. 2023 Dec 1;62(12):3785-3800.

doi: 10.1093/rheumatology/kead289.

Systemic pharmacological treatment of digital ulcers in systemic sclerosis: a systematic literature review

Laura Ross¹, Nancy Maltez², Michael Hughes^{3

4}, Jan W Schoones⁵, Murray Baron⁶, Lorinda Chung⁷, Dilia Giuggioli⁸, Pia Moinzadeh⁹, Yossra A Suliman¹⁰, Corrado Campochiaro¹¹, Yannick Allanore¹², Christopher P Denton^{13

14}, Oliver Distler¹⁵, Tracy Frech¹⁶, Daniel E Furst¹⁷, Dinesh Khanna¹⁸, Thomas Krieg⁸, Masataka Kuwana¹⁹, Marco Matucci-Cerinic²⁰, Janet Pope²¹, Alessia Alunno^{22

23}

Affiliations

¹ Department of Medicine and Rheumatology, University of Melbourne at St Vincent's Hospital, Melbourne, Victoria, Australia.
² Department of Medicine, Division of Rheumatology, Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada.
³ Department of Rheumatology, Northern Care Alliance NHS Foundation Trust, Salford Care Organisation, Salford, UK.
⁴ Division of Musculoskeletal and Dermatological Sciences, University of Manchester, Manchester, UK.
⁵ Directorate of Research Policy (formerly Walaeus Library), Leiden University Medical Center, Leiden, The Netherlands.
⁶ Division of Rheumatology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
⁷ Department of Rheumatology, Stanford University School of Medicine and Palo Alto VA Health Care System, Palo Alto, CA, USA.
⁸ Department of Rheumatology, Division of Rheumatology, University of Modena and Reggio Emilia, Policlinico of Modena, Modena, Italy.
⁹ Department of Dermatology and Venereology, University Hospital Cologne, Cologne, Germany.
¹⁰ Department of Rheumatology and Rehabilitation, Assiut University Hospital, Assiut, Egypt.
¹¹ Department of Immunology, Rheumatology, Allergy and Rare Diseases, Raffaele Hospital, Vita-Salute San Raffaele Università, Milan, Italy.
¹² Department of Rheumatology, Cochin Hospital, AP-HP, Paris Descartes University, Paris, France.
¹³ Centre for Rheumatology and Connective Tissue Diseases, Royal Free Hospital, London, UK.
¹⁴ UCL Division of Medicine, University College London, London, UK.
¹⁵ Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
¹⁶ Department of Medicine, Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Veterans Affairs Medical Center, Nashville, TN, USA.
¹⁷ Department of Rheumatology and Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁸ Department of Rheumatology, University of Michigan, Ann Arbor, MI, USA.
¹⁹ Department of Allergy and Rheumatology, Nippon Medical School, Tokyo, Japan.
²⁰ Department of Experimental and Clinical Medicine, Division of Rheumatology, Careggi University Hospital, University of Florence, Florence, Italy.
²¹ Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
²² Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.
²³ Internal Medicine and Nephrology Division, ASL1 Avezzano-Sulmona-L'Aquila, L'Aquila, Italy.

PMID: 37335850
PMCID: PMC10691932
DOI: 10.1093/rheumatology/kead289

Systemic pharmacological treatment of digital ulcers in systemic sclerosis: a systematic literature review

Laura Ross et al. Rheumatology (Oxford). 2023.

. 2023 Dec 1;62(12):3785-3800.

doi: 10.1093/rheumatology/kead289.

Authors

Affiliations

¹ Department of Medicine and Rheumatology, University of Melbourne at St Vincent's Hospital, Melbourne, Victoria, Australia.
² Department of Medicine, Division of Rheumatology, Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada.
³ Department of Rheumatology, Northern Care Alliance NHS Foundation Trust, Salford Care Organisation, Salford, UK.
⁴ Division of Musculoskeletal and Dermatological Sciences, University of Manchester, Manchester, UK.
⁵ Directorate of Research Policy (formerly Walaeus Library), Leiden University Medical Center, Leiden, The Netherlands.
⁶ Division of Rheumatology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
⁷ Department of Rheumatology, Stanford University School of Medicine and Palo Alto VA Health Care System, Palo Alto, CA, USA.
⁸ Department of Rheumatology, Division of Rheumatology, University of Modena and Reggio Emilia, Policlinico of Modena, Modena, Italy.
⁹ Department of Dermatology and Venereology, University Hospital Cologne, Cologne, Germany.
¹⁰ Department of Rheumatology and Rehabilitation, Assiut University Hospital, Assiut, Egypt.
¹¹ Department of Immunology, Rheumatology, Allergy and Rare Diseases, Raffaele Hospital, Vita-Salute San Raffaele Università, Milan, Italy.
¹² Department of Rheumatology, Cochin Hospital, AP-HP, Paris Descartes University, Paris, France.
¹³ Centre for Rheumatology and Connective Tissue Diseases, Royal Free Hospital, London, UK.
¹⁴ UCL Division of Medicine, University College London, London, UK.
¹⁵ Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
¹⁶ Department of Medicine, Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Veterans Affairs Medical Center, Nashville, TN, USA.
¹⁷ Department of Rheumatology and Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁸ Department of Rheumatology, University of Michigan, Ann Arbor, MI, USA.
¹⁹ Department of Allergy and Rheumatology, Nippon Medical School, Tokyo, Japan.
²⁰ Department of Experimental and Clinical Medicine, Division of Rheumatology, Careggi University Hospital, University of Florence, Florence, Italy.
²¹ Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
²² Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.
²³ Internal Medicine and Nephrology Division, ASL1 Avezzano-Sulmona-L'Aquila, L'Aquila, Italy.

PMID: 37335850
PMCID: PMC10691932
DOI: 10.1093/rheumatology/kead289

Abstract

Objective: To evaluate the evidence concerning systemic pharmacological treatments for SSc digital ulcers (DUs) to inform the development of evidence-based treatment guidelines.

Methods: A systematic literature review of seven databases was performed to identify all original research studies of adult patients with SSc DUs. Randomized controlled trials (RCTs) and prospective longitudinal observational studies (OBSs) were eligible for inclusion. Data were extracted, applying the patient, intervention, comparison, outcome framework, and risk of bias (RoB) was assessed. Due to study heterogeneity, narrative summaries were used to present data.

Results: Forty-seven studies that evaluated the treatment efficacy or safety of pharmacological therapies were identified among 4250 references. Data from 18 RCTs of 1927 patients and 29 OBSs of 661 patients, at various RoB (total 2588 patients) showed that i.v. iloprost, phosphodiesterase-5 inhibitors and atorvastatin are effective for the treatment of active DUs. Bosentan reduced the rate of future DUs in two RCTs (moderate RoB) and eight OBSs at low to high RoB. Two small studies (moderate RoB) indicate that Janus kinase inhibitors may be effective for the treatment of active DUs, otherwise there are no data to support the use of immunosuppression or anti-platelet agents in the management of DUs.

Conclusion: There are several systemic treatments, across four medication classes, that are effective therapies for the management of SSc DUs. However, a lack of robust data means it is not possible to define the optimal treatment regimen for SSc DUs. The relatively low quality of evidence available has highlighted further areas of research need.

Keywords: SSc (scleroderma); digital ulcers; management; pharmacotherapy; systemic treatment.

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Figures

**Figure 1.**
PRISMA flowchart of study selection

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Systemic pharmacological treatment of digital ulcers in systemic sclerosis: a systematic literature review

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Systemic pharmacological treatment of digital ulcers in systemic sclerosis: a systematic literature review

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