THERAPEUTIC APPROACHES IN SYSTEMIC SCLEROSIS – WHAT’S OLD AND WHAT’S NEW? A LITERATURE REVIEW
DOI:
https://doi.org/10.31435/ijitss.3(47).2025.3758Keywords:
Systemic Sclerosis, Biological Drugs, Disease-Modifying Anti-Rheumatic Drugs, Nintedanib, Tocilizumab, RituximabAbstract
Introduction: Systemic sclerosis (SSc) is an autoimmune disease that, because of its heterogeneity, presents clinicians with many therapeutic challenges. The hallmarks of its pathogenesis are vasculopathies, cutaneous or visceral fibrosis and the presence of scleroderma-related antibodies, however, the course of the disease is different in every case. Therefore it is important to adjust the treatment process individually to each patient's needs. In this manuscript we aim to describe options available for therapeutic management of SSc.
Materials and methods: An electronic literature search was performed using PubMed, Cochrane Library and Evidence-Based Medicine Reviews. Search terms included “systemic sclerosis”, “methotrexate”, “mycophenolate mofetil” “cyclophosphamide”, “autologous hematopoietic stem cell transplantation”, “tocilizumab”, “nintedanib”, “belimumab”, “rituximab”, “abatacept”, “lenabasum” as keywords. The review focused on articles published in English from their inception until 2025.
Conclusions: However, the disease-modifying anti-rheumatic drugs are widely used in systemic sclerosis, currently the biological therapeutics are objects of dynamic researches due to their good benefit-risk ratio. Numerous biological drugs are implemented for alleviating the course of Interstitial Lung Disease as it remains main cause of death among SSc patients. Additionally, some clinical manifestations of SSc, including Raynaud phenomenon (RP) and Pulmonary Artery Hypertension (PAH) are treating rather symptomatically then causatively. We hope our manuscript contributed to better understanding of therapeutic approaches of systemic sclerosis.
References
Ahl, A., Ipalawatte, H., Ghias, S., & Gower, A. (2025). A Rare Case of Scleroderma Renal Crisis. Journal of Investigative Medicine High Impact Case Reports, 13, 23247096251336565. https://doi.org/10.1177/23247096251336565
Allanore, Y., Borderie, D., Lemaréchal, H., Ekindjian, O. G., & Kahan, A. (2004). Acute and sustained effects of dihydropyridine-type calcium channel antagonists on oxidative stress in systemic sclerosis. The American Journal of Medicine, 116(9), 595–600. https://doi.org/10.1016/j.amjmed.2003.11.022
Allanore, Y., Borderie, D., Meune, C., Cabanes, L., Weber, S., Ekindjian, O. G., & Kahan, A. (2003). N-terminal pro-brain natriuretic peptide as a diagnostic marker of early pulmonary artery hypertension in patients with systemic sclerosis and effects of calcium-channel blockers. Arthritis and Rheumatism, 48(12), 3503–3508. https://doi.org/10.1002/art.11345
Allanore, Y., Meune, C., Vonk, M. C., Airo, P., Hachulla, E., Caramaschi, P., Riemekasten, G., Cozzi, F., Beretta, L., Derk, C. T., Komócsi, A., Farge, D., Balbir, A., Riccieri, V., Distler, O., Chialà, A., Del Papa, N., Simic, K. P., Ghio, M., … EUSTAR co-authors. (2010). Prevalence and factors associated with left ventricular dysfunction in the EULAR Scleroderma Trial and Research group (EUSTAR) database of patients with systemic sclerosis. Annals of the Rheumatic Diseases, 69(1), 218–221. https://doi.org/10.1136/ard.2008.103382
Allison, A. C., & Eugui, E. M. (2000). Mycophenolate mofetil and its mechanisms of action. Immunopharmacology, 47(2–3), 85–118. https://doi.org/10.1016/s0162-3109(00)00188-0
Andrigueti, F. V., Ebbing, P. C. C., Arismendi, M. I., & Kayser, C. (2017). Evaluation of the effect of sildenafil on the microvascular blood flow in patients with systemic sclerosis: A randomised, double-blind, placebo-controlled study. Clinical and Experimental Rheumatology, 35 Suppl 106(4), 151–158.
