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Article

Identifying Patients with Systemic Sclerosis and Progressive Pulmonary Fibrosis in a Real-World Setting: Data from UK Tertiary Rheumatology and ILD Centres

by
Rosalind Benson
1,*,
Mahin Ahmad
2,
Lisa G. Spencer
3,
Freddy Frost
4,
Madhu Paravasthu
5 and
Theresa Barnes
6
1
Rheumatology, NHS University Hospitals of Liverpool Group, Liverpool L9 7AL, UK
2
Respiratory, Manchester University NHS Foundation Trust, Manchester M13 9WL, UK
3
Respiratory, NHS University Hospitals of Liverpool Group, Liverpool L9 7AL, UK
4
Liverpool Heart and Chest Hospital NHS Foundation Trust, Liverpool L14 3PE, UK
5
Radiology, NHS University Hospitals of Liverpool Group, Liverpool L9 7AL, UK
6
Rheumatology, Countess of Chester Hospital NHS Foundation Trust, Chester CH2 1UL, UK
*
Author to whom correspondence should be addressed.
Sclerosis 2025, 3(3), 25; https://doi.org/10.3390/sclerosis3030025
Submission received: 12 May 2025 / Revised: 27 June 2025 / Accepted: 27 June 2025 / Published: 1 July 2025
(This article belongs to the Special Issue Clinical Advances and New Insights in Systemic Sclerosis)
Browse Figure
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Abstract

Objectives: Systemic sclerosis-related interstitial lung disease (SSc-ILD) has high associated morbidity and mortality. With early diagnosis and treatment, we can improve clinical outcomes with immunosuppression. Some patients develop progressive pulmonary fibrosis (PPF) and are eligible for anti-fibrotic therapy. There are limited data on the incidence and prevalence of PPF in the SSc ILD cohort to guide case finding. We investigated this using data from UK tertiary Rheumatology and ILD centres. Methods: Patients with systemic sclerosis across two UK rheumatology units were identified using electronic records searched from 2021 to 2023 and were compared against established PPF diagnostic criteria. Results: 255 patients were identified. Prevalence of PPF was 5.49% and in those with established SSc-ILD, 23%. Median time to development of PPF was 5 years. In 64% of patients with PPF diagnosis, they had had systemic sclerosis for over 10 years. Incidence of PPF in patients with SSc was 3.9% and in those with known SSc-ILD 16.%. Only 50% of patients who met criteria for PPF had been referred to respiratory for consideration of antifibrotic initiation. Patients with a predominantly fibrotic baseline radiological pattern (UIP) had a trend towards development of PPF (p = 0.07). No patient with a predominantly inflammatory baseline pattern developed PPF (p = 0.021). Conclusions: Real world data have shown a prevalence of PPF in the SSc-ILD cohort of 23% with a median time of 5 years to development from diagnosis of SSc. Our data show active case finding may be incomplete and rheumatologists must be cognisant of PPF when evaluating patients with SSc.

1. Introduction

Systemic sclerosis (SSc) is a rare multisystem autoimmune disease resulting in both vasculopathy and progressive fibrosis of skin and internal organs. SSc-related interstitial lung disease (SSc-ILD) not only causes significant morbidity but is the highest cause of mortality in patients with SSc [1]. In patients with SSc, the prevalence of SSc-ILD is estimated to be between 18 and 52% [2,3,4]. Inclusion of both clinically significant disease and radiological presence of ILD in epidemiological analyses contributes to this variance.
Patients with SSc-ILD are a heterogenous group. Some patients have indolent diseases whilst others progress [5]. Disease progression is assessed by symptoms, pulmonary function tests and radiological progression. It is established that more extensive disease on baseline imaging is associated with disease progression and increased mortality [6,7]. Immunosuppression can improve the disease trajectory [7].
Current funded treatment options in the UK for SSc-ILD include mycophenolate, cyclophosphamide [8], less commonly azathioprine [9] and tacrolimus [10]. In other countries, rituximab and tocilizumab are available [7,11]. Immunosuppressive therapy (IS) can stabilise or slow down ILD disease progression even temporarily, improving lung volumes by modifying the inflammatory component of SSc-ILD disease [7,12]. Despite appropriate use of IS, some patients can then go on to develop an overtly progressive fibrotic pattern of ILD on imaging. This is associated with increased symptoms (shortness of breath on exertion and cough), progressive fibrotic change on radiology and falling pulmonary function tests. This progressive fibrotic disease behaviour (despite use of IS) is termed progressive fibrosing ILD (PF-ILD) [13] or progressive pulmonary fibrosis (PPF) [14].
Prior to 2019, there was no evidence-based therapy to try and treat this fibrotic phase of SSc-ILD disease progression until the publication of the INBUILD and SENSCIS studies [13,15]. These landmark trials demonstrated that an anti-fibrotic drug, Nintedanib (a tyrosine kinase inhibitor), can slow the rate of FVC decline in patients with PPF. This drug is now licensed for use in PPF in many countries. In the UK in 2021, the National Institute for Clinical Excellence (NICE) approved and funded within the NHS the use of Nintedanib in patients with PPF based on the INBUILD criteria [13]. It should be noted that the definition of PPF is slightly different in countries. Some adopted the INBUILD study criteria; others the later published criteria in the ATS/ERS PPF guideline [13,14].
What is less clear is what percentage of those with SSc-ILD go on to develop PPF (defined using the INBUILD criteria) in a real-world UK clinical setting and whether there are any predisposing clinical characteristics. Previous estimates have used varying definitions of PPF or only captured patients already referred to respiratory physicians [16,17]. Establishing disease incidence and prevalence in all patients with SSc who meet PPF criteria is important to ensure all eligible for the drug are identified and facilitates calculation of healthcare costs.
Aim:
To calculate the incidence and prevalence of PPF in a cohort of SSc patients across two specialist systemic sclerosis units in the northwest of England. We also sought to identify clinical characteristics that may be associated with the development of PPF in SSc-ILD to aid case identification and service planning.

