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 Table of Contents  
Year : 2017  |  Volume : 12  |  Issue : 6  |  Page : 194-203

Newer insights into the management of interstitial lung disease in systemic sclerosis

1 Division of Rheumatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
2 Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, USA

Date of Web Publication23-Nov-2017

Correspondence Address:
Ashima Makol
Department of Internal Medicine, Division of Rheumatology, Mayo Clinic, 200 1st St. SW, Rochester 55905, MN
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-3698.219084

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Interstitial lung disease (ILD) is a debilitating complication of systemic sclerosis (SSc) and now the leading cause of death in SSc patients, largely from progressive respiratory failure or advanced pulmonary hypertension. Despite significant advances in our understanding of the epidemiology and pathogenesis of SSc-ILD, there are significant uncertainties in the approach to managing these patients given the heterogeneity of presentation, substantial variability in progression, and presence of comorbid cardiopulmonary conditions, particularly pulmonary hypertension and esophageal dilation with recurrent aspiration pneumonitis that portend poor prognosis. Early detection of progressive lung involvement based on worsening pulmonary physiology and quantification of fibrosing alveolitis severity on high-resolution computed tomography is critical as response to immunomodulatory agents is usually best when initiated earlier in the disease course. A selected group of patients may benefit from early referral for hematopoietic stem cell transplantation or lung/heart–lung transplant. The last decade has seen a significant advance in evidence-based approaches to treatment of SSc-ILD with immune suppressants, and there are several ongoing treatment trials with recent advances in understanding of the role of pro-inflammatory and profibrotic cytokines in SSc-ILD. The efficacy of antifibrotic agents in idiopathic pulmonary fibrosis has also provided another promising avenue for utilization in these patients. In this review, we will provide an up-to-date review of the treatment options for SSc-ILD, the ongoing studies moving this field forward, emerging treatments for SSc-ILD, and propose a management algorithm for SSc-ILD, based on the available evidence in the literature and our experience.

Keywords: Antifibrotic treatment, connective tissue diseases, immunosuppressive agents, interstitial lung disease, interstitial, lung diseases, systemic sclerosis

How to cite this article:
Mango RL, Ryu JH, Makol A. Newer insights into the management of interstitial lung disease in systemic sclerosis. Indian J Rheumatol 2017;12, Suppl S1:194-203

How to cite this URL:
Mango RL, Ryu JH, Makol A. Newer insights into the management of interstitial lung disease in systemic sclerosis. Indian J Rheumatol [serial online] 2017 [cited 2022 Jun 27];12, Suppl S1:194-203. Available from:

  Introduction Top

Systemic sclerosis (SSc) is a rare autoimmune disease with diffuse microangiopathy, immune dysregulation, and widespread fibrosis often leading to multiorgan dysfunction. While skin sclerosis and Raynaud phenomenon are the most common presenting symptoms, respiratory symptoms are common and multifactorial in etiology [Table 1]. Pulmonary involvement is seen in over 80% of patients,[1] second in frequency only to esophageal involvement as a visceral complication of the disease.
Table 1: Differential diagnosis of dyspnea in patients with systemic sclerosis

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Interstitial lung disease (ILD) is a diffuse parenchymal infiltrative process characterized by fibrosing alveolitis that is identifiable by chest imaging or histopathology. This can lead to restrictive lung physiology, making ILD a debilitating and difficult to control syndrome, and a leading cause of death among patients with SSc.[2],[3] The prevalence of SSc-ILD varies depending on the population studied, case definition, and the methods of case ascertainment. Clinically relevant ILD affects up to 42% patients, but ILD is evident in over 80% patients in autopsy series.[4] In a population-based study, the presence of ILD increased the risk of death in SSc by 2.9-fold.[3] The disease course of ILD is variable, remaining indolent with stable pulmonary physiology or progressing rapidly, resulting in worsening dyspnea, exercise intolerance, respiratory failure, oxygen dependence, and death. In the EULAR Scleroderma Trials and Research cohort of over 5800 SSc patients,[5] 35% of deaths were directly attributable to ILD and 26% to pulmonary arterial hypertension (PAH). Therefore, pulmonary disease is critical to identify and treat early and aggressively to improve long-term prognosis.

