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Management of Scleroderma-Associated Pulmonary Involvement

Opinion statement

In the absence of a disease-modifying treatment for systemic sclerosis (SSc), the management of the main causes of morbidity and mortality is essential to offer the best possible patient care. Accordingly, early diagnosis and treatment of lung involvement plays a central role. Several new agents against pulmonary artery hypertension (PAH) have driven a notable progress in managing this complication in the recent years. Prostacyclin derivates, endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, or guanylate cyclase stimulators are used today in single or combined therapy to improve the prognosis of PAH patients. Regarding interstitial lung disease (ILD) cyclophosphamide remains the most evidence-based therapy for SSc ILD. Small-scale interventional or observational studies support mycophenolate mofetil for either first-line or maintenance therapy after an initial course of cyclophosphamide. Observational studies also show promising results for biologic agents like Rituximab, and autologous stem cell transplant appears to be an option for severe and carefully selected cases. Moreover, nintedanib and pirfenidone have been shown to be effective in recent studies for idiopathic lung fibrosis. Randomized controlled trials are needed to test the effects of these potential therapies in SSc-ILD. The development of targeted therapies for lung involvement in SSc, together with the increasing knowledge regarding patient selection and management of the available drugs, will help to improve care of SSc patients with lung involvement.


Pulmonary involvement, in its two major entities pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD), is frequent in systemic sclerosis (SSc) and represents the most important determinant of SSc-related mortality in the modern management era [1].

PAH is a progressive vascular disorder involving the pulmonary circulation and ultimately causing right heart failure and death [2]. PAH is a rare condition with a prevalence of 15–50/million in the Western countries [3, 4]. Systemic sclerosis (SSc) PAH is the leading cause of connective tissue disease (CTD)-associated PAH, which represents 15–30 % of PAH cases [3, 4]. In SSc, PAH is a rather common complication, with a prevalence of around 10 % [57]. In the 2000s in France, the prevalence and yearly incidence of SSc-PAH were 7.85 and 0.61 %, respectively [6, 8]. Despite the development of innovative therapies [9], long-term outcomes are poor, PAH being a leading cause of death in SSc-PAH patients who respond less well to PAH therapy when compared to idiopathic PAH [1, 2, 10].

Interstitial lung diseases represent a heterogeneous group, the two most frequent entities being idiopathic pulmonary fibrosis (IPF) and connective-tissue associated ILD, among which SSc-ILD has highest frequency [11]. There is no standard definition for SSc-ILD, and due to the different diagnostic methods, the prevalence rates vary considerably across studies. On average, clinically manifest pulmonary fibrosis (PF) in the form of ILD affects about 40 % of patients with SSc [1]. HRCT-defined ILD has been reported with a prevalence of 60–91 % [12], and fibrotic changes in lung parenchyma have been found extensively on autopsy series [13]. ILD is a major cause of morbidity and mortality in SSc patients. According to a recent analysis based on the EUSTAR cohort, lung fibrosis can be accounted for 35 % of SSc-related deaths [14]. Despite the fact that the pathogenesis of SSc-ILD remains incompletely understood, key molecular pathways have been identified, and some progress has also been achieved in the recent years in terms of multidisciplinary disease management, early diagnosis, and prognostic assessment [15]. This progress has led to several novel targeted therapeutic approaches that are currently about to be tested in clinical trials.

In this review, we will focus on the management and treatment of SSc-PAH, its relation to cardiac manifestations, and on the management and treatment of SSc-ILD.

Pulmonary Arterial Hypertension and Heart Involvement in Systemic Sclerosis

Early Detection and Diagnosis

PAH is characterized by a prolonged pre-symptomatic period early in the disease process [16]. The most common initial symptom of PAH is progressive dyspnea with exertion [4]. However, dyspnea is nonspecific and may be confounded by overall dysfunction from SSc disease and concomitant musculoskeletal disease [16]. Signs of right ventricular dysfunction only appear in advanced disease.

Because early PAH detection should translate into improved long-term outcomes, it is widely believed that facilitating early detection or screening is of paramount importance in SSc [17•, 18••]. Of note, some patient’s characteristics have been associated with an increased risk of developing PAH (limited SSc, late-age onset, longstanding disease, and reduction in the diffusing capacity of carbon monoxide (DLCO) [18••].

However, screening and early detection of SSc-PAH remain challenging [2, 18••]. Most recommendations attempt to define abnormal transthoracic Doppler echocardiography findings suggestive of pulmonary hypertension. The tricuspid regurgitant jet velocity (allowing to estimate systolic PAP) is the most widely used screening tool [2, 18••, 19]. Although several studies have demonstrated reasonable correlations between estimated systolic PAP and invasive measurements by right heart catheterization (RHC), there are significant limitations to this echocardiographic technique, especially in early disease [2, 18••, 19]. Thus, when pulmonary hypertension is suspected, RHC is of course mandatory to confirm and characterize it [19]. Other parameters such as DLCO, alone or in combination with NT-proBNP, have been used in some screening programs by clinicians [18••]. Recently, the DETECT study group published the first screening study to undertake systematic RHC in a cohort of SSc patients for diagnosis of PAH [20•]. This analysis suggested a stepwise algorithm using clinical data and noninvasive tests for earlier identification of PAH in an SSc population with a higher risk of developing PAH (DLCO < 60 % and SSc diagnosed since at least 3 years). The DETECT algorithm recommended RHC in 62 % of patients (referral rate) and missed 4 % of PAH patients (false negatives) [20•]. By comparison, applying ESC/ERS guidelines to these patients, 29 % of diagnoses were missed while requiring an RHC referral rate of 40 % [2, 20•]. Based on current knowledge, a group of experts suggested that screening pulmonary function tests with single breath DLCO, transthoracic Doppler echocardiography, and measurement of NT-proBNP should be performed in all patients with SSc as soon as any new signs or symptoms suggestive of pulmonary hypertension develop; further, they considered that DLCO and Doppler echocardiography should be performed annually in all SSc patients.[18••] This approach is illustrated in Fig. 1. The proceedings of the Fifth World Symposium on Pulmonary Hypertension (Nice, 2013) indicated that (i) annual screening for PAH is recommended in (cardiopulmonary) asymptomatic patients with the SSc spectrum of diseases, although there is a lack of evidence-based data; (ii) screening of patients with the SSc spectrum of diseases without clinical signs and symptoms of PH should include a two-step approach using clinical assessment for the presence of telangiectasia, anticentromere antibodies, PFT and DLCO measurements, electrocardiogram, and biomarkers (NT-proBNP and uric acid) in the initial stage, followed by echocardiography and consideration of RHC in patients with abnormal findings, although there is a lack of data with DLCO >60 %; and (iii) the above-mentioned screening programs for patients with SSc should be part of a scientific protocol, or a registry, whenever possible [19].

Fig. 1

Consensus-based approach for screening for PAH in patients with connective tissue diseases (adapted from Khanna et al. [18••]).

A definite diagnosis of SSc-PAH also requires exclusion of other causes of pulmonary hypertension such as left heart and/or chronic lung disease [2, 19]. In PAH, RHC will demonstrate an elevated mean pulmonary artery pressure (PAP) > 25 mmHg, a pulmonary capillary wedge pressure <15 mmHg, and pulmonary vascular resistance >3 Wood units [21].

