Background: Digital ulcers (DU) are common in systemic sclerosis (SSc) and associated with reduced survival, high morbidity and poor quality of life. Recommendations have previously been proposed for DU management yet there remains significant unmet patient need. Therefore the World Scleroderma Foundation DU Working Group intends to develop practical evidence based recommendations for DU management.

Objectives: To summarise data on efficacy and safety of systemic treatments for SSc DU.

Methods: A systematic literature review to May 2021 was performed. PubMed, MEDLINE, Embase, Web of Science, Cochrane Library, Emcare (OVID) and Academic Search Premier databases were searched for original studies on adult patients with SSc DU treated with systemic pharmacological treatment. Based on the PICO framework, eligibility criteria were defined and references were independently screened by two reviewers. Reviewers independently assessed the full text of eligible articles. Owing to interstudy heterogeneity narrative summaries were used to present data.

Results: The search strategy identified 1271 references of which 45 eligible articles were included. Seventeen studies were randomised placebo controlled trials (RCT) pertaining to PDE5 antagonists (PDE5i) (n=3), endothelin receptor antagonists (ERA) (n=3), prostanoids (n=7), antiplatelet agents (n=1) and other (n=3) ( Table 1 ). No head to head RCT was retrieved. All other studies were observational studies (OBS). Studies were highly heterogeneous with application of differing definition of DU, variable study eligibility criteria, clinical endpoints and follow up periods. This limited the calculation of effect size and comparison across studies.

Several RCT found improved DU healing with treatment: two with PDE5i, one with iloprost and one showed improved DU healing and prevention with atorvastatin. Two RCT demonstrated effective prevention of new DU with bosentan. OBS studies with a total of 621 patients showed variable improvements in the healing of DU with CCB, PDE5i, ERA, statins, N-acetylcysteine, prostanoids and ketanserin and prevention of new DU with ERA.

Regarding safety, all treatments were generally tolerated with few serious adverse events. Treatment was ceased in 6.25-17.5% of patients in RCT due to treatment related side effects.

Conclusion: Despite several studies assessing the efficacy and safety of systemic pharmacological treatment of SSc DU, it is not possible to draw solid conclusions due to study heterogeneity. Small RCT have shown treatment benefit with PDE5i, iloprost and atorvastatin. Large studies demonstrated effective prevention of new DU with bosentan. Our results highlight the urgent need for improved clinical trial design to generate more robust evidence and novel therapies to guide the management SSc DU.

Acknowledgements: This work was supported by the World Scleroderma Foundation.

Disclosure of Interests: Nancy Maltez: None declared, Laura Ross: None declared, Michael Hughes Speakers bureau: Actelion Pharmaceuticals, Eli Lilly and Pfizer outside of the submitted work., Jan Schoones: None declared, Murray Baron: None declared, Lorinda Chung Consultant of: Eicos, Corrado Campochiaro: None declared, Yossra A. Suliman: None declared, Dilia Giuggioli: None declared, Pia Moinzadeh Speakers bureau: Actelion Pharmaceuticals, Boehringer Ingelheim, Yannick Allanore: None declared, Christopher P Denton: None declared, Oliver Distler Speakers bureau: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Medscape, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Prometheus, Roivant, Sanofi and Topadur., Consultant of: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Medscape, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Prometheus, Roivant, Sanofi and Topadur., Grant/research support from: Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143), Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Medscape, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Prometheus, Roivant, Sanofi and Topadur., Tracy Frech: None declared, Daniel Furst: None declared, Dinesh Khanna Consultant of: Eicos Sciences Inc, Janssen, Thomas Krieg: None declared, Masataka Kuwana Speakers bureau: Speaker fees from AbbVie, Asahi Kasei Pharma, Astellas, Boehringer Ingelheim, Chugai, Eisai, GlaxoSmithKline, Janssen, Nippon Shinyaku, Ono Pharmaceuticals, Tanabe-Mitsubishi, and consultancy fees from AstraZeneca, Boehringer Ingelheim, Corbus, Kissei, Mochida outside of the submitted work., Marco Matucci-Cerinic: None declared, Janet Pope: None declared, Alessia Alunno: None declared