
Targeted therapy for systemic sclerosis: how close are we?
- Select a language for the TTS:
- UK English Female
- UK English Male
- US English Female
- US English Male
- Australian Female
- Australian Male
- Language selected: (auto detect) - EN
Play all audios:
ABSTRACT Despite recent etiopathogenetic advances, systemic sclerosis continues to be one of the most complex systemic autoimmune disease in terms of its therapeutic management. There is no
drug tested for any autoimmune disease that has not also been tested for systemic sclerosis, but none have proven effective. Substantial changes have occurred in the last decade, however,
with the appearance of new therapeutic targets and the consequent development of highly selective drugs, some of which, such as endothelin antagonists, are now widely used and others, such
as tyrosine kinase inhibitors, in which much hope has been placed. There is also increasing interest in evaluating drugs that are capable of blocking fibrotic processes mediated by
transforming growth factor β, which are currently used in nonautoimmune diseases (such as antidiabetic drugs or statins). Unfortunately, recent trials on these new molecules have produced
negative results. Increasing research into disease-specific therapies targeting distinct biological pathways should continue. In the future, it is hoped that the simultaneous or sequential
use of different drugs will provide better results than currently available monotherapies in patients with systemic sclerosis. KEY POINTS * Systemic sclerosis (SSc) is a systemic autoimmune
disease with a complex etiopathogenic scenario combining autoimmune, vascular and fibrotic damage * Oral endothelin antagonists are a highly specific outpatient treatment for the vascular
complications of SSc, which include pulmonary arterial hypertension, digital ulcers and complicated Raynaud phenomenon * Etiopathogenic advances have opened the door to the use of drugs
commonly used in other areas of medicine such as statins and antidiabetic agents * The development of selective therapies blocking fibrotic pathways is one of the principal novel and
promising therapeutic approaches in SSc * Studies suggest a change in approach from monotherapy to combined therapy, as the blockade of various pathways could produce better, longer-lasting
results * Improved prognostic classification and serological markers are needed to help quantify the contribution of each major etiopathogenic pathway in a given patient at a given time
Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this
journal Receive 12 print issues and online access $209.00 per year only $17.42 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now
Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer
support SIMILAR CONTENT BEING VIEWED BY OTHERS SYSTEMIC LUPUS ERYTHEMATOSUS: UPDATED INSIGHTS ON THE PATHOGENESIS, DIAGNOSIS, PREVENTION AND THERAPEUTICS Article Open access 17 March 2025
TREAT-TO-TARGET IN SYSTEMIC LUPUS ERYTHEMATOSUS: ADVANCING TOWARDS ITS IMPLEMENTATION Article 17 January 2022 STATE-OF-THE-ART EVIDENCE IN THE TREATMENT OF SYSTEMIC SCLEROSIS Article 27
February 2023 REFERENCES * Gabrielli, A., Avvedimento, E. V. & Krieg, T. Scleroderma. _N. Engl. J. Med._ 360, 1989–2003 (2009). Article CAS PubMed Google Scholar * Charles, C.,
Clements, P. & Furst, D. E. Systemic sclerosis: hypothesis-driven treatment strategies. _Lancet_ 367, 1683–1691 (2006). Article PubMed Google Scholar * Black, C. M., Matucci-Cerinic,
M. & Guillevin, L. Progress in systemic sclerosis: a 10-year perspective. _Rheumatology (Oxford)_ 48, iii1–iii2 (2009). Article Google Scholar * Pope, J. E. Connective tissue diseases:
new evidence-based guidelines for treating SSc. _Nat. Rev. Rheumatol._ 5, 300–302 (2009). Article PubMed Google Scholar * Boin, F. & Wigley, F. Connective tissue diseases:
immunosuppressive therapy in SSc: what is the target? _Nat. Rev. Rheumatol._ 5, 357–358 (2009). Article CAS PubMed Google Scholar * Hunzelmann, N. _ et al_. High frequency of
corticosteroid and immunosuppressive therapy in patients with systemic sclerosis despite limited evidence for efficacy. _Arthritis Res. Ther._ 11, R30 (2009). Article PubMed PubMed Central
CAS Google Scholar * Simeón-Aznar, C. P. _ et al_. Intravenous cyclophosphamide pulse therapy in the treatment of systemic sclerosis-related interstitial lung disease: a long term study.
