Pharmacological management of digital ulcers in systemic sclerosis - what is new?

References

• Hughes M, Allanore Y, Chung L, et al. Raynaud phenomenon and digital ulcers in systemic sclerosis. Nature Reviews Rheumatol. 2020;16(4):208–221. DOI:10.1038/s41584-020-0386-4
   PubMed Web of Science ®Google Scholar
• Nihtyanova SI, Brough GM, Black CM, et al. Clinical burden of digital vasculopathy in limited and diffuse cutaneous systemic sclerosis. Ann Rheum Dis. 2008;67(1):120–123.
   PubMed Web of Science ®Google Scholar
• Matucci-Cerinic M, Krieg T, Guillevin L, et al. Elucidating the burden of recurrent and chronic digital ulcers in systemic sclerosis: long-term results from the DUO Registry. Ann Rheum Dis. 2016;75(10):1770–1776. DOI:10.1136/annrheumdis-2015-208121
   PubMed Web of Science ®Google Scholar
• Castellvi I, Eguiluz S, Escudero-Contreras A, et al. LAUDES Study: impact of digital ulcers on hand functional limitation, work productivity and daily activities, in systemic sclerosis patients. Rheumatol Int. 2019;39(11):1875–1882. DOI:10.1007/s00296-019-04436-z
   PubMed Web of Science ®Google Scholar
• Hughes M, Pauling JD, Jones J, et al. Multicenter qualitative study exploring the patient experience of digital ulcers in systemic sclerosis. Arthritis Care Res. 2020;72(5):723–733. DOI:10.1002/acr.24127
   Web of Science ®Google Scholar
• van Leeuwen NM, Ciaffi J, Liem SIE, et al. Health-related quality of life in patients with systemic sclerosis: evolution over time and main determinants. Rheumatology. 2021;60(8):3646–3655. DOI:10.1093/rheumatology/keaa827
   PubMed Web of Science ®Google Scholar
• Morrisroe K, Stevens W, Sahhar J, et al. Digital ulcers in systemic sclerosis: their epidemiology, clinical characteristics, and associated clinical and economic burden. Arthritis Res Ther. 2019;21(1):299. DOI:10.1186/s13075-019-2080-y
   PubMed Web of Science ®Google Scholar
• Nevskaya T, Calderon LM, Baron M, et al. on behalf of the canadian scleroderma research group. Health care utilization in systemic sclerosis patients with digital ulcers. Arthritis Care Research. 2022. doi:10.1002/acr.24902.
   Web of Science ®Google Scholar
• Suliman AS, Bruni C, Johnson SR, et al. Defining skin ulcers in systemic sclerosis: systematic literature review and proposed world scleroderma foundation (WSF) Definition. J Scleroderma Relat Disord. 2017;2(2):115–120. DOI:10.5301/jsrd.5000236
   PubMedGoogle Scholar
• Hughes M, Tracey A, Bhushan M, et al. Reliability of digital ulcer definitions as proposed by the UK scleroderma study group: a challenge for clinical trial design. J Scleroderma Relat Disord. 2018;3(2):170–174. DOI:10.1177/2397198318764796
   PubMed Web of Science ®Google Scholar
• Hughes M, Murray A, Denton CP, et al. Should all digital ulcers be included in future clinical trials of systemic sclerosis-related digital vasculopathy? Med Hypotheses. 2018;116:101–104.
   PubMed Web of Science ®Google Scholar
• Korn JH, Mayes M, Matucci-Cerinic M, et al. Digital ulcers in systemic sclerosis. Prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum. 2004;50(12):3985–3993. DOI:10.1002/art.20676
   PubMed Web of Science ®Google Scholar
• Matucci-Cerinic M, Denton CP, Furst DE, et al. Bosentan treatment of digital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial. Ann Rheum Dis. 2011;70(1):32–38. DOI:10.1136/ard.2010.130658
   PubMed Web of Science ®Google Scholar
• Hachulla E, Hatron P-Y, Carpentier P, et al. Efficacy of sildenafil on ischaemic digital ulcer healing in systemic sclerosis: the placebo controlled SEDUCE study. Ann Rheum Dis. 2016;75(6):1009–1015. DOI:10.1136/annrheumdis-2014-207001
   PubMed Web of Science ®Google Scholar
• Khanna D, Denton CP, Merkel PA, et al. Effect of macitentan on the development of new ischemic digital ulcers in patients with systemic sclerosis. DUAL-1 and DUAL-2 randomized clinical trials. JAMA. 2016;315:1975–1988.