Prognosis in SSc-ILD is not uniform, and much effort has been made toward early identification of patients at greatest risk of developing SSc-ILD or progressing once diagnosed [Table 2].
Table 2: Risk factors for systemic sclerosis-related interstitial lung disease

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Large trials conducted in SSc-ILD, thus far have also provided important information on feasibility, reliability, and validity of outcome measures. Forced vital capacity (FVC) percentage predicted is the most reliable primary outcome measure, but quantitative evaluation of changes on chest imaging and patient-reported measures of dyspnea and quality of life are equally important to integrate.[6] The OMERACT Working group also recently endorsed domains and a clinically meaningful progression definition for SSc-ILD trials.[7] Excellent recommendations for future trial design include the concept of “cohort enrichment” have been proposed to select patients are greatest risk of progression, and the readers are directed to this recent review for additional reading.[6]

Despite advances in the understanding of SSc pathogenesis, there is no clearly efficacious treatment for the overall syndrome. Treatment options for SSc-ILD are currently limited, and evidence-based therapies that exist have modest benefit. However, this field is rapidly changing, with recent practice-relevant randomized controlled trial data and promising new approaches on the horizon. This review will highlight the recent evidence informing the monitoring and treatment of SSc-ILD, including both the established and emerging modalities. We will present a stepwise approach to manage SSc-ILD based on the available evidence in the literature, to help guide the management of these complex patients.

  Screening and Early Diagnosis of Interstitial Lung Disease in Systemic Sclerosis Top

Once a diagnosis of SSc is made, patients should be regularly screened for lung involvement. It is helpful to establish baseline lung physiology (FVC, and diffusion capacity of the lung for carbon monoxide [DLCO]) and estimated right ventricular systolic pressure on transthoracic echocardiogram even in the absence of any pulmonary symptoms. Early detection of ILD should be sought if there is concern based on symptoms, clinical examination, and yearly pulmonary function tests. High-resolution computed tomography (HRCT) is the most sensitive means of identifying SSc-ILD. The only drawback is the frequent presence of subclinical abnormalities that do not necessarily progress or warrant intervention. HRCT patterns often correlate well with the underlying histopathologic pattern and lung biopsies are not usually indicated, unless there are diagnostic dilemmas. Similarly, although bronchoalveolar lavage was previously done routinely, it does not predict the presence or progression of SSc-ILD reliably [8] and should not be a part of routine evaluation for these patients.

Efforts at prognostication have been based on staging schemes developed for idiopathic pulmonary fibrosis (IPF). For instance, the ILD-GAP model (gender, age, and lung physiology) predicts mortality for patients with connective tissue disease (CTD)-related ILD, based on the sex, age, FVC, and DLCO.[9] The SADL model, which depends on smoking history, age, and DLCO, was specifically developed for SSc-ILD.[10] Other models have been validated for IPF, and incorporate forced expiratory volume in 1 s,[11] change in FVC over 6 months,[12] recent hospitalization,[12] and a 6 min walk test.[13] Furthermore, the rate of change in FVC and DLCO has been found to predict outcomes in an SSc-ILD cohort.[14] The performance of these models highlights the importance of pulmonary function testing for initial and follow-up pulmonary risk assessment.

Imaging also provides prognostically useful information. Those with usual interstitial pneumonia (UIP) pattern of ILD have lower survival rates than those with nonspecific interstitial pneumonia (NSIP), both in idiopathic interstitial pneumonias [15],[16] and SSc.[17] Outcomes in our own SSc-ILD cohort support this, with the ILD-GAP and SADL models underestimating mortality in those with UIP on imaging (unpublished data, manuscript under review). Because HRCT often precludes the need for lung biopsy in identification of ILD patterns, it has become an important part of the initial risk stratification [Figure 1]. It has also been shown that the extent of lung involvement on CT correlates with pulmonary function,[18] and that CT findings can change over time in response to treatment.[19] Although it has not yet been standardized, there is emerging evidence that lung ultrasound may be a useful alternative to CT, in diagnosis,[20] early disease monitoring,[21] and evaluation of disease progression.[22] From a monitoring and management perspective, it can be helpful to separate the “mild” (FVC >70% predicted and HRCT involvement <20% lung volume) versus “extensive” (FVC <70% and HRCT >20% lung volume) SSc-ILD. Those with mild disease require monitoring less often than those in the extensive disease group.
Figure 1: High-resolution computed tomography of the chest demonstrating patterns of systemic sclerosis-interstitial lung disease. (a) Nonspecific interstitial pneumonia pattern is most commonly seen (>70% patients) – note the predominance of ground glass opacities and traction bronchiectasis. (b) Usual interstitial pneumonia pattern of systemic sclerosis-interstitial lung disease – note the peripheral predominance of reticular opacities and subpleural honeycombing