Barnes, H., Brown, Z., Burns, A., & Williams, T. (2019). Phosphodiesterase 5 inhibitors for pulmonary hypertension. The Cochrane Database of Systematic Reviews, 1(1), CD012621. https://doi.org/10.1002/14651858.CD012621.pub2
Benjamin, O., Goyal, A., & Lappin, S. L. (2025). Disease-Modifying Antirheumatic Drugs (DMARD). In StatPearls. StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK507863/
Bruera, S., Sidanmat, H., Molony, D. A., Mayes, M. D., Suarez-Almazor, M. E., Krause, K., & Lopez-Olivo, M. A. (2022). Stem cell transplantation for systemic sclerosis. The Cochrane Database of Systematic Reviews, 2022(7), CD011819. https://doi.org/10.1002/14651858.CD011819.pub2
Bukiri, H., & Volkmann, E. R. (2022). Current Advances in the Treatment of Systemic Sclerosis. Current Opinion in Pharmacology, 64, 102211. https://doi.org/10.1016/j.coph.2022.102211
Castellví, I., Elhai, M., Bruni, C., Airò, P., Jordan, S., Beretta, L., Codullo, V., Montecucco, C. M., Bokarewa, M., Iannonne, F., Balbir, A., Hsu, V. M., Distler, O., Matucci-Cerinic, M., Allanore, Y., & for EUSTAR network. (2020). Safety and effectiveness of abatacept in systemic sclerosis: The EUSTAR experience. Seminars in Arthritis and Rheumatism, 50(6), 1489–1493. https://doi.org/10.1016/j.semarthrit.2019.12.004
Cocchiara, E., Spinella, A., Magnani, L., Lumetti, F., Palermo, A., Baiocchi, G., Salvarani, C., & Giuggioli, D. (2019). AB0645 CANNABINOIDS IN THE TREATMENT OF PAIN RELATED TO SYSTEMIC SCLEROSIS SKIN ULCERS: OUR EXPERIENCE. Annals of the Rheumatic Diseases, 78, 1784. https://doi.org/10.1136/annrheumdis-2019-eular.6004
Coghlan, J. G., Galiè, N., Barberà, J. A., Frost, A. E., Ghofrani, H.-A., Hoeper, M. M., Kuwana, M., McLaughlin, V. V., Peacock, A. J., Simonneau, G., Vachiéry, J.-L., Blair, C., Gillies, H., Miller, K. L., Harris, J. H. N., Langley, J., Rubin, L. J., & AMBITION investigators. (2017). Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): Subgroup analysis from the AMBITION trial. Annals of the Rheumatic Diseases, 76(7), 1219–1227. https://doi.org/10.1136/annrheumdis-2016-210236
Cole, A., Ong, V. H., & Denton, C. P. (2023). Renal Disease and Systemic Sclerosis: An Update on Scleroderma Renal Crisis. Clinical Reviews in Allergy & Immunology, 64(3), 378–391. https://doi.org/10.1007/s12016-022-08945-x
Cronstein, B. N., & Aune, T. M. (2020). Methotrexate and its mechanisms of action in inflammatory arthritis. Nature Reviews. Rheumatology, 16(3), 145–154. https://doi.org/10.1038/s41584-020-0373-9
Del Galdo, F., Lescoat, A., Conaghan, P. G., Bertoldo, E., Čolić, J., Santiago, T., Suliman, Y. A., Matucci-Cerinic, M., Gabrielli, A., Distler, O., Hoffmann-Vold, A.-M., Castellví, I., Balbir-Gurman, A., Vonk, M., Ananyeva, L., Rednic, S., Tarasova, A., Ostojic, P., Boyadzhieva, V., … Allanore, Y. (2025). EULAR recommendations for the treatment of systemic sclerosis: 2023 update. Annals of the Rheumatic Diseases, 84(1), 29–40. https://doi.org/10.1136/ard-2024-226430
Denton, C. P., De Lorenzis, E., Roblin, E., Goldman, N., Alcacer-Pitarch, B., Blamont, E., Buch, M. H., Carulli, M., Cotton, C., Del Galdo, F., Derrett-Smith, E., Douglas, K., Farrington, S., Fligelstone, K., Gompels, L., Griffiths, B., Herrick, A., Hughes, M., Pain, C., … Ong, V. H. (2024). The 2024 British Society for Rheumatology guideline for management of systemic sclerosis. Rheumatology (Oxford, England), 63(11), 2956–2975. https://doi.org/10.1093/rheumatology/keae394
Denton, C. P., Hachulla, É., Riemekasten, G., Schwarting, A., Frenoux, J.-M., Frey, A., Le Brun, F.-O., Herrick, A. L., & Raynaud Study Investigators. (2017). Efficacy and Safety of Selexipag in Adults With Raynaud’s Phenomenon Secondary to Systemic Sclerosis: A Randomized, Placebo-Controlled, Phase II Study. Arthritis & Rheumatology (Hoboken, N.J.), 69(12), 2370–2379. https://doi.org/10.1002/art.40242
Di Maggio, G., Confalonieri, P., Salton, F., Trotta, L., Ruggero, L., Kodric, M., Geri, P., Hughes, M., Bellan, M., Gilio, M., Lerda, S., Baratella, E., Confalonieri, M., Mondini, L., & Ruaro, B. (2023). Biomarkers in Systemic Sclerosis: An Overview. Current Issues in Molecular Biology, 45(10), 7775–7802. https://doi.org/10.3390/cimb45100490
Distler, O., Highland, K. B., Gahlemann, M., Azuma, A., Fischer, A., Mayes, M. D., Raghu, G., Sauter, W., Girard, M., Alves, M., Clerisme-Beaty, E., Stowasser, S., Tetzlaff, K., Kuwana, M., Maher, T. M., & SENSCIS Trial Investigators. (2019). Nintedanib for Systemic Sclerosis-Associated Interstitial Lung Disease. The New England Journal of Medicine, 380(26), 2518–2528. https://doi.org/10.1056/NEJMoa1903076
Farge, D., Burt, R. K., Oliveira, M.-C., Mousseaux, E., Rovira, M., Marjanovic, Z., de Vries-Bouwstra, J., Del Papa, N., Saccardi, R., Shah, S. J., Lee, D. C., Denton, C., Alexander, T., Kiely, D. G., & Snowden, J. A. (2017). Cardiopulmonary assessment of patients with systemic sclerosis for hematopoietic stem cell transplantation: Recommendations from the European Society for Blood and Marrow Transplantation Autoimmune Diseases Working Party and collaborating partners. Bone Marrow Transplantation, 52(11), 1495–1503. https://doi.org/10.1038/bmt.2017.56
Feghali, C. A., Bost, K. L., Boulware, D. W., & Levy, L. S. (1992). Mechanisms of pathogenesis in scleroderma. I. Overproduction of interleukin 6 by fibroblasts cultured from affected skin sites of patients with scleroderma. The Journal of Rheumatology, 19(8), 1207–1211.
