Systemic Sclerosis and Fibrotic Conditions

RMMJ Rambam Maimonides Medical Journal Rambam Health Care Campus 2016 October; 7(4): e0030. ISSN: 2076-9172
Published online 2016 October 31. doi: 10.5041/RMMJ.10257
Special Issue on Rheumatology
Guest Editor: Alexandra Balbir-Gurman, M.D.

Targeted Therapy in Systemic Sclerosis

Murray Baron, M.D.*

Chief Division of Rheumatology, Jewish General Hospital, Montreal, Quebec, Canada; and Professor of Medicine, McGill University, Montreal, Quebec, Canada


Targeted therapies use an understanding of the pathophysiology of a disease in an individual patient. Although targeted therapy for systemic sclerosis (SSc, scleroderma) has not yet reached the level of patient-specific treatments, recent developments in the understanding of the global pathophysiology of the disease have led to new treatments based on the cells and pathways that have been shown to be involved in the disease pathogenesis. The presence of a B cell signature in skin biopsies has led to the trial of rituximab, an anti-CD20 antibody, in SSc. The well-known properties of transforming growth factor (TGF)-β in promoting collagen synthesis and secretion has led to a small trial of fresolimumab, a human IgG4 monoclonal antibody capable of neutralizing TGF-β. Evidence supporting important roles for interleukin-6 in the pathogenesis of SSc have led to a large trial of tocilizumab in SSc. Soluble guanylate cyclase (sGC) is an enzyme that catalyzes the production of cyclic guanosine monophosphate (cGMP) upon binding of nitric oxide (NO) to the sGC molecule. Processes such as cell growth and proliferation are regulated by cGMP. Evidence that sGC may play a role in SSc has led to a trial of riociguat, a molecule that sensitizes sGC to endogenous NO. Tyrosine kinases (TKs) are involved in a wide variety of physiologic and pathological processes including vascular remodeling and fibrogenesis such as occurs in SSc. This has led to a trial of nintedanib, a next-generation tyrosine-kinase (TK) inhibitor which targets multiple TKs, in SSc.

Keywords: Drug treatment, scleroderma, systemic sclerosis, targeted, therapy


Systemic sclerosis (SSc, or scleroderma) is a serious multi-system disorder of connective tissue disease characterized clinically by thickening and fibrosis of the skin and involvement of internal organs, most commonly the lungs, gastrointestinal tract, and heart. Systemic sclerosis affects predominantly women in the prime of their life and is associated with increased morbidity and mortality. Systemic sclerosis is a rare disease with prevalence estimates varying from 30 to 443/million population.1,2

Because the disease is so heterogeneous and rare, it has been difficult to perform high-quality randomized controlled clinical trials. Unfortunately, the few such trials performed, especially early ones, have not been uniformly successful. Therapies studied in randomized controlled trials that have failed include ketanserin,3 5-fluorouracil,4 ketotifen,5 interferon-gamma,6 interferon-alpha,7 penicillamine,8 relaxin,9,10 methotrexate,11 oral collagen,12 imatinib,13,14 IVIG,15 macitentan,16 and bosentan.17,18 More recently there have been some hopeful positive trials with statins,19 cyclophosphamide,20 and autologous stem cell transplantation.21,22

Could we be more successful with a more targeted approach to therapy in SSc, similar to that taken in other diseases such as cancer? For example, in melanoma, BRAF kinase-activating mutations can turn BRAF into an oncogene, and the presence of such mutations has led to specific therapy.23 Similar analyses of non-small cell lung cancer has found that mutations in the epidermal growth factor receptor (EGFR), translocations involving the anaplastic lymphoma kinase (ALK) tyrosine kinase, oncogenic RAS mutations, and other driver mutations, such as BRAF, can be treated with therapy targeted at these abnormalities.24

In SSc we are entering a very exciting and hopeful era with 316 trials for SSc listed on Some of these trials have used, or are using, new biologic agents or kinase inhibitors such as abatacept,26 rituximab,25 imatinib, dasatinib, fasudil,27 nintedanib,28 and fresolimumab, an anti-transforming growth factor (TGF) antibody.29 A phase III trial of tocilizumab is underway. Some of these trials are based on the concept of targeting specific pathophysiologic abnormalities that have been found in SSc. We have thus hopefully moved away from general immunosuppressives such as cyclophosphamide or methotrexate to drugs that inhibit specific pathways or cells thought to be active in SSc. These represent the first steps toward personalized targeted medicine in SSc.


