Neuroimmune Modulation for Drug-Refractory Rheumatoid Arthritis: Long-Term Safety and Efficacy in Patients Enrolled in a Pilot Vagus Nerve Stimulation Study.

IF 2.9 3区医学 Q2 RHEUMATOLOGY

Rheumatology and Therapy Pub Date : 2025-10-10 DOI:10.1007/s40744-025-00798-y

Norman B Gaylis, David Sikes, Alan Kivitz, Diane Lewis Horowitz, Melissa Evangelista, Yaakov A Levine, David Chernoff

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引用次数: 0

Abstract

Introduction: Vagus nerve stimulation activates neuroimmune reflexes that modulate systemic inflammation and may represent a novel non-pharmacologic treatment modality for autoimmune diseases like rheumatoid arthritis (RA). In a 3-month first-in-human, double-blind trial, 50% of patients with drug-refractory RA improved clinically, two patients achieved remission, and pro-inflammatory cytokines declined by 30-50% with daily stimulation. The current study is a 36-month extension of that trial, designed to assess the sustained safety and efficacy of the neuroimmune modulation device in patients with multidrug-refractory RA.

Methods: Patients (N = 14) with active RA and prior insufficient response to at least two different biological or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) with at least two mechanisms of action were implanted with a novel neuroimmune modulation device that stimulates the cervical vagus nerve, treated for 12 weeks, and then assessed for safety and clinical effectiveness in an open-label 36-month extension.

Results: Eleven patients completed the extension study through month 36. Patients had previously failed an average of 4.8 different drugs, with 64% (9/14) having failed a tsDMARD before enrolling in the study. The median change in clinical disease activity index (CDAI) score from day 0 to month 36 was - 17.8 (SEM 4.9). At month 36, 64% (7/11) of patients achieved a CDAI response that met or exceeded the minimal clinically important difference. Two of these seven patients were treated with daily stimulation alone, while five patients combined stimulation with an adjunctive b/tsDMARD. No device-related infections, cardiac events, surgical revisions, or device explants were reported. Two adverse events related to the device occurred in a single patient: a mild sore throat and moderate tenderness near the implant site. These events were non-serious, anticipated, and resolved.

Conclusion: In this first-in-human long-term extension study, neuroimmune modulation was well tolerated among patients with multidrug-refractory RA, with reductions of clinical disease activity that were maintained through 36 months.

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神经免疫调节治疗药物难治性类风湿关节炎：迷走神经刺激试验患者的长期安全性和有效性

导览：迷走神经刺激激活神经免疫反射，调节全身炎症，可能代表一种新的非药物治疗自身免疫性疾病如类风湿关节炎（RA）的方式。在一项为期3个月的首次人体双盲试验中，50%的药物难治性RA患者临床改善，2例患者获得缓解，每日刺激促炎细胞因子下降30-50%。目前的研究是该试验的36个月的延长，旨在评估神经免疫调节装置在多药难治性RA患者中的持续安全性和有效性。方法：对至少两种不同生物或靶向合成抗风湿药物（b/tsDMARDs）反应不足且至少有两种作用机制的活动性RA患者（N = 14）植入一种刺激颈迷走神经的新型神经免疫调节装置，治疗12周，然后在开放标签36个月的延长期中评估安全性和临床有效性。结果：11例患者在第36个月完成了扩展研究。患者之前平均失败了4.8种不同的药物，其中64%（9/14）在参加研究之前失败了tsDMARD。临床疾病活动指数（CDAI）评分从第0天到第36个月的中位变化为- 17.8 （SEM为4.9）。在第36个月，64%（7/11）的患者达到了CDAI反应，达到或超过了最小的临床重要差异。这7例患者中有2例仅接受每日刺激治疗，而5例患者将刺激与辅助b/tsDMARD联合治疗。没有器械相关感染、心脏事件、手术修复或器械外植体的报道。与该装置相关的两个不良事件发生在单个患者中：轻度喉咙痛和植入部位附近的中度压痛。这些事件并不严重，可以预见并得到解决。结论：在这项首次人体长期扩展研究中，神经免疫调节在多药难治性RA患者中具有良好的耐受性，临床疾病活动性降低维持了36个月。

