Abstract
Background:
Interstitial lung disease is the leading cause of morbidity and mortality in systemic sclerosis, but it is characterized by significant heterogeneity in patient outcomes. So far, little is known about the influence of anti-U1RNP antibodies on lung outcomes in systemic sclerosis–associated interstitial lung disease patients.
Methods:
European Scleroderma Trials and Research group systemic sclerosis patients with radiological-confirmed interstitial lung disease, available %predicted forced vital capacity, and autoantibody status were included. Baseline demographic and disease features were compared between anti-U1RNP positive and anti-U1RNP negative patients. Moreover, longitudinal analyses were done measuring relative change in %predicted forced vital capacity over 12 ± 6, 24 ± 6, and 36 ± 6 months, and changes were classified into stable (⩽ 4%), mild (5%–9%), and major progression (⩾ 10%). Predictors associated with death of any cause or major interstitial lung disease progression were evaluated in systemic sclerosis–associated interstitial lung disease patients with or without anti-U1RNP antibodies. Logistic regression analyses and Cox proportional hazards models adjusted for age and FVC were applied.
Results:
A total of 6043 systemic sclerosis–associated interstitial lung disease patients were included for the analysis, among which 327 (5.4%) were positive for anti-U1RNP antibodies. Mean age was 56.8 ± 13.2 years and 4971 (82.3%) were women. Anti-U1RNP + systemic sclerosis–associated interstitial lung disease patients had more frequently limited cutaneous systemic sclerosis (63.5.5% vs 53.3%, p < 0.001), higher frequency of joint synovitis (18.1% vs 13.9%, p = 0.039), and myositis (24.0% vs 19.5%, p = 0.048). Anti-U1RNP + patients had a baseline lower mean forced vital capacity (82.0% vs 86.0%, p < 0.001) and lower mean %predicted diffusing capacity for carbon monoxide (57.0% vs 60.5%, p = 0.003). Periods of mild or major FVC decline and mortality rates were not statistically different between the groups.
Conclusion:
Systemic sclerosis–associated interstitial lung disease patients positive for anti-U1RNP antibodies have more impaired baseline lung function but similar trajectories of forced vital capacity changes and mortality during the first 3 years of follow-up.
Keywords: Systemic sclerosis, interstitial lung disease, anti-U1RNP, progression, death, prognosis
Key messages
anti-U1RNP + systemic sclerosis–associated interstitial lung disease (SSc-ILD) patients have more impaired baseline lung function but similar rate of progression during follow-up; anti-U1RNP + SSc-ILD patients may require specific management and follow-up.
Introduction
Systemic sclerosis (SSc) is a rare and complex autoimmune condition characterized by fibrosis of the skin and internal organs.1,2 SSc-associated interstitial lung disease (SSc-ILD) is a common complication and stands out as a significant contributor to morbidity and has been identified as the leading cause of death in patients with SSc.3 –5 Data from different SSc cohorts report a prevalence of ILD on high-resolution chest-computed tomography scan (HRCT) that varies from 22% to 84%. 6 The ILD pattern observed in SSc is usually nonspecific interstitial pneumonia (NSIP) rather than usual interstitial pneumonia (UIP), 7 and approximately 30% of patients with SSc-ILD will undergo ILD progression. 8 A number of factors have been associated with a higher risk of developing SSc-ILD including male gender, ethnicity, the diffuse cutaneous disease subset, and anti-topoisomerase I (ATA) positivity.9 –12 Moreover, multiple risk factors for progressive ILD in SSc patients have been identified. Extensive disease baseline HRCT, lower FVC% and DLCO%, lower SpO2 after a 6-min walk test, older age, and the presence of arthritis have all been associated with progressive lung disease.13 –15 Biomarkers in particular autoantibodies may be of value in SSc-ILD prognostication. Several studies have reported that the presence of ATA and the absence of anticentromere antibodies (ACA) indicate an increased likelihood of progressive SSc-ILD.10,16
Autoantibodies against U1RNP are a cornerstone serological marker for mixed connective tissue disease (MCTD) but can also be detected in patients with a definite diagnosis of SSc. 17 In the context of MCTD, ILD is a common complication and has been identified as a marker of bad prognosis in these patients. 18 Moreover, SSc patients with anti-U1RNP autoantibodies appear to experience a more severe and early disease onset, exhibiting features including arthritis and myositis, along with a higher prevalence of ILD.19 –21 However, a previous study reported no significant survival differences among SSc-ILD patients with ACA, ATA, or anti-U1RNP autoantibodies. 22 The relationship between anti-U1RNP autoantibodies and SSc-ILD, and their role in the severity and outcomes of these patients, has not been evaluated in large multicenter series and this remains to be clarified.