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While PAH is not the focus of this review, regular screening of SSc patients for PAH with an echocardiogram is recommended on an annual basis, according to a consensus statement by the Scleroderma Foundation and Pulmonary Hypertension Association in 2013.[23] While PAH in SSc can be primary or secondary to ILD, it is an independent risk factor for mortality [3] and is itself the target of a number of emerging therapies. Echocardiograms, together with HRCT and PFTs, form the basis of disease activity monitoring in SSc-ILD [Figure 2].
Figure 2: Our approach to the management of systemic sclerosis-interstitial lung disease (SSc-ILD). PFTs: Pulmonary function tests, HRCT: High-resolution computed tomography of the chest, FVC: Forced vital capacity, RVSP: Estimated Right ventricular systolic pressure, MMF: Mycophenolate mofetil, AZA: azathioprine, CYC: cyclophosphamide

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  Treatment Approaches in Systemic Sclerosis-Interstitial Lung Disease Top

Not all patients with SSc-ILD warrant therapeutic intervention, and those with mild and/or asymptomatic disease may be best served with monitoring and observation. A combination of worsening exertional dyspnea with decline in pulmonary physiology or progression on HRCT is an indication to consider immunomodulating approaches with the goal of preventing further decline and stabilizing lung function by reversing active inflammation and preventing further fibrosis. To this end, the approach has been to use low-dose corticosteroids in combination with immunosuppression. Note, however, that currently, there are no Food and Drug Administration (FDA)-approved therapies for the treatment of SSc or SSc-ILD.

  Cyclophosphamide Top

Conventional treatment for SSc-ILD has long been considered cyclophosphamide, an alkylating agent that decreases lymphocyte responses. Early evidence showed that effects were modest at best, with FVC levels increasing by 4% in 39 patients versus falling by 7% in 30 untreated patients in one series.[24] It was evaluated for efficacy in systemic sclerosis-related ILD in two landmark randomized control trials reported in 2006.[25],[26] In the Fibrosing Alveolitis in Scleroderma Trial (FAST), patients were randomized to monthly intravenous cyclophosphamide for 6 months followed by azathioprine for maintenance versus placebo. The primary outcome did not reach statistical significance, likely due to the small size of the cohort.[25] The scleroderma lung study (SLS I) randomized patients to daily oral cyclophosphamide or placebo for 12 months, a strategy that resulted in higher cumulative doses than in the FAST trial. The SLS I trial did find a statistically significant improvement in FVC (P = 0.03) and dyspnea scores, with similar absolute improvement in FVC as in FAST, and modest improvements in secondary end points including skin scores and quality of life.[26] A follow-up study showed that all of the gains made in the cyclophosphamide arm were lost by 2 years,[27] prompting the desire for an agent that could be continued past the recommended 12-month limitation on cyclophosphamide, for maintenance. These two studies prompted the EULAR to endorse the use of cyclophosphamide as a suitable therapy in SSc-ILD.[28] Unfortunately, the small gain (FVC improvement <5%) came with a significant risk of side effects in the SLS I study. It also became apparent that both studies lacked patients that would have been more likely to benefit from the intervention. In SLS I, patients with limited disease on HRCT (>50% of the cohort) had no treatment effect, whereas those with extensive disease noted FVC improvement >10%.[26] Both studies also lacked an active control arm and provided data only for 1st year of therapy. It was also felt that progression of disease was more rapid in the active treatment arm postcompletion of trial. There was thus a need to evaluate maintenance medication to maintain the gains achieved, which would be routinely done in clinical practice.