Gaine, S., Chin, K., Coghlan, G., Channick, R., Di Scala, L., Galiè, N., Ghofrani, H.-A., Lang, I. M., McLaughlin, V., Preiss, R., Rubin, L. J., Simonneau, G., Sitbon, O., Tapson, V. F., & Hoeper, M. M. (2017). Selexipag for the treatment of connective tissue disease-associated pulmonary arterial hypertension. The European Respiratory Journal, 50(2), 1602493. https://doi.org/10.1183/13993003.02493-2016
Galdo, F. D., Lescoat, A., Conaghan, P. G., Bertoldo, E., Čolić, J., Santiago, T., Suliman, Y. A., Matucci-Cerinic, M., Gabrielli, A., Distler, O., Hoffmann-Vold, A.-M., Castellví, I., Balbir-Gurman, A., Vonk, M., Ananyeva, L., Rednic, S., Tarasova, A., Ostojic, P., Boyadzhieva, V., … Allanore, Y. (2024). EULAR recommendations for the treatment of systemic sclerosis: 2023 update. Annals of the Rheumatic Diseases. https://doi.org/10.1136/ard-2024-226430
Gernert, M., Tony, H.-P., Schwaneck, E. C., Gadeholt, O., Fröhlich, M., Portegys, J., Strunz, P.-P., & Schmalzing, M. (2022). Lymphocyte subsets in the peripheral blood are disturbed in systemic sclerosis patients and can be changed by immunosuppressive medication. Rheumatology International, 42(8), 1373–1381. https://doi.org/10.1007/s00296-021-05034-8
Ghiringhelli, F., Larmonier, N., Schmitt, E., Parcellier, A., Cathelin, D., Garrido, C., Chauffert, B., Solary, E., Bonnotte, B., & Martin, F. (2004). CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. European Journal of Immunology, 34(2), 336–344. https://doi.org/10.1002/eji.200324181
Gonzalez, E. G., Selvi, E., Balistreri, E., Akhmetshina, A., Palumbo, K., Lorenzini, S., Lazzerini, P. E., Montilli, C., Capecchi, P. L., Lucattelli, M., Baldi, C., Gianchecchi, E., Galeazzi, M., Pasini, F. L., & Distler, J. H. W. (2012). Synthetic cannabinoid ajulemic acid exerts potent antifibrotic effects in experimental models of systemic sclerosis. Annals of the Rheumatic Diseases, 71(9), 1545–1551. https://doi.org/10.1136/annrheumdis-2011-200314
Gordon, J. K., Martyanov, V., Franks, J. M., Bernstein, E. J., Szymonifka, J., Magro, C., Wildman, H. F., Wood, T. A., Whitfield, M. L., & Spiera, R. F. (2018). Belimumab for the Treatment of Early Diffuse Systemic Sclerosis: Results of a Randomized, Double-Blind, Placebo-Controlled, Pilot Trial. Arthritis & Rheumatology (Hoboken, N.J.), 70(2), 308–316. https://doi.org/10.1002/art.40358
Gumkowska-Sroka, O., Kotyla, K., & Kotyla, P. (2024). Immunogenetics of Systemic Sclerosis. Genes, 15(5), 586. https://doi.org/10.3390/genes15050586
Haque, A., Kiely, D. G., Kovacs, G., Thompson, A. A. R., & Condliffe, R. (2021). Pulmonary hypertension phenotypes in patients with systemic sclerosis. European Respiratory Review: An Official Journal of the European Respiratory Society, 30(161), 210053. https://doi.org/10.1183/16000617.0053-2021
Herrick, A. L., Assassi, S., & Denton, C. P. (2022). Skin involvement in early diffuse cutaneous systemic sclerosis: An unmet clinical need. Nature Reviews. Rheumatology, 18(5), 276–285. https://doi.org/10.1038/s41584-022-00765-9
Highland, K. B., Distler, O., Kuwana, M., Allanore, Y., Assassi, S., Azuma, A., Bourdin, A., Denton, C. P., Distler, J. H. W., Hoffmann-Vold, A. M., Khanna, D., Mayes, M. D., Raghu, G., Vonk, M. C., Gahlemann, M., Clerisme-Beaty, E., Girard, M., Stowasser, S., Zoz, D., … SENSCIS trial investigators. (2021). Efficacy and safety of nintedanib in patients with systemic sclerosis-associated interstitial lung disease treated with mycophenolate: A subgroup analysis of the SENSCIS trial. The Lancet. Respiratory Medicine, 9(1), 96–106. https://doi.org/10.1016/S2213-2600(20)30330-1
Hinchcliff, M., Toledo, D. M., Taroni, J. N., Wood, T. A., Franks, J. M., Ball, M. S., Hoffmann, A., Amin, S. M., Tan, A. U., Tom, K., Nesbeth, Y., Lee, J., Ma, M., Aren, K., Carns, M. A., Pioli, P. A., & Whitfield, M. L. (2018). Mycophenolate Mofetil Treatment of Systemic Sclerosis Reduces Myeloid Cell Numbers and Attenuates the Inflammatory Gene Signature in Skin. The Journal of Investigative Dermatology, 138(6), 1301–1310. https://doi.org/10.1016/j.jid.2018.01.006
