Submitted Successfully!
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Ver. Summary Created by Modification Content Size Created at Operation
1 -- 1871 2022-08-15 09:08:57 |
2 layout Meta information modification 1871 2022-08-15 09:25:23 |

Video Upload Options

Do you have a full video?


Are you sure to Delete?
If you have any further questions, please contact Encyclopedia Editorial Office.
Ebata, S.;  Yoshizaki-Ogawa, A.;  Sato, S.;  Yoshizaki, A. Systemic Sclerosis Treatment. Encyclopedia. Available online: (accessed on 04 December 2023).
Ebata S,  Yoshizaki-Ogawa A,  Sato S,  Yoshizaki A. Systemic Sclerosis Treatment. Encyclopedia. Available at: Accessed December 04, 2023.
Ebata, Satoshi, Asako Yoshizaki-Ogawa, Shinichi Sato, Ayumi Yoshizaki. "Systemic Sclerosis Treatment" Encyclopedia, (accessed December 04, 2023).
Ebata, S.,  Yoshizaki-Ogawa, A.,  Sato, S., & Yoshizaki, A.(2022, August 15). Systemic Sclerosis Treatment. In Encyclopedia.
Ebata, Satoshi, et al. "Systemic Sclerosis Treatment." Encyclopedia. Web. 15 August, 2022.
Systemic Sclerosis Treatment

Systemic sclerosis (SSc) is a connective tissue disease caused by abnormal activation of the immune system. Characterized by vascular damage and fibrosis in various organs, the disease has a high frequency of complications, a poor prognosis, and high unmet medical needs.

systemic sclerosis interstitial lung disease nintedanib tocilizumab rituximab

1. Introduction

Systemic sclerosis (SSc) is a connective tissue disease caused by abnormal activation of the immune system [1][2][3]. Characterized by vascular damage and fibrosis in various organs, the disease has a high frequency of complications, a poor prognosis, and high unmet medical needs [4][5][6][7][8].
Among the complications of SSc, potent therapeutic agents have already been found for the vascular complications of renal crisis and SSc-associated pulmonary arterial hypertension (SSc-PAH). Advances in treatment algorithms have resulted in lower mortality rates from these complications than in the past [9][10][11][12][13][14][15][16][17][18]. For renal crisis, treatment of hypertension with angiotensin-converting enzyme inhibitors has markedly improved prognosis [19]. SSc-PAH remains a difficult complication to manage, but treatment with pulmonary vasodilators early in the course of the disease has improved outcomes. A sub-analysis of the AMBITION study revealed that the combination of ambrisentan, an endothelin receptor antagonist, and tadalafil, a phosphodiesterase type 5 inhibitor, was greatly effective in the treatment of SSc-PAH [20].
In contrast, the development of sufficiently effective and safe therapies for the fibrosis symptoms caused by SSc, such as skin sclerosis and SSc-associated interstitial lung disease (SSc-ILD), has been slow and remains a major challenge [18][21][22][23]. Previously, cyclophosphamide was the only drug shown to be effective for skin sclerosis or ILD in SSc patients in a double-blind, randomized, or placebo-controlled trial [24]. However, cyclophosphamide is carcinogenic and cannot be administered long-term. The therapeutic effects of cyclophosphamide on SSc do not last for 2 years [25]. Other than cyclophosphamide, immunosuppressive therapy with methotrexate or mycophenolate mofetil may be used for fibrotic lesions in SSc. However, methotrexate failed to show significant improvements in skin sclerosis compared with the placebo in previous randomized controlled trials [26][27]. Mycophenolate mofetil was reported in the SLS II study to be not clearly different from cyclophosphamide in improving FVC for patients with SSc-ILD. However, mycophenolate mofetil failed to show superiority over cyclophosphamide in this study [28]. Additionally, the efficacy of mycophenolate mofetil has not been validated in a placebo-controlled randomized controlled trial. For these reasons, neither methotrexate nor mycophenolate mofetil is approved for SSc and is off-label when used. Autologous hematopoietic stem cell transplantation (HSCT) has been reported to significantly improve skin sclerosis and SSc-ILD compared to cyclophosphamide in open-label, randomized, and controlled trials [29][30][31][32]. However, a major problem with autologous HSCT is the high rate of treatment-related adverse events and mortality. Safety issues require careful consideration of the indications for autologous HSCT and limit the patients for whom it should be indicated [33].