Cardiac Involvement and its Relation to PAH

In addition to vascular involvement, other vital organs are commonly affected in SSc. Heart involvement affects the myocardium, pericardium, and/or small vessels [2225]. Myocardium involvement includes fibrosis and impaired microcirculation in around half of SSc patients, leading to left heart disease with a high reported prevalence of a range of abnormalities detected by echocardiography including left ventricular hypertrophy, diastolic left ventricular dysfunction, and left atrial enlargement. Pericardial effusion is also more common in SSc-PAH, as compared to idiopathic PAH [16]. Effusions may be due to progressive right heart failure and/or to the underlying inflammatory processes. In addition, conduction abnormalities and hormonal and metabolic dysfunctions (elevated NT-proBNP and hyponatremia) are more common in SSc-PAH as compared to idiopathic PAH [16]. Of note, SSc-PAH patients typically have less severe hemodynamic impairment compared to idiopathic PAH [16, 26].

Right ventricle adaptation to the increased cardiac load is the main determinant of outcome in PAH [27]. Importantly, right ventricle contractility is lower in patients with SSc-PAH than in idiopathic PAH, supporting that right ventricle systolic dysfunction is more common in SSc [28]. Thus, inability of the right ventricle to compensate for higher afterload (rather than differences in afterload) may explain at least in part SSc-PAH worst outcomes.

Approved and Novel Therapies of SSc-PAH

Basic treatment of SSc-PAH includes supplemental oxygen in patients who are hypoxic at rest or with exercise, diuretics for the management of volume overload and right heart failure, and digoxin for right heart failure complicated by atrial arrhythmias [10]. Although widely used in patients with SSc for treatment of Raynaud’s phenomenon, there is little role, if any, for calcium channel blockers in the treatment of SSc-PAH [29]. There are no robust data on the role of anticoagulation in SSc-PAH. The analysis of a recent registry has suggested that anticoagulation was associated with a survival benefit in patients with idiopathic PAH but not in patients with SSc-PAH [30]. Indeed, the risk of bleeding is higher in SSc-PAH when compared to idiopathic cases [31].

Several drugs have been approved for PAH in recent years [32]. These agents target endothelial cell dysfunction with prostacyclin derivatives, endothelin receptor antagonists, and agents improving the defective nitric oxide pathway (phosphodiesterase type 5 inhibitors or guanylate cyclase stimulators) [32]. In SSc-PAH, continuous intravenous epoprostenol improves exercise capacity and hemodynamics compared with conventional therapy [33]. However, the need for continuous infusion, meticulous catheter care, and daily preparation of the medication can be challenging in patients whose manual dexterity may be impaired by scleroderma. Other prostacyclin analogues such as subcutaneous, nebulized, or intravenous treprostinil or iloprost can be used in SSc-PAH [32]. PAH treatment with dual endothelin receptor antagonists (bosentan and macitentan) or selective endothelin-A receptor antagonist (ambrisentan) improves functional class, exercise capacity, time to clinical worsening, and hemodynamics in PAH. Of note, macitentan has been shown to improve a combined morbidity/mortality primary endpoint in a large event-driven study [3234]. In subgroup analyses of patients with SSc-PAH, similar trends were observed, and these agents are approved for treatment of SSc-PAH. Safety signals include liver transaminase elevations with bosentan, hemoglobin level reduction with macitentan, and peripheral edema with ambrisentan [3234]. Sildenafil, a phosphodiesterase type 5 inhibitor that reduces the catabolism of cGMP, leading to enhanced effects of nitric oxide, has been widely employed in the treatment of PAH [35]. Improvements in 6-min walking distance, functional class, and hemodynamics after 12 weeks have been described in PAH and CTD-PAH [36]. Similarly, tadalafil studies reported statistically significant improvements in exercise capacity although the proportion of patients with SSc was not reported [37]. Riociguat, a stimulator of soluble guanylate cyclase, significantly improved exercise capacity in patients with PAH including CTD-PAH (the proportion of CTD patients with SSc was not reported) [38].

Combination therapy has become common practice in the management of PAH [32],[39]. While sequential combination therapy has been convincingly tested in many studies and adopted in published guidelines, the exact positioning of upfront combination therapy in PAH-SSc remains debated [32, 40].

While imatinib demonstrated improvements in hemodynamic measurements in phase II/III studies, imatinib is neither approved nor recommended in PAH because of a number of severe bleeding episodes (subdural hematomas) [32, 41]. Given the potential role of autoimmunity in the pathogenesis of SSc-PAH, a randomized clinical trial of rituximab, an anti-CD20 therapy that depletes B-cell lineages, is specifically and exclusively enrolling SSc-PAH patients who are already on concomitant PAH therapy to assess hemodynamic response [32].

Despite the advances in medical therapy for PAH, lung transplantation remains the ultimate therapeutic option for many eligible PAH patients [2, 32]. SSc multiorgan involvement increases perioperative and postoperative risk. In particular, esophageal dysmotility increases markedly the risk of aspiration and posttransplant dysfunction. Clinical and subclinical renal disease may also increase complications related to the use of nephrotoxic immunosuppressive agents. For these reasons, SSc-PAH patients are often denied lung transplantation. However, eligible patients with SSc have similar rates of survival after lung transplantation compared with patients with pulmonary fibrosis or idiopathic PAH [42, 43•].

Inflammation and autoimmunity are recognized as important factors in PAH and may be future treatment targets [16, 4447].

Investigation, Prognostic Evaluation, and Monitoring of Systemic Sclerosis–Interstitial Lung Disease (SSc-ILD)

The Identification of SSc-ILD

As there is no current consensus on a routine screening protocol [e.g., pulmonary function tests (PFTs), high-resolution computed tomography (HRCT)], clinicians often base investigation on symptoms (which are highly nonspecific) and chest radiography (which is notoriously insensitive) [48]. Exercise intolerance is usually multifactorial, with variable contributions from SSc-ILD, SSc-PAH, cardiac involvement, musculoskeletal involvement, fatigue, weight gain, and loss of fitness. In occasional patients, it is helpful to reproduce exertional dyspnea by means of a 6-min walk test or maximal exercise testing on room air. The absence of oxygen desaturation at the limit of exercise tolerance excludes major cardiopulmonary limitation.

SSc-ILD is present on HRCT in over 50 % of SSc patients and in over 90 % of SSc patients with abnormal PFTs [49, 50]. HRCT appearances usually consist of a variable combination of ground-glass attenuation and fine reticulation. Honeycombing is present in a minority, but in a series of over 200 patients with SSc-ILD, HRCT appearances were, on average, identical to those in idiopathic nonspecific interstitial pneumonia (NSIP) [51]. Atypical HRCT appearances should alert the clinician to concurrent disease processes (e.g., smoking-related interstitial lung disease, drug-induced lung disease) with consolidation (typically seen in lung disease in inflammatory myopathy [52]), suggesting an underlying overlap syndrome or, when it is unifocal and does not regress with time, lung adenocarcinoma. Ground-glass attenuation on HRCT tends to be reversible when present in isolation, but this presentation is infrequent. More often, ground glass is admixed with a reticular pattern [53] or associated with traction bronchiectasis [54], represents fine intra-lobular fibrosis, and seldom regresses on serial HRCT [55].

PFTs are not sensitive in the early identification of SSc-ILD. An unequivocally restrictive ventilatory defect is strongly indicative of lung involvement. However, in early disease, forced vital capacity (FVC) values often lie within the normal range (of 80–120 % of predicted from age, gender, and height). For example, a measured FVC value of 85 % in an individual patient might be “normal” for that patient, but might also represent a major decline of a premorbid value of 110–120 %. The DLCO is more sensitive but is also influenced by pulmonary vascular limitation and smoking-related damage [56]. It has long been concluded that isolated abnormalities in bronchoalveolar lavage cellularity are not predictive of the subsequent development of SSc-ILD.