2. Materials and Methods

Study design: We conducted a retrospective observational cohort study across two NHS England commissioned specialist SSc centres in the Northwest of England (Liverpool University Hospitals NHS Foundation Trust and Countess of Chester Hospital NHS Foundation Trust) which are part of an established network with the tertiary ILD service at Liverpool University Hospitals NHS Foundation Trust.
Study population: A comprehensive search of outpatient clinical electronic records was undertaken using key diagnostic terms ‘systemic sclerosis’ and ‘scleroderma’ covering a 2-year period—1 January 2021 to 1 January 2023. Only patients who met the ACR/EULAR classification criteria of diagnosis of SSc were included. All patients were over 18 years. Patients were excluded who did not meet the diagnostic criteria for SSc or who were lost to follow up.

2.1. Data Collection

The following data were collected:
Demographical data-age, sex and smoking status.
Clinical data- SSc disease duration. In patients whose disease onset was not clearly recorded AND pre-dated implementation of electronic clinical records 10 years ago, it was reported as >10 years duration.
Presence of other clinical features including interstitial lung disease (including duration), myositis and inflammatory arthritis. Current and historical IS and treatment with nintedanib (antifibrotic medication) was captured.

2.2. Investigations

Pulmonary Function tests: All PFTs were performed in respiratory laboratories within secondary care hospital sites and to the standards as stipulated by international guidelines [18]. FEV1, FVC, TLco (actual values and % predicted) and FEV1/FVC ratio were collected from 2019 onwards to review physiology and trend over at least 2 years.
Laboratory results: Autoantibody status related to connective tissue disease. C-reactive protein (CRP) in the preceding 24 months corresponding to the collection of respiratory physiology data.
History of raised creatinine kinase (CK) subsequent to diagnosis of SSc was collected aiming to identify all patients with a potential history of muscle inflammation. If present, further investigations for myositis were recorded including muscle biopsy and muscle MRI results to establish significance of hyperCKaemia.
Radiology: All available CT chest imaging was reviewed by specialist ILD respiratory clinicians. Those patients with a possible diagnosis of ILD had their CT images reviewed by a thoracic ILD radiologist. Baseline and subsequent CT scans were reviewed, and comments were made on pattern classification on their baseline and latest CT scan, percentage of lung involved and progression. These assessments were made by thoracic radiologists and fibrosis was quantified visually.

2.3. Definition of PPF Used

We defined PPF using the INBUILD trial criteria, which are the criteria used by NICE in the UK to make funded prescribing decisions for use of nintedanib.
All patients had to have >10% of the total lung volume affected by a fibrotic ILD process on CT chest imaging as determined by a thoracic ILD radiologist, plus at least one of the following markers of ILD disease progression that had occurred over the last 2 years:
  • >10% absolute decline in FVC or
  • >5–<10% absolute decline in FVC plus fibrotic disease progression evident on radiology or
  • Progression on radiology plus progression in symptoms
We did not use decline in TLco as it is not part of the NICE drug eligibility criteria in the UK.
Clinical records were reviewed to assess for documented progression in symptoms including shortness of breath or reduced exercise tolerance not attributable to another cause.

2.4. Statistical Analysis

Descriptive analysis was performed to summarise patient characteristics. Characteristics were compared at the baseline, which was the point of study entry. Univariate comparisons were performed using a Chi or t-test for binary and continuous data, respectively. Multivariable logistical regression models were developed to investigate the relationship between clinical characteristics and different disease groups. Model variable selection took the results of univariable analysis and biologic plausibility into account. Survival comparisons between group were performed and presented in Kaplan–Meier plots. No imputations for missing data were performed. All statistical analyses were conducted in R v4.2.2 [19].

3. Results

3.1. Patient Demographics

A total of 283 patients with SSc were identified from the initial search. On review, 28 did not meet the ACR/EULAR criteria for SSc or had been lost to follow-up and were subsequently removed from analysis. Analysis was conducted on the remaining 255 (see Table 1).

3.2. Baseline Patient Characteristics of Whole Systemic Sclerosis Cohort

Mean age was 61.8 years (SD ± 14.2). Predominantly female 224 (87.8%). Current smokers, 30 (11.7%), 79 (31%) ex-smokers and 124 (48.6%) never smokers.
In 6/255 (10%), no antibodies associated with SSc were identified and antibody status was unknown in 11/255 (4%); however, in both these groups, they still fulfilled classification criteria for SSc.

3.3. Identification and Treatment of SSc-ILD with Immunosuppressive Treatment

Identification of SSc-ILD based on CT findings was seen in 61/255 (23.9%) of the whole SSc cohort. Just over half, 34/61 (56%), had ILD present at the time of diagnosis of their systemic sclerosis and 27/61 (44%) developed ILD subsequently (see Figure 1).
Discussion in the tertiary ILD multidisciplinary team (MDT) meeting had taken place for 35/61 (57%) patients and 28/61 (46%) had been seen in a specialist ILD clinic.
In 17/61 (28%) of patients, no formal respiratory input despite radiological evidence of ILD had occurred but they were undergoing regular monitoring by the rheumatology team with 13/17 (76%) of these patients on IS for another disease manifestation already.
IS had been started specifically for SSc-ILD in 28/255 (11%). In total, 97/255 (38%) of patients were on IS for a clinical manifestation of their SSc during the study period (mycophenolate (38%) and methotrexate (12%)).
Of those with SSc-ILD, 33/61 (54%) were on mycophenolate, 6/61 (10%) methotrexate, 15/61 (25%) had been treated with cyclophosphamide at some point and 4/61 (7%), rituximab.

