Highlights
- The first large randomized, double-blind, placebo-controlled trial demonstrated that perispinal administration of etanercept is safe but does not improve quality of life in patients with chronic stroke.
- No significant difference in improvement of SF-36v2 scores was observed between etanercept and placebo groups at 28 days post-injection.
- Recruitment challenges limited patient numbers, but the study provided Class I evidence discouraging the routine clinical use of perispinal etanercept for chronic stroke impairments.
- Although TNF-α inhibition is mechanistically plausible for reducing post-stroke inflammation, clinical efficacy requires further exploration and alternative delivery or targets.
Background
Stroke is one of the most prevalent causes of long-term disability worldwide, often resulting in persistent neurological deficits and reduced quality of life (QoL). Despite advances in acute stroke management, effective treatments targeting chronic post-stroke impairments remain limited. Neuroinflammation plays a pivotal role in secondary injury cascade post-stroke, with tumor necrosis factor-alpha (TNF-α) identified as a key pro-inflammatory cytokine contributing to neuronal damage and functional deficits.
Etanercept, a recombinant fusion protein acting as a competitive inhibitor of TNF-α, is approved for inflammatory diseases including rheumatoid arthritis. Preclinical studies and preliminary clinical observations suggested that targeted TNF-α inhibition via perispinal subcutaneous delivery could bypass the blood-brain barrier, potentially ameliorating chronic stroke-related neurological dysfunctions. This rationale prompted rigorous evaluation through randomized controlled trials to determine the safety and efficacy of perispinal etanercept in this setting.
Key Content
Clinical Trial Evidence: The Perispinal Etanercept for Stroke Outcomes Study (2020–2023)
The pivotal study by Thijs et al. (2025) was a randomized, double-blind, placebo-controlled, parallel group trial conducted across three ambulatory clinical research sites in Australia and New Zealand. It enrolled adult patients aged 18–70 years who had experienced ischemic or hemorrhagic stroke between 1 and 15 years prior, a modified Rankin Scale (mRS) score of 2–5, and demonstrably reduced quality of life as assessed by the 36-Item Short Form Survey version 2 (SF-36v2).
Patients (N=126) were randomized in a 1:1 ratio to receive a single 25 mg perispinal injection of etanercept or placebo, and followed for safety and efficacy outcomes at days 28 and 56 post-injection. The primary outcome was the proportion of participants achieving a ≥5-point improvement in SF-36v2 QoL score at 28 days relative to baseline.
Efficacy Outcomes
Contrary to earlier observational reports and smaller pilot studies, the trial found no statistically significant difference between treatment groups for QoL improvement. Specifically, 53% of patients in the etanercept arm demonstrated the primary outcome versus 58% in the placebo group (adjusted odds ratio 0.82, 95% CI 0.40–1.67). Secondary analyses of other functional and clinical parameters similarly showed no meaningful benefit with etanercept.
Safety Outcomes
The incidence of serious adverse events was comparable between study arms over 28 days, indicating that a single dose of perispinal etanercept had an acceptable safety profile in this population.
Supporting Evidence and Context
Prior to this trial, the Perispinal Etanercept to Improve Stroke Outcomes (PESTO) protocol outlined a multicenter, international effort to robustly evaluate perispinal etanercept’s safety and efficacy (Rothwell et al., 2024). Smaller open-label and observational studies had suggested symptomatic improvements in some post-stroke impairments with such TNF-α blockade, but the heterogeneous and uncontrolled nature limited wider clinical acceptance.
Furthermore, the role of TNF-α antagonists in other inflammatory and cardiovascular conditions, including rheumatoid arthritis and heart failure, supports their pharmacological safety but illustrates the complexity of translating anti-inflammatory effects into clinical benefit for heterogeneous neurological diseases (Weisman et al., 1999; Smith et al., 2023).
Methodological Considerations and Limitations
Although the study was terminated early due to funding constraints, recruitment of 126 patients allowed for a sufficiently powered analysis for the primary outcome. The randomized, double-blind design and intention-to-treat analysis enhance the trial’s methodological rigor.
However, challenges include the chronicity and heterogeneity of stroke pathology, possible suboptimal dosing or administration frequency (single injection), and the relatively short primary endpoint period (28 days). These factors may limit detection of subtle or delayed therapeutic effects.
Expert Commentary
The negative efficacy findings from this rigorously designed RCT challenge earlier optimistic reports from uncontrolled studies regarding perispinal etanercept for chronic stroke. This underlines the importance of well-conducted randomized trials to validate novel therapies before broad clinical application.
Mechanistically, while TNF-α is implicated in post-stroke neuroinflammation, the ability of etanercept to penetrate the central nervous system sufficiently via perispinal subcutaneous injection remains debatable. In addition, stroke pathophysiology is multifactorial, involving excitotoxicity, oxidative stress, and microvascular dysfunction, which may not be fully addressed by TNF-α antagonism alone.
Current stroke rehabilitation guidelines do not recommend TNF-α inhibitors for chronic stroke impairments, reflecting insufficient evidence of efficacy. This trial’s results further support this stance. Nonetheless, modulation of neuroinflammation remains a promising research avenue, encouraging exploration of alternative anti-inflammatory agents, delivery methods, or combination therapies.
Conclusion
The Perispinal Etanercept for Stroke Outcomes trial provides Class I evidence confirming the safety but refuting the efficacy of a single 25 mg perispinal etanercept injection in improving quality of life in patients with chronic ischemic or hemorrhagic stroke. This finding highlights the critical need for large-scale, methodologically robust trials in evaluating innovative treatments targeting post-stroke neuroinflammation.
Future research should focus on optimizing drug delivery strategies, identifying patient subgroups that may benefit, longer follow-up periods, and multi-modal approaches integrating pharmacological and rehabilitative therapies to address complex sequelae of chronic stroke.
References
- Thijs VN, Cloud GC, Gilchrist N, Parsons B, Tilvawala F, Ho JK, et al. Safety and Efficacy of Perispinal Etanercept for Chronic Stroke: A Randomized Clinical Trial. Neurology. 2025 Sep 23;105(6):e213981. doi: 10.1212/WNL.0000000000213981. PMID: 40906977; PMCID: PMC12418806.
- Rothwell PM, Bernhardt J, Bath PMW, et al. Perispinal Etanercept to improve STroke Outcomes (PESTO): Protocol for a multicenter, international, randomized placebo-controlled trial. Eur Stroke J. 2024 Sep;9(3):789-795. doi: 10.1177/23969873241249248. PMID: 38676623.
- Weisman MH, Bowman L, et al. Safety and efficacy of a soluble P75 tumor necrosis factor receptor (Enbrel, etanercept) in patients with advanced heart failure. Circulation. 1999 Jun 29;99(25):3224-6. doi: 10.1161/01.cir.99.25.3224. PMID: 10385494.
- Smith T, Patel K, et al. Rheumatoid arthritis disease activity and adverse events in patients receiving tofacitinib or tumor necrosis factor inhibitors: analysis of ORAL Surveillance. Ther Adv Musculoskelet Dis. 2023 Nov 6;15:1759720X231201047. doi: 10.1177/1759720X231201047. PMID: 37942277.