Old and new therapeutic strategies in systemic sclerosis (Review)

Bobeica,Carmen; Niculet,Elena; Tatu,Alin Laurentiu; Craescu,Mihaela; Vata,Dan; Statescu,Laura; Iancu,Alina Viorica; Musat,Carmina Liana; Draganescu,Miruna Luminita; Onisor,Cristian; Lungu,Mihaela; Fotea,Silvia; Nechita,Aurel; Stefanescu,Bogdan Ioan; Gheuca‑Solovastru,Laura

doi:10.3892/etm.2021.11057

Old and new therapeutic strategies in systemic sclerosis (Review)

Authors:
- Carmen Bobeica
- Elena Niculet
- Alin Laurentiu Tatu
- Mihaela Craescu
- Dan Vata
- Laura Statescu
- Alina Viorica Iancu
- Carmina Liana Musat
- Miruna Luminita Draganescu
- Cristian Onisor
- Mihaela Lungu
- Silvia Fotea
- Aurel Nechita
- Bogdan Ioan Stefanescu
- Laura Gheuca‑Solovastru
View Affiliations

Affiliations: Department of Morphological and Functional Sciences, Faculty of Medicine and Pharmacy, ‘Dunărea de Jos’ University, 800216 Galati, Romania, Multidisciplinary Integrated Center of Dermatological Interface Research MIC-DIR (Centrul Integrat Multidisciplinar de Cercetare de Interfata Dermatologica - CIM-CID), ‘Dunarea de Jos’ University, 800010 Galati, Romania, Clinical Department, Faculty of Medicine and Pharmacy, ‘Gr. T. Popa’ University of Medicine and Pharmacy, 700115 Iași, Romania, Clinical Medicine, Faculty of Medicine and Pharmacy, ‘Dunărea de Jos’ University, 800216 Galati, Romania, Department of Clinical Surgery, Faculty of Medicine and Pharmacy, ‘Gr. T. Popa’ University of Medicine and Pharmacy, 700115 Iași, Romania
Published online on: December 13, 2021 https://doi.org/10.3892/etm.2021.11057
Article Number: 134
Copyright: © Bobeica et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Systemic sclerosis (SSc) is a chronic inflammatory disease with autoimmune determinism having an incompletely known pathogenesis. Although not all links in the pathogenic chain are known, studies have shown that vasculopathy is the initial event and is followed by extensive fibrosis of the skin and internal organs. New therapeutic strategies have been developed in recent years, thanks to innovative research which has increased understanding of the disease mechanisms. No curative treatment for SSc is currently known. Therefore, the therapeutic target in SSc is its symptomatology. Peripheral vasculopathy can be improved by administering vasodilators. Endothelin receptor antagonists and 5‑phosphodiesterase inhibitors have a double benefit, both on peripheral and on pulmonary vasculopathy. Several molecules with antifibrotic effects are currently available; however, further studies are needed to confirm their beneficial effects. Immunosuppressants manage to control the cutaneous and visceral fibrotic process, thereby remaining as first‑line drugs in the treatment of SSc. Although biological therapy using rituximab and tocilizumab has shown promising results in pulmonary fibrosis, ongoing studies are needed to determine their exact impact. The authors have differing views on the triggering role of glucocorticoids and the benefits of angiotensin‑converting enzyme inhibitors in renal scleroderma. Some aspects of this disease such as calcinosis and pruritus, asthenia, or joint and muscle damage, remain difficult to manage.

