Systemic Sclerosis-Associated ILD: Insights and Limitations of ScleroID

1. Introduction

Systemic sclerosis (SSc) is a rare autoimmune disease characterized by widespread vasculopathy and progressive fibrosis of the skin and internal organs [1]. SSc-associated interstitial lung disease (SSc-ILD) is among the most severe complications, further impairing functional capacity and survival [2]. Assessing quality of life (QoL) in SSc-ILD is challenging, as SSc is a multisystem, inflammatory, and vasculopathic condition in which multiple organ domains contribute to overall disease burden [3,4]. This multifaceted involvement alters physical, emotional, and social well-being, yet the point at which patients begin to experience meaningful declines in daily functioning remains poorly defined [5].

Accurate evaluation of disease burden requires integrating both clinical assessments and the patient’s perspective. Traditional physician-derived indices—such as the European Scleroderma Study Group Activity Index (EScSG-AI), the Scleroderma Clinical Trials Consortium Activity Index (SCTC-AI), and the Medsger Severity Scale (MSS)—capture clinician-observed parameters but may not fully reflect the functional limitations and QoL impact experienced by patients [6,7,8].

In clinical studies of SSc-ILD, a variety of patient-reported outcome measures (PROMs) have been used to capture the impact of the disease and its treatments on QoL. Organ-specific instruments, such as the St. George’s Respiratory Questionnaire (SGRQ), King’s Brief Interstitial Lung Disease Questionnaire (K-BILD), and Functional Assessment of Chronic Illness Therapy–Dyspnea Scale (FACIT-D), primarily assess respiratory symptoms and their functional impact [9,10,11]. Generic PROMs, including the Short Form-36 Health Survey (SF-36), Health Assessment Questionnaire–Disability Index (HAQ-DI), and Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29), evaluate overall health status and disability [12,13,14]. In the SENSCIS trial [15], PROMs included the SGRQ, FACIT-D, and HAQ-DI, incorporating the Scleroderma HAQ Visual Analogue Scale (SHAQ VAS) assessed at baseline and week 52 for associations with SSc-ILD severity [16]. Other commonly applied tools include the Leicester Cough Questionnaire (LCQ), Mahler’s Dyspnea Index (MDI), and Baseline and Transition Dyspnea Indices (BDI/TDI) [17,18,19]. Recent studies, such as a prospective investigation correlating QoL with disease parameters and the Phase 2 ATHENA-SSc-ILD trial evaluating PRA023, have also integrated PROMs to assess patient-centered outcomes and the impact of therapeutic interventions on QoL [20,21].

Building on previous work, a novel PROM, the EULAR Systemic Sclerosis Impact of Disease (ScleroID), was recently introduced [22]. The ScleroID is a brief, patient-derived questionnaire designed to capture self-assessed disease severity in SSc. It comprises 10 items across multiple domains, including physical function and organ involvement, with two items on fatigue and respiratory difficulty, which may be particularly relevant in patients with pulmonary involvement. ScleroID has been validated across multiple European centers, including Romania, showing strong internal consistency, high reliability (intraclass correlation coefficient = 0.839), and sensitivity to change over time. Its role capturing the impact of SSc-ILD on patients’ daily functioning and QoL remains unclear, prompting the present investigation into its relationship with lung function. This reinforces the importance of integrating objective measures of organ involvement with patient-reported outcomes. , as recommended in recent EULAR and SCTC guidelines for comprehensive SSc assessment [23,24]..

2. Materials and Methods

2.1. Study Design

This prospective observational study was conducted from 15 October 2023 to 30 August 2025. Patients with SSc-ILD confirmed by high-resolution computed tomography (HRCT) of the thorax were recruited from the rheumatology clinic. All participants met the 2013 American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) classification criteria for SSc [25]. Written informed consent was obtained from all participants. SSc patients without evidence of ILD were excluded. The study complies with the Declaration of Helsinki and approved by the Research Ethics Committee of „Sfanta Maria” Clinical Hospital (IRB Number:41520).