Thus, treatment for skin sclerosis and ILD, important complications of SSc, has not been well established. Skin sclerosis is the most important indicator in the diagnostic criteria for SSc [34]. Its degree has been reported to correlate with poor prognosis in SSc patients [35]. In addition, SSc-ILD is the most common direct cause of death in SSc, surpassing renal crisis and SSc-PAH [4][36]. The development of therapies for fibrotic lesions in SSc is highly desirable.

2. Nintedanib

Nintedanib, an indolinone derivative, is a triple kinase inhibitor that strongly inhibits vascular endothelial growth factor receptor, fibroblast growth factor receptor, and platelet-derived growth factor receptor [37]. It suppresses fibroblast proliferation by blocking mitogen-activated protein kinase and Akt signaling pathways in three types of cells involved in angiogenesis: endothelial cells, pericytes, and smooth muscle cells [38].
Nintedanib was first clinically applied for idiopathic pulmonary fibrosis (IPF). In the INPULSIS studies, nintedanib was shown to significantly suppress the annual rate of decrease in forced vital capacity (FVC) in patients with IPF compared with the placebo [39]. The adjusted annual rate of change in FVC was −114.7 mL in the nintedanib group and −239.9 mL in the placebo group in the INPULSIS-1 study (difference 125.3 [95% CI 77.7 to 172.8]; p < 0.001), and −113.6 mL in the nintedanib group and −207.3 mL in the placebo group in the INPULSIS-2 study (difference 93.7 [95% CI 44.8 to 142.7]; p < 0.001). This means that while nintedanib did not improve IPF, it suppressed the degree of FVC reduction by approximately half. Approved by the FDA in October 2014 for the treatment of IPF, nintedanib is recommended for conditional use in the IPF treatment guidelines of the American Thoracic Society, the European Respiratory Society, the Japanese Respiratory Society, and the Latin American Thoracic Association [40].
Having demonstrated antifibrotic effects in patients with IPF, nintedanib was subsequently investigated to expand its application in SSc, a prototype of systemic fibrosis. From 2015 to 2018, the SENSCIS study was conducted on 576 SSc-ILD patients from 32 countries [41]. Patients were randomized 1:1 to orally receive 150 mg of nintedanib twice daily or the placebo and were evaluated 52 weeks after initiation of the study drug. The adjusted annual change in FVC was −52.4 mL/year in the nintedanib group and −93.3 mL/year in the placebo group (difference 41.0 [95% CI 2.9 to 79.0]; p = 0.04). As with IPF, nintedanib did not improve or maintain FVC, but significantly suppressed the degree of FVC reduction. Based on the results of this study, nintedanib for SSc-ILD is now covered by insurance in many regions, with approval from the FDA in September 2019, the Japanese MHLW in December 2019, and the EMA in April 2020.
A unique aspect of the SENSCIS study was that the study drug was allowed to be administered in combination with immunosuppressive agents, such as mycophenolate mofetil. Post-hoc analyses showed that the mean adjusted annual decrease in FVC for patients taking mycophenolate mofetil at baseline was −40.2 mL in the nintedanib group and −66.5 mL in the placebo group (difference 26.3 [95% CI −27.9 to 80.6]). For patients not taking mycophenolate mofetil at baseline, the mean adjusted annual decrease in FVC was −63.9 mL in the nintedanib group and −119.3 mL in the placebo group (difference 55.4 [95% CI 2.3 to 108.5]) [42]. Nintedanib, with or without mycophenolate mofetil, demonstrated better treatment results than the placebo. When nintedanib was used in combination with mycophenolate mofetil, the degree of inhibition of FVC reduction was greater than when it was used alone. Nintedanib, an antifibrotic agent, has a different mechanism of action than the immunosuppressive agents that have been the standard treatment for SSc-ILD. It has been suggested that the combination of an antifibrotic and an immunosuppressive agent may increase the therapeutic efficacy against lung fibrosis in SSc patients.

