|Year : 2016 | Volume
| Issue : 3 | Page : 153-163
Emerging evidence-based therapies for systemic sclerosis
Jasmin Raja1, Christopher P Denton2
1 Division of Rheumatology, Department and Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
2 Centre for Rheumatology and Connective Tissue Diseases, UCL Medical School, Royal Free Campus, London NW3 2QG, UK
|Date of Web Publication||11-Aug-2016|
Christopher P Denton
Centre for Rheumatology and Connective Tissue Diseases, UCL Medical School, Royal Free Campus, London NW3 2QG
Source of Support: None, Conflict of Interest: None
Systemic sclerosis (SSc) (scleroderma) is an uncommon multisystem connective tissue disease with high unmet need and mortality. There has been an improvement in overall outcome and survival over the past three decades, but it still has the highest mortality among any of the autoimmune rheumatic diseases. Progress in its management has come through more organized assessment and treatment together with the emergence of therapies that can target specific complications of the disease such as renal crisis and pulmonary arterial hypertension. In addition, there is a growing understanding of pathogenesis that allows more targeted approaches to therapy to be explored in clinical trials. In this review, several aspects of SSc management including the more targeted therapies including strategies to block specific pathways or mediators have been discussed.
Keywords: Immunosuppressants, scleroderma, systemic sclerosis, therapies, treatments
|How to cite this article:|
Raja J, Denton CP. Emerging evidence-based therapies for systemic sclerosis. Indian J Rheumatol 2016;11:153-63
| Introduction|| |
Systemic sclerosis (SSc) is an uncommon multisystem connective tissue disease with three main pathogenetic components - immunological, microvasculopathy, and tissue fibrosis. The key histological features of SSc are indicated in [Figure 1] and provide a template for the aspects of the disease that need to be addressed to achieve therapeutic success in the skin and internal organs affected by SSc. High burden of disease morbidity and mortality is seen among SSc patients with or without major organ involvement. Over the past few decades, despite some data showing improvement in the trend in mortality in SSc patients, the mortality risk remains high with cardiopulmonary involvement as a leading cause. , High prevalence of SSc-related causes of mortality was observed in the EULAR Scleroderma Trials and Research (EUSTAR) cohort involving 284 fatalities, also mainly attributed to cardiopulmonary causes. 
|Figure 1: Pathological hallmarks of lesional skin in systemic sclerosis. Systemic sclerosis leads to damage of epithelial, vascular and dermal structures within the skin. Inflammation is generally perivascular and more prominent in early stage disease but is much less prominent than in some other skin diseases including localized scleroderma (morphea). The consequences of these processes are dermal fibrosis. Similar changes in internal organs underlie the major burden of disease including both life-threatening and nonlethal manifestations|
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The 10-year survival rate, however, has improved significantly in those with scleroderma renal crisis (SRC) with the introduction of angiotensin-converting enzyme (ACE) inhibitors in the 1980s.  The outcome in SSc patients was also found to be improving with increased awareness and ascertainment of organ-based complications, particularly lung complications.  In the future, prediction models for organ complications can be a useful tool for patient risk stratification and to predict long-term outcome of SSc.  Together with this, it is crucial to treat the manifestations in the earliest stage possible for a better prognosis, outcome, and survival. The therapies which target specific organ manifestations have emerged over the years from intensive research studies and clinical trials, in addition to a growing understanding of pathogenesis in SSc. This article reviews the general approach to management and highlights areas that are improving based on the results of recent clinical trials. In addition, the prospects for more targeted therapies including strategies to block specific pathways or mediators are reviewed. The potential links between different components of pathogenesis in SSc mean that it is likely that more specific targeted therapies may have beneficial effects on more than one aspect of the disease.
| Emerging Support for Broad-spectrum Immunosuppression|| |
Although the pathogenesis of SSc is complex and multifaceted, it is clear that altered immunological reactivity is an important component of the disease. Thus, genetic studies as well as examination of tissue samples and cultured cells for patients all point to abnormalities in both innate and adaptive immune systems. In this context, it is striking that immunosuppression is the most widely used approach for treating SSc and major complication such as lung fibrosis. There is an increasing evidence base to support this, and the results of several key recent studies are summarized below. Conventional disease-modifying therapies have shown to be beneficial in the treatment of SSc. These broad-spectrum immunosuppressants are often used as organ-based therapy and are outlined below.
Cyclophosphamide is an alkylating agent that produces immunosuppressive effects possibly through a cytotoxic effect on lymphocytes. Cyclophosphamide has shown to be efficacious in the treatment of SSc interstitial lung disease (ILD). In the Scleroderma Lung Study I (SLS I), treatment with oral cyclophosphamide showed significant beneficial effect on both lungs and skin compared to placebo.  Similarly, the FAST study suggests that cyclophosphamide is beneficial for lung function over 1 year in SSc patients.  Cyclophosphamide is also given in patients with rapidly progressive fibrotic activity, either in skin or lungs.
Mycophenolate mofetil (MMF) interferes with T- and B-cell proliferation by acting as a potent inhibitor of the enzyme inosine monophosphate dehydrogenase. The use of MMF is encouraging for manifestations of skin, lungs, and muscles with reasonable tolerated gastrointestinal symptoms. ,, MMF was used in several studies for induction, for maintenance, for both induction and maintenance.  A recent landmark study, SLS II trial's (MMF vs. oral cyclophosphamide) preliminary analyses, showed comparable improvement in forced vital capacity (FVC) in both treatment groups. 
Methotrexate (MTX) is an antimetabolite that has shown not only reduction of proinflammatory cytokine production but also inhibition of antigen-induced T-cell activation and adhesion molecules.  Improvement in skin scores was observed in several randomized control trials (RCTs) and has been recommended by EULAR-EUSTAR experts as an option for the treatment of skin manifestations of early diffuse SSc. ,,
The therapeutic concept of B-cell depletion in SSc provides a better-defined treatment and evidence-based following demonstration of clinical efficacy in observational studies and open-label trials. , In tight skin (tsk) mice, the CD20 monoclonal antibody has shown to reduce profibrogenic cytokines such as transforming growth factor-β (TGF-β) and significantly suppress skin fibrosis.  Interestingly, autoantibody production and hypergammaglobulinemia were also suppressed following B-cell depletion in the mouse model. In SSc patients, rituximab has shown beneficial effects in fibrotic activity of skin and prevention of worsening of lung fibrosis,  suggesting that B-cells and autoantibodies are the primary drivers of fibrosis in skin and lung tissue. Significant improvement in pulmonary function was demonstrated in case-control analyses, with promising results where rituximab could be considered as a treatment option in patients who are not able to tolerate cyclophosphamide or have contraindication for it. However, further research is needed while awaiting validation for efficacy of rituximab in an RCT.