The efficacy of cyclophosphamide was confirmed again in the recently published SLS II.[29] In SLS II, oral cyclophosphamide for 1 year was compared to oral mycophenolate mofetil (MMF) for 2 years, for initial treatment. As in SLS I, there were significant but modest improvements in the cyclophosphamide arm in FVC and HRCT changes, as well as secondary outcome measures such as the modified Rodnan Skin Scores (mRSSs). Unlike in SLS I, the cyclophosphamide arm also maintained its benefits at 24 months even though cyclophosphamide was discontinued at 12 months. Leukopenia (thirty vs. four patients) and thrombocytopenia (four vs. none) occurred more often in patients given cyclophosphamide than MMF. More patients on cyclophosphamide than on MMF prematurely withdrew from study drug (32 vs. 20). The time to stopping treatment was shorter in the cyclophosphamide group (P = 0·019). Therefore, cyclophosphamide continues to be a viable evidence-based option for SSc-ILD but compares unfavorably to MMF in terms of risks and side effect profile.[29]

  Mycophenolate Mofetil Top

Since MMF can be continued for a longer period, it was expected that it would outperform cyclophosphamide at 2 years in SLS II, with long-lasting treatment effects and fewer side effects. Although MMF was better tolerated and associated with less toxicity, it did not have greater efficacy at 24 months than cyclophosphamide.[29] There was no placebo group in SLS II because cyclophosphamide had already been established as the standard of care. However, a post hoc analysis compared the MMF arm in SLS II to the placebo arm in SLS I.[30] When adjusting for disease severity, MMF outperformed placebo. However, the magnitude of clinical improvement remains modest. For instance, in SLS II, there was an absolute improvement in the FVC of 2.18% predicted in the MMF group.[29] The difference between cyclophosphamide and placebo in SLS I at 12 months was 2.5% predicted.[26]

As predicted, there were fewer adverse events with MMF than with cyclophosphamide in SLS II,[29] which argues for the use of MMF as a first-line agent. MMF itself has certain adverse effects (e.g., diarrhea), which can limit the dose to <3 g/day utilized in SLS II. Nevertheless, PFT and HRCT improvements after MMF use have also been shown in a retrospective cohort study, despite the fact that the majority of the patients were on <3 g/day, with the median dose 1.5 g.[31] We recommend using the full dose of 3 g/day, or the maximum tolerated dose, for treatment in routine clinical practice.

  Azathioprine Top

Azathioprine has long been used in combination with cyclophosphamide as a maintenance therapy after the 1st year, and this has been described in a number of single-arm studies,[32],[33] as well as in the FAST study.[25] It has also outperformed mycophenolate as a maintenance therapy in one study.[34] A recent study of patients with SSc-ILD compared ILD progression in those treated with mycophenolate (18 patients) or azathioprine (29 patients) and demonstrated stabilization of pulmonary function tests for both though the azathioprine group had more stable PFTs before treatment, potentially revealing a selection bias.[35] Azathioprine has not been shown more effective than placebo in an RCT but may still have a role in maintenance therapy when other options have been exhausted.

  Glucocorticoids Top

Unlike in other CTD-ILDs, use of high dose GC is not usually advised in patients with SSc-ILD given their association with scleroderma renal crisis. Many clinicians thus consider GC as completely contraindicated in SSc although the association between renal crisis and prednisone was documented with doses >15 mg/day.[36] There is no evidence for or against the use of low doses (<15 mg/day) and they can be used on a case-by-case basis in SSc-ILD. We do advise avoiding prednisone doses >20 mg daily for SSc patients.

  Rituximab Top

A few uncontrolled reports show promise with rituximab, a monoclonal antibody-targeting CD20, which acts by depleting circulating B-cells. A case series of 8 SSc-ILD patients treated with rituximab for 2 years demonstrated improvement in FVC and DLCO.[37] A more recent series of 14 patients with SSc-ILD showed a lack of decline of FVC, with imaging improvements in some patients.[38] More broadly, a retrospective cohort of 24 patients with CTD-related ILD treated with rituximab was published in 2012. In this study, FVC improved slightly and DLCO remained steady for the duration of follow-up.[39] Another similar study with 33 CTD-ILD patients on rituximab showed clear reversal of declining FVC and DLCO measures.[40] Another study specifically evaluated the efficacy of rituximab in antisynthetase syndrome, a type of myositis. Over 52 months, the 24 patients in the long-term cohort had statistically significant improvements in their PFTs.[41] However, another small study did not show any benefit.[42] Without prospective controlled trials, it is difficult to determine how to interpret these data. An ongoing randomized clinical trial in the UK (RECITAL study; Identifier NCT01862926) is comparing rituximab to cyclophosphamide for ILD associated with SSc, inflammatory myositis, and mixed CTD.[43] In routine clinical practice, we recommend using rituximab in patients with progressive SSc-ILD despite the use of conventional treatments mentioned above. More data from prospective trials are needed before it can become standard of care.