3. Tocilizumab

Tocilizumab is a recombinant humanized antihuman interleukin 6 (IL-6) receptor monoclonal antibody that binds to the IL-6 receptor with high affinity [43]. IL-6 is a known inflammatory cytokine. For example, in rheumatoid arthritis (RA), IL-6 is produced locally in the joints, causing joint swelling and elevated C-reactive protein. Tocilizumab suppresses inflammation by inhibiting downstream signaling of IL-6 and is effective against various inflammatory diseases [43][44]. The drug is approved in many countries for RA, Castleman’s disease and juvenile idiopathic arthritis, and is also expected to have therapeutic effects on giant cell arteritis, polymyalgia rheumatica, and large-vessel vasculitis [44]. Tocilizumab was also approved for severe COVID-19 treatment by the EMA in 2021 [45].
IL-6 is thought to be involved in the pathogenesis of SSc. It has been reported that serum IL-6 levels in SSc patients correlate with mRSS [46], and that peripheral blood mononuclear cells of SSc patients produce more IL-6 than those of healthy controls [47]. Among SSc patients, the elevation of serum IL-6 levels is particularly prominent in diffuse cutaneous SSc patients with an early onset of the disease, suggesting a strong influence of IL-6 in the disease progression of SSc [48].
Based on these findings, two double-blind, randomized, and placebo-controlled trials of tocilizumab for SSc were conducted. First, the FaSScinate trial was carried out between 2012 and 2015 in 87 patients with SSc in five countries (Canada, France, Germany, the United Kingdom, and the United States) [49]. Patients were randomized 1:1 to receive 162 mg of tocilizumab or the placebo subcutaneously every week. The primary endpoint of the study was the change from baseline in mRSS after 24 weeks of the study drug administration. The mRSS improved by 3.92 in the tocilizumab group and 1.22 in the placebo group, with the difference between the two groups not being statistically significant (difference −2.70 [95% CI −5.85 to 0.45]; p = 0.09). Subsequently, from 2015 to 2019, the FocuSSced trial was conducted on 210 SSc patients from 20 countries in Europe, North America, Latin America, and Japan [50]. As in the FaSScinate trial, patients were randomized 1:1 to receive weekly subcutaneous 162 mg of tocilizumab or the placebo. The primary endpoint of the FocuSSced study was the change in mRSS from baseline at 48 weeks after the study drug administration. The change in mRSS was −6.14 for the tocilizumab group and −4.41 for the placebo group, with no significant difference between the two groups (difference −1.73 [95% CI −3.78–0.32]; p = 0.10). In both the FaSScinate and FocuSSced studies, there was a greater improvement in mRSS in the tocilizumab group than in the placebo group, but the difference did not reach statistical significance. The effect of tocilizumab on improving skin fibrosis in SSc patients seems promising, but it has not yet been fully validated and further studies are needed.

4. Rituximab

Rituximab is a chimeric antibody against CD20, a cell membrane molecule specifically expressed in B cells. It affects the calcium ion regulatory function of CD20, inhibiting B cell signaling and the cell cycle, thereby eliminating B cells. Antibody-dependent cell-mediated cytotoxic effects and complement-dependent cytotoxic effects are also thought to be involved in the elimination of B cells by rituximab [51].