Autologous hematopoietic stem cell transplant
Autologous hematopoietic stem cell transplant (ASCT) is a promising emerging therapy for the management of SSc after several studies including Phase I and Phase II trials have shown efficacy in a subgroup of SSc patients with poor prognosis. Positive outcomes were observed in reversal of skin fibrosis, improvement in lung function, quality of life, and functional ability. ,,,, The phase II ASSIST trial compared safety and efficacy of autologous nonmyeloablative ASCT in diffuse cutaneous SSc (dcSSc) to a control group that received six cycles of monthly intravenous cyclophosphamide. Both mRSS and FVC improved significantly for up to two years in the group that received ASCT.  In the ASTIS phase III study, ASCT conferred a significant long-term event-free survival benefit in SSc patients despite an early treatment-related death of 10.1% and increase in serious adverse events.  This treatment is considered for SSc patients with early diffuse cutaneous disease who have a poor outcome. Safer transplant regimens and better patient selection may improve the outcome of ASCT for SSc. The ongoing SCOT trial is much awaited and would be important to further determine the efficacy and safety of ASCT in SSc. 
Other immunomodulatory strategies
Antithymocyte globulin (ATG) has been long used in the treatment of renal allograft rejection and induction agent for kidney transplantation. ATG has been studied in small open-label trials and found to have mixed results. ,, The overall outcome of this treatment is discouraging including adverse reaction of serum sickness.
Aimspro ® (anti-inflammatory immunosuppressive product) (hyperimmune caprine sera (HICS))
A novel agent, hyperimmune goat serum, Aimspro conferred potential benefit for skin fibrosis in established dcSSc with no safety concerns in a recent Phase II RCT conducted. 
Experimental evidence demonstrated identification of a variety of autoantigens in SSc patients, ,, including type I collagen leading to trials that have demonstrated successful treatment with orally administered bovine type I collagen. Late-phase dcSSc patients treated with oral collagen experienced a significant reduction in the mRSS compared with that in the placebo-treated patients in a subanalysis of data from an RCT study involving 168 dcSSc patients.  In addition to improvement in skin fibrosis, an open-label study reported significant reductions in interferon-γ, interleukin (IL)-10 in peripheral blood mononuclear cells culture supernatants, and sIL-2r levels following oral administration of type I collagen in SSc patients suggesting reduction in T-cell reactivity to human type I collagen. 
Intravenous immunoglobulin (IVIG) is generally considered a safe immunomodulatory therapy used for a wide range of immune-mediated conditions. The use of IVIG in SSc has been studied in both tsk mouse models and patients with SSc focusing on skin fibrosis and inflammatory myopathy overlap in SSc. ,, Following administration of IVIG in SSc tsk experimental models, downregulation of type 1 procollagen with decreased collagen deposition was observed. In addition to modulation of metalloproteinase activity, inhibitory effects on IL-4 and TGF-β were also reported. , Interesting data from a recently published observational study revealed sustained beneficial effect of IVIG in established gastrointestinal complications in SSc patients. 
Treatment of vascular complications
Endothelin receptor antagonist
Endothelin-1 (ET-1) is a potent vasoconstrictor implicated in the development of vascular dysfunction and cardiovascular disease. Proliferative vascular remodeling properties lead to complication of pulmonary arterial hypertension (PAH) when overexpression of ET-1 results in abnormal growth pattern of endothelial cells, smooth muscle cells, fibroblasts, and pericytes. , Given the prominent role of the endothelin system in PAH, a variety of endothelin receptor antagonist (ERA) agents are used in the treatment of PAH in SSc. , Bosentan, a dual ERA of both ET (A) and ET (B) receptors, is licensed in the treatment of PAH in SSc and improves survival. , The RAPIDS-2 study reported an additional benefit of bosentan for the treatment of reducing the number of new digital ulcers even though beneficial effect was not seen on the healing of preexisting digital ulcers.  Further encouragement for the targeting of endothelin comes from other agents, including ambrisentan and macitentan. ,, In addition, there is evidence that combination of bosentan with sildenafil may have a better treatment effect from one small recent study. 
Phosphodiesterase 5 inhibitor
Nitric oxide has an important role as a mediator of endothelium-dependent vasodilation and its production is impaired in PAH. Sildenafil, through phosphodiesterase V, inhibits cyclic guanosine monophosphate degradation resulting in increased level of nitric oxide. Data from the Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) study suggest that sildenafil at a dose of 20 mg improved exercise capacity (6-minute walk distance [6MWD]), hemodynamic measures, and functional class after 12 weeks of therapy.  Clinical studies have reported positive encouraging results for the treatment of sildenafil in vascular complications of SSc such as PAH, Raynaud's phenomenon, and digital ulcers. , There is evidence that sildenafil may benefit digital ulcer disease in SSc  and it is used, as are other drugs in this class, to treat this complication of SSc.
Tadalafil is another oral phosphodiesterase 5 inhibitor (PDE5-i) approved for the PAH treatment. Improvement in 6MWD and its sustained results were observed in the Pulmonary Arterial Hypertension and Response to Tadalafil Study trial.  Upfront combination therapy with ambrisentan and tadalafil also significantly improved hemodynamics, right ventricle structure and function, and functional status in treatment-naive patients with SSc-PAH.  The study of tadalafil for the treatment of ILD in SSc is completed. 
Iloprost is a prostacyclin analog with dual vasodilatory and antiplatelet inhibitory effects. Several studies have reported efficacy of parenteral iloprost in the treatment of vascular manifestations in SSc, particularly Raynaud's phenomenon and healing of digital ulcers. ,,, Epoprostenol, another intravenous preparation of prostacyclin, is approved for the treatment of PAH. Patients were also noted to have fewer digital ulcers compared to those without this therapy.  The efficacy of the oral formulation of treprostinil compound has also been studied in an open-label study.  Interestingly, a pilot study to evaluate the safety and efficacy of oral treprostinil in the treatment of calcinosis in SSc patients is underway. 
