Scleroderma-associated Interstitial Lung Disease Research Articles

Gene expression meta-analysis reveals aging and cellular senescence signatures in scleroderma-associated interstitial lung disease.

Aging and cellular senescence are increasingly recognized as key contributors to pulmonary fibrosis. However, our understanding in the context of scleroderma-associated interstitial lung disease (SSc-ILD) is limited. To investigate, we leveraged previously established lung aging- and cell-specific senescence signatures to determine their presence and potential relevance to SSc-ILD. We performed a gene expression meta-analysis of lung tissues from 38 SSc-ILD and 18 healthy controls and found that markers (GDF15, COMP, and CDKN2A) and pathways (p53) of senescence were significantly increased in SSc-ILD. When probing the established aging and cellular senescence signatures, we found that epithelial and fibroblast senescence signatures had a 3.6- and 3.7-fold enrichment, respectively, in the lung tissue of SSc-ILD and that lung aging genes (CDKN2A, FRZB, PDE1A, and NAPI12) were increased in SSc-ILD. These signatures were also enriched in SSc skin and associated with degree of skin involvement (limited vs. diffuse cutaneous). To further support these findings, we examined telomere length (TL), a surrogate for aging, in the lung tissue and found that, independent of age, SSc-ILD had significantly shorter telomeres than controls in type II alveolar cells in the lung. TL in SSc-ILD was comparable to idiopathic pulmonary fibrosis, a disease of known aberrant aging. Taken together, this study provides novel insight into the possible mechanistic effects of accelerated aging and aberrant cellular senescence in SSc-ILD pathogenesis.

Unveiling the complexities of lung transplantation in situs inversus

BackgroundLung transplantation for situs inverse is considered technically challenging because of the reverse positioning of the organs. By providing a detailed description of the surgical procedure, perioperative care, and post-transplant follow-up, we aim to contribute valuable information to the existing knowledge base. We presented two cases of successful bilateral sequential lung transplantation in situs inverse patients.Case presentationOur first patient was a 28-year-old, non-smoking woman with Kartagener syndrome and advanced bronchiectasis that developed into pneumonia and required repeated hospital admissions. She underwent double lung transplantation. During the lung transplant procedure, venoarterial extracorporeal membrane oxygenation (VA ECMO) support was provided. The recipient’s morphologically right (anatomically left) lung was explanted. The right main bronchus was anastomosed, followed by the pulmonary artery and left atrial anastomoses. Afterward, we proceeded with the left side. Similar to the right side, left pneumonectomy and implantation were performed using the same methods. The duration of VA ECMO support was 147 min with a 328-min ischemic time. Because of the significant size mismatch, nonanatomic lung volume reduction over the right middle and left upper lobes was necessary. The patient had no complications postoperatively and was discharged on post-operative day (POD) 12. Our second patient was a 51-year- old man with scleroderma-associated interstitial lung disease with situs inversus. Bilateral sequential lung transplantation was performed. Similar to case 1, a clamshell incision was made at the fourth intercostal space entry. The patient then received VA ECMO support identical to that in case 1. The total VA ECMO support time was 155 min with 295 min of ischemic time. The patient recovered uneventfully and was discharged on POD 13.ConclusionsLung transplantation for situs inverse can be a viable treatment option without modifying established transplantation procedures.

Targeting the NLRP3 inflammasome and associated cytokines in scleroderma associated interstitial lung disease.

SSc-ILD (scleroderma associated interstitial lung disease) is a complex rheumatic disease characterized in part by immune dysregulation leading to the progressive fibrotic replacement of normal lung architecture. Because improved treatment options are sorely needed, additional study of the fibroproliferative mechanisms mediating this disease has the potential to accelerate development of novel therapies. The contribution of innate immunity is an emerging area of investigation in SSc-ILD as recent work has demonstrated the mechanistic and clinical significance of the NLRP3 inflammasome and its associated cytokines of TNFα (tumor necrosis factor alpha), IL-1β (interleukin-1 beta), and IL-18 in this disease. In this review, we will highlight novel pathophysiologic insights afforded by these studies and the potential of leveraging this complex biology for clinical benefit.