The Evaluation of the Clinical Significance of SSc-ILD

The sensitivity of HRCT not only offers major advantages but also poses problems, due to the detection of nonprogressive subclinical abnormalities. In a series of over 200 consecutive SSc-ILD patients, interstitial abnormalities were trivial or very limited in extent in over 40 % of cases. The integration of HRCT appearances and PFTs are central to the accurate characterization of disease severity. SSc-ILD is characterized by a restrictive defect and a reduction in DLCO [56]. In the absence of SSc-PAH, arterial oxygen levels tend to be well preserved until lung disease is advanced. PFT are strongly predictive of outcome in SSc [5759] and SSc-ILD [60] alike. DLCO levels correlate better than other PFT with disease extent on HRCT [61], reflecting the fact that DLCO captures the total combined impact of SSc-ILD on alveolar volume and pulmonary blood volume.

A final judgment on the clinical significance of SSc-ILD is essentially a multidisciplinary exercise in which symptoms, PFTs, HRCT appearances, and findings on echocardiography are integrated. The means by which this is done is not an exact process, but one in which the clinician seeks plausibility and consistency across the four domains. The first step is to quantify severity more accurately than is possible with a single variable, and the second step is to understand the determinants of severity. Sometimes, it becomes obvious, based on HRCT evaluation and echocardiography that symptoms and functional impairment result primarily from smoking-related damage or SSc-PAH and not from SSc-ILD.

Prognostic Evaluation in SSc-ILD

It is uniformly accepted that immediate treatment is not warranted in asymptomatic patients with SSc-ILD that is obviously “clinically insignificant”. It is also widely agreed that treatment should be instituted when there is major inflammatory or progressive fibrotic lung involvement. However, many patients with SSc-ILD lie between these two poles. When lung disease is mild to moderate (i.e., not subclinical), careful observation without intervention can often be justified. However, such decisions are not always easy. Studies of outcome in lung disease in connective tissue disease mostly consist of SSc data. Due to a lack of definitive evidence, current prognostic evaluation, summarized in a recent review [62••], is based equally on cohort studies and a traditional mixture of accumulated clinical experience, logic, and common sense. As no single variable consistently predicts disease progression, it has been argued that three important general factors should be considered [62••], as shown in Table 1.

Table 1 The prediction of progression of pulmonary disease in relation to individual variables: the past, the present, and the likely future

First is the duration of systemic disease. The view that SSc-ILD is more likely to progress early in the course of systemic disease is based on accumulated clinical experience including the data of Steen [57, 63]. It appears that progression occurs much more frequently in the first 2 years of systemic disease and especially when the onset of lung disease precedes the cutaneous manifestations of SSc.

Second is the disease severity. The threshold for instituting therapy is much lower in severe disease for two reasons. By its very presence, severe disease implies that progression has occurred repeatedly in the past and is likely to continue, if untreated. Equally important is the fact that when a patient has a very poor respiratory reserve, failure to prevent disease progression may have catastrophic effects on quality of life. However, as treatment decisions are dichotomous (i.e., to treat or to observe), key severity thresholds on which to base management are needed by clinicians. The first SSc-ILD staging system, the UK Raynauds and Scleroderma Association (UKRSA) staging system, was based on optimal HRCT and FVC thresholds, validated against mortality [64]. In essence, disease is categorized as “mild” or “extensive” when it is immediately obvious on rapid HRCT evaluation that SSc-ILD occupies less than (mild) or more than (extensive) 20 % of the total lung volume. In cases considered to be indeterminate on HRCT, an FVC threshold of 70 % is used. The prognostic value of the UKRSA value system has been confirmed [12], and it is reassuring that similar HRCT and FVC thresholds were predictive of disease progression in the placebo arm of the Scleroderma Lung Study of oral cyclophosphamide in SSc-ILD [65].

Third is the ongoing progression. Strangely, the prognostic value of disease progression against subsequent mortality has yet to be definitively evaluated in SSc-ILD, although well established in IPF [66]. However, based on analogies with other interstitial lung diseases, it is universally accepted that evidence of recent disease progression is an indication for therapy.

It appears that most clinicians favor the introduction of therapy when two of three adverse prognostic factors are present. However, such decisions are often very close calls, and patient preferences often dictate an initial policy of careful observation at three to six monthly intervals, with immediate intervention in the event of disease progression. A prognostically accurate biomarker would greatly facilitate management: Preliminary data suggests that serum levels of KL-6, SP-D, or IL6 [6771] may provide added value, but no serum biomarker is currently validated.

Monitoring SSc-ILD

Unless disease progression is major, no single method of detecting change (symptoms, PFT trends, and HRCT change) is uniformly reliable. Symptomatic change is often misleading: The multifactorial nature of exertional dyspnea, discussed earlier, is further confounded by low-grade infection, especially in patients receiving immunosuppressive therapy. Serial pulmonary function tests are central to routine monitoring but must be reconciled with clinical information and, in selected patients, serial HRCT evaluation. Based on studies of the reproducibility of PFTs in healthy subjects, a change from baseline in FVC or DLCO of 10 or 15 %, respectively, is viewed as evidence of true change, not ascribable to measurement variation. However, serial estimation of both FVC and DLCO allows earlier detection of disease progression. Concordant decline, even when not reaching threshold values (e.g., a reduction in FVC of 9 %, a reduction in DLCO of 13 %), is strongly indicative of true change. Serial HRCT should not be performed routinely by protocol, due to radiation constraints, but should be reserved for specific clinical questions (e.g., a change in disease severity is suspected but is uncertain due to discrepancies between other serial variables).

Early in the course of disease, repetition of FVC and DLCO at three to six monthly intervals is appropriate, with the exact timing influenced by baseline disease severity. In patients with SSc-ILD that has been stable for over 12 months, the time interval between serial PFTs can be gradually increased, but unless SSc-ILD is truly subclinical, annual PFT monitoring should continue in the long term.

Management of Systemic Sclerosis–Interstitial Lung Disease

The current treatment of SSc-ILD is mostly based on immunosuppressive agents. Recent randomized clinical trials (RCTs) allowed shifting from early empirical approaches towards an increasingly evidence-based therapeutic management of SSc-ILD. However, many open questions still have to be addressed until high-quality treatment recommendations for SSc-ILD can be developed.

One of the key steps towards a better management of SSc-ILD treatment is to identify which patients are likely to respond to the selected therapy. The duration and dosage of the immunosuppressive treatment relies largely on expert opinion and on the individual case characteristics—most importantly on drug tolerability and therapeutic response [72].

In the following paragraphs, we will focus on the main therapeutic agents currently in use for the treatment of SSc-ILD and introduce potential perspectives for future therapies.


The European League for Rheumatology (EULAR) treatment recommendations state that CYC should be considered for the management of SSc-ILD [72]. These recommendations are based on two prospective, double-blind, placebo-controlled RCTs, the Scleroderma Lung Study (SLS) and the Fibrosing Alveolitis in Scleroderma Trial (FAST) [65, 72, 73]. Both studies found a positive improvement in lung function at 12 months in the CYC treatment group. The favorable difference in FVC% change between the treatment and placebo group was nevertheless modest with 2.5 % in SLS [65] and 4.2 % in FAST [73]. There was also significant, but overall mild beneficial effect on additional outcomes such as the Mahler dyspnea index, modified Rodnan skin score, health-related quality of life, and an HRCT fibrosis score [74].

