Anne Claire Desbois

Patrice Cacoub
email: patrice.cacoub@aphp.fr.

Prof Patrice Cacoub

Systemic sclerosis: An update in 2016

Keywords: systemic sclerosis, autoimmune disease, treatment

Systemic sclerosis (SSc) is a chronic immune disorder of unknown origin, dominated by excessive fibrosis responsible for cutaneous and pulmonary fibrosis, and by vascular endothelial dysfunction at the origin of skin ischemia, renal and pulmonary artery lesions.

Renal and pulmonary complications are mainly responsible for the severity of the disease.

Recent advances led to a better understanding of pathological mechanisms and a more accurate classification of patients according to clinical and biological (auto-antibodies) phenotype. Recent trials provided interesting data on different therapeutic strategies, depending on organ involvement. These data are of particular importance in such disease, still characterized by increased mortality and morbidity rates. In this review, we aim to synthetize recent advances in diagnosis and prognosis leading to better classification of SSc patients, and in therapeutic management.

Key points:

 Recent revised classification criteria of the American College of Rheumatology provide important advances to identify early SSc patients or SSc patients with unusual features.

 Biological markers (autoantibodies) are useful to better define the phenotype and the prognosis of SSc patients.

 Based on better understanding pathophysiology, targeted therapies (anti-fibrotic agents, anti-CD20 antibodies…) are currently investigated, depending on organ involvement.

Systemic sclerosis (SSc) is a chronic immune disorder of unknown origin, characterized by vascular damages and extensive fibrosis. Women are more frequently affected. It is the auto-immune rheumatic disease with the highest disease-related mortality and morbidity with an impaired quality of life [START_REF] Almeida | Quality of life in systemic sclerosis[END_REF]. Diffuse SSc cases, defined by a skin thickening involving the proximal limbs or trunk, have a higher frequency of heart, lung or kidney involvement. There have been advances in understanding of pathogenesis. This remains incompletely understood but has reached a point where key cell types and potential mediators can be defined and has started to inform clinical development and trials.

Consequently, there have been advances in the management of systemic sclerosis that have led to better overall survival, especially for the most severe diffuse form of the disease. In this review, we aim to synthetize recent advances in diagnosis, in prognosis leading to better classification of SSc patients and in therapeutic management.

Clinical features

In the EUSTAR register on 9,149 SSc patients, the female/male sex ratio was 6 [START_REF] Elhai | A gender gap in primary and secondary heart dysfunctions in systemic sclerosis: a EUSTAR prospective study[END_REF]. Female prevalence was lower in patients with a diffuse cutaneous form (4/1) and young patients (8:1 before 30 years vs. 5:1 after 60 years). Main features of SSc are indicated in Table 1, according to clinico-biological phenotypes of the disease. Besides these specific symptoms, SSc is associated with a high frequency of fatigue, depression, sleeping disorders and sexual dysfunction that also lead to disability and a reduced quality of life [START_REF] Almeida | Quality of life in systemic sclerosis[END_REF][START_REF] Bruni | The clinical relevance of sexual dysfunction in systemic sclerosis[END_REF].

Skin lesions

The Raynaud's phenomenon is almost constant (95%). It often precedes other signs of scleroderma. It is bilateral and can also affect feet, nose and ears. The capillaroscopy helps clinicians to evoke a SSc pattern (see diagnosis section). In prospective registries of patients followed for a Raynaud's phenomenon (VEDOSS cohort, EUSTAR study), the association of puffy fingers and antinuclear antibodies showed a positive predictive value of 88% for developing scleroderma [START_REF] Minier | Preliminary analysis of the Very Early Diagnosis of Systemic Sclerosis (VEDOSS) EUSTAR multicentre study: evidence for puffy fingers as a pivotal sign for suspicion of systemic sclerosis[END_REF]. Skin thickening begins in fingers (sclerodactily), extending proximal to metacarpophalangeal joints. The extension and degree of sclerosis is quantified using the modified Rodnan score [START_REF] Clements | Skin thickness score in systemic sclerosis: an assessment of interobserver variability in 3 independent studies[END_REF]. Cutaneous sclerosis can affect the limbs, the back and the face. The fibrosis limits mouth opening and makes the face inexpressive. Digital ulcers and fingertip pitting scars are found in 42 % of diffuse scleroderma and 33% in the limited forms. They can lead to a severe discomfort such as pain, infection, functional impairment, gangrene and amputation [START_REF] Walker | Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials And Research group database[END_REF][START_REF] Almeida | Quality of life in systemic sclerosis[END_REF]. In a recent study from EUSTAR database (n=4,288 SSc), the presence of digital ulcers at presentation was associated with worsening of cardiovascular status (elevated systolic arterial pulmonary pression and left ventricular failure) and decreased survival [START_REF] Mihai | Digital ulcers predict a worse disease course in patients with systemic sclerosis[END_REF]. Many other cutaneous signs are frequently found as limbs ulcerations (40%), telangiectasia (75%), hyperpigmentation of thickened skin (30%), and cutaneous calcifications affecting soft tissues, fingers, forearms, elbows and knees (25%). Less frequently, patients may present achromic areas.

Pulmonary involvement

Main pulmonary manifestations of scleroderma include interstitial lung disease and pulmonary hypertension, with or without lung fibrosis. The pulmonary hypertension (defined as a mean pulmonary arterial pressure> 25mmHg [START_REF] Galiè | ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT)[END_REF] may be secondary to vascular disease associated to scleroderma (SSc-PAH), or to pulmonary fibrosis, with different prognosis.

The pulmonary arterial hypertension, related to direct vascular involvement of scleroderma (PAH-SSc), is defined by a capillary pressure equal or less than 15mmHg. It is related to the occlusion and the remodelling of small pulmonary arterioles. The prevalence of PAH-SSc is variable according to the screening tool, found in 8-12% of patients when using right catheterization and in up to 38% when using echocardiography [START_REF] Mukerjee | Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach[END_REF][START_REF] Hachulla | The three-year incidence of pulmonary arterial hypertension associated with systemic sclerosis in a multicenter nationwide longitudinal study in France[END_REF]. In a French prospective study, the incidence of SSc-PAH was 0.61/100 person-years [START_REF] Hachulla | The three-year incidence of pulmonary arterial hypertension associated with systemic sclerosis in a multicenter nationwide longitudinal study in France[END_REF]. The symptoms are non-specific, consisting in dyspnoea, chest pain or syncope. In SSc patients, main risk factors for developing a pulmonary arterial hypertension are summarized in Table 2 [START_REF] Hassoun | Lung involvement in systemic sclerosis[END_REF]. The major poor prognostic factors of SSc-PAH include impaired function of the right ventricle at diagnosis, the presence of a pericardial effusion and a decreased cardiac output. Making early SSc-PAH diagnosis remains a challenge in order to initiate early the appropriate treatment and to improve the prognosis. Recently, a new algorithm (DETECT study) was proposed to reduce the rate of undiagnosed SSc-PAH [START_REF] Coghlan | Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study[END_REF]. Indeed, among patients with a high risk of PAH [i.e. more than 3 years of SSc evolution, DLCO (Diffusing Capacity of Carbon Monoxyde) <60%, FVC (Forced Vital Capacity) >40%] and a diagnosis on right catheterization, 36% had a tricuspid regurgitation velocity below 2.8 mm/s on echocardiography. This algorithm showed negative and positive predictive values of 98% and 35%, respectively. Only 4% of SSc-PAH patients would not have been diagnosed while a right catheterization would have been performed in 62% of patients and negative for 65%.

With current recommendations of the European Society of Cardiology, 29% of SSc-PAH patients would not have been diagnosed and right catheterization would have been performed in 40% patients [START_REF] Coghlan | Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study[END_REF].

The prevalence of pulmonary parenchymal lesions is variable depending on the subgroups studied (25 to 90%) [START_REF] Hassoun | Lung involvement in systemic sclerosis[END_REF]. The cutaneous diffuse disease with positive anti-Scl70 antibody is known to be associated with interstitial lung disease [START_REF] Walker | Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials And Research group database[END_REF]. In a large study including more than 3,500 SSc patients, 50% of patients with diffuse SSc showed interstitial lung disease versus 34% of those with a limited form [START_REF] Walker | Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials And Research group database[END_REF]. Factors associated with the occurrence of pulmonary fibrosis were diffuse cutaneous form [relative risk (RR 1.7)], the presence of antitopoisomerase I antibodies (RR 1.8), a forced vital capacity <65% (RR 3.2) and a DLCO <55% (RR 3.0) [START_REF] Nihtyanova | Prediction of pulmonary complications and long-term survival in systemic sclerosis[END_REF]. The most frequently described features include a nonspecific interstitial pneumonia pattern (NSIP) and a pulmonary fibrosis pattern [usual interstitial pneumonia (UIP)]. Among 22 patients with scleroderma and pulmonary interstitial disease who had a pulmonary histology, 64% had a NSIP pattern and 36% a UIP pattern, with a median survival of 15 versus 3 years, respectively [START_REF] Fischer | Clinically Significant Interstitial Lung Disease in Limited SclerodermaHistopathology, Clinical Features, and Survival[END_REF]. The presence of an extensive pulmonary fibrosis, defined by lesions extent above 20% on high resolution-CT scan and/or FVC below 70%, was associated with a 5-year mortality rate of 60% [START_REF] Papagoras | Heart involvement in systemic sclerosis: a combined echocardiographic and scintigraphic study[END_REF].

Digestive involvement

An oesophageal involvement concerns 70% of SSc patients. The symptoms include retrosternal burns, dysphagia, atypical chest pain, nausea, vomiting, regurgitation... They are mostly related to gastro-oesophageal reflux or peristaltic disorders of the oesophagus. They are revealed on oesophageal manometry by a decreased amplitude of contractions in the lower third of the oesophagus and a hypotonic lower oesophageal sphincter (which can lead to oesophagus dilatation). Gastric motility disorders (25%) may lead to food stasis. Gastric bleeding are rare and may be related to telangiectasia sometimes leading to a so-called "watermelon" stomach. The small intestine involvement (20%) can result in a chronic intestinal pseudo-obstruction syndrome and/or a malabsorption promoted by bacterial overgrowth. The findings of a recent study suggest that fecal calprotectin may be a helpful test in identifying the group of SSc patients at high risk for small intestinal bacterial overgrowth (SIBO) requiring glucose breath tets and to assess SIBO eradication [START_REF] Marie | Fecal calprotectin in systemic sclerosis and review of the literature[END_REF]. A colic involvement is less frequent and is responsible for constipation, colic pain, alternating diarrhea and constipation. Anal incontinence may be observed.