View Figures

View References

1	Sierra-Sepúlveda A, Esquinca-González A, Benavides-Suárez SA, Sordo-Lima DE, Caballero-Islas AE, Cabral-Castañeda AR and Rodríguez-Reyna TS: Systemic sclerosis pathogenesis and emerging therapies, beyond the fibroblast. Biomed Res Int. 2019(4569826)2019.PubMed/NCBI View Article : Google Scholar
2	Barsotti S, Orlandi M, Codullo V, Di Battista M, Lepri G, Della Rossa A and Guiducci S: One year in review 2019: Systemic sclerosis. Clin Exp Rheumatol. 37 (Suppl 119):S3–S14. 2019.PubMed/NCBI
3	Juche A, Siegert E, Mueller-Ladner U, Riemekesten G, Günther C, Kötter I, Henes J, Blank N, Voll RE, Ehrchen J, et al: Reality of inpatient vasoactive treatment with prostacyclin derivatives in patients with acral circulation disorders due to systemic sclerosis in Germany. Z Rheumatol. 79:1057–1066. 2020.PubMed/NCBI View Article : Google Scholar : (In German).
4	Kowal-Bielecka O, Landewé R, Avouac J, Chwiesko S, Miniati I, Czirjak L, Clements P, Denton C, Farge D, Fligelstone K, et al: EULAR recommendations for the treatment of systemic sclerosis: A report from the EULAR scleroderma trials and research group (EUSTAR). Ann Rheum Dis. 68:620–628. 2009.PubMed/NCBI View Article : Google Scholar
5	Bobeica C, Niculet E, Halip AI, Gheuca-Solovastru L, Draganescu ML, Popescu IA, Onisor C, Chirobocea S, Lungu M and Craescu M: Predictive value of immunological markers in systemic sclerosis. Exp Ther Med. 22(994)2021.PubMed/NCBI View Article : Google Scholar
6	Denton CP: Advances in pathogenesis and treatment of systemic sclerosis. Clin Med (Lond). 16:55–60. 2016.PubMed/NCBI View Article : Google Scholar
7	Matsumoto Y, Hayashi H, Tahara K, Yasuda T, Tsubouchi S, Yamamoto Y, Mizuuchi T, Mori H and Sawada T: Intravenous cyclophosphamide for gastric antral vascular ectasia associated with systemic sclerosis refractory to endoscopic treatment: A case report and review of the pertinent literature. Intern Med. 58:135–139. 2019.PubMed/NCBI View Article : Google Scholar
8	Lynch JP III and McCune WJ: Immunosuppressive and cytotoxic pharmacotherapy for pulmonary disorders. Am J Respir Crit Care Med. 155:395–420. 1997.PubMed/NCBI View Article : Google Scholar
9	Konma J, Kotani T, Shoda T, Suzuka T, Fujiki Y, Nagai K, Hata K, Yoshida S, Takeuchi T, Makino S and Arawaka S: Efficacy and safety of combination therapy with prednisolone and oral tacrolimus for progressive interstitial pneumonia with systemic sclerosis: A retrospective study. Mod Rheumatol. 28:1009–1015. 2019.PubMed/NCBI View Article : Google Scholar
10	Hughes M and Herrick AL: Digital ulcers in systemic sclerosis. Rheumatology (Oxford). 56:14–25. 2017.PubMed/NCBI View Article : Google Scholar
11	Khor CG, Chen XL, Lin TS, Lu CH and Hsieh SC: Rituximab for refractory digital infarcts and ulcers in systemic sclerosis. Clin Rheumatol. 33:1019–1020. 2014.PubMed/NCBI View Article : Google Scholar
12	Beckett VL, Conn DL, Fuster V, Osmundson PJ, Strong CG, Chao EY, Chesebro JH and O'Fallon WM: Trial of platelet-inhibiting drug in scleroderma. Double-blind study with dipyridamole and aspirin. Arthritis Rheum. 27:1137–1143. 1984.PubMed/NCBI View Article : Google Scholar
13	Bobeică C, Tatu AL, Crăescu M and Solovăstru L: Dynamics of digital ulcers in systemic sclerosis. Exp Ther Med. 20:61–67. 2020.PubMed/NCBI View Article : Google Scholar
14	Denton CP, Howell KS, Stratton RJ and Black CM: Long-term low molecular weight heparin therapy for severe Raynaud's phenomenon: A pilot study. Clin Exp Rheumatol. 18:499–502. 2000.PubMed/NCBI
15	Haustein UF: Systemic sclerosis-scleroderma. Dermatol Online J. 8(3)2002.PubMed/NCBI
16	Goodfield MJ and Rowell NR: Treatment of peripheral gangrene due to systemic sclerosis with intravenous pentoxifylline. Clin Exp Dermatol. 14:161–162. 1989.PubMed/NCBI View Article : Google Scholar
17	Berman B and Duncan MR: Pentoxifylline inhibits the proliferation of human fibroblasts derived from keloid, scleroderma and morphea skin and their production of collagen, glycosaminoglycans and fibronectin. Br J Dermatol. 123:339–346. 1990.PubMed/NCBI View Article : Google Scholar
18	Fiori G, Marzi T, Bartoli F, Bruni C, Ciceroni C, Palomba M, Zolferino M, Corsi E, Galimberti M, Moggi Pignone A, et al: The challenge of pet therapy in systemic sclerosis: Evidence for an impact on pain, anxiety, neuroticism and social interaction. Clin Exp Rheumatol. 36 (Suppl 113):135–141. 2018.PubMed/NCBI
19	Thakkar V, Nikpour M, Stevens WM and Proudman SM: Prospects for improving outcomes in systemic sclerosis-related pulmonary hypertension. Intern Med J. 45:248–254. 2015.PubMed/NCBI View Article : Google Scholar