Notably, the effects on these outcome measures appeared to be transitory and disappeared 1 year after treatment discontinuation in the open-label extension of the SLS study [65, 75, 76]. However, most of the patients in the open-label extension study did not receive maintenance therapy. These results highlight the need for a long-term management strategy after discontinuation of CYC [76]. Unfortunately, controlled studies analyzing the effects of different maintenance therapies such as azathioprine or mycophenolate mophetil (MMF) after CYC treatment are not available. In addition, the optimal treatment duration with CYC is not known [77].

The route of CYC administration, either oral or intravenous (IV), largely depends on local availability and traditional use. Various studies report beneficial effects from both approaches, but there is limited data comparing the benefits and safety profile of these two routes of administration in SSc patients [78]. In SSc-ILD, IV pulse therapy is considered to have a lower risk for hemorrhagic cystitis and, most likely, also for bladder cancer, compared to long-term oral CYC therapy [73, 79]. On the other hand, a report comparing adverse events in patients with systemic autoimmune diseases treated with IV or oral CYC shows a higher frequency of gastrointestinal discomfort (nausea, vomiting, abdominal pain, and diarrhea), alopecia, and dizziness in the IV group [80]. Overall, the most frequent adverse effects reported in SSc-ILD patients undergoing CYC treatment are nausea and vomiting [81, 82] or mild leukopenia (responsive to dose reduction) [82]. The main reasons for treatment discontinuation were hemorrhagic cystitis, pneumonia, intolerable nausea, and worsening PFTs [82].

Having in mind the significant side-effect profile and the overall modest clinical benefit, it is important to select the adequate patients for therapy with CYC. A retrospective analysis of the SLS identified that patients with extensive reticular changes on HRCT (>50 %) and/or a high mRSS (>23 points) at baseline had a twofold higher benefit from CYC treatment (as reflected by the decrease in FVC% predicted) at 12 and 18 months [83]. These findings still need validation in prospective studies but, nonetheless, could allow a more evidence based selection of patients for CYC treatment, thus maximizing the therapeutic benefit and avoiding unnecessary use of a potentially toxic agent.

In our clinical practice, if we decide to treat patients with CYC, we use IV pulse therapy for 6 months and continue with MMF or azathioprine maintenance therapy. In general, we only use low-dose corticosteroids because of the association of medium and high-dose corticosteroids with renal crisis.


The number and quality of studies available for MMF and thus the clinical evidence for the efficacy of MMF is lower than for CYC. Nevertheless, several reports from small case series describe a positive outcome in SSc-ILD patients treated with MMF, with stabilization or mild improvement of PFTs and HRCT fibrosis after 6 up to 24 months of therapy [8488]. Stabilization of lung function has also been observed in a recent, uncontrolled, prospective study including early, immunosuppressive therapy-naive dcSSc patients, with a median treatment duration of 18 months [89]. Similarly, a retrospective study on 98 patients treated with MMF has shown stable PFTs [90].

Accordingly, a retrospective controlled trial including a large cohort of 109 MMF-treated patients showed a lower frequency of clinically significant lung fibrosis (defined as a ≥15 % reduction in FVC from baseline or FVC < 55 %) and a better 5-year survival in patients receiving MMF compared to other immunosuppressives [91].

Mycophenolate sodium (MS), a related compound, was also shown to stabilize SSc-ILD after 12 months of treatment in a recent, small-scale, prospective study [92].

These reports suggest that MMF or MS treatment is well-tolerated in patients with SSc-ILD [85, 89, 92, 93]. Frequently reported side effects are gastrointestinal disorders, lymphopenia, or infections [89].

However, it is still to be proven whether MMF or MS is superior to placebo and how it performs in comparison to CYC. A recent small, case–control, longitudinal study in SSc-ILD showed significant worsening of HRCT findings in the MMF group compared to CYC-treated patients; no significant differences regarding PFTs were found [87]. The ongoing double blind RCT Scleroderma Lung Study II (NCT00883129), which includes an oral CYC and an MMF arm [94], will hopefully shed light on the comparative performance and tolerability of these agents.

Other Emerging Treatments—Biologics and Stem Cell Transplantation

Several targeted therapies with different biologics have recently been tested in SSc-ILD. Following smaller uncontrolled studies, a recent multicenter, nested case–control, observational study on the EUSTAR cohort showed that patients with SSc-ILD treated with rituximab (RTX) had significantly less decline of FVC compared with matched controls (N = 9; 0.4 ± 4.4 % vs −7.7 ± 3.6 %; p = 0.02). These promising results need to be confirmed in RCTs, but support the rationale for RTX therapy in SSc-ILD [95•]. A double-blind RCT comparing RTX to CYC in CTD-ILD is ongoing (NCT01862926).

A preliminary exploratory analysis from the Tocilizumab (TCZ) phase 2/3 RCT “faSScinate” (NCT01532869) showed a reduced frequency of FVC decline in the TCZ-treated group compared to placebo (3 vs 27 % with a decline in FVC ≥10 %, p = 0.009) [96]. FVC was an exploratory outcome in this trial.

Human autologous stem cell transplantation (HSCT) represents an untargeted, more global therapeutic approach. Three controlled trials on HSCT in SSc have been published so far [77]. The Autologous Stem Cell Transplantation International Scleroderma (ASTIS) Trial revealed that HSCT-treated patients had significant better long-term event-free survival (defined as death or major organ failure), with the cost of a higher treatment-related mortality in the first year after therapy. At baseline, 87 % of patients in the HSCT arm and 80 % of patients in the CYC arm had SSc-ILD as diagnosed by HRCT. Mean changes in lung function parameters from baseline until 2 years’ follow-up showed a significant amelioration in the HSCT treated group versus the CYC group [97••]. Given its high treatment-related mortality, we consider HSCT as a treatment option in selected cases with very poor prognosis. An ongoing RCT, the STAT trial (NCT01413100), also including 2 years of post-transplant maintenance therapy with MMF, is under way.

Recent Advances in the Treatment of IPF and Their Translational Potential to SSc-ILD

SSc-ILD and IPF are inherently related and, given their rarity, cross-over research is highly informative. The SSc-ILD phenotype differs from IPF in various aspects including the overall slower decline in lung function, presence of ground-glass infiltrates on HRCT, correlation with autoantibody status, histological evidence of NSIP in contrast to the usual interstitial pneumonia (UIP) seen in IPF, as well as the occasional regression and response to immunosuppressive drugs [98]. Recently, two RCTs in IFP have been published with positive results: Nintedanib, a tyrosine-kinase inhibitor, significantly reduced the annual rate of decline in FVC vs placebo [99•]. Pirfenidone reduced the frequency of progression (≥10 % decline in FVC or death) by 48 % at 52 weeks as compared to placebo [100•]. Future trials testing these agents in SSc-ILD are needed.


The recent years have brought important advances in the clinical and therapeutic management of SSc lung disease. Early diagnosis, improved patient selection, and monitoring are key elements to consider in the current management of SSc lung disease. Alongside, new targeted therapies and agents with an improved safety profile are under development.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.

    Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972–2002. Ann Rheum Dis. 2007;66(7):940–4.

    Article  PubMed Central  PubMed  Google Scholar 

  2. 2.

    Galie N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J. 2009;34(6):1219–63.

    Article  CAS  PubMed  Google Scholar 

  3. 3.

    McGoon MD, Benza RL, Escribano-Subias P, Jiang X, Miller DP, Peacock AJ, et al. Pulmonary arterial hypertension: epidemiology and registries. J Am Coll Cardiol. 2013;62(25 Suppl):D51–9.