3.4. Identification and Treatment of PPF Cases

PPF was identified in 14/255 patients. This equates to a PPF prevalence of 23% of those with known SSc-ILD (14/61) and 5.49% of all those with SSc. 12/14 (86%) were on immunosuppression at the time of the PPF diagnosis.
Criteria for diagnosis of PPF had been met within the preceding 12 months for 10/14 (71%) patients.
Of those patients diagnosed with PPF, 9/14 (64%) had had a diagnosis of SSc for more than 10 years.
Of the patients we identified as meeting the criteria for PPF, seven (50%) had been referred to the tertiary ILD specifically for consideration of antifibrotics, with two patients starting the drug, although over their disease course, 11/14 (79%) had received respiratory input.

3.5. Clinical Characteristics of the Whole SSc Cohort Versus SSc-ILD Cohort

There was no significant difference in mean age or sex between those who had evidence of SSc-ILD compared to those without. Those with anti-topoisomerase antibody (p < 0.001) and anti-PMScl100 (p < 0.019) were more likely to have ILD (see Table 2). Whereas anti-centromere antibody was more commonly found in those without evidence of ILD (p < 0.001).
Those who were current or ex-smokers were less likely to have SSc-ILD (p value 0.005) than never smokers.

3.6. Clinical Characteristics of the SSc-ILD Cohort Versus PPF-ILD Cohort

There were no significant differences in characteristics including demographics, biochemical and immunological markers or physiology between those with SSc-ILD and those who developed PPF (see Table 3). Although there was a trend towards an increase in PPF in patients with inflammatory arthritis.

3.7. Myositis

Inflammatory myositis was seen in 12/255 (4.7%). A total of 40/255 (30.1% of patients) had a raised CK (>200) recorded since diagnosis with SSc. Of those with no raised CK but diagnosis of myositis, two out of three were amyopathic with clinical features of dermatomyositis. Two had longstanding diagnoses of myositis and had been on IS pre-dating the accessible clinical records and blood results.
Multivariate logistic regression analysis showed patients with a diagnosis of myositis had increased risk of SSc-ILD (adjusted OR 1.8 and p value 0.048); however, raised CK was not an independent predictor for ILD (adjusted OR 1.0, 95%CI 0.67–1.43) or CRP (adjusted OR 1.0 95%CI 0.99–1.01).
Exploration of myositis as a risk for PPF was limited due to small numbers.

3.8. Inflammatory Arthritis

Inflammatory arthritis was present in 42/255 (16%), of whom 9/255 (3.5%) had a recorded diagnosis of rheumatoid arthritis (three of these patients were anti-CCP positive). A total of 35/42 (83%) of patients with inflammatory arthritis were on IS. CRP was taken as a surrogate marker for disease activity in this group. Over the study period, mean CRP in this group was 17 mg/L compared with 23 mg/L overall. No patient with inflammatory arthritis and ILD developed PPF.

3.9. Radiological Patterns of ILD

A total of 182 patients (71%) had at least one CT chest performed. Fibrotic pattern ILD (40/61 (65.5%)) was more prevalent with the most common pattern being fibrotic nonspecific interstitial pneumonia (FNSIP) (21/61 34%) (see Table 4).
A total of 14 patients showed evidence of progression from one radiological pattern to another, of whom seven progressed from an inflammatory pattern to a fibrotic pattern. One showed resolution from cellular NSIP (they had received mycophenolate).
Those with a usual interstitial pneumonia (UIP) pattern were older (71 years versus 59 years p = 0.018), had a lower average FVC (0.97 L vs. 2.26 L p = 0.011) and a higher mortality (30% vs. 2% p = 0.01) over the study period.
All patients who went on to develop PPF had predominantly fibrotic disease on their baseline CT scan (see Table 5). Of note, no patient who had cellular NSIP went on to develop PPF (p = 0.021).