We retrieved pulmonary function tests (PFTs) and electronic lung HRCT image files from both baseline and the last available follow-up visit. The extent of lung fibrosis on HRCT, characterized by the presence of reticular changes and/or honeycombing, was classified as either <20% or ≥ 20% relative to the total lung volume [26]. PFTs including diffusing lung capacity for carbon monoxide (DLCO), forced vital capacity (FVC), and forced expiratory volume during the first second (FEV1) were conducted following the guidelines of the American Thoracic Society/European Respiratory Society (ERS) [27]. We also recorded the 6-minute walk test (6-MWT) and assessed dyspnea symptoms using functional classes [28]. Documentation of right heart catheterization (RHC) was noted when performed, and pulmonary hypertension (PH) was diagnosed according to the 2015 European Society of Cardiology/ERS guidelines, defining PH as a mean pulmonary arterial pressure (mPAP) ≥25 mm Hg, measured with RHC [29]. In the absence of RHC, PH was defined as a systolic arterial pressure (sPAP) >40mmHg on the echocardiography. Patients with available data over a 10-year follow-up period were evaluated for ILD progression, which was assessed by absolute changes in percentage predicted from baseline to follow-up, and defined as severe (total FVC decline >10%), moderate (FVC decline, 5-10%), or stable FVC (≤ 5% change) [30,31,32].

The study aimed to evaluate the associations between the ScleroID, disease activity, and severity scores with baseline lung involvement in SSc-ILD patients. Disease activity was assessed using the European Scleroderma Study Group Activity Index (EScSG-AI) and the Scleroderma Clinical Trials Consortium Activity Index (SCTC-AI), both of which combine clinical and laboratory domains, with higher indicating greater disease activity. Disease severity was assessed using the Medsger Severity Scale (MSS), which rates major organ involvement on a 0–4 scale (0 = no involvement, 4 = severe involvement). QoL was measured using the self-administered validated Romanian version of the ScleroID questionnaire, in addition to the clinical indices above [33].

Besides demographic data, collected information included SSc subtype (limited vs diffuse), disease duration calculated from the onset of non-Raynaud’s phenomenon, routine hematologic and immunologic tests, and nailfold capillaroscopy findings [34,35,36]. Clinical features such as digital ulcers, telangiectasia, tendon friction rubs, PH, muscle weakness, and upper and lower gastrointestinal symptoms, (if ever present) were recorded. Data on mortality related to ILD was also included.

2.2. Statistics

Baseline characteristics of the cohort were summarized using descriptive statistics, and the distribution of continuous variables was assessed with the Shapiro-Wilk test. Group comparisons were performed using two-sample t-tests, Chi-square tests, Kruskal-Wallis tests, or Mann-Whitney U tests, as appropriate. Relationships between patient-reported outcomes, disease activity and severity indices, and lung-specific measures were explored using Spearman’s rank correlation coefficient (rho). Patients were stratified by HRCT-assessed lung fibrosis extent (10–20% vs. ≥20%) to determine whether associations differed by fibrosis severity. All statistical tests were two-sided, and a p-value <0.05 was considered statistically significant. Analyses were conducted using IBM SPSS Statistics version 31.0.0.0, and graphical representations of correlations and group comparisons were generated to visualize trends in disease activity, severity, and patient-reported impact across fibrosis strata.

2.3. Results

2.3.1. Baseline Characteristics

Mean age was 56.0 (±10.8) years and median time since first non-Raynaud’s symptom was 4.2 (±4.7) years. Mean FVC% predicted was 76.8%, and mean DLCO% pre dicted was 54.3%. Mean baseline EscSG-AI total score was 6.1 (±1.7), baseline SCTC-AI was 34.5 (±14.8), Medsger severity score was 9.6 (±3.8), ScleroID total 4.1 (±2.4), and breathlesness item of ScleroID score was 3.8 (±2.9). No significant differences were observed by sex, age, or disease duration; however, patients with diffuse cutaneous SSc had higher SCTC-AI scores (p = 0.03), ATA positivity was associated with higher EscSG-AI scores (p = 0.04), while dyspnea of NYHA class > III and FVC < 80% predicted correlated with higher EscSG-AI scores (p = 0.05 and p = 0.04, respectively); notably, an HRCT fibrosis extent >20% and the presence of pulmonary hypertension were both linked to significantly higher scores across all instruments (p < 0.001) (Table 1).

Patients with ≥ 20% fibrosis on HRCT at baseline reported worse mean scores in most ScleroID items than those between 10-20%, again reflecting worse QoL in patients with more severe disease: Fatigue 5.56 vs 3.97 (p=0.02), Social life 5.23 vs 2.88 (p=0.001), Body mobility 5.10 vs 3.32 (p=0.01), Breahlesness 4.64 vs 2.61 (p=0,003). Similarly, NYHA functional class and worst Borg scale during the 6-MWD reported worse mean scores (Figure 1).

2.3.2. Cross-sectional Associations Between ScleroID Items and Baseline Lung Parameters

Higher ScleroID scores were associated with worse lung function and exercise capacity, reflected by lower FVC% and shorter 6-minute walk distance. In addition, both total and individual ScleroID items showed positive associations with ILD extent on HRCT, indicating that greater patient-reported disease impact corresponds not only to functional impairment but also to more extensive radiographic lung involvement (Figure 2).

