Botulinum Toxin for Refractory Digital Ischemia and Ulcers in Systemic Sclerosis

Importance Acute digital ischemia, digital ulcers, and gangrene are debilitating complications of systemic sclerosis and other vasculopathies and are often refractory to standard vasodilator and immunosuppressive therapies. Botulinum toxin (BTX) has emerged as a potential rescue therapy, but its clinical effectiveness and safety remain unclear. Objective To evaluate the effectiveness and safety of BTX injections for ischemic digital complications and identify predictors of treatment response using individual participant data (IPD). Data Sources MEDLINE (PubMed), Embase (Ovid), and Scopus were searched from inception through April 20, 2024. Study Selection Eligible studies included patients who presented with acute digital ischemia, ischemic digital ulcers, or gangrene. Studies were limited to Raynaud disease without digital ulcers or gangrene were excluded. Two reviewers independently screened articles using Covidence, with discrepancies resolved by consensus with the senior author. Of 116 studies screened, 31 (27%) met inclusion criteria. Data Extraction and Synthesis Data were extracted in duplicate and study quality was assessed using the Joanna Briggs Institute checklist. Descriptive statistics were used to summarize baseline characteristics, treatment regimens, and outcomes. Main Outcomes and Measures The primary outcome was complete response (CR), which was defined as resolution of ischemia or ulcer healing. Secondary outcomes included adverse events and time to response. Cox regression was used to identify factors associated with CR. Results This systematic review and IPD meta-analysis included 119 patients (72 female individuals [75.0%]; mean [SD] age, 49.0 [15.1] years). BTX was associated with high CR rates for ischemia (93.1%), ulcers (90.1%), and gangrene (87.5%). Adverse events were infrequent, with transient muscle weakness (7.6%) and injection site pain (5.9%) being most common. No associated factors reached statistical significance in multivariable models, but autoimmune etiology and younger age were associated with faster response in Kaplan-Meier analyses. Conclusions and Relevance The results of this systematic review and IPD meta-analysis suggest that BTX injections appear to be a safe and effective adjunct for refractory digital ischemia in systemic sclerosis. Prospective trials are needed to confirm long-term effectiveness and standardize administration protocols.