4. Discussion

Our study found that by combining data from two large rheumatology clinics over a 2-year period, the prevalence of PPF was 5.49% in our total systemic sclerosis cohort. In patients with known SSc-ILD, 23% met criteria for PPF and subsequently were eligible to be considered for antifibrotic treatment. The incidence of PPF over the preceding 12 months in patients with systemic sclerosis was 3.9% and in those with known SSc-ILD, 16.4%.
We focused this study on those who would be eligible for treatment using criteria used by NICE to make a PPF diagnosis. Only half of our eligible cohort had been referred to an ILD centre to access antifibrotic treatment at the point PPF criteria had been met. This suggests that active case finding of PPF could potentially be improved. Wider education about PPF and new access to treatments may assist with this.
Our calculated prevalence sits within results from other studies which have reported a PPF prevalence between 2.8 and 26.1% [20]. A wide variation in prevalence has been reported in part because studies have used differing PPF diagnostic criteria [13,14]. Lee et al. used three different PPF criteria to assess a mixed CTD-ILD cohort; this included SSc patients. This resulted in an 18% difference (20–38%) in prevalence of PPF in the same cohort [21].
Patients with a diagnosis of SSc will primarily be under the care of a rheumatologist. Rheumatologists are experienced with monitoring ILD as a complication of many of the autoimmune diseases that they manage [22]. Only 71% of patients with SSc-ILD had received a formal respiratory review. Notably, of those without respiratory input, 12/17 (71%) had lung involvement of <10%. This suggests rheumatologists are comfortable in monitoring early SSc-ILD alone. Consequently, real-world analyses dependent upon patient identification following referral to an ILD service may not capture all patients with SSc-ILD and consequently we may not see a true picture of the burden of PPF in patients with SSc-ILD [17].
Although prevalence has been widely reported, there are few data on incidence rates and no studies utilising the INBUILD criterion for PPF. Our results demonstrate an incidence rate of PPF development in SSc-ILD of 16%.
Morrisroe et al. described incident PPF (presence of PPF in SSc-ILD within the first 12 months of diagnosis) and reported this as 38.8% in an Australian cohort study [23]. We noted incident PPF as 14% (2/14 patients). This variation in figures is in part accounted for by the different definitions of PPF used.
There is a varying natural history to SSc-ILD. Volkman describes the phenotypes as progressors (rapid and gradual) and non-progressors (stabilisers and improvers) [5]. This was reflected in our cohort; some had minimal change in pulmonary physiology despite no IS. Whereas others (5/11) on IS had a declining FVC of 10–30% over the same 24-month period. Of note, whether a ‘non progressor’ or ‘progressor’, PPF patterns were identified over time in both phenotypes.
Mean time to development of PPF was 5 years (median 0–>10 years) from SSc diagnosis. This demonstrates that ongoing surveillance both of symptomatology but also pulmonary function and radiology are required to identify whether PPF has developed regardless of phenotype.
We have increasing understanding of poor prognostic factors relating to development of progressive ILD (including the presence of anti-topoisomerase antibody, African American race, male sex and shorter disease duration) [4,23]. However, as yet, which characteristics predispose to an increased risk of PPF is less understood. Increased risk of developing PPF in CTD-ILD has been noted in those with a fibrotic HRCT pattern at the baseline, steroid treatment and diabetes mellitus and higher CRP at the baseline [24,25].
In common with Chiu et al., our findings support the association of a predominantly fibrotic pattern (UIP) with a trend towards development of PPF (p = 0.07). No patient with the predominantly inflammatory pattern of cellular NSIP developed PPF (p = 0.021). This suggests that those with a radiological pattern more sensitive to IS may be less likely to develop PPF if treated with IS.
Patients with a diagnosis of myositis were more likely to also have SSc-ILD (p = 0.048); however, exploration of this as a risk for PPF was limited due to small numbers. Analysis using CK alone showed no statistical difference between groups. Data collection limitations meant that for some patients with a long history of both myositis and subsequent IS we were unable to access baseline CK and, consequently, with a subsequently well controlled disease CK values would have been often within the normal range. Furthermore, two patients had an amyopathic myositis which typically has a normal CK which could have affected this analysis. Conversely, there are a plethora of reasons for a raised CK, so in some cases identified it may not have correlated with significant muscle inflammation.
All patients with myositis were on IS and only one developed PPF. Again, this raises the question ‘could IS be halting the subsequent development of PPF?’. Larger numbers will be required to answer this. We found no association between the presence of inflammatory arthritis and raised CRP with the development of either SSc-ILD or PPF, but there was a trend towards fewer cases of PPF in this group (p = 0.084). Therefore, as 35/42 (83%) of those with inflammatory arthritis were on IS, it further supports the need to establish whether prior IS reduces development of PPF, which has biological plausibility.
It is well established in other rheumatic diseases such as rheumatoid arthritis that a history of smoking increases the risk of associated ILD and a more aggressive disease course [26]. Conversely, we found that SSc-ILD was seen less often in ever smokers compared with never smokers (p = 0.005). The relationship between smoking and CTD-ILD is unclear and has not been shown to be an independent risk factor for SSc-ILD development [27,28]. Furthermore, a recent EUSTAR database analysis has added to previous research showing reduced anti-topoisomerase antibody positivity in female SSc patients who smoke compared with ever smokers. It has been hypothesised that smoking may reduce auto antibody production of anti-topoisomerase; however, this requires further investigation in large studies [29,30].
Smoking is known to be associated with increased mortality in the general population [31]. Therefore, it is unclear whether (and this seems unlikely) smoking has a protective mechanism against the development of both ILD and PPF; instead, it could be that the results display survival bias.
Due to the small number who developed PPF, it is hard to identify risk factors. Furthermore, as we have demonstrated the use of IS for many of the disease manifestations of SSc is a confounder when assessing lung disease as it may be limiting the development of PPF.
As is the case with all real-world analyses, there are subsequent limitations. For example, as a tertiary centre with specialism in CTD-ILD the patient group observed herein may not be generalisable to other settings. Similarly, the commissioning structure for anti-fibrotic treatment in the UK is focused on specialist centres and as such there is a risk of selection bias in this cohort. We were unable to obtain sufficient data on modified Rodnan skin scores to enable comment. The 2-year observational period means survival data are limited; however, trends were starting to develop and would benefit from extension of the study period. Limitations surrounding access to non-computerised clinical records in patients with greater than 10 years’ duration have meant analysis surrounding disease duration and development of ILD and PPF has been limited with a decision made to cohort all patients with a disease duration > 10 years. However, we think the impact of this is minimal, accounting for a recent real world study of 52 patients that found mean time to development of PPF in CTD ILD was 36 months [25]. Not all our patients will have had a CT chest at time of diagnosis, and radiological imaging is typically guided by pulmonary physiology and symptomatology in clinical practice. New ACR guidance [32] will prompt a future change in practice. Consequently, in our cohort there may exist a small number of patients with mild undiagnosed SSc-ILD; this is balanced by some who will have had incidental findings of SSc-ILD following imaging performed for reasons other than surveillance.
Recently published British Society for Rheumatology guidance outlines the importance of baseline HRCT and pulmonary function testing and with close monitoring if SSc-ILD is identified, including a repeat CT scan within the first 1–3 years [33]. We would support these recommendations as this will aid the identification of PPF. We would recommend the development of referral pathways to enable close collaboration between respiratory and rheumatology colleagues to enable swift identification and treatment initiation in PPF. In our specialist centres, rheumatologists are able to access a weekly virtual ILD MDT led by the lead ILD respiratory physicians and specialist thoracic radiologists. This is a very transferable model of care. We would also highlight the importance of regular joint education between rheumatology and respiratory physicians to ensure that all are aware of these pathways and the risk stratification of patients at risk of developing SSc-ILD as well as the role of anti-fibrotic in PPF.