Therefore, we aimed at determining the clinical features and the prognostic potential of anti-U1RNP positivity in a large cohort of SSc-ILD patients from the European Scleroderma Trials and Research (EUSTAR) group cohort.
Methods
Analysis of the EUSTAR database
Patient population and characteristics
Post hoc analyses were performed on patient data collected prospectively from the EUSTAR database. The online database’s structure, the compiled dataset, and the definitions of clinical variables have been thoroughly detailed in previous descriptions.9,23 Patients registered since 2010 in the EUSTAR database (start of the online version), aged ⩾ 18 years, who fulfilled the 2013 American College of Rheumatology/European League Against Rheumatism SSc classification criteria; 24 with the presence of ILD by HRCT or X-ray; recorded disease duration; with available autoantibody status; and with available measurements of FVC% and DLCO were included. Autoantibodies were detected by each center according to local practice, and information on autoantibody detection method is not collected in the EUSTAR database.
Anti-U1RNP positive patients were included in this analysis when the anti-U1RNP status was reported at least once in the database and were excluded in cases with no information or unknown status. Patients were considered positive for anti-U1RNP when the test was positive in at least one determination, at the baseline or during the follow-up. At baseline, defined as the date of inclusion, we conducted two analyses: (1) patients positive for anti-U1RNP in combination with SSc-specific autoantibodies and (2) patients positive for anti-U1RNP without other SSc-specific autoantibodies. The patients’ age, sex, smoking status, disease duration, clinical, laboratory, imaging data (HRCT), pulmonary function tests (PFTs) and treatments, were recorded at baseline and compared between positive and negative anti-U1RNP SSc-ILD patients. For each patient, a clinical manifestation was considered as present if reported in at least one of the visits recorded.
Progressive ILD measured by FVC changes in a 36-month period
The prevalence of annual FVC% relative changes was assessed prospectively in patients who had at least three yearly separated FVC measurements over a 3-year period (baseline and yearly up to 36 ± 6 months). We assessed FVC% relative changes between baseline and last available FVC measurement, considering periods of 12 months. Relative change in FVC% predicted was classified into stable (⩽ 4%), moderate (5%–9%), and major progression (⩾ 10%) as previously described. 8 Relative change in FVC% from baseline to the last available measurement and all-cause mortality were compared between SSc-ILD patients with positive and negative anti-U1RNP autoantibodies. To avoid confounding effects, a primary analysis was performed comparing patients positive for anti-U1RNP without other SSc-specific autoantibodies to those negative for anti-U1RNP. A secondary analysis compared overlap patients with anti-U1RNP and ATA or ACA double positivity to patients negative for anti-U1RNP but positive for ATA or ACA. Two separate analyses were conducted at 1 and 3 years.
Ethical considerations
Each EUSTAR center received approval from the local ethics committee, and written informed consent was locally acquired for registered patients (ethics committee approval by number of the lead center: 2008-A00624-51 (Comité de Protection des Personnes CPP Ile de France III); approval date: 3 October 2008). The study protocol was reviewed and approved by the EUSTAR board (project no. CP 116). Informed consent was obtained from all subjects involved in the study.