_Open Respir. Med. J._ 2, 39–45 (2008). Article PubMed PubMed Central CAS Google Scholar * van den Hoogen, F. H. _ et al_. 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). Article CAS PubMed Google Scholar * Pope,
J. E. _ et al_. A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma. _Arthritis Rheum._ 44, 1351–1358 (2001). Article CAS PubMed Google Scholar *
Nannini, C., West, C. P., Erwin, P. J. & Matteson, E. L. Effects of cyclophosphamide on pulmonary function in patients with scleroderma and interstitial lung disease: a systematic review
and meta-analysis of randomized controlled trials and observational prospective cohort studies. _Arthritis Res. Ther._ 10, R124 (2008). Article PubMed PubMed Central CAS Google Scholar
* Tashkin, D. P. _ et al_. Effects of 1-year treatment with cyclophosphamide on outcomes at 2 years in scleroderma lung disease. _Am. J. Respir. Crit. Care Med._ 176, 1026–1034 (2007).
Article CAS PubMed PubMed Central Google Scholar * Kowal-Bielecka, O. _ 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). Article CAS PubMed Google Scholar * Airò, P. _ et al_. Intravenous cyclophosphamide for interstitial lung disease
associated to systemic sclerosis: results with an 18 month long protocol including a maintenance phase. _Clin. Exp. Rheumatol._ 25, 293–296 (2007). PubMed Google Scholar * Pakas, I. _ et
al_. Cyclophosphamide with low or high dose prednisolone for systemic sclerosis lung disease. _J. Rheumatol._ 29, 298–304 (2002). CAS PubMed Google Scholar * Yiannopoulos, G. _ et al_.
Combination of intravenous pulses of cyclophosphamide and methyprednisolone in patients with systemic sclerosis and interstitial lung disease. _Rheumatol. Int._ 27, 357–361 (2007). Article
CAS PubMed Google Scholar * Bérezné, A. _ et al_. Therapeutic strategy combining intravenous cyclophosphamide followed by oral azathioprine to treat worsening interstitial lung disease
associated with systemic sclerosis: a retrospective multicenter open-label study. _J. Rheumatol._ 35, 1064–1072 (2008). PubMed Google Scholar * Hoyles, R. K. _ et al_. A multicenter,
prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in
scleroderma. _Arthritis Rheum._ 54, 3962–3970 (2006). Article CAS PubMed Google Scholar * Zamora, A. C. Use of mycophenolate mofetil to treat scleroderma-associated interstitial lung
disease. _Respir. Med._ 102, 150–155 (2008). Article PubMed Google Scholar * Vanthuyne, M. _ et al_. A pilot study of mycophenolate mofetil combined to intravenous methylprednisolone
pulses and oral low-dose glucocorticoids in severe early systemic sclerosis. _Clin. Exp. Rheumatol._ 25, 287–292 (2007). CAS PubMed Google Scholar * Gerbino, A. J., Goss, C. H. &
Molitor, J. A. Effect of mycophenolate mofetil on pulmonary function in scleroderma-associated interstitial lung disease. _Chest_ 133, 455–460 (2008). Article CAS PubMed Google Scholar *
Saketkoo, L. A. & Espinoza, L. R. Experience of mycophenolate mofetil in 10 patients with autoimmune-related interstitial lung disease demonstrates promising effects. _Am. J. Med. Sci._
337, 329–335 (2009). Article PubMed Google Scholar * ClinicalTrials.gov: a service of the US National Institutes of Health. Mycophenolate mofetil in systemic sclerosis, [online] (2010).