5. Conclusions

This real-world evaluation of a representative systemic sclerosis population from rheumatology clinics identified the incidence and prevalence of PPF (5.49% and 23%).
No patient with an inflammatory radiological pattern on their baseline CT scan went on to develop PPF as opposed to the trend towards significance in those with the fibrotic pattern of UIP. More work is required to elucidate whether those patients with SSc who have a more inflammatory phenotype (pulmonary, muscle, joint involvement) and are responsive to IS are subsequently less likely to develop PPF.
Our study would suggest that there may well be patients with PPF who are not currently being identified, particularly those who have had a long history of SSc-ILD. Rheumatologists must be cognisant of the PPF criteria when reviewing their patients with systemic sclerosis to ensure that we appropriately identify those who would benefit from anti-fibrotic therapy. Establishing prevalence of PPF in our systemic sclerosis cohort patient will serve as a guide to help clinicians evaluate their population. It will also steer the development of services to enable the prescribing of antifibrotic therapies. Multi-specialty engagement in the management of these patients is vital to ensure that we optimise treatment.

Author Contributions

Conceptualisation T.B., L.G.S. and R.B.; methodology, T.B., L.G.S. and R.B.; formal analysis, R.B., M.A., F.F. and M.P.; writing—original draft preparation, R.B. and M.A.; writing—review and editing, T.B., L.G.S. and R.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Ethical review and approval were not required for this study, however registration of the service evaluation with the trust audit department was undertaken in participating sites. The reference number for the audit at the Countess of Chester Hospital is AUH25040, and for the Liverpool University Hospitals group, it is 11642.

Informed Consent Statement

Patient consent was not required because the data were collected as part of an audit.