Stratifying patients based on the extent of lung fibrosis showed that ScleroID domains (fatigue, social impact, mobility, and breathlessness) were strongly interrelated in both subgroups. In patients with 10–20% and >20% fibrosis, fatigue correlated with social impact (r = 0.700 vs. 0.686, p < 0.001), mobility (r = 0.618 vs. 0.778, p < 0.001), and breathlessness (r = 0.598 vs. 0.737, p < 0.001), and mobility correlated with breathlessness (r = 0.772 vs. 0.588, p < 0.001). NYHA class was consistently associated with fatigue (r = 0.466 in both groups) and, in the >20% group, also with social impact (r = 0.608, p < 0.001) and mobility (r = 0.568, p < 0.001). Differences emerged in functional correlations: in the 10–20% group, mobility and breathlessness were linked to exercise-induced desaturation (r = –0.561 and –0.602) and worst Borg scores (r = 0.641 and 0.531), whereas in the >20% group, correlations with FVC% and 6-MWD remained weak. Overall, the pattern of interrelated symptoms and associations with NYHA was similar across subgroups, but exercise-induced limitation and perceived exertion were more pronounced in patients with 10–20% fibrosis.

2.3.3. Impact of SSc Disease Activity and Damage on QoL in the Studied SSc-ILD Cohort

Regarding the correlation between disease activity, severity, and ScleroID, fatigue, social impact, and mobility were the domains most related to activity and severity scores. In patients with >20% fibrosis, fatigue correlated with Medsger total (r = 0.373, p = 0.019), mobility with ESsSG AI (r = 0.384, p = 0.016) and Medsger total (r = 0.525, p < 0.001), and all three domains correlated with SCTC total (r = 0.515–0.635, all p < 0.001). In the 10–20% group, correlations were weak or absent, with fatigue showing only weak negative correlations with SCTC total (r = –0.341, p = 0.045) and ESsSG AI (r = –0.359, p = 0.034). Breathlessness showed minimal associations in both groups (Figure 3).

4. Discussion

In this study, we evaluated baseline patient-reported outcomes using ScleroID in a cohort of SSc patients with varying degrees of ILD, examining their associations with clinical measures of disease activity, organ involvement, and QoL. Our findings provide novel insights into how patient-perceived disease impact aligns—or sometimes diverges—from objective measures of organ involvement and functional status.

Functional impairments, such as NYHA class > III dyspnea and FVC < 80% predicted, were associated with higher ESsSG-AI scores, underscoring the influence of pulmonary function on both clinician-assessed and patient-reported disease activity. Interestingly, even in patients with significant pulmonary involvement—such as those with FVC below 80% predicted or experiencing a decline greater than 10%—the mean ScleroID score remained relatively low (4.8 ± 2.3). This suggests that factors beyond objective pulmonary function contribute to patient-reported outcomes in SSc. Paradoxically, patients with less severe dyspnea (NYHA class < III) sometimes reported higher ScleroID scores, highlighting the complex interplay between symptoms, perception, and disease burden.

Overall, higher ScleroID scores corresponded to greater fatigue, reduced mobility, social limitations, and breathlessness, highlighting the tool’s sensitivity to patient-perceived disease burden and quality of life, independent of objective lung function or fibrosis extent. In our cohort, ScleroID reliably reflected the patient-perceived impact of SSc-associated ILD (SSc-ILD) across all stages of lung fibrosis. In patients with 10–20% fibrosis, correlations with objective measures such as FVC% and 6-MWT were generally weak, whereas associations with exercise-induced desaturation and Borg scores were more pronounced. This suggests that in early-to-moderate fibrosis, patients primarily experience disease impact through symptoms and functional limitations rather than ventilatory impairment alone. In patients with >20% fibrosis, ScleroID scores were strongly interrelated and clearly associated with NYHA class, yet correlations with FVC% and 6-MWT remained modest. This indicates that even in more extensive lung involvement, ScleroID primarily captures patient-perceived limitations and quality of life rather than radiographic or physiological severity. Overall, these findings demonstrate that higher ScleroID scores correspond to greater fatigue, mobility and social limitations, and breathlessness, highlighting the tool’s sensitivity to patient-reported disease burden independently of objective pulmonary function. These observations align with prior studies emphasizing that patient-reported outcomes provide complementary insights to traditional measures, particularly in chronic, multisystem diseases such as SS [28,38,39,40].