Hoffmann-Vold, A.-M., Fretheim, H., Halse, A.-K., Seip, M., Bitter, H., Wallenius, M., Garen, T., Salberg, A., Brunborg, C., Midtvedt, Ø., Lund, M. B., Aaløkken, T. M., & Molberg, Ø. (2019). Tracking Impact of Interstitial Lung Disease in Systemic Sclerosis in a Complete Nationwide Cohort. American Journal of Respiratory and Critical Care Medicine, 200(10), 1258–1266. https://doi.org/10.1164/rccm.201903-0486OC
Hudson, M., Baron, M., Tatibouet, S., Furst, D. E., Khanna, D., & International Scleroderma Renal Crisis Study Investigators. (2014). Exposure to ACE inhibitors prior to the onset of scleroderma renal crisis-results from the International Scleroderma Renal Crisis Survey. Seminars in Arthritis and Rheumatism, 43(5), 666–672. https://doi.org/10.1016/j.semarthrit.2013.09.008
Iannone, F., Riccardi, M. T., Guiducci, S., Bizzoca, R., Cinelli, M., Matucci-Cerinic, M., & Lapadula, G. (2008). Bosentan regulates the expression of adhesion molecules on circulating T cells and serum soluble adhesion molecules in systemic sclerosis-associated pulmonary arterial hypertension. Annals of the Rheumatic Diseases, 67(8), 1121–1126. https://doi.org/10.1136/ard.2007.080424
Impens, A. J., Phillips, K., & Schiopu, E. (2011). PDE-5 Inhibitors in Scleroderma Raynaud Phenomenon and Digital Ulcers: Current Status of Clinical Trials. International Journal of Rheumatology, 2011, 392542. https://doi.org/10.1155/2011/392542
Jang, J. H., Her, M., Oh, J. H., Park, J. H., Jung, S. Y., Ko, J., & Lee, J. H. (2025). Rituximab in systemic sclerosis-associated interstitial lung disease: A systematic review and meta-analysis. Science Progress, 108(2), 368504251333912. https://doi.org/10.1177/00368504251333912
Johnson, S. R., Bernstein, E. J., Bolster, M. B., Chung, J. H., Danoff, S. K., George, M. D., Khanna, D., Guyatt, G., Mirza, R. D., Aggarwal, R., Allen, A., Assassi, S., Buckley, L., Chami, H. A., Corwin, D. S., Dellaripa, P. F., Domsic, R. T., Doyle, T. J., Falardeau, C. M., … Ivlev, I. (2024). 2023 American College of Rheumatology (ACR)/American College of Chest Physicians (CHEST) Guideline for the Screening and Monitoring of Interstitial Lung Disease in People with Systemic Autoimmune Rheumatic Diseases. Arthritis & Rheumatology (Hoboken, N.J.), 76(8), 1201–1213. https://doi.org/10.1002/art.42860
Kato, M., Sasaki, S., Nakamura, T., Kurokawa, K., Yamada, T., Ochi, Y., Ihara, H., Takahashi, F., & Takahashi, K. (2019). Gastrointestinal adverse effects of nintedanib and the associated risk factors in patients with idiopathic pulmonary fibrosis. Scientific Reports, 9(1), 12062. https://doi.org/10.1038/s41598-019-48593-4
Khanna, D., Denton, C. P., Jahreis, A., van Laar, J. M., Frech, T. M., Anderson, M. E., Baron, M., Chung, L., Fierlbeck, G., Lakshminarayanan, S., Allanore, Y., Pope, J. E., Riemekasten, G., Steen, V., Müller-Ladner, U., Lafyatis, R., Stifano, G., Spotswood, H., Chen-Harris, H., … Furst, D. E. (2016). Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): A phase 2, randomised, controlled trial. Lancet (London, England), 387(10038), 2630–2640. https://doi.org/10.1016/S0140-6736(16)00232-4
Khanna, D., Lin, C. J. F., Furst, D. E., Wagner, B., Zucchetto, M., Raghu, G., Martinez, F. J., Goldin, J., Siegel, J., & Denton, C. P. (2022). Long-Term Safety and Efficacy of Tocilizumab in Early Systemic Sclerosis-Interstitial Lung Disease: Open-Label Extension of a Phase 3 Randomized Controlled Trial. American Journal of Respiratory and Critical Care Medicine, 205(6), 674–684. https://doi.org/10.1164/rccm.202103-0714OC
Khanna, D., Spino, C., Johnson, S., Chung, L., Whitfield, M. L., Denton, C. P., Berrocal, V., Franks, J., Mehta, B., Molitor, J., Steen, V. D., Lafyatis, R., Simms, R. W., Gill, A., Kafaja, S., Frech, T. M., Hsu, V., Domsic, R. T., Pope, J. E., … Furst, D. E. (2020). Abatacept in Early Diffuse Cutaneous Systemic Sclerosis: Results of a Phase II Investigator-Initiated, Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial. Arthritis & Rheumatology (Hoboken, N.J.), 72(1), 125–136. https://doi.org/10.1002/art.41055