    Article  PubMed  Google Scholar 

  4. 4.

    Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med. 2006;173(9):1023–30.

    Article  PubMed  Google Scholar 

  5. 5.

    Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D34–41.

    Article  PubMed  Google Scholar 

  6. 6.

    Hachulla E, Gressin V, Guillevin L, Carpentier P, Diot E, Sibilia J, et al. Early detection of pulmonary arterial hypertension in systemic sclerosis: a French nationwide prospective multicenter study. Arthritis Rheum. 2005;52(12):3792–800.

    Article  PubMed  Google Scholar 

  7. 7.

    Avouac J, Airo P, Meune C, Beretta L, Dieude P, Caramaschi P, et al. Prevalence of pulmonary hypertension in systemic sclerosis in European Caucasians and metaanalysis of 5 studies. J Rheumatol. 2010;37(11):2290–8.

    Article  PubMed  Google Scholar 

  8. 8.

    Hachulla E, de Groote P, Gressin V, Sibilia J, Diot E, Carpentier P, et al. The three-year incidence of pulmonary arterial hypertension associated with systemic sclerosis in a multicenter nationwide longitudinal study in France. Arthritis Rheum. 2009;60(6):1831–9.

    Article  PubMed  Google Scholar 

  9. 9.

    Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004;351(14):1425–36.

    Article  CAS  PubMed  Google Scholar 

  10. 10.

    Humbert M, Sitbon O, Yaici A, Montani D, O’Callaghan DS, Jais X, et al. Survival in incident and prevalent cohorts of patients with pulmonary arterial hypertension. Eur Respir J. 2010;36(3):549–55.

    Article  CAS  PubMed  Google Scholar 

  11. 11.

    Gutsche M, Rosen GD, Swigris JJ. Connective tissue disease-associated interstitial lung disease: a review. Curr Respir Care Rep. 2012;1:224–32.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. 12.

    Moore OA, Goh N, Corte T, Rouse H, Hennessy O, Thakkar V, et al. Extent of disease on high-resolution computed tomography lung is a predictor of decline and mortality in systemic sclerosis-related interstitial lung disease. Rheumatology (Oxford). 2013;52(1):155–60.

    Article  Google Scholar 

  13. 13.

    Bauer PR, Schiavo DN, Osborn TG, Levin DL, St Sauver J, Hanson AC, et al. Influence of interstitial lung disease on outcome in systemic sclerosis: a population-based historical cohort study. Chest. 2013;144(2):571–7.

    Article  PubMed Central  PubMed  Google Scholar 

  14. 14.

    Tyndall AJ, Bannert B, Vonk M, Airo P, Cozzi F, Carreira PE, et al. Causes and risk factors for death in systemic sclerosis: a study from the EULAR scleroderma trials and research (EUSTAR) database. Ann Rheum Dis. 2010;69(10):1809–15.

    Article  PubMed  Google Scholar 

  15. 15.

    Wells AU, Margaritopoulos GA, Antoniou KM, Denton C. Interstitial lung disease in systemic sclerosis. Semin Respir Crit Care Med. 2014;35(2):213–21.

    Article  PubMed  Google Scholar 

  16. 16.

    Gashouta MA, Humbert M, Hassoun PM. Update in systemic sclerosis-associated pulmonary arterial hypertension. Presse Med. 2014;43(10 Pt 2):e293–304.

    Article  PubMed  Google Scholar 

  17. 17.•

    Humbert M, Yaici A, de Groote P, Montani D, Sitbon O, Launay D, et al. Screening for pulmonary arterial hypertension in patients with systemic sclerosis: clinical characteristics at diagnosis and long-term survival. Arthritis Rheum. 2011;63(11):3522–30. Indirect evidence that early PAH detection might translate into better long-term outcomes in systemic sclerosis.

    Article  PubMed  Google Scholar 

  18. 18.••

    Khanna D, Gladue H, Channick R, Chung L, Distler O, Furst DE, et al. Recommendations for screening and detection of connective tissue disease-associated pulmonary arterial hypertension. Arthritis Rheum. 2013;65(12):3194–201. Recent recommendations for screening for CTD-associated PAH.

    Article  PubMed  Google Scholar 

  19. 19.

    Hoeper MM, Bogaard HJ, Condliffe R, Frantz R, Khanna D, Kurzyna M, et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D42–50.

    Article  PubMed  Google Scholar 

  20. 20.•

    Coghlan JG, Denton CP, Grunig E, Bonderman D, Distler O, Khanna D, et al. Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study. Ann Rheum Dis. 2014;73(7):1340–9. Evidence-based PAH detection score in a subset of systemic sclerosis patients diagnosed for more than 3 years and with a DLCO<60%.

    Article  PubMed Central  PubMed  Google Scholar 

  21. 21.

    Distler JH, Hoeper MM, Distler O. Diagnosis of pulmonary arterial hypertension in a patient with systemic sclerosis. Nat Clin Pract Rheumatol. 2008;4(3):160–4.

    Article  PubMed  Google Scholar 

  22. 22.

    Parks JL, Taylor MH, Parks LP, Silver RM. Systemic sclerosis and the heart. Rheum Dis Clin N Am. 2014;40(1):87–102.

    Article  Google Scholar 

  23. 23.

    Kahan A, Coghlan G, McLaughlin V. Cardiac complications of systemic sclerosis. Rheumatology (Oxford). 2009;48(3):45–8.

    Google Scholar 

  24. 24.

    Coghlan G. Does left heart disease cause most systemic sclerosis associated pulmonary hypertension? Eur Respir J. 2013;42(4):888–90.

    Article  PubMed  Google Scholar 

  25. 25.

    Fox BD, Shimony A, Langleben D, Hirsch A, Rudski L, Schlesinger R, et al. High prevalence of occult left heart disease in scleroderma-pulmonary hypertension. Eur Respir J. 2013;42(4):1083–91.

    Article  PubMed  Google Scholar 

  26. 26.

    Fisher MR, Mathai SC, Champion HC, Girgis RE, Housten-Harris T, Hummers L, et al. Clinical differences between idiopathic and scleroderma-related pulmonary hypertension. Arthritis Rheum. 2006;54(9):3043–50.

    Article  PubMed  Google Scholar 

  27. 27.

    Vonk-Noordegraaf A, Westerhof N. Describing right ventricular function. Eur Respir J. 2013;41(6):1419–23.

    Article  PubMed  Google Scholar 

  28. 28.

    Overbeek MJ, Lankhaar JW, Westerhof N, Voskuyl AE, Boonstra A, Bronzwaer JG, et al. Right ventricular contractility in systemic sclerosis-associated and idiopathic pulmonary arterial hypertension. Eur Respir J. 2008;31(6):1160–6.

    Article  CAS  PubMed  Google Scholar 

  29. 29.

    Montani D, Savale L, Natali D, Jais X, Herve P, Garcia G, et al. Long-term response to calcium-channel blockers in non-idiopathic pulmonary arterial hypertension. Eur Heart J. 2010;31(15):1898–907.

    Article  CAS  PubMed  Google Scholar 

  30. 30.

    Olsson KM, Delcroix M, Ghofrani HA, Tiede H, Huscher D, Speich R, et al. Anticoagulation and survival in pulmonary arterial hypertension: results from the comparative, prospective registry of newly initiated therapies for pulmonary hypertension (COMPERA). Circulation. 2014;129(1):57–65.

    Article  CAS  PubMed  Google Scholar 

  31. 31.