Bilateral Lung Transplantation With Donor Positive for COVID-19 Infection on Bronchoalveolar Lavage: A Case Report

Initial experience with lung transplant of COVID-19-positive donors was marked by disappointing results, including a reported case of mortality through donor to recipient transmission of infection. However, since that time a number of improvements in preventative and therapeutic measures against COVID-19 have been developed. We present the case of a 51-year-old woman with scleroderma-associated interstitial lung disease who was awaiting lung transplant. A potential donor with excellent lung physiology was located; however, initial testing on bronchoalveolar lavage (BAL) was positive for COVID-19. The donor had tested positive 2 weeks prior and had symptomatically recovered. Our patient had been fully vaccinated but not seroconverted. Given the history of a donor with recovering COVID infection and a fully immunized recipient, our multidisciplinary team elected to proceed with the transplant. The patient successfully underwent bilateral lung transplant with standard induction immunosuppression. Bebtelovimab was given post-transplant day 1 because the recipient remained seronegative to COVID-19. Serial bronchoalveolar lavages post transplant have been negative for COVID-19. The patient has done well after transplant. She was seen in the clinic 2 months post transplant and is ambulatory without supplemental oxygen requirements. To our knowledge, this represents the first reported successful case of lung transplant with a donor positive for COVID-19 on lower respiratory tract sampling.

Mycophenolate in scleroderma-associated interstitial lung disease: Real-world data from rheumatology and pulmonology clinics in South Asia.

There is a paucity of real-world data on mycophenolate mofetil/mycophenolate sodium in systemic sclerosis-related interstitial lung disease. To study the efficacy of mycophenolate mofetil/ mycophenolate sodium in systemic sclerosis-related interstitial lung disease. In this single-centre study, clinical, laboratory and imaging details of consecutive patients with systemic sclerosis-related interstitial lung disease receiving mycophenolate mofetil/mycophenolate sodium from rheumatology and pulmonology clinics between January 2008 and March 2017 were retrospectively retrieved. The change in percentage of predicted normal forced vital capacity at last follow-up visit as compared with baseline was studied. In addition, high-resolution computed tomography scans at baseline and 2-year follow-up visit were scored as either stable/improved or worsened by experienced thoracic radiologists blinded to the clinical details of patients. Altogether, 88 patients (85.2% females) with mean age (SD) of 33.8 years (± 11.3) and median (interquartile range) duration of disease since non-Raynaud's symptoms of 36 months (13.5-60) were studied. Diffuse systemic sclerosis comprised 85.2% of them. The mean baseline forced vital capacity was 61.2 ± 17.9% and median scores for ground glass opacities and fibrosis in high-resolution computed tomography were 0.5 (0-1.3) and 1 (0-1.3), respectively. At a median follow-up duration of 30 months (interquartile range = 16.5-49), the percentage of forced vital capacity improved by 1.8% (-3.82 to 9.07) as compared with baseline visit (p = 0.02). In the 2-year follow-up, the ground glass opacity and fibrosis scores in high-resolution computed tomography improved in 17.3% and 7.7% of patients and stabilized in 63.5% and 78.8% patients, respectively. Mycophenolate mofetil/mycophenolate sodium was efficacious in improving /stabilizing forced vital capacity irrespective of the baseline high-resolution computed tomography lung scores in our patients with systemic sclerosis-related interstitial lung disease during the ⩾ 2-year follow-up period.

The rationale for targeting the JAK/STATpathway in scleroderma-associated interstitial lung disease.

The etiopathogenesis of systemic sclerosis (SSc)-associated interstitial lung disease (ILD) is still debated and no therapeutic options haveproved fully effective to date. The intracellular Janus kinase (JAK)/signal transducer and activator of transcription(STAT)pathway is highly conserved among either immune or nonimmune cells and involved in inflammation and fibrosis. Evidence from preclinical studies shows that the JAK/STATsignaling cascade has a crucial role in the differentiation of autoreactive cells as well as in theextracellular matrix remodeling that occurs in SSc. Therefore, it is likely that the use oforal small moleculeJAK-inhibitors, especially if prescribed early, may prevent or slow the progression of SSc-associated ILD, but few clinical studies currently support this hypothesis.