* ClinicalTrials.gov: a service of the US National Institutes of Health. Comparison of Therapeutic Regimens for Scleroderma Interstitial Lung Disease (The Scleroderma Lung Study II) (SLSII),
[online] (2010). * Antoniou, K. M. _ et al_. Infliximab therapy in pulmonary fibrosis associated with collagen vascular disease. _Clin. Exp. Rheumatol._ 25, 23–28 (2007). CAS PubMed
Google Scholar * Denton, C. P. _ et al_. An open-label pilot study of infliximab therapy in diffuse cutaneous systemic sclerosis. _Ann. Rheum. Dis._ 68, 1433–1439 (2009). Article CAS
PubMed Google Scholar * Ramos-Casals, M. _ et al_. Autoimmune diseases induced by TNF-targeted therapies: analysis of 233 cases. _Medicine (Baltimore)_ 86, 242–251 (2007). Article Google
Scholar * Lafyatis, R. _ et al_. B cell depletion with rituximab in patients with diffuse cutaneous systemic sclerosis. _Arthritis Rheum._ 60, 578–583 (2009). Article PubMed PubMed
Central Google Scholar * Smith, V. P. _ et al_. Rituximab in diffuse cutaneous systemic sclerosis: an open-label clinical and histopathological study. _Ann. Rheum. Dis._ 69, 193–197
(2010). Article CAS PubMed Google Scholar * Cancro, M. P., D'Cruz, D. P. & Khamashta, M. A. The role of B lymphocyte stimulator (BLyS) in systemic lupus erythematosus. _J. Clin.
Invest._ 119, 1066–1073 (2009). Article CAS PubMed PubMed Central Google Scholar * Tyndall, A., Matucci-Cerinic, M. & Müller-Ladner, U. Future targets in the management of systemic
sclerosis. _Rheumatology (Oxford)_ 48, iii49–iii53 (2009). Article Google Scholar * Matsushita, T. _ et al_. Elevated serum BAFF levels in patients with systemic sclerosis: enhanced BAFF
signaling in systemic sclerosis B lymphocytes. _Arthritis Rheum._ 54, 192–201 (2006). Article CAS PubMed Google Scholar * Nevskaya, T. _ et al_. Autologous progenitor cell implantation
as a novel therapeutic intervention for ischaemic digits in systemic sclerosis. _Rheumatology (Oxford)_ 48, 61–64 (2009). Article CAS Google Scholar * Nikolov, N. P. & Pavletic, S. Z.
Technology insight: hematopoietic stem cell transplantation for systemic rheumatic disease. _Nat. Clin. Pract. Rheumatol._ 4, 184–191 (2008). Article PubMed Google Scholar * Vonk, M. C.
_ et al_. Long-term follow-up results after autologous haematopoietic stem cell transplantation for severe systemic sclerosis. _Ann. Rheum. Dis._ 67, 98–104 (2008). Article CAS PubMed
Google Scholar * Nash, R. A. _ et al_. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis: long-term follow-up of the US
multicenter pilot study. _Blood_ 110, 1388–1396 (2007). Article CAS PubMed PubMed Central Google Scholar * van Laar, J. M., Farge, D. & Tyndall, A. Stem cell transplantation: a
treatment option for severe systemic sclerosis? _Ann. Rheum. Dis._ 67, iii35–iii38 (2008). Article PubMed Google Scholar * McLaughlin, V. _ et al_. Pulmonary arterial hypertension: the
most devastating vascular complication of systemic sclerosis. _Rheumatology (Oxford)_ 48, iii25–iii31 (2009). Article Google Scholar * Sitbon, O. _ et al_. Long-term intravenous
epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. _J. Am. Coll. Cardiol._ 40, 780–788 (2002). Article CAS PubMed Google Scholar * McLaughlin, V.
V., Shillington, A. & Rich, S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. _Circulation_ 106, 1477–1482 (2002). Article CAS PubMed Google Scholar
* Badesch, D. B. _ et al_. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized controlled trial. _Ann. Intern. Med._ 132,
425–434 (2000). Article CAS PubMed Google Scholar * Barst, R. J. _ et al_. Long-term outcome in pulmonary arterial hypertension patients treated with subcutaneous treprostinil. _Eur.
Respir. J._ 28, 1195–1203 (2006). Article CAS PubMed Google Scholar * Oudiz, R. J. _ et al_. Treprostinil, a prostacyclin analogue, in pulmonary arterial hypertension associated with
connective tissue disease. _Chest_ 126, 420–427 (2004). Article CAS PubMed Google Scholar * Olschewski, H. _ et al_. Inhaled iloprost for severe pulmonary hypertension. _N. Engl. J.
Med._ 347, 322–329 (2002). Article CAS PubMed Google Scholar * Wigley, F. M. _ et al_. Intravenous iloprost infusion in patients with Raynaud phenomenon secondary to systemic sclerosis.