One promising approach to possible biomarkers that may indicate that a certain subset may respond to specific targeted therapy has come from the study of the gene expression found in skin biopsies.2937 Early work demonstrated that some patients with SSc had a skin gene expression signature consistent with the presence of active B cells.31 This observation has led directly to two trials of rituximab (RTX), an anti-CD20 monoclonal antibody, in SSc.38,39 In the first publication 15 patients with diffuse cutaneous systemic sclerosis (dcSSc) received two doses of rituximab 1 g each, 2 weeks apart.39 The mean change in the modified Rodnan skin score (MRSS) between baseline and 6 months was not significant. Results of pulmonary function tests and other measures of major organ involvement were stable. The modest B cell infiltrates that were present in most skin biopsy specimens at baseline were completely depleted at 6 months in most patients. In the other trial, 14 patients with SSc were evaluated.38 Eight patients were randomized to receive two cycles of RTX at baseline and 24 weeks, whereas six patients (control group) received standard treatment alone. There was a significant increase of forced vital capacity (FVC) in the RTX group compared with baseline. The median percentage of improvement of FVC in the RTX group was 10.25%, whereas that of deterioration in the controls was 5.04% (P=0.002). Skin thickening, assessed with the MRSS, improved significantly in the RTX group compared with the baseline score (mean±SD 13.5±6.84 versus 8.37±6.45 at baseline versus 1 year, respectively, P<0.001). Rituximab depleted both circulating B cells and dermal B cells. In the RTX-treated group, there was a significant reduction of collagen deposition in the papillary dermis at 24 weeks compared with baseline which was not seen in the control group. The EUSTAR group also published an observational study assessing the effects of RTX on skin and lung fibrosis in patients with SSc.40 Comparison between RTX-treated patients and matched controls revealed a significant difference in favor of RTX. However, to this author’s knowledge, rituximab has not strictly been employed as targeted therapy such as treating only those patients with a skin biopsy showing B cell activation or analyzing the results in patients with skin biopsies that show B cell activation versus those with no such pattern.


It is well-known that TGF-β promotes collagen synthesis, secretion, processing, and cross-linking as well as secretion of other matrix molecules, such as fibronectin and thrombospondin.41 This has led to an interest in using anti-TGF-β in SSc. The first trial of CAT-192, a recombinant human antibody that neutralizes TGF-β1, was not successful.42 However, a more recent study tested fresolimumab, a first-in-class human IgG4 κ monoclonal antibody capable of neutralizing all mammalian isoforms of TGF-β.29 There is a four-gene, pharmacodynamic biomarker of SSc skin disease, based on gene expression in a mid-forearm skin biopsy.29 Two of the four genes making up the biomarker, thrombospondin-1 (THBS1) and cartilage oligomeric protein (COMP), are highly regulated by TGF-β. In this open uncontrolled trial, the predefined primary efficacy outcome was change in COMP and THBS1 mRNA expression in skin after treatment compared with that at baseline. Subjects showed rapid declines in THBS1 and COMP gene expression in skin biopsies after treatment with fresolimumab. THBS1 and COMP gene expression was strikingly higher in SSc patient cohorts than in healthy control skin, and changes in gene expression in study patients generally correlated with changes in MRSS.


