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Abstract
Background In this study, we investigated the impact of the new haemodynamic definition of pulmonary arterial hypertension (PAH) as proposed by the 6th PH World Symposium on phenotypes and survival in patients with systemic sclerosis (SSc).
Methods In SSc patients who were prospectively and consecutively screened for PAH including right heart catheterisation in Heidelberg or Zurich, haemodynamic and clinical variables have been reassessed according to the new PAH definition. Patients have been followed for 3.7±3.7 (median 3.4) years; Kaplan-Meier survival analysis was performed. Patients with significant lung or left heart disease were excluded from comparative analyses.
Results The final dataset included 284 SSc patients, 146 patients (49.2%) had mean pulmonary arterial pressure (mPAP) ≤20 mm Hg, 19.3% had mPAP 21–24 mm Hg and 29.4% had mPAP ≥25 mm Hg. In the group of mildly elevated mPAP, only four patients (1.4% of the whole SSc cohort) had pulmonary vascular resistance (PVR) values ≥3 Wood Units (WU) and could be reclassified as manifest SSc-APAH. Twenty-eight (9.8%) patients with mPAP of 21–24 mm Hg and PVR ≥2 WU already presented with early pulmonary vascular disease with decreased 6 min walking distance (6MWD) (p<0.001), TAPSE (p=0.004) and pulmonary arterial compliance (p<0.001). A PVR ≥2 WU was associated with reduced long-term survival (p=0.002). PVR and 6MWD were independent prognostic predictors in multivariate analysis.
Conclusion The data of this study show that a PVR threshold ≥3 WU is too high to enable an early diagnosis of PAH. A PVR threshold ≥2 WU was already associated with pulmonary vascular disease, significantly reduced survival and would be more appropriate in SSc patients with mild PAH.
- systemic sclerosis
- outcomes research
- treatment
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Key messages
What is already known about this subject?
Patients with systemic sclerosis-associated pulmonary arterial hypertension present with severely impaired survival rates. The new haemodynamic classification of pulmonary hypertension will lead to changes in classification of manifest disease and possibly treatment decisions.
What does this study add?
This study shows that patients with mildly elevated mean pulmonary arterial pressure and pulmonary vascular resistance (PVR) ≥2 Wood Units (WU) already present with early pulmonary vascular disease and impaired survival. Furthermore, PVR has presented as independent prognostic parameter.
How might this impact on clinical practice or future developments?
The PVR threshold of ≥3 WU may prevent from an early diagnosis in this patient cohort and should be carefully reconsidered.
Introduction
Pulmonary hypertension (PH) often aggravates systemic sclerosis (SSc) with negative consequences on exercise capacity, quality of life and survival.1 2 SSc patients may develop PH due to left heart or lung disease3 or precapillary PH as pulmonary arterial hypertension (PAH) during the course of the disease, which is the main cause of mortality.4 Itinerair Scleroderma and evidence-based detection of pulmonary arterial hypertension in systemic sclerosis (DETECT) studies enabled an early diagnosis of PAH among SSc patients (SSc-APAH).5 6 In the DETECT study, most of the newly diagnosed SSc-APAH patients presented with only slightly elevated mean pulmonary arterial pressure (mPAP), normal or near-normal mean cardiac output (CO) at rest, slightly elevated right atrial (RA) size and a pulmonary vascular resistance (PVR) values <3 Wood Units (WU).5 Early diagnosis of SSc-APAH is of utmost importance, since it leads to significant improvement of survival rates through the implementation of PAH therapies, as demonstrated in the Itinerair Scleroderma cohort.7
Therefore, a new haemodynamic definition of PAH was proposed at the 6th World Symposium of PH,8 which lowered the cut-off for mPAP from ≥25 mm Hg (stated in the actual PH guidelines)9 to >20 mm Hg in combination with pulmonary arterial wedge pressure (PAWP) ≤15 mm Hg and PVR ≥3 WU. The change in the haemodynamic definition of precapillary PH represents a step towards the upper limit of physiological haemodynamic thresholds as shown in a systematic review of Kovacs et al 10 including 1187 healthy subjects presenting with an upper limit of normal for mPAP of 20.6 mm Hg (mean+2 SDs). Subsequent studies performed mainly in SSc patients reported that patients with mildly elevated mPAP (21–24 mm Hg) had reduced exercise capacity, impaired quality of life, decreased right ventricular (RV) output reserve, abnormal pulmonary arterial compliance (PAC) and survival.11–13 Furthermore, it has been shown that SSc patients with exercise PH assessed by right heart catheterisation (RHC) had a similarly impaired survival as SSc patients with manifest resting PAH.14