Collaboration between patient organisations and a clinical research sponsor in a rare disease condition: learnings from a community advisory board and best practice for future collaborations

Introduction Transparent collaborations between patient organisations (POs) and clinical research sponsors (CRS) can identify and address the unmet needs of patients and caregivers. These insights can improve clinical trial participant...

Scleroderma-associated interstitial lung disease – new therapeutic approach

Scleroderma is a systematic autoimmune disease characterized by endothelial dysfunction which causes small vessel disease, fibroblastic disorder with excessive production of collagen and fibrosis, as well as immunological disorders. Direct lung damage leading to interstitial lung disease is developed early after diagnosis. The result is a rapid decline in pulmonary function with worsening of quality of life and severe disability in these patients. The purpose of this review is to present all known medicaments for treatment of patients with scleroderma-associated interstitial lung disease – not only approved, but also those still being researched. Modern tendencies require the therapy to be guided by both rheumatologists and pulmonologists, as well as the participation of highly qualified radiologists. Correct clinical approach will enable the achievement of maximum results aimed at improving the quality of life and its duration in this group of patients.

Combined anti-fibrotic and anti-inflammatory properties of JAK-inhibitors on macrophages in vitro and in vivo: Perspectives for scleroderma-associated interstitial lung disease

Janus kinase (JAK) inhibitors (also termed Jakinibs) constitute a family of small drugs that target various isoforms of JAKs (JAK1, JAK2, JAK3 and/or tyrosine kinase 2 (Tyk2)). They exert anti-inflammatory properties linked, in part, to the modulation of the activation state of pro-inflammatory M1 macrophages. The exact impact of JAK inhibitors on a wider spectrum of activation states of macrophages is however still to be determined, especially in the context of disorders involving concomitant activation of pro-inflammatory M1 macrophages and profibrotic M2 macrophages. This is especially the case in autoimmune pulmonary fibrosis like scleroderma-associated interstitial lung disease (ILD), in which M1 and M2 macrophages play a key pathogenic role. In this study, we directly compared the anti-inflammatory and anti-fibrotic effects of three JAK inhibitors (ruxolitinib (JAK2/1 inhibitor); tofacitinib (JAK3/2 inhibitor) and itacitinib (JAK1 inhibitor)) on five different activation states of primary human monocyte-derived macrophages (MDM). These three JAK inhibitors exert anti-inflammatory properties towards macrophages, as demonstrated by the down-expression of key polarization markers (CD86, MHCII, TLR4) and the limited secretion of key pro-inflammatory cytokines (CXCL10, IL-6 and TNFα) in M1 macrophages activated by IFNγ and LPS or by IFNγ alone. We also highlighted that these JAK inhibitors can limit M2a activation of macrophages induced by IL-4 and IL-13, as notably demonstrated by the down-regulation of the M2a associated surface marker CD206 and of the secretion of CCL18. Moreover, these JAK inhibitors reduced the expression of markers such as CXCL13, MARCO and SOCS3 in alternatively activated macrophages induced by IL-10 and dexamethasone (M2c + dex) or IL-10 alone (M2c MDM). For all polarization states, Jakinibs with inhibitory properties over JAK2 had the highest effects, at both 1 μM or 0.1 μM. Based on these in vitro results, we also explored the effects of JAK2/1 inhibition by ruxolitinib in vivo, on mouse macrophages in a model of HOCl-induced ILD, that mimics scleroderma-associated ILD. In this model, we showed that ruxolitinib significantly prevented the upregulation of pro-inflammatory M1 markers (TNFα, CXCL10, NOS2) and pro-fibrotic M2 markers (Arg1 and Chi3L3). These results were associated with an improvement of skin and pulmonary involvement. Overall, our results suggest that the combined anti-inflammatory and anti-fibrotic properties of JAK2/1 inhibitors could be relevant to target lung macrophages in autoimmune and inflammatory pulmonary disorders that have no efficient disease modifying drugs to date.