   PubMed Web of Science ®Google Scholar
• Seibold JR, Wigley FM, Schiopu E, et al. Digital ulcers in SSc treated with oral treprostinil: a randomized, double-blind, placebo-controlled study with open-label follow-up. J Scleroderma Relat Disord. 2017;2(1):42–49. DOI:10.5301/jsrd.5000232
   Google Scholar
• Barsotti S, Venturini V, Di Battista M, et al. The impact of skin calcinosis on digital ulcers in patients with SSc: clinical and prognostic stratification using the “wound bed score”. Int Wound J. 2020;17(6):1783–1790. DOI:10.1111/iwj.13467
   PubMed Web of Science ®Google Scholar
• Giuggioli D, Magnani L, Spinella A, et al. Infections of scleroderma digital ulcers: a single center cohort retrospective study. Dermatol Reports. 2021;13:9075.
   PubMedGoogle Scholar
• Giuggioli D, Manfredi A, Colaci M, et al. Osteomyelitis complicating scleroderma digital ulcers. Clin Rheumatol. 2013;32(5):623–627. DOI:10.1007/s10067-012-2161-7
   PubMed Web of Science ®Google Scholar
• Herrick AL. Raynaud’s phenomenon and digital ulcers: advances in evaluation and management. Curr Opin Rheumatol. 2021;33(6):453–462.
   PubMed Web of Science ®Google Scholar
• Lebedoff N, Frech TM, Shanmugam VK, et al. Review of local wound management for scleroderma-associated digital ulcers. J Scleroderma Relat Disord. 2018;3(1):66–70. DOI:10.5301/jsrd.5000268
   PubMed Web of Science ®Google Scholar
• Muir L, Herrick AL. Surgical approaches including sympathectomy. In: In: Matucci-Cerinic M Denton Ceditors Atlas of Ulcers in Systemic Sclerosis 2019. Springer;Cham:10.1007/978-3-319-98477-3_21
   Google Scholar
• Hughes M, Alcacer-Pitarch B, Gheorghiu AM, et al. Digital ulcer debridement in systemic sclerosis: a systematic literature review. Clin Rheumatol. 2020;39(3):805–811. DOI:10.1007/s10067-019-04924-4
   PubMed Web of Science ®Google Scholar
• Braschi F, Bartoli F, Bruni C, et al. Lidocaine controls pain and allows safe wound bed preparation and debridement of digital ulcers in systemic sclerosis: a retrospective study. Clin Rheumatol. 2017;36(1):209–212. DOI:10.1007/s10067-016-3414-7
   PubMed Web of Science ®Google Scholar
• Momeni A, Sorice SC, Valenzuela A, et al. Surgical treatment of systemic sclerosis - is it justified to offer peripheral sympathectomy earlier in the disease process? Microsurgery. 2015;35:441–446.