In a recent study reanalysing SSc patients assessed by RHC, the updated definition did not have a significant impact on reclassification, with only 5% of patients being reclassified as PAH.15 However, the authors of this study suggested that the PVR criterion ≥3 WU is too conservative since a larger proportion of their patients with mild PH (mPAP of 21–24 mm Hg) had PVR <3 WU. A systematic review by Kovacs et al 10 16 supports this assertion showing an upper limit of normal of PVR <1.5 WU throughout all age categories. The addition of 2 SD to this upper limit of normal leads to a PVR threshold of 2 WU. The arbitrarily high cut-off of PVR ≥3 WU was consensus during the 6th World Symposium on PH (WSPH) meeting in order to avoid misclassification of PAH.8
The aim of the current study was to analyse the impact of the new haemodynamic definition of precapillary PH in a large cohort of SSc patients referred to two reference PH centres. Clinical characteristics of SSc patients with mPAP 21–24 mm Hg and PVR ≥2 WU were compared with patients with manifest PAH and those with normal haemodynamic values. Furthermore, this study investigates for the first time survival of patients according to PVR (threshold 2 WU) and mPAP.
Methods
Study population
Consecutive SSc patients with diffuse cutaneous SSc (dc-SSc) or limited cutaneous SSc (lc-SSc)17 fulfilling the classification criteria of the American College of Rheumatology/European League against Rheumatism18 were prospectively enrolled within the scope of an early detection of PH programme as previously described.5 13 15 The patients were referred to two PH centres (Centre for Pulmonary Hypertension of the Thoraxklinik at Heidelberg University Hospital, Germany, and Departments of Rheumatology and Pulmonology, University Hospital Zurich, Switzerland). A part of this cohort has already been analysed and published before.5 13 15
The referring specialists were rheumatologists, cardiologists, pulmonologists and general practitioners. Individuals were excluded, if they had an already diagnosed PH via RHC prior to enrolment, an ongoing treatment with PAH drugs, renal insufficiency, systemic arterial hypertension with blood pressure values >180/95 mm Hg at rest or >230/120 mm Hg during exercise despite optimised medical treatment, previous evidence of clinically relevant left heart disease, significant lung disease or if they were pregnant.
All patients underwent a detailed clinical work-up, echocardiography and RHC (for details see online supplementary material).19
Supplemental material
Study design
In order to evaluate the impact of the new PH definition, patients were divided into three groups according to their resting mPAP values: normal mPAP (mPAP ≤20 mm Hg), mildly elevated mPAP (21–24 mm Hg) and manifest PH (mPAP ≥25 mm Hg). Each group was further divided according to PVR. The frequency of patients with mPAP 21–24 mm Hg as well as mPAP ≥25 mm Hg was analysed using different PVR cut-off values (2, 2.5 and 3 WU). Patients with significant lung disease (VCmax <70% and/or signs of significant interstitial lung disease in CT of the lungs) or significant left heart disease (PAWP >15 mm Hg) were reported in the respective haemodynamic subgroups and were excluded from further comparative analysis. Clinical characteristics, 6 min walking distance (6MWD), RA and RV area, tricuspid annular plane systolic excursion (TAPSE), PAC and N-terminal pro-brain natriuretic peptide (NT-proBNP) were compared between patients with mPAP 21–24 mm Hg and PVR ≥2 WU, SSc patients with normal haemodynamics (mPAP ≤20 mm Hg and PVR <2 WU) and patients with manifest PAH according to the current haemodynamic definition (mPAP ≥25 mm Hg and PVR ≥3 WU). Finally, we compared the survival rates of patients according to PVR values (threshold 2 WU).
Statistical methods
Statistical analyses were conducted by a statistician (NB). Data are described as mean±SD. The frequency distribution of different haemodynamic subgroups and further frequency data are given as number and per cent, respectively.