Clinical trials have looked at the oral drug riociguat, a soluble guanylate cyclase stimulator, as a new approach to treat pulmonary hypertension. ,, It is now licensed for chronic thromboembolic pulmonary hypertension and also for PAH including SSc-associated disease. There is the possibility based on preclinical studies that riociguat may also have some broader antifibrotic benefit, and this is being assessed in the ongoing RISE-SSc study (Riociguat Safety and Efficacy in patients with dcSSc). This clinical trial has been initiated to evaluate the efficacy of riociguat on skin, lungs, and digital ulcers on SSc patients. This study will include 130 patients at more than 60 sites in 15 countries. 
Angiotensin-converting enzyme inhibitor
SRC was once the most common cause of mortality in SSc. The 10-year survival rate has improved significantly with the introduction of ACE inhibitors in the 1980s.  Contributing risk factors of developing SRC are diffuse cutaneous or rapidly progressive forms of SSc, treatment with high dose of corticosteroid and presence of anti-RNA polymerase III antibody.  Patients on ACE inhibitors (captopril or enalapril) had a significantly better survival rates, up to 90% at 5 years and 85% at 8 years. , The need for permanent dialysis too decreased following treatment of ACE inhibitor in SRC. Prophylactic ACE inhibitors have not been shown to improve outcomes.
The use of fluoxetine, a selective serotonin reuptake inhibitor, reduced the Raynaud's phenomenon attack frequency and severity.  Losartan (an angiotensin receptor blocker) showed greater improvement in both primary and secondary Raynaud's phenomenon symptoms when compared to nifedipine.  Interdigital injections of botulinum toxin and sympathectomy are used in resistant cases. , The first randomized, placebo-controlled trial on the use of botulinum toxin to treat Raynaud's phenomenon in SSc patients is ongoing. 
Challenging aspects of the disease - nonlethal burden
With the advances in treatment and improved survival from better management of life-threatening complications, the nonlethal aspect of SSc becomes an important aspect of the disease even though it is hard to treat with the challenges remain. This is important since it is often these aspects of the disease that patients find most challenging. In addition, it is likely that some of the emerging disease modifying treatments may benefit broader aspects of the disease, and so they should continue to be assessed in clinical trials and also receive focus in basic laboratory research.
Patients with digital ulcers have significant cost and disease burden including impairment in productivity and daily activity. The higher disease burden is reported to be experienced by SSc patients with recurrent and chronic digital ulcers compared with patients with no digital ulcers and episodic digital ulcers. 
Fatigue is a disabling and difficult-to-manage problem. Severe fatigue is present in 41-57% of patients with rheumatic disease including SSc.  Fatigue and pain should be taken into account in the management of SSc. Graded exercise which is matched to patient's physical abilities could help improve patient's physical functioning and reduce fatigue. Solving sleep problems or changing negative coping behavior could also help patients to have less fatigue. 
Pruritus is a common problem in SSc with higher rate occurrence in early disease. Greater skin involvement and greater gastrointestinal involvement were reported to be independently associated with pruritus.  Unfortunately, pruritus has limited treatment options in this disease. The use of low-dose naltrexone hydrochloride in its treatment is encouraging from case series reports. 
Medical benefit of calcinonsis in SSc is limited. An open-label study demonstrated that minocycline is a potentially useful drug in the treatment of calcinosis in SSc. The mechanism of action proposed is may be mainly through matrix metalloproteinases inhibitory activity and anti-inflammatory effects. Calcium binding properties and antibacterial actions may also have a role. 
The psychological consequence in patients with SSc is increasingly recognized. , Emotional burden such as depression and anxiety is common among SSc patients. While in some studies, depressive symptoms were shown to be independently associated with severity and physical functioning of the disease such as pain and fatigue, ,, other studies did not reflect the above findings. ,, Some studies also included psychological measures such as cognition acceptance and emotional or social support received and found these to be independently associated with depressive symptoms. , Focus should be given by clinicians to treat the psychosocial aspect of the disease and should be integrated into interdisciplinary care.
The changes in facial appearance and hands have an effect on appearance self-esteem and body image satisfaction.  Depressive symptoms are also recognized in addition to psychosocial impairment in SSc population.  The physical change in SSc patients also affects sexuality, especially in females.  The brief-satisfaction with appearance scale (Brief-SWAP) has been validated for SSc. 
Sexual dysfunction is a concern for both male and female SSc patients and has a major contribution to nonlethal burden of disease.  Erectile dysfunction is seen in up to 81% sexually active SSc male population. ,, As a first-line pharmacological treatment option, PDE5-i should be considered for the treatment of erectile dysfunction. Female sexual dysfunction (FSD) is significantly more prevalent than in the general population. Multiple factors contribute to FSD in terms of psychological and physical components and this may interfere with sexual act. Body image as a consequence of skin fibrosis is an important predictor of FSD; however, it is reported to be less important than pain in determining sexual function.  In SSc, psychological burden and emotional burden such as depressive symptoms and marital distress were associated with impaired sexual functioning in SSc. , Evaluation of strategies and development of intervention to improve the overall sexual functioning are important to address this issue. A referral to a specialist may be warranted.
Work disability continues to be a major burden in individuals with rheumatic diseases including SSc and accounts for a large fraction of its costs. It has been shown to be prevalent even in early disease of SSc.  Clinical manifestations such as lung involvement, fatigability, pain, diffuse disease, disease duration, and severity were reported to correlate with work disability. , SSc patients with psychosocial factors and less social support too tend to have association with work disability. 
Management of gastrointestinal complications
Proton pump inhibitor
Gastroesophageal manifestations are seen in up to 90% of SSc patients with increased frequency of gastroesophageal reflux disease (GORD) and esophageal dysmotility contributing to morbidity of the disease.  Besides lifestyle modification and avoidance of aggravating factors, proton pump inhibitor (PPI) either a single or double dose helps relieve symptoms of GORD. The traditional PPIs available include omeprazole, lansoprazole, pantoprazole, and rabeprazole. , H2-receptor antagonists can be added if symptoms of GORD persist despite on PPIs. These agents are usually added at bedtime for overnight symptoms as nocturnal acid secretion is influenced by histamine secretion. ,
Prokinetics are mainstay of treatment for esophageal dysmotility and gastroparesis. , It is recommended when patients have persistent symptoms of dysphagia, poor acid control of GORD, or symptoms of delayed gastric emptying. Examples of prokinetics used are metoclopramide, dopamine receptor antagonist domperidone, and the macrolide antibiotic, erythromycin. Prokinetics must be used with caution in view of risk of cardiac arrhythmias. 