Mitochondrial DNA-Laden Extracellular Vesicles are Associated with Toll-Like Receptor 9 Activation and Disease Progression in Scleroderma Associated Interstitial Lung Disease

Background: The pathogenesis of scleroderma associated interstitial lung disease (SSc-ILD) involves the uncontrolled differentiation of normal human lung fibroblasts (NHLFs) to alpha-smooth muscle actin (αSMA) expressing myofibroblasts mediated by transforming growth factor-β1 (TGF-β1). SSc-ILD has a highly variable clinical trajectory as some patients experience rapid deterioration in their ventilatory function while others remain stable. The association between the toll-like receptor 9 (TLR9) ligand mitochondrial DNA (mtDNA) and fibroblast activation and clinical outcomes in SSc-ILD has yet to be explored. Methods: NHLFs grown in the absence and presence of TGFβ1, CpG DNA, and chloroquine were assayed for αSMA expression and extracellular mtDNA release using qPCR for the human MT-ATP6 gene. This approach was then used to detect plasma mtDNA concentrations in two SSc-ILD cohorts, Boston and Yale, and demographically matched controls. TLR9 activation was quantified using commercially available human TLR9-expressing HEK 293 cells. Isolation of extracellular vesicles (EVs) were performed in the plasma from controls and Yale SSc-ILD subjects, and EVs were analyzed for mtDNA content and proteomics via mass spectrometry. Findings: TLR9 activity modulates αSMA expression and extracellular mtDNA release. Plasma mtDNA concentrations are increased in two independent SSc-ILD cohorts and activates TLR9. Longitudinal analysis reveals that plasma mtDNA predicts ventilatory decline and is cargoed by EVs. Proteomic analysis reveals a multicellular origin of EVs that involves cellular pathways that could act as mediators of the SSc-ILD state. Interpretation: These findings demonstrate an unrecognized connection with TLR9 activation mediated by extravesicular mtDNA and myofibroblast differentiation and clinical outcomes in SSc-ILD. Further study into the interactions between TLR9 and mtDNA could lead to novel mechanistic and therapeutic insights in this difficult to manage disease. Funding Statement: Parker B. Francis Foundation, Foundation for Sarcoidosis Research, Scleroderma Foundation, American Thoracic Society, National Institutes of Health, Gabriel and Alma Elias Research Fund, and Greenfield Foundation. Declaration of Interests: The authors have no relevant conflicts of interest to disclose. Ethical Approval Statement: All human studies were performed with informed consent on protocols approved by the Institutional Review Board at each institution.

Longitudinal assessment of interstitial lung disease in single lung transplant recipients with scleroderma.

To investigate the natural history of fibrotic lung disease in recipients of a single lung transplant for scleroderma-associated interstitial lung disease (ILD). Global ILD (including ground glass, nodular opacities and fibrosis) was categorized into severity quintiles on first and last post-transplant CT scans, and percent fibrosis by manual contouring was also determined, in nine single lung transplant recipients. Quantitative mean lung densities and volumes for the native and allograft lungs were also acquired. In the native lung, global ILD severity quintile worsened in two cases and percent fibrosis worsened in four cases (range 5-28%). In the lung allograft, one case each developed mild, moderate and severe ILD; of these, new fibrotic ILD (involving <10% of lung) occurred in two cases and acute cellular rejection occurred in one. The average change in native lung density over time was +2.2 Hounsfield Units per year and lung volume +1.4 ml per year, whereas the allograft lung density changed by -5.5 Hounsfield Units per year and total volume +27 ml per year (P = 0.011 and P = 0.039 for native vs allograft density and volume comparisons, respectively). While the course of ILD in the native and transplanted lungs varied in this series, these cases illustrate that disease progression is common in the native lung, suggesting that either the immune process continues to target autoantigens or ongoing fibrotic pathways are active in the native lung. Mild lung disease may occur in the allograft after several years due to either allograft rejection or recurrent mild ILD.

Chitinase 1 regulates pulmonary fibrosis by modulating TGF-β/SMAD7 pathway via TGFBRAP1 and FOXO3.