A multicenter, placebo-controlled, double-blind study. _Ann. Intern. Med._ 120, 199–206 (1994). Article CAS PubMed Google Scholar * Rademaker, M. _ et al_. Comparison of intravenous
infusions of iloprost and oral nifedipine in treatment of Raynaud's phenomenon in patients with systemic sclerosis: a double blind randomised study. _BMJ_ 298, 561–564 (1989). Article
CAS PubMed PubMed Central Google Scholar * Scorza, R. _ et al_. Effects of longterm cyclic iloprost therapy in systemic sclerosis with Raynaud's phenomenon. A randomized, controlled
study. _Clin. Exp. Rheumatol._ 19, 503–508 (2001). CAS PubMed Google Scholar * Mayes, M. D. Endothelin and endothelin receptor antagonists in systemic rheumatic disease. _Arthritis
Rheum._ 48, 1190–1199 (2003). Article CAS PubMed Google Scholar * Channick, R. N. _ et al_. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary
hypertension: a randomised placebo-controlled study. _Lancet_ 358, 1119–1123 (2001). Article CAS PubMed Google Scholar * Rubin, L. J. _ et al_. Bosentan therapy for pulmonary arterial
hypertension. _N. Engl. J. Med._ 346, 896–903 (2002). Article CAS PubMed Google Scholar * McLaughlin, V. V. Survival in patients with pulmonary arterial hypertension treated with
first-line bosentan. _Eur. J. Clin. Invest._ 36, 10–15 (2006). Article CAS PubMed Google Scholar * Williams, M. H. _ et al_. Systemic sclerosis associated pulmonary hypertension:
improved survival in the current era. _Heart_ 92, 926–932 (2006). Article CAS PubMed Google Scholar * Galie, N. _ et al_. Treatment of patients with mildly symptomatic pulmonary arterial
hypertension with bosentan (EARLY study): a double-blind, randomized controlled trial. _Lancet_ 371, 2093–2100 (2008). Article CAS PubMed Google Scholar * Korn, J. H. _ et al_. Digital
ulcers in systemic sclerosis. Prevention by treatment with bosentan, an oral endothelin receptor antagonist. _Arthritis Rheum._ 50, 3985–3993 (2004). Article CAS PubMed Google Scholar *
Seibold, J. R. _ et al_. Bosentan reduces the number of new digital ulcers in patients with systemic sclerosis [abstract]. _Ann. Rheum. Dis._ 65 (Suppl. 2), 90 (2006). Google Scholar *
Ramos-Casals, M. _ et al_. Successful treatment of severe Raynaud's phenomenon with bosentan in four patients with systemic sclerosis. _Rheumatology (Oxford)_ 43, 1454–1456 (2004).
Article CAS Google Scholar * Funauchi, M. _ et al_. Effects of bosentan on the skin lesions: an observational study from a single center in Japan. _Rheumatol. Int._ 29, 769–775 (2009).
Article CAS PubMed Google Scholar * García de la Peña-Lefebvre, P. _ et al_. Long-term experience of bosentan for treating ulcers and healed ulcers in systemic sclerosis patients.
