Scleroderma-Specific Autoantibodies and Disease Trajectories in Early Systemic Sclerosis: Insights From a Single-Center Prospective Registry.

INTRODUCTION

Systemic sclerosis (SSc, also known as scleroderma) is a rare and clinically heterogeneous autoimmune disease characterized by immune dysregulation, vasculopathy, and progressive fibrosis of the skin and internal organs. 1 Among connective tissue diseases, SSc carries the highest disease‐specific mortality and substantially impairs quality of life. 2 Clinically, SSc is categorized into limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc), with dcSSc representing approximately one‐third of patients and associated with rapid internal organ involvement and poorer outcomes. 3 Interstitial lung disease (ILD) and cardiac complications, including pulmonary hypertension (PH), are the leading contributors to SSc‐related morbidity and mortality. 4

Immune‐mediated processes are most pronounced during early dcSSc, making timely diagnosis and accurate risk stratification essential for guiding early immunosuppressive therapy. 5 , 6 , 7 However, predicting individual disease trajectories in very early dcSSc remains challenging due to disease rarity, clinical heterogeneity, and limited prospective data from this early phase. Existing multicenter and observational cohorts often include patients with heterogeneous disease durations or focus on single‐organ involvement, which may not capture contemporary clinical practice. 8

Autoantibodies are central to SSc diagnosis, classification, and risk stratification. Three major disease‐specific autoantibodies—anticentromere antibody (ACA), anti‐topoisomerase I antibody (Scl70), and anti‐RNA polymerase III antibody (RNAP3)—are associated with distinct clinical subsets and organ involvement patterns. 9 , 10 , 11 Scl70 is primarily linked to dcSSc, higher prevalence of ILD, and worse overall prognosis. 10 , 12 , 13 ACA is associated with lcSSc, digital ulcers, and isolated PH, whereas RNAP3 is linked to rapidly progressive diffuse skin involvement, scleroderma renal crisis (SRC), and increased malignancy risk. 10 , 12 , 13 Comprehensive profiling of autoantibody presence, combinations, and relative frequencies may enhance early risk stratification and guide individualized management.

Beyond classic SSc‐specific autoantibodies, patients frequently harbor autoantibodies against extractable nuclear antigens, including anti–Sjögren's‐syndrome‐related antigen A/B (SSA/SSB), anti‐Th/To, anti‐PM‐Scl, anti‐Ku, anti‐U3RNP (fibrillarin), and anti‐U1RNP antibodies. 10 , 14 , 15 , 16 , 17 SSA/SSB, comprising Ro52 and Ro60 proteins, is detected in 10% to 35% of patients with SSc and may indicate overlap with Sjögren's syndrome. 12 Although SSA/SSB has been proposed as a marker of specific clinical subsets or organ involvement, its prognostic significance remains controversial, and evidence regarding associations with ILD or mortality is limited. Anti‐U1RNP antibodies are detected in a subset of patients with SSc, often in association with overlap features or mixed connective tissue disease phenotypes. 18 However, their prognostic relevance in very early or at‐risk dcSSc, particularly for longitudinal organ outcomes, remains poorly defined.

In addition to qualitative profiles, quantitative autoantibody titers may provide further prognostic information. Post hoc analyses of a single‐center cohort demonstrated that higher titers of Scl70, ACA, and RNAP3 were associated with greater baseline skin involvement, measured by the modified Rodnan skin score (mRSS). 19 These findings indicate that combining autoantibody specificity and titers may refine early risk stratification, particularly for skin fibrosis, although their utility for long‐term outcomes remains uncertain.

To address these knowledge gaps, the University of Michigan's early SSc registry enrolls patients with very early or at‐risk dcSSc, offering a unique opportunity to evaluate baseline clinical features, autoantibody profiles, quantitative titers, and longitudinal outcomes during this critical early phase. Leveraging this cohort, the present study aimed to characterize the prevalence, titers, and clinical associations of SSc‐specific and overlapping autoantibodies—including SSA/SSB—and to investigate their relationships with disease trajectories, organ involvement, and long‐term outcomes. By delineating early immunologic and clinical patterns, this study seeks to inform personalized management strategies and improve prognostication in very early or at‐risk dcSSc.