Kowalska-Kępczyńska, A. (2022). Systemic Scleroderma—Definition, Clinical Picture and Laboratory Diagnostics. Journal of Clinical Medicine, 11(9), 2299. https://doi.org/10.3390/jcm11092299
Kucharz, E. J., & Kopeć-Mędrek, M. (2017). Systemic sclerosis sine scleroderma. Advances in Clinical and Experimental Medicine: Official Organ Wroclaw Medical University, 26(5), 875–880. https://doi.org/10.17219/acem/64334
Kumar, U., Sankalp, G., Sreenivas, V., Kaur, S., & Misra, D. (2013). Prospective, open-label, uncontrolled pilot study to study safety and efficacy of sildenafil in systemic sclerosis-related pulmonary artery hypertension and cutaneous vascular complications. Rheumatology International, 33(4), 1047–1052. https://doi.org/10.1007/s00296-012-2466-5
Launay, D., Sitbon, O., Le Pavec, J., Savale, L., Tchérakian, C., Yaïci, A., Achouh, L., Parent, F., Jais, X., Simonneau, G., & Humbert, M. (2010). Long-term outcome of systemic sclerosis-associated pulmonary arterial hypertension treated with bosentan as first-line monotherapy followed or not by the addition of prostanoids or sildenafil. Rheumatology (Oxford, England), 49(3), 490–500. https://doi.org/10.1093/rheumatology/kep398
Lefèvre, G., Dauchet, L., Hachulla, E., Montani, D., Sobanski, V., Lambert, M., Hatron, P.-Y., Humbert, M., & Launay, D. (2013). Survival and prognostic factors in systemic sclerosis-associated pulmonary hypertension: A systematic review and meta-analysis. Arthritis and Rheumatism, 65(9), 2412–2423. https://doi.org/10.1002/art.38029
Lepri, G., Di Battista, M., Codullo, V., Bonomi, F., Sulis, A., Guiducci, S., & Della Rossa, A. (2024). Systemic sclerosis: One year in review 2024. Clinical and Experimental Rheumatology, 42(8), 1517–1528. https://doi.org/10.55563/clinexprheumatol/is29he
Lescoat, A., Huang, S., Carreira, P. E., Siegert, E., de Vries-Bouwstra, J., Distler, J. H. W., Smith, V., Del Galdo, F., Anic, B., Damjanov, N., Rednic, S., Ribi, C., Bancel, D. F., Hoffmann-Vold, A.-M., Gabrielli, A., Distler, O., Khanna, D., Allanore, Y., & EUSTAR collaborators. (2023). Cutaneous Manifestations, Clinical Characteristics, and Prognosis of Patients With Systemic Sclerosis Sine Scleroderma: Data From the International EUSTAR Database. JAMA Dermatology, 159(8), 837–847. https://doi.org/10.1001/jamadermatol.2023.1729
Lescoat, A., Sandler, R. D., Zimmermann, F., Roofeh, D., Hughes, M., Pauling, J. D., Murphy, S. L., Chen, Y. T., Townsend, W., Buch, M. H., & Khanna, D. (2022). Domains and outcome measures for the assessment of limited cutaneous systemic sclerosis: An international collaborative scoping review. Rheumatology (Oxford, England), 61(8), 3132–3148. https://doi.org/10.1093/rheumatology/keac049
Macrea, M., Ghazipura, M., Herman, D., Barnes, H., Knight, S. L., Silver, R. M., Montesi, S. B., Raghu, G., & Hossain, T. (n.d.). Rituximab in Patients with Systemic Sclerosis–associated Interstitial Lung Disease: A Systematic Review and Meta-Analysis. Annals of the American Thoracic Society, 21(2), 317–327. https://doi.org/10.1513/AnnalsATS.202301-055OC
Maehara, T., Kaneko, N., Perugino, C. A., Mattoo, H., Kers, J., Allard-Chamard, H., Mahajan, V. S., Liu, H., Murphy, S. J., Ghebremichael, M., Fox, D., Payne, A. S., Lafyatis, R., Stone, J. H., Khanna, D., & Pillai, S. (2020). Cytotoxic CD4+ T lymphocytes may induce endothelial cell apoptosis in systemic sclerosis. The Journal of Clinical Investigation, 130(5), 2451–2464. https://doi.org/10.1172/JCI131700
Mankikian, J., Caille, A., Reynaud-Gaubert, M., Agier, M.-S., Bermudez, J., Bonniaud, P., Borie, R., Brillet, P.-Y., Cadranel, J., Court-Fortune, I., Crestani, B., Debray, M.-P., Gomez, E., Gondouin, A., Hirschi-Santelmo, S., Israel-Biet, D., Jouneau, S., Juvin, K., Leger, J., … EVER-ILD investigators and the OrphaLung network. (2023). Rituximab and mycophenolate mofetil combination in patients with interstitial lung disease (EVER-ILD): A double-blind, randomised, placebo-controlled trial. The European Respiratory Journal, 61(6), 2202071. https://doi.org/10.1183/13993003.02071-2022