Statistical analysis
Frequencies and percentages were compared using chi-square test or Fisher’s exact test for categorical variables, and Student’s t tests or Mann–Whitney U tests for continuous variables, as appropriate. To identify the clinical associations of anti-U1RNP, multivariable logistic regression analysis was performed by selecting covariates based on the research question (clinical associations of anti-U1RNP) and plausible independent variables, which were a priori selected among demographical, clinical and laboratory parameters. Odds ratios (OR) were calculated with 95% confidence interval (CI).
Results
Clinical associations of anti-U1RNP autoantibodies in SSc-ILD patients at baseline
Anti-U1RNP status was available in 6043 SSc-ILD patients from the EUSTAR database, mean age was 56.8 ± 13.2 years and 4971 (82.3%) were women. Overall, 327 (5.4%) were positive for anti-U1RNP. Among them, 124 (38.0%) had also one or more SSc-specific autoantibody positivity (30 (9.2%) ACA+, 79 (24.2%) ATA+ and 15 (4.6%) ARA+). For the subsequent analysis, the 327 anti-U1RNP positive patients were compared with 5716 anti-U1RNP negative patients. Among them, 1238 (21.7%) were positive for ACA, 2980 (52.1%) were positive for ATA, and 254 (4.4%) were positive for anti-RNA polymerase III (ARA). Anti-U1RNP + SSc-ILD patients were younger (50.8 ± 15.1 vs 57.1 ± 13.3 years, p < 0.001), were more commonly of non-Caucasian ethnicities (25.3% vs 5.0%, p < 0.001), had more frequently limited cutaneous involvement (63.5.5% vs 53.3%, p < 0.001), higher frequency of joint synovitis (18.1% vs 13.9%, p = 0.039), and myositis (24.0% vs 19.5%, p = 0.048). Involvement of more than 20% of lung parenchyma on HRCT was non-significantly more frequent in anti-U1RNP positive patients compared to anti-U1RNP-negative patients (26.9% vs 21.2%, p = 0.324). Anti-U1RNP positive patients had a baseline lower mean FVC% although being within the normal range (82.0% vs 86.0%, p < 0.001) and lower mean DLCO% (57.0% vs 60.5%, p = 0.003) (Table 1).
Table 1.
Univariable analysis of the EUSTAR database comparing anti-U1RNP+ and anti-U1RNP− SSc-ILD patients at baseline.
| Total (n = 6043) | Anti-U1RNP− (n = 5716) |
Anti-U1RNP + (n = 327) |
p-value | |
|---|---|---|---|---|
| Age, mean (SD) | 56.8 (13.2) | 57.1 (13.3) | 50.8 (15.1) | <0.001 |
| Female, n (%) | 4971/6042 (82.3) | 4692/5715 (82.1) | 279/327 (85.3) | 0.157 |
| Non-Caucasian, n (%) | 309/5048 (6.1) | 247/4971 (5.0) | 62/257 (25.3) | <0.001 |
| Smoking, n (%) | 970/3140 (30.9) | 923/2985 (30.9) | 47/155 (30.3) | 0.929 |
| Disease duration years, M (SD) | 9.4 (8.6) | 9.4 (8.5) | 9.6 (8.2) | 0.668 |