Data Availability Statement

The datasets presented in this article are not readily available due to ethical restriction. Requests to access the datasets should be directed to the corresponding author.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Tyndall, A.J.; Bannert, B.; Vonk, M.; Airò, P.; Cozzi, F.; Carreira, P.E.; Bancel, D.F.; Allanore, Y.; Müller-Ladner, U.; Distler, O.; et al. Causes and risk factors for death in systemic sclerosis: A study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann. Rheum. Dis. 2010, 69, 1809–1815. [Google Scholar] [CrossRef] [PubMed]
  2. Steele, R.; Hudson, M.; Lo, E.; Baron, M.; The Canadian Scleroderma Research Group. Clinical decision rule to predict the presence of interstitial lung disease in systemic sclerosis. Arthritis Care Res. 2012, 64, 519–524. [Google Scholar] [CrossRef] [PubMed]
  3. Bergamasco, A.; Hartmann, N.; Wallace, L.; Verpillat, P. Epidemiology of systemic sclerosis and systemic sclerosis-associated interstitial lung disease. Clin. Epidemiol. 2019, 11, 257–273. [Google Scholar] [CrossRef] [PubMed]
  4. Vonk, M.C.; Broers, B.; Heijdra, Y.F.; Ton, E.; Snijder, R.; van Dijk, A.P.J.; van Laar, J.M.; Bootsma, H.; van Hal, P.T.W.; Hoogen, F.H.J.v.D.; et al. Systemic sclerosis and its pulmonary complications in The Netherlands: An epidemiological study. Ann. Rheum. Dis. 2009, 68, 961–965. [Google Scholar] [CrossRef] [PubMed]
  5. Volkmann, E.R. Natural History of Systemic Sclerosis-Related Interstitial Lung Disease: How to Identify a Progressive Fibrosing Phenotype. J. Scleroderma Relat. Disord. 2020, 5 (Suppl. 2), 31–40. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  6. Goh, N.S.L.; Desai, S.R.; Veeraraghavan, S.; Hansell, D.M.; Copley, S.J.; Maher, T.M.; Corte, T.J.; Sander, C.R.; Ratoff, J.; Devaraj, A.; et al. Interstitial lung disease in systemic sclerosis: A simple staging system. Am. J. Respir. Crit. Care Med. 2008, 177, 1248–1254. [Google Scholar] [CrossRef] [PubMed]
  7. Vonk, M.C.; Smith, V.; Sfikakis, P.P.; Cutolo, M.; del Galdo, F.; Seibold, J.R. Pharmacological treatments for SSc-ILD: Systematic review and critical appraisal of the evidence. Autoimmun. Rev. 2021, 20, 102978. [Google Scholar] [CrossRef] [PubMed]
  8. Tashkin, D.P.; Roth, M.D.; Clements, P.J.; Furst, D.E.; Khanna, D.; Kleerup, E.C.; Goldin, J.; Arriola, E.; Volkmann, E.R.; Kafaja, S.; et al. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): A randomised controlled, double-blind, parallel group trial. Lancet Respir. Med. 2016, 4, 708–719. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  9. Hoyles, R.K.; Ellis, R.W.; Wellsbury, J.; Lees, B.; Newlands, P.; Goh, N.S.L.; Roberts, C.; Desai, S.; Herrick, A.L.; McHugh, N.J.; et al. A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma. Arthritis Rheum. 2006, 54, 3962–3970. [Google Scholar] [CrossRef] [PubMed]
  10. Kiboshi, T.; Kotani, T.; Konma, J.; Makino, H.; Matsuda, S.; Suzuka, T.; Wada, Y.; Shiba, H.; Hata, K.; Shoda, T.; et al. Comparison of therapeutic effects of combination therapy with prednisolone and tacrolimus or azathioprine on progressive interstitial pneumonia with systemic sclerosis. Mod. Rheumatol. 2022, 32, 358–364. [Google Scholar] [CrossRef]
  11. A Johannson, K.; Chaudhuri, N.; Adegunsoye, A.; Wolters, P.J. Treatment of fibrotic interstitial lung disease: Current approaches and future directions. Lancet 2021, 398, 1450–1460. [Google Scholar] [CrossRef] [PubMed]
  12. Tashkin, D.P.; Elashoff, R.; Clements, P.J.; Goldin, J.; Roth, M.D.; Furst, D.E.; Arriola, E.; Silver, R.; Strange, C.; Bolster, M.; et al. Cyclophosphamide versus placebo in scleroderma lung disease. N. Engl. J. Med. 2006, 354, 2655–2666. [Google Scholar] [CrossRef] [PubMed]
  13. Flaherty, K.R.; Wells, A.U.; Cottin, V.; Devaraj, A.; Walsh, S.L.; Inoue, Y.; Richeldi, L.; Kolb, M.; Tetzlaff, K.; Stowasser, S.; et al. Nintedanib in Progressive Fibrosing Interstitial Lung Diseases. N. Engl. J. Med. 2019, 381, 1718–1727. [Google Scholar] [CrossRef] [PubMed]
  14. Raghu, G.; Remy-Jardin, M.; Richeldi, L.; Thomson, C.C.; Inoue, Y.; Johkoh, T.; Kreuter, M.; Lynch, D.A.; Maher, T.M.; Martinez, F.J.; et al. Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis in Adults: An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am. J. Respir. Crit. Care Med. 2022, 205, e18–e47. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  15. Distler, O.; Highland, K.B.; Gahlemann, M.; Azuma, A.; Fischer, A.; Mayes, M.D.; Raghu, G.; Sauter, W.; Girard, M.; Alves, M.; et al. Nintedanib for Systemic Sclerosis-Associated Interstitial Lung Disease. N. Engl. J. Med. 2019, 380, 2518–2528. [Google Scholar] [CrossRef] [PubMed]
  16. Cottin, V.; Teague, R.; Nicholson, L.; Langham, S.; Baldwin, M. The Burden of Progressive-Fibrosing Interstitial Lung Diseases. Front. Med. 2022, 9, 799912. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  17. Simpson, T.; Barratt, S.L.; Beirne, P.; Chaudhuri, N.; Crawshaw, A.; Crowley, L.E.; Fletcher, S.; Gibbons, M.A.; Hallchurch, P.; Horgan, L.; et al. The burden of progressive fibrotic interstitial lung disease across the UK. Eur. Respir. J. 2021, 58, 2100221. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  18. Graham, B.L.; Steenbruggen, I.; Miller, M.R.; Barjaktarevic, I.Z.; Cooper, B.G.; Hall, G.L.; Hallstrand, T.S.; Kaminsky, D.A.; McCarthy, K.; McCormack, M.C.; et al. Standardization of spirometry 2019 update. An official American Thoracic Society and European Respiratory Society technical statement. Am. J. Respir. Crit. Care Med. 2019, 200, e70–e88. [Google Scholar] [CrossRef]
  19. R Foundation for Statistical Computing. Available online: https://www.R-project.org/ (accessed on 6 June 2023).
  20. Olson, A.; Hartmann, N.; Patnaik, P.; Wallace, L.; Schlenker-Herceg, R.; Nasser, M.; Richeldi, L.; Hoffmann-Vold, A.-M.; Cottin, V. Estimation of the Prevalence of Progressive Fibrosing Interstitial Lung Diseases: Systematic Literature Review and Data from a Physician Survey. Adv. Ther. 2021, 38, 854–867. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  21. Lee, J.; Kim, K.; Jo, Y.S. Comparison of the diagnostic criteria for progressive pulmonary fibrosis in connective tissue disease related interstitial lung disease. Respir. Med. 2023, 212, 107242. [Google Scholar] [CrossRef] [PubMed]
  22. Mehta, P.; Hoyles, R.K.; Gunawardena, H.; Gooptu, B.; Chaudhuri, N.; Heightmann, M.J.; Garthwaite, H.; Penn, H.; Datta, A.; Hamdulay, S.; et al. Rheumatologists have an important role in the management of interstitial lung disease (ILD): A cross-speciality, multi-centre, UK perspective. Rheumatology 2022, 61, 1748–1751. [Google Scholar] [CrossRef]