Comparisons of clinical parameters between patients with mPAP 21–24 mm Hg and PVR ≥2 WU versus patients with normal haemodynamics (mPAP ≤20 mm Hg and PVR <2 WU) as well as comparison of patients with mPAP 21–24 mm Hg and PVR ≥2 WU versus manifest PAH (mPAP ≥25 mm Hg and PVR ≥3 WU) were made with Wilcoxon-Mann-Whitney test. Clinical parameters included 6MWD, TAPSE, RA and RV area, NT-proBNP and PAC.
Survival analysis with comparison of different subgroups with mPAP (≤20, 21–24, ≥25 mm Hg) and PVR (<2, ≥2 WU) was performed with Kaplan-Meier analysis and age-adjusted Cox regression analysis. Multivariate Cox regression analysis was performed for parameters at baseline, including age, mPAP, PVR, CO, cardiac index, PAWP, stroke volume, PAC, TAPSE, 6MWD, sex and WHO functional class. The RHC assessment date was set as baseline for survival analysis. Death was defined as death due to any cause.
Three risk stratification models, including REVEAL 2.0,20 COMPERA/Swedish approach21 22 and the French approach,23 were applied to the whole cohort and subsets of the cohort with PVR <2 and ≥2 WU.
The frequency of different phenotypes was calculated from all patients who were included into the study and had valid haemodynamic data, including patients with cardiac or pulmonary disease. Comparisons between haemodynamic subgroups and survival analyses comprised of patients without significant lung disease or PAWP >15 mm Hg.
All analyses have been performed using IBM SPSS 25 (SPSS Statistics V.25, IBM Corporation, Somers, New York, USA).
Patient and public involvement statement
This analysis was aimed at investigating the impact of the new haemodynamic definition of PH. The findings of this analysis will be presented to physicians at national and international congresses and to patients during patient organisation meetings (patient organisations for SSc and for PH) in order to raise awareness of the condition and its early diagnosis. We hope that early detection, diagnosis and possibly early treatment of this patient population may be enhanced by our study results.
Results
Baseline characteristics
A total of 287 patients with SSc were screened for PH. Three patients were excluded from the study because of missing haemodynamic data. Thus, the final study group consisted of 284 patients, 182 patients have been assessed in Heidelberg and 102 in Zurich (figure 1, table 1). In the patients included in this study, overt significant lung or left heart disease had been excluded. However, during the assessment at the time of RHC, in 36 out of the 284 patients previously unknown significant lung disease (n=6) or left heart disease with a PAWP >15 mm Hg (n=30) was diagnosed. These 36 patients were excluded from the haemodynamic subgroup analysis, leading to a study cohort without comorbidities of 248 patients (baseline characteristics of analysis set without significant comorbidities, see table 1).
Study flow chart and different PVR thresholds in patients with mPAP 21–24 and ≥25 mm Hg. The flow chart characterises the frequency of haemodynamic subgroups according to mPAP and PVR threshold of 3 WU. The number of patients excluded due to significant lung disease and/or PAWP >15 mm Hg is given for patients with mPAP 21–24 and ≥25 mm Hg. For both haemodynamic groups according to mPAP values, patient numbers are given for different PVR thresholds. According to the new haemodynamic definition, four additional patients with manifest pulmonary arterial hypertension were identified. 6MWD, 6 min walking distance; mPAP, mean pulmonary arterial pressure; PAH, pulmonary arterial hypertension; PAWP, pulmonary arterial wedge pressure; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; SSc, systemic sclerosis; WHO-FC, WHO functional class; WU, Wood Units.
Clinical characteristics of the study cohort with and without concomitant left heart or lung disease
The mean age of the 284 patients of the whole cohort was 58.3±12.7 years, 81.0% were female, 50.7% had dc-SSc and 49.3% lc-SSc. The mean 6MWD was 443.6±109.3 m, 51% were functionally limited with functional class (WHO FC) II, 28.5% had WHO FC III and 0.8% had WHO FC IV (baseline characteristics of analysis set of whole cohort, see table 1).