| Disease duration < 5 years, n (%) | 2767/6042 (45.8) | 2629/5715 (46.0) | 138/327 (42.2) | 0.189 |
| NYHA class | N = 4679 | N = 4377 | N = 259 | 0.238 |
| - 1 | 1990 (42.9) | 1866 (42.6) | 124 (47.9) | |
| - 2 | 1885 (40.7) | 1782 (40.7) | 103 (39.8) | |
| - 3 | 671 (14.5) | 642 (14.7) | 29 (11.2) | |
| - 4 | 90 (1.9) | 87 (2.0) | 3 (1.2) | |
| HRCT | N = 5703 | N = 5422 | N = 281 | |
| Involvement > 20%, n (%) | 222/1035 (21.4) | 208/983 (21.2) | 14/52 (26.9) | 0.324 |
| Ground glass, n (%) | 2315/4495 (51.5) | 2189/4235 (51.6) | 126/260 (48.5) | 0.312 |
| Honeycombing, n (%) | 348/1586 (21.9) | 331/1508 (21.9) | 17/78 (21.7) | 0.974 |
| PFTs | N = 6043 | N = 5716 | N = 327 | |
| FVC%, M (SD) | 85.8 (22.4) | 86.0 (22.2) | 82.0 (20.4) | <0.001 |
| FVC% < 80%, n (%) | 2380 (39.4) | 2242 (39.2) | 139 (42.5) | 0.295 |
| FVC% < 60%, n (%) | 700 (11.6) | 655 (12.2) | 46 (14.1) | 0.213 |
| DLCO%, M (SD) | 60.4 (19.8) | 60.5 (19.8) | 57.0 (19.1) | 0.003 |
| Extent of skin involvement | N = 4878 | N = 4604 | N = 274 | |
| Sine scleroderma, n (%) | 198 (4.1) | 192 (4.2) | 6 (2.2) | 0.116 |
| Limited, n (%) | 2628 (53.9) | 2454 (53.3) | 174 (63.5) | <0.001 |
| Diffuse, n (%) | 2052 (42.1) | 1958 (42.5) | 94 (34.3) | 0.008 |
| PAH, n (%) | 952/4413 (21.6) | 895/4164 (21.5) | 57/249 (22.9) | 0.580 |
| Digital ulcers, n (%) | 1540/3149 (48.9) | 1471/3001 (49.0) | 69/148 (46.6) | 0.614 |
| Joint synovitis, n (%) | 831/5884 (14.1) | 772/5564 (13.9) | 58/320 (18.1) | 0.039 |
| Myositis, n (%) | 1174/5948 (19.7) | 1096/5623 (19.5) | 78/325 (24.0) | 0.048 |
| Renal crisis, n (%) | 114/5942 (1.9) | 112/5620 (1.9) | 2/322 (0.6) | 0.092 |
| Upper GI involvement, n (%) | 3977/5959 (66.7) | 3773/5632 (67.0) | 224/327 (68.5) | 0.723 |
| Lower GI involvement, n (%) | 1396/5954 (23.4) | 1322/5631 (24.5) | 74/323 (22.9) | 0.893 |
| ATA, n (%) | 3059/6043 (50.6) | 2980/5715 (52.1) | 79/327 (24.2) | <0.001 |
| ACA, n (%) | 1268/6043 (21.0) | 1238/5715 (21.7) | 30/327 (9.2) | <0.001 |
| ARA, n (%) | 269/6043 (4.5) | 254/5715 (4.4) | 15/327 (4.6) | 0.890 |
| CRP elevation, n (%) | 1365/4643 (29.4) | 1295/4381 (29.6) | 70/262 (26.7) | 0.364 |
| Immunosuppression, n (%) | 2646/3631 (72.9) | 2491/3420 (72.8) | 155/211 (73.5) | 0.126 |
NYHA: New York Heart Association; HRCT: high-resolution computed tomography; PFTs: pulmonary function tests; FVC: forced vital capacity; DLCO: diffusing capacity of the lungs for carbon monoxide; PAH; pulmonary arterial hypertension; GI: gastrointestinal; ANA: anti-nuclear autoantibodies; ATA: anti-topoisomerase I autoantibodies; ACA: anticentromere autoantibodies; ARA: anti-RNA polymerase III autoantibodies; CRP: C-reactive protein. In bold: p-values <0.05.