   PubMed Web of Science ®Google Scholar
• Daumas A, Magalon J, Jouve E, et al. Long-term follow-up after autologous adipose-derived stromal vascular fraction injection into fingers in systemic sclerosis patients. Current Res Translational Med. 2017;65(1):40–43. DOI:10.1016/j.retram.2016.10.006
   PubMed Web of Science ®Google Scholar
• Ahijon-Lana M, Baragano-Ordonez E, Veiga-Cabello R, et al. Treatment of raynaud phenomenon and ischemic ulcers associated to systemic sclerosis with hyperbaric oxygen. Reumatol Clin. 2022;18(4):246–248. DOI:10.1016/j.reumae.2021.05.004
   PubMed Web of Science ®Google Scholar
• van Rhijn-Brouwer FCC, Gremmels H, Fledderus JO, et al. A randomised placebo-controlled double-blind trial to assess the safety of intramuscular administration of allogeneic mesenchymal stromal cells for digital ulcers in systemic sclerosis: the MANUS Trial protocol. BMJ Open. 2018;8(8):e020479. DOI:10.1136/bmjopen-2017-020479
   PubMed Web of Science ®Google Scholar
• Costedoat I, Masson M, Barnetche T, et al. Locoregional treatments for digital ulcers in systemic sclerosis: a systematic review. Acta Derm Venereol. 2021;101(6):adv00478. DOI:10.2340/00015555-3839
   PubMedGoogle Scholar
• Rirash F, Tingey PC, Harding SE, et al. Calcium channel blockers for primary and secondary Raynaud’s phenomenon. Cochrane Database Syst Rev. 2017;12(12):CD000467. DOI:10.1002/14651858.CD000467.pub2
   PubMedGoogle Scholar
• Roustit M, Blaise S, Allanore Y, et al. Phosphodiesterase-5 inhibitors for the treatment of secondary Raynaud’s phenomenon: systematic review and meta-analysis of randomised trials. Ann Rheum Dis. 2013;72:1696–1699.
   PubMed Web of Science ®Google Scholar
• Khouri C, Lepelley M, Bailly S, et al. Comparative efficacy and safety of treatments for secondary Raynaud’s phenomenon: a systematic review and network meta-analysis of randomised trials. Lancet Rheumatol. 2019;1:e237–46.
   Google Scholar
• Kowal-Bielecka O, Fransen J, Avouac J, et al. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis. 2017;76:1327–1339.
   PubMed Web of Science ®Google Scholar
• de Vries-Bouwstra JK, Allanore Y, Matucci-Cerinic M, et al. Worldwide expert agreement on updated recommendations for the treatment of systemic sclerosis. J Rheumatol. 2020;47:249–254.
   PubMed Web of Science ®Google Scholar
• Walker KM, Pope J, participating members of the Scleroderma Clinical Trials Consortium (SCTC); Canadian Scleroderma Research Group (CSRG). Treatment of systemic sclerosis complications: what to use when first-line treatment fails–a consensus of systemic sclerosis experts. Sem Arthritis Rheum. 2012;42:42–45.
   PubMed Web of Science ®Google Scholar
• Fernandez-Codina A, Walker KM, Pope JE, et al. Treatment algorithms for systemic sclerosis according to experts. Arthritis Rheum. 2018;70:1820–1828.
   PubMed Web of Science ®Google Scholar
• Tingey T, Shu J, Smuczek J, et al. Meta-analysis of healing and prevention of digital ulcers in systemic sclerosis. Arthritis Care Res. 2013;65:1460–1471.
   PubMed Web of Science ®Google Scholar
• Denton CP, Hughes M, Gak N, et al. BSR and BHPR guideline for the treatment of systemic sclerosis. Rheumatology. 2016;55:1906–1910.
   PubMed Web of Science ®Google Scholar
• Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022;43:3618–3731.
   PubMed Web of Science ®Google Scholar
• Phat TN, Luong VH, Minh VN, et al. Bosentan versus nifedipine in the treatment of vasculopathy in systemic sclerosis patients: a randomized control trial. Asian Pac J Allergy Immunol. 2022. DOI:10.12932/AP-070722-1406)
   PubMedGoogle Scholar
• Clinical commissioning policy: sildenafil and bosentan for the treatment of digital ulceration in systemic sclerosis in adults reference: nHS England 210302P [1911] first published: may 2021 version number: 1.0. https://www.england.nhs.uk/wp-content/uploads/2022/01/clinical-commissioning-policy-sildenafil-bosentan-treatment-of-digitalulceration-in-systemic-sclerosis.pdf
   Google Scholar
• Chang SH, Jun JB, Lee YJ, et al. A clinical comparison of an endothelin receptor antagonist and phosphodiesterase type 5 inhibitors for treating digital ulcers of systemic sclerosis. Rheumatology. 2021;60:5814–5819.