_Rheumatology (Oxford)_ 47, 464–466 (2008). Article Google Scholar * Riccardi, M. T. _ et al_. Treatment of digital ulcers in systemtic sclerosis with endothelin-1 receptor antagonist
(bosentan) [Italian]. _Reumatismo._ 59, 135–139 (2007). CAS PubMed Google Scholar * Hettema, M. E., Zhang, D., Bootsma, H. & Kallenberg, C. G. Bosentan therapy for patients with
severe Raynaud's phenomenon in systemic sclerosis. _Ann. Rheum. Dis._ 66, 1398–1399 (2007). Article CAS PubMed PubMed Central Google Scholar * Launay, D. _ et al_. Bosentan for
treatment of active digital ulcers in patients with systemic sclerosis [French]. _Presse Med._ 35, 587–592 (2006). Article PubMed Google Scholar * Gore, J. & Silver, R. Oral
sildenafil for the treatment of Raynaud's phenomenon and digital ulcers secondary to systemic sclerosis. _Ann. Rheum. Dis._ 64, 1387 (2005). Article CAS PubMed PubMed Central Google
Scholar * Fries, R., Shariat K, von Wilmowsky, H. & Böhm, M. Sildenafil in the treatment of Raynaud's phenomenon resistant to vasodilatory therapy. _Circulation_ 112, 2980–2985
(2005). Article CAS PubMed Google Scholar * Tsifetaki, N. _ et al_. Bosentan for digital ulcers in patients with systemic sclerosis: a prospective 3-year followup study. _J. Rheumatol._
36, 1550–1552 (2009). Article PubMed Google Scholar * King, T. E. Jr _ et al_. Bosentan for the treatment of idiopathic pulmonary fibrosis: randomized, double-blind, placebo-controlled
BUILD 1 study. _Am. J. Respir. Crit. Care Med._ 177, 75–81 (2008). Article CAS PubMed Google Scholar * Seibold, J. R. _ et al_. Bosentan versus placebo in interstitial lung disease
secondary to systemic sclerosis (SSc): the BUILD-2 study [abstract]. _Am. J. Respir. Crit. Care Med._ 173, A243 (2006). Google Scholar * Barst, R. J. _ et al_. Sitaxsentan therapy for
pulmonary arterial hypertension. _Am. J. Respir. Crit. Care Med._ 169, 441–447 (2004). Article PubMed Google Scholar * Barst, R. J. _ et al_. Treatment of pulmonary arterial hypertension
with the selective endothelin-A receptor antagonist sitaxsentan. _J. Am. Coll. Cardiol._ 47, 2049–2056 (2006). Article CAS PubMed Google Scholar * Girgis, R. E. _ et al_. Selective
endothelin A receptor antagonism with sitaxsentan for pulmonary arterial hypertension associated with connective tissue disease. _Ann. Rheum. Dis._ 66, 1467–1472 (2007). Article CAS PubMed
PubMed Central Google Scholar * Benza, R. L. _ et al_. Sitaxsentan treatment for patients with pulmonary arterial hypertension discontinuing bosentan. J. _Heart Lung Transplant._ 26,
63–69 (2007). Article Google Scholar * Humbert, M. _ et al_. Results of European post-marketing surveillance of bosentan in pulmonary hypertension. _Eur. Respir. J._ 30, 338–344 (2007).
Article CAS PubMed Google Scholar * Galie, N. _ et al_. Sildenafil citrate therapy for pulmonary arterial hypertension. _N. Engl. J. Med._ 353, 2148–2157 (2005). Article CAS PubMed
Google Scholar * Badesch, D. B. _ et al_. Sildenafil for pulmonary arterial hypertension associated with connective tissue disease. _J. Rheumatol._ 34, 2417–2422 (2007). PubMed Google
Scholar * Rosato, E. _ et al_. Plasma adrenomedullin and endothelin-1 levels are reduced and Raynaud's phenomenon improved by daily tadalafil administration in male patients with
systemic sclerosis. _J. Biol. Regul. Homeost. Agents_ 23, 23–29 (2009). CAS PubMed Google Scholar * Schiopu, E. _ et al_. Randomized placebo-controlled crossover trial of tadalafil in
Raynaud's phenomenon secondary to systemic sclerosis. _J. Rheumatol._ 36, 2264–2268 (2009). Article CAS PubMed Google Scholar * Galiè, N. _ et al_. Tadalafil therapy for pulmonary
arterial hypertension. _Circulation_ 119, 2894–2903 (2009). Article PubMed CAS Google Scholar * Denton, C. P., Black, C. M. & Abraham, D. J. Mechanisms and consequences of fibrosis
in systemic sclerosis. _Nat. Clin. Pract. Rheumatol._ 2, 134–144 (2006). Article PubMed Google Scholar * Distler, J. H. & Distler, O. Criteria to select molecular targets for
anti-fibrotic therapy. _Rheumatology (Oxford)_ 47 (Suppl. 5), v12–v13 (2008). Article CAS Google Scholar * Chung, L. _ et al_. Molecular framework for response to imatinib mesylate in
systemic sclerosis. _Arthritis Rheum._ 60, 584–591 (2009). Article CAS PubMed PubMed Central Google Scholar * Pannu, J. _ et al_. Smad1 pathway is activated in systemic sclerosis
fibroblasts and is targeted by imatinib mesylate. _Arthritis Rheum._ 58, 2528–2537 (2008). Article CAS PubMed Google Scholar * Distler, J. H. _ et al_. Imatinib mesylate reduces
production of extracellular matrix and prevents development of experimental dermal fibrosis. _Arthritis Rheum._ 56, 311–322 (2007). Article CAS PubMed Google Scholar * Kantarjian, H. _
et al_. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. _N. Engl. J. Med._ 354, 2542–2551 (2006). Article PubMed Google Scholar * Talpaz, M. _ et al_.
Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. _N. Engl. J. Med._ 354, 2531–2541 (2006). Article CAS PubMed Google Scholar * Hehlmann, R., Hochhaus, A. &
Baccarani, M. Chronic myeloid leukaemia. _Lancet_ 370, 342–350 (2007). Article CAS PubMed Google Scholar * Kerkela, R. _ et al_. Cardiotoxicity of the cancer therapeutic agent imatinib
mesylate. _Nat. Med._ 12, 908–916 (2006). Article PubMed CAS Google Scholar * Akhmetshina, A. _ et al_. Treatment with imatinib prevents fibrosis in different preclinical models of
systemic sclerosis and induces regression of established fibrosis. _Arthritis Rheum._ 60, 219–224 (2009). Article CAS PubMed Google Scholar * Akhmetshina, A. _ et al_. Dual inhibition of
c-abl and PDGF receptor signaling by dasatinib and nilotinib for the treatment of dermal fibrosis. _FASEB J._ 22, 2214–2222 (2008). Article CAS PubMed Google Scholar * van Daele, P. L.
_ et al_. Is imatinib mesylate a promising drug in systemic sclerosis? _Arthritis Rheum._ 58, 2549–2552 (2008). Article CAS PubMed Google Scholar * Sfikakis, P. P. _ et al_. Imatinib for
the treatment of refractory, diffuse systemic sclerosis. _Rheumatology (Oxford)_ 47, 735–737 (2008). Article CAS Google Scholar * Sabnani, I. _ et al_. A novel therapeutic approach to
the treatment of scleroderma-associated pulmonary complications: safety and efficacy of combination therapy with imatinib and cyclophosphamide. _Rheumatology (Oxford)_ 48, 49–52 (2009).
Article CAS Google Scholar * Sgonc, R. & Wick, G. Pro- and anti-fibrotic effects of TGF-beta in scleroderma. _Rheumatology (Oxford)_ 47 (Suppl. 5), v5–v7 (2008). Article CAS Google
Scholar * Varga, J. & Pasche, B. Transforming growth factor beta as a therapeutic target in systemic sclerosis. _Nat. Rev. Rheumatol._ 5, 200–206 (2009). Article CAS PubMed PubMed
Central Google Scholar * Belvisi, M. G. & Hele, D. J. Peroxisome proliferator-activated receptors as novel targets in lung disease. _Chest_ 134, 152–157 (2008). CAS PubMed Google
Scholar * Wu, M. _ et al_. Rosiglitazone abrogates bleomycin-induced scleroderma and blocks profibrotic responses through peroxisome proliferator-activated receptor-gamma. _Am. J. Pathol._
174, 519–533 (2009). Article CAS PubMed PubMed Central Google Scholar * Yamada, H. _ et al_. Tranilast inhibits collagen synthesis in normal, scleroderma and keloid fibroblasts at a
late passage culture but not at an early passage culture. _J. Dermatol. Sci._ 9, 45–47 (1995). Article CAS PubMed Google Scholar * Li, C. _ et al_. Inhibitory effect of pravastatin on
transforming growth factor beta1-inducible gene h3 expression in a rat model of chronic cyclosporine nephropathy. _Am. J. Nephrol._ 25, 611–620 (2005). Article CAS PubMed Google Scholar
* Del Papa, N. _ et al_. Simvastatin reduces endothelial activation and damage but is partially ineffective in inducing endothelial repair in systemic sclerosis. _J. Rheumatol._ 35,
1323–1328 (2008). CAS PubMed Google Scholar * Kuwana, M. _ et al_. Increase in circulating endothelial precursors by atorvastatin in patients with systemic sclerosis. _Arthritis Rheum._
53, 1946–1951 (2006). Article CAS Google Scholar * Abou-Raya, A. _ et al_. Statins: potentially useful therapy of systemic sclerosis-related Raynaud's phenomenon and digital ulcers.