When comparing anti-U1RNP positive patients without other SSc-specific autoantibodies (n = 217) to anti-U1RNP negative patients at baseline, anti-U1RNP positivity remained associated with younger age at diagnosis (50.7 ± 15.6 vs 57.1 ± 13.3 years, p < 0.001), non-Caucasian ethnicities (25.9% vs 5.0%, p < 0.001), lower FVC% (83.5% vs 86.0%, p < 0.001) and DLCO% (57.3% vs 60.5%, p = 0.003), and limited skin involvement (66.5.5% vs 53.3%, p < 0.001). However, joint synovitis and myositis were no longer statistically different between the two groups (Supplementary Table 1).
Prevalence of progressive ILD at 1 year
A total of 81 (24.8%) anti-U1RNP positive without other SSc-specific autoantibodies and 2304 (40.3%) anti-U1RNP negative SSc-ILD patients had at least > 1 FVC measurements available during the 12 ± 6 months follow-up period.
At 1 year, we found that among the 81 anti-U1RNP positive patients, 7 patients (8.6%) exhibited major FVC decline (⩾ 10%). In comparison, among the 2304 anti-U1RNP negative patients, 291 patients exhibited major FVC decline (12.6%). This difference was not statistically significant (p = 0.286).
Similarly, there were 15 (18.5%) anti-U1RNP positive patients showing moderate FVC decline (5%–9%) as compared to 382 (16.9%) anti-U1RNP negative patients (p = 0.212).
Finally, there were 59 (72.8%) anti-U1RNP positive patients with stable FVC changes (< 5%) as compared to 1633 (70.9%) anti-U1RNP negative patients. This difference was also not statistically significant (p = 0.70).
Subgroup analysis comparing double positive anti-U1RNP and ATA patients to ATA patients who did not show any significant differences in terms of progressors. The same was observed when comparing double positive anti-U1RNP and ACA to ACA patients (data not shown).
Prevalence of progressive ILD at 3 years
A total of 25 (7.6%) anti-U1RNP positive without other SSc-specific autoantibodies and 800 (14.0%) anti-U1RNP negative SSc-ILD patients had at least ⩾ 3 yearly FVC measurements available during the 36 ± 6 months follow-up period.
To evaluate the overall disease course, we assessed yearly FVC in SSc-ILD patients. When analyzing the prevalence of progressive ILD, we found that among the 25 anti-U1RNP positive patients, there were six periods of major FVC decline (⩾ 10%) out of a total of 75 (8.0%) periods. In comparison, among the 800 anti-U1RNP negative patients, there were 282 periods of major FVC decline out of a total of 2400 (11.8%) periods. This difference was not statistically significant (p = 0.46).
Similarly, there were 12 periods of moderate FVC decline (5%–9%) out of a total of 75 (16.0%) periods in anti-U1RNP positive patients as compared to 382 periods of a total of 2400 (15.9%) periods in anti-U1RNP negative patients (p = 0.99).
There were 57 periods of stable FVC changes (< 5%) out of a total of 75 (76.0%) periods in anti-U1RNP positive patients as compared to 1736 periods of a total of 2400 (72.3%) periods in anti-U1RNP negative patients. This difference was also not statistically significant (p = 0.52). Progression rates between anti-U1RNP negative and positive patients are represented in Figure 1.
Figure 1.
Periods of FVC changes during 36 ± 6 months follow-up among SSc-ILD patients with anti-RNP positive and anti-U1RNP negative autoantibodies in the EUSTAR database (percentage of patients per category).
Finally, after 3 years, no significant decrease was observed in the differential percentage of predicted forced vital capacity (%pFVC) in patients who were anti-U1RNP positive as compared with anti-U1RNP negative patients. The rate of change among the anti-U1RNP unique positive patients was −0.59% versus 0.95% among anti-U1RNP negative patients (p = 0.19).
As with the 1-year follow-up, the 3-year subgroup analysis comparing double positive anti-U1RNP and ATA patients to ATA patients showed no significant differences in terms of progressors. Similarly, no differences were observed when comparing double positive anti-U1RNP and ACA patients to ACA patients (data not shown).
In Figure 2, we illustrate the progression of SSc-ILD among patients with anti-U1RNP positive without other SSc-specific autoantibodies over 3 years of follow-up. Patients are categorized into stable, moderate, and major progression at the first, second, and third year.