   PubMed Web of Science ®Google Scholar
• Curtiss P, Schwager Z, Lo Sicco K, et al. The clinical effects of l-arginine and asymmetric dimethylarginine: implications for treatment in secondary Raynaud’s phenomenon. J Eur Acad Dermatol Venereol. 2019;33:497–503.
   PubMed Web of Science ®Google Scholar
• Teh L-S, Manning J, Moore T, et al. Sustained-release transdermal glyceryl trinitrate patches as a treatment for primary and secondary Raynaud’s phenomenon. Br J Rheumatol. 1995;34:636–641.
   PubMedGoogle Scholar
• Anderson ME, Moore TL, Hollis S, et al. Digital vascular response to topical glyceryl trinitrate, as measured by laser Doppler imaging, in primary Raynaud’s phenomenon and systemic sclerosis. Rheumatology. 2002;41:324–328.
   PubMed Web of Science ®Google Scholar
• Hughes M, Moore T, Manning J, et al. Reduced perfusion in systemic sclerosis digital ulcers (both fingertip and extensor) can be increased by topical application of glyceryl trinitrate. Microvasc Research. 2017;111:32–36.
   PubMed Web of Science ®Google Scholar
• Moinzadeh P, Riemekasten G, Siegert E, et al. Vasoactive therapy in systemic sclerosis: real-life therapeutic practice in more than 3000 patients. J Rheumatol. 2016;43:66–74.
   PubMed Web of Science ®Google Scholar
• Panopoulos S, Chatzidionysiou K, Tektonidou MG, et al. Treatment modalities and drug survival in a systemic sclerosis real-life patient cohort. Arthritis Res Ther. 2020;22:56.
   PubMed Web of Science ®Google Scholar
• Blagojevic J, Abignano G, Avouac J, et al. Use of vasoactive/vasodilating drugs for systemic sclerosis (SSc)-related digital ulcers (DUs) in expert tertiary centres: results from the analysis of the observational real-life DeSScipher study. Clin Rheumatol. 2020;39:27–36.
   PubMed Web of Science ®Google Scholar
• Bellando-Randone S, Lepri G, Bruni C, et al. Combination therapy with bosentan and sildenafil improves Raynaud’s phenomenon and fosters the recovery of microvascular involvement in systemic sclerosis. Clin Rheumatol. 2016;35:127–132.
   PubMed Web of Science ®Google Scholar
• Rademacher JG, Wincup C, Tampe B, et al. Combination therapy with bosentan and sildenafil for refractory digital ulcers and Raynaud’s phenomenon in a 30-year-old woman with systemic sclerosis: case report and literature review. J Scleroderma Related Disorders. 2020;5:159–164.
   PubMed Web of Science ®Google Scholar
• Nagaraja V, Spino C, Bush E, et al. A multicenter randomized, double-blind, placebo-controlled pilot study to assess the efficacy and safety of riociguat in systemic sclerosis-associated digital ulcers. Arthritis Res Ther. 2019;21:202.
   PubMed Web of Science ®Google Scholar
• Wigley FM, Wise RA, Seibold JR, et al. Intravenous iloprost infusion in patients with Raynaud phenomenon secondary to systemic sclerosis. A multicenter, placebo-controlled, double-blind study. Ann Intern Med. 1994;120:199–206.
   PubMed Web of Science ®Google Scholar
• Pope J, Fenlon D, Thompson A, et al. Iloprost and cisaprost for Raynaud’s phenomenon in progressive systemic sclerosis. Cochrane Database Syst Rev. 2000;1998(2):CD000953.
   PubMedGoogle Scholar
• Tsou PS, Palisoc PJ, Flavahan NA, et al. Dissecting the cellular mechanism of prostacyclin analog iloprost in reversing vascular dysfunction in scleroderma. Arthritis Rheumatol. 2021;73:520–529.
   PubMed Web of Science ®Google Scholar
• Cruz JE, Ward A, Anthony S, et al. Evidence for the use of epoprostenol to treat Raynaud’s phenomenon with or without digital ulcers. Ann Pharmacother. 2016;50:1060–1067.