In both fibrosis subgroups, ScleroID domains—fatigue, social impact, mobility limitations, and breathlessness—were strongly interrelated, indicating that SSc patients experience a coherent construct of disease burden. The EULAR ScleroID has been compared with other PROMs, demonstrating its validity and reliability in capturing the disease impact in SSc patients [22]. The EULAR Systemic Sclerosis Impact of Disease (ScleroID) questionnaire serves as a comprehensive patient-reported outcome measure, capturing the multifaceted impact of systemic sclerosis (SSc) on patients' lives. Our findings indicate that ScleroID domains exhibit stronger correlations with disease activity and severity in patients with greater than 20% fibrosis, while such correlations are weaker or absent in those with 10–20% fibrosis. Fatigue emerged as a significant correlate of disease activity in the >20% fibrosis subgroup, with a moderate positive correlation to the Medsger total score (r = 0.373, p = 0.019). This aligns with previous studies highlighting fatigue as a prevalent and debilitating symptom in SSc, significantly affecting patients' quality of life and social participation [41].

The association between fatigue and disease activity underscores its importance as a clinical indicator, particularly in advanced stages of fibrosis. Mobility demonstrated a strong positive correlation with both the Medsger total score (r = 0.525, p < 0.001) and the ESsSG AI (r = 0.384, p = 0.016) in the >20% fibrosis group. This finding is consistent with research indicating that musculoskeletal complications, including contractures and muscle weakness, significantly impair mobility and diminish quality of life in SSc patients [42]. The robust relationship between mobility and disease severity in advanced fibrosis stages highlights the utility of mobility assessments in monitoring disease progression. The social impact domain exhibited moderate to strong positive correlations with the SCTC total score (r = 0.515–0.635, all p < 0.001) in patients with >20% fibrosis. The interplay between fatigue and social impact underscores the broader implications of disease activity on patients' social well-being, particularly in advanced stages of fibrosis. In contrast, patients with 10–20% fibrosis exhibited weak or absent correlations between ScleroID domains and clinical measures of disease activity and severity. Notably, fatigue showed only weak negative correlations with the SCTC total (r = –0.341, p = 0.045) and ESsSG AI (r = –0.359, p = 0.034). These findings suggest that in the early to moderate stages of fibrosis, the impact of disease activity on patient-reported outcomes may be less pronounced, potentially due to the compensatory mechanisms or subclinical manifestations characteristic of these stages. Breathlessness demonstrated minimal associations with disease activity and severity in both fibrosis subgroups.

Figure 3. Relationship Between ScleroID Domains (Fatigue, Mobility, Social Impact) and Disease Activity/Severity Scores Stratified by Skin Fibrosis Extend

Figure 3. Relationship Between ScleroID Domains (Fatigue, Mobility, Social Impact) and Disease Activity/Severity Scores Stratified by Skin Fibrosis Extend

This may be attributed to the relatively preserved pulmonary function in patients with <20% fibrosis, as indicated by studies showing no significant difference in ScleroID scores between patients with forced vital capacity (FVC) ≤80% and those with FVC >80% [40]. The limited impact of pulmonary involvement on disease activity in early fibrosis stages may account for the weak correlations observed. The differential correlations observed between ScleroID domains and disease activity across fibrosis subgroups have important implications for clinical practice. In patients with >20% fibrosis, ScleroID domains, particularly fatigue, mobility, and social impact, serve as valuable indicators of disease activity and severity, aiding in monitoring disease progression and informing treatment strategies. Conversely, in patients with 10–20% fibrosis, clinicians may consider supplementing ScleroID assessments with other measures to capture the subtler manifestations of disease activity characteristic of this stage.

This study has several limitations. First, the analysis was based on baseline, cross-sectional data, which limits the ability to infer causal relationships between ScleroID scores and disease progression. Second, the sample sizes of fibrosis-based subgroups were relatively small, which may affect statistical power and generalizability. Additionally, ScleroID is a patient-reported outcome measure, and scores may be influenced by psychosocial factors or comorbidities not captured in this study. Finally, not all clinical manifestations and functional parameters (e.g., high-resolution imaging or specific inflammatory markers) were included, which may limit the comprehensive interpretation of correlations with disease activity and severity.

5. Conclusions

PROMs provide essential insights into the broad impact of SSc, especially in patients with early to moderate ILD. The ScleroID tool captures key aspects of disease burden—fatigue, mobility limitations, and social participation—that are often overlooked by traditional clinical measures. Even when lung function appears preserved, PROs reveal significant patient-perceived limitations, highlighting the importance of including subjective assessments in routine care to support personalized management.