PATIENTS AND METHODS

Study participants

This retrospective analysis used prospectively collected data from an institutional review board–approved, single‐center observational registry of patients with early SSc at a large scleroderma center. The registry was established in April 2012, and a subset of consecutive patients with very early disease enrolled between October 2012 and July 2021 (last patient enrolled) was included. Participants underwent standardized clinical assessments at regular study visits, and all available longitudinal follow‐up data through June 2026 (data cutoff) were analyzed.

Eligible participants were adults (≥18 years) with very early dcSSc, defined as disease duration less than two years from the first non‐Raynaud phenomenon (RP) symptom, or individuals considered at risk for dcSSc based on the presence of swollen hands or sclerodactyly with Scl70 or RNAP3 antibodies and/or tendon friction rubs despite the absence of extensive skin involvement. 8 All participants provided written informed consent before enrollment.

Autoantibody testing and classification

Autoantibody testing was performed according to established protocols as described in a recent publication. 20 The panel included ACA, Scl70, RNAP3, SSA/SSB, Sm/RNP, U1RNP, Jo‐1, ribosomal protein, and chromatin antibodies, measured using a multiplex assay, and Scl70 was confirmed by immunodiffusion. 20

Participants were classified into three primary autoantibody‐defined groups: RNAP3+, Scl70+, and triple‐negative (defined as negative for RNAP3, Scl70, and ACA). Patients in the triple‐negative group could still have other autoantibodies, including SSA/SSB or U1RNP. Accordingly, SSA, SSB, and U1RNP were recorded separately, and participants were categorized as positive or negative for each of these antibodies.

Outcomes and follow‐up

Data were collected at baseline and every 6 months (±3 months) during routine clinical visits. Case report forms included demographic information (age, sex, and race), past and current immunosuppressive medication use, and SSc‐specific autoantibodies. Clinical assessments comprised the mRSS and routine investigations such as pulmonary function tests (PFTs), right‐sided heart catheterization (RHC), transthoracic echocardiography (TTE), and chest imaging (chest x‐ray or high‐resolution computed tomography [HRCT]). At each visit, physicians completed standardized assessments of vascular, cardiopulmonary, gastrointestinal, and renal involvement. Participants also completed the Health Assessment Questionnaire–Disability Index (HAQ‐DI).

PH was defined as a mean pulmonary artery pressure (mPAP) ≥25 mm Hg measured by RHC, in accordance with international guidelines. 21 Although recent guidelines have revised the hemodynamic definition of PH to mPAP >20 mm Hg, we retained the ≥25 mm Hg threshold for consistency with the historical study definition and analyses. Dates of RP onset and the first non‐RP symptom were retrospectively recorded at baseline to determine disease duration. Skin disease progression was defined as a clinically significant worsening of skin fibrosis, specified as either an absolute increase of ≥5 mRSS units or a relative increase of ≥25% from baseline. 22 For the patients who had a relative increase of ≥25% from baseline, they also had to worsen by more than three units (intrarater variability of mRSS). Lung involvement was assessed as absolute decline in forced vital capacity (FVC) of ≥10% predicted from baseline. 23 Cardiac involvement was assessed by a left ventricular ejection fraction (LVEF) ≤45% on TTE during follow‐up. Musculoskeletal involvement was based on standardized physician clinical assessment documented at each study visit. Imaging‐based confirmation of synovitis (eg, ultrasound or magnetic resonance imaging) was not done. All immunosuppressive therapies, including prednisone exposure, were captured at each visit. Prednisone usage was captured as the use of any dose of prednisone during follow‐up. Vital status and cause of death were ascertained through review of medical records and death certificates.