New dysmotility agents
A novel agent serotonin (5-HT4) receptor agonist, prucalopride, was shown to have remarkable prokinetic properties resulting in improvement in gastroenteric transit and functional constipation.  A randomized placebo controlled drug trial is currently ongoing. 
Sacral neuromodulation and posterior tibial nerve stimulation
Fecal incontinence in SSc patients is a challenging condition to treat and has a considerable impact on patient's quality of life. The use of conventional methods is often unsuccessful. Sacral neuromodulation is a well-established treatment for refractory cases of fecal incontinence; however, mixed results are reported from case series on its efficacy in treating fecal incontinence in SSc including poor medium term efficacy. , Posterior tibial nerve stimulation (PTNS) is an alternative to modulate the sacral plexus indirectly. Preliminary data demonstrated significant effects of PTNS in the treatment of fecal incontinence in SSc in a recently conducted RCT. 
Recent clinical trials and emerging treatments
Lysophosphatidic acid 1 antagonist
Lysophosphatidic acid (LPA), a lysophospholipid mediator, is derived from stored lipid precursors and is found to be elevated in the sera of SSc patients, providing a rationale in considering a targeted therapy in SSc.  The antifibrotic effect of LPA1 on dermal and lung fibrosis is supported in mouse models. , Promising results were seen in a study that used a novel orally active LPA1 antagonist demonstrating inhibition of lung fibrosis in bleomycin-induced mouse model via reduction of vascular leakage, tissue injury, and profibrotic cytokine production. 
Tocilizumab is an IL-6 receptor blocker. High levels of IL-6 expression was found in sera and dermal fibroblast of SSc patients, implicating the role of IL-6 in the pathogenesis of SSc. Studies also demonstrate associations with progression of lung fibrosis and survival. ,, The clinical benefits of tocilizumab in SSc is by direct blocking of the profibrotic property of IL-6 on fibroblasts and by suppression of inflammation through tolerance regulatory T-cell upregulation and reduction of the polarization of pathogenic Th17 cells.  The safety and efficacy of tocilizumab in adults with SSc was explored in the faSScinate trial. The week 48 data suggest a positive risk/benefit profile for tocilizumab in SSc in terms of skin fibrosis, patient-reported outcome, and pulmonary function, supporting further assessment on the use of tocilizumab in SSc patients.  A large phase III clinical trial is underway to confirm and extend data about the potential efficacy of this agent in early stage diffuse SSc with evidence of an increased acute phase response.
Pirfenidone is an orally active small molecule with anti-inflammatory and antifibrotic actions. Pirfenidone modulates cytokines and growth factors, particularly suppressing TGF-β.  In an open-label trial of pirfenidone in SSc-ILD, mixed results in pulmonary function and minor changes in mRSS were reported. Pirfenidone was generally tolerated. 
Nintedanib is a tyrosine kinase inhibitor that has recently been demonstrated to reduce the decline in FVC, and hence slow down the disease progression in idiopathic pulmonary fibrosis.  Its efficacy as a potent antifibrotic agent has now shown to be evident in mouse models of SSc.  A phase III clinical trial, SENSCIS, is underway which would allow exploration of the treatment Nintedanib in patients with SSc-ILD that may prove to be effective. 
The human monoclonal antibody fresolimumab targets all three TGF-β isoforms. The effect of this drug on expression of molecular markers in the skin and on skin scarring was evaluated in SSc patients after a brief duration of 7 weeks treatment. Rapid inhibition of TGF-β regulated gene expression and improvement in the mRSS skin score in response to Fresolimumab provides further encouraging data on TGF-β as a potential targeted therapy in SSc. 
Although outcome of some aspects of SSc is improved, there remain major challenges. As there is better treatment of complications, other manifestations emerge to challenge patients and physicians. In addition, there is a much clearer understanding of the abnormal biology underlying SSc and this permits more logical choices to be made in selecting new candidate therapies and linking them to the most promising disease manifestations. [Figure 2] summarizes the multiple ways in which pathobiology may be targeted for disease modification. There has been clearer progress in diffuse SSc, and so limited disease now represents an important challenge. In addition, the nonlethal burden of the disease needs to be tackled as people are living longer with the diagnosis rather than dying early for the most severe complications of SSc. Symptoms such as fatigue, pruritus, anorectal incontinence, and calcinosis remain an enormous unmet medical need. Since SSc is an orphan indication, it will hopefully see disproportionate progress over the coming years. The recent results from trials and development of promising phase II studies offer hope that within the next few years more effective and better tolerated treatments for SSc and its major manifestations will merge.
|Figure 2: Targeting of systemic sclerosis pathogenesis: Strategies for disease modification. The key cellular players implicated in the pathogenesis of systemic sclerosis that underlie the classical histopathological feature of the disease are indicted together with some of the established and emerging treatment options that may permit disease modifying therapy that may potentially impact upon the multiple facets of pathobiology|
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| References|| |
Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972-2002. Ann Rheum Dis 2007;66:940-4.
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 (Oxford) 2012;51:1017-26.
Tyndall AJ, Bannert B, Vonk M, Airò P, Cozzi F, Carreira PE, 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;69:1809-15.
Nihtyanova SI, Tang EC, Coghlan JG, Wells AU, Black CM, Denton CP. Improved survival in systemic sclerosis is associated with better ascertainment of internal organ disease: A retrospective cohort study. QJM 2010;103:109-15.
Nihtyanova SI, Schreiber BE, Ong VH, Rosenberg D, Moinzadeh P, Coghlan JG, et al.
Prediction of pulmonary complications and long-term survival in systemic sclerosis. Arthritis Rheumatol 2014;66:1625-35.
Tashkin DP, Elashoff R, Clements PJ, Goldin J, Roth MD, Furst DE, et al.
Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 2006;354:2655-66.
