Clinical bottom line
Refractory Raynaud’s phenomenon (RP) in systemic sclerosis (SSc) remains a challenging clinical problem with significant morbidity, including digital ulcers and ischemic complications. Emerging therapies such as botulinum toxin B injections show promise in improving symptoms and reducing ulcer burden in patients unresponsive to conventional vasodilatory treatments. However, evidence is limited to small trials and observational studies, and the pathophysiology of refractory RP in SSc involves complex ischemic and immune-mediated mechanisms that may require multimodal therapeutic approaches. Clinicians should consider novel therapies as adjuncts in refractory cases while awaiting larger controlled trials.
What the evidence shows
Raynaud’s phenomenon in systemic sclerosis is characterized by episodic digital ischemia triggered by vasospasm, progressing in some patients to persistent ischemia and tissue injury (Pauling et al., 2020). The transition from primary vasospastic RP to secondary ischemic vasculopathy in SSc involves an “ischemic switch” mediated by autoallergic mast cell activation and endothelial dysfunction (Artlett et al., 2026). This complex pathophysiology underpins the refractory nature of RP in some patients despite standard vasodilator therapy.
Botulinum toxin B (BTX-B) injections have been investigated as a novel local therapy targeting neurovascular dysregulation. In a single-blind randomized trial, Perera Buddhini et al. (2017) demonstrated that BTX-B injections significantly improved RP severity scores and reduced the frequency of digital ulcers in SSc patients with refractory RP compared to placebo. The treatment was generally well tolerated, with transient local weakness as the main adverse event. These findings suggest BTX-B may modulate sympathetic nerve-mediated vasoconstriction and improve digital blood flow.
Imaging modalities such as multispectral imaging and optical coherence tomography angiography have enhanced understanding of microvascular changes in SSc-related RP and may help distinguish refractory cases from primary RP (Erturk et al., 2023; Rheumatology, 2015). These tools could facilitate early identification of patients likely to benefit from novel therapies.
Case reports and clinical images further illustrate the severe ischemic complications of refractory RP in SSc, including painful digital ulcers and tissue loss (Wigley et al., 2011; Sia et al., 2026). These underscore the unmet clinical need for effective interventions beyond standard vasodilators.
Caveats and uncertainty
The evidence base for novel therapies in refractory RP is limited by small sample sizes, short follow-up durations, and heterogeneous patient populations. The BTX-B trial by Perera Buddhini et al. (2017) was single-blind and relatively small, warranting confirmation in larger, double-blind randomized controlled trials. Long-term safety and optimal dosing regimens remain unclear.
The pathophysiology of refractory RP in SSc is multifactorial, involving immune, vascular, and neural components. Thus, single-agent therapies may have limited efficacy in isolation. The role of combination therapy targeting multiple pathways requires further study.
Imaging techniques, while promising for diagnosis and monitoring, are not yet standardized or widely available in clinical practice. Their utility in guiding therapy decisions remains investigational.
How this may change practice
For rheumatologists managing patients with SSc and refractory RP, botulinum toxin B injections represent a promising adjunctive therapy to consider, particularly in those with recurrent digital ulcers or severe ischemic symptoms unresponsive to calcium channel blockers and phosphodiesterase inhibitors. Referral to specialized centers with expertise in BTX-B administration and microvascular imaging may optimize patient selection and outcomes.
Ongoing research into the ischemic switch and immune mechanisms in SSc-related RP may lead to targeted therapies addressing underlying vasculopathy and inflammation. Clinicians should remain alert to emerging evidence and incorporate novel diagnostic tools to better stratify risk and personalize treatment.
Ultimately, a multidisciplinary approach combining vascular specialists, rheumatologists, and wound care teams is essential for managing refractory RP and preventing complications.