Rituximab was originally used to treat B-cell lymphomas. In recent years, its efficacy against various auto-inflammatory diseases caused by B cells, such as RA, microscopic polyangiitis, and granulomatosis with polyangiitis, has been successively validated [52]. Although the pathogenesis of SSc remains unclear, B cells are thought to play a central role [53][54]. Abnormal B cell function has been identified in SSc, with increased expression of CD19, which is specifically expressed in B cells [55][56]. Therefore, B-cell removal therapy with rituximab was anticipated to be beneficial in the treatment of SSc.
From 2017 to 2019, the DESIRES study was conducted in Japan with 56 SSc patients [57]. Participants were randomized 1:1 to receive either rituximab 375 mg/m2 or the placebo intravenously for four consecutive weeks. The primary endpoint was the change in mRSS from baseline after 24 weeks of the study drug administration. The placebo group showed a 2.14 worsening of mRSS while the rituximab group improved by 6.30, indicating that mRSS was significantly improved in the rituximab group compared to the placebo group (difference −8.44 [95% CI −11.00 to 5.88]; p < 0.00001). Rituximab, in the DESIRES study, is the first SSc therapeutic agent to demonstrate efficacy in a double-blind, randomized, or placebo-controlled trial with a primary endpoint of a measure of skin sclerosis. Based on the results, rituximab was approved for SSc in Japan in September 2021. However, the DESIRES study included only Japanese patients, and rituximab has not been approved for SSc in the United States or Europe.
Rituximab is anticipated to be effective for complications besides fibrotic lesions of SSc, and is currently being tested in clinical trials outside of the DESIRES study. The RESTORE sub-study, a randomized-controlled trial, examined the effect of rituximab on SSc-PAH [58]. Although no statistically significant differences were observed in this study, there was a trend toward a more favorable change in 6-min walking distance in the rituximab group compared with the placebo group, suggesting that rituximab is a promising treatment for SSc-PAH [59]. Rituximab has also been reported to be effective against SSc-related polyarthritis in retrospective studies [60]. If the efficacy of rituximab in these complications is also validated, rituximab will considerably change the treatment strategy for SSc.


  1. LeRoy, E.C.; Black, C.; Fleischmajer, R.; Jablonska, S.; Krieg, T.; Medsger, T.A., Jr.; Rowell, N.; Wollheim, F. Scleroderma (systemic sclerosis): Classification, subsets and pathogenesis. J. Rheumatol. 1988, 15, 202–205.
  2. Allanore, Y.; Simms, R.; Distler, O.; Trojanowska, M.; Pope, J.; Denton, C.P.; Varga, J. Systemic sclerosis. Nat. Rev. Dis. Primers 2015, 1, 15002.
  3. Denton, C.P.; Khanna, D. Systemic sclerosis. Lancet 2017, 390, 1685–1699.
  4. Tyndall, A.J.; Bannert, B.; Vonk, M.; Airò, P.; Cozzi, F.; Carreira, P.E.; Bancel, D.F.; Allanore, Y.; Müller-Ladner, U.; Distler, O.; et al. Causes and risk factors for death in systemic sclerosis: A study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann. Rheum. Dis. 2010, 69, 1809–1815.
  5. Rubio-Rivas, M.; Royo, C.; Simeón, C.P.; Corbella, X.; Fonollosa, V. Mortality and survival in systemic sclerosis: Systematic review and meta-analysis. Semin. Arthritis Rheum. 2014, 44, 208–219.
  6. Elhai, M.; Meune, C.; Avouac, J.; Kahan, A.; Allanore, Y. Trends in mortality in patients with systemic sclerosis over 40 years: A systematic review and meta-analysis of cohort studies. Rheumatology 2012, 51, 1017–1026.
  7. Winthrop, K.L.; Weinblatt, M.E.; Bathon, J.; Burmester, G.R.; Mease, P.J.; Crofford, L.; Bykerk, V.; Dougados, M.; Rosenbaum, J.T.; Mariette, X.; et al. Unmet need in rheumatology: Reports from the Targeted Therapies meeting 2019. Ann. Rheum. Dis. 2020, 79, 88–93.