  Maintenance Therapy Top

Although there are no guidelines or evidence to make an informed decision, given that lung disease is usually an early feature of the disease and its progression reaches a peak during the first 4–5 years of the disease, we recommend continuing maintenance immunosuppression for at least 4–5-year postclinical stabilization of their SSc-ILD. This is most commonly with azathioprine as discussed previously or with mycophenolate.

  Newer and Emerging Treatment Approaches Top

  Anti-Fibrotic Therapy Top

In 2014, the FDA gave fast-track approval to two antifibrotic drugs (pirfenidone and nintedanib) for the treatment of IPF, a disease with high mortality and no previously approved therapy, where progressive lung fibrosis is the hallmark. Both SSc-ILD and IPF present with dyspnea on exertion, which may be accompanied by cough, basilar inspiratory crackles on lung examination, and fibrosis on HRCT. However, despite some overlap in clinical features and pathogenesis, SSc-ILD and IPF have differences, with significant implications for diagnosis, evaluation, and management.[44] Inflammation and autoimmunity are clearly features of SSc-ILD while this is not evident for IPF. IPF patients demonstrate poor or no response to immunosuppressants. NSIP is the most common histological pattern in SSc-ILD, whereas UIP is the defining characteristic of IPF. Although antifibrotics delay decline in lung function in IPF, they do not improve lung function and their impact on survival remains unclear.


Pirfenidone is an antifibrotic agent, which has shown promise in IPF.[45] Despite extensive investigation, the mechanism of action is not entirely certain, but it has pleiotropic effects on the antifibrotic pathways and inhibits fibroblast proliferation. This has been evaluated for safety and tolerability in SSc-ILD with no concerning results.[46] This 16-week trial did not find any changes in pulmonary outcomes, but it was not designed to do so. Importantly, there were no documented interactions with concurrent mycophenolate therapy, which is now considered the standard of care. The combination of the two seems logical and rational. The SLS-III is currently being planned as a Phase II double-blind, parallel group, randomized placebo-controlled trial ( Identifier NCT03221257), in which SSc-ILD patients will be randomized in a 1:1 assignment to receive either oral MMF and a placebo or a combination of oral MMF and oral pirfenidone, with both regimens administered for 18 months. The primary hypothesis is that the rapid onset and anti-fibrotic effects of pirfenidone, observed in the treatment of IPF, will complement the delayed anti-inflammatory and immunosuppressive effects of MMF, to produce a significantly more rapid and/or greater improvement in lung function.


Nintedanib is another antifibrotic agent that works by inhibiting multiple receptor and nonreceptor tyrosine kinases. It is also pleiotropic in its effects, has shown promise in IPF,[47] and has been approved by the FDA for this indication. A double-blind, randomized, placebo-controlled Phase 3 trial evaluating efficacy and safety of oral nintedanib versus placebo for 52 weeks in SSc-ILD in currently ongoing (SENSCIS).[48]


Endothelin-1 is known to induce fibroblast chemotaxis and proliferation, promote collagen deposition, and increase levels of fibronectin. Bosentan is a nonselective endothelin receptor antagonist, licensed for the treatment of PAH, including PAH associated with SSc, and has a favorable safety profile in patients with SSc. A multicenter placebo-controlled trial of bosentan (BUILD-2) for 12 months was negative in SSc-ILD and failed to demonstrate any effect on pulmonary physiology, patient functional status, or the frequency of clinically meaningful deterioration in pulmonary function. We do not recommend the use of bosentan for SSc-ILD unless there is another indication to use it such as recurrent digital ulcerations or PAH.