   PubMed Web of Science ®Google Scholar
• Law ST, Farber HW, Simms RW. Use of intravenous epoprostenol as a treatment for the digital vasculopathy associated with the scleroderma spectrum of diseases. J Scleroderma Relat Disord. 2017;2:208–212.
   Google Scholar
• Marasini B, Massarotti M, Bottasso B, et al. Comparison between iloprost and alprostadil in the treatment of Raynaud’s phenomenon. Scand J Rheumatol. 2004;33:253–256.
   PubMed Web of Science ®Google Scholar
• Bellando-Randone S, Bruni C, Lepri G, et al. The safety of iloprost in systemic sclerosis in a real-life experience. Clin Rheumatol. 2018;37:1249–1255.
   PubMed Web of Science ®Google Scholar
• Negrini S, Magnani O, Matucci-Cerinic M, et al. Iloprost use and medical management of systemic sclerosis-related vasculopathy in Italian tertiary referral centers: results from the PROSIT study. Clin Exp Med. 2019;19:357–366.
   PubMed Web of Science ®Google Scholar
• Barsotti S, Lorenzoni V, Di Battista M, et al. Prostanoids in scleroderma microangiopathy: clinical and pharmacoeconomic comparison between two intravenous regimens. Scand J Rheumatol. 2021;50:307–313.
   PubMed Web of Science ®Google Scholar
• Bixio R, Adami G, Bertoldo E, et al. Higher body mass index is associated with a lower iloprost infusion rate tolerance and higher iloprost-related adverse events in patients with systemic sclerosis. Ther Adv Musculoskelet Dis. 2022;14:1759720X221137125.
   PubMed Web of Science ®Google Scholar
• Schioppo T, Orenti A, Boracchi P, et al. Acute and chronic effects of two different intravenous iloprost regimens in systemic sclerosis: a pragmatic non-randomized trial. Rheumatology. 2018;57:1408–1416.
   PubMed Web of Science ®Google Scholar
• Ingegnoli F, Schioppo T, Allanore Y, et al. Practical suggestions on intravenous iloprost in Raynaud’s phenomenon and digital ulcer secondary to systemic sclerosis: systematic literature review and expert consensus. Sem Arthritis Rheum. 2019;48:686–693.
   PubMed Web of Science ®Google Scholar
• Jamart C, Levesque H, Thietart S, et al. Iloprost duration for digital ulcers in systemic sclerosis: french retrospective study at two centers and literature review. Frontiers Med. 2022;9:878970.
   Web of Science ®Google Scholar
• Fraticelli P, Martino GP, Murri M, et al. A novel iloprost administration method with portable syringe pump for the treatment of acral ulcers and Raynaud’s phenomenon in systemic sclerosis patients. A pilot study (ILOPORTA). Clin Exp Rheumatol. 2017;35(Suppl 106):173–178.
   PubMedGoogle Scholar
• Braga Temido MH F, Gomes M, Parente F, et al. Iloprost infusion through elastomeric pump in the treatment of Raynaud’s phenomenon and digital ulcers. J Scleroderma Rel Disord. 2019;4:NP1–4.
   Web of Science ®Google Scholar
• Shah AA, Schiopu E, Chatterjee S, et al. The recurrence of digital ulcers in patients with systemic sclerosis after discontinuation of oral treprostinil. J Rheumatol. 2016;43:1665–1671.
   PubMed Web of Science ®Google Scholar
• Ughi N, Crotti C, Ingegnoli F. Effectiveness and safety of oxycodone/naloxone in the management of chronic pain in patients with systemic sclerosis with recurrent digital ulcers: two case reports. Clinical Intervent Aging. 2016;11:307–311.
   PubMed Web of Science ®Google Scholar
• Abou-Raya A, Abou-Raya S, Helmii M. Statins: potentially useful in therapy of systemic sclerosis-related Raynaud’s phenomenon and digital ulcers. J Rheumatol. 2008;35:1801–1808.