Heart involvement

The cardiac involvement, probably underestimated, concerns the pericardium and myocardium. The pericardial disease is manifested by acute pericarditis, chronic pericarditis and rarely constrictive pericarditis. Myocardial damages are most often linked to ischemic injury associated to disorders of the coronary microcirculation that may lead to myocardial fibrosis. Up to 60% of patients showed perfusion defects on myocardial scintigraphy [START_REF] Papagoras | Heart involvement in systemic sclerosis: a combined echocardiographic and scintigraphic study[END_REF]. In a large international series of 3,656 SSc patients, 24-27% of patients had palpitations, 11-13% a conduction block, 15% a diastolic dysfunction and 5% a reduced left ventricular systolic function [START_REF] Walker | Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials And Research group database[END_REF]. In a French multicenter study of 570 SSc patients, 22% had left ventricular hypertrophy and 17% a diastolic dysfunction [START_REF] De Groote | Evaluation of cardiac abnormalities by Doppler echocardiography in a large nationwide multicentric cohort of patients with systemic sclerosis[END_REF].

Articular involvement

Joint involvement is very frequent (45-90%), including arthralgia and less frequently symmetrical arthritis, affecting small joints of the hands, wrists, knees and ankles. Joint stiffness may also be related to the cutaneous thickening or to calcified peri-arthritis. Arthritis are usually non-erosive. Synovitis and tendon friction rubs are more common in diffuse cutaneous forms [START_REF] Minier | Preliminary analysis of the Very Early Diagnosis of Systemic Sclerosis (VEDOSS) EUSTAR multicentre study: evidence for puffy fingers as a pivotal sign for suspicion of systemic sclerosis[END_REF], and are associated with rapid skin progression and early kidney disease onset [START_REF] Avouac | Joint and tendon involvement predict disease progression in systemic sclerosis: a EUSTAR prospective study[END_REF]. Osteolysis of the distal phalanx of the fingers is present in 20% of patients.

Kidney disease

Renal involvement is a rare (4-6%) but severe manifestation in patients with SSc and is more frequent in cutaneous diffuse (4%) than in cutaneous limited form (2%) [START_REF] Minier | Preliminary analysis of the Very Early Diagnosis of Systemic Sclerosis (VEDOSS) EUSTAR multicentre study: evidence for puffy fingers as a pivotal sign for suspicion of systemic sclerosis[END_REF]. Severe hypertension (90%), sometimes associated with hypertensive encephalopathy or heart failure, rapid deterioration of renal function and thrombotic microangiopathy (40 %), are the main manifestations of scleroderma renal crisis. Biological abnormalities include frequently nonnephrotic proteinuria, hematuria and moderate thrombocytopenia. Scleroderma renal crisis is defined by: (i) a severe or worsening arterial hypertension >150/85mmHg twice in twenty four hours, without another explanation AND (ii) a rapidly progressive kidney failure, sometimes oligo-anuric, without further explanation [START_REF] Steen | Scleroderma renal crisis[END_REF][START_REF] Mouthon | Scleroderma renal crisis[END_REF]. The elements supporting the diagnosis are the presence of mechanic hemolytic anemia, hypertensive retinopathy, renal sodium overload or pulmonary oedema, oligo-anuria and suggestive abnormalities on renal biopsy. The typical renal lesion is the "onion bulb" aspect related to endothelial injury, associated with intimal proliferation and vascular remodeling, leading to the obstruction of the vascular lumen and to the reduction of glomerular filtration rate. Platelet activation is observed, leading to the formation of thrombosis. The lesions are localized in small and medium arteries, i.e. arterioles and inter-lobular arched, with adventitial fibrosis and intraglomerular thrombosis. The main risk factors of scleroderma renal crisis are a diffuse and rapidly progressive cutaneous form, the presence of anti-RNA polymerase III antibodies, a new onset of anemia, a recent cardiovascular event, the administration of high doses of corticosteroids (> 15mg per day) and a recent development of scleroderma (<4 years) [START_REF] Papagoras | Heart involvement in systemic sclerosis: a combined echocardiographic and scintigraphic study[END_REF][START_REF] Marie | Fecal calprotectin in systemic sclerosis and review of the literature[END_REF].

Neurological involvement

In a recent meta-analysis on 6,028 SSc patients, 177 (2.9%) patients had a central neurological disorder. Main reported features included headache (23.7%), epilepsy (13.6%), and cognitive disorders (8.5%). In addition, 442 (7.3%) patients presented with a peripheral neuromuscular disorder, i.e. myopathy, trigeminal nerve disorder, motor and sensory neuropathy and carpal tunnel syndrome [START_REF] Amaral | Neurologic involvement in scleroderma: A systematic review[END_REF]. Psychiatric signs were found in 1,490/2,712 (54.9%) patients, consisting in depressive symptoms (73.2%) and anxiety (23.9%).

Specific forms

Scleroderma sine scleroderma

Scleroderma without skin thickening is an uncommon form of the disease (2-8%). Such pattern may be related to an initial misclassification of patients with a discrete skin disease and a relatively slow evolution. Patients with scleroderma sine scleroderma share clinical features with those with cutaneous limited form, i.e. lower frequency of telangiectasia, digital ulcers, anti-topoisomerase I and anti-RNA polymerase III antibodies. However, anticentromere antibodies are frequently observed. The prevalence of visceral involvements seems similar in forms with or without skin sclerosis i.e. oesophageal disorders (56-83%), lung involvement (25-57%), and scleroderma renal crisis (2.5-3.7%) [START_REF] Diab | Systemic Sclerosis Sine Scleroderma: A Multicenter Study of 1417 Subjects[END_REF][START_REF] Marangoni | Systemic sclerosis sine scleroderma: distinct features in a large Brazilian cohort[END_REF].

Muscular involvement

Patients with anti-PmScl antibodies have overlap syndromes between myositis and scleroderma. They are more likely to have myopathy and pulmonary disease [START_REF] Bhansing | Sclerodermapolymyositis overlap syndrome versus idiopathic polymyositis and systemic sclerosis: a descriptive study on clinical features and myopathology[END_REF]. Patients with scleroderma and anti-PmScl antibodies had fewer digital ulcers and cutaneous thickening or diffuse form while they had better pulmonary prognosis [START_REF] Castillo | Good outcome of interstitial lung disease in patients with scleroderma associated to anti-PM/Scl antibody[END_REF]. In the EULAR register [START_REF] Walker | Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials And Research group database[END_REF], muscle weakness and creatinine phosphokinase increase were significantly associated to diffuse cutaneous form (37.1% vs. 11.3%) and anti-Scl70 antibodies (32.2% vs. 8.7%).

Myopathy predicted deaths of all origins and scleroderma-related deaths [START_REF] Elhai | A gender gap in primary and secondary heart dysfunctions in systemic sclerosis: a EUSTAR prospective study[END_REF]. A creatinine phosphokinase increase was associated with the development of heart disease [RR 2.64 (95CI 1.2; 5.81)].

Pathophysiology of systemic sclerosis

Systemic sclerosis is characterized by vasculopathy, fibrosis and inflammation. To date, mechanisms contributing to fibrosis and vasculopathy are not completely elucidated.

Environmental factors may contribute to SSc occurrence. SSc occurrence was associated with silica exposure, chlorinated solvents, trichloroethylene, welding fumes for men, aromatic solvents and ketones for women and white spirit for both genders [START_REF]Systemic sclerosis and occupational exposure: towards an extension of legal recognition as occupational disorder in 2014?[END_REF]. In U.S cohorts, first degree relatives were identified to have increased susceptibility to develop SSc with a RR 10 to 16. Several studies found an association between SSc and genes implicated in immune system, notably polymorphisms of the interferon-regulatory factor 5 (IRF5) involved in activation of interferon targets and the ligand of CD134 (OX40L) involved in antigen presentation and T and B cells activation. The combination of signal transducer and activator of transcription 4 (STAT4) and IRF5 was associated with an increased risk of pulmonary fibrosis occurrence. Genome wide association studies identified an association with a variant of c-src tyrosine kinase (CSK) which modulates signalling through the T-cell receptor and CD247 (encoding a sub-unit of the T cell receptor) [START_REF] Martin | Identification of CSK as a systemic sclerosis genetic risk factor through Genome Wide Association Study follow-up[END_REF][START_REF] Radstake | Genomewide association study of systemic sclerosis identifies CD247 as a new susceptibility locus[END_REF]. Other studies have shown an association between BANK1 (B-cell gene) variants and diffuse phenotype of SSc in Caucasians, confirming the major role of B cells [START_REF] Rueda | BANK1 functional variants are associated with susceptibility to diffuse systemic sclerosis in Caucasians[END_REF][START_REF] Dieudé | STAT4 is a genetic risk factor for systemic sclerosis having additive effects with IRF5 on disease susceptibility and related pulmonary fibrosis[END_REF]. Studies of polymorphisms of the Major Histocompatibility Complex found associations with SSc in Caucasians and Hispanics for DRB1*1104, DQA1*0501, and DQB1*0301 [START_REF] Arnett | Major histocompatibility complex (MHC) class II alleles, haplotypes and epitopes which confer susceptibility or protection in systemic sclerosis: analyses in 1300 Caucasian, African-American and Hispanic cases and 1000 controls[END_REF]. In addition, DRB1*1101 and DPB1*1301 alleles were associated with the presence of anti-topoisomerase I antibodies while DRB1*0401-22 and DRB1*0801-11 alleles were associated with anti-centromere antibodies. [START_REF] Gilchrist | Class II HLA associations with autoantibodies in scleroderma: a highly significant role for HLA-DP[END_REF] SSc patients display arterial hyper-reactivity and remodelling with myo-intimal proliferation, which can lead to arterial occlusion in skin, heart, lung and kidney. Several mechanisms have been proposed to explain perturbation of vascular tone. Increased endothelin-1 levels, known to enhance vasoconstriction, inflammation and vascular remodelling, were found in sera, lung or kidney biopsies as well as defective prostacyclin synthesis. Patients with diffuse SSc, without fingertips ulcers and anti-Scl70 antibody positive were found to have higher levels of vascular epidermal growth factor (VEGF) compared with healthy controls and SSc patients with digital ulcers [START_REF] Distler | Angiogenic and angiostatic factors in systemic sclerosis: increased levels of vascular endothelial growth factor are a feature of the earliest disease stages and are associated with the absence of fingertip ulcers[END_REF]. Excess levels of VEGF have been shown to aggravate fibrosis and might lead to impaired angiogenesis [START_REF] Maurer | Vascular endothelial growth factor aggravates fibrosis and vasculopathy in experimental models of systemic sclerosis[END_REF]. Increased serum levels of the anti-angiogenic VEGF165b isoform have been reported which could explain the lack of sufficient angiogenesis despite elevated VEGF levels [START_REF] Manetti | Increased plasma levels of the VEGF165b splice variant are associated with the severity of nailfold capillary loss in systemic sclerosis[END_REF]. Sufficient angiogenesis depends on the tight regulation of VEGF expression. Prolonged exposure may have deleterious effects on angiogenesis while very high concentrations of pro-angiogenic VEGF isoforms are needed to overcome the inhibitory effects of anti-angiogenic factors (to have beneficial effects in the prevention and therapy of fingertip ulcers). Elevated levels of pentraxin 3 was found as an independent factor associated with the presence of digital ulcers and pulmonary hypertension and as a predictor of future occurrence of new digital ulcers, suggesting its suppressing effect on vasculogenesis [START_REF] Shirai | Elevated Levels of Pentraxin 3 in Systemic Sclerosis: Associations With Vascular Manifestations and Defective Vasculogenesis: PTX3 and SSc Vasculopathy[END_REF]. Increased MCP-1 (Monocyte Chemoattractant Protein 1) and VCAM-1 (Vascular Cell Adhesion Molecule 1) expressions by endothelial cells enhance leucocytes recruitment and promote inflammation. Anti-endothelial cell antibodies have been reported to induce endothelial cell apoptosis [START_REF] Dumoitier | Pathophysiology of systemic sclerosis: state of the art in 2014[END_REF].