TGF-β1 is a critical mediator of tissue fibrosis in health and disease whose effects are augmented by chitinase 1 (CHIT1). However, the mechanisms that CHIT1 uses to regulate TGF-β1-mediated fibrotic responses have not been defined. Here, we demonstrate that CHIT1 enhances TGF-β1-stimulated fibrotic cellular and tissue responses and TGF-β1 signaling. Importantly, we also demonstrate that these effects are mediated by the ability of CHIT1 to inhibit TGF-β1 induction of its feedback inhibitor, SMAD7. CHIT1 also interacted with TGF-β receptor associated protein 1 (TGFBRAP1) and forkhead box O3 (FOXO3) with TGFBRAP1 playing a critical role in CHIT1 enhancement of TGF-β1 signaling and effector responses and FOXO3 playing a critical role in TGF-β1 induction of SMAD7. These pathways were disease relevant because the levels of CHIT1 were increased and inversely correlated with SMAD7 in tissues from patients with idiopathic pulmonary fibrosis or scleroderma-associated interstitial lung disease. These studies demonstrate that CHIT1 regulates TGF-β1/SMAD7 axis via TGFBRAP1 and FOXO3 and highlight the importance of these pathways in the pathogenesis of pulmonary fibrosis.

Emphysematous change with scleroderma-associated interstitial lung disease: the potential contribution of vasculopathy?

BackgroundPulmonary emphysema combined with systemic sclerosis (SSc)-associated interstitial lung disease (ILD) occurs more often in smokers but also in never-smokers. This study aimed to describe a new finding characterized by peculiar emphysematous change with SSc-associated ILD (SSc-ILD).MethodsWe conducted a retrospective review of 21 consecutive patients with SSc-ILD diagnosed by surgical lung biopsy and focused on the radio-pathological correlation of the emphysematous change.ResultsPathological pulmonary emphysema (p-PE) with SSc-ILD was the predominant complication in 16 patients (76.2%) with/without a smoking history, of whom 62.5% were never-smokers. A low attenuation area (LAA) within interstitial abnormality on high-resolution computed tomography (HRCT) was present in 31.3%. Diffusing capacity of the lung for carbon monoxide (DLCO) was lower, disease extent on HRCT higher, and intimal/medial thickening in muscular pulmonary arteries more common in the patients with p-PE with SSc-ILD. However, forced vital capacity (FVC) was well preserved regardless of whether p-PE was observed. Most SSc-ILD patients had pulmonary microvasculature changes in arterioles (90.5%), venules (85.7%), and interlobular veins (81.0%).ConclusionsPulmonary emphysematous changes (LAA within interstitial abnormalities on HRCT and destruction of fibrously thickened alveolar walls) are specific and novel radio-pathological features of SSc-ILD. Peripheral vasculopathy may help to destroy the fibrously thickened alveolar walls, resulting in emphysematous change in SSc-ILD.

Semi-quantification image methods for assessing severity of scleroderma-associated interstitial lung disease according to computed tomography data

The aim of this study was to compare three semi-quantification scales for prospective assessment of scleroderma-associated interstitial lung disease (SS-ILD) severity. Methods. From 110 prospectively followed patients with SS-ILD, we selected 12 patients (mean age, 42 ± 13 years, 11 females) with obvious improvement (n = 6) or worsening (n = 6) of lung lesions on high resolution computed tomography (HRCT) during a year. The patients had diffuse (n = 7) or limited (n = 7) SS with mean length of the disease of 8.5 ± 6.7 years (range, 1 to 23 years). HRCT was done at baseline (inclusion in the study) and in a year. CT scans were quantitatively assessed by four radiologists including one experienced radiologist. A blinded analysis of HRCT scans was done using three scales: J.H.Warrick et al. (1991), A.U.Wells et al. (1997), and E.A.Kazerooni et al. (1997). The intraclass correlation coefficient (ICC) was calculated to evaluate the assessment reliability. T-test for independent samples was used to evaluate reproducibility of the assessments. Agreement between independent experts' opinions was evaluated using Kendall's rank correlation coefficient. Results. The measurements were significantly divergent between the radiologists, both for the baseline and the follow-up HRCT scans. ICCs for investigated radiological parameters were 0.56 to 0.76. The highest ICC (0.76) was obtained for A.U.Wells' scale. All scales used to assess HRCT scans had lower interoperator reproducibility. Conclusion. Combined use of currently available semi-quantification methods for follow-up assessment of HRCT in SS-ILD patients allowed thorough qualitative evaluation of lung lesions, but the reliability of the radiological parameters in detecting 1-year fibrosis progression in SS patients was low. The risk of significant interoperator bias limited the use of the radiological parameters in clinical trials of SS-ILD patients.