   PubMed Web of Science ®Google Scholar
• Garaiman A, Steigmiller K, Gebhard C, et al. Use of platelet inhibitors for digital ulcers related to systemic sclerosis: eUSTAR study on derivation and validation of the DU-VASC model. Rheumatology. 2023;62(SI):SI91–100.
   PubMedGoogle Scholar
• Lautenbach G, Dobrota R, Mihai C, et al. Evaluation of botulinum toxin a injections for the treatment of refractory chronic digital ulcers in patients with systemic sclerosis. Clin Exp Rheumatol. 2020;38(Suppl 125):S154–60.
   PubMedGoogle Scholar
• Martina E, Diotallevi F, Radi G, et al. Therapeutic use of botulinum neurotoxins in dermatology: systematic review. Toxins (Basel). 2021;13:120.
   PubMed Web of Science ®Google Scholar
• Ennis D, Ahmad Z, Anderson MA, et al. Botulinum toxin in the management of primary and secondary Raynaud’s phenomenon. Best Practice Res Clin Rheum. 2021;35:101684.
   PubMed Web of Science ®Google Scholar
• Motegi SI, Sekiguchi A, Saito S, et al. Successful treatment of Raynaud’s phenomenon and digital ulcers in systemic sclerosis patients with botulinum toxin B injection: assessment of peripheral vascular disorder by angiography and dermoscopic image of nail fold capillary. J Dermatol. 2018;45:349–352.
   PubMed Web of Science ®Google Scholar
• Zhou Y, Liu Y, Hao Y, et al. The mechanism of botulinum a on Raynaud syndrome. Drug Des Dev Ther. 2018;12:1905–1915.
   PubMed Web of Science ®Google Scholar
• Shenavandeh S, Sepaskhah M, Dehghani S, et al. A 4-week comparison of capillaroscopy changes, healing effect, and cost-effectiveness of botulinum toxin-A vs prostaglandin analog infusion in refractory digital ulcers in systemic sclerosis. Clin Rheumatol. 2022;41:95–104.
   PubMed Web of Science ®Google Scholar
• Bello RJ, Cooney CM, Melamed E, et al. The therapeutic efficacy of botulinum toxin in treating scleroderma-associated Raynaud’s phenomenon: a randomized, double-blind, placebo-controlled clinical trial. Arthritis Rheum. 2017;69:1661–1669.
   PubMed Web of Science ®Google Scholar
• Senet P, Maillard H, Diot E, et al. Efficacy and safety of botulinum toxin in adults with Raynaud’s phenomenon secondary to systemic sclerosis: a multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum. 2023;75(3):459–467 .
   Web of Science ®Google Scholar
• Goldberg SH, Akoon A, Kirchner HL, et al. The effects of botulinum toxin a on pain in ischemic vasospasm. J Hand Surg Am. 2021;46:513.e1.
   Web of Science ®Google Scholar
• Bruni C, Ngcozana T, Braschi F, et al. Preliminary validation of the digital ulcer clinical assessment score in systemic sclerosis. J Rheumatol. 2019;46:603–608.
   PubMed Web of Science ®Google Scholar
• Mouthon L, Poiraudeau S, Vernon M, et al. Psychometric validation of the hand disability in systemic sclerosis-digital ulcers (HDISS-DU) patient-reported outcome instrument. Arthritis Res Ther. 2020;22:3.
   PubMed Web of Science ®Google Scholar
• Williams HJ, Furst DE, Dahl SL, et al. Double-blind, multicenter controlled trial comparing topical dimethyl sulfoxide and normal saline for treatment of hand ulcers in patients with systemic sclerosis. Arthritis & Rheumatism. 1985;28:308–314.
   PubMedGoogle Scholar
• Simpson V, Hughes M, Wilkinson J, et al. Quantifying digital ulcers in systemic sclerosis: reliability of computer-assisted planimetry in measuring lesion size. Arthritis Care Res. 2018;70:486–490.
   Web of Science ®Google Scholar
• Davison AK, Dinsdale G, New P, et al. Feasibility study of mobile phone photography as a possible outcome measure of systemic sclerosis-related digital lesions. Rheumatology Adv Practice. 2022;6(3):rkac105.