Figure 2.
Flow of patients with SSc-ILD disease and anti-U1RNP positive autoantibodies, categorized by stable, moderate, and major progression at the first, second, and third year of follow-up (number of patients per category). This figure highlights the heterogeneity of SSc-ILD progression in patients with anti-U1RNP positive antibodies.
Mortality
Of the 91 anti-U1RNP positive SSc-ILD patients with available mortality data during the 3-year follow-up period, 4 (4.4%) died. Among the 2363 anti-U1RNP negative SSc-ILD patients, 157 (6.6%) died during this period. This difference in mortality rates was not statistically different between the two groups (p = 0.519).
Discussion
This study investigated the clinical associations and prognostic implications of positive anti-U1RNP autoantibodies in SSc-ILD patients using data from the EUSTAR database. Our findings reveal several noteworthy observations: while anti-U1RNP positivity was associated with specific baseline features and disease manifestations, particularly younger age at disease onset and more severe lung disease with lower pulmonary function parameters, its impact on lung progression and mortality outcomes appears to be limited.
Positivity for anti-U1RNP was found in 5.4% of > 6000 SSc-ILD patients and notably, a substantial proportion of these patients (38.0%) also exhibited positivity for other SSc-specific autoantibodies. Indeed, ACA and ATA are the commonest autoantibodies in SSc where the former is found in over 50% of patients, whereas the later can be found in up to 42% of patients and is associated with an increased risk of developing ILD.25,26 However, anti-U1RNP is considered to be the hallmark of MCTD. 27 Since SSc is a heterogeneous disease where the clinical manifestations depend on the disease subtype, delineation from other CTDs, particularly MCTD can be challenging. Moreover, in the context of ILD, the most common pattern observed in both SSc and MCTD is NSIP 28 thus making the distinction between these two entities even more challenging. To address this issue, Hoffmann-Vold et al. 29 evaluated the ability of the 2013 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) criteria to discriminate between SSc and MCTD. Interestingly, the authors observed that 96% of patients in the SSc subgroup met these criteria compared with 10% of patients in the MCTD subgroup, giving a 90% specificity of the 2013 ACR/EULAR criteria toward SSc. Furthermore, SSc-specific autoantibodies are considered to be very specific and mutually exclusive, this is particularly true for the three major SSc-specific autoantibodies (i.e. ACA, ATA, and ARA).30 –32 Notably, in a previous cohort of 72 SSc patients with at least two SSc-specific autoantibodies, the authors found that the autoantibody that most frequently associated with a double positivity was anti-U1RNP (72% of the patients). 21 The frequency of combinations with ATA and ACA with anti-U1RNP and ATA was 35% and 13%, respectively, which is line with our data. In addition, the authors also observed that patients anti-U1RNP and ATA or anti-U1RNP and ACA double positivity were significantly younger and had significantly more frequent overlap features including joint synovitis and myositis. Given that anti-U1RNP double positivity can be observed in the context of SSc, we chose to include both single and double positivity in our analysis to investigate the effects of anti-U1RNP positivity on the SSc-ILD phenotype.