Matucci-Cerinic, M., Denton, C. P., Furst, D. E., Mayes, M. D., Hsu, V. M., Carpentier, P., Wigley, F. M., Black, C. M., Fessler, B. J., Merkel, P. A., Pope, J. E., Sweiss, N. J., Doyle, M. K., Hellmich, B., Medsger, T. A., Morganti, A., Kramer, F., Korn, J. H., & Seibold, J. R. (2011). Bosentan treatment of digital ulcers related to systemic sclerosis: Results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial. Annals of the Rheumatic Diseases, 70(1), 32–38. https://doi.org/10.1136/ard.2010.130658
McMahan, Z. H., & Volkmann, E. R. (2020). An update on the pharmacotherapeutic options and treatment strategies for systemic sclerosis. Expert Opinion on Pharmacotherapy, 21(16), 2041–2056. https://doi.org/10.1080/14656566.2020.1793960
Milio, G., Corrado, E., Genova, C., Amato, C., Raimondi, F., Almasio, P. L., & Novo, S. (2006). Iloprost treatment in patients with Raynaud’s phenomenon secondary to systemic sclerosis and the quality of life: A new therapeutic protocol. Rheumatology (Oxford, England), 45(8), 999–1004. https://doi.org/10.1093/rheumatology/kel038
Morath, C., Reuter, H., Simon, V., Krautkramer, E., Muranyi, W., Schwenger, V., Goulimari, P., Grosse, R., Hahn, M., Lichter, P., & Zeier, M. (2008). Effects of mycophenolic acid on human fibroblast proliferation, migration and adhesion in vitro and in vivo. American Journal of Transplantation: Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 8(9), 1786–1797. https://doi.org/10.1111/j.1600-6143.2008.02322.x
Nassar, M., Ghernautan, V., Nso, N., Nyabera, A., Castillo, F. C., Tu, W., Medina, L., Ciobanu, C., Alfishawy, M., Rizzo, V., Eskaros, S., Mahdi, M., Khalifa, M., & El-Kassas, M. (2022). Gastrointestinal involvement in systemic sclerosis: An updated review. Medicine, 101(45), e31780. https://doi.org/10.1097/MD.0000000000031780
Neupane, B., Shukla, P., Slim, M., Martin, A., Petri, M., Bertsias, G. K., Kim, A. H. J., Fanouriakis, A., Levy, R. A., Chauhan, D., & Ballew, N. (2023). Belimumab versus anifrolumab in adults with systemic lupus erythematosus: An indirect comparison of clinical response at 52 weeks. Lupus Science & Medicine, 10(1), e000907. https://doi.org/10.1136/lupus-2023-000907
Nihtyanova, S. I., Brough, G. M., Black, C. M., & Denton, C. P. (2008). Clinical burden of digital vasculopathy in limited and diffuse cutaneous systemic sclerosis. Annals of the Rheumatic Diseases, 67(1), 120–123. https://doi.org/10.1136/ard.2007.072686
Pan, Z., Marra, A. M., Benjamin, N., Eichstaedt, C. A., Blank, N., Bossone, E., Cittadini, A., Coghlan, G., Denton, C. P., Distler, O., Egenlauf, B., Fischer, C., Harutyunova, S., Xanthouli, P., Lorenz, H.-M., & Grünig, E. (2019). Early treatment with ambrisentan of mildly elevated mean pulmonary arterial pressure associated with systemic sclerosis: A randomized, controlled, double-blind, parallel group study (EDITA study). Arthritis Research & Therapy, 21(1), 217. https://doi.org/10.1186/s13075-019-1981-0
Papadimitriou, T.-I., van Caam, A., van der Kraan, P. M., & Thurlings, R. M. (2022). Therapeutic Options for Systemic Sclerosis: Current and Future Perspectives in Tackling Immune-Mediated Fibrosis. Biomedicines, 10(2), 316. https://doi.org/10.3390/biomedicines10020316
Parisi, S., Peroni, C. L., Laganà, A., Scarati, M., Ambrogio, F., Bruzzone, M., & Fusaro, E. (2013). Efficacy of ambrisentan in the treatment of digital ulcers in patients with systemic sclerosis: A preliminary study. Rheumatology (Oxford, England), 52(6), 1142–1144. https://doi.org/10.1093/rheumatology/ket019
