Background/Purpose: Secukinumab is a monoclonal antibody that neutralises IL-17A, which plays a key role in the IL-23/17A axis underlying the pathophysiology of psoriatic arthritis (PsA).  In this disease, Th17 cells produce IL-17A to trigger the release of chemoattractants such as CXCL8 and CCL20, leading to the infiltration of other immune cells including neutrophils. Activated neutrophils can themselves generate numerous chemokines and cytokines that can amplify and sustain inflammation.  Therapeutic targeting of IL-17 with biologics such as secukinumab in PsA may block this inflammatory cycle, but such inhibition should not have deleterious effects on other aspects of immunity associated with host defence.

This study measured changes in the functions of circulating neutrophils in PsA patients pre-therapy, compared to age- and sex-matched healthy controls, and determined if these functions changed in PsA patients prior to and during secukinumab therapy.

Methods: Neutrophils were isolated from venous blood of 20 PsA patients due to start secukinumab and 10 healthy controls. Key neutrophil functions such as: reactive oxygen species (ROS) production; phagocytosis; apoptosis (+/- TNF and GM-CSF); receptor expression and chemotaxis, were measured at baseline and 12 weeks.  Changes in gene expression pre- and 12-weeks post-therapy (n=5 PsA) were measured by RNAseq, and pre-treatment PsA neutrophil transcriptomes were also compared to healthy controls.

Results: There were no significant differences in ROS production, phagocytosis or chemotaxis in PsA patients at baseline (compared to healthy controls) or during therapy. RNA-seq analysis  revealed many genes with altered expression between PsA neutrophils at baseline and healthy controls.  For example, up-stream cytokines predicted to be regulating neutrophil gene expression in PsA included CSF2 (G-CSF), CD40LG, oncostatin M, interferons-a and -g, and TNFa. Ingenuity analysis revealed that signalling pathways associated with IL-8 signalling, toll-like receptor signalling and apoptosis signalling were among those significantly down-regulated by secukinumab. Of note, none of the patients treated with secukinumab contracted Covid-19.

Conclusion: Selective up- and down-regulation of neutrophil transcription was observed in PsA neutrophils compared to healthy controls, and in PSA neutrophils post treatment with secukinumab. However, while these changes may alter the pro-inflammatory function of neutrophils in PsA in response to IL-17A blockade, they did not adversely affect the ability of these neutrophils to carry out their role in host defence against infections.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/proinflammatory-neutrophil-function-is-modulated-during-secukinumab-therapy-in-psoriatic-arthritis-without-compromising-host-defence/