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来源期刊

Rheumatology and Therapy RHEUMATOLOGY-

CiteScore

6.00

自引率

5.30%

发文量

审稿时长

6 weeks

期刊介绍： Aims and Scope Rheumatology and Therapy is an international, open access, peer reviewed, rapid publication journal dedicated to the publication of high-quality clinical (all phases), observational, real-world and health outcomes research around the discovery, development, and use of rheumatologic therapies. Studies relating to diagnosis, pharmacoeconomics, public health, quality of life, and patient care, management, and education are also welcomed. Areas of focus include, but are not limited to, rheumatoid arthritis, gout, gouty arthritis, psoriatic arthritis, osteoarthritis, juvenile idiopathic/rheumatoid arthritis, systemic lupus erythematosus, axial spondyloarthritis, Pompe’s disease, inflammatory joint conditions, musculoskeletal conditions, systemic sclerosis, and fibromyalgia. The journal is of interest to a broad audience of healthcare professionals and publishes original research, reviews, case reports, trial protocols, communications and letters. The journal is read by a global audience and receives submissions from all over the world. Rheumatology and Therapy will consider all scientifically sound research be it positive, confirmatory or negative data. Submissions are welcomed whether they relate to an international and/or a country-specific audience, something that is crucially important when researchers are trying to target more specific patient populations. This inclusive approach allows the journal to assist in the dissemination of all scientifically and ethically sound research. Ethics and Disclosures The journal is a member of the Committee on Publication Ethics (COPE) and subscribes to its principles on how to deal with acts of misconduct thereby committing to investigate allegations of misconduct in order to ensure the integrity of research. Content in this journal is peer-reviewed (Single-blind). For more information on our publishing ethics policies, please see here: https://www.springer.com/gp/editorial-policies Rapid Publication The journal’s rapid publication timelines aim for a peer review decision within 2 weeks of submission. If an article is accepted it will be published online 3-4 weeks from acceptance. These rapid timelines are achieved through the combination of a dedicated in-house editorial team, who closely manage article workflow, and an extensive Editorial and Advisory Board who assist with rapid peer review. This allows the journal to support the rapid dissemination of research, whilst still providing robust peer review. Combined with the journal’s open access model this allows for the rapid and efficient communication of the latest research and reviews, allowing the advancement of rheumatologic therapies. Personal Service The journal’s dedicated in-house editorial team offer a personal “concierge service” meaning that authors will always have a personal point of contact able to update them on the status of their manuscript. The editorial team check all manuscripts to ensure that articles conform to the most recent COPE, GPP and ICMJE publishing guidelines. This supports the publication of ethically sound and transparent research. We also encourage pre-submission enquiries and are always happy to provide a confidential assessment of manuscripts. Digital Features Rheumatology and Therapy offers a range of additional features designed to increase the visibility, readership and educational value of the journal’s content. Each article is accompanied by key summary points, giving a time-efficient overview of the content to a wide readership. Articles may be accompanied by plain language summaries to assist readers who have some knowledge of, but not in-depth expertise in, the area to understand the scientific content and overall implications of the article. The journal also provides the option to include various types of digital features including animated abstracts, video abstracts, slide decks, audio slides, instructional videos, infographics, podcasts and animations. All additional features are peer reviewed to the same high standard as the article itself. If you consider that your paper would benefit from the inclusion of a digital feature, please let us know. Our editorial team are able to create high-quality slide decks and infographics in-house, and video abstracts through our partner Research Square, and would be happy to assist in any way we can. For further information about digital features, please contact the journal editor (see ‘Contact the Journal’ for email address), and see the ‘Guidelines for digital features and plain language summaries’ document under ‘Submission guidelines’. For examples of digital features please visit: https://springerhealthcare.com/expertise/publishing-digital-features/ Preprints We encourage posting of preprints of primary research manuscripts on preprint servers, authors'' or institutional websites, and open communications between researchers whether on community preprint servers or preprint commenting platforms. Posting of preprints is not considered prior publication and will not jeopardize consideration in our journals. Authors should disclose details of preprint posting during the submission process or at any other point during consideration in the journal. 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At least two extensive reviews are required to make the editorial decision. Where reviewer recommendations are conflicted, the editorial board will be contacted for further advice and a presiding decision. Manuscripts are then either accepted, rejected or authors are required to make major or minor revisions (both reviewer comments and editorial comments may need to be addressed). Once a revised manuscript is re-submitted, it is assessed along with the responses to reviewer comments and if it has been adequately revised it will be accepted for publication. Accepted manuscripts are then copyedited and typeset by the production team before online publication. Appeals against decisions following peer review are considered on a case-by-case basis and should be sent to the journal editor, and authors are welcome to make rebuttals against individual reviewer comments if appropriate. Considering the time and effort required for a detailed peer review we reward our regular reviewers with the opportunity to publish without publication fees (pending peer review) for every three reviews completed per calendar year. Copyright Rheumatology and Therapy is published under the Creative Commons Attribution-Noncommercial License, which allows users to read, copy, distribute, and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited. The author assigns the exclusive right to any commercial use of the article to Springer. For more information about the Creative Commons Attribution-Noncommercial License, click here: http://creativecommons.org/licenses/by-nc/4.0. Publication Fees Upon acceptance of an article, authors will be required to pay the mandatory Rapid Service Fee of €5,250/$6,000/£4,300. The journal will consider fee discounts and waivers for developing countries and this is decided on a case-by-case basis. Open Access All articles published by Rheumatology and Therapy are published open access. Contact For more information about the journal, including pre-submission enquiries, please contact charlotte.maddocks@springernature.com.