Oxidative stress plays a major role in the pathogenesis of SSc. Endothelial cells and fibroblasts exposure to sera of SSc patients has been shown to induce Reactive Oxygen Species (ROS) production, which is associated to increased fibroblasts proliferation. SSc is characterized by collagen accumulation in skin, the consequence of fibroblast activation.

Phenotypical changes of fibroblasts in SSc have been observed, with an increase of differentiation into myo-fibroblasts. Transforming growth factor (TGF-β) plays a major role in fibroblast activation and phenotypical modifications. Increased TGF-β levels have been shown in lung and dermal SSc lesions [START_REF] Kawakami | Increased expression of TGF-beta receptors by scleroderma fibroblasts: evidence for contribution of autocrine TGF-beta signaling to scleroderma phenotype[END_REF]. Other actors as the platelet derived growth factor (PDGF-R) and the connective tissue growth factor (CTGF) are involved in late stage fibrosis development in scleroderma. IL-4, a Th-2 cytokine, is pro-fibrotic and has been shown to be increased in SSC patient sera. It is over-expressed by activated TCD8 + lymphocytes in bronchoalveolar fluid and skin of SSc patients [START_REF] Parel | Presence of CD4+CD8+ double-positive T cells with very high interleukin-4 production potential in lesional skin of patients with systemic sclerosis[END_REF][START_REF] Luzina | Occurrence of an activated, profibrotic pattern of gene expression in lung CD8+ T cells from scleroderma patients[END_REF].

Immune system is also implicated in vasculopathy and in skin fibrosis observed in SSc patients. The presence of specific auto-antibodies (anti-centromere, anti-topoisomerase I, anti-RNA polymerase III…) indirectly suggests a role of B cells in the SSc pathogenesis. SSc patients display phenotypical changes of B cells, with over-expression of CD19 and CD21

[two activation co-receptors of the B cell receptor (BCR)] and of CD86 and CD95 in memory B cells [START_REF] Sato | Altered blood B lymphocyte homeostasis in systemic sclerosis: expanded naive B cells and diminished but activated memory B cells[END_REF]. Levels of anti-endothelin A receptor and anti-angiotensin type 1 receptor antibodies were significantly higher in patients with SSc-PAH (n = 81) and connective tissue disease-associated PAH (n=110) compared with other forms of PAH/pulmonary hypertension (n=106). High levels of angiotensin type 1 receptor and endothelin A receptor antibodies predicted the development of SSc-PAH and SSc-PAH-related mortality. The transfer of SSc-IgG containing both auto-antibodies into healthy C57BL/6J mice led to more abundant vascular and airway α-smooth muscle actin expression and inflammatory pulmonary vasculopathy [START_REF] Becker | Vascular receptor autoantibodies in pulmonary arterial hypertension associated with systemic sclerosis[END_REF]. Serum levels of IL-6 levels, known to stimulate collagen secretion by fibroblasts, were also found to be increased in SSc patients and correlated with skin fibrosis [START_REF] Sato | Serum levels of interleukin-6 and interleukin-10 correlate with total skin thickness score in patients with systemic sclerosis[END_REF]. TNFα also plays a role in the recruitment of inflammatory cells. T cells also appear to be involved in mechanisms of SSc, with a Th-2 bias leading to IL-4 and IL-13 secretion and B cells stimulation. IL-4 antibody might prevent skin fibrosis [START_REF] Chizzolini | T cells, B cells, and polarized immune response in the pathogenesis of fibrosis and systemic sclerosis[END_REF]. Proteome-wide analysis showed that CXCL4 is the predominant protein secreted by plasmacytoid dendritic cells in systemic sclerosis, especially in early SSc, both in the circulation and in the skin. High levels of CXCL4 were associated with lung fibrosis and pulmonary hypertension. CXCL4 predicted the risk of progression of systemic sclerosis. In vitro, CXCL4 induces endothelin-1 and potentiates responses of toll-like receptors. In vivo, CXCL4 induces the influx of inflammatory cells and skin thickening [START_REF] Van Bon | Proteome-wide Analysis and CXCL4 as a Biomarker in Systemic Sclerosis[END_REF].

Biomarkers, diagnostic criteria and prognostic factors a. Biomarkers

The most frequently found autoantibodies are anti-centromere (ACA) in 15-43% of patients, anti-topoisomerase I (anti-Scl70) in 21-34%, anti-RNA polymerase III in 5% and anti-RNP in 5% [START_REF] Mehra | Autoantibodies in systemic sclerosis[END_REF][START_REF] Van Den Hoogen | classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative[END_REF]. Anti-Scl70 antibodies were positive in 47% of diffuse cutaneous forms versus 14% of limited cutaneous forms, whereas anti-centromere antibodies were found only in limited forms (69%) [START_REF] Sobanski | Prevalence of Anti-RNA Polymerase III Antibodies in Systemic Sclerosis: New Data From a French Cohort and a Systematic Review and Meta-Analysis: Prevalence of Anti-RNAP III in SSc[END_REF]. The ACA prevalence varies from one population to another, with lower rates among African/Americans. The ACA are associated with limited cutaneous forms and with a longer time to onset of visceral complications. Patients ACA-positive often have pulmonary hypertension, but have less frequently digital ulcers, parenchymal lung disease, myocardial and kidney involvements and lower mortality rate [START_REF] Mehra | Autoantibodies in systemic sclerosis[END_REF]. Anti-Scl70 (antitopoisomerase I) antibodies recognize the 70 kDa protein of topoisomerase I, and are associated with diffuse cutaneous disease. These antibodies appear to be associated with a poor prognosis, increased lung and heart involvements and higher mortality rates. Patients with anti-topoisomerase I antibodies develop Raynaud's phenomenon earlier and have a more severe cutaneous presentation. The prevalence of anti-RNA polymerase III antibodies was 11% with a great geographical variability, i.e. 20% in South America,16-20% in North America, 11-15% in Asia and <10% in Europe. In a recent French study, the anti-RNA polymerase III antibodies overall prevalence was 6 to 9% in 133 SSc patients, i.e. 11-19% in diffuse cutaneous versus 3-5% in limited cutaneous forms [START_REF] Sobanski | Prevalence of Anti-RNA Polymerase III Antibodies in Systemic Sclerosis: New Data From a French Cohort and a Systematic Review and Meta-Analysis: Prevalence of Anti-RNAP III in SSc[END_REF]. The presence of anti-RNA polymerase I and III is associated with diffuse cutaneous forms (OR 6.4), scleroderma renal crisis (OR 3.8), tendon contractures (OR 2.5) and a cancer diagnosis within the 5 first years after SSc diagnosis (OR 4.2) [START_REF] Hesselstrand | Scleroderma renal crisis in a Swedish systemic sclerosis cohort: survival, renal outcome, and RNA polymerase III antibodies as a risk factor[END_REF][START_REF] Nikpour | Prevalence, correlates and clinical usefulness of antibodies to RNA polymerase III in systemic sclerosis: a cross-sectional analysis of data from an Australian cohort[END_REF]. After a mean follow-up of 1.9 years, in patients without anti-RNA polymerase III antibodies, the probability of occurrence of scleroderma renal crisis and cancer was of 2 and 4%, respectively [START_REF] Nikpour | Prevalence, correlates and clinical usefulness of antibodies to RNA polymerase III in systemic sclerosis: a cross-sectional analysis of data from an Australian cohort[END_REF]. The presence of anti-RNA polymerase III antibodies was significantly associated with the occurrence of cancer, i.e. 14.2% of patients with anti-RNA polymerase III versus 6.3% of those with anti-Scl70 and 6.8% of those with ACA. Patients with anti-RNA polymerase III antibodies were 6 times more likely to have a cancer within 3 years following the first signs of scleroderma [START_REF] Moinzadeh | Association of anti-RNA polymerase III autoantibodies and cancer in scleroderma[END_REF]. Anti-U1RNP antibodies are found in 90% of mixed connective disease and are often associated with the presence of other antibodies (anti-SSA, anti-SSB). They are associated with the onset of pulmonary arterial hypertension whereas renal disease is less common. Patients with arterial pulmonary hypertension and anti-U1RNP antibodies have a poorer prognosis than those with ACA [START_REF] Graf | South Australian Scleroderma Register: autoantibodies as predictive biomarkers of phenotype and outcome[END_REF].

Other autoantibodies are more rarely found in SSc patients. Anti-Th/Tho antibodies (0.2-6%) are associated with limited cutaneous SSc, renal crisis and a reduced survival rate [START_REF] Mitri | A comparison between anti-Th/To-and anticentromere antibody-positive systemic sclerosis patients with limited cutaneous involvement[END_REF].

Patients with anti-Th/Tho antibodies develop more frequently interstitial lung disease and pericarditis but less frequently digital ulcers [START_REF] Mitri | A comparison between anti-Th/To-and anticentromere antibody-positive systemic sclerosis patients with limited cutaneous involvement[END_REF][START_REF] Ceribelli | Anti-Th/To are common antinucleolar autoantibodies in Italian patients with scleroderma[END_REF]. Anti-Fibrillarin/U3 ribonucleoprotein antibodies (4-18%) are associated with African/American people, muscular involvement, increased risk of PAH, a younger age at onset, higher frequency of digital ulcers, pericarditis and severe lower gastrointestinal involvement, but less severe lung involvement. The impact of anti-fibrillarin antibodies on survival rates is conflicting [START_REF] Sharif | Anti-fibrillarin antibody in African American patients with systemic sclerosis: immunogenetics, clinical features, and survival analysis[END_REF][START_REF] Aggarwal | Anti-U3 RNP autoantibodies in systemic sclerosis[END_REF].

b. Diagnostic criteria

Diagnosis of SSc is based on a set of clinical, immunological (specific antibodies) and capillaroscopic features. The first classification criteria of the American College of Rheumatology in 1980, defined scleroderma by the presence of a proximal cutaneous sclerosis associated with at least 2 of the 3 following criteria: sclerodactyly, digital ulcers, and pulmonary fibrosis. Such criteria did not take into account immunological parameters, patients with limited cutaneous involvement or with an early form. Criteria established by LeRoy et al. in 1988 included capillaroscopic and immunological features. Diffuse forms have been defined as they include a proximal and distal skin thickening, capillary loss on capillaroscopy and the absence of ACA. They are more often associated with antitopoisomerase I antibodies and early visceral involvements as pulmonary, renal, myocardial and gastrointestinal damages. Limited cutaneous forms include a distal skin involvement, systemic vascular disorders such as late onset PAH and a high ACA prevalence. To enable earlier diagnosis, criteria for "early" scleroderma were proposed as Raynaud's phenomenon associated with suggestive capillaroscopic abnormalities and/or the presence of specific antibodies (ACA, anti-Scl70, anti-RNA polymerase III, anti-PmScl or anti Th/To) [START_REF] Leroy | Criteria for the classification of early systemic sclerosis[END_REF].