Statistical analysis

Demographic and baseline information—including musculoskeletal data, antibodies other than RNAP3, Scl70, and ACA, PFT measurements, medication usage, and medications used at any time during follow‐up—were tabulated for the whole cohort and by antibody groups (triple‐negative, RNAP3+, and Scl70+). Means and SDs were reported for numeric variables, except for disease duration, for which the median and first and third quartiles (Q1, Q3) were reported. Analysis of variance tests were used to compare group differences for normally distributed continuous variables, and Kruskal–Wallis tests were used for skewed continuous variables. Counts and percentages were reported for categorical variables, and chi‐squared tests or Fisher exact tests were applied, as appropriate, to compare group differences. Similarly, counts and percentages of first new events were reported by antibody group. Cumulative incidence curves for each event were generated by the antibody group to display the probability that a specific event has occurred by a given time. Cumulative incidence was calculated as one minus survival probability, and log‐rank tests were performed to compare the three antibody groups. Cancer data were reported for the whole cohort, as well as by the antibody group. For cancers that occurred after SSc diagnosis, the duration from SSc diagnosis to cancer diagnosis was calculated and reported as median (Q1, Q3); for cancers that occurred before SSc diagnosis, the duration from cancer diagnosis to SSc diagnosis was calculated and reported as median (Q1, Q3). In a similar method, death data were reported for the whole cohort, as well as by antibody groups, and duration from SSc diagnosis to death was calculated and reported as median (Q1, Q3). All statistical analyses were performed in SAS (version 9.4) with a significance level of 0.05, and P values were not adjusted for multiple comparisons and should be interpreted descriptively, scatter plots were created in SAS, and cumulative incidence curves were created in RStudio (version 4.4.3).

RESULTS

Cohort characteristics and follow‐up

Among 115 patients with available autoantibody data, 6 patients with ACA positivity were excluded from subgroup analyses due to the small sample size. The final analytic cohort included 109 patients. The study design, cohort selection, and analytical framework are summarized in Supplementary Figure S1 .

The overall mean age was 51.1 (SD 14.7) years, 65.1% were female, and most patients were White (77.1%), followed by Black (16.5%) and other races (6.4%) (Table 1 ). dcSSc was present in 85.3% of patients, and the median disease duration from first non‐RP symptom was 1.0 (interquartile range [IQR] 0.7–1.5) year. At baseline, 61.5% of patients were receiving immunosuppressive therapy, and 92.7% received at least one immunosuppressive agent during follow‐up (Table 2 ). Mycophenolate mofetil was the most commonly prescribed immunosuppressive medication (78.9%), followed by prednisone (44.0%), methotrexate (19.3%), hydroxychloroquine (15.6%), and cyclophosphamide (10.1%). In addition to standard immunosuppressive therapy, 24 of 109 patients (22.0%) in the autoantibody subgroup analysis received investigational therapies or participated in interventional studies, including 16 of 42 (38.1%) RNAP3+ patients, 2 of 29 (6.9%) Scl70+ patients, and 6 of 38 (15.8%) triple‐negative patients. Immunomodulatory trial agents included tofacitinib (n = 10), abatacept (n = 5), an autotaxin inhibitor (n = 4), brentuximab (n = 1), and abituzumab (n = 1). For vasodilatory therapy trials, six patients participated in an intravenous iloprost trial for RP and one patient in a riociguat trial. Seven patients (6.1%) underwent autologous hematopoietic stem cell transplantation (HSCT) during follow‐up.

Autoantibody distribution and subgroup characteristics

Of the 115 patients, 42 (36.5%) were RNAP3+, 29 (25.2%) were Scl70+, 6 (5.2%) were ACA+, and 38 (33.0%) were triple‐negative. Anti‐SSA/SSB antibodies were detected in 18 patients (16.5%), most commonly among Scl70+ patients (10 of 29, 34.5%), whereas anti‐U1RNP antibodies were present in 16 patients (14.7%), predominantly in the triple‐negative (8 of 38, 21.1%) and Scl70+ (6 of 29, 20.7%) groups.

RNAP3+ patients were significantly older (mean 56.0 years) compared to Scl70+ (47.0 years) and triple‐negative (48.7 years) patients ( P = 0.02), but sex and racial distributions did not differ ( P = not significant). The prevalence of dcSSc was highest in RNAP3+ patients (97.6%), followed by triple‐negative (81.6%) and Scl70+ (72.4%) patients ( P < 0.01), whereas median disease duration from first non‐RP symptoms was similar across groups.

