Reumatología Clínica

Reumatología Clínica

Volume 17, Issue 6, June–July 2021, Pages 357-363
Reumatología Clínica

Review Article
Is 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

https://doi.org/10.1016/j.reuma.2020.04.006Get rights and content

Abstract

Introduction

In systemic sclerosis (SSc), peripheral vasculopathy presents typically as Raynaud Phenomenon (RP) and Digital Ulceration (DU). Over the last decade, botulinum toxin (BT) has been reported effective in this scenario. Our goal was to review existing literature evaluating the efficacy of BT on RP/DU in SSc.

Materials and methods

We performed a search in Pubmed with the MeSH terms “systemic sclerosis” and “botulinum toxin”. Original studies evaluating BT in the treatment of SSc-associated RP/DU were considered for inclusion. Results were screened by title, abstract and full-text.

Results

We identified 30 results, of which 5 original papers were included: 2 randomized controlled trials (RCT), 2 case series and 1 case control study, from a total of 133 patients. Only one RCT showed negative results, with worse blood flow in treated arm, but with lower dose of BT. Despite this, all 5 included studies reported improvement of at least 1 RP/hand function outcome measure. Concerning DU healing, resolution of baseline DU at the end of follow-up was reported in 75–100% of the patients, with 1 RCT showing superiority over placebo. The only reported adverse effect was transient hand weakness, affecting only 0–16.7% of patients. BT injection protocols were highly heterogeneous.

Conclusion

Despite conflicting results in 1 RCT, evidence points BT as an option in the treatment of SSc-related peripheral vasculopathy. However, future larger prospective trials are necessary to corroborate this hypothesis.

Resumen

Introducción

En la esclerosis sistémica (ES), la vasculopatía periférica se presenta normalmente como fenómeno de Raynaud (FR) y ulceración digital (UD). En el último decenio se ha reportado la efectividad de la toxina botulínica (TB) en este escenario. Nuestro objetivo fue revisar la literatura existente que evalúa la eficacia de la TB en el FR/UD en la ES.

Materiales y métodos

Realizamos una búsqueda en Pubmed con los términos MeSH «esclerosis sistémica» y «toxina botulínica». Se consideraron para inclusión los estudios originales que evaluaban la TB en el tratamiento del FR/UD asociados a ES. Se cribaron los resultados por título, resumen y texto completo.

Resultados

Identificamos 30 resultados, de los cuales se incluyeron 5 documentos originales: 2 ensayos controlados aleatorizados (ECA), 2 series de casos y un estudio de control de caso, de un total de 133 pacientes. Únicamente un ECA reflejó resultados negativos con peor flujo sanguíneo en el brazo tratado, aunque con menor dosis de TB. A pesar de ello, los 5 estudios incluidos reportaron una mejora de al menos una medida del resultado FR/función de la mano. En cuanto a la sanación de la UD, la resolución de la UD basal al final del seguimiento se reportó en el 75-100% de los pacientes, y un ECA reflejó superioridad con respecto al placebo. El único efecto adverso reportado fue debilidad transitoria en la mano, que afectó únicamente al 0-16,7% de los pacientes. Los protocolos de inyección de la TB fueron altamente homogéneos.

Conclusión

A pesar de los resultados conflictivos en un ECA, la evidencia apunta a la TB como opción para el tratamiento de la vasculopatía periférica asociada a la ES. Sin embargo, son necesarios ensayos prospectivos futuros más amplios para corroborar esta hipótesis.

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

  • Treatment of peripheral vasculopathy (RP/DU) in SSc can pose a difficult challenge in clinical practice.

  • BT, through inhibition of sympathetic adrenergic vasoconstriction and endothelin-1, has emerged as an alternative treatment in this scenario.

  • 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.

  • 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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  • Cited by (0)

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