Patients with manifest PAH (mPAP ≥25 mm Hg, PVR ≥3 WU, PAWP ≤15 mm Hg) were treated with PAH medication according to the guidelines. Patients who did not meet the criteria of manifest PAH were not treated with continuous PAH medication. PAH-targeted therapies including bosentan that is also used for prevention of digital ulcers in SSc were given as non-continuous treatment in less than 5% of patients.
Impact of the new definition of PAH
Out of 284 patients, 146 patients had mPAP ≤20 mm Hg, 55 patients 21–24 mm Hg (mildly elevated mPAP) and 83 patients had mPAP ≥25 mm Hg (figure 1). In the group of mildly elevated mPAP, four patients could be reclassified as manifest SSc-APAH according to the new haemodynamic definition of PAH (1.4% of the whole cohort or 8% among patients with mPAP 21–24 mm Hg; table 2). In these four patients, significant lung or left heart disease had been excluded. The clinical characteristics of these patients are summarised in table 2.
Detailed characteristics of newly identified patients according to the new haemodynamic definition
Among the patients in the group with mPAP 21–24 mm Hg, 28 (9.85% of total cohort) had a PVR ≥2 WU with no significant left heart or lung disease and would be newly diagnosed as SSc-APAH using this PVR threshold. In patients with mPAP 21–24 mm Hg and PVR ≥2 WU, 21 out of 25 patients who received exercise RHC could be defined as exercise PH with mPAP >30 mm Hg and total pulmonary resistance >3 WU. No patient had a PAWP >25 mm Hg. Among patients with mPAP ≥25 mm Hg and PAWP ≤15 mm Hg (n=54), 33 had a PVR ≥3 WU, another 19 patients (6.7% of the total cohort) had a PVR ≥2 WU and would be classified as SSc-APAH with a lower PVR threshold. Three out of 146 SSc patients with mPAP ≤20 mm Hg had a PVR ≥3 WU.
Comparison of clinical parameters
The comparisons of clinical parameters have been performed in the cohort without cardiac or pulmonary comorbidities (n=248). Patients with mPAP 21–24 mm Hg and PVR ≥2 WU showed reduced TAPSE (20.6±5.7 vs 23.8±3.9 mm, p=0.004) (table 3) and decreased 6MWD (413.5±99.6 vs 487.7±100.6 m, p<0.001) compared with patients with normal haemodynamics (figure 2).
Characteristics of haemodynamic subgroups
Six-minute walking distance (6MWD) and pulmonary arterial compliance (PAC) in different haemodynamic subgroups. Patients with mPAP 21–24 mm Hg and PVR ≥2 WU showed a significantly lower 6MWD than patients with mPAP ≤20 mm Hg (t-test p=0.001), but did not significantly differ from patients with mPAP ≥25 mm Hg. Patients with mPAP 21–24 mm Hg and PVR ≥2 WU also showed a significantly lower PAC than patients with mPAP ≤20 mm Hg (t-test p<0.0001), and a significantly higher PAC than patients with mPAP ≥25 mm Hg (t-test p<0.0001). The bracket ends in the graph point to the two groups that were compared by Student’s t-test. mPAP, mean pulmonary arterial pressure; PVR, pulmonary vascular resistance; WU, Wood Units.
PAC significantly differed between patients with mildly elevated mPAP with PVR ≥2 WU and patients with normal haemodynamics (4.02±1.32 vs 6.16±2.84 mL/mm Hg, p<0.001), as well as between mildly elevated mPAP with PVR ≥2 WU and SSc patients with manifest PAH with PVR ≥3 WU (4.02±1.32 vs 2.28±0.99 mL/mm Hg, p<0.001) (figure 2). Stroke volume index (SVI) and diffusing capacity of the lung for carbon monoxide did not significantly differ between groups. RA area significantly differed between patients with mPAP 21–24 mm Hg and PVR ≥2 WU and patients with manifest PAH (p=0.043); RV area showed a difference in trend (p=0.065). NT-proBNP showed comparable results in patients with normal haemodynamics and mPAP 21–24 mm Hg and PVR ≥2 WU. Patients with manifest PAH had significantly higher NT-proBNP than patients with mPAP 21–24 mm Hg and PVR ≥2 WU (p=0.003).