Typical capillaroscopic scleroderma abnormalities include the presence of enlarged capillaries and capillary loss with or without peri-capillary haemorrhages. Patients meeting these criteria have a high risk of developing scleroderma in the following twenty years, i.e. 79.5% for patients with Raynaud's phenomenon, specific antibodies and capillaroscopic abnormalities and 35.4% among those having a Raynaud's phenomenon and specific antibodies without capillaroscopic specific abnormality [START_REF] Koenig | Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud's phenomenon to systemic sclerosis: a twenty-year prospective study of 586 patients, with validation of proposed criteria for early systemic sclerosis[END_REF]. Of note, systemic involvement (cardiac, pulmonary, digestive ...) was present in 42% of patients with an "early" scleroderma [START_REF] Valentini | Early systemic sclerosis: assessment of clinical and pre-clinical organ involvement in patients with different disease features[END_REF]. Recently, new classification criteria have been proposed by the EULAR in order to further increase the sensitivity of SSc criteria including early forms or those without skin thickening (Table 3) [START_REF] Van Den Hoogen | classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative[END_REF]. These criteria concern patients with a suspicion of scleroderma and exclude patients with cutaneous sclerosis sparing fingers or with a "scleroderma-like disorder" better explained by another disease (i.e. nephrogenic sclerosing fibrosis, generalised morphea, eosinophilic fasciitis, scleredema diabeticorum, scleromyxedema, erythromyalgia, porphyria, lichen sclerosis, graft-versus-host disease, diabetic cheiroarthropathy...).

c. Prognostic factors

Male gender was significantly associated with some clinical features: myopathy (RR 1.93), diffuse cutaneous forms (RR 1.68), digital ulcers (RR 1.28), pulmonary hypertension (RR 3.01), and proteinuria (RR 1.54). Male gender was also reported to be predictive of new onset of pulmonary hypertension (RR 2.66) and heart failure (RR 2.22) [START_REF] Elhai | A gender gap in primary and secondary heart dysfunctions in systemic sclerosis: a EUSTAR prospective study[END_REF].

Data from the EUSTAR database indicated that more than half of deaths are attributed directly to SSc i.e. pulmonary fibrosis (35%), PAH (26%) and cardiac causes (26%). Non-SSc causes of deaths included infections, malignancies and cardiovascular diseases. Independent risk factors for mortality included proteinuria, the presence of PAH on echocardiography, pulmonary restriction or dyspnoea or decreased DLCO, an elevated age at Raynaud's phenomenon onset and an increased modified Rodnan score.

Despite similar hemodynamic indices, patients with SSc-PAH have a higher mortality rate and are less responsive to specific therapy than patients with idiopathic PAH [START_REF] Clements | The pulmonary arterial hypertension quality enhancement research initiative: comparison of patients with idiopathic PAH to patients with systemic sclerosis-associated PAH[END_REF]. In the REVEAL register, patients with SSc-PAH (n=500) showed higher mortality rates than patients with non SSc-CTD-PAH (1 year survival of 82% vs 94-96% in systemic lupus erythematosus and rheumatoid arthritis) [START_REF] Chung | Characterization of connective tissue disease-associated pulmonary arterial hypertension from REVEAL: identifying systemic sclerosis as a unique phenotype[END_REF]. Predictors of mortality in the SSc-PAH group were male gender, age>60 years, a low systolic blood pressure or 6-min walk distance (6MWD), and a high mean right atrial pressure (mRAP) or pulmonary vascular resistance (PVR) [START_REF] Chung | Unique predictors of mortality in patients with pulmonary arterial hypertension associated with systemic sclerosis in the reveal registry[END_REF].

The extent of lung disease on high resolution CT scan independently predicted both mortality and Interstitial Lung Disease (ILD) progression in SSc patients. Other parameters found to be associated with mortality or ILD progression included male gender, presence of honeycombing, elevated KL-6 values (a mucinous high-molecular weight glycoprotein, expressed on type 2 pneumonocytes) and increased alveolar epithelial permeability [START_REF] Winstone | Predictors of mortality and progression in scleroderma-associated interstitial lung disease: a systematic review[END_REF][START_REF] Iudici | Where are we going in the management of interstitial lung disease in patients with systemic sclerosis?[END_REF].

Treatment of systemic sclerosis complications a. Management of Raynaud's phenomenon (RP) and digital ulcers

Besides pharmacological treatments, the eviction of aggravation factors remains a major issue. Patients should stop smoking, avoid the use of vasoconstrictive drugs and protect his/her hands against cold and keep them warm. Proximal arterial lesions should be always investigated and treated.

In SSc patients presenting with RP, calcium antagonists are recommended as first line therapy. Intravenous prostanoids should be used in severe refractory RP. Nifedipine and intravenous iloprost reduced the frequency and severity of SSc-RP attacks [START_REF] Kowal-Bielecka | EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR)[END_REF]. One metaanalysis, including six randomised placebo-controlled trials [nifedipine (n=5), [START_REF] Valentini | Early systemic sclerosis: assessment of clinical and pre-clinical organ involvement in patients with different disease features[END_REF] SSc patients] showed over a 2-week period that calcium antagonists compared with placebo reduced the number of ischaemic attacks by 8.3 (95% CI 0.9-15.7) and were associated with a 35% improvement of RP severity score [START_REF] Kowal-Bielecka | EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR)[END_REF][START_REF] Thompson | Calcium-channel blockers for Raynaud's phenomenon in systemic sclerosis[END_REF]. A second meta-analysis included five randomized controlled trials with intravenous iloprost, one randomized controlled trial with oral iloprost and one randomized controlled trial with oral cisaprost (332 SSc patients). Iloprost i.v. (0.5 to 3 ng/kg/min for 3 to 5 consecutive days) or orally (50 to 150 mg twice a day) improved the RP severity score in comparison with placebo. [START_REF] Pope | Iloprost and cisaprost for Raynaud's phenomenon in progressive systemic sclerosis[END_REF]. Two other randomized controlled trials showed that i.v. iloprost (0.5 to 3 ng/kg/min, every 6-8 weeks) was superior to nifedipine (30-60 mg/day) in improving SSc-RP symptoms [START_REF] Scorza | Effects of long-term cyclic iloprost therapy in systemic sclerosis with Raynaud's phenomenon. A randomized, controlled study[END_REF][START_REF] Rademaker | 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[END_REF]. A meta-analysis analysed main results with PDE-5 inhibitors, including six randomized controlled trials [sildenafil (n=1), modified-release sildenafil (n=1), tadalafil (n=3) vardenafil (n=1)]. Use of PDE-5 inhibitors significantly improved Raynaud's score and the daily frequency and duration of RP attacks [START_REF] Roustit | Phosphodiesterase-5 inhibitors for the treatment of secondary Raynaud's phenomenon: systematic review and metaanalysis of randomised trials[END_REF]. Finally, treatment with fluoxetine was shown to be superior to nifedipine to reduce both RP attack frequency (P = 0.003) and attack severity (P = 0.0002) [START_REF] Hughes | Consensus best practice pathway of the UK Systemic Sclerosis Study Group: digital vasculopathy in systemic sclerosis[END_REF].

For the treatment of SSc-digital ulcers, i.v. iloprost (3 to 5 consecutive days) proved to reduce the number of digital ulcers in comparison with placebo [START_REF] Wigley | Intravenous iloprost treatment of Raynaud's phenomenon and ischemic ulcers secondary to systemic sclerosis[END_REF]. Bosentan should be considered to avoid ulcers recurrences in patients with multiple digital ulcers, after failure of calcium antagonists. Bosentan (62.5 mg twice a day for 4 weeks, followed by 125 mg twice a day for another 12 weeks) reduced the number of new digital ulcers by 48% compared to placebo [START_REF] Korn | Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist[END_REF]. The efficacy of bosentan was confirmed, especially in diffuse SSc patients with a 61% reduction of new digital ulcers over 16 weeks [START_REF] Matucci-Cerinic | Bosentan treatment of digital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial[END_REF]. Bosentan did not prove to be effective in healing of SSc-related active digital ulcers. The available evidence concerning calcium antagonists and prostanoids in the prevention of new digital ulcers in SSc patients is less robust and long term clinical experience suggests a good safety profile. A meta-analysis showed a benefit of PDE-5 inhibitors [sildenafil (50 mg or 100 mg) or tadalafil (20 mg)] compared to placebo on both digital ulcers healing [RR 3.28 (95CI 1.32-8.13)] and improvement [RR 4.29 (95CI 1.73-10.66)] [START_REF] Tingey | Meta-analysis of healing and prevention of digital ulcers in systemic sclerosis[END_REF]. The randomized placebo-controlled SEDUCE study showed a significant decrease in the number of digital ulcers in the sildenafil group compared with placebo at week8 and week12 [START_REF] Hachulla | Efficacy of sildenafil on ischaemic digital ulcer healing in systemic sclerosis: the placebo-controlled SEDUCE study[END_REF]. Tociluzimab was shown to be efficient in ulcers healing in some case-reports [START_REF] Das Neves | Treatment of systemic sclerosis with tocilizumab[END_REF].

b. Kidney involvement

Glucocorticoids should be avoided as they are associated to scleroderma renal crisis (SRC) occurrence; if absolutely necessary glucocorticoids should be given at low doses (<15 mg/d of prednisone). Use of ACE inhibitors remains important for SRC treatment, although controlled data are not available. A case control study of 108 patients with SRC showed that patients on ACE inhibitors had better 1-and 5-years survival rates compared to patients not on ACE inhibitors (76% vs. 15% and 66% vs. 10%, respectively, p=0.001) [START_REF] Steen | Outcome of renal crisis in systemic sclerosis: relation to availability of angiotensin converting enzyme (ACE) inhibitors[END_REF]. An ACE inhibitor treatment should be continued even while the patient is on dialysis, as patients have the potential to improve their renal function after a SRC [START_REF] Steen | Kidney involvement in systemic sclerosis[END_REF]. Patients who develop a normotensive renal crisis should also receive ACE inhibitors, as these drugs can be lifesaving during acute SRC. A recent prospective cohort showed an increased mortality rate in patients with SRC who were already receiving ACE inhibitors [hazard ratio 2.42 (95CI 1.02-5.75); p<0.05] but results were no more significant after adjustment for pre-existing hypertension [hazard ratio 2.17 (95CI 0.88-5.33); p=0.09] [START_REF] Hudson | Exposure to ACE inhibitors prior to the onset of scleroderma renal crisis-Results from the International Scleroderma Renal Crisis Survey[END_REF].

c. Scleroderma-related PAH

Management of SSc-related PAH remains challenging for clinicians. Most studies included idiopathic PAH with a minority of SSc patients and subgroup analysis were not always performed. Tolerance of treatments, especially combination therapies, might be poorer in SSc patients due to oesophageal dysmotility, gastroparesis, malabsorption, hepatotoxicity, renal disease… Recent findings have shown that variation of 6MWT did not predict change in haemodynamics in SSc patients with PAH [START_REF] Sanges | A prospective study of the 6 min walk test as a surrogate marker for haemodynamics in two independent cohorts of treatment-naïve systemic sclerosis-associated pulmonary arterial hypertension[END_REF].