Another promising therapy consists of inhibition of interleukin (IL)-6. Evidence supports important roles for IL-6 in the pathogenesis of SSc, e.g. dermal fibroblasts from SSc patients constitutively express higher levels of IL-6 than found in healthy controls; serum and skin levels of IL-6 are elevated in SSc patients with early disease and in patients with SSc or SSc-interstitial lung disease (ILD), and increased IL-6 levels have been associated with higher mortality, more severe skin involvement, and increased incidence of progressive pulmonary decline.4348 Strategies to block the IL-6 response resulted in a significant reduction of procollagen type I in cultured SSc fibroblasts and myofibroblastic differentiation in dermal fibroblasts in a bleomycin-induced model of dermal sclerosis.49,50 Some indirect evidence of increased effect of IL-6 in SSc derives from the fact that CRP is elevated in SSc although not to levels associated with diseases such as rheumatoid arthritis.51 C-reactive protein (CRP) levels in dcSSc are higher than in limited cutaneous SSc (lcSSc).51,52

These findings have led to a phase II trial of tocilizumab in early dcSSc.53 The primary end-point showed a treatment difference of −2.70 MRSS units in favor of tocilizumab at week 24 but did not quite reach statistical significance. Exploratory analysis of lung function showed that fewer patients in the tocilizumab arm had a decline in percentage-predicted forced vital capacity than in the placebo arm by comparison of the cumulative distribution by week 48. Tocilizumab specifically downregulated the expression of myeloid-associated genes in the skin and decreased circulating levels of CCL18, a chemokine associated with fibrosis and progression of SSc-associated lung disease. A phase III trial is underway.


Soluble guanylate cyclase (sGC) is an enzyme that catalyzes the production of cyclic guanosine monophosphate (cGMP) upon binding of nitric oxide (NO) to the sGC molecule. Once released by the sGC, cGMP can act as a second messenger to activate further downstream targets, such as cGMP-regulated ion channels, protein kinases (G-kinases), and phosphodiesterases (PDEs). Through those effectors, cGMP regulates a variety of physiological processes, including cell growth and proliferation, vascular tone and remodeling, immune responses, and neuronal transmission. Riociguat is a molecule that sensitizes sGC to endogenous NO by stabilizing NO–sGC binding.54,55 Riociguat also directly stimulates sGC, independent of NO, resulting in increased generation of cGMP. Riociguat has been shown in large randomized controlled clinical trials to be effective in patients with different forms of pulmonary hypertension including patients with SSc-related pulmonary arterial hypertension (PAH).

There is evidence that sGC may play a role in SSc. Soluble guanylate cyclase activators inhibited the release of TGF-β-induced extracellular matrix proteins from primary dermal fibroblasts obtained from both normal volunteers and SSc subjects, and dermal fibrosis was reduced in the bleomycin skin fibrosis model of SSc.56,57 Riociguat has been shown in large randomized controlled clinical trials to be effective in patients with different forms of pulmonary hypertension, including patients with SSc-related PAH,58 and is now in a trial for the skin thickening of SSc.


The last molecule that we will briefly address is nintedanib, a next-generation, potent, indolinone-derived small molecule tyrosine-kinase (TK) inhibitor which targets multiple TKs.5961 Tyrosine kinases are involved in a wide variety of physiologic and pathological processes including vascular remodeling and fibrogenesis. Nintedanib leads to inhibition of several central molecules involved in fibroblast activation such as PDFGR-α and PDFGR-β, FGFR-1, FGFR-2, FGFR-3, VEGFR-1, VEGFR-2, VEGFR-3, and Src.

Nintedanib reduced differentiation of myofibroblasts and the release of collagen of dermal fibroblasts from patients with SSc and healthy individuals. Nintedanib also showed anti-fibrotic effects in a dose-dependent manner in different animal models of SSc, including the bleomycin skin fibrosis model both in preventive and therapeutic applications, the chronic graft-versus-host disease model, and the Tsk-1 model. Interestingly, in the Fra-2 tg mouse model, nintedanib did not only inhibit skin and lung fibrosis but also improved the pulmonary vascular lesions resembling PAH.61 Based on these results, a large, randomized, placebo-controlled trial with nintedanib is currently initiated in patients with SSc for pulmonary fibrosis.


Although we are in an exciting new era of drug trials for SSc, and although the drugs discussed here are being used because of their abilities to interfere with specific cells or pathways that have been found to be involved in SSc or SSc models, the field of targeted therapy has not yet progressed quite as far as it has in cancer. The next big step will be to understand if the new drugs are effective specifically in patients who demonstrate abnormalities of the cells or pathways that are inhibited or activated by these new medications. Then we will be closer to developing a truly personalized approach to the treatment of this serious disease.