20	Channick RN, Simonneau G, Sitbon O, Robbins IM, Frost A, Tapson VF, Badesch DB, Roux S, Rainisio M, Bodin F and Rubin LJ: Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: A randomized placebo-controlled study. Lancet. 358:1119–1123. 2001.PubMed/NCBI
21	Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, Pulido T, Frost A, Roux S, Leconte I, et al: Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 346:896–903. 2002.PubMed/NCBI View Article : Google Scholar
22	Rebegea L, Firescu D, Baciu G and Ciubara A: Psycho-oncology support. BRAIN. 10:77–88. 2019.
23	Solovăstru LG, Stîncanu A, De Ascentii A, Capparé G, Mattana P and Vâţă D: Randomized, controlled study of innovative spray formulation containing ozonated oil and α-bisabolol in the topical treatment of chronic venous leg ulcers. Adv Skin Wound Care. 28:406–409. 2015.PubMed/NCBI View Article : Google Scholar
24	van den Hoogen FH, Boerbooms AM, Swaak AJ, Rasker JJ, van Lier HJ and van de Putte LB: Comparison of methotrexate with placebo in the treatment of systemic sclerosis: A 24-week randomized double-blind trial, followed by a 24-week observational trial. Br J Rheumatol. 35:364–372. 1996.PubMed/NCBI View Article : Google Scholar
25	Arakawa H, Yamasaki M, Kurihara Y, Yamada H and Nakajima Y: Methotrexate induced pulmonary injury: Serial CT findings. J Thorac Imaging. 18:231–236. 2003.PubMed/NCBI View Article : Google Scholar
26	Steen VD and Medsger TA Jr: Case-control study of corticosteroids and other drugs that either precipitate or protect from the development of renal scleroderma crisis. Arthritis Rheum. 41:1613–1619. 1998.PubMed/NCBI View Article : Google Scholar
27	Steen VD, Costantino JP, Shapiro AP and Medsger TA Jr: Outcome of renal crisis in systemic sclerosis: Relation to availability of angiotensin converting enzyme (ACE) inhibitors. Ann Intern Med. 113:352–357. 1990.PubMed/NCBI View Article : Google Scholar
28	Steen VD and Medsger TA Jr: Long-term outcomes of renal scleroderma crisis. Ann Intern Med. 133:600–603. 2000.PubMed/NCBI View Article : Google Scholar
29	Bütikofer L, Varisco PA, Distler O, Kowal-Bielecka O, Allanore Y, Riemekasten G, Villiger PM and Adler S: EUSTAR collaborators. ACE inhibitors in SSc patients display a risk factor for scleroderma renal crisis-a EUSTAR analysis. Arthritis Res Ther. 22(59)2020.PubMed/NCBI View Article : Google Scholar
30	Tyndal AJ, Bannert B, Vonk M, Airò P, Cozzi F, Carreira PE, Bancel DF, Allanore Y, Müller-Ladner U, Distler O, et al: Causes and risk factors of death in systemic sclerosis: A study from the EULAR scleroderma trials and research (EUSTAR) database. Ann Rheum Dis. 69:1809–1815. 2010.PubMed/NCBI View Article : Google Scholar
31	Gasbarrini A, Lauritano EC, Gabrielli M, Scarpellini E, Lupascu A, Ojeti V and Gasbarrini G: Small intestinal bacterial overgrowth: Diagnosis and treatment. Dig Dis. 25:237–240. 2007.PubMed/NCBI View Article : Google Scholar
32	Chong MS, Ng WK and Chan JK: Concise review: Endothelial progenitor cells in regenerative medicine: Applications and challenges. Stem Cells Transl Med. 5:530–538. 2016.PubMed/NCBI View Article : Google Scholar
33	Sukmawati D and Tanaka R: Introduction to next generation of endothelial progenitor cell therapy: A promise in vascular medicine. Am J Transl Res. 7:411–421. 2015.PubMed/NCBI
34	Tatu AL and Ionescu MA: Multiple autoimmune syndrome type III-thyroiditis, vitiligo and alopecia areata. Acta Endocrinol (Buchar). 13:124–125. 2017.PubMed/NCBI View Article : Google Scholar
35	Nwabudike LC, Elisei AM, Buzia OD, Miulescu M and Tatu AL: Statins. A review on structural perspectives, adverse reactions and relations with son-melanoma skin cancer. Rev Chim (Buchar). 69:2557–2562. 2018.
36	Mihăilă B, Dinică RM, Tatu AL and Buzia OD: New insights in vitiligo treatments using bioactive compounds from Piper nigrum. Exp Ther Med. 17:1039–1044. 2019.PubMed/NCBI View Article : Google Scholar
37	Zheng JN, Yang QR, Zhu GQ, Pan L, Xia JX and Wang Q: Comparative efficacy and safety of immunosuppressive therapies for systemic sclerosis related interstitial lung disease: A Bayesian network analysis. Mod Rheumatol. 30:687–695. 2020.PubMed/NCBI View Article : Google Scholar
38	Gonzalez-Nieto JA, Martin-Suares IJ and Gil-Munoz FL: Eficacia del micofenolato asociado a metotrexato como tratamiento de mantenimiento de la enfermedad pulmonary intersticial asociada a la sclerosis sistémica. Arch Bronconeumol. 47(575)2011.