Botulinum toxin injection for refractory Raynaud phenomenon and digital ulcers in systemic sclerosis.

Abstract

Systemic sclerosis (SSc) is an autoimmune connective tissue disease characterized by tissue and organ fibrosis and vasculopathy.1 Digital ulcers (DU) and Raynaud phenomenon (RP) are the presentations of vasculopathy found in SSc. Raynaud phenomenon is a process in which extremities undergo an episodic color change upon cold exposure. As a result, patients suffer from severe pain and disability, which markedly impairs their life quality. The mechanism of SSc-related RP comprises amplified sympathetic-mediated vasoconstriction and dysfunctional endothelial cells.2 Digital ulcers occur in around half of SSc cases, they result in complications such as pain, impaired function, and even gangrenous changes.1 Nowadays, calcium-channel blockers, prostacyclin analogs, endothelin receptor antagonists, and phosphodiesterase inhibitors are the primary pharmacological treatments for DU and RP.3 Surgical intervention such as sympathectomy is indicated for severe cases that are refractory to medical management. Nevertheless, intractable RP and DU still pose a significant challenge in clinical practice. There is preliminary evidence that SSc-related peripheral vasculopathy benefits from local injections of botulinum toxin (BTX). Studies propose that BTX could target sympathetic adrenergic vasoconstriction and endothelial exocytosis to induce therapeutic effects on RP/DU.2 In the past two decades, several clinical trials have been conducted to determine if local injections with BTX into hands could be efficacious in controlling intractable RP/DU in patients with SSc.4-8 BTX injection protocol differed between clinical trials. Most clinical trials used BTX-A, whereas Motegi et al chose BTX-B.5 Both dorsal and palmar approaches were introduced regarding injection sites on hands. Some studies selected injection sites near the neurovascular plexus. BTX dosages in former clinical trials were heterogeneous, ranging from 20 to 100 units per hand; however, whether the efficacy of BTX injections was dose-dependent required further investigation. Motegi et al5 suggested that the improvements in RP/DU were more remarkable in the intervention group with higher doses. Most clinical trials selected participants who were refractory to traditional drug therapy, and vasoactive drugs were continued during the trials. Hence, whether BTX injection efficacy is derived from BTX alone or combined with other vasoactive drugs needs to be clarified. Follow-up time points varied between trials, ranging from 1 to 4 months. Different follow-up time points may affect the study results because the effects of RP/DU might decrease with time. For example, Motegi et al proposed that the efficacy of local BTX injections could sustain for 4 months, whereas Dhaliwal et al found that hand function decreased by 3 months after BTX injections.5, 9 The outcome assessments use aspects such as RP severity, tissue perfusion, and hand function (Table 1). Standard measures for RP severity include the Raynaud condition score and visual analog scale. Most clinical trials reported a statistically significantly faster decline of Raynaud condition score in patients with BTX injections, including clinical trials published in 2022.7, 8 An improved pain score was presented in several studies, but some did not reach statistical significance. As for tissue perfusion, it was measured by methods such as change in blood flow with laser Doppler imaging and pulse oximetry. Picasso et al10 suggested that a newly developed ultrasound technique using ultra-high frequency has the potential to disclose subtle abnormalities in distal digital arterioles. The study by Bello et al4 was one of the best-conducted studies in which blood flow change was set as the primary outcome. However, the results showed that local BTX injections did not significantly improve blood flow to the patients’ hands. Decreased DU number after BTX injection therapy was reported in many clinical studies.5, 6 Regarding hand function, the “Quick Disabilities of the Arm, Shoulder and Hand” questionnaire (QuickDASH) was the most used outcome measure. Many clinical trials also reported significantly improved QuickDASH scores after BTX therapy. It is noteworthy that the ethnicity of enrolled participants differed between clinical trials. Emil et al11 proposed that the ethnic, genetic, and population variables could affect the onset, prevalence, and outcomes of SSc. As a result, the role of ethnicity and genetic background cannot be ignored when evaluating the outcomes of BTX injections. Local BTX injections seem to be safe in most trials. Reported complications included pain and weakness over injected hands. Shenavandeh et al6 suggested that BTX injections were cost-effective and time-saving. Local injections could be performed at outpatient departments, which is especially convenient during the COVID-19 pandemic. In conclusion, a few clinical trials support the efficacy of BTX local injections for RP/DU in SSc patients. Local BTX injections have emerged as a safe and cost-effective nonsurgical treatment for refractory SSc-related RP/DU. However, more extensive double-blinded randomized controlled trials are still required to confirm the benefits of BTX injections and propose the optimal injection protocol.