Hoyles RK, Ellis RW, Wellsbury J, Lees B, Newlands P, Goh NS, 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 2006;54:3962-70.
Le EN, Wigley FM, Shah AA, Boin F, Hummers LK. Long-term experience of mycophenolate mofetil for treatment of diffuse cutaneous systemic sclerosis. Ann Rheum Dis 2011;70:1104-7.
Clements PJ, Tashkin D, Roth M, Khanna D, Furst DE, Tseng CH, et al
. The Scleroderma Lung Study II (SLS II) shows that both oral cyclophosphamide (CYC) and mycophenolate mofitil (MMF) are efficacious in treating progressive interstitial lung disease (ILD) in patients with systemic sclerosis (SSc) [abstract]. Arthritis Rheumatol 2015;67 (suppl 10).
Omair MA, Alahmadi A, Johnson SR. Safety and effectiveness of mycophenolate in systemic sclerosis. A systematic review. PLoS One 2015;10:e0124205.
Johnston A, Gudjonsson JE, Sigmundsdottir H, Ludviksson BR, Valdimarsson H. The anti-inflammatory action of methotrexate is not mediated by lymphocyte apoptosis, but by the suppression of activation and adhesion molecules. Clin Immunol 2005;114:154-63.
van den Hoogen FH, Boerbooms AM, Swaak AJ, Rasker JJ, van Lier HJ, 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 1996;35:364-72.
Pope JE, Bellamy N, Seibold JR, Baron M, Ellman M, Carette S, et al.
A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma. Arthritis Rheum 2001;44:1351-8.
Kowal-Bielecka O, Landewé R, Avouac J, Chwiesko S, Miniati I, Czirjak L, et al.
EULAR recommendations for the treatment of systemic sclerosis: A report from the EULAR Scleroderma Trials and Research group (EUSTAR). Ann Rheum Dis 2009;68:620-8.
Bosello S, De Luca G, Tolusso B, Lama G, Angelucci C, Sica G, et al.
B cells in systemic sclerosis: A possible target for therapy. Autoimmun Rev 2011;10:624-30.
McQueen FM, Solanki K. Rituximab in diffuse cutaneous systemic sclerosis: Should we be using it today? Rheumatology (Oxford) 2015;54:757-67.
Hasegawa M, Hamaguchi Y, Yanaba K, Bouaziz JD, Uchida J, Fujimoto M, et al.
B-lymphocyte depletion reduces skin fibrosis and autoimmunity in the tight-skin mouse model for systemic sclerosis. Am J Pathol 2006;169:954-66.
Jordan S, Distler JH, Maurer B, Huscher D, van Laar JM, Allanore Y, 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.
Nash RA, McSweeney PA, Crofford LJ, Abidi M, Chen CS, Godwin JD, 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 2007;110:1388-96.
Binks M, Passweg JR, Furst D, McSweeney P, Sullivan K, Besenthal C, et al.
Phase I/II trial of autologous stem cell transplantation in systemic sclerosis: Procedure related mortality and impact on skin disease. Ann Rheum Dis 2001;60:577-84.
Launay D, Marjanovic Z, de Bazelaire C, Florea L, Zohar S, Keshtmand H, et al.
Autologous hematopoietic stem cell transplant in systemic sclerosis: Quantitative high resolution computed tomography of the chest scoring. J Rheumatol 2009;36:1460-3.
Burt RK, Oliveira MC, Shah SJ, Moraes DA, Simoes B, Gheorghiade M, 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;381:1116-24.
van Laar JM, Farge D, Sont JK, Naraghi K, Marjanovic Z, Larghero J, 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.
Burt RK, Shah SJ, Dill K, Grant T, Gheorghiade M, Schroeder J, 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.
Stratton RJ, Wilson H, Black CM. Pilot study of anti-thymocyte globulin plus mycophenolate mofetil in recent-onset diffuse scleroderma. Rheumatology (Oxford) 2001;40:84-8.
Tarkowski A, Andersson-Gäre B, Aurell M. Use of anti-thymocyte globulin in the management of refractory systemic autoimmune diseases. Scand J Rheumatol 1993;22:261-6.
Matteson EL, Shbeeb MI, McCarthy TG, Calamia KT, Mertz LE, Goronzy JJ. Pilot study of antithymocyte globulin in systemic sclerosis. Arthritis Rheum 1996;39:1132-7.
Quillinan NP, McIntosh D, Vernes J, Haq S, Denton CP. Treatment of diffuse systemic sclerosis with hyperimmune caprine serum (AIMSPRO): A phase II double-blind placebo-controlled trial. Ann Rheum Dis 2014;73:56-61.
Stuart JM, Postlethwaite AE, Kang AH. Evidence for cell-mediated immunity to collagen in progressive systemic sclerosis. J Lab Clin Med 1976;88:601-7.
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;73:493-6.
Huffstutter JE, DeLustro FA, LeRoy EC. Cellular immunity to collagen and laminin in scleroderma. Arthritis Rheum 1985;28:775-80.
Postlethwaite AE, Wong WK, Clements P, Chatterjee S, Fessler BJ, Kang AH, 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.
McKown KM, Carbone LD, Bustillo J, Seyer JM, Kang AH, Postlethwaite AE. Induction of immune tolerance to human type I collagen in patients with systemic sclerosis by oral administration of bovine type I collagen. Arthritis Rheum 2000;43:1054-61.
Poelman CL, Hummers LK, Wigley FM, Anderson C, Boin F, Shah AA. Intravenous immunoglobulin may be an effective therapy for refractory, active diffuse cutaneous systemic sclerosis. J Rheumatol 2015;42:236-42.
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 2 Suppl 76:151-6.
Raja J, Nihtyanova SI, Murray CD, Denton CP, Ong VH. Sustained benefit from intravenous immunoglobulin therapy for gastrointestinal involvement in systemic sclerosis. Rheumatology (Oxford) 2016;55:115-9.
Blank M, Levy Y, Amital H, Shoenfeld Y, Pines M, Genina O. The role of intravenous immunoglobulin therapy in mediating skin fibrosis in tight skin mice. Arthritis Rheum 2002;46:1689-90.
Asano Y, Ihn H, Asashima N, Yazawa N, Mimura Y, Jinnin M, et al.