Endothelin receptor antagonists such as bosentan and ambrisentan are associated with improved exercise capacity, hemodynamics and time to clinical worsening in idiopathic-PAH.

The efficacy of bosentan in SSc patients seems to be less important, with poorer survival rates compared to I-PAH patients [START_REF] Girgis | Long-term outcome of bosentan treatment in idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension associated with the scleroderma spectrum of diseases[END_REF]. In the SERAPHIN study, macitentan was shown to reduce a composite endpoint that included death, atrial septostomy, lung transplantation, initiation of intravenous prostanoids and worsening of PAH [START_REF] Pulido | Macitentan and morbidity and mortality in pulmonary arterial hypertension[END_REF]. Treatments implicated in the nitric oxide pathway such as PDE-5 inhibitors [sildenafil, tadalafil] showed increased exercise capacity, hemodynamics and time to clinical worsening in PAH and in the subgroup of CTD-PAH patients. Riociguat, a soluble guanylate cyclase stimulator, enhances the NO-cGMP pathway by stimulating cGMP production. Riociguat showed favourable results on exercise capacity, hemodynamics and time to clinical worsening in PAH including CTD-PAH patients. Of note, the combination of riociguat and PDE-5 inhibitors is contra-indicated (risk of hypotension).

Drugs involved in the prostacyclin pathway include i.v. epoprostenol, iloprost and treprostinil.

Epopronestol improves exercise capacity, respiratory symptoms and hemodynamics. It is the only treatment that proved to reduce mortality rate in a randomized trial in I-PAH, but not in SSc-PAH patients [START_REF] Badesch | Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial[END_REF]. The difficulty of administration (infusion pump) can be challenging for patients whose manual dexterity may be impaired. Inhaled iloprost has also been evaluated but requires frequent administration.

Recently Galié et al have proposed a treatment algorithm of PAH, according to World Health Organization functional class [START_REF] Galiè | Updated Treatment Algorithm of Pulmonary Arterial Hypertension[END_REF]. First line treatment should include general measures as rehabilitation and exercise training within symptoms limit, to improve functional capacity and quality of life. However, exercise training may difficult in SSc patients with musculoskeletal involvement with joint and muscle involvements. Anticoagulation is recommended for PAH patients with advanced disease, although the risk of bleeding is increased in SSc patients.

Diuretics and oxygen use are recommended. Acute vasoreactivity should be searched in all PAH-patients, and vasoreactive patients should receive calcium channel blockers. However, vasoreactivity concerns only a minority of SSc patients (<1%). No evidence-based treatment azathioprine or mycophenolate mofetil has been suggested by small cohorts in uncontrolled studies [START_REF] Fischer | Clinically Significant Interstitial Lung Disease in Limited SclerodermaHistopathology, Clinical Features, and Survival[END_REF][START_REF] Yilmaz | Two-year experience with mycophenolate mofetil in patients with scleroderma lung disease: a case series[END_REF][START_REF] Koutroumpas | Mycophenolate mofetil in systemic sclerosis-associated interstitial lung disease[END_REF]. In patients with severe CTD-ILD (median FVC 44%) refractory to immunosuppressants, rituximab was found to significantly improve FVC after 12 months [START_REF] Keir | Rituximab in severe, treatment-refractory interstitial lung disease[END_REF]. Rituximab has been reported to increase both FVC and DLCO in open-label uncontrolled studies [START_REF] Daoussis | Effect of long-term treatment with rituximab on pulmonary function and skin fibrosis in patients with diffuse systemic sclerosis[END_REF][START_REF] Giuggioli | Rituximab in the treatment of patients with systemic sclerosis. Our experience and review of the literature[END_REF]. Rituximab prevented further decline of FVC in SSc patients with interstitial lung disease compared with matched controls (0.4 ± 4.4% vs. -7.7 ± 3.6%, respectively; p=0.02) [START_REF] Jordan | Performance of the new ACR/EULAR classification criteria for systemic sclerosis in clinical practice[END_REF].

Anti-fibrotic agents have been evaluated in SSc associated-lung fibrosis. In a phase I/IIa pilot study [START_REF] Khanna | A one-year, phase I/IIa, open-label pilot trial of imatinib mesylate in the treatment of systemic sclerosis-associated active interstitial lung disease[END_REF], Imatinib (up to 600 mg/day) did not show improvement in FVC and DLCO. In addition, five (25%) patients discontinued the treatment due to imatinib-related adverse events. Imatinib (200 mg/day) have been tested in a phase II study of 30 SSc patients with active ILD unresponsive to CYC. It showed an improvement or stabilization of lung disease in 15% and 58% of patients, respectively [START_REF] Fraticelli | Low-dose oral imatinib in the treatment of systemic sclerosis interstitial lung disease unresponsive to cyclophosphamide: a phase II pilot study[END_REF].

e. Skin disease

Two randomized controlled trials suggested that methotrexate may improve skin scores in early diffuse SSc [START_REF] Kowal-Bielecka | EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR)[END_REF]. Cyclophosphamide has been shown to improve skin fibrosis in a randomized placebo-controlled trial [START_REF] Tashkin | Cyclophosphamide versus placebo in scleroderma lung disease[END_REF]. Mycophenolate mofetil showed, only in uncontrolled trials, to improve significantly skin thickness [START_REF] Le | Long-term experience of mycophenolate mofetil for treatment of diffuse cutaneous systemic sclerosis[END_REF][START_REF] Mendoza | A prospective observational study of mycophenolate mofetil treatment in progressive diffuse cutaneous systemic sclerosis of recent onset[END_REF]. Intravenous immunoglobulins have been shown to improve skin fibrosis in few case-reports and small size open-label trials [START_REF] Poelman | Intravenous immunoglobulin may be an effective therapy for refractory, active diffuse cutaneous systemic sclerosis[END_REF]. However, Takehara et al., did not demonstrate efficacy of one course of intravenous immunoglobulins compared to placebo in a randomized placebo-controlled trial [START_REF] Takehara | A randomized, double-blind, placebo-controlled trial: intravenous immunoglobulin treatment in patients with diffuse cutaneous systemic sclerosis[END_REF].

Rituximab improved the mean skin score in 20 SSc patients during the 48 months follow-up (mRss 9.8 ± 7.2 vs. 22.3 ± 9.5; p<0.0001). All but one patient experienced an improvement of more than 10%, with a median decrease of 50.2% [START_REF] Bosello | Long-term efficacy of B cell depletion therapy on lung and skin involvement in diffuse systemic sclerosis[END_REF]. A case-control study in patients with severe diffuse SSc showed that mRSS changes were greater in the rituximab group than in controls (-24.0 ± 5.2% vs. -7.7 ± 4.3%, respectively; p=0.03) [START_REF] Jordan | Performance of the new ACR/EULAR classification criteria for systemic sclerosis in clinical practice[END_REF]. Other studies confirmed the efficacy of rituximab on SSc skin involvement [START_REF] Giuggioli | Rituximab in the treatment of patients with systemic sclerosis. Our experience and review of the literature[END_REF]. Tocilizumab was shown to decrease skin scores in some case-reports [START_REF] Das Neves | Treatment of systemic sclerosis with tocilizumab[END_REF].

Anti-fibrotic agents have also been evaluated in SSc skin fibrosis. Nintedanib, a tyrosine kinase inhibitor, was able to prevent in a dose-dependent manner bleomycin-induced skin fibrosis in mice and was effective in the treatment of established skin fibrosis. Treatment with nintedanib ameliorated fibrosis in the chronic graft-versus-host disease model and in mice [START_REF] Huang | Nintedanib inhibits fibroblast activation and ameliorates fibrosis in preclinical models of systemic sclerosis[END_REF]. In an open pilot clinical trial of ten patients with diffuse and early SSc treated with nilotinib (a tyrosine kinase inhibitor), three patients discontinued the treatment due to drugrelated adverse events (two due to nilotinib-related prolonged QTc and one due to coronary artery disease), and seventy one adverse events were observed. The mRSS improved by a mean of 4.2 points (16 %) at 6 months and by 6.3 points (23%) at 12 months (p=0.02 and 0.01, respectively) [START_REF] Gordon | Nilotinib (Tasigna TM ) in the treatment of early diffuse systemic sclerosis: an open-label, pilot clinical trial[END_REF]. An open-label trial evaluated the benefit of fresolimumab (a TGF-β inhibitor) in fifteen patients with early diffuse cutaneous SSc. Skin fibrosis dramatically and rapidly decreased after only one injection of 5mg/kg or two injections of 1mg/kg of fresolimumab. TGF-β-regulated biomarker genes and dermal myofibroblast infiltration significantly decreased. However, drug-related adverse events were frequent [START_REF] Rice | Fresolimumab treatment decreases biomarkers and improves clinical symptoms in systemic sclerosis patients[END_REF].

f. High-dose immunosuppressive therapy and autologous hematopoietic stem cell transplantation

In phase 1 and small-size phase 2 trials, high-dose immunosuppressive therapy and autologous hematopoietic stem cell transplantation (HSCT) seem promising in the treatment of SSc. Non-myeloablative autologous HSCT improved skin and pulmonary function in 10 patients with SSc, without increase of mortality rate [START_REF] Burt | Autologous nonmyeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomised phase 2 trial[END_REF]. A phase 3, multicenter, randomized, trial, [Autologous Stem Cell Transplantation International Scleroderma (ASTIS)] including 156 patients with early diffuse cutaneous SSc, have evaluated the benefit of HSCT compared to i.v. pulse CYC. HSCT was associated with an increased treatment-related mortality within the first year although it conferred a significantly better long-term event free survival after the first year. HSCT significantly improved some SSc-related involvements at 2 years such as skin thickness and lung disease [START_REF] Van Laar | Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial[END_REF].

In summary, systemic sclerosis is an immune disease dominated by excessive fibrosis responsible for cutaneous and pulmonary fibrosis, and vascular endothelial dysfunction at the origin of skin ischemia, renal and pulmonary artery lesions. Renal and pulmonary complications are responsible for the severity of the disease. The different autoantibodies disease help to better define the phenotype and prognosis of patients. Therapeutic strategy depends on organ involvements. Further prospective and controlled studies are warranted in SSc patients, in particular in lung and pulmonary artery diseases.