ALK anaplastic lymphoma kinase
cGMP cyclic guanosine monophosphate
COMP cartilage oligomeric protein
dcSSc diffuse cutaneous systemic sclerosis
EGFR epidermal growth factor receptor
FVC forced vital capacity
G-kinases protein kinases
GMP guanosine monophosphate
IL-6 interleukin-6
ILD interstitial lung disease
lcSSc limited cutaneous systemic sclerosis
MRSS modified Rodnan skin score
NO nitric oxide
PDEs phosphodiesterases
RTX rituximab
sGC soluble guanylate cyclase
SSc systemic sclerosis, scleroderma
TGF-β transforming growth factor beta
THBS1 thrombospondin-1
TK tyrosine kinase


Conflict of interest: No potential conflict of interest relevant to this article was reported.

Bernatsky S, Joseph L, Pineau CA, Belisle P, Hudson M, Clarke AE. Scleroderma prevalence: demographic variations in a population-based sample. Arthritis Rheum. 2009;61:400–4.
Chifflot H, Fautrel B, Sordet C, Chatelus E, Sibilia J. Incidence and prevalence of systemic sclerosis: a systematic literature review. Semin Arthritis Rheum. 2008;37:223–35.
Ortonne JP, Torzuoli C, Dujardin P, Fraitag B. Ketanserin in the treatment of systemic sclerosis: a double-blind controlled trial. Br J Dermatol. 1989;120:261–6.
Casas JA, Saway PA, Villarreal I, et al. 5-fluorouracil in the treatment of scleroderma: a randomised, double blind, placebo controlled international collaborative study. Ann Rheum Dis. 1990;49:926–8.
Gruber BL, Kaufman LD. A double-blind randomized controlled trial of ketotifen versus placebo in early diffuse scleroderma. Arthritis Rheum. 1991;34:362–6.
Polisson RP, Gilkeson GS, Pyun EH, Pisetsky DS, Smith EA, Simon LS. A multicenter trial of recombinant human interferon gamma in patients with systemic sclerosis: effects on cutaneous fibrosis and interleukin 2 receptor levels. J Rheumatol. 1996;23:654–8.
Black CM, Silman AJ, Herrick AI, et al. Interferon-alpha does not improve outcome at one year in patients with diffuse cutaneous scleroderma: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 1999;42:299–305.;2-R.
Clements PJ, Seibold JR, Furst DE, et al. High-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis trial: lessons learned. Semin Arthritis Rheum. 2004;33:249–63.
Seibold JR, Korn JH, Simms R, et al. Recombinant human relaxin in the treatment of scleroderma. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2000;132:871–9.
Khanna D, Clements PJ, Furst DE, et al. Recombinant human relaxin in the treatment of systemic sclerosis with diffuse cutaneous involvement: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2009;60:1102–11.
Pope JE, Bellamy N, Seibold JR, et al. A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma. Arthritis Rheum. 2001;44:1351–8.;2-I.
Postlethwaite AE, Wong WK, Clements P, et al. A multicenter, randomized, double-blind, placebo-controlled trial of oral type I collagen treatment in patients with diffuse cutaneous systemic sclerosis: I. oral type I collagen does not improve skin in all patients, but may improve skin in late-phase disease. Arthritis Rheum. 2008;58:1810–22.
Pope J, McBain D, Petrlich L, et al. Imatinib in active diffuse cutaneous systemic sclerosis: results of a six-month, randomized, double-blind, placebo-controlled, proof-of-concept pilot study at a single center. Arthritis Rheum. 2011;63:3547–51.
Prey S, Ezzedine K, Doussau A, et al. Imatinib mesylate in scleroderma-associated diffuse skin fibrosis: a phase II multicentre randomized double-blinded controlled trial. Br J Dermatol. 2012;167:1138–44.
Takehara K, Ihn H, Sato S. A randomized, double-blind, placebo-controlled trial: intravenous immunoglobulin treatment in patients with diffuse cutaneous systemic sclerosis. Clin Exp Rheumatol. 2013;31:151–6.