    Henkens IR, Hazenoot T, Boonstra A, Huisman MV, Vonk-Noordegraaf A. Major bleeding with vitamin K antagonist anticoagulants in pulmonary hypertension. Eur Respir Jrnal. 2013;41(4):872–8.

    Article  CAS  Google Scholar 

  32. 32.

    Humbert MLE, Montani D, Jaïs X, Sitbon O, Simonneau G. Advances in therapeutic interventions for patients with pulmonary arterial hypertension. Circulation 2014;130(24):2189–208.

  33. 33.

    Badesch DB, Tapson VF, McGoon MD, Brundage BH, Rubin LJ, Wigley FM, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann Intern Med. 2000;132(6):425–34.

    Article  CAS  PubMed  Google Scholar 

  34. 34.

    Pulido T, Adzerikho I, Channick RN, Delcroix M, Galie N, Ghofrani HA, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369(9):809–18.

    Article  CAS  PubMed  Google Scholar 

  35. 35.

    Galie N, Badesch D, Oudiz R, Simonneau G, McGoon MD, Keogh AM, et al. Ambrisentan therapy for pulmonary arterial hypertension. J Am Coll Cardiol. 2005;46(3):529–35.

    Article  CAS  PubMed  Google Scholar 

  36. 36.

    Galie N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005;353(20):2148–57.

    Article  CAS  PubMed  Google Scholar 

  37. 37.

    Galie N, Brundage BH, Ghofrani HA, Oudiz RJ, Simonneau G, Safdar Z, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation. 2009;119(22):2894–903.

    Article  CAS  PubMed  Google Scholar 

  38. 38.

    Ghofrani HA, Galie N, Grimminger F, Grunig E, Humbert M, Jing ZC, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369(4):330–40.

    Article  CAS  PubMed  Google Scholar 

  39. 39.

    Simonneau G, Rubin LJ, Galie N, Barst RJ, Fleming TR, Frost AE, et al. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. Ann Intern Med. 2008;149(8):521–30.

    Article  PubMed  Google Scholar 

  40. 40.

    Sitbon O, Jais X, Savale L, Cottin V, Bergot E, Macari EA, et al. Upfront triple combination therapy in pulmonary arterial hypertension: a pilot study. Eur Respir J. 2014;43(6):1691–7.

    Article  PubMed  Google Scholar 

  41. 41.

    Hoeper MM, Barst RJ, Bourge RC, Feldman J, Frost AE, Galie N, et al. Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study. Circulation. 2013;127(10):1128–38.

    Article  CAS  PubMed  Google Scholar 

  42. 42.

    Schachna L, Medsger Jr TA, Dauber JH, Wigley FM, Braunstein NA, White B, et al. Lung transplantation in scleroderma compared with idiopathic pulmonary fibrosis and idiopathic pulmonary arterial hypertension. Arthritis Rheum. 2006;54(12):3954–61.

    Article  PubMed  Google Scholar 

  43. 43.•

    Launay D, Savale L, Berezne A, Le Pavec J, Hachulla E, Mouthon L, et al. Lung and heart–lung transplantation for systemic sclerosis patients. A monocentric experience of 13 patients, review of the literature and position paper of a multidisciplinary working group. Presse Med. 2014;43(10):e345–63. A position paper attempting to identify the SSc patients who are best candidates for lung transplantation.

    Article  PubMed  Google Scholar 

  44. 44.

    Hassoun PM, Mouthon L, Barbera JA, Eddahibi S, Flores SC, Grimminger F, et al. Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol. 2009;54(1 Suppl):S10–9.

    Article  CAS  PubMed  Google Scholar 

  45. 45.

    Dorfmuller P, Humbert M, Perros F, Sanchez O, Simonneau G, Muller KM, et al. Fibrous remodeling of the pulmonary venous system in pulmonary arterial hypertension associated with connective tissue diseases. Hum Pathol. 2007;38(6):893–902.

    Article  PubMed  Google Scholar 

  46. 46.

    O’Callaghan DS, Dorfmuller P, Jais X, Mouthon L, Sitbon O, Simonneau G, et al. Pulmonary veno-occlusive disease: the bete noire of pulmonary hypertension in connective tissue diseases? Presse Med. 2011;40(1 Pt 2):e65–78.

    PubMed  Google Scholar 

  47. 47.

    Tamby MC, Humbert M, Guilpain P, Servettaz A, Dupin N, Christner JJ, et al. Antibodies to fibroblasts in idiopathic and scleroderma-associated pulmonary hypertension. Eur Respir J. 2006;28(4):799–807.

    Article  CAS  PubMed  Google Scholar 

  48. 48.

    Schurawitzki H, Stiglbauer R, Graninger W, Herold C, Polzleitner D, Burghuber OC, et al. Interstitial lung disease in progressive systemic sclerosis: high-resolution CT versus radiography. Radiology. 1990;176(3):755–9.

    Article  CAS  PubMed  Google Scholar 

  49. 49.

    Launay D, Remy-Jardin M, Michon-Pasturel U, Mastora I, Hachulla E, Lambert M, et al. High resolution computed tomography in fibrosing alveolitis associated with systemic sclerosis. J Rheumatol. 2006;33(9):1789–801.

    PubMed  Google Scholar 

  50. 50.

    De Santis M, Bosello S, La Torre G, Capuano A, Tolusso B, Pagliari G, et al. Functional, radiological and biological markers of alveolitis and infections of the lower respiratory tract in patients with systemic sclerosis. Respir Res. 2005;6:96.

    Article  PubMed Central  PubMed  Google Scholar 

  51. 51.

    Desai SR, Veeraraghavan S, Hansell DM, Nikolakopolou A, Goh NS, Nicholson AG, et al. CT features of lung disease in patients with systemic sclerosis: comparison with idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia. Radiology. 2004;232(2):560–7.

    Article  PubMed  Google Scholar 

  52. 52.

    Douglas WW, Tazelaar HD, Hartman TE, Hartman RP, Decker PA, Schroeder DR, et al. Polymyositis-dermatomyositis-associated interstitial lung disease. Am J Respir Crit Care Med. 2001;164(7):1182–5.

    Article  CAS  PubMed  Google Scholar 

  53. 53.

    Wells AU, Hansell DM, Corrin B, Harrison NK, Goldstraw P, Black CM, et al. High resolution computed tomography as a predictor of lung histology in systemic sclerosis. Thorax. 1992;47(9):738–42.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. 54.

    Remy-Jardin M, Giraud F, Remy J, Copin MC, Gosselin B, Duhamel A. Importance of ground-glass attenuation in chronic diffuse infiltrative lung disease: pathologic-CT correlation. Radiology. 1993;189(3):693–8.

    Article  CAS  PubMed  Google Scholar 

  55. 55.

    Shah RM, Jimenez S, Wechsler R. Significance of ground-glass opacity on HRCT in long-term follow-up of patients with systemic sclerosis. J Thorac Imaging. 2007;22(2):120–4.

    Article  PubMed  Google Scholar 

  56. 56.

    Wells AU. Pulmonary function tests in connective tissue disease. Semin Respir Crit Care Med. 2007;28(4):379–88.

    Article  PubMed  Google Scholar 

  57. 57.

    Steen VD, Conte C, Owens GR, Medsger Jr TA. Severe restrictive lung disease in systemic sclerosis. Arthritis Rheum. 1994;37(9):1283–9.

    Article  CAS  PubMed  Google Scholar 

  58. 58.