Scleroderma overlap syndromes

Scleroderma overlap syndromes

A New Era in the Treatment of Scleroderma-associated Interstitial Lung Disease?

Pulmonary involvement in systemic sclerosis or scleroderma (SSc) is mainly represented by SSc-associated interstitial lung disease (SSc-ILD) and pulmonary hypertension1,2. SSc-ILD is a major challenge: It is both a very frequent and a very severe complication of SSc. According to the literature, SSc-ILD is or will be present in around one-half of patients with diffuse SSc, and one-third of patients with limited cutaneous SSc3. SSc-ILD is now one of the leading causes of death in SSc4. This explains why much effort has been expended to understand and better know the characteristics of patients with SSc-ILD as well as to manage them properly. However, despite decades of observational studies and a few randomized ones, the optimal management of patients with SSc-ILD is still a matter of debate. From an historic point of view, the cornerstone of SSc-ILD treatment has mainly been immunosuppressants. This can be explained by the fact that SSc is a connective tissue disease in which inflammation and immune abnormalities play a central role5. The immune system, especially in regards to B and T lymphocytes, is fully involved in fibroblast activation and fibrogenesis by secreting proinflammatory and profibrotic cytokines and growth factors6. The most common immunosuppressant, cyclophosphamide (CYC), has been tested in many open-label studies and a few randomized control trials (RCT), as well as being recommended in the European League Against Rheumatism Scleroderma Trials and Research group guidelines7. However, the results of those RCT are still dividing the medical community. In the FAST study, there was no significant … Address correspondence to Prof. D. Launay, Service de Medecine Interne, Hopital Claude-Huriez, CHRU Lille, rue Michel Polonovski, F-59037 LILLE Cedex, France. E-mail: david.launay{at}univ-lille2.fr

Management of Systemic-Sclerosis-Associated Interstitial Lung Disease.

Although scleroderma-associated interstitial lung disease (SSc-ILD) is a significant contributor to both morbidity and mortality, its pathogenesis is largely unclear. Pulmonary function tests and high-resolution computed tomographic scanning continue to be the most effective tools to screen for lung involvement and to monitor for disease progression. More research and better biomarkers are needed to identify patients most at risk for developing SSc-ILD as well as to recognize which of these patients will progress to more severe disease. Although immunosuppression remains the mainstay of treatment, antifibrotic agents may offer new avenues of treatment for patients with SSc-ILD in the future.

ANCA-associated renal vasculitis and acute exacerbation of scleroderma-associated interstitial lung disease: A case report

In this report, we describe a patient with the unusual concomitant presentation of an acute exacerbation of systemic sclerosis-associated interstitial lung disease with the development of anti-neutrophil cytoplasmic antibody-associated active renal vasculitis. Systemic sclerosis is a connective tissue disease characterized by systemic autoimmunity and organ fibrosis and vasculopathy. Interstitial lung disease is identified in the majority of patients with systemic sclerosis and may have varying degrees of severity. Patients with systemic sclerosis-associated interstitial lung disease rarely develop acute exacerbations of interstitial lung disease. An overlap of systemic vasculitis has been reported to occur in patients with systemic sclerosis – yet this too is a rare occurrence. This case is unique in that it demonstrates the concomitant presentation of these rare clinical scenarios and serves to highlight the importance of a comprehensive and multidiscciplinary approach to the evaluation of patients in general, and systemic autoimmune patients in particular.

Update on scleroderma-associated interstitial lung disease.