  8. Smith, V.; Scirè, C.A.; Talarico, R.; Airo, P.; Alexander, T.; Allanore, Y.; Bruni, C.; Codullo, V.; Dalm, V.; De Vries-Bouwstra, J.; et al. Systemic sclerosis: State of the art on clinical practice guidelines. RMD Open 2018, 4, e000782.
  9. Woodworth, T.G.; Suliman, Y.A.; Li, W.; Furst, D.E.; Clements, P. Scleroderma renal crisis and renal involvement in systemic sclerosis. Nat. Rev. Nephrol. 2018, 14, 137.
  10. Nagaraja, V. Management of scleroderma renal crisis. Curr. Opin. Rheumatol. 2019, 31, 223–230.
  11. Bose, N.; Chiesa-Vottero, A.; Chatterjee, S. Scleroderma renal crisis. Semin. Arthritis Rheum. 2015, 44, 687–694.
  12. Zanatta, E.; Polito, P.; Favaro, M.; Larosa, M.; Marson, P.; Cozzi, F.; Doria, A. Therapy of scleroderma renal crisis: State of the art. Autoimmun. Rev. 2018, 17, 882–889.
  13. Lynch, B.M.; Stern, E.P.; Ong, V.; Harber, M.; Burns, A.; Denton, C.P. UK Scleroderma Study Group (UKSSG) guidelines on the diagnosis and management of scleroderma renal crisis. Clin. Exp. Rheumatol. 2016, 34, 106–109.
  14. Almaaitah, S.; Highland, K.B.; Tonelli, A.R. Management of Pulmonary Arterial Hypertension in Patients with Systemic Sclerosis. Integr. Blood Press. Control 2020, 13, 15–29.
  15. Chaisson, N.F.; Hassoun, P.M. Systemic sclerosis-associated pulmonary arterial hypertension. Chest 2013, 144, 1346–1356.
  16. Sundaram, S.M.; Chung, L. An Update on Systemic Sclerosis-Associated Pulmonary Arterial Hypertension: A Review of the Current Literature. Curr. Rheumatol. Rep. 2018, 20, 10.
  17. Williams, M.H.; Das, C.; Handler, C.E.; Akram, M.R.; Davar, J.; Denton, C.P.; Smith, C.J.; Black, C.M.; Coghlan, J.G. Systemic sclerosis associated pulmonary hypertension: Improved survival in the current era. Heart 2006, 92, 926–932.
  18. Denton, C.P.; Ong, V.H. Challenges in evidence-based therapy for systemic sclerosis associated interstitial lung disease. Lancet Respir. Med. 2020, 8, 226–227.
  19. Steen, V.D.; Costantino, J.P.; Shapiro, A.P.; Medsger, T.A., Jr. Outcome of renal crisis in systemic sclerosis: Relation to availability of angiotensin converting enzyme (ACE) inhibitors. Ann. Intern. Med. 1990, 113, 352–357.
  20. 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.; et al. Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): Subgroup analysis from the AMBITION trial. Ann. Rheum. Dis. 2017, 76, 1219–1227.
  21. Herrick, A.; Assassi, S.; Denton, C.P. Skin involvement in early diffuse cutaneous systemic sclerosis: An unmet clinical need. Nat. Rev. Rheumatol. 2022, 18, 276–285.
  22. Hachulla, E.; Agard, C.; Allanore, Y.; Avouac, J.; Bader-Meunier, B.; Belot, A.; Berezne, A.; Bouthors, A.S.; Condette-Wojtasik, G.; Constans, J.; et al. French recommendations for the management of systemic sclerosis. Orphanet. J. Rare Dis. 2021, 16, 322.