_J. Rheumatol._ 35, 1801–1808 (2008). CAS PubMed Google Scholar * Blagojevic, J. & Matucci-Cerinic, M. Are statins useful for treating vascular involvement in systemic sclerosis?
_Nat. Clin. Pract. Rheumatol._ 5, 70–71 (2009). Article CAS PubMed Google Scholar * Denton, C. P. _ et al_. Recombinant human anti-transforming growth factor beta1 antibody therapy in
systemic sclerosis: a multicenter, randomized, placebo-controlled phase I/II trial of CAT-192. _Arthritis Rheum._ 56, 323–333 (2007). Article CAS PubMed Google Scholar * Trojanowska, M.
Role of PDGF in fibrotic diseases and systemic sclerosis. _Rheumatology (Oxford)_ 47 (Suppl. 5), v2–v4 (2008). Article CAS Google Scholar * Baroni, S. S. _ et al_. Stimulatory
autoantibodies to the PDGF receptor in systemic sclerosis. _N. Engl. J. Med._ 354, 2667–2676 (2006). Article CAS PubMed Google Scholar * Classen, J. F. _ et al_. Lack of evidence of
stimulatory autoantibodies to platelet-derived growth factor receptor in patients with systemic sclerosis. _Arthritis Rheum._ 60, 1137–1144 (2009). Article CAS PubMed Google Scholar *
Ponticos, M. _ et al_. Pivotal role of connective tissue growth factor in lung fibrosis: MAPK-dependent transcriptional activation of type I collagen. _Arthritis Rheum._ 60, 2142–2155
(2009). Article CAS PubMed Google Scholar * Abraham, D. Connective tissue growth factor: growth factor, matricellular organizer, fibrotic biomarker or molecular target for anti-fibrotic
therapy in SSc? _Rheumatology (Oxford)_ 47 (Suppl. 5), v8–v9 (2008). Article CAS Google Scholar * Hemmatazad, H. _ et al_. Histone deacetylase 7, a potential target for the antifibrotic
treatment of systemic sclerosis. _Arthritis Rheum._ 60, 1519–1529 (2009). Article PubMed Google Scholar * Cantin, A. M., North, S. L., Fells, G. A., Hubbard, R. C. & Crystal, R. G.
Oxidant-mediated epithelial cell injury in idiopathic pulmonary fibrosis. _J. Clin. Invest._ 79, 1665–1673 (1987). Article CAS PubMed PubMed Central Google Scholar * Azuma, A. _ et al_.
Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. _Am. J. Respir. Crit. Care Med._ 171, 1040–1047 (2005). Article PubMed Google Scholar
* Levitt, J. & Gould, M. K. Poor choice of primary outcome in a clinical trial of pirfenidone in patients with IPF. _Am. J. Respir. Crit. Care Med._ 172, 1228–1229 (2005). Article
PubMed Google Scholar * Nagai, S. _ et al_. Open-label compassionate use one year-treatment with pirfenidone to patients with chronic pulmonary fibrosis. _Intern. Med._ 41, 1118–1123
(2002). Article CAS PubMed Google Scholar * Behr, J., Degenkolb, B., Krombach, F. & Vogelmeier, C. Intracellular glutathione and bronchoalveolar cells in fibrosing alveolitis:
effects of _N_-acetylcysteine. _Eur. Respir. J._ 19, 906–911 (2002). Article CAS PubMed Google Scholar * Demedts, M. _ et al_. High-dose acetylcysteine in idiopathic pulmonary fibrosis.
_N. Engl. J. Med._ 353, 2229–2242 (2005). Article CAS PubMed Google Scholar * Rosato, E., Borghese, F., Pisarri, S. & Salsano, F. The treatment with _N_-acetylcysteine of
Raynaud's phenomenon and ischemic ulcers therapy in sclerodermic patients: a prospective observational study of 50 patients. _Clin. Rheumatol._ 28, 1379–1384 (2009). Article PubMed
Google Scholar * Samuel, C. S., Lekgabe, E. D. & Mookerjee, I. The effects of relaxin on extracellular matrix remodeling in health and fibrotic disease. _Adv. Exp. Med. Biol._ 612,
88–103 (2007). Article PubMed Google Scholar * Samuel, C. S. _ et al_. The relaxin gene knockout mouse: a model of progressive scleroderma. _J. Invest. Dermatol._ 125, 692–699 (2005).
