Abstract
Axial spondyloarthritis (SpA), is a major cause of chronic pain and disability that profoundly alters the quality of life of patients. Nearly half of patients with SpA usually develop drug resistance. Non-pharmacological treatments targeting inflammation are an attractive alternative to drug administration. Vagus nerve stimulation (VNS), by promoting a cholinergic anti-inflammatory reflex holds promise for treating inflammatory disease. Inflammatory reflex signaling, which is enhanced by electrically stimulating the vagus nerve, significantly reduces cytokine production and attenuates disease severity in animal models of endotoxemia, sepsis, colitis, and other preclinical models of inflammatory diseases. It has been proposed that vagal efferent fibers release acetylcholine (Ach), which can interact with α7-subunit-containing nicotinic receptors expressed by tissue macrophages and other immune cells to rapidly inhibit the synthesis/release of pro-inflammatory cytokines such as TNFα, IL-1β, IL-6, and IL-18. External vagal nerve stimulation devices are now available that do not require surgery nor implantation to non-invasively stimulate the vagal nerve. This double-blind randomized cross-over clinical trial aims to study the change in SpA disease activity, according to Assessment in Ankylosing Spondylitis 20 (ASAS20) definition, after 12 weeks of non-invasive VNS treatment vs. non-specific dummy stimulation (control group). One hundred and twenty adult patients with drug resistant SpA, meeting the ASAS classification criteria, will be included in the study. Patients will be randomized into two parallel groups according to a cross over design: either active VNS for 12 weeks, then dummy stimulation for 12 weeks, or dummy stimulation for 12 weeks, then active VNS for 12 weeks. The two stimulation periods will be separated by a 4 weeks wash-out period. A transcutaneous auricular vagus nerve stimulator Tens Eco Plus SCHWA MEDICOTM France will be used in this study. The active VNS stimulation will be applied in the cymba conchae of the left ear upon the auricular branch of the vagus nerve, using low intensity (2–5 mA), once à week, during 1 h. Dummy stimulation will be performed under the same conditions and parameters as active VNS stimulation, but at an irrelevant anatomical site: the left ear lobule. This multicenter study was registered on ClinicalTrials.gov: NCT04286373.
Highlights
Axial spondyloarthritis (SpA) is a chronic inflammatory disease primarily affecting the sacroiliac and spinal joints that usually begins in young adults and is a major cause of chronic pain and disability that profoundly alter the quality of life of patients (Taurog et al, 2016)
The primary objective of this study is to evaluate the change in SpA disease activity, according to ASsessment in AS International Working Group criteria for 20% improvement criteria Assessment in Ankylosing Spondylitis 20 (ASAS20) (Anderson et al, 2001) after 12 weeks of Vagus nerve stimulation (VNS) treatment in comparison with dummy stimulation period
The study was registered at www.clinicaltrials.gov (NCT04286373) prior to enrollment, and is part of the SMART-VNS(TM) project, aimed at promoting research, development and technological innovation in the field of vagal neuromodulation therapy
Summary
Axial spondyloarthritis (SpA) is a chronic inflammatory disease primarily affecting the sacroiliac and spinal joints that usually begins in young adults and is a major cause of chronic pain and disability that profoundly alter the quality of life of patients (Taurog et al, 2016). Only half of the patients respond to these treatments and many of them are only partially relieved. These treatments are expensive and can lead to serious side effects (Braun and Sieper, 2002; Wendling and Prati, 2011; Wendling et al, 2018). VNS which has been used for decades as a treatment of drug-resistant epilepsy and depression (O’Reardon et al, 2006) is known to generate a cholinergic anti-inflammatory reflex (Huston and Tracey, 2011; Cheng et al, 2014).
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