  23. Hoffmann-Vold, A.M.; Maher, T.M.; Philpot, E.E.; Ashrafzadeh, A.; Barake, R.; Barsotti, S.; Bruni, C.; Carducci, P.; Carreira, P.E.; Castellví, I.; et al. The identification and management of interstitial lung disease in systemic sclerosis: Evidence-based European consensus statements. Lancet Rheumatol. 2020, 2, e71–e83.
  24. Tashkin, D.P.; Elashoff, R.; Clements, P.J.; Goldin, J.; Roth, M.D.; Furst, D.E.; Arriola, E.; Silver, R.; Strange, C.; Bolster, M.; et al. Cyclophosphamide versus placebo in scleroderma lung disease. N. Engl. J. Med. 2006, 354, 2655–2666.
  25. Tashkin, D.P.; Elashoff, R.; Clements, P.J.; Roth, M.D.; Furst, D.E.; Silver, R.M.; Goldin, J.; Arriola, E.; Strange, C.; Bolster, M.B.; et al. Effects of 1-year treatment with cyclophosphamide on outcomes at 2 years in scleroderma lung disease. Am. J. Respir. Crit. Care Med. 2007, 176, 1026–1034.
  26. van den Hoogen, F.H.; Boerbooms, A.M.; Swaak, A.J.; Rasker, J.J.; van Lier, H.J.; van de Putte, L.B. 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. 1996, 35, 364–372.
  27. Pope, J.E.; Bellamy, N.; Seibold, J.R.; Baron, M.; Ellman, M.; Carette, S.; Smith, C.D.; Chalmers, I.M.; Hong, P.; O’Hanlon, D.; et al. A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma. Arthritis Rheum. 2001, 44, 1351–1358.
  28. 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.; et al. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): A randomised controlled, double-blind, parallel group trial. Lancet Respir. Med. 2016, 4, 708–719.
  29. Sullivan, K.M.; Goldmuntz, E.A.; Keyes-Elstein, L.; McSweeney, P.A.; Pinckney, A.; Welch, B.; Mayes, M.D.; Nash, R.A.; Crofford, L.J.; Eggleston, B.; et al. Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma. N. Engl. J. Med. 2018, 378, 35–47.
  30. van Laar, J.M.; Farge, D.; Sont, J.K.; Naraghi, K.; Marjanovic, Z.; Larghero, J.; Schuerwegh, A.J.; Marijt, E.W.; Vonk, M.C.; Schattenberg, A.V.; et al. Autologous hematopoietic stem cell transplantation vs. intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: A randomized clinical trial. JAMA 2014, 311, 2490–2498.
  31. Burt, R.K.; Oliveira, M.C.; Shah, S.J.; Moraes, D.A.; Simoes, B.; Gheorghiade, M.; Schroeder, J.; Ruderman, E.; Farge, D.; Chai, Z.J.; et al. Cardiac involvement and treatment-related mortality after non-myeloablative haemopoietic stem-cell transplantation with unselected autologous peripheral blood for patients with systemic sclerosis: A retrospective analysis. Lancet 2013, 381, 1116–1124.
  32. Burt, R.K.; Shah, S.J.; Dill, K.; Grant, T.; Gheorghiade, M.; Schroeder, J.; Craig, R.; Hirano, I.; Marshall, K.; Ruderman, E.; et al. Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): An open-label, randomised phase 2 trial. Lancet 2011, 378, 498–506.
  33. Burt, R.K.; Farge, D. Systemic sclerosis: Autologous HSCT is efficacious, but can we make it safer? Nat. Rev. Rheumatol. 2018, 14, 189–191.
  34. van den Hoogen, F.; Khanna, D.; Fransen, J.; Johnson, S.R.; Baron, M.; Tyndall, A.; Matucci-Cerinic, M.; Naden, R.P.; Medsger, T.A., Jr.; Carreira, P.E.; et al. 2013 classification criteria for systemic sclerosis: An American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum. 2013, 65, 2737–2747.