Survival among SSC patients
The survival analyses have been performed in the cohort without comorbidities (n=248) (figure 3). Patients with PVR ≥2 WU showed a significantly worse survival than patients with PVR <2 WU with 1-, 3-, 5- and 7-year survival rate of 97.7%, 90.7%, 79.4% and 54.3% versus 100%, 94.2%, 91% and 84.2% (Kaplan-Meier p=0.002; age-adjusted Cox regression p=0.028). Survival according to mPAP also significantly differed between groups (Kaplan-Meier p=0.007; age-adjusted Cox regression different in trend p=0.064). In patients with mPAP 21–24 mm Hg, PVR ≥2 WU was identified as significant predictor of survival (Kaplan-Meier p=0.047). Age-adjusted Cox regression showed inconsistent results (p>0.05). In the multivariate analysis at baseline, PVR and 6MWD were independent prognostic parameters for survival.
Survival analysis in different haemodynamic groups according to PVR and mPAP. Age-adjusted Cox regression is shown on the left hand, Kaplan Meier analysis on the right hand. Patients with PVR <2 WU showed a significantly better survival than patients with PVR ≥2 WU with 1-, 3-, 5- and 7-year survival rate of 100%, 94.2%, 91% and 84.2% versus 97.7%, 90.7%, 79.4% and 54.3%. Survival of haemodynamic subgroups according to mPAP significantly differed between groups (Kaplan-Meier p=0.007; age-adjusted Cox regression different in trend p=0.064) (figure 7). Patients with significant left heart or lung disease were excluded from the analysis. mPAP, mean pulmonary arterial pressure; PVR, pulmonary vascular resistance; WU, Wood Units
In patients with PVR <2 WU, 12 out of 147 patients (8.2%) died during follow-up (mean follow-up time 4.2±2.7 years). In patients with PVR ≥2 WU, 18 out of 101 patients (17.8%) died during follow-up (mean follow-up time 3.5±2.6 years). Reasons for death were related to pulmonary vascular disease PAH (3 vs 9 in PVR <2 WU and ≥2 WU, respectively) and not related to pulmonary vascular disease (9 vs 9 in PVR <2 WU and ≥2 WU, respectively). Death was unknown in 4 versus 2 patients with PVR <2 WU and ≥2 WU, respectively.
Three risk stratification models showed significantly different survival for the different risk scores: COMPERA/Swedish approach (p<0.0001)21 22 and REVEAL 2.0 (p<0.0001),20 French approach (p=0.001).23 When stratifying the cohort according to the PVR threshold <2 WU and ≥2 WU, the REVEAL risk score showed significantly different survival for both cohorts (both p<0.0001), whereas COMPERA/Swedish approach did not show significant differences for patients with PVR <2 WU (p=0.35), but for PVR ≥2 WU (p<0.0001) and the French approach did not show significant differences for PVR <2 WU (0.26), but was significant in trend for ≥2 WU (p=0.078).
The application of risk stratification models in patients with mPAP 21–24 mm Hg and PVR 2–3 WU demonstrates that low-risk patients could be detected. The REVEAL risk score was 0–6 (low risk) in 20 out of 28 patients, COMPERA/Swedish approach showed a low risk in 6, a moderate risk for 8 out of 14 patients and the French approach showed a score ≥3/4 (low risk) in 16 out of 28 patients.
Discussion
This is the first large study showing that patients with mild PAH (mPAP 21–24 mm Hg and PVR ≥2 WU, PAWP <15 mm Hg, no significant lung or left heart disease) had already a clinically meaningful pulmonary vascular disease, RV dysfunction and markedly reduced long-term survival. The new haemodynamic definition of PAH as proposed during the 6th WSPH did not have a significant impact on reclassification in the cohort of this study, with only 4 out of 284 patients being newly classified as PAH (1.4% of the total cohort; 8.0% of patients with mild PAH). The number of newly diagnosed patients with mild PAH would however markedly increase to 9.85% in this cohort, if a physiological haemodynamic threshold for PVR (ie, ≥2 WU) would be used. PVR and 6MWD were identified as independent prognostic parameters for survival. Thus, the data of this study show that a PVR threshold ≥3 WU is too high to enable an early diagnosis of PAH and should be replaced by a cut-off value of ≥2 WU.