Article CAS PubMed Google Scholar * Giordano, N. _ et al_. Serum relaxin in systemic sclerosis. _J. Rheumatol._ 32, 2164–2166 (2005). CAS PubMed Google Scholar * Seibold, J. R. _ et
al_. Recombinant human relaxin in the treatment of scleroderma. A randomized, double-blind, placebo-controlled trial. _Ann. Intern. Med._ 132, 871–879 (2000). Article CAS PubMed Google
Scholar * Khanna, D. _ et al_. Recombinant human relaxin in the treatment of systemic sclerosis with diffuse cutaneous involvement: a randomized, double-blind, placebo-controlled trial.
_Arthritis Rheum._ 60, 1102–1111 (2009). Article CAS PubMed PubMed Central Google Scholar * McLaughlin, V. V. _ et al_. Randomized study of adding inhaled iloprost to existing bosentan
in pulmonary arterial hypertension. _Am. J. Respir. Crit. Care Med._ 174, 1257–1263 (2006). Article CAS PubMed Google Scholar * Humbert, M. _ et al_. Combination of bosentan with
epoprostenol in pulmonary arterial hypertension: BREATHE-2. _Eur. Respir. J._ 24, 353–359 (2004). Article CAS PubMed Google Scholar * Simonneau, G. _ et al_. Addition of sildenafil to
long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. _Ann. Intern. Med._ 149, 521–530 (2008). Article PubMed Google Scholar *
Gruenig, E. _ et al_. Acute hemodynamic effects of single-dose sildenafil when added to established bosentan therapy in patients with pulmonary arterial hypertension: results of the
COMPASS-1 study. _J. Clin. Pharmacol._ 49, 1343–1352 (2009). Article CAS PubMed Google Scholar * Catapano-Minotti, G., Corsonello, A., Guadalupi, G., Spani, R. & Antonelli-Incalzi,
R. Treatment of severe pulmonary hypertension secondary to scleroderma: a three-drug approach. _Intern. Med._ 47, 511–513 (2008). Article PubMed Google Scholar * Corriveau, M. P. _ et
al_. The fibrotic phenotype of systemic sclerosis fibroblasts varies with disease duration and severity of skin involvement: reconstitution of skin fibrosis development using a tissue
engineering approach. _J. Pathol._ 217, 534–542 (2009). Article PubMed Google Scholar Download references ACKNOWLEDGEMENTS The authors wish to thank David Buss for his editorial
assistance with this Review. Charles P. Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and
answers of the MedscapeCME-accredited continuing medical education activity associated with this article. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Laboratory of Autoimmune Diseases
Josep Font, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain Manuel Ramos-Casals & Pilar Brito-Zerón *
Department of Internal Medicine, Hospital Vall d'Hebron, Passeig Vall d'Hebron 119–129, 08035, Barcelona, Spain Vicent Fonollosa-Pla * Primary Care Research Group, IDIBAPS,
University of Barcelona, CAP Les Corts, GESCLINIC, 08028, Barcelona, Spain Antoni Sisó-Almirall Authors * Manuel Ramos-Casals View author publications You can also search for this author
inPubMed Google Scholar * Vicent Fonollosa-Pla View author publications You can also search for this author inPubMed Google Scholar * Pilar Brito-Zerón View author publications You can also
search for this author inPubMed Google Scholar * Antoni Sisó-Almirall View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence
to Manuel Ramos-Casals. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE
THIS ARTICLE Ramos-Casals, M., Fonollosa-Pla, V., Brito-Zerón, P. _et al._ Targeted therapy for systemic sclerosis: how close are we?. _Nat Rev Rheumatol_ 6, 269–278 (2010).
https://doi.org/10.1038/nrrheum.2010.48 Download citation * Published: 13 April 2010 * Issue Date: May 2010 * DOI: https://doi.org/10.1038/nrrheum.2010.48 SHARE THIS ARTICLE Anyone you share
the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer
Nature SharedIt content-sharing initiative