  35. Wu, W.; Jordan, S.; Graf, N.; de Oliveira Pena, J.; Curram, J.; Allanore, Y.; Matucci-Cerinic, M.; Pope, J.E.; Denton, C.P.; Khanna, D.; et al. Progressive skin fibrosis is associated with a decline in lung function and worse survival in patients with diffuse cutaneous systemic sclerosis in the European Scleroderma Trials and Research (EUSTAR) cohort. Ann. Rheum. Dis. 2019, 78, 648–656.
  36. Cottin, V.; Brown, K.K. Interstitial lung disease associated with systemic sclerosis (SSc-ILD). Respir. Res. 2019, 20, 13.
  37. Hilberg, F.; Roth, G.J.; Krssak, M.; Kautschitsch, S.; Sommergruber, W.; Tontsch-Grunt, U.; Garin-Chesa, P.; Bader, G.; Zoephel, A.; Quant, J.; et al. BIBF 1120: Triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008, 68, 4774–4782.
  38. Wollin, L.; Wex, E.; Pautsch, A.; Schnapp, G.; Hostettler, K.E.; Stowasser, S.; Kolb, M. Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis. Eur. Respir. J. 2015, 45, 1434–1445.
  39. Richeldi, L.; du Bois, R.M.; Raghu, G.; Azuma, A.; Brown, K.K.; Costabel, U.; Cottin, V.; Flaherty, K.R.; Hansell, D.M.; Inoue, Y.; et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N. Engl. J. Med. 2014, 370, 2071–2082.
  40. Raghu, G.; Rochwerg, B.; Zhang, Y.; Garcia, C.A.; Azuma, A.; Behr, J.; Brozek, J.L.; Collard, H.R.; Cunningham, W.; Homma, S.; et al. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis. An Update of the 2011 Clinical Practice Guideline. Am. J. Respir. Crit. Care Med. 2015, 192, e3–e19.
  41. Distler, O.; Highland, K.B.; Gahlemann, M.; Azuma, A.; Fischer, A.; Mayes, M.D.; Raghu, G.; Sauter, W.; Girard, M.; Alves, M.; et al. Nintedanib for Systemic Sclerosis-Associated Interstitial Lung Disease. N. Engl. J. Med. 2019, 380, 2518–2528.
  42. 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.; et al. Efficacy and safety of nintedanib in patients with systemic sclerosis-associated interstitial lung disease treated with mycophenolate: A subgroup analysis of the SENSCIS trial. Lancet Respir. Med. 2021, 9, 96–106.
  43. Scott, L.J. Tocilizumab: A Review in Rheumatoid Arthritis. Drugs 2017, 77, 1865–1879.
  44. Sheppard, M.; Laskou, F.; Stapleton, P.P.; Hadavi, S.; Dasgupta, B. Tocilizumab (Actemra). Hum. Vaccin. Immunother. 2017, 13, 1972–1988.
  45. Yin, J.; Li, C.; Ye, C.; Ruan, Z.; Liang, Y.; Li, Y.; Wu, J.; Luo, Z. Advances in the development of therapeutic strategies against COVID-19 and perspectives in the drug design for emerging SARS-CoV-2 variants. Comput. Struct. Biotechnol. J. 2022, 20, 824–837.
  46. Sato, S.; Hasegawa, M.; Takehara, K. Serum levels of interleukin-6 and interleukin-10 correlate with total skin thickness score in patients with systemic sclerosis. J. Dermatol. Sci. 2001, 27, 140–146.
  47. Gurram, M.; Pahwa, S.; Frieri, M. Augmented interleukin-6 secretion in collagen-stimulated peripheral blood mononuclear cells from patients with systemic sclerosis. Ann. Allergy 1994, 73, 493–496.
  48. Hasegawa, M.; Sato, S.; Fujimoto, M.; Ihn, H.; Kikuchi, K.; Takehara, K. Serum levels of interleukin 6 (IL-6), oncostatin M, soluble IL-6 receptor, and soluble gp130 in patients with systemic sclerosis. J. Rheumatol. 1998, 25, 308–313.
