were included. Regression was used to assess for associations of absolute neutrophil count (ANC) and neutrophil percentage, with measures of functional capacity determined using the Bath Ankylosing Spondylitis Functional Index (BASFI) Test.

Results: We induced disease in neutrophil-sufficient or -deficient SKG mice. Five days post-zymosan (disease induction), neutrophil-sufficient SKG mice developed autoreactive Th17 responses and arthritis; however, neutrophil-deficient SKG mice had decreased Th17 responses and no signs of arthritis, indicating a role for neutrophils in induction of arthritis. Conversely, 8 weeks post-zymosan neutrophil depletion resulted in worsened disease indicating neutrophils play a protective role during established/chronic disease. In human subjects, both absolute neutrophil count (ANC) (p=0.002) and neutrophil percentage (p=0.008) were associated with increased disease severity, as indicated by BASFI scores. On average, for every increasing increment of 5,000 neutrophils/mm³, disability status worsened by approximately 15% (∆BASFI of 1.5). These associations were also present in treatment-naïve SpA subjects, further supporting a role for neutrophils in SpA pathogenesis rather than an artifact of treatment. In corroboration with SKG mice, treatment-naïve SpA subjects within 5 years of diagnosis (earlier disease) had greater ANC than controls (p < 0.001), whereas subjects with more established disease demonstrated lower ANCs.

Conclusion: Our data suggest neutrophils may play a role in initiation of pathogenic Th17 responses and disease in Spa patients. Future studies aimed at understanding how dysregulation of neutrophil numbers and function contributes to SpA will inform development of novel therapeutics.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-role-for-neutrophils-in-disease-onset-and-severity-of-spondyloarthritis/