Table 1 : Main clinical features of Systemic sclerosis (SSc) according to phenotypes and auto-antibodies

 1 [START_REF] Walker | Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials And Research group database[END_REF][START_REF] Graf | South Australian Scleroderma Register: autoantibodies as predictive biomarkers of phenotype and outcome[END_REF][START_REF] Mierau | Frequency of disease-associated and other nuclear autoantibodies in patients of the German Network for Systemic Scleroderma: correlation with characteristic clinical features[END_REF]

		Limited	Diffuse	Anti-	Anti-	Anti-RNA
		cutaneous	cutaneous	centromeres	Topoisomerase	polymerase
		SSc	SSc	antibodies	I	III
					antibodies	antibodies
	Digital ulcers	33-38%	43%	18-42%	40-45%	20%
	Interstitial lung	35%	53%	13-21%	30-60%	20%
	disease
	Renal crisis	1%	4-11%	1%	2-4%	20%
	Pulmonary arterial	9%	6%	5-10%	13-17%	10%
	hypertension
	(without pulmonary
	fibrosis)
	Oesophagus	67%	68%	64-71%	68%	60%
	involvement
	Cardiac involvement	6%	8%	9%	17%	15%
	Muscular	22%	37%	23-40%	32-50%	50%
	involvement

Table 2 : Risk factors/parameters associated to pulmonary arterial hypertension (PAH) in patients with systemic sclerosis (SSc

 2 )[START_REF] Hassoun | Lung involvement in systemic sclerosis[END_REF] Biological parameters High serum NT-pro BNP levels (brain natriuretic peptide)  Anti-RNP antibodies

	Clinical parameters
	 Limited cutaneous SSc
	 Older age at SSc symptoms onset
	 Digital ulcers
	 Capillary loss on capillaroscopy
	 Multiple telangiectasia
	Respiratory parameters
	 Decreased DLCO (Diffusion )
	 FVC/DLCO >1.6

can be proposed in WHO-functional class II or III patients. In WHO-functional class IV patients, i.v. epoprostenol is recommended as first-line therapy and most experts consider other treatments as a second line or in case of impossible use of epoprostenol.

Given the synergic effects of the available specific PAH treatments, combination therapies have become a more common practice. Studies have shown efficacy of combination therapy, notably sildenafil plus bosentan in PAH. A double or triple combination therapy is suggested in case of inadequate clinical response or in severely ill patients (WHO functional class III or IV).

Lung transplantation is the ultimate therapeutic option. Although CTD is not an absolute contraindication to lung transplantation, as SSc patients tend to have multi-organ disease and many comorbidities that increase peri-and post-operative risk and mortality, such approach is rarely feasible.

d. Lung disease

Cyclophosphamide (CYC) is recommended as first-line therapy in SSc patients with ILD.

Two high quality randomized controlled trials tested the efficacy of oral (the Scleroderma Lung Study) [START_REF] Tashkin | Cyclophosphamide versus placebo in scleroderma lung disease[END_REF] or pulse (Fibrosing Alveolitis in Scleroderma Trials) CYC compared to placebo [START_REF] Hoyles | 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[END_REF]. Tashkin et al, reported in a double blind, randomized placebo-controlled trial on 158 SSc patients with active and symptomatic ILD, that one year of oral CYC had a significant beneficial effect on lung function tests, dyspnea and health-related quality of life.

The effects on lung function were maintained through the twenty-four months follow-up [START_REF] Tashkin | Cyclophosphamide versus placebo in scleroderma lung disease[END_REF].

Hoyles et al., in a randomized placebo-controlled trial on 45 ILD-SSc, did not find improvement in the primary (forced vital capacity or DLCO) or secondary end points in the i.v. CYC group [START_REF] Hoyles | 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[END_REF]. A meta-analysis of three randomized trials and six observational studies did not find significant change in forced vital capacity [2.83% (95CI 0.35-5.31] or DLCO [4.56% (95CI -0.21-9.33)] after 12 months of CYC therapy (iv or oral) [START_REF] Nannini | 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[END_REF]. The efficacy of

(maximum)

The total score is determined by adding the maximum weight (score) in each category. Patients with a total score of ≥9 are classified as having definite systemic sclerosis. Sensibility 91% [CI95% 87%; 94%] and Specificity 92% [CI95% 86%; 96%].


Albert Banal-Estañol

Jeremy Eckhause

Olivier Massol

Incentives for early adoption of carbon capture technology: further considerations from a European perspective

Keywords: Tax incentives, Carbon Capture and Storage, Learning effects, Levelized cost, Coordination failure

 aimed at favoring the early adoption of Carbon Capture (CC) technology in the next generation of thermal-based power plants to be installed in the United States. First, we examine the implications of a worst-case scenario in which no new CC is adopted internationally beyond what is in place in 2014. Second, we show the potential, under the original proposed subsidy, for the emergence of coordination failures capable of hampering the desired early CC deployment. We propose and evaluate modified schedules of tax-credits sufficient to overcome these concerns. These additions strengthen the argument in the original article: namely, though higher incentive levels are necessary, our findings confirm that the cost of the proposed policy is not out of reach.

Introduction

The prohibitively high cost of Carbon Capture (CC) technology for first-of-a-kind plants is recurrently cited as a major barrier to its large-scale deployment. To overcome this problem, [START_REF] Comello | Incentives for early adoption of carbon capture technology[END_REF] recently articulate an innovative policy proposal to enable substantial cost reductions by leveraging the sizeable deployment of thermal-based power generation projected in the U.S. during the period 2017-2027. The proposal combines two ingredients: a binding and inflexible emission standard; and the "Accelerated Carbon Capture Deployment" (ACCD) -a preannounced schedule of Investment Tax Credits (ITC) and Production Tax Credits (PTC) -aimed at providing an incentive for newly built power plants in the U.S. to adopt CC immediately. This note extends the analysis by considering two issues. In a first section, we apply the framework detailed in the original article 1 to generate a schedule of tax-credits that is robust to alternative scenarios for CC deployments outside the U.S. In a second section, we reflect on the possible emergence of a coordination game capable of hampering the desired early deployment of that technology and propose a modified schedule of tax-credits that is sufficient to overcome that problem.

-The role of early CC deployments outside the U.S.

Using a list of proposed but still undecided projects [START_REF] Gccsi | Global CCS Institute Status of CCS Project Database[END_REF], the authors assume the installation of nearly 3 GW of foreign CC capabilities between 2014 and 2020. However, in Europe, the funding of large CC projects has recently proven to be difficult, causing delays and several project cancelations [START_REF] Lupion | NER300: Lessons learnt in attempting to secure CCS projects in Europe[END_REF]. As early foreign projects are posited to engender international spillovers, one may wonder whether these withdrawals could undermine the proposal's success.

To render the proposal robust to the vicissitudes impacting foreign projects, we consider a 'worstcase' scenario whereby foreign deployments are restricted to the unique Canadian 130MW power plant finalized in 2014. To compensate for the absence of foreign early investments, augmented ITC 1 The two authors must be praised for having made their data and spreadsheet model readily available to readers. and PTC schedules are needed (cf., Figure 1) but this robust version is almost as attractive as the initial version (cf. Table 1). 2

[ INSERT FIGURE 1]

[ INSERT TABLE 1]

-Strategic interactions among CC adopters

Recent European literature on CC and storage has highlighted the interactions that exist among CC adopters connected to a common infrastructure system [START_REF] Mendelevitch | The role of CO2-EOR for the development of a CCTS infrastructure in the North Sea Region: A techno-economic model and applications[END_REF][START_REF] Massol | Joining the CCS Club! The economics of CO 2 pipeline projects[END_REF]. In the present paper, infrastructure issues are neglected but the use of an experience curve de facto generates some interactions. It is instructive to examine these interactions further.

A -Notation

To begin, we introduce our notation. We consider a given year t in { } 2017,..., 2027 and let: t K denote the total planned capacity of all the power plants to be started during that year; and t CK denote the cumulated CC capacity of all the plants installed during the preceding years τ with t τ < . 3 For an investor that considers installing a power plant during that year, we let: R t c denote the LCOE obtained in case of a 'last-minute retrofit' by the end of 2027, 4 and ( )

N t c x be the continuous and strictly decreasing function that gives the LCOE if that plants adopts CC immediately given x , the cumulated CC in operation at that date. 5 The condition ( )

R N t t c c x <
is assumed to hold for any x 2 For the sake of brevity, this note solely summarizes our main conclusions. Further details on the methods used to generate the results are provided in a Supporting Document to be disseminated as a companion file to this paper.

CK K τ τ = +
is the cumulated CC capacity in operation at that time. 5 In the original paper, the effects of learning are allowed to commence only after 3GW of cumulative CC capacity has been deployed. Thus, ( )

N t c
x is a constant if 3 x < GW and is a continuous and strictly decreasing function if 3 x ≥ GW.

The discussion hereafter therefore concentrates on this second case. with 2017 2017

t x CK K τ τ = ≤ +
indicating that, absent any subsidy, it is less costly to delay the adoption of CC capabilities.

In year t , we do not model the tax-credits but simply assume that their effect is to lower the LCOE measured on a power plant that early adopts CC capabilities. We let t S be the levelized subsidy and ( ) ( )

: N N t t t c x c x S =
denote the subsidized LCOE function.

B -The subsidy scheme in Comello and Reichelstein (2014)

We now review the evaluation of the schedule of tax-credits used in the original policy proposal.

Recall that the ACCD tax-credits are set so that, for a facility to be installed in a given year, it becomes advantageous to adopt CC capabilities immediately compared to retrofitting that plant by the end of 2027. The evaluation of the schedule of tax-credits presented in the original paper is detailed in an associated spreadsheet model: the "NGCC + CC Calculator" [START_REF] Comello | Incentives for early adoption of carbon capture technology[END_REF]. In this model, CC adoption at the maximum level is assumed in each year before t . The tax-credits are calibrated so that t S , the levelized subsidy implemented in year t , verifies

- = = + . ( 1
)
This threshold is evaluated assuming that all the plants installed during the preceding years have early adopted CC capabilities.

The authors underline that, by construction, the tax-credits prevent possible 'deviation' from an 'equilibrium path' of early CC adoption. Indeed, one can model CC adoption as a sequence of 11 irrevocable decisions whereby, in each year, a single decision-maker: (i) controls the capacity t K , (ii) faces a binary choice with respect to the early adoption of CC capability, and (iii) is posited to have full information on the learning curve so that he knows how his own decision modifies the LCOE incurred in case of early adoption. Within this framework, the proposed schedule of tax-credits in the original article is such that adoption is decided in each year and thus provides the desired policy outcome.

C -Is that proposed subsidy sufficient?

However, the capacity forecasts and the standard plant size used by the authors together suggest that several power stations will be installed in some years (particularly during the period 2023 -2027). As these plants are likely to be owned by independent companies, one may wonder whether, in each year t , the threshold level t S is sufficient to induce the joint early adoption of CC capability by all players.

To address this issue, one has to examine the strategic interactions among these investors. We focus on a given year t and assume that early CC adoption has systematically been achieved during the preceding years so that The objective of each player is to minimize its LCOE.

As in the original "NGCC + CC Calculator", we assume that each player knows how the LCOE incurred in case of early adoption is modified by the capacity decided at that time. Thus, under these assumptions, the LCOE incurred by a player i is as follows:

• If 'delayed adoption' is chosen by that player (i.e., 0

i δ = ), he incurs R t c .
• If that player decides to early adopt CC capabilities (i.e.,

1 i δ = ), he incurs the subsidized LCOE 1 N n t j t i t j j t j i c CK K K α δ α = ≠ + +
which is a function of the other players' decisions in year t .