Pestaña-Fernández, M., Rubio-Rivas, M., Tolosa-Vilella, C., Guillén-Del-Castillo, A., Freire, M., Vargas-Hitos, J. A., Todolí-Parra, J. A., Rodríguez-Carballeira, M., Marín-Ballvé, A., Espinosa, G., Colunga-Argüelles, D., Ortego-Centeno, N., Trapiella-Martínez, L., Carbonell-Muñoz, C., Pla-Salas, X., Perales-Fraile, I., Corbella, X., Fonollosa-Pla, V., Simeón-Aznar, C. P., & RESCLE investigators, Autoimmune Diseases Study Group (GEAS). (2020). Longterm Efficacy and Safety of Monotherapy versus Combination Therapy in Systemic Sclerosis-associated Pulmonary Arterial Hypertension: A Retrospective RESCLE Registry Study. The Journal of Rheumatology, 47(1), 89–98. https://doi.org/10.3899/jrheum.180595
Pope, J. E., Denton, C. P., Johnson, S. R., Fernandez-Codina, A., Hudson, M., & Nevskaya, T. (2023). State-of-the-art evidence in the treatment of systemic sclerosis. Nature Reviews. Rheumatology, 19(4), 212–226. https://doi.org/10.1038/s41584-023-00909-5
Romano, E., Rosa, I., Fioretto, B. S., Matucci-Cerinic, M., & Manetti, M. (2021). New Insights into Profibrotic Myofibroblast Formation in Systemic Sclerosis: When the Vascular Wall Becomes the Enemy. Life (Basel, Switzerland), 11(7), 610. https://doi.org/10.3390/life11070610
Roofeh, D., Lin, C. J. F., Goldin, J., Kim, G. H., Furst, D. E., Denton, C. P., Huang, S., & Khanna, D. (2021). Tocilizumab Prevents Progression of Early Systemic Sclerosis Associated Interstitial Lung Disease. Arthritis & Rheumatology (Hoboken, N.J.), 73(7), 1301–1310. https://doi.org/10.1002/art.41668
Roustit, M., Blaise, S., Allanore, Y., Carpentier, P. H., Caglayan, E., & Cracowski, J.-L. (2013). Phosphodiesterase-5 inhibitors for the treatment of secondary Raynaud’s phenomenon: Systematic review and meta-analysis of randomised trials. Annals of the Rheumatic Diseases, 72(10), 1696–1699. https://doi.org/10.1136/annrheumdis-2012-202836
Rubio-Rivas, M., Homs, N. A., Cuartero, D., & Corbella, X. (2021). The prevalence and incidence rate of pulmonary arterial hypertension in systemic sclerosis: Systematic review and meta-analysis. Autoimmunity Reviews, 20(1), 102713. https://doi.org/10.1016/j.autrev.2020.102713
Sitbon, O., Channick, R., Chin, K. M., Frey, A., Gaine, S., Galiè, N., Ghofrani, H.-A., Hoeper, M. M., Lang, I. M., Preiss, R., Rubin, L. J., Di Scala, L., Tapson, V., Adzerikho, I., Liu, J., Moiseeva, O., Zeng, X., Simonneau, G., McLaughlin, V. V., & GRIPHON Investigators. (2015). Selexipag for the Treatment of Pulmonary Arterial Hypertension. The New England Journal of Medicine, 373(26), 2522–2533. https://doi.org/10.1056/NEJMoa1503184
Smith, V., Herrick, A. L., Ingegnoli, F., Damjanov, N., De Angelis, R., Denton, C. P., Distler, O., Espejo, K., Foeldvari, I., Frech, T., Garro, B., Gutierrez, M., Gyger, G., Hachulla, E., Hesselstrand, R., Iagnocco, A., Kayser, C., Melsens, K., Müller-Ladner, U., … EULAR Study Group on Microcirculation in Rheumatic Diseases and the Scleroderma Clinical Trials Consortium Group on Capillaroscopy. (2020). Standardisation of nailfold capillaroscopy for the assessment of patients with Raynaud’s phenomenon and systemic sclerosis. Autoimmunity Reviews, 19(3), 102458. https://doi.org/10.1016/j.autrev.2020.102458
Spiera, R., Hummers, L., Chung, L., Frech, T. M., Domsic, R., Hsu, V., Furst, D. E., Gordon, J., Mayes, M., Simms, R., Lafyatis, R., Martyanov, V., Wood, T., Whitfield, M. L., Constantine, S., Lee, E., Dgetluck, N., & White, B. (2020). Safety and Efficacy of Lenabasum in a Phase II, Randomized, Placebo-Controlled Trial in Adults With Systemic Sclerosis. Arthritis & Rheumatology (Hoboken, N.J.), 72(8), 1350–1360. https://doi.org/10.1002/art.41294
Spiera, R., Kuwana, M., Khanna, D., Hummers, L., Frech, T. M., Stevens, W., Matucci-Cerinic, M., Kafaja, S., Distler, O., Jun, J.-B., Levy, Y., Leszcyzński, P., Gordon, J., Steen, V., Lee, E. B., Jankowski, T., Litinsky, I., Chung, L., Hsu, V., … RESOLVE-1 Study Group. (2023). Efficacy and Safety of Lenabasum, a Cannabinoid Type 2 Receptor Agonist, in a Phase 3 Randomized Trial in Diffuse Cutaneous Systemic Sclerosis. Arthritis & Rheumatology (Hoboken, N.J.), 75(9), 1608–1618. https://doi.org/10.1002/art.42510