Impact of the new haemodynamic definition of PH
The results of this bicentric study are in line with data recently published by Jaafar et al 15, reporting a small addition to the SSc-APAH diagnosed patients of 4% from the single-centre cohort of the University of Michigan. In addition to the study of Jaafar et al, the data of our cohorts document the reduced survival and its association with PVR as independent prognostic predictor. The very useful editorial comment by Kovacs and Olschewski24 pointed to another important issue that is also addressed in our study. Nineteen out of 50 patients (38%, or 6.7% out of the total cohort) with clearly elevated mPAP (≥25 mm Hg) and no relevant left heart (PAWP <15 mm Hg) or lung disease failed to fulfil the haemodynamic criteria of precapillary PH, because they had a PVR <3 WU but ≥2 WU. As already shown in the DETECT study, many of the patients diagnosed by a systematic screening programme including RHC have a normal CO at rest5 and therefore rarely present with PVR values ≥3 WU. However, in these patients, we previously detected an RV dysfunction with markedly impaired cardiac reserve (reduced CO during exercise).13 The strength of our study is the addition of survival data, supporting the hypothesis that a PVR ≥2 WU is already of great prognostic importance for the patients.
Furthermore, the data of this study document for the first time that patients with mPAP 21–24 mm Hg and PVR ≥2 WU already show impaired exercise capacity, right heart systolic function and PAC. SVI did not significantly differ between groups, though this parameter has been shown to be an important prognostic predictor of outcomes.25 26 Exercise performance and right heart systolic function could therefore already be damaged with an only slight increase of PVR and still normal right heart size, stroke volume and NT-proBNP. Natriuretic peptides are released in response to myocardial stretch and patients with an early stage of the disease usually have normal right heart size.27 Right heart enlargement is typically a hallmark of advanced disease, more prominent when haemodynamic decompensation occurs.28
Thus, in an update of the proposed PAH definition, the PVR threshold should be lowered to ≥2 WU, since only this value would allow an early diagnosis of precapillary PH. The PVR cut-off value ≥3 WU does not allow an early PAH diagnosis and is associated with a markedly reduced long-term survival in patients with SSc and early pulmonary vascular disease.
Clinical implications
Today, there are no sufficient data whether patients with mildly elevated mPAP (21–24 mm Hg) and PVR ≥2 WU should be treated with PAH medication. Two open-labelled pilot studies investigating the effect of endothelin receptors antagonists showed promising results.29 30 A recent double-blind randomised controlled trial early treatment of borderline pulmonary arterial hypertension associated with SSc (EDITA) testing the effect of ambrisentan among SSc patients with mildly elevated mPAP and/or exercise PH failed to change the primary endpoint change of mPAP at rest but showed an improvement of PVR as secondary endpoint,31 which may be of prognostic relevance in this patient cohort. Further research in this field is needed.
Two of three risk stratification models only showed significant differences between groups in patients with PVR ≥2 WU. Thus, our data show that the application of different risk models to our cohort is mainly applicable in patients with early pulmonary vascular disease (PVR ≥2 WU) and not in patients with normal haemodynamics (<2 WU).
Strengths and study limitations
This study provides important insights for the diagnosis of early SSc-APAH. All patients were screened in experienced centres and had a thorough clinical assessment including RHC and were followed up taking their comorbidities (heart or lung diseases) into account. RHC follow-up data to describe the subsequent clinical course of the patients would have been desirable and should be aimed for with future studies.
The highest proportion of patients with dc-SSc could be found in the group of patients with mPAP 21–24 mm Hg and PVR ≥2 WU (60.8%), whereas the lowest proportion (39.4%) was in the group with mPAP ≥25 mm Hg and PVR ≥3 WU. The higher proportion of dc-SSc may well have influenced 6MWD, as these patients show lower exercise capacity.32 However, as dc-SSc has shown to have less severe alteration of haemodynamics,32 our findings are congruent with early pulmonary vascular disease.
Conclusion
The data of this study show that a PVR threshold ≥3 WU is likely too high to enable an early diagnosis of PAH. In the group of mildly elevated mPAP, only four patients (1.4% of the whole SSc-cohort) had PVR values ≥3 WU and could be reclassified as manifest SSc-APAH according to the new definition. A PVR threshold ≥2 WU was already associated with pulmonary vascular disease and significantly reduced survival and would be more appropriate for the early diagnosis of SSc-APAH among this high-risk population. Further studies are needed to analyse the impact of the new PAH definition in other risk groups and to investigate whether patients with mildly elevated mPAP (21–24 mm Hg) and PVR ≥2 WU should be treated with PAH medication.