A case of diffuse scleroderma successfully treated with high-dose intravenous immune globulin infusion. Rheumatology (Oxford) 2005;44:824-6.
Chizzolini C, Raschi E, Rezzonico R, Testoni C, Mallone R, Gabrielli A, et al.
Autoantibodies to fibroblasts induce a proadhesive and proinflammatory fibroblast phenotype in patients with systemic sclerosis. Arthritis Rheum 2002;46:1602-13.
Tamby MC, Chanseaud Y, Humbert M, Fermanian J, Guilpain P, Garcia-de-la-Peña-Lefebvre P, et al.
Anti-endothelial cell antibodies in idiopathic and systemic sclerosis associated pulmonary arterial hypertension. Thorax 2005;60:765-72.
Sweiss NJ, Hushaw L, Thenappan T, Sawaqed R, Machado RF, Patel AR, et al.
Diagnosis and management of pulmonary hypertension in systemic sclerosis. Curr Rheumatol Rep 2010;12:8-18.
McLaughlin V, Humbert M, Coghlan G, Nash P, Steen V. Pulmonary arterial hypertension: The most devastating vascular complication of systemic sclerosis. Rheumatology (Oxford) 2009;48 Suppl 3:iii25-31.
Valerio CJ, Handler CE, Kabunga P, Smith CJ, Denton CP, Coghlan JG. Clinical experience with bosentan and sitaxentan in connective tissue disease-associated pulmonary arterial hypertension. Rheumatology (Oxford) 2010;49:2147-53.
Williams MH, Das C, Handler CE, Akram MR, Davar J, Denton CP, et al.
Systemic sclerosis associated pulmonary hypertension: Improved survival in the current era. Heart 2006;92:926-32.
Matucci-Cerinic M, Denton CP, Furst DE, Mayes MD, Hsu VM, Carpentier P, et al.
Bosentan treatment of digital ulcers related to systemic sclerosis: Results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial. Ann Rheum Dis 2011;70:32-8.
Saggar R, Khanna D, Shapiro S, Furst DE, Maranian P, Clements P, et al.
Brief report: Effect of ambrisentan treatment on exercise-induced pulmonary hypertension in systemic sclerosis: A prospective single-center, open-label pilot study. Arthritis Rheum 2012;64:4072-7.
Cipriani P, Di Benedetto P, Ruscitti P, Verzella D, Fischietti M, Zazzeroni F, et al.
Macitentan inhibits the transforming growth factor-ß profibrotic action, blocking the signaling mediated by the ETR/TßRI complex in systemic sclerosis dermal fibroblasts. Arthritis Res Ther 2015;17:247.
Kholdani CA, Fares WH, Trow TK. Macitentan for the treatment of pulmonary arterial hypertension. Vasc Health Risk Manag 2014;10:665-73.
Hachulla E, Hatron PY, Carpentier P, Agard C, Chatelus E, Jego P, et al.
Efficacy of sildenafil on ischaemic digital ulcer healing in systemic sclerosis: The placebo-controlled SEDUCE study. Ann Rheum Dis 2016;75:1009-15.
Badesch DB, Hill NS, Burgess G, Rubin LJ, Barst RJ, Galiè N, et al.
Sildenafil for pulmonary arterial hypertension associated with connective tissue disease. J Rheumatol 2007;34:2417-22.
Fries R, Shariat K, von Wilmowsky H, Böhm M. Sildenafil in the treatment of Raynaud′s phenomenon resistant to vasodilatory therapy. Circulation 2005;112:2980-5.
Brueckner CS, Becker MO, Kroencke T, Huscher D, Scherer HU, Worm M, et al.
Effect of sildenafil on digital ulcers in systemic sclerosis: Analysis from a single centre pilot study. Ann Rheum Dis 2010;69:1475-8.
Oudiz RJ, Brundage BH, Galiè N, Ghofrani HA, Simonneau G, Botros FT, et al.
Tadalafil for the treatment of pulmonary arterial hypertension: A double-blind 52-week uncontrolled extension study. J Am Coll Cardiol 2012;60:768-74.
Hassoun PM, Zamanian RT, Damico R, Lechtzin N, Khair R, Kolb TM, et al.
Ambrisentan and tadalafil up-front combination therapy in scleroderma-associated pulmonary arterial hypertension. Am J Respir Crit Care Med 2015;192:1102-10.
Wigley FM, Seibold JR, Wise RA, McCloskey DA, Dole WP. Intravenous iloprost treatment of Raynaud′s phenomenon and ischemic ulcers secondary to systemic sclerosis. J Rheumatol 1992;19:1407-14.
McHugh NJ, Csuka M, Watson H, Belcher G, Amadi A, Ring EF, et al.
Infusion of iloprost, a prostacyclin analogue, for treatment of Raynaud′s phenomenon in systemic sclerosis. Ann Rheum Dis 1988;47:43-7.
Abraham S, Steen V. Optimal management of digital ulcers in systemic sclerosis. Ther Clin Risk Manag 2015;11:939-47.
Wigley FM, Wise RA, Seibold JR, McCloskey DA, Kujala G, Medsger TA Jr., et al.
Intravenous iloprost infusion in patients with Raynaud phenomenon secondary to systemic sclerosis. A multicenter, placebo-controlled, double-blind study. Ann Intern Med 1994;120:199-206.
Badesch DB, Tapson VF, McGoon MD, Brundage BH, Rubin LJ, Wigley FM, et al.
Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann Intern Med 2000;132:425-34.
Shah AA, Schiopu E, Hummers LK, Wade M, Phillips K, Anderson C, et al.
Open label study of escalating doses of oral treprostinil diethanolamine in patients with systemic sclerosis and digital ischemia: Pharmacokinetics and correlation with digital perfusion. Arthritis Res Ther 2013;15:R54.
Mittendorf J, Weigand S, Alonso-Alija C, Bischoff E, Feurer A, Gerisch M, 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.
Grimminger F, Weimann G, Frey R, Voswinckel R, Thamm M, Bölkow D, et al.
First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension. Eur Respir J 2009;33:785-92.
Ghofrani HA, Voswinckel R, Gall H, Schermuly R, Weissmann N, Seeger W, et al.
Riociguat for pulmonary hypertension. Future Cardiol 2010;6:155-66.