We now present a series of findings derived from the analytical developments detailed in a Supporting Document to this paper. 7 To begin, we assume that the levelized subsidy t S is chosen so as to verify

t t S S
≥ , where t S is the threshold level considered in the original "NGCC + CC Calculator".

Finding 1 -Any levelized subsidy t S with t t

S S

≥ , where t S is defined in (1), is sufficient to make the strategy vector stating 'early CC adoption' for every player a pure strategy Nash Equilibrium (NE).

This finding conveys an important result as it shows that the condition t t

S S

≥ , where t S is defined as above, is sufficient to make "generalized early adoption" a NE. Sadly, the proposition below indicates that such a subsidy is not sufficient to obtain the uniqueness of that NE.

Finding 2 -The condition t t

S S ≥

where t S is defined in (1), is not sufficient to make the strategy vector stating 'early CC adoption' for every player the unique NE.

Together, these two findings suggest that implementing a levelized subsidy that solely verifies t t

S S

≥ could lead to a coordination game with possibly several NEs.

The selection of a NE where some emitters rationally prefer to delay CC adoption in year t is a source of concern from both a static and a dynamic perspective. From a static perspective, such an equilibrium de facto implies that early CC adoption is not achieved at the desired level t K . From a dynamic perspective, the following finding indicates that this lower-than-expected level of early CC adoption in year t may also have adverse consequences on the decisions to be taken in subsequent 7 For the sake of brevity, all formal proofs are provided in this Supporting Document.

years because the proposed levelized subsidy proposed in year 1 t + may no longer be large enough to achieve generalized early CC adoption.

Finding 3 -Possible existence of a "snowball" effect: If delayed adoption were to be decided by some players in year t , a levelized subsidy 1 t S + that verifies the condition

1 1 t t S S + + ≥
, where 1 t S + is the threshold value defined in (1) for year 1 t + , 8 is not sufficient to make the strategy vector stating 'early CC adoption' for every player in year 1 t + a pure strategy NE.

D -A remedy

Because such coordination failures may jeopardize the desired policy outcomes, one may desire that the schedule of levelized subsidies rules out any possibility for the investors in any given year t to pick up a NE that does not lead to generalized early CC adoption.

Proposition -

: t t CK CK K τ τ - = = +
, is sufficient to make the strategy vector stating 'early CC adoption' for every player the unique NE.

As t t S S > , the condition t t

S S

≥ is more restrictive than the one considered in the original article.

Nevertheless, one should note that this proposition holds for any number of players and any repartition of the capacity among them, which makes it preferable to opt for that larger threshold level. 9

E -Application

This subsection reports the results obtained using the threshold t S under two capacity deployment scenarios: the original one (cf., Figure 2) and the robust one discussed in Section 1 (cf., Figure 3). 10

8 That is ( ) Our evaluations indicate that the magnitude of the ITC levels remains similar; however, augmented PTC are needed. Under the original scenario, strictly larger expenditures for the U.S. Treasury are needed in each year which confirms that the incentives in the original article are not sufficient to obtain the desired unique equilibrium (cf., Figure 2.C). In case of a robust deployment scenario, substantially increased PTC rates are needed to guarantee the uniqueness of the NE (cf. Figure 3.B.).

1 1 1 1 1 : N R t t

[ INSERT FIGURE 2] [ INSERT FIGURE 3]

Table 2 summarizes the cumulative (undiscounted) foregone tax revenue to the U.S. Treasury under the four policy options obtained by combining the two capacity deployments scenarios with the two thresholds. Ceteris paribus, the cost increase generated by solely one of two effects discussed in this paper (i.e., a robust capacity deployment scenario with the original methodology, or our revised methodology with the original scenario) remains modest. In contrast, the joint presence of these two effects generates a substantial increase in the cost of that policy: about $14.1 billion. This is a 113% increase over the $6.6 billion figure obtained in the original article. Nevertheless, we believe that this cost figure remains tolerable for such an ambitious policy that would now be rendered robust to both foreign adverse events and domestic gaming issues.

[ INSERT TABLE 2]

Conclusions

This note discusses the feasibility of the policy proposal in [START_REF] Comello | Incentives for early adoption of carbon capture technology[END_REF]. Two lines of arguments have been considered. First, we have examined the effects of early CC deployments outside the U.S. Second, we have determined that the original ACCD schedule can be insufficient to engender the desired generalized early adoption of CC capabilities because of the possible coexistence of multiple Nash equilibria. In both cases, an appropriately modified incentive policy has 10 For the sake of brevity, this note solely summarizes our main conclusions. Further details on the methods used to generate the results are provided in a Supporting Document to be disseminated as a companion file to this paper.

been proposed and calibrated to overcome those issues. Though higher incentive levels are obtained, our findings confirm that the cost of the revised ACCD policy to the U.S. Treasury is not out of reach.

This modified policy thus represents an interesting instrument to break the 'vicious circle' that currently hampers the deployment of CC technologies.

Table 1. The main findings obtained under the robust scenario

The key findings

• The Levelized Cost of Electricity (LCOE) obtained with a facility that becomes operational by the end of 2027 is approximately 7.9 ¢/kWh if CC technology is consistently adopted by all the newly built U.S. thermal power plants. (a) • The magnitude of the tax-credit levels remain politically acceptable (cf., Figure 1).

• Overall, the cumulated undiscounted foregone tax revenue to the U.S. Treasury reaches about $8.2 billion. (b) This robust schedule of incentives thus represents a cost-effective solution for achieving a large scale deployment of this innovative technology.

A.2 Methodology

We proceed as in [START_REF] Comello | Incentives for early adoption of carbon capture technology[END_REF] and identify the minimum incentives required to bridge the gap between: (i) the Levelized Cost of Electricity (LCOE) of a facility that is retrofitted in 2027, and (ii) the LCOE of a plant that immediately adopts CC capabilities. For each year, the minimum investment tax credit (respectively production tax credits) is calibrated so that the levelized capacity (respectively variable) cost in case of immediate CC adoption 1 is equal to those incurred in case of a retrofit in 2027. 2

A.3 Results

In Table A.2, we detail the "Accelerated Carbon Capture Deployment" (ACCD) tax credits obtained in the robust scenario.

1 For the sake of comparability, this levelized cost is determined using the fiscal depreciation schedules and the 10% first-ofa-kind premium defined in [START_REF] Comello | Incentives for early adoption of carbon capture technology[END_REF].

2 Note that these minimum tax credits schedule are not necessarily tiered. The use of different fiscal depreciation schedules between two successive years can generate a situation whereby the investment tax credit needed in a given year is larger than that needed during the previous year. To overcome that issue, we proceed as in the NGCC+CC Calculator and generate tiered schedules. In this paper, a linear programming approach is implemented to obtain these tiered schedules. The linear program is aimed at determining the tiered tax credit schedule that minimizes the cumulative foregone tax revenue to the U.S. Treasury and verifies two types of constraints: (i) the tiered tax credit in a given year must not be lower than that of the subsequent year, and (ii) the tiered tax credits must not be lower than the minimum values required for the LCOE of a new plant to be lower than the LCOE of a plant retrofitted in 2027. Note: MACRS indicates that all capital expenditures will be eligible for the five-year accelerated depreciation schedule according to MACRS; 150% DB indicates that all capital expenditures will be subject to the current 150% balance, 20-year depreciation schedule.

Appendix B -Mathematical proofs

This Appendix presents the formal proofs of the results stated in Section 2. Unless otherwise specified, the notation is based on the one introduced in the paper.

∑

, is sufficient to make the strategy vector stating 'early CC adoption' for every player a pure strategy Nash Equilibrium (NE).

Proof: One has to verify whether a player has or not an incentive to deviate from the strategy vector stating 1 i for every player. In case of a deviation from that vector, that player would incur the LCOE, R t c . In contrast, the subsidized LCOE obtained in case of early adoption is With that subsidy level * t S , the strategy vector 1,1,...,1 is a NE (cf. Finding 1). Now, let us examine the strategy vector 0,..., 0 that states generalized delayed adoption and compare, for each player i the LCOE incurred with that vector (i.e., R t c ) with the LCOE obtained in case of a unilateral deviation (i.e., the subsidized LCOE

1 N n t j t i t j j t j i c CK K K       ∑ ɶ which is equal to N t t
1 N N n t t j t i t j j t t i t j i c CK K K c CK K       ∑ ɶ ɶ as 0 j
for any player j with j i which means that player i has no incentive to deviate from the strategy vector 0,..., 0 because the associated LCOE is always lower than the subsidized LCOE incurred in case of a unilateral deviation. As this condition holds for any player, the strategy vector 0,..., 0 is also a pure strategy NE. Hence, the condition t t

S S ≥

is not sufficient to make 1,1,...,1 the unique NE.

Q.E.D.

Finding 3 -Possible existence of a "snowball" effect: If delayed adoption were to be decided by some players in year t , a levelized subsidy

c CK k K K c CK k K       ∑ ɶ ɶ
. We consider the levelized subsidy

1 1 t t S S .
In that case As players are symmetric, this condition indicates that 0,..., 0 is also a N.E.

1 1 1 1 1 1 1 N N N R t t
Q.E.D.

C.2 Results

In Table C.1 (respectively C.2) , we detail the "Accelerated Carbon Capture Deployment" (ACCD) tax credits obtained in the original (respectively robust) scenario when the incentives are derived from the levelized subsidy discussed in the Proposition in Section 2. 3 Note: MACRS indicates that all capital expenditures will be eligible for the five-year accelerated depreciation schedule according to MACRS; 150% DB indicates that all capital expenditures will be subject to the current 150% balance, 20-year depreciation schedule. Note: MACRS indicates that all capital expenditures will be eligible for the five-year accelerated depreciation schedule according to MACRS; 150% DB indicates that all capital expenditures will be subject to the current 150% balance, 20-year depreciation schedule.

  to make an irrevocable decision regarding the immediate installation of CC capabilities. The decision has a binary nature and we let respectively 0) indicates the early (respectively delayed) adoption of CC capabilities.

Figure 1 .

 1 Figure 1. The modified ACCD tax credits schedule under a robust scenario

  Note:(a) This figure remains close to the 7.8 ¢/kWh obtained in the original article(Comello and Reichelstein, 2014 -Finding 3); (b) This 25% increase over the base-case scenario reveals the positive externality provided by foreign early investments in first-of-a-kind CC plants.

Figure 2 .

 2 Figure 2. The tax credit schedule needed to obtain a unique NE (original deployment scenario)

  In each year t , any tax-credit yielding a levelized subsidy t S that verifies

	t ≥ , with S S t	S	t	( ) t c CK : N t =	-	R t c	and	2017	1 2017

Table 2 . The cumulative foregone tax revenue to the U.S. Treasury under the four various situations ($ billion)

 2

			Methodology used to determine the tax credit
				schedule
			Original	"Unique NE"
			t S S ≥	t	t S S ≥	t
	CC capacity	Original	6.6 *		8.9
	deployment
	scenario	"Robust"	8.2 **		14.1
	Note: "Robust" refers to the CC capacity deployment detailed in Section 1 and "Unique NE" refers to
	the new methodology discussed in Section 2.D. The asterisks

* and ** respectively indicate the policy discussed in

[START_REF] Comello | Incentives for early adoption of carbon capture technology[END_REF]

and the incentive policy presented in Section 1.

