Botulinum toxin injections were associated with high complete response rates in patients with digital ischemia, ulcers, and gangrene, with few adverse events, according to a systematic review and individual participant data meta-analysis.
In an analysis of 31 studies including 119 patients, researchers evaluated botulinum toxin for acute digital ischemia, ischemic digital ulcers, and gangrene—conditions that often persist despite vasodilators and immunosuppressive therapy. Most patients were female (75%), with a mean age of 49 years, and systemic sclerosis was the most common underlying condition (61%).
The primary outcome—complete response, defined as resolution of ischemia or ulcer healing—was achieved in 93% of patients with acute digital ischemia, 90% of patients with ulcers, and 88% of patients with gangrene. Time to response varied by presentation, with the fastest improvement observed in acute ischemia (mean 12 days), followed by gangrene (25 days) and ulcers (54 days). Most patients required a single injection session.
Botulinum toxin was administered using multiple formulations, most commonly onabotulinumtoxinA. Injections were typically delivered to interdigital neurovascular bundles at doses of 5 to 10 units per digit side, with higher doses associated with higher complete response rates.
Subgroup findings suggested that treatment effects varied by etiology. Botulinum toxin demonstrated consistent benefits in autoimmune-related ischemia, including systemic sclerosis and other rheumatic diseases, where pain relief and tissue recovery were commonly observed. Responses were less consistent in patients with peripheral arterial disease, vasopressor-associated ischemia, and some drug-related cases.
Among patients with ulcers, 91 of 101 achieved complete reepithelialization, including many cases that had not responded to prior vasodilator therapy. Observational data showed response rates approaching 97% within 14 to 180 days. In patients with gangrene, complete response occurred in seven of eight cases, with the strongest responses observed in autoimmune-associated disease.
The individual participant data meta-analysis included 90 patients and used Cox proportional hazards models to evaluate predictors of response. No clinical variables—including age, sex, disease etiology, or dose—were significantly associated with time to complete response in multivariable analyses. However, Kaplan-Meier analyses showed faster responses among patients with autoimmune disease and younger patients with ulcers.
Adverse events were uncommon. Transient muscle weakness occurred in 8% of patients, and injection site pain in 6%. No systemic or irreversible adverse events were reported.
The analysis followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses individual participant data guidelines and included randomized trials, observational studies, case series, and case reports identified through MEDLINE, Embase, and Scopus from inception through April 20, 2024. Data extraction was performed in duplicate, and study quality was assessed using Joanna Briggs Institute tools.
Limitations included reliance on small, heterogeneous studies, variation in dosing and injection techniques, and incomplete individual-level data for approximately 40% of studies. Subgroup analyses, particularly for gangrene, were underpowered.
“Botulinum toxin demonstrates high efficacy and safety in treating digital ischemia, ulcers, and gangrene, particularly in autoimmune-mediated disease,” wrote lead study researcher Catherine Zhu, MD, of the Faculty of Medicine at McGill University in Canada, and colleagues.
Disclosures can be found in the published study.
Source: JAMA Dermatology