Denton CP, Lapadula G, Mouthon L, Müller-Ladner U. Renal complications and scleroderma renal crisis. Rheumatology (Oxford) 2009;48 Suppl 3:iii32-5.
Steen VD, Costantino JP, Shapiro AP, Medsger TA Jr. Outcome of renal crisis in systemic sclerosis: Relation to availability of angiotensin converting enzyme (ACE) inhibitors. Ann Intern Med 1990;113:352-7.
Steen VD, Medsger TA Jr. Long-term outcomes of scleroderma renal crisis. Ann Intern Med 2000;133:600-3.
Coleiro B, Marshall SE, Denton CP, Howell K, Blann A, Welsh KI, et al.
Treatment of Raynaud′s phenomenon with the selective serotonin reuptake inhibitor fluoxetine. Rheumatology (Oxford) 2001;40:1038-43.
Dziadzio M, Denton CP, Smith R, Howell K, Blann A, Bowers E, et al.
Losartan therapy for Raynaud′s phenomenon and scleroderma: Clinical and biochemical findings in a fifteen-week, randomized, parallel-group, controlled trial. Arthritis Rheum 1999;42:2646-55.
Iorio ML, Masden DL, Higgins JP. Botulinum toxin A treatment of Raynaud′s phenomenon: A review. Semin Arthritis Rheum 2012;41:599-603.
Drake DB, Kesler RW, Morgan RF. Digital sympathectomy for refractory Raynaud′s phenomenon in an adolescent. J Rheumatol 1992;19:1286-8.
Matucci-Cerinic M, Krieg T, Guillevin L, Schwierin B, Rosenberg D, Cornelisse P, et al
. Elucidating the burden of recurrent and chronic digital ulcers in systemic sclerosis: Long-term results from the DUO Registry. Ann Rheum Dis 2015;doi:10.1136/annrheumdis-2015-208121.
Overman CL, Kool MB, Da Silva JA, Geenen R. The prevalence of severe fatigue in rheumatic diseases: An international study. Clin Rheumatol 2016;35:409-15.
Kwakkenbos L, van Lankveld WG, Vonk MC, Becker ES, van den Hoogen FH, van den Ende CH. Disease-related and psychosocial factors associated with depressive symptoms in patients with systemic sclerosis, including fear of progression and appearance self-esteem. J Psychosom Res 2012;72:199-204.
Razykov I, Levis B, Hudson M, Baron M, Thombs BD; Canadian Scleroderma Research Group. Prevalence and clinical correlates of pruritus in patients with systemic sclerosis: An updated analysis of 959 patients. Rheumatology (Oxford) 2013;52:2056-61.
Frech T, Novak K, Revelo MP, Murtaugh M, Markewitz B, Hatton N, et al.
Low-dose naltrexone for pruritus in systemic sclerosis. Int J Rheumatol 2011;2011:804296.
Robertson LP, Marshall RW, Hickling P. Treatment of cutaneous calcinosis in limited systemic sclerosis with minocycline. Ann Rheum Dis 2003;62:267-9.
Thombs BD, van Lankveld W, Bassel M, Baron M, Buzza R, Haslam S, et al.
Psychological health and well-being in systemic sclerosis: State of the science and consensus research agenda. Arthritis Care Res (Hoboken) 2010;62:1181-9.
Thombs BD, Taillefer SS, Hudson M, Baron M. Depression in patients with systemic sclerosis: A systematic review of the evidence. Arthritis Rheum 2007;57:1089-97.
Nietert PJ, Mitchell HC, Bolster MB, Curran MY, Tilley BC, Silver RM. Correlates of depression, including overall and gastrointestinal functional status, among patients with systemic sclerosis. J Rheumatol 2005;32:51-7.
Thombs BD, Hudson M, Taillefer SS, Baron M; Canadian Scleroderma Research Group. Prevalence and clinical correlates of symptoms of depression in patients with systemic sclerosis. Arthritis Rheum 2008;59:504-9.
Hyphantis TN, Tsifetaki N, Pappa C, Voulgari PV, Siafaka V, Bai M, et al.
Clinical features and personality traits associated with psychological distress in systemic sclerosis patients. J Psychosom Res 2007;62:47-56.
Van Lankveld WG, Teunissen H, Näring G, Vonk MC, van den Hoogen FH. Social support, disease-related cognitions and coping as predictors of depressed mood in systemic sclerosis. Cogn Ther Res 2008;32:434-47.
Roca RP, Wigley FM, White B. Depressive symptoms associated with scleroderma. Arthritis Rheum 1996;39:1035-40.
Heinberg LJ, Kudel I, White B, Kwan A, Medley K, Wigley F, et al.
Assessing body image in patients with systemic sclerosis (scleroderma): Validation of the adapted Satisfaction with Appearance Scale. Body Image 2007;4:79-86.
Benrud-Larson LM, Heinberg LJ, Boling C, Reed J, White B, Wigley FM, et al.
Body image dissatisfaction among women with scleroderma: Extent and relationship to psychosocial function. Health Psychol 2003;22:130-9.
Bruni C, Raja J, Denton CP, Matucci-Cerinic M. The clinical relevance of sexual dysfunction in systemic sclerosis. Autoimmun Rev 2015;14:1111-5.
Jewett LR, Hudson M, Haythornthwaite JA, Heinberg L, Wigley FM, Baron M, et al.
Development and validation of the brief-satisfaction with appearance scale for systemic sclerosis. Arthritis Care Res (Hoboken) 2010;62:1779-86.
Lally EV, Jimenez SA. Erectile failure in systemic sclerosis. N Engl J Med 1990;322:1398-9.
Sukenik S, Horowitz J, Buskila D, Abarbanel JM, Lismer L, Avinoach I. Impotence in systemic sclerosis. Ann Intern Med 1987;106:910-1.
Lotfi MA, Varga J, Hirsch IH. Erectile dysfunction in systemic sclerosis. Urology 1995;45:879-81.
Knafo R, Haythornthwaite JA, Heinberg L, Wigley FM, Thombs BD. The association of body image dissatisfaction and pain with reduced sexual function in women with systemic sclerosis. Rheumatology (Oxford) 2011;50:1125-30.
Schouffoer AA, van der Marel J, Ter Kuile MM, Weijenborg PT, Voskuyl A, Vliet Vlieland CW, et al.