Therapies directed to transforming growth factor-β

TGF-β has been recognized as a central mediator of fibrosis in SSc [49] and an important therapeutic target. An open-label trial of fresolimumab, a monoclonal antibody against TGF-β, compared two doses of the drug in patients with early dcSSc (<2 years).[50] In both groups, there was a rapid decrease in mRSS and in TGF-β regulated biomarker genes, in particular thrombospondin-1, suggesting that targeting TGF-β may be an effective treatment strategy. There were a number of cases of GI bleeding and anemia in both groups, which will need further evaluation in the future, larger studies. SSc-ILD was not a focus of this study.

TGFβ also plays a homeostatic role in inflammation, immune regulation, and carcinogenesis, and thus a better strategy for TGFβ inhibition might be to specifically target tissue-restricted activators of TGFβ, such as the αvβ6 integrin. In patients with IPF and SSc-ILD with a UIP pattern, the αvβ6 integrin is highly upregulated on lung epithelium, implicating this pathway in TGFβ activation.[51] Abituzumab, a monoclonal antibody against αv integrin, is currently being evaluated in a Phase 2 trial for SSc-ILD ( Identifier: NCT02745145).

  Biologic Therapies Top

Abatacept and tocilizumab

Abatacept is a cytotoxic T-lymphocyte antigen-4 analog which blocks T-cell costimulation and is approved for use in rheumatoid arthritis (RA). Tocilizumab is an interleukin-6 receptor inhibitor, which is also approved for moderate-to-severe RA. While a large retrospective cohort study confirmed improvement in skin scores, inflammatory polyarthritis and myositis with both in SSc patients, no significant change in lung function was seen for either.[52] The faSScinate study ( Identifier NCT01532869) is a Phase II randomized controlled trial studying the safety and efficacy of tocilizumab in SSc. Recently published results from an open-label extension phase of the study showed skin score improvement and FVC stabilization in the double-blind period in placebo-treated patients who transitioned to tocilizumab and were maintained in the open-label period.[53] Safety data indicated increased serious infections in patients with SSc but no new safety signals with tocilizumab. Both abatacept ( identifier NCT02161406) and tocilizumab ( Identifier NCT02453256) are currently being evaluated in randomized controlled trials for the treatment of diffuse cutaneous SSc, and change in FVC is incorporated as a secondary outcome in these trials. If positive signals are noted, these could prompt further study in SSc-ILD. At this time, there is little evidence for the use of these agents in SSc-ILD.

  Autologous Hematopoietic Stem Cell Transplantation Top

In Phase I and II trials, autologous HSCT demonstrated impressive reversal of skin fibrosis, improved functionality and quality of life and stabilization of internal organ function, but initial studies were complicated by significant treatment-related mortality.[54] Treatment-related mortality was reduced by better pretransplant evaluation to exclude patients with compromised cardiac function and by treating patients earlier in disease, allowing selected patients the option of autologous HSCT treatment. The ASTIS trial enrolled 156 patients, and compared to patients receiving cyclophosphamide, there was a significant improvement in FVC of >9% predicted.[55] In the ASSIST trial in 19 patients, FVC had also improved, and the improvement was sustained over the 2-year follow-up.[56] Pulmonary data from the SCOT trial are still forthcoming, but as HSCT for SSc becomes more widely practiced, this may a viable option for a select group of patients with severe progressive SSc-ILD, but who are well enough to tolerate myeloablative therapy.

  Conclusions Top

Accumulating evidence from recent large clinical trials in SSc-ILD is helping make informed decisions in the treatment of these patients. However, ongoing studies may provide insights into the role of certain biologics, antifibrotics, and perhaps in a select group of patients autologous HSCT. Currently, based on the evidence available thus far, MMF is considered the first-line drug for the treatment for SSc-ILD, and cyclophosphamide reserved for progressive or refractory cases along with consideration of rituximab for rescue therapy [Figure 2]. Management of SSc and SSc-ILD is a rapidly changing field, and in the near future, more robust and promising options may be available, including the early use of combination therapy with immunosuppressants and antifibrotics, which could revolutionize the current prognosis in this complex disease.

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Conflicts of interest

There are no conflicts of interest.

  References Top

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This article has been cited by
1 Assessment of recent evidence for the management of patients with systemic sclerosis-associated interstitial lung disease: a systematic review
Anna-Maria Hoffmann-Vold,Toby M. Maher,Edward E. Philpot,Ali Ashrafzadeh,Oliver Distler
ERJ Open Research. 2021; 7(1): 00235-2020
[Pubmed] | [DOI]


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