Our study suggests that patients with SSc-ILD and anti-U1RNP positivity have more impaired lung function at baseline, suggesting a more severe ILD. When comparing pulmonary function parameters at baseline between our anti-U1RNP positive SSc-ILD patients and those from a previous cohort of 150 MCTD with associated ILD and anti-U1RNP positivity, 18 we observe that FVC and DLCO are very similar, thus indicating a similar ILD phenotype between these two entities and a direct role of anti-U1RNP autoantibodies. Recently, in a monocentric case–control study, Chevalier et al. 33 showed that SSc anti-U1RNP positive patients more frequently developed ILD when compared to SSc anti-U1RNP negative patients. Consequently, the hypothesis of a pattern of more rapid declining FVC in these patients was raised. However, despite a negative impact of anti-U1RNP on baseline lung function, our findings suggest that anti-U1RNP positivity did not significantly influence the rate of lung progression in terms of FVC decline in our multicenter large series. We observed differences in the proportions of major (⩾ 10%) and moderate (5%–9%) FVC declines between anti-U1RNP positive and negative patients, yet these variations were not statistically significant. One possible explanation might be related to the number of analyzed anti-U1RNP positive patients with at least three FVC measurements (n = 25) which was significantly lower compared to the number of anti-U1RNP negative patients (n = 821), potentially too low to demonstrate any differences. Moreover, ILD patterns in patients with SSc-ILD are very heterogeneous, with most patients showing both progressive and stable periods. 8 In our study, due to a lack of long-term prospective lung function data in anti-U1RNP positive patients, we decided to define a 3-year follow-up period, which was probably too short to reveal any significant differences in the behavior and progression of ILD between the two groups.
Regarding mortality outcomes, we observed no significant difference in mortality rates between anti-U1RNP positive and negative SSc-ILD patients during the 3-year follow-up period. Despite a lower mortality rate observed among anti-U1RNP positive patients (4.4%) compared to anti-U1RNP negative patients (6.6%), this disparity did not reach statistical significance. Once again, the short follow-up period might not have been sufficient to reveal any differences in mortality in this chronic and progressive condition.
Limitations of our study are inherent to its nature of a large, international, multicenter study, related to variations in data collection methods, laboratory protocols for autoantibody identification, ILD screening, and lung function evaluation Specifically, PFT results are subject to variability due to differences in test performance, patient condition, and the accuracy of testing equipment. Variations in testing accuracy across facilities may have influenced the reliability of our results, highlighting the challenges related to such a broad and diverse database. Another possible limitation is related to the lack of complete data regarding the long-term outcomes of ILD particularly PFTs. Furthermore, there are ethnic variations that are known to influence the severity and outcomes of SSc-ILD; 34 however, this variable was not available for a sufficient number of patients to be analyzed within this study. In addition, HRCT findings were not centrally reviewed. The data included in this study were entered directly by investigators based on local assessments rather than centrally reviewed data. While this may introduce variability, it reflects real-world practice across multiple centers. Finally, we observed some discrepancies between PFT findings and HRCT/clinical data. Some of these differences may stem from non-ILD-related factors, such as anemia or other respiratory conditions; however, these were not specifically analyzed in this study.
In conclusion, the analysis of the largest series of anti-U1RNP + SSc-ILD patients so far reported provides insights into the clinical characteristics and prognostic implications of anti-U1RNP in this subgroup of patients. While anti-U1RNP positivity was associated with specific baseline features and disease manifestations, including younger age, non-Caucasian ethnicity, and lower pulmonary function parameters, its impact on disease progression and mortality outcomes appears to be limited. Further research with longer follow-up periods is warranted to validate these findings.