   Google Scholar
• Hughes M, Moore T, Manning J, et al. A pilot study using high-frequency ultrasound to measure digital ulcers: a possible outcome measure in systemic sclerosis clinical trials? Clin Exp Rheumatol. 2017;35(Suppl 106):S218–219.
   PubMedGoogle Scholar
• Suliman YA, Kafaja S, Fitzgerald J, et al. Ultrasound characterization of cutaneous ulcers in systemic sclerosis. Clin Rheumatol. 2018;37:1555–1561.
   PubMed Web of Science ®Google Scholar
• Barsotti S, d’Ascanio A, Valentina V, et al. Is there a role for laser speckle contrast analysis (LASCA) in predicting the outcome of digital ulcers in patients with systemic sclerosis? Clin Rheumatol. 2020;39:69–75.
   PubMed Web of Science ®Google Scholar
• Marjanovic E, Moore TL, Manning JB, et al. Systemic sclerosis-related digital ulcers: a pilot study of cutaneous oxygenation and perfusion. Rheumatology. 2020;59:3573–3575.
   PubMed Web of Science ®Google Scholar
• Fernandez-Codina A, Kazem M, Pope JE. Possible benefit of tadalafil cream for the treatment of Raynaud’s phenomenon and digital ulcers in systemic sclerosis. Clin Rheumatol. 2020;39:963–965.
   PubMed Web of Science ®Google Scholar
• Guigui A, Mazet R, Blaise S, et al. Treprotinil hydrogel iontophoresis in systemic sclerosis-related digital skin ulcers: a safety study. J Clin Pharmacol. 2020;60:758–767.
   PubMed Web of Science ®Google Scholar
• Spinella A, de Pinto M, Baraldi C, et al. Topical cannabidiol in the treatment of digital ulcers in patients with scleroderma: comparative analysis and literature review. Adv Skin Wound Care. 2023;36:18–23.
   PubMed Web of Science ®Google Scholar
• Naef R, Tenor H, Koch G. TOP-N53: a clinical drug candidate for the treatment of non-healing wounds. Chimia (Aarau). 2020;74:814–817.
   PubMed Web of Science ®Google Scholar
• Karalilova RV, Batalov ZA, Sapundzhieva TL, et al. Tofacitinib in the treatment of skin and musculoskeletal involvement in patients with systemic sclerosis, evaluated by ultrasound. Rheum Int. 2021;41:1743–1753.
   PubMed Web of Science ®Google Scholar
• Hou Z, Su X, Han G, et al. JAK1/2 inhibitor baricitinib improves skin fibrosis and digital ulcers in systemic sclerosis. Front Med (Lausanne). 2022;9:859330.
   PubMed Web of Science ®Google Scholar
• Seibold JR, Jageneau AH. Treatment of Raynaud’s phenomenon with ketanserin, a selective antagonist of the serotonin2 (5-HT2) receptor. Arthritis Rheum. 1984;27:139–146.
   PubMedGoogle Scholar
• Bruni C, Cometi L, Gigante A, et al. Prediction and primary prevention of major vascular complications in systemic sclerosis. Eur J Int Med. 2021;87:51–58.
   PubMed Web of Science ®Google Scholar
• Zanin-Silva DC, Santana-Goncalves M, Kawashima-Vasconcelos MY, et al. Management of endothelial dysfunction in systemic sclerosis: current and developing strategies. Frontiers Med. 2021;8:788250.
   PubMed Web of Science ®Google Scholar
• Di Luigi L, Sgro P, Duranti G, et al. Sildenafil reduces expression and release of IL-6 and IL-8 induced by reactive oxygen species in systemic sclerosis fibroblasts. Int J Molecular Sci. 2020;21:3161.
   PubMed Web of Science ®Google Scholar
• Herrick AL, Berks M, Taylor C. Quantitative nailfold capillaroscopy - update and possible next steps. Rheumatology. 2021;60:2054–2065.
   PubMed Web of Science ®Google Scholar