Novel In-Office Injectables for the Dermatology–Rheumatology Patient: Botulinum Toxin, Sodium Thiosulfate, and Hyaluronidase
Abstract
Patients with systemic sclerosis (SSc) and related systemic autoimmune rheumatic diseases experience cutaneous complications that systemic immunosuppression and vasodilators frequently fail to control. These include refractory Raynaud phenomenon with digital ischemia, calcinosis cutis, and perioral fibrosis with microstomia. Three physician-administered injectable therapies can be readily incorporated in a routine dermatology office at modest cost using widely available equipment: botulinum toxin A (BoNT-A) for digital ischemia, sodium thiosulfate (STS) for calcinosis cutis, and hyaluronidase for microstomia. All three treatments are used off-label, and are supported primarily by observational evidence. This review summarizes the mechanistic rationale, current evidence, injection technique, dosing, and safety of each agent, supplemented by practical observations derived from five years of clinical experience.
References
Del Galdo F, Lescoat A, Conaghan PG, Bertoldo E, Čolić J, Santiago T, et al. EULAR recommendations for the treatment of systemic sclerosis: 2023 update. Ann Rheum Dis. 2025;84(1):29-40. doi:10.1136/ard-2024 226430
Hundal S, Cappelli J, Zhu C, Netchiporouk E. Comparative value of botulinum toxin versus traditional systemic vasodilators for digital ulcers in systemic sclerosis. J Am Acad Dermatol. 2026;95(2):561-564. doi:10.1016/j.jaad.2026.04.1934
Zhu C, Peri K, Silotch C, Prosty C, BinJadeed H, Muntyanu A, et al. Botulinum toxin for refractory digital ischemia and ulcers in systemic sclerosis: a systematic review and meta-analysis. JAMA Dermatol. 2026;162(1):47-54. doi:10.1001/ jamadermatol.2025.4929. Erratum in: JAMA Dermatol. 2026;162(1):103. doi:10.1001/jamadermatol.2025.5957
Zhou Y, Liu Y, Hao Y, Feng Y, Pan L, Liu W, et al. The mechanism of botulinum A on Raynaud syndrome. Drug Des Devel Ther. 2018;12:1905-1915. doi:10.2147/ DDDT.S161113
Matak I, Bölcskei K, Bach-Rojecky L, Helyes Z. Mechanisms of botulinum toxin type a action on pain. Toxins (Basel). 2019;11(8). doi:10.3390/ toxins11080459
Zhou Y, Yu Y, Bi S, Cen Y. Botulinum toxins for the treatment of Raynaud Phenomenon: a systematic review with meta-analysis. J Clin Rheumatol. 2023;29(5):e92-e99. doi:10.1097/ RHU.0000000000001965
Pinto-Pulido EL, Polo-Rodríguez I, García-Verdú E, Merlo-Gómez P, Martínez-Alcalde L, Ruiz-Gutiérrez L, et al. Botulinum toxin for Raynaud’s phenomenon: a decade of real-world evidence. J Am Acad Dermatol. 2025;92(1):173-175. doi:10.1016/j.jaad.2024.09.034
Curtiss P, Svigos K, Schwager Z, Lo Sicco K, Franks AG Jr. Part II: the treatment of primary and secondary Raynaud’s phenomenon. J Am Acad Dermatol. 2024;90(2):237-248. doi:10.1016/j.jaad.2022.05.067
Koshy JC, Sharabi SE, Feldman EM, Hollier LH Jr, Patrinely JR, Soparkar CNS. Effect of dietary zinc and phytase supplementation on botulinum toxin treatments. J Drugs Dermatol. 2012;11(4):507-512.
Cohen JL. Scientific skepticism and new discoveries: an analysis of a report of zinc/phytase supplementation and the efficacy of botulinum toxins in treating cosmetic facial rhytides, hemifacial spasm and benign essential blepharospasm. J Cosmet Laser Ther. 2014;16(5):258-262. doi:10.3109/14764172.2014.94 8882
Mallat F, Kaikati J, Kechichian E. Botulinum toxins and zinc: from theory to practice-a systematic review. Clin Neuropharmacol. Published online June 20, 2023. doi:10.1097/WNF.0000000000000557
Traineau H, Aggarwal R, Monfort JB, Senet P, Oddis CV, Chizzolini C, et al. Treatment of calcinosis cutis in systemic sclerosis and dermatomyositis: a review of the literature. J Am Acad Dermatol. 2020;82(2):317 325. doi:10.1016/j.jaad.2019.07.006
Winter AR, Klager S, Truong R, Foley A, Sami N, Weinstein D. Efficacy of intralesional sodium thiosulfate for the treatment of dystrophic calcinosis cutis: a double-blind, placebo-controlled pilot study. JAAD Int. 2020;1(2):114-120. doi:10.1016/j. jdin.2020.07.002
Gunasekera NS, Maniar LEG, Lezcano C, Laga AC, Merola JF. Intralesional sodium thiosulfate treatment for calcinosis cutis in the setting of lupus panniculitis. JAMA Dermatol. 2017;153(9):944-945. doi:10.1001/ jamadermatol.2017.0966
Giacometti E, Martineau J, Petrou IG, Kalbermatten DF, Scampa M. Calcinosis cutis universalis: a review of therapeutic strategies and surgical management. J Clin Med. 2026;15(3). doi:10.3390/jcm15030959
Davuluri S, Lood C, Chung L. Calcinosis in systemic sclerosis. Curr Opin Rheumatol. 2022;34(6):319-327. doi:10.1097/BOR.0000000000000896
Ricardo JW, Sun HY, Gorji M, Sebaratnam DF. Topical sodium thiosulfate as treatment of calcinosis cutis: case series and systematic review. J Am Acad Dermatol. 2022;87(2):443-444. doi:10.1016/j. jaad.2021.09.013
Di Donato S, Alegre-Sancho JJ, Batalov A, Batalov Z, Bellando-Randone S, Coccia C, et al. Longitudinal clinical response to Janus kinase inhibitors in systemic sclerosis: a real-life multicentric study across multiple clinical domains. Clin Rheumatol. 2026;45(7):4335-4344. doi:10.1007/s10067-026 08168-x
Webber J, Meran S, Steadman R, Phillips A. Hyaluronan orchestrates transforming growth factor-beta1 dependent maintenance of myofibroblast phenotype. J Biol Chem. 2009;284(14):9083-9092. doi:10.1074/ jbc.M806989200
Melvin OG, Hunt KM, Jacobson ES. Hyaluronidase treatment of scleroderma-induced microstomia. JAMA Dermatol. 2019;155(7):857-859. doi:10.1001/ jamadermatol.2019.0585
Min MS, Goldman N, Mazori DR, Guo LN, Vleugels RA, LaChance AH. Hyaluronidase Injections for Oral Microstomia in Systemic Sclerosis and Mixed Connective Tissue Disease. JAMA Dermatol. 2023;159(12):1393-1395. doi:10.1001/ jamadermatol.2023.3893
Zhu C, Barnawi G, Grigorchuk E, Bendayan E, Peri K, Lagacé F, et al. Hyaluronidase for microstomia in fibrosing skin disease: systematic review and case series. JAAD Int. 2025;24:287-290. doi:10.1016/j. jdin.2025.11.012 .