Supplemental Material
Supplemental material, sj-pdf-1-jso-10.1177_23971983251324827 for Interstitial lung disease in anti-U1RNP systemic sclerosis patients: A European Scleroderma Trials and Research analysis by Gonçalo Boleto, Corrado Campochiaro, Oliver Distler, Andra Balanescu, David Launay, Christina Bergmann, Paolo Airò, Fahrettin Oksel, Ana Maria Gheorghiu, Branimir Anic, Luc Mouthon, Sule Yavuz, Cristina-Mihaela Tanaseanu, Marco Matucci-Cerinic and Yannick Allanore in Journal of Scleroderma and Related Disorders
Appendix 1
List of EUSTAR collaborators: EUSTAR collaborators:
Serena Guiducci (Florence, Italy), Ulrich Andreas Walker (Basel, Switzerland), Florenzo Iannone (Bari, Italy), Maurizio Cutolo (Genova, Italy), Vasiliki Liakouli (Naples, Italy), Elise Siegert (Berlin, Germany), Simona Rednic (Cluj-Napoca, Romania), Patricia Carreira (Madrid, Spain), Gábor Kumánovics (Pecs, Hungary), Michele Iudici (Geneva, Switzerland), Elisabetta Zanatta (Padova, Italy), Bernard Coleiro (Balzan, Malta), Gianluca Moroncini (Ancona, Italy), Dominique Farge-Bancel (Paris, France), Kristofer Andréasson (Lund, Sweden), Alexandra Balbir-Gurman (Haifa, Israel), Annamaria Iagnocco (Torino, Italy), Luca Idolazzi (Verona, Italy), Joerg Henes (Tübingen, Germany), Johannes Pflugfelder (Stuttgart, Germany), Dorota Krasowska (Lublin, Poland), Bojana Stamenkovic (Niska Banja, Serbia), Lidia P. Ananieva (Moscow, Russia), Philipp Klemm (Bad Nauheim, Germany), Valeria Riccieri (Rome, Italy), Andra Balanescu (Bucharest, Romania), Francesca Ingegnoli (Milan, Italy), Vanessa Smith (Gent, Belgium), Francesco Paolo Cantatore (Foggia, Italy), Mette Mogensen (Copenhagen, Denmark), Marie Vanthuyne (Brussels, Belgium), Ellen De Langhe (Leuven, Belgium), Carolina de Souza Müller (Curitiba, Brazil), Svetlana Agachi (Chisinau, Republic of Moldova), Edoardo Rosato (Rome, Italy), Figen Yargucu Zhini (Bornova—Izmir, Turkey), Rosario Foti (Catania, Italy), Jorge Juan Gonzalez Martin (Madrid, Spain), Breno Valdetaro Bianchi (Rio de Janeiro, Brazil), Antonella Marcoccia (Rome, Italy), Vivien Hsu (New Brunswick, USA), Tim Schmeiser (Wuppertal-Elberfeld, Germany), Gabriela Riemekasten (Lübeck, Germany), Giovanna Cuomo (Naples, Italy), Jeska de Vries-Bouwstra (Leiden, Netherlands).
The statement: The Editor/ Editorial Board Member of JSRD is an author of this article; therefore, the peer review process was managed by alternative members of the Board and the submitting Editor/Board member had no involvement in the decision-making process.
Footnotes
Data availability statement: The data underlying this article will be shared on reasonable request to the corresponding author. The data are not publicly available due to data protection.
Author contributions: G.B., C.C. and Y.A. contributed to conceptualization of the study; G.B. and C.C. involved in formal analysis; G.B., C.C, O.D., A.B., D.L., C.B., P.A., F.O., A.M.G., B.A., L.M., S.Y., C-M.T., M.M-C., and Y.A. curated the data; G.B., C.C. and Y.A. participated in writing—original draft; G.B., C.C, O.D., A.B., D.L., C.B., P.A., F.O., A.M.G., B.A., L.M., S.Y., C-M.T., M.M-C., and Y.A. participated in writing—review & editing; Supervision, Y.A. All authors have read and agreed to the published version of the article.
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iDs: Gonçalo Boleto 
https://orcid.org/0000-0001-5891-1868
Corrado Campochiaro
https://orcid.org/0000-0001-6806-3794
Oliver Distler
https://orcid.org/0000-0002-0546-8310
Supplemental material: Supplemental material for this article is available online.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplemental material, sj-pdf-1-jso-10.1177_23971983251324827 for Interstitial lung disease in anti-U1RNP systemic sclerosis patients: A European Scleroderma Trials and Research analysis by Gonçalo Boleto, Corrado Campochiaro, Oliver Distler, Andra Balanescu, David Launay, Christina Bergmann, Paolo Airò, Fahrettin Oksel, Ana Maria Gheorghiu, Branimir Anic, Luc Mouthon, Sule Yavuz, Cristina-Mihaela Tanaseanu, Marco Matucci-Cerinic and Yannick Allanore in Journal of Scleroderma and Related Disorders