    Peters-Golden M, Wise RA, Hochberg MC, Stevens MB, Wigley FM. Carbon monoxide diffusing capacity as predictor of outcome in systemic sclerosis. Am J Med. 1984;77(6):1027–34.

    Article  CAS  PubMed  Google Scholar 

  59. 59.

    Morgan C, Knight C, Lunt M, Black CM, Silman AJ. Predictors of end stage lung disease in a cohort of patients with scleroderma. Ann Rheum Dis. 2003;62(2):146–50.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. 60.

    Wells AU, Cullinan P, Hansell DM, Rubens MB, Black CM, Newman-Taylor AJ, et al. Fibrosing alveolitis associated with systemic sclerosis has a better prognosis than lone cryptogenic fibrosing alveolitis. Am J Respir Crit Care Med. 1994;149(6):1583–90.

    Article  CAS  PubMed  Google Scholar 

  61. 61.

    Wells AU, Hansell DM, Rubens MB, King AD, Cramer D, Black CM, et al. Fibrosing alveolitis in systemic sclerosis: indices of lung function in relation to extent of disease on computed tomography. Arthritis Rheum. 1997;40(7):1229–36.

    Article  CAS  PubMed  Google Scholar 

  62. 62.••

    Wells AU, Denton CP. Interstitial lung disease in connective tissue disease-mechanisms and management. Nature reviews Rheumatology. 2014;10(12):728–39. Comprehensive review on the current knowledge on interstitial lung disease in connective tissue disorders, including a section on SSc ILD.

  63. 63.

    Steen V. Predictors of end stage lung disease in systemic sclerosis. Ann Rheum Dis. 2003;62(2):97–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  64. 64.

    Goh NS, Desai SR, Veeraraghavan S, Hansell DM, Copley SJ, Maher TM, et al. Interstitial lung disease in systemic sclerosis: a simple staging system. Am J Respir Crit Care Med. 2008;177(11):1248–54.

    Article  PubMed  Google Scholar 

  65. 65.

    Tashkin DP, Elashoff R, Clements PJ, Goldin J, Roth MD, Furst DE, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med. 2006;354(25):2655–66.

    Article  CAS  PubMed  Google Scholar 

  66. 66.

    Latsi PI, Wells AU. Evaluation and management of alveolitis and interstitial lung disease in scleroderma. Curr Opin Rheumatol. 2003;15(6):748–55.

    Article  PubMed  Google Scholar 

  67. 67.

    Hant FN, Ludwicka-Bradley A, Wang HJ, Li N, Elashoff R, Tashkin DP, et al. Surfactant protein D and KL-6 as serum biomarkers of interstitial lung disease in patients with scleroderma. J Rheumatol. 2009;36(4):773–80.

    Article  CAS  PubMed  Google Scholar 

  68. 68.

    Ohnishi H, Yokoyama A, Kondo K, Hamada H, Abe M, Nishimura K, et al. Comparative study of KL-6, surfactant protein-A, surfactant protein-D, and monocyte chemoattractant protein-1 as serum markers for interstitial lung diseases. Am J Respir Crit Care Med. 2002;165(3):378–81.

    Article  PubMed  Google Scholar 

  69. 69.

    Hasegawa M, Fujimoto M, Hamaguchi Y, Matsushita T, Inoue K, Sato S, et al. Use of serum clara cell 16-kDa (CC16) levels as a potential indicator of active pulmonary fibrosis in systemic sclerosis. J Rheumatol. 2011;38(5):877–84.

    Article  CAS  PubMed  Google Scholar 

  70. 70.

    Bonella F, Volpe A, Caramaschi P, Nava C, Ferrari P, Schenk K, et al. Surfactant protein D and KL-6 serum levels in systemic sclerosis: correlation with lung and systemic involvement. Sarcoidosis Vasc Diffuse Lung Dis. 2011;28(1):27–33.

    CAS  PubMed  Google Scholar 

  71. 71.

    De Lauretis A, Sestini P, Pantelidis P, Hoyles R, Hansell DM, Goh NS, et al. Serum interleukin 6 is predictive of early functional decline and mortality in interstitial lung disease associated with systemic sclerosis. J Rheumatol. 2013;40(4):435–46.

    Article  PubMed  Google Scholar 

  72. 72.

    Kowal-Bielecka O, Landewe R, Avouac J, Chwiesko S, Miniati I, Czirjak L, et al. EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR). Ann Rheum Dis. 2009;68(5):620–8.

    Article  CAS  PubMed  Google Scholar 

  73. 73.

    Hoyles RK, Ellis RW, Wellsbury J, Lees B, Newlands P, Goh NS, et al. A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma. Arthritis Rheum. 2006;54(12):3962–70.

    Article  CAS  PubMed  Google Scholar 

  74. 74.

    Goldin J, Elashoff R, Kim HJ, Yan X, Lynch D, Strollo D, et al. Treatment of scleroderma-interstitial lung disease with cyclophosphamide is associated with less progressive fibrosis on serial thoracic high-resolution CT scan than placebo: findings from the scleroderma lung study. Chest. 2009;136(5):1333–40.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  75. 75.

    Khanna D, Yan X, Tashkin DP, Furst DE, Elashoff R, Roth MD, et al. Impact of oral cyclophosphamide on health-related quality of life in patients with active scleroderma lung disease: results from the scleroderma lung study. Arthritis Rheum. 2007;56(5):1676–84.

    Article  CAS  PubMed  Google Scholar 

  76. 76.

    Tashkin DP, Elashoff R, Clements PJ, Roth MD, Furst DE, Silver RM, et al. Effects of 1-year treatment with cyclophosphamide on outcomes at 2 years in scleroderma lung disease. Am J Respir Crit Care Med. 2007;176(10):1026–34.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  77. 77.

    Nagaraja V, Denton CP, Khanna D. Old medications and new targeted therapies in systemic sclerosis. Rheumatology (Oxford). 2014.

  78. 78.

    Berezne A, Valeyre D, Ranque B, Guillevin L, Mouthon L. Interstitial lung disease associated with systemic sclerosis: what is the evidence for efficacy of cyclophosphamide? Ann N Y Acad Sci. 2007;1110:271–84.

    Article  CAS  PubMed  Google Scholar 

  79. 79.

    Monach PA, Arnold LM, Merkel PA. Incidence and prevention of bladder toxicity from cyclophosphamide in the treatment of rheumatic diseases: a data-driven review. Arthritis Rheum. 2010;62(1):9–21.

    Article  CAS  PubMed  Google Scholar 

  80. 80.

    Li J, Dai G, Zhang Z. General adverse response to cyclophosphamide in Chinese patients with systemic autoimmune diseases in recent decade—a single-center retrospective study. Clin Rheumatol. 2014. doi:10.1007/s10067-014-2748-2.

  81. 81.

    Abhishek A, Yazdani R, Pearce F, Regan M, Lim K, Hubbard R, et al. Outcome of systemic sclerosis associated interstitial lung disease treated with intravenous cyclophosphamide. Clin Rheumatol. 2011;30(8):1099–104.

    Article  PubMed  Google Scholar 

  82. 82.

    Poormoghim H, Moradi Lakeh M, Mohammadipour M, Sodagari F, Toofaninjed N. Cyclophosphamide for scleroderma lung disease: a systematic review and meta-analysis. Rheumatol Int. 2012;32(8):2431–44.

    Article  CAS  PubMed  Google Scholar 

  83. 83.

    Roth MD, Tseng CH, Clements PJ, Furst DE, Tashkin DP, Goldin JG, et al. Predicting treatment outcomes and responder subsets in scleroderma-related interstitial lung disease. Arthritis Rheum. 2011;63(9):2797–808.