Khanna D, Denton CP, Merkel PA, et al. Effect of macitentan on the development of new ischemic digital ulcers in patients with systemic sclerosis: DUAL-1 and DUAL-2 randomized clinical trials. JAMA. 2016;315:1975–88.
Seibold JR, Denton CP, Furst DE, et al. Randomized, prospective, placebo-controlled trial of bosentan in interstitial lung disease secondary to systemic sclerosis. Arthritis Rheum. 2010;62:2101–8.
Korn JH, Mayes M, Matucci Cerinic M, et al. Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum. 2004;50:3985–93.
Abou-Raya A, Abou-Raya S, Helmii M. Statins: potentially useful in therapy of systemic sclerosis-related Raynaud’s phenomenon and digital ulcers. J Rheumatol. 2008;35:1801–8.
Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med. 2006;354:2655–66.
Burt RK, Shah SJ, Dill K, 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.
van Laar JM, Farge D, Sont JK, et al. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA. 2014;311:2490–8.
Wellbrock C, Hurlstone A. BRAF as therapeutic target in melanoma. Biochem Pharmacol. 2010;80:561–7.
Janne PA, Shaw AT, Pereira JR, et al. Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol. 2013;14:38–47.
Clinical Trials Gov. Systemic sclerosis. 2016. Available at:
Clinical Trials Gov. Abatacept Scleroderma. 2016. Available at:
Clinical Trials Gov. Scleroderma Rituximab Trials. 2016. Available at:
Minier T, Pentek M, Brodszky V, et al. Cost-of-illness of patients with systemic sclerosis in a tertiary care centre. Rheumatology (Oxford). 2010;49:1920–8.
Rice LM, Padilla CM, McLaughlin SR, et al. Fresolimumab treatment decreases biomarkers and improves clinical symptoms in systemic sclerosis patients. J Clin Invest. 2015;12:2795–807.
Chakravarty EF, Martyanov V, Fiorentino D, et al. Gene expression changes reflect clinical response in a placebo-controlled randomized trial of abatacept in patients with diffuse cutaneous systemic sclerosis. Arthritis Res Ther. 2015;17:159.
Whitfield ML, Finlay DR, Murray JI, et al. Systemic and cell type-specific gene expression patterns in scleroderma skin. Proc Natl Acad Sci U S A. 2003;100:12319–24.
Pendergrass SA, Whitfield ML, Gardner H. Understanding systemic sclerosis through gene expression profiling. Curr Opin Rheumatol. 2007;19:561–7.
Sargent JL, Milano A, Connolly MK, Whitfield ML. Scleroderma gene expression and pathway signatures. Curr Rheumatol Rep. 2008;10:205–11.
Milano A, Pendergrass SA, Sargent JL, et al. Molecular subsets in the gene expression signatures of scleroderma skin. PLoS One. 2008;3:e2696.
Chung L, Fiorentino DF, Benbarak MJ, et al. Molecular framework for response to imatinibmesylate in systemic sclerosis. Arthritis Rheum. 2009;60:584–91.
Sargent JL, Milano A, Bhattacharyya S, et al. A TGFbeta-responsive gene signature is associated with a subset of diffuse scleroderma with increased disease severity. J Invest Dermatol. 2010;130:694–705.
Sargent, J.; Milano, A.; Bhattacharyya, S., et al. A transforming growth factor-β (TGFβ)-responsive gene signature predicts more severe skin disease and occurrence of interstitial lung disease (ILD) in diffuse cutaneous systemic sclerosis (dcSSc) [Poster]. [accessed August 24, 2016]. Available at:
Daoussis D, Liossis SN, Tsamandas AC, et al. Experience with rituximab in scleroderma: results from a 1-year, proof-of-principle study. Rheumatology (Oxford). 2010;49:271–80.
Lafyatis R, Kissin E, York M, et al. B cell depletion with rituximab in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheum. 2009;60:578–83.