Systemic sclerosis (SSc), or scleroderma, is a heterogeneous and complex autoimmune disease characterized by varying degrees of skin and organ fibrosis and obliterative vasculopathy. The disease results in significant morbidity and mortality, and to date, available treatments are limited. Lung involvement is the leading cause of death of patients with SSc. Over the past year, significant advances have been made in our understanding of SSc-associated lung disease, and this review attempts to encapsulate these most recent findings and place them in context. We divide our discussion of the most recent literature into the following: first, clinical aspects of SSc lung management, including classification, imaging, biomarkers, and treatment; second, promising new animal models that may improve our ability to accurately study this disease; and third, studies that advance or change our understanding of SSc lung disease pathogenesis, thereby raising the potential for new targets for therapeutic intervention. Recent advances have resulted in a better understanding of SSc-associated lung disease, the development of new in-vivo models for exploring disease pathogenesis, and the identification of potential novel targets for the development of therapies.

Predictors of Mortality and Progression in Scleroderma-Associated Interstitial Lung Disease: A Systematic Review

BACKGROUND Interstitial lung disease (ILD) is the leading cause of morbidity and mortality in patients with systemic sclerosis (SSc); however, prognostication of SSc-associated ILD (SSc-ILD) remains challenging. We conducted a systematic review to identify variables that predict mortality and ILD progression in SSc-ILD. METHODS Three databases were searched to identify all studies relating to predictors of mortality or ILD progression in SSc-ILD. Studies were eligible if they were published in English and included ≥ 10 adults with SSc-ILD. Two authors independently reviewed and extracted data from acceptable studies. RESULTS The initial search identified 3,145 unique citations. Twenty-seven studies, including six abstracts, met the inclusion criteria. A total of 1,616 patients with SSc-ILD were included. Patient-specific, ILD-specific, and SSc-specific variables predicted mortality and progression; however, most predictors were identified in only one study. Most studies did not fully account for potential confounders, and none of the studies included a validation cohort. Older age, lower FVC, and lower diffusing capacity of carbon monoxide predicted mortality in more than one study. Male sex, extent of disease on high-resolution CT (HRCT) scan, presence of honeycombing, elevated KL-6 values, and increased alveolar epithelial permeability were identified as predictors of both mortality and ILD progression on unadjusted analysis. The extent of disease on HRCT scan was the only variable that independently predicted both mortality and ILD progression. CONCLUSIONS Mortality and ILD progression were predicted by several patient-specific, ILD-specific, and SSc-specific factors. Additional prospective studies are required to validate these preliminary findings and to identify combinations of variables that accurately predict the prognosis of SSc-ILD. Interstitial lung disease (ILD) is the leading cause of morbidity and mortality in patients with systemic sclerosis (SSc); however, prognostication of SSc-associated ILD (SSc-ILD) remains challenging. We conducted a systematic review to identify variables that predict mortality and ILD progression in SSc-ILD. Three databases were searched to identify all studies relating to predictors of mortality or ILD progression in SSc-ILD. Studies were eligible if they were published in English and included ≥ 10 adults with SSc-ILD. Two authors independently reviewed and extracted data from acceptable studies. The initial search identified 3,145 unique citations. Twenty-seven studies, including six abstracts, met the inclusion criteria. A total of 1,616 patients with SSc-ILD were included. Patient-specific, ILD-specific, and SSc-specific variables predicted mortality and progression; however, most predictors were identified in only one study. Most studies did not fully account for potential confounders, and none of the studies included a validation cohort. Older age, lower FVC, and lower diffusing capacity of carbon monoxide predicted mortality in more than one study. Male sex, extent of disease on high-resolution CT (HRCT) scan, presence of honeycombing, elevated KL-6 values, and increased alveolar epithelial permeability were identified as predictors of both mortality and ILD progression on unadjusted analysis. The extent of disease on HRCT scan was the only variable that independently predicted both mortality and ILD progression. Mortality and ILD progression were predicted by several patient-specific, ILD-specific, and SSc-specific factors. Additional prospective studies are required to validate these preliminary findings and to identify combinations of variables that accurately predict the prognosis of SSc-ILD.