    Article  PubMed Central  PubMed  Google Scholar 

  84. 84.

    Koutroumpas A, Ziogas A, Alexiou I, Barouta G, Sakkas LI. Mycophenolate mofetil in systemic sclerosis-associated interstitial lung disease. Clin Rheumatol. 2010;29(10):1167–8.

    Article  PubMed  Google Scholar 

  85. 85.

    Zamora AC, Wolters PJ, Collard HR, Connolly MK, Elicker BM, Webb WR, et al. Use of mycophenolate mofetil to treat scleroderma-associated interstitial lung disease. Respir Med. 2008;102(1):150–5.

    Article  PubMed  Google Scholar 

  86. 86.

    Gerbino AJ, Goss CH, Molitor JA. Effect of mycophenolate mofetil on pulmonary function in scleroderma-associated interstitial lung disease. Chest. 2008;133(2):455–60.

    Article  CAS  PubMed  Google Scholar 

  87. 87.

    Panopoulos ST, Bournia VK, Trakada G, Giavri I, Kostopoulos C, Sfikakis PP. Mycophenolate versus cyclophosphamide for progressive interstitial lung disease associated with systemic sclerosis: a 2-year case control study. Lung. 2013;191(5):483–9.

    Article  PubMed  Google Scholar 

  88. 88.

    Liossis SN, Bounas A, Andonopoulos AP. Mycophenolate mofetil as first-line treatment improves clinically evident early scleroderma lung disease. Rheumatology (Oxford). 2006;45(8):1005–8.

    Article  CAS  Google Scholar 

  89. 89.

    Mendoza FA, Nagle SJ, Lee JB, Jimenez SA. A prospective observational study of mycophenolate mofetil treatment in progressive diffuse cutaneous systemic sclerosis of recent onset. J Rheumatol. 2012;39(6):1241–7.

    Article  CAS  PubMed  Google Scholar 

  90. 90.

    Le EN, Wigley FM, Shah AA, Boin F, Hummers LK. Long-term experience of mycophenolate mofetil for treatment of diffuse cutaneous systemic sclerosis. Ann Rheum Dis. 2011;70(6):1104–7.

    Article  CAS  PubMed  Google Scholar 

  91. 91.

    Nihtyanova SI, Brough GM, Black CM, Denton CP. Mycophenolate mofetil in diffuse cutaneous systemic sclerosis—a retrospective analysis. Rheumatology (Oxford). 2007;46(3):442–5.

    Article  CAS  Google Scholar 

  92. 92.

    Simeon-Aznar CP, Fonollosa-Pla V, Tolosa-Vilella C, Selva-O’Callaghan A, Solans-Laque R, Vilardell-Tarres M. Effect of mycophenolate sodium in scleroderma-related interstitial lung disease. Clin Rheumatol. 2011;30(11):1393–8.

    Article  PubMed  Google Scholar 

  93. 93.

    Swigris JJ, Olson AL, Fischer A, Lynch DA, Cosgrove GP, Frankel SK, et al. Mycophenolate mofetil is safe, well tolerated, and preserves lung function in patients with connective tissue disease-related interstitial lung disease. Chest. 2006;130(1):30–6.

    CAS  PubMed  Google Scholar 

  94. 94.

    Khanna D, Roth M, Furst D, Clements P, Goldin J, Arriola E, et al. FRI0396 Double-blind comparison of mycophenolate mofetil and oral cyclophosphamide for treatment of scleroderma-related interstitial lung disease (scleroderma lung study [SLS] II): rationale, design, methods, baseline characteristics and patient disposition. Ann Rheum Dis. 2013;72 Suppl 3:A507.

    Google Scholar 

  95. 95.•

    Jordan S, Distler JH, Maurer B, Huscher D, van Laar JM, Allanore Y, et al. Effects and safety of rituximab in systemic sclerosis: an analysis from the European Scleroderma Trial and Research (EUSTAR) group. Ann Rheum Dis. 2014. doi:10.1136/annrheumdis-2013-204522.Observational evidence that Rituximab can reduce the decline in lung function in patients with SSc ILD.

  96. 96.

    Khanna D DC, van Laar JM, Jahreis A, Cheng S, Spotswood H, Siegel J, Furst DE, on behalf of FaSScinate Clinical Trial in Patients With SS. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis: week 24 data from a phase 2/3 trial. Arthritis and Rheumatology. 2014;66(11 (Supplement)):S386.

  97. 97.••

    van Laar JM, Farge D, Sont JK, Naraghi K, Marjanovic Z, Larghero J, et al. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. Jama. 2014;311(24):2490–8. First phase 3 randomized controlled trial showing longer event-free survival and improvement in lung function in scleroderma patients treated with hematopoietic stem cell transplantation.

    Article  PubMed  Google Scholar 

  98. 98.

    Herzog EL, Mathur A, Tager AM, Feghali-Bostwick C, Schneider F, Varga J. Review: interstitial lung disease associated with systemic sclerosis and idiopathic pulmonary fibrosis: how similar and distinct? Arthritis Rheumatol. 2014;66(8):1967–78.

    Article  CAS  PubMed  Google Scholar 

  99. 99.•

    Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071–82. Randomized controlled study showing a significant reduction in the annual rate of decline in FVC in patients with idiopathic lung fibrosis treated with nintedanib vs placebo.

    Article  CAS  PubMed  Google Scholar 

  100. 100.•

    King Jr TE, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2083–92. Randomized controlled trials showing a significantly decreased progression of the decline in lung function in patients with idiopathic lung fibrosis treated with pirfenidone.

    Article  CAS  PubMed  Google Scholar 

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Conflict of Interest

Rucsandra Dobrota reports grants from Pfizer and Actelion, outside the submitted work.

Oliver Distler has/had consultancy relationship and/or has received research funding in the area of systemic sclerosis and related conditions from Actelion, Pfizer, Ergonex, BMS, Sanofi-Aventis, United BioSource, Roche/Genentech, Medac, Biovitrium, Boehringer, Novartis, 4D Science, Active Biotec, Bayer, Sinoxa, Serodapharm, EpiPharm, Biogen, Pharmacyclics, Inventiva, and GSK.

Athol Wells has no disclosures.

Marc Humbert reports grants, personal fees, and non-financial support from Actelion; personal fees and non-financial support from Astrazeneca; grants, personal fees and non-financial support from Bayer; grants, personal fees, and non-financial support from GSK; personal fees and non-financial support from Novartis; grants, personal fees, and non-financial support from Pfizer; personal fees from TEVA, outside the submitted work.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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Correspondence to Oliver Distler MD.

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Dobrota, R., Distler, O., Wells, A. et al. Management of Scleroderma-Associated Pulmonary Involvement. Curr Treat Options in Rheum 1, 51–67 (2015).

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  • Systemic sclerosis
  • Pulmonary arterial hypertension
  • Pulmonary hypertension
  • Right heart failure
  • Left heart failure
  • Echocardiography
  • Right heart catheterisation
  • Hemodynamics
  • Pulmonary function tests
  • DLCO
  • High-resolution computed tomography of the chest
  • Interstitial lung disease
  • Lung fibrosis
  • Early diagnosis
  • Cyclophosphamide
  • Mycophenolate
  • Biologics
  • Rituximab
  • Tocilizumab
  • Endothelin receptor antagonists
  • Type 5 phosphodiesterase inhibitors
  • Prostacyclin derivatives
  • Human autologous stem cell transplantation
  • Lung transplantation