RNAP3+ patients demonstrated more severe skin and musculoskeletal involvement, with the highest baseline mRSS, HAQ‐DI scores, and frequency of tendon friction rubs (all P < 0.01; Table 1 ). In contrast, Scl70+ patients had the highest prevalence of SSA/SSB positivity ( P < 0.01). Baseline pulmonary function, including FVC percent predicted and diffusing capacity for carbon monoxide percent predicted, was similar across the three autoantibody groups, although ILD on HRCT was numerically more common among Scl70+ patients. Baseline immunosuppressive treatment did not differ significantly between groups; however, cumulative immunosuppressive therapy during follow‐up differed significantly, with RNAP3+ patients receiving immunosuppressive therapy less frequently than the other subgroups ( P = 0.04; Table 2 ).

Clinical events during follow‐up

Of the 109 patients, 17 experienced a qualifying clinical event before registry enrollment and were excluded from the time‐to‐event analysis (Table 3 ). These included five with SRC, three with PH, seven with LVEF ≤45%, one each with SRC + LVEF ≤45%, and PH + LVEF ≤45%. Among the 92 patients included in the time‐to‐event analysis, 50 (54.3%) experienced at least one new clinical event during follow‐up (Table 3 ). Although no statistically significant differences were observed between antibody subgroups, the proportion of patients with any event was numerically higher in the RNAP3+ group (59.4%), followed by Scl70+ (57.1%) and triple‐negative patients (46.9%, P = 0.57). Eighteen (19.6%) patients were positive for anti‐SSA/SSB antibodies, and the frequency of any event in this subgroup (44.4%) was similar to that of double‐negative patients (56.8%; P = 0.35). Fifteen (16.3%) were positive for U1RNP antibodies, and the frequency of any event in this subgroup (46.7%) was similar to that of U1RNP‐negative patients (55.8%; P = 0.51).

Among the 92 patients included in the time‐to‐first‐event analysis, mRSS worsening occurred in 11 patients (12.0%), FVC decline in 12 (13.0%), HAQ‐DI worsening in 16 (17.4%), PH in 5 (5.4%), left ventricular systolic dysfunction in 1 (1.1%), and mortality in 4 (4.3%) (Table 3 ). The frequencies of these first clinical events did not differ significantly among the three SSc‐specific autoantibody groups. SRC occurred in three patients (3.3%), exclusively in the RNAP3+ (6.3%) and Scl70+ (3.6%) subgroups, with no cases among triple‐negative patients, although this difference was not statistically significant. Four deaths were recorded as the first clinical event, including three in the RNAP3+ group and one in the Scl70+ group. Two deaths were attributable to progressive ILD, one to metastatic squamous cell carcinoma, and one to sepsis associated with methotrexate toxicity.

When all clinical events during follow‐up were considered (Supplementary Table S1 ), event frequencies were higher because recurrent or subsequent events were also captured. Overall, mRSS worsening occurred in 16.3% of patients, FVC decline in 18.5%, HAQ‐DI worsening in 19.6%, PH in 8.7%, and mortality in 8.7%. SRC developed in four patients (4.3%) and was the only clinical event significantly associated with autoantibody subgroup ( P = 0.02), occurring predominantly in RNAP3+ patients.

Time‐to‐event analyses demonstrated that skin progression occurred primarily during the first two years after baseline, whereas declines in pulmonary function, disability progression, and mortality accumulated more gradually throughout follow‐up (Figure 1 ). Although RNAP3+ patients tended to experience a greater cumulative incidence of overall clinical events and SRC, and Scl70+ patients showed greater skin progression over time, differences between antibody groups were not statistically significant by log‐rank testing.

Malignancy

Overall, 28 of 109 (25.7%) patients had malignancy, accounting for 41 cancer diagnoses (Table 4 ). Five cancer events had missing dates, whereas among the remaining cancers, 13 occurred before SSc onset and 23 developed after SSc onset. The median interval from cancer diagnosis to SSc onset was 4 years (IQR 3–8 years) for pre‐SSc cancers, whereas cancers diagnosed after SSc onset occurred a median of 7 years (IQR 4–8 years) after disease onset.

Cancer prevalence was numerically highest in the RNAP3+ subgroup (35.7%), followed by the Scl70+ (24.1%) and triple‐negative (15.8%) subgroups. RNAP3+ patients also accounted for the greatest number of cancer diagnoses (21 of 41 cancers).