  49. 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.; et al. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): A phase 2, randomised, controlled trial. Lancet 2016, 387, 2630–2640.
  50. Khanna, D.; Lin, C.J.F.; Furst, D.E.; Goldin, J.; Kim, G.; Kuwana, M.; Allanore, Y.; Matucci-Cerinic, M.; Distler, O.; Shima, Y.; et al. Tocilizumab in systemic sclerosis: A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir. Med. 2020, 8, 963–974.
  51. Harcia-Montoya, L.; Villota-Eraso, C.; Md Yusof, M.Y.; Vital, E.M.; Emery, P. Lessons for rituximab therapy in patients with rheumatoid arthritis. Lancet Rheumatol. 2020, 2, e497–e509.
  52. Lee, D.S.W.; Rojas, O.L.; Gommerman, J.L. B cell depletion therapies in autoimmune disease: Advances and mechanistic insights. Nat. Rev. Drug Discov. 2021, 20, 179.
  53. Yoshizaki, A. Pathogenic roles of B lymphocytes in systemic sclerosis. Immunol. Lett. 2018, 195, 76–82.
  54. De Luca, G.; Tomelleri, A.; Dagna, L.; Matucci-Cerinic, M. The target on B cells in Systemic Sclerosis: A “midsummer dream” to extinguish inflammation and prevent early disease progression to fibrosis. Clin. Rheumatol. 2021, 40, 2529.
  55. Sato, S.; Fujimoto, M.; Hasegawa, M.; Takehara, K.; Tedder, T.F. Altered B lymphocyte function induces systemic autoimmunity in systemic sclerosis. Mol. Immunol. 2004, 41, 1123–1133.
  56. Tsuchiya, N.; Kuroki, K.; Fujimoto, M.; Murakami, Y.; Tedder, T.F.; Tokunaga, K.; Takehara, K.; Sato, S. Association of a functional CD19 polymorphism with susceptibility to systemic sclerosis. Arthritis Rheum. 2004, 50, 4002–4007.
  57. Ebata, S.; Yoshizaki, A.; Oba, K.; Kashiwabara, K.; Ueda, K.; Uemura, Y.; Watadani, T.; Fukasawa, T.; Miura, S.; Yoshizaki-Ogawa, A.; et al. Safety and efficacy of rituximab in systemic sclerosis (DESIRES): A double-blind, investigator-initiated, randomised, placebo-controlled trial. Lancet Rheumatol. 2021, 3, e489–e497.
  58. Zamanian, R.T.; Badesch, D.; Chung, L.; Domsic, R.T.; Medsger, T.; Pinckney, A.; Keyes-Elstein, L.; D’Aveta, C.; Spychala, M.; White, R.J.; et al. Safety and Efficacy of B-Cell Depletion with Rituximab for the Treatment of Systemic Sclerosis-associated Pulmonary Arterial Hypertension: A Multicenter, Double-Blind, Randomized, Placebo-controlled Trial. Am. J. Respir. Crit. Care Med. 2021, 204, 209–221.
  59. Zhang, Y.; Michelakis, E.D. A Phase-2 NIH-sponsored Randomized Clinical Trial of Rituximab in Scleroderma-associated Pulmonary Arterial Hypertension Did Not Reach Significance for Its Endpoints: End of Story? Not So Fast! Am. J. Respir. Crit. Care Med. 2021, 204, 123–125.
  60. Tuğsal, H.Y.; Zengin, B.; Kenar, G.; Önen, F.; Birlik, M. Rituximab on lung, skin, and joint involvement in patients with systemic sclerosis: A case series study and review of the literature. Int. J. Rheum. Dis. 2022, 25, 755–768.
Subjects: Rheumatology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to : , , ,
View Times: 403
Revisions: 2 times (View History)
Update Date: 15 Aug 2022