Acta Dermato-Venerelogica Issue No 7, 2017 97-7CompleteContent | Page 20

CLINICAL REPORT Efficacy of Botulinum Toxin B Injection for Raynaud’s Phenomenon and Digital Ulcers in Patients with Systemic Sclerosis Sei-ichiro MOTEGI 1 , Akihito UEHARA 1 , Kazuya YAMADA 1 , Akiko SEKIGUCHI 1 , Chisako FUJIWARA 1 , Sayaka TOKI 1 , Yuki DATE 2 , Tetsuya NAKAMURA 2 and Osamu ISHIKAWA 1 Department of Dermatology, and 2 Clinical Investigation and Research Unit, Gunma University Graduate School of Medicine, Maebashi, Japan 1 The efficacy and safety of botulinum toxin B (BTX-B) for treatment of Raynaud’s phenomenon and digital ulcers in patients with systemic sclerosis was asses- sed. A total of 45 patients with systemic sclerosis who had Raynaud’s phenomenon were blinded and divided randomly into 4 groups: a no-treatment control group, and 3 treatment groups, using 250, 1,000 or 2,000 in- ternational units (U) of BTX-B injections in the hand with more severe symptoms. Four weeks after injec- tion, pain/numbness visual analogue scale scores and Raynaud’s score in the groups treated with 1,000 and 2,000 U BTX-B were significantly lower than in the control group and the group treated with 250 U BTX-B. These beneficial effects were sustained until 16 weeks after the single injection. At 4 weeks after injection skin temperature recovery in the group treated with 2,000 U BTX-B was significantly improved. The num- bers of digital ulcers in the groups treated with 1,000 and 2,000 U BTX-B were significantly lower than in the control group. In conclusion, 1,000 and 2,000 U BTX- B injections significantly suppressed the activity of Raynaud’s phenomenon and digital ulcers in patients with SSc without serious adverse events. Key words: systemic sclerosis; botulinum toxin B; Raynaud’s phenomenon; digital ulcers; clinical trial. Accepted Mar 27, 2017; Epub ahead of print Mar 30, 2017 Acta Derm Venereol 2017; 97: 843–850. 843 Corr: Sei-ichiro Motegi, Department of Dermatology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan. E-mail: [email protected] S ystemic sclerosis (SSc) is an autoimmune gene- ralized connective tissue disorder characterized by vascular dysfunction, and fibrosis of the skin and internal organs (1–3). More than 90% of patients with SSc develop Raynaud’s phenomenon (RP) and often develop digital ulcers (DUs). Several studies have reported that SSc patients with chronic DUs tend to have complications, including interstitial lung disease (ILD), cardiac involvement and decreased survival (4, 5). Cold exposure or emotional stress induce spasmodic contraction of the peripheral vessels that supply blood to the skin of the fingers and toes. The pathogenesis of RP in SSc is complex and still undetermined. It has been suggested that episodic vasospasm may be caused by dysregulation of the balance between vasoconstric- tion and vasodilation, and that dysregulation of the autonomic nervous response may be involved in the pathogenesis of RP (6). It has also been suggested that cold- or stress-induced noradrenaline stimulates adrenergic receptor α (ARα) on pericytes and/or vas- cular smooth muscle cells, resulting in vasoconstriction (7, 8). In addition, ARα responses are increased in the digital arteries in patients with SSc (8), suggesting that noradrenaline might be involved in the pathogenesis of RP in SSc. We reported recently that noradrenaline is also associated with the pathogenesis of fibrosis in SSc (9). Noradrenaline and other neurotransmitters, including substance P, glutamate, and calcitonin gene- related peptide, are increased in peripheral nerves of the affected skin and induce severe pain and numbness of fingers in patients with RP (10–14). Pharmacological treatments of RP have targeted the regulation of vasodilation and/or vasoconstriction, and calcium channel blockers, antiplatelet agents, sarpogre- late hydrochloride, cilostazol, and oral and intravenous prostanoids have been administered. The endothelin receptor antagonist bosentan and phosphodiesterase-5 inhibitors may be beneficial for functional impairment in patients with SSc-related RP (15, 16). However, a satisfactory outcome for RP in SSc remains elusive. Se- veral recent studies have shown the beneficial effects of botulinum toxin-A (BTX-A) on RP in patients with SSc (17–24). BTX-A at a dose of 10–100 international units (U) per hand on each neurovascular bundle at the level of the metacarpophalangeal joint was injected in patients with SSc with RP. The majority reported an improvement in severe resting pain and a reduction in the frequencies of RP. DU was also healed after BTX-A injection. There were a few adverse effects, such as intrinsic weakness and dysesthesia. However, these symptoms disappeared within 2–5 months after treatment. These results suggest that BTX-A might have therapeutic potential for RP and RP-related DU in patients with SSc. Of 7 serotypes of BTX (A–G), BTX-A and BTX-B have been used widely for various therapeutic and cos- metic i ndications. BTX-A and BTX-B cleave SNARE proteins SNAP-25 and VAMP, respectively (25). Se- veral studies demonstrated that the efficacy of BTX-B treatment appeared sooner than that of BTX-A, and that BTX-B was more effective than BTX-A in patients with diseases regulated by the autonomic nervous system (26–28). However, the efficacy of BTX-B injection for RP has not been examined. The objective of this study This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2017 Acta Dermato-Venereologica. doi: 10.2340/00015555-2665 Acta Derm Venereol 2017; 97: 843–850