Acknowledgments
We would like to thank all patients who participated in the study. This work was the doctoral thesis of NM.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
NB and OD are joint senior authors.
PX and SJ are joint first authors.
Handling editor Josef S Smolen
Contributors PX, SJ and NM made substantial contributions to the acquisition, analysis and interpretation of data, drafting and revision of the work. This is the doctorate thesis of NM. VT, ML and AMM made substantial contributions to the acquisition and interpretation of data and drafting of the work. NBlank made substantial contributions to the conception, acquisition and interpretation of data, and revision of the work. BE, MG, SH, CN, CB and SU made substantial contributions to the acquisition and interpretation of data, and revision of the work. H-ML and EG made substantial contributions to the conception, acquisition, analysis and interpretation of data, revision of the work. NBenjamin made substantial contributions to the conception, acquisition, data analysis and interpretation of data, drafting and revision of the work. OD made substantial contributions to the conception, acquisition, analysis and interpretation of data, drafting and revision of the work. All authors read and approved the manuscript and agree to all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests PX has received personal fees from MSD and OMT. AM has received personal fees from Bayer, outside the submitted work. NBlank has received consulting fees, speaker fees and/or honoraria from MSD, GSK, Actelion and Bayer Vital. BE received travel fees, consulting fees, speaking fees and/or honoraria from Actelion, MSD, Bayer and OMT (less than $10 000 each). MG serves on an advisory Board for Bayer AG and receives lecture fees from Pfizer, MSD and Actelion Pharmaceuticals. SH has received personal fees from Bayer, MSD, Actelion and GSK, outside the submitted work. H-ML has received consulting fees, speaking fees and/or honoraria from AbbVie, BMS, Pfizer, Cellgene, Medac, GSK, Roche, Chugai, Novartis, UCB, Janssen-Cilag, AstraZeneca and Lilly (less than $10 000 each) and research support from AbbVie, MSD, BMS, Cellgene, Medac, GSK, Roche, Chugai, Novartis, UCB, Janssen-Cilag, AstraZeneca, Lilly, Baxter, SOBI, Biogen, Actelion, Bayer Vital, Shire, Octapharm, Sanofi, Hexal, Mundipharm and Thermo Fisher. CN has received consulting fees, speaking fees and/or honoraria from Actelion, MSD, Boehringer, Novartis, Bayer and AstraZeneca (less than $10 000 each). CB received travel support from Actelion SA and Orpha Swiss and speakers’ fee from MSD. SU received grants from the Swiss National Science foundation and the Zurich Lung League, travel support and speakers’ fees from Actelion SA, Switzerland, Bayer SA, Germany, MSD, Switzerland and Orpha Swiss. EG has received grants and personal fees from Actelion, Bayer AG and MSD; grants from GSK, Novartis, and United Therapeutics; and personal fees from SCOPE, OrPha Swiss GmbH, and Zurich Heart House (less than $10 000 each). NBenjamin received speaker fees from Actelion pharmaceuticals, Bayer HealthCare and MSD. OD has received grants and personal fees from research consultancies from AM, Acceleron Pharma, Amgen, AnaMar, Bayer, Beacon Discovery, Boehringer Ingelheim, Catenion, CSL Behring, ChemomAb, Ergonex, GSK, Inventiva, Italfarmaco, iQone, iQvia, Lilly, medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Blade Therapeutics, Glenmark Pharmaceuticals, Target Bio Science and UCB, outside the submitted work, to investigate potential treatments of scleroderma and its complications. In addition, OD has a patent mir-29 for the treatment of systemic sclerosis issued (US8247389, EP2331143).
Patient consent for publication Not required.
Ethics approval The ethics committees of the Medical Faculty Heidelberg (S360/2009 and S231/2019) and Zurich (EUSTAR—database 839/BASEC Nr. 2016-01515 and cohort study BASEC-Nr. 2018-02165) had no objection against the conduct of the trial.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request.