Skin cancers were the most common malignancies, particularly squamous cell carcinoma (15 events), followed by basal cell carcinoma (7 events) and melanoma (4 events). Breast cancer accounted for seven events, while eight additional malignancies were classified as other cancer types (Table 4 ).

Mortality

During follow‐up, 14 (12.8%) patients died (Table 5 ). The median time from SSc onset to death was 4.0 years (IQR 2.3–7.6). Five deaths were attributed to SSc‐related causes, including PH‐ILD (n = 3) and ILD (n = 2), whereas nine deaths were unrelated to SSc and were primarily due to metastatic squamous cell carcinoma (n = 2), sepsis (n = 2), and other causes (n = 5).

Mortality was numerically highest among RNAP3+ patients (14.3%), followed by triple‐negative (13.2%) and Scl70+ patients (10.3%). SSc‐related deaths were proportionally more common in the triple‐negative and Scl70+ subgroups, whereas most deaths in the RNAP3+ subgroup were unrelated to SSc. Among non‐SSc‐related deaths, metastatic squamous cell carcinoma and sepsis were the most frequent causes.

Association between autoantibody titers and clinical measures

We examined correlations between Scl70 and RNAP3 antibody titers and baseline and longitudinal changes in FVC percent and mRSS (Supplementary Table S2 ) in a subset of patients. At baseline, Scl70 titers had moderate correlations with mRSS and FVC percent predicted (ρ = –0.399, P = 0.10, ρ = –0.368, P = 0.20) but not for RNAP3 titers with mRSS (ρ = 0.317, P = 0.07) and FVC percent predicted (ρ = –0.156, P = 0.41).

During follow‐up, higher Scl70 titers showed a significant positive correlation with change in FVC percent (ρ = 0.308, P < 0.01), whereas RNAP3 titers were significantly inversely correlated with change in FVC (ρ = –0.277, P < 0.01). Correlations between antibody titers and change in mRSS were small and not statistically significant (Scl70: ρ = 0.148, P = 0.11; RNAP3: ρ = –0.078, P = 0.26). These relationships are illustrated in Supplementary Figure S2 .

DISCUSSION

This study provides a longitudinal analysis of prospectively collected data from a single‐center cohort of patients with very early or at‐risk dcSSc, integrating autoantibody profiles, quantitative antibody titers, and clinical outcomes over a median follow‐up of 5.5 years. Distinct phenotypic differences were observed across autoantibody‐defined subgroups. RNAP3+ patients demonstrated greater skin and musculoskeletal involvement, characterized by higher mRSS, greater disability burden, and a higher frequency of tendon friction rubs and large‐joint contractures, whereas Scl70+ patients had the highest prevalence of ILD. In contrast, triple‐negative patients generally exhibited fewer severe baseline manifestations. During follow‐up, more than half of patients experienced at least one new clinical event, with numerically higher event rates among RNAP3+ and Scl70+ patients compared with triple‐negative patients. However, organ‐specific outcomes, including skin progression, FVC decline, SRC, PH, and mortality, occurred at similar frequencies across autoantibody groups, although RNAP3+ patients demonstrated numerically higher frequencies of severe outcomes such as SRC and death.

These findings are consistent with previous studies describing distinct clinical phenotypes associated with SSc‐specific autoantibodies. RNAP3 positivity has been associated with rapidly progressive skin involvement, SRC, and increased malignancy risk, whereas Scl70 positivity has been linked to ILD development and poorer pulmonary outcomes. 24 , 25

Treatment exposure likely influenced the observed disease trajectories. More than 90% of patients received immunosuppressive therapy during follow‐up, predominantly mycophenolate mofetil, and approximately one‐quarter participated in interventional clinical trials or underwent HSCT. Although baseline treatment exposure was similar across autoantibody groups, cumulative immunosuppressive use during follow‐up differed, with RNAP3+ patients receiving immunosuppressive therapy less frequently than other subgroups, consistent with their higher participation in interventional studies and receipt of biologic therapies or stem cell transplantation. These differences may reflect individualized treatment decisions influenced by disease phenotype and perceived clinical risks, including efforts to minimize glucocorticoid exposure among patients at increased risk for SRC. Therefore, the clinical course observed in this cohort likely reflects the combined effects of underlying disease biology and contemporary treatment strategies rather than the natural history of untreated disease.