Table A .1. Projected U.S. Capacity Deployments of NGCC Facilities and International Capacity Deployments of Carbon Capture Technology in the Robust Scenario

 A

	Year	Projected Annual Int'l Additions of Capture Unit Capacity (GCCSI) [MW]	Projected Annual Capacity Additions 2017-2027 (EIA) [MW]	Total Annual Capacity Additions [MW]	Total Cumulative Capacity Additions [MW]	Projected Net NGCC Capacity 2017-2027 (EIA) [MW]
	2014	130		130	130	189 939
	2015	0		0	130	192 122
	2016	0		0	130	192 447
	2017	0	0	0	130	192 447
	2018	0	0	0	130	192 220
	2019	0	690	690	820	192 910
	2020	0	432	432	1 252	193 342
	2021		272	272	1 524	193 615
	2022		450	450	1 974	194 064
	2023		5350	5 350	7 324	199 414
	2024		2389	2 389	9 712	201 803
	2025		5907	5 907	15 619	207 710
	2026		4307	4 307	19 926	212 017
	2027		6828	6 828	26 754	218 845

Table A .2. The ACCD tax credits in the Robust Scenario

 A

	Year	Fiscal Depreciation Schedule	Schedule of Investment Tax Credits	Schedule of Production Tax Credits [¢/kWh]
	2017	MACRS	22.4%	2.41
	2018	MACRS	20.9%	2.41
	2019	MACRS	19.1%	2.41
	2020	MACRS	17.4%	2.41
	2021	MACRS	15.2%	2.41
	2022	MACRS	13.1%	2.41
	2023	MACRS	10.0%	0.94
	2024	150% DB	10.0%	0.84
	2025	150% DB	4.4%	0.48
	2026	150% DB	0.2%	0.21
	2027	150% DB	0.0%	0.00

  ).

			Using			both			the			definition	of	the	subsidized	LCOE
	N t c CK ɶ	t	i t K			N t c CK	t		i t K		S	* t			and	the	condition
	* t S c CK K N t t	t	Max	j	j		1,...,	n		R t c , the subsidized LCOE verifies the condition:
	N t c CK	t	i t K			N t c CK K t	t	Max	j	j	1,...,	n	R t c	N t c CK ɶ	t	i t K	. As	N t c x is
	a		strictly				decreasing				function,	the	condition
	N t c CK	t	i t K	≥	N t c CK K t	t	Max	j j	1,...,	n	is also verified. Together, the last two
	conditions indicate that	R t c	N t c CK ɶ	t	i t K

  has to be considered to obtain the desired unique NE. Second, this threshold depends neither on the number of players (beyond one) nor on the relative capacity they control.

	t , 1 CK N t c	' j j t K CK is strictly decreasing, this parameter verifies 1 n j i t t j i K ∑ . As N t c is a strictly decreasing function, the inequality * 1 0 ≥ . We consider an * n -player
	N t c CK    ɶ game where t	' j j t K n verifies the condition * 1 N n t j i t j i K c CK    ∑ ɶ * 1 t * n	hold. and each player controls an identical share of As t t S S ≥ , the condition
	N t c x S c x S is thus valid for any x . Inserting the value N t t t K . Now, we consider the strategy vector 0,..., 0 , whereby each player the capacity t x CK and replacing t delays the adoption of CC capabilities. By deviating from that vector, a player would incur the
	t S by its definition, the condition ' 1 N n t j t i t j j t j i c CK K K       subsidized LCOE N t c CK    ɶ ∑ ɶ that this player would obtain a strictly lower LCOE by unilaterally deviating from the strategy N R t t t c CK c ɶ holds. As we have already shown that N t t c CK * 1 t t K n    . As * * 1 , the condition n ɶ , these last two conditions together indicate * * 1 N N t t t t t t c CK K c CK K n       ɶ ɶ is verified. Replacing * by its value, we have
	vector ' which obviously contradicts the assumption of ' being a NE. * N R t t t t c CK K c ɶ and thus the condition * 1 N R t t t c c CK K n    ɶ	t	  	Q.E.D. is verified which
	From this proposition, two interesting points deserve to be highlighted. First, t S S indicates that a t indicates that, for a player, it does not pay to deviate from the strategy vector 0,..., 0 .
	t c CK k K ɶ and 1 N t c is a strictly decreasing function, the subsidized LCOE verifies t t t t t t t t t t c CK k K c CK K K c . As t t k K 1 1 1 N R t t t t t c CK k K c ɶ indicating that this player has an incentive to unilaterally deviate from the strategy vector 1,1,...,1 . Q.E.D. more generous threshold that that any subsidy policy t S in the range t t t S S S ≥ cannot guarantee the existence of a unique
	Proposition -In each year t , any tax-credits yielding a levelized subsidy t S that verifies NE for any structure of the game to be played in year t .	t ≥ , S S t
	with Corollary -We consider a given year t such that the cumulated CC capacity decided during the : N R t t t t S c CK c and 1 2017 : t t CK CK K ∑ , is sufficient to make the strategy vector 2017 stating 'early CC adoption' for every player the unique NE. previous periods is 1 2017 2017 : t t CK CK K ∑ . For any tax-credits yielding a levelized subsidy t S
	that verifies	t S S S , there exists at least one industrial configuration (i.e., a number of players t t
	Proof: We assume that a subsidy t S that verifies and a distribution of the capacity t K among them) such that the uniqueness of the Nash equilibrium t t S S ≥ is implemented. As N t c is a strictly
	decreasing function, we can notice that t S S , which indicates that the subsidy t t S is 1,1,...,1 is not verified.
	sufficient to make the strategy vector Proof: We assume that a subsidy t S that verifies 1,1,...,1 a NE (cf. Proposition 1). Now, we t t t S S S is implemented. As t t S S ,
	concentrate on the uniqueness and assume that there exists a second NE: i.e., a strategy vector ' with at least one player i deciding to delay the adoption (i.e., ' 0 i ) that also verifies the the strategy vector 1,1,...,1 is a NE. By construction, the condition t t t S S S
	conditions for a NE. With that vector, player i incurs the LCOE R t c . We now examine indicates that N R N t t t t t t t c CK K S c c CK is verified. As the function N t c that gives
	' j j t K the LCOE in case of early CC adoption is both continuous and strictly decreasing over the 1 N n t j t i t j i c CK K       ∑ ɶ the subsidized LCOE that would be incurred by that player interval , t t t CK CK K , this function can be inverted and we let , 1 N t c denote that inverse
	i by deviating from the strategy vector ' . As the individual shares are positive, we have function. We let , 1 * : N R t t t t t c c S CK K . As N R N t t t t t t t c CK K S c c CK and

Hence, no matter what the industrial concentration in each year is (i.e., no matter the number of players and their relative size), this threshold is always sufficient to make generalized early CC adoption the unique NE which is the desired outcome. In contrast, the following corollary indicates

Table C .1. The ACCD tax credits needed to obtain a unique NE (Original Scenario)

 C

		Total Cumulative
		Capacity Additions
	Year	decided during the previous years t K ∑	Fiscal Depreciation Schedule	Schedule of Investment Tax Credits	Schedule of Production Tax Credits [¢/kWh]
		[MW]
	2017	885	MACRS	22.6%	1.84
	2018	2,020	MACRS	21.1%	1.84
	2019	2,370	MACRS	19.3%	1.84
	2020	3,260	MACRS	12.2%	1.32
	2021	4,222	MACRS	10.2%	1.32
	2022	4,494	MACRS	10.2%	1.32
	2023	4,943	MACRS	10.2%	1.32
	2024	10,293	150% DB	10.2%	0.86
	2025	12,682	150% DB	5.9%	0.82
	2026	18,589	150% DB	1.1%	0.49
	2027	22,896	150% DB	0.0%	0.15

Table C .2. The ACCD tax credits needed to obtain a unique NE (Robust Scenario)

 C

		Total Cumulative
		Capacity Additions
	Year	decided during the previous years t K ∑	Fiscal Depreciation Schedule	Schedule of Investment Tax Credits	Schedule of Production Tax Credits [¢/kWh]
		[MW]
	2017	130	MACRS	22.4%	2.78
	2018	130	MACRS	20.9%	2.78
	2019	130	MACRS	19.1%	2.78
	2020	820	MACRS	17.4%	2.78
	2021	1,252	MACRS	15.2%	2.78
	2022	1,524	MACRS	13.1%	2.78
	2023	1,974	MACRS	11.2%	2.78
	2024	7,324	150% DB	11.2%	1.11
	2025	9,712	150% DB	6.7%	1.05
	2026	15,619	150% DB	1.4%	0.62
	2027	19,926	150% DB	0.0%	0.00

3

These results have been generated using adapted versions of the original NGCC+CC Calculator respectively named "NGCC+CC Cost Calculator_Section 2_Original.xlsx" "NGCC+CC Cost Calculator_Section 2_Robust.xlsx" that can be downloaded from Olivier Massol's webpage: https://sites.google.com/site/oliviermassolshomepage

This definition of the threshold level has been derived from a meticulous examination of the original "NGCC + CC Calculator". A document summarizing this analysis and explaining how this threshold can be traced back in the original spreadsheet model can be obtained from the authors upon request.

Acknowledgements

We wish to express our gratitude to two anonymous referees for their helpful suggestions, which led to substantial improvements. In addition, we thank Christian von Hirschhausen, Franziska Holz, Roman Mendelevitch, seminar participants at DIW Berlin and TU Berlin and participants at the FERC Workshop/Trans-Atlantic Infraday (Washington DC, 2015) for useful discussions. Any remaining errors are our sole responsibility.

Supporting Document:

Incentives for early adoption of carbon capture technology: Further considerations from a European perspective

A.1 Assumptions

Table A.1 details the projected annual capacity deployments by year retained in the 'worst case' scenario. This conservative projection has been derived from Comello and Reichelstein (2014, Supporting document -Table A.1.) by restraining the amount of international capacity to the unique 130 MW Carbon Capture (CC) power plant that is currently in operation in Canada. Capacity deployment excepted, our assumptions are the ones discussed in the original article.

Appendix C -A robust schedule of ITC and PTC that is immune to strategic gaming considerations

This Appendix details the assumptions and results commented in Section 2.

C.1 Assumptions and methodology

We follow the methodology in Appendix A.2 except that the tax credits are now calibrated so as to provide a levelized subsidy that is at least as large as the threshold level mentioned in the Proposition in Section 2. These tax credits thus prevent the existence of Nash equilibriums where some emitters could rationally prefer to delay CC adoption.

The simulation are successively conducted using: (i) the original projected capacity deployment scenario used in [START_REF] Comello | Incentives for early adoption of carbon capture technology[END_REF], and (ii) the projected capacity deployments retained in Appendix A (Table A.1).