Jordan S, Distler JH, Maurer B, et al. Effects and safety of rituximab in systemic sclerosis: an analysis from the European Scleroderma Trial and Research (EUSTAR) group. Ann Rheum Dis. 2015;74:1188–94.
Varga J, Whitfield ML. Transforming growth factor-beta in systemic sclerosis (scleroderma). Front Biosci (Schol Ed). 2009;1:226–35.
Denton CP, Merkel PA, Furst DE, 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. 2007;56:323–33.
O’Reilly S, Ciechomska M, Cant R, Hugle T, van Laar JM. Interleukin-6, its role in fibrosing conditions. Cytokine Growth Factor Rev. 2012;23:99–107.
Khan K, Xu S, Nihtyanova S, et al. Clinical and pathological significance of interleukin 6 overexpression in systemic sclerosis. Ann Rheum Dis. 2012;71:1235–42.
Kadono T, Kikuchi K, Ihn H, Takehara K, Tamaki K. Increased production of interleukin 6 and interleukin 8 in scleroderma fibroblasts. J Rheumatol. 1998;25:296–301.
Schmidt K, Martinez-Gamboa L, Meier S, et al. Bronchoalveoloar lavage fluid cytokines and chemokines as markers and predictors for the outcome of interstitial lung disease in systemic sclerosis patients. Arthritis Res Ther. 2009;11:R111.
Needleman BW, Wigley FM, Stair RW. Interleukin-1, interleukin-2, interleukin-4, interleukin-6, tumor necrosis factor alpha, and interferon-gamma levels in sera from patients with scleroderma. Arthritis Rheum. 1992;35:67–72.
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;25:308–13.
Kitaba S, Murota H, Terao M, et al. Blockade of interleukin-6 receptor alleviates disease in mouse model of scleroderma. Am J Pathol. 2012;180:165–76.
Desallais L, Avouac J, Frechet M, et al. Targeting IL-6 by both passive or active immunization strategies prevents bleomycin-induced skin fibrosis. Arthritis Res Ther. 2014;16:R157.
Muangchan C, Harding S, Khimdas S, Bonner A, Baron M, Pope J. Association of C-reactive protein with high disease activity in systemic sclerosis: results from the Canadian Scleroderma Research Group. Arthritis Care Res (Hoboken). 2012;64:1405–14.
Liu X, Mayes MD, Pedroza C, et al. Does C-reactive protein predict the long-term progression of interstitial lung disease and survival in patients with early systemic sclerosis? Arthritis Care Res (Hoboken). 2013;65:1375–80.
Khanna D, Denton CP, Jahreis A, et al. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial. Lancet. 2016;387:2630–40.
Belik J. Riociguat, an oral soluble guanylate cyclase stimulator for the treatment of pulmonary hypertension. Curr Opin Investig Drugs. 2009;10:971–9.
Mittendorf J, Weigand S, Alonso-Alija C, et al. Discovery of riociguat (BAY 63-2521): a potent, oral stimulator of soluble guanylate cyclase for the treatment of pulmonary hypertension. ChemMedChem. 2009;4:853–65.
Beyer C, Reich N, Schindler SC, et al. Stimulation of soluble guanylate cyclase reduces experimental dermal fibrosis. Ann Rheum Dis. 2012;71:1019–26.
Dees C, Beyer C, Distler A, et al. Stimulators of soluble guanylate cyclase (sGC) inhibit experimental skin fibrosis of different aetiologies. Ann Rheum Dis. 2015;74:1621–5.
Hambly N, Granton J. Riociguat for the treatment of pulmonary hypertension. Expert Rev Respir Med. 2015;9:679–95.
Antoniu SA, Kolb MR. Intedanib, a triple kinase inhibitor of VEGFR, FGFR and PDGFR for the treatment of cancer and idiopathic pulmonary fibrosis. IDrugs. 2010;13:332–45.
Roth GJ, Binder R, Colbatzky F, et al. Nintedanib: from discovery to the clinic. J Med Chem. 2015;58:1053–63.
Wollin L, Wex E, Pautsch A, et al. Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis. Eur Respir J. 2015;45:1434–45.