Spierings, J., van Rhenen, A., Welsing, P. M., Marijnissen, A. C., De Langhe, E., Del Papa, N., Dierickx, D., Gheorghe, K. R., Henes, J., Hesselstrand, R., Kerre, T., Ljungman, P., van de Loosdrecht, A. A., Marijt, E. W., Mayer, M., Schmalzing, M., Schroers, R., Smith, V., Voll, R. E., … van Laar, J. M. (2021). A randomised, open-label trial to assess the optimal treatment strategy in early diffuse cutaneous systemic sclerosis: The UPSIDE study protocol. BMJ Open, 11(3), e044483. https://doi.org/10.1136/bmjopen-2020-044483
Stubbe, B., Opitz, C. F., Halank, M., Habedank, D., & Ewert, R. (2021). Intravenous prostacyclin-analogue therapy in pulmonary arterial hypertension—A review of the past, present and future. Respiratory Medicine, 179, 106336. https://doi.org/10.1016/j.rmed.2021.106336
Tashkin, D. P., Elashoff, R., Clements, P. J., Goldin, J., Roth, M. D., Furst, D. E., Arriola, E., Silver, R., Strange, C., Bolster, M., Seibold, J. R., Riley, D. J., Hsu, V. M., Varga, J., Schraufnagel, D. E., Theodore, A., Simms, R., Wise, R., Wigley, F., … Scleroderma Lung Study Research Group. (2006). Cyclophosphamide versus placebo in scleroderma lung disease. The New England Journal of Medicine, 354(25), 2655–2666. https://doi.org/10.1056/NEJMoa055120
Tashkin, D. P., Roth, M. D., Clements, P. J., Furst, D. E., Khanna, D., Kleerup, E. C., Goldin, J., Arriola, E., Volkmann, E. R., Kafaja, S., Silver, R., Steen, V., Strange, C., Wise, R., Wigley, F., Mayes, M., Riley, D. J., Hussain, S., Assassi, S., … Elashoff, R. M. (2016). Mycophenolate Mofetil versus Oral Cyclophosphamide in Scleroderma-related Interstitial Lung Disease: Scleroderma Lung Study II (SLS-II), a double-blind, parallel group, randomised controlled trial. The Lancet. Respiratory Medicine, 4(9), 708–719. https://doi.org/10.1016/S2213-2600(16)30152-7
Thompson, A. E., & Pope, J. E. (2005). Calcium channel blockers for primary Raynaud’s phenomenon: A meta-analysis. Rheumatology (Oxford, England), 44(2), 145–150. https://doi.org/10.1093/rheumatology/keh390
van den Hoogen, F., Khanna, D., Fransen, J., Johnson, S. R., Baron, M., Tyndall, A., Matucci-Cerinic, M., Naden, R., Riemekasten, G., Carreira, P., Gabrielli, A., Distler, O., van Laar, J. M., Valentini, G., Denton, C. P., Kowal-Bielecka, O., Inanc, M., Allanore, Y., Walker, U. A., … Pope, J. (2013). Classification Criteria for Systemic Sclerosis: An ACR-EULAR Collaborative Initiative. Arthritis and Rheumatism, 65(11), 2737–2747. https://doi.org/10.1002/art.38098
van Laar, J. M., Farge, D., Sont, J. K., Naraghi, K., Marjanovic, Z., Larghero, J., Schuerwegh, A. J., Marijt, E. W. A., Vonk, M. C., Schattenberg, A. V., Matucci-Cerinic, M., Voskuyl, A. E., van de Loosdrecht, A. A., Daikeler, T., Kötter, I., Schmalzing, M., Martin, T., Lioure, B., Weiner, S. M., … EBMT/EULAR Scleroderma Study Group. (2014). Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: A randomized clinical trial. JAMA, 311(24), 2490–2498. https://doi.org/10.1001/jama.2014.6368
Volkmann, E. R., Andréasson, K., & Smith, V. (2023). Systemic sclerosis. Lancet (London, England), 401(10373), 304–318. https://doi.org/10.1016/S0140-6736(22)01692-0
Wachsmuth, L. P., Patterson, M. T., Eckhaus, M. A., Venzon, D. J., Gress, R. E., & Kanakry, C. G. (n.d.). Posttransplantation cyclophosphamide prevents graft-versus-host disease by inducing alloreactive T cell dysfunction and suppression. The Journal of Clinical Investigation, 129(6), 2357–2373. https://doi.org/10.1172/JCI124218
Zanatta, E., Polito, P., Favaro, M., Larosa, M., Marson, P., Cozzi, F., & Doria, A. (2018). Therapy of scleroderma renal crisis: State of the art. Autoimmunity Reviews, 17(9), 882–889. https://doi.org/10.1016/j.autrev.2018.03.012
Zanin-Silva, D. C., Santana-Gonçalves, M., Kawashima-Vasconcelos, M. Y., & Oliveira, M. C. (2021). Management of Endothelial Dysfunction in Systemic Sclerosis: Current and Developing Strategies. Frontiers in Medicine, 8, 788250. https://doi.org/10.3389/fmed.2021.788250
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