Impaired sexual function in women with systemic sclerosis: A cross-sectional study. Arthritis Rheum 2009;61:1601-8.
Impens AJ, Rothman J, Schiopu E, Cole JC, Dang J, Gendrano N, et al.
Sexual activity and functioning in female scleroderma patients. Clin Exp Rheumatol 2009;27 3 Suppl 54:38-43.
Hudson M, Steele R, Lu Y, Thombs BD; Canadian Scleroderma Research Group, Baron M. Work disability in systemic sclerosis. J Rheumatol 2009;36:2481-6.
Sharif R, Mayes MD, Nicassio PM, Gonzalez EB, Draeger H, McNearney TA, et al.
Determinants of work disability in patients with systemic sclerosis: A longitudinal study of the GENISOS cohort. Semin Arthritis Rheum 2011;41:38-47.
Raja J, Ng CT, Sujau I, Chin KF, Sockalingam S. High-resolution oesophageal manometry and 24-hour impedance-pH study in systemic sclerosis patients: Association with clinical features, symptoms and severity. Clin Exp Rheumatol 2016. [Epub ahead of print]. PMID: 26843456.
Nagaraja V, McMahan ZH, Getzug T, Khanna D. Management of gastrointestinal involvement in scleroderma. Curr Treatm Opt Rheumatol 2015;1:82-105.
Sallam H, McNearney TA, Chen JD. Systematic review: Pathophysiology and management of gastrointestinal dysmotility in systemic sclerosis (scleroderma). Aliment Pharmacol Ther 2006;23:691-712.
Leite LP, Johnston BT, Just RJ, Castell DO. Persistent acid secretion during omeprazole therapy: A study of gastric acid profiles in patients demonstrating failure of omeprazole therapy. Am J Gastroenterol 1996;91:1527-31.
Wang Y, Pan T, Wang Q, Guo Z. Additional bedtime H2-receptor antagonist for the control of nocturnal gastric acid breakthrough. Cochrane Database Syst Rev 2009;(4):CD004275.
Sjogren RW. Gastrointestinal motility disorders in scleroderma. Arthritis Rheum 1994;37:1265-82.
Mercado U, Arroyo de Anda R, Avendaño L, Araiza-Casillas R, Avendaño-Reyes M. Metoclopramide response in patients with early diffuse systemic sclerosis. Effects on esophageal motility abnormalities. Clin Exp Rheumatol 2005;23:685-8.
Tonini M, De Ponti F, Di Nucci A, Crema F. Review article: Cardiac adverse effects of gastrointestinal prokinetics. Aliment Pharmacol Ther 1999;13:1585-91.
Boeckxstaens GE, Bartelsman JF, Lauwers L, Tytgat GN. Treatment of GI dysmotility in scleroderma with the new enterokinetic agent prucalopride. Am J Gastroenterol 2002;97:194-7.
Kenefick NJ, Vaizey CJ, Nicholls RJ, Cohen R, Kamm MA. Sacral nerve stimulation for faecal incontinence due to systemic sclerosis. Gut 2002;51:881-3.
Butt SK, Alam A, Cohen R, Krogh K, Buntzen S, Emmanuel A. Lack of effect of sacral nerve stimulation for incontinence in patients with systemic sclerosis. Colorectal Dis 2015;17:903-7.
Butt SK, Alam A, Raeburn A, Liwanag J, Ong VH, Denton CP, et al
. Preliminary significant findings from a randomised control trial of posterior tibial nerve stimulation in systemic sclerosis associated faecal incontinence. Abstract PWE-183. Gut 2014;63:A206.
Tokumura A, Carbone LD, Yoshioka Y, Morishige J, Kikuchi M, Postlethwaite A, et al.
Elevated serum levels of arachidonoyl-lysophosphatidic acid and sphingosine 1-phosphate in systemic sclerosis. Int J Med Sci 2009;6:168-76.
Castelino FV, Seiders J, Bain G, Brooks SF, King CD, Swaney JS, et al.
Amelioration of dermal fibrosis by genetic deletion or pharmacologic antagonism of lysophosphatidic acid receptor 1 in a mouse model of scleroderma. Arthritis Rheum 2011;63:1405-15.
Ohashi T, Yamamoto T. Antifibrotic effect of lysophosphatidic acid receptors LPA1 and LPA3 antagonist on experimental murine scleroderma induced by bleomycin. Exp Dermatol 2015;24:698-702.
Swaney JS, Chapman C, Correa LD, Stebbins KJ, Bundey RA, Prodanovich PC, et al.
A novel, orally active LPA(1) receptor antagonist inhibits lung fibrosis in the mouse bleomycin model. Br J Pharmacol 2010;160:1699-713.
Khan K, Xu S, Nihtyanova S, Derrett-Smith E, Abraham D, Denton CP, et al.
Clinical and pathological significance of interleukin 6 overexpression in systemic sclerosis. Ann Rheum Dis 2012;71:1235-42.
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;27:140-6.
O′Reilly S, Cant R, Ciechomska M, van Laar JM. Interleukin-6: A new therapeutic target in systemic sclerosis? Clin Transl Immunology 2013;2:e4.
Khanna D, Denton CP, Jahreis A, van Laar JM, Frech TM, Anderson ME, 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.
Schaefer CJ, Ruhrmund DW, Pan L, Seiwert SD, Kossen K. Antifibrotic activities of pirfenidone in animal models. Eur Respir Rev 2011;20:85-97.
Khanna D, Albera C, Fischer A, Seibold JR, Raghu G, Khalidi N, et al
. Safety and tolerability of pirfenidone in patients with systemic sclerosis-associated interstitial lung disease - The Lotuss study. Abstract SAT0433. Ann Rheum Dis 2015;74:816.
Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, et al.
Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014;370:2071-82.
Huang J, Beyer C, Palumbo-Zerr K, Zhang Y, Ramming A, Distler A, et al.
Nintedanib inhibits fibroblast activation and ameliorates fibrosis in preclinical models of systemic sclerosis. Ann Rheum Dis 2016;75:883-90.
Rice LM, Padilla CM, McLaughlin SR, Mathes A, Ziemek J, Goummih S, et al.
Fresolimumab treatment decreases biomarkers and improves clinical symptoms in systemic sclerosis patients. J Clin Invest 2015;125:2795-807.
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