We also evaluated the potential prognostic significance of non–SSc‐specific autoantibodies. Anti‐SSA/SSB antibodies were present in approximately one‐sixth of patients and were more common among Scl70+ individuals, whereas U1RNP antibodies were observed primarily in Scl70+ and triple‐negative patients. Neither antibody was associated with an increased risk of longitudinal clinical events or mortality. Although previous studies have reported associations between anti‐SSA antibodies and more severe ILD or reduced survival, our findings did not confirm these observations. 12 , 26 Differences in study populations, disease duration, and sample size may account for these discrepancies, particularly because our cohort consisted exclusively of patients with very early or at‐risk disease.

Consistent with previous publications, malignancy occurred most frequently among RNAP3+ patients. 27 , 28 Similarly, deaths attributable to SSc were primarily related to progressive ILD or PH, emphasizing the continued importance of cardiopulmonary complications as the leading causes of mortality in SSc.

We also investigated quantitative autoantibody titers as potential biomarkers of disease severity and progression. In our cohort, baseline Scl70 and RNAP3 titers demonstrated exploratory correlations with baseline mRSS and FVC percent predicted, although these associations did not reach statistical significance. However, higher Scl70 titers were positively correlated with longitudinal changes in FVC percent predicted, whereas higher RNAP3 titers were inversely correlated with changes in FVC percent predicted. Interestingly, a recent analysis from the Zurich EUSTAR cohort demonstrated that higher levels of SSc‐specific autoantibodies, particularly RNAP3 and ACA, were associated with greater baseline skin fibrosis, although antibody levels did not predict longitudinal changes in mRSS. 19 Together, these findings suggest that quantitative autoantibody levels may provide additional prognostic information beyond antibody positivity alone and warrant further investigation as potential biomarkers of organ‐specific disease progression in larger prospective cohorts. 19 , 20

The strengths of this study include the prospective design of the underlying registry, standardized longitudinal clinical assessments, detailed serologic characterization, and prolonged follow‐up beginning early in the disease course. Studying patients within two years of the first non‐RP symptom provides a unique opportunity to characterize disease evolution during the period when irreversible organ damage is most likely to develop. Several limitations should also be acknowledged. The study was conducted at a single tertiary referral center, limiting generalizability. Subgroup sample sizes and the relatively small number of outcome events reduced statistical power to detect differences between autoantibody groups, even when we saw trends among different autoantibodies. Finally, not all known SSc‐associated autoantibodies were systematically evaluated, and quantitative titer analyses were available only for a subset of participants.

In conclusion, SSc‐specific autoantibodies remain valuable markers of baseline clinical phenotype in patients with very early or at‐risk dcSSc and show a trend toward distinct organ involvement and progression over time. Large multicenter studies with greater statistical power and comprehensive longitudinal biomarker assessment are needed to further clarify the independent prognostic value of autoantibody profiles in early SSc.

AUTHOR CONTRIBUTIONS

All authors contributed to at least one of the following manuscript preparation roles: conceptualization AND/OR methodology, software, investigation, formal analysis, data curation, visualization, and validation AND drafting or reviewing/editing the final draft. As corresponding author, Dr Khanna confirms that all authors have provided the final approval of the version to be published and takes responsibility for the affirmations regarding article submission (eg, not under consideration by another journal), the integrity of the data presented, and the statements regarding compliance with institutional review board/Declaration of Helsinki requirements.

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ACKNOWLEDGMENT

The authors used a large language model (ChatGPT) to assist with language editing and sentence clarity. All scientific content, data interpretation, and conclusions were generated solely by the authors.

1 Scleroderma Program, University of Michigan, Ann Arbor, MI, USA; 2 Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.

Additional supplementary information cited in this article can be found online in the Supporting Information section ( https://acrjournals.onlinelibrary.wiley.com/doi/10.1002/acr2.90142 ).

Author disclosures and graphical abstract are available at https://onlinelibrary.wiley.com/doi/10.1002/acr2.90142 .

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Associated Data

Supplementary Materials

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Data S2 : Supporting Information