  23. Morrisroe, K.; Hansen, D.; Stevens, W.; Ross, L.; Sahhar, J.; Ngian, G.-S.; Hill, C.L.; Host, L.; Walker, J.; Proudman, S.; et al. Progressive pulmonary fibrosis and its impact on survival in systemic sclerosis-related interstitial lung disease. Rheumatology 2024, 63, 1874–1881. [Google Scholar] [CrossRef] [PubMed]
  24. Chiu, Y.-H.; Spierings, J.; de Jong, P.A.; Hoesein, F.M.; Grutters, J.C.; van Laar, J.M.; Voortman, M. Predictors for progressive fibrosis in patients with connective tissue disease associated interstitial lung diseases. Respir. Med. 2021, 187, 106579. [Google Scholar] [CrossRef] [PubMed]
  25. Cen, Z.; Cen, T.; Ding, Q.; Zhang, Y.; Tang, P.; Lv, C.; Wu, T. Outcomes and predictors of progression in progressive pulmonary fibrosis. Ann. Med. 2024, 56, 2406439. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  26. Wang, D.; Zhang, J.; Lau, J.; Wang, S.; Taneja, V.; Matteson, E.L.; Vassallo, R. Mechanisms of lung disease development in rheumatoid arthritis. Nat. Rev. Rheumatol. 2019, 15, 581–596. [Google Scholar] [CrossRef] [PubMed]
  27. Shao, T.; Shi, X.; Yang, S.; Zhang, W.; Li, X.; Shu, J.; Alqalyoobi, S.; Zeki, A.A.; Leung, P.S.; Shuai, Z. Interstitial Lung Disease in Connective Tissue Disease: A Common Lesion With Heterogeneous Mechanisms and Treatment Considerations. Front. Immunol. 2021, 12, 684699. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  28. Winstone, T.A.; Assayag, D.; Wilcox, P.G.; Dunne, J.V.; Hague, C.J.; Leipsic, J.; Collard, H.R.; Ryerson, C.J. Predictors of mortality and progression in scleroderma-associated interstitial lung disease: A systematic review. Chest 2014, 146, 422–436. [Google Scholar] [CrossRef] [PubMed]
  29. Ciaffi, J.; Liem, S.; Wiland, P.; Atsumi, T.; Szücs, G.; Pellerito, R.; Balbir-Gurman, A.; Czirják, L.; Zanatta, E.; Koetter, I.; et al. Smoking influence on autoantibody profile and disease progression in systemic sclerosis: An EUSTAR database analysis. Ann. Rheum. Dis. 2023, 82, 975. [Google Scholar] [CrossRef]
  30. Ciaffi, J.; van Leeuwen, N.M.; Huizinga, T.W.J.; de Vries-Bouwstra, J.K. Smoking and systemic sclerosis: Influence on microangiopathy and expression of anti-topoisomerase I antibodies in a monocentric cohort. Clin. Exp. Rheumatol. 2020, 38 (Suppl. 125), 25–28. [Google Scholar] [PubMed]
  31. Janssen, F. Smoking’s impact on mortality in Europe. Popul. Soc. 2019, 571, 1–4. [Google Scholar] [CrossRef]
  32. Johnson, S.R.; Bernstein, E.J.; Bolster, M.B.; Chung, J.H.; Danoff, S.K.; George, M.D.; Khanna, D.; Guyatt, G.; Mirza, R.D.; Aggarwal, R.; et al. 2023 American College of Rheumatology (ACR)/American College of Chest Physicians (CHEST) Guideline for the Treatment of Interstitial Lung Disease in People with Systemic Autoimmune Rheumatic Diseases. Arthritis Rheumatol. 2024, 76, 1182–1200. [Google Scholar] [CrossRef] [PubMed]
  33. Denton, C.P.; De Lorenzis, E.; Roblin, E.; Goldman, N.; Alcacer-Pitarch, B.; Blamont, E.; Buch, M.H.; Carulli, M.; Cotton, C.; Del Galdo, F.; et al. The 2024 British Society for Rheumatology guideline for management of systemic sclerosis. Rheumatology 2024, 63, 2956–2975. [Google Scholar] [CrossRef]
Sclerosis 03 00025 g001
Figure 1. ILD involvement in cohort based on CT findings.
Figure 1. ILD involvement in cohort based on CT findings.
Sclerosis 03 00025 g001
Table 1. Baseline characteristics of study population.
Table 1. Baseline characteristics of study population.
Total number of patients, n255
Age: mean (±SD)61.88 (14.2)
Female (%)224 (87.8)
Smoking status n, (%)
Never124 (48.6)
Current30 (11.7)
Ex-smoker79 (31)
Unknown22 (8.6)
Current Immunosuppression, n (%)
Hydroxychloroquine17 (7)
Cyclophosphamide22 (9)
Methotrexate31 (12)
Mycophenolate mofetil96 (38)
Rituximab8 (3)
Prednisolone20 (8)
Abatacept5 (2)
Tocilizumab2 (0.8)
Sulfasalazine1 (0.4)
Ciclosporin4 (1.6)
Tacrolimus1 (0.4)
Diagnosis of ILD n (%)61 (24)
Antibody status n, (%) *
Anti-centromere99 (38.8)
Anti-topoisomerase30 (11.8)
Anti-PMScl 7513 (5.1)
Anti-PMScl 10010 (3.9)
Anti Ku3 (1.2)
Anti RNP13 (5.1)
Anti RNA3 polymerase6 (2.4)
Clinical disease features n, (%)
Myositis12 (4.7)
Inflammatory arthritis41 (16)
Disease duration
Less than 10 years108 (42%)
Greater than 10 years136 (53%)
Unknown11 (4%)
Mortality within the 2-year study period n, (%)10 (3.9)
* Some patients were positive for multiple auto-antibodies; only those with relevance to their diagnosis of systemic sclerosis are included in the table.
Table 2. Univariate analysis of ILD compared to non-ILD patients in the SSc cohorts.
Table 2. Univariate analysis of ILD compared to non-ILD patients in the SSc cohorts.
No-ILDILDp Value
Total number of patients, n19461
Age (±SD)61.97 (14.34)61.59 (13.87)0.856
Sex (%)25 (12.9)6 (9.8)0.681
Inflammatory Arthritis (%)30 (15.5)12 (19.7)0.565
Myositis (%)6 (3.1)6 (9.8)0.068
Anti Centromere Ab (%)92 (47.4)7 (11.5)<0.001
Anti Topoisomerase Ab (%)13 (6.7)17 (27.9)<0.001
Anti PmScl75(%)9 (4.6)4 (6.6)0.795
Anti PmScl100 (%)4 (2.1)6 (9.8)0.019
AntiRNA3Poly (%)5 (2.6)1 (1.6)1
AntiKu (%)3 (1.5)0 (0.0)0.767
Anti- RNP (%)10 (5.2)3 (4.9)1
Ck raised (%)29 (27.6)11 (40.7)0.276
CRP (mean (SD))22.01 (57.98)26.85 (55.22)0.609
Table 3. Univariate analysis of PPF compared to non PPF cohorts in the SSc-ILD group.
Table 3. Univariate analysis of PPF compared to non PPF cohorts in the SSc-ILD group.
Non-PPF ILD CohortPPF Cohortp
Total number of patients, n4714
Age mean (±SD) *60.55 (12.80)65.07 (17.08)0.289
Sex (%)3 (6.4)3 (21.4)0.251
Inflammatory arthritis (%)12 (25.5)0 (0.0)0.084
Myositis (%)3 (6.4)3 (21.4)0.251
Telangiectasia (%)13 (27.7)3 (21.4)0.905
Anti Centromere (%)6 (12.8)1 (7.1)0.919
Anti Topoisomerase (%)14 (29.8)3 (21.4)0.785
Anti PMScl 75 (%)3 (6.4)1 (7.1)1
Anti PMScl 100 (%)4 (8.5)2 (14.3)0.9
Anti RNA3Poly (%)1 (2.1)0 (0.0)1
Anti Ku (%)47 (100.0)14 (100.0)NA
Anti RNP (%)2 (4.3)1 (7.1)1
CK Raised (%)9 (42.9)2 (33.3)1
CRP (mean (SD))28.05 (60.45)21.67 (22.78)0.758
Current Smoker (%)1 (2.4)0 (0.0)1
NSIP (%)31 (66.0)7 (50.0)0.443
Cellular NSIP (%)17 (36.2)0 (0.0)0.021
Fibrotic NSIP (%)14 (29.8)7 (50.0)0.282
UIP (%)5 (10.6)5 (35.7)0.07
Mortality within the 2 year study period n, (%)3 (6.4)1 (7.1)1
*All values are mean (±standard deviation) unless otherwise noted.
Table 4. Radiological patterns of disease.
Table 4. Radiological patterns of disease.
ILD Pattern on Most Recent CT ScanPatients N = 61(%)
Definite UIP8 (13.1)
Probable UIP4 (65.6%)
Cellular NSIP14 (22.9)
Fibrotic NSIP21 (34.4)
Mixed NSIP (fibrotic and cellular)6 (9.8)
Other3 (4.9)
Unclassifiable5 (8.1)
Table 5. Characteristics of patients with PPF.
Table 5. Characteristics of patients with PPF.
Radiological pattern at
baseline		Definite UIP2
Probable UIP2
FNSIP7
Mixed NSIP2
Unclassifiable1
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MDPI and ACS Style

