Review ArticleIs Botulinum Toxin Useful in Systemic Sclerosis Related Peripheral Vasculopathy? A Literature Review¿Es la toxina botulínica útil en la vasculopatía periférica de la esclerosis sistémica? Una revisión sistemática
Introduction
Systemic sclerosis (SSc) is an orphan connective tissue disease where diffuse microangiopathy and immune system dysregulation result in collagen hyperproduction with skin and internal organs fibrosis.1 Raynaud Phenomenon (RP) is a consequence of peripheral microvasculopathy, triggered by endothelium dysfunction.1, 2 It is highly prevalent in SSc (95% of patients) and consists on an episodic colour change of the extremities in response to cold exposure.3 Moreover, it is typically the initial manifestation and precedes by years major organ involvement.1 Digital ulcers (DU) are a serious consequence of SSc related vasculopathy. They occur in up to 58% of patients, either in the diffuse or limited subtype. With an extended time to healing, DU may result in critical ischaemia and soft tissue/bone infections, thus demanding aggressive treatment. Moreover, they also point to a worse prognosis.4
As vascular injury performs a major role in SSc pathogenesis, several treatment options focuses on it, not only for RP and DU, but also pulmonary arterial hypertension. Nowadays, calcium channel blockers, prostacyclin analogues, endothelin receptor antagonists and phosphodiesterase inhibitors are the main pharmacologic representatives to target this pathway.5 Nevertheless, in daily clinical practice, RP and DU still pose a challenge for both physicians and patients.
In the last two decades, botulinum toxin (BT) has emerged as a nonsurgical treatment for vasospastic disease.6Through local hand injections, numerous reports showed an improvement in RP severity and DU healing,6, 7 including in patients with SSc.
The aim of this review was to evaluate the available evidence concerning the use of BT in the treatment of SSc related RP/DU.
Section snippets
Data source and search strategy
A literature review was devised, fitting the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines in order to identify all full-text manuscripts that focused on the use of BT in the treatment of SSc related RP/DU. The search was performed on Pubmed, with the following MeSH terms: ‘systemic sclerosis’ and ‘botulinum toxin’, with the boolean term “AND”. No other keywords were added, in order to avoid an excessively restrictive search string that would exclude
Results
Thirty results were obtained from the search through Pubmed. No article was obtained by reference checking. After the screening phase, 5 reports were considered for the qualitative analysis (see Fig. 1). Ratings according to the NIH are presented in supplement 1. Only 1 was considered as Good Quality.8
Discussion
BT first emerged in the 1970s in the treatment of strabismus, as it prevents muscular contraction by inhibiting the release of acetylcholine in the neuromuscular junctions.13 This mechanism justifies most of the clinical indications of this neurotoxin.14, 15 However, evidence suggests the additional role of pain transmission blockage (for example, substance P).16, 17, 18 BT also inhibits sympathetic adrenergic vasoconstriction and endothelial exocytosis of endothelin-1,19 through a
Conclusion
Despite not conclusive, evidence suggests that BT has a position to claim in the treatment of SSc-related vasculopathy – it may not be necessarily an anchor therapy, but an effective and safe adjuvant to the vasodilating drugs presently recommended in the treatment of RP/DU. However, in face of conflicting results of one RCT, more robust studies are needed to clarify its true efficacy, as well as the optimal dose and injection protocol.
Key points
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Treatment of peripheral vasculopathy (RP/DU) in SSc can pose a difficult challenge in clinical practice.
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BT, through inhibition of sympathetic adrenergic vasoconstriction and endothelin-1, has emerged as an alternative treatment in this scenario.
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Current evidence supports a positive effect of BT on RP severity and DU healing, but is held back by several methodological limitations of the studies performed to date.
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Future investigation is required to further clarify the findings of this review,
Contributions
MG – Ideation of the study, substantial contributions to the design of the study, acquisition of data, analysis and interpretation of data, drafting of the article, critical revision of the intellectual content, final approval of the version to be published.
DF – Acquisition of data, substantial contributions to the design of the study, acquisition of data, analysis and interpretation of data, critical revision of the intellectual content, final approval of the version to be published.
BS –
Funding
No funding received.
Conflict of interest
None to declare.
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