Botulinum Toxin in the Treatment of Raynaud Phenomenon in SSc

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Botulinum Toxin in the Treatment of Raynaud Phenomenon in Patients with Systemic Sclerosis: A Systematic Review

Raynaud phenomenon (RP), a transient vasospastic disorder, is a hallmark manifestation of systemic sclerosis (SSc). Characterized by episodic digital ischemia triggered by cold or stress, RP in SSc patients often progresses to recurrent digital ulcers (DUs) and critical ischemic complications. Conventional therapies, including lifestyle modifications, vasodilatory medications, and surgical interventions, frequently fail to achieve rapid symptom relief or prevent ischemic damage. Botulinum toxin (BTX), a neurotoxin with vasodilatory and antinociceptive properties, has emerged as a promising treatment for refractory SSc-associated RP (SSc-RP). This systematic review synthesizes evidence on BTX’s efficacy, optimal administration protocols, and safety in managing SSc-RP.

Methodology

The review was prospectively registered on PROSPERO (ID: CRD42020158574). A comprehensive search strategy combining terms such as “scleroderma,” “systemic sclerosis,” “SSc,” “botulinum toxin,” and “clostridium botulinum toxins” was applied to PubMed, Cochrane Library, Embase, and Web of Science (January 2021). Studies published between 1995 and 2021 were screened, yielding 251 initial records. After applying inclusion criteria—studies focusing on BTX for SSc-RP with clinical outcomes—five articles (three case series, two randomized controlled trials [RCTs]) involving 155 patients were selected. Risk of bias assessment revealed variability in study designs, with case series demonstrating higher bias risks compared to RCTs.

Patient Characteristics and Disease Severity

The cohort comprised 89.7% females (139/155) and 10.3% males (16/155), reflecting the female predominance in SSc. All patients had severe, treatment-refractory SSc-RP, with many experiencing recurrent DUs unresponsive to standard therapies. Subgroup analyses highlighted that patients with diffuse SSc subtype or prolonged RP duration (>15.56 years) exhibited poorer responses to BTX, suggesting disease chronicity and subtype influence therapeutic outcomes.

BTX Administration Protocols

Studies utilized varying BTX formulations, doses, and injection techniques:

  • BTX Type: Four studies used BTX-A (onabotulinumtoxinA), while one RCT employed BTX-B (rimabotulinumtoxinB).
  • Dosing:
    • BTX-A: Doses ranged from 10 to 100 units per hand. Case series reported efficacy even at lower doses (10–50 units), while an RCT testing 50–100 units found nonsignificant improvements.
    • BTX-B: Doses of 250–2000 units were tested, with 1000–2000 units showing superior efficacy in improving skin temperature and reducing DU counts.
  • Injection Sites:
    • Palmar Approach: Three studies injected BTX into the palmar neurovascular bundles near the metacarpophalangeal joints, targeting digital arteries.
    • Dorsal Approach: Two studies administered BTX dorsally near the proximal phalanx base, but one RCT using this method reported nonsignificant outcomes, suggesting palmar injections may optimize drug delivery to affected vasculature.

Clinical Outcomes

Symptom Improvement

Four studies (115 patients) demonstrated BTX’s efficacy in alleviating RP symptoms. Primary endpoints included Raynaud Condition Score (frequency, duration, pain, color changes), pain Visual Analog Scale (VAS), and DU healing. Key findings:

  • Raynaud Score Reduction: Motegi et al. (2016) reported significant post-BTX improvements in Raynaud scores (p<0.05), with sustained effects for 4–6 months.
  • Pain Relief: Pain VAS scores decreased by 30–50% within 2–4 weeks post-injection. Uppal et al. (2014) noted pain improvement in 80% of patients.
  • DU Healing: Complete ulcer healing occurred in 75% of patients within 12 weeks, particularly in studies using palmar BTX-A injections.

Functional and Vascular Improvements

  • Hand Function: Uppal et al. observed enhanced finger mobility and grip strength in 70% of patients.
  • Thermal Recovery: Skin temperature recovery after cold challenge improved by 1.5–2.5°C in BTX groups compared to controls.

Comparative Efficacy of BTX-A vs. BTX-B

BTX-B required higher doses (20–40× BTX-A) for comparable effects. Motegi et al. (2017) found 1000–2000 units of BTX-B reduced DU counts by 60% and accelerated temperature recovery. Despite pharmacological differences, both serotypes showed similar safety profiles.

Safety and Tolerability

Adverse events were mild and transient, including injection-site pain (15–20%), bruising (10%), and transient hand weakness (5%). No systemic toxicity or anaphylaxis was reported. Higher BTX-B doses (2000 units) correlated with increased minor side effects but no dose-limiting toxicities.

Limitations and Future Directions

Heterogeneity in injection protocols, small sample sizes, and limited long-term data constrain definitive conclusions. The sole negative RCT (Bello et al., 2017) highlighted the need for standardized protocols, as dorsal injections and patient selection (e.g., advanced SSc) may underlie nonsignificant results. Future studies should prioritize:

  1. Dose Optimization: Head-to-head trials comparing BTX-A and BTX-B dosing.
  2. Injection Standardization: Palmar vs. dorsal approaches, ultrasound-guided techniques.
  3. Predictive Biomarkers: Identifying responders via capillaroscopy or vascular imaging.
  4. Long-Term Outcomes: Durability beyond 6 months and effects on disease progression.

Conclusion

BTX injections offer a safe, effective adjunct for severe SSc-RP, particularly in patients with DUs and rapid symptom progression. Palmar BTX-A injections (50–100 units) or BTX-B (1000 units) provide optimal symptom relief and ulcer healing, with effects lasting 4–6 months. While current evidence supports BTX’s role in refractory cases, multicenter RCTs with standardized protocols are essential to establish consensus guidelines and expand access to this promising therapy.

doi.org/10.1097/CM9.0000000000001903

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