Benson, R.; Ahmad, M.; Spencer, L.G.; Frost, F.; Paravasthu, M.; Barnes, T. Identifying Patients with Systemic Sclerosis and Progressive Pulmonary Fibrosis in a Real-World Setting: Data from UK Tertiary Rheumatology and ILD Centres. Sclerosis 2025, 3, 25. https://doi.org/10.3390/sclerosis3030025

AMA Style

Benson R, Ahmad M, Spencer LG, Frost F, Paravasthu M, Barnes T. Identifying Patients with Systemic Sclerosis and Progressive Pulmonary Fibrosis in a Real-World Setting: Data from UK Tertiary Rheumatology and ILD Centres. Sclerosis. 2025; 3(3):25. https://doi.org/10.3390/sclerosis3030025

Chicago/Turabian Style

Benson, Rosalind, Mahin Ahmad, Lisa G. Spencer, Freddy Frost, Madhu Paravasthu, and Theresa Barnes. 2025. "Identifying Patients with Systemic Sclerosis and Progressive Pulmonary Fibrosis in a Real-World Setting: Data from UK Tertiary Rheumatology and ILD Centres" Sclerosis 3, no. 3: 25. https://doi.org/10.3390/sclerosis3030025

APA Style

Benson, R., Ahmad, M., Spencer, L. G., Frost, F., Paravasthu, M., & Barnes, T. (2025). Identifying Patients with Systemic Sclerosis and Progressive Pulmonary Fibrosis in a Real-World Setting: Data from UK Tertiary Rheumatology and ILD Centres. Sclerosis, 3(3), 25. https://doi.org/10.3390/sclerosis3030025

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