Clinical Correlations with Disease-Associated Auto-Antibodies in a Chinese Cohort with Systemic Sclerosis
Systemic sclerosis (SSc) is a complex autoimmune disorder marked by progressive fibrosis of the skin and internal organs, microvascular dysfunction, and dysregulated immune responses. A hallmark of SSc is the presence of circulating auto-antibodies (AAbs), which are detected in 90%–95% of patients. Among these, anti-topoisomerase I antibody (ATA), anti-centromere antibody (ACA), and anti-RNA polymerase III antibody (ARA) are the most prevalent, collectively accounting for 60%–80% of cases. These antibodies are integral to the 2013 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for SSc due to their high diagnostic specificity. However, the clinical implications of these AAbs, particularly in diverse ethnic populations, remain an area of active research. This study investigates the associations between SSc-associated AAbs and clinical phenotypes in a Chinese cohort, providing insights into disease heterogeneity, organ involvement, and prognostic markers.
Study Cohort and Methodology
The cross-sectional analysis included 144 patients diagnosed with SSc per the 2013 ACR/EULAR criteria from June 2018 to August 2020 at Huashan Hospital, Fudan University. Inclusion criteria mandated a chest high-resolution computed tomography (HRCT) scan and serological testing for ATA, ACA, and anti-nuclear-ribonuclear-protein (nRNP) antibodies. A subset of 64 patients underwent extended testing for ARA, anti-fibrillarin, anti-Th/To, anti-NOR90, and anti-platelet-derived growth factor receptor (PDGFR) antibodies. Patients were stratified into four disease subsets: diffuse cutaneous SSc (dcSSc), limited cutaneous SSc (lcSSc), overlap syndrome (with features of other autoimmune diseases), and SSc sine scleroderma (visceral involvement without skin changes).
Clinical data collection encompassed demographics (age at onset, gender, smoking history), disease duration (from Raynaud’s phenomenon [RP] or first non-RP symptom), and organ-specific manifestations. Skin fibrosis was quantified using the modified Rodnan skin thickness score (mRSS). Interstitial lung disease (ILD) was confirmed via HRCT, pulmonary arterial hypertension (PAH) by echocardiography (mean systolic pulmonary arterial pressure ≥40 mmHg), and scleroderma renal crisis (SRC) by acute renal dysfunction with hypertension or biopsy findings.
Auto-Antibody Profiles and Prevalence
The cohort exhibited distinct AAb patterns:
- ATA: 42.4% (61/144)
- ACA: 23.6% (34/144)
- ARA: 17.2% (11/64)
- Anti-nRNP: 10.6% (15/144)
- Anti-NOR90: 9.4% (6/64)
- Anti-fibrillarin: 6.3% (4/64)
- Anti-Ku: 3.5% (5/144)
- Anti-Th/To: 3.1% (2/64)
- Anti-PM-Scl: 2.8% (3/144)
Anti-PDGFR antibodies were absent in all tested patients. Notably, 17.2% (11/64) of the subset tested for extended AAbs were negative for all ten antibodies, termed “SSc-AAbs (–).” Due to low sample sizes for anti-fibrillarin, anti-Th/To, and others (<10 patients per group), statistical analyses focused on ATA, ACA, ARA, anti-nRNP, and SSc-AAbs (–) subgroups.
Clinical Correlations with Auto-Antibodies
Anti-Topoisomerase I (ATA)
ATA-positive patients demonstrated aggressive fibrotic phenotypes:
- Earlier Disease Onset: Mean age at onset was 44.8 ± 13.3 years vs. 50.0 ± 14.0 in ATA-negative patients (P=0.02).
- Severe Skin Fibrosis: Median mRSS was 8.0 (interquartile range [IQR]: 4.0–18.0) vs. 4.0 (IQR: 2.0–10.3) in ATA-negative patients (P=0.003).
- Higher ILD Prevalence: 64.6% of the cohort had ILD, with ATA positivity strongly associated with ILD (P<0.0001).
- Disease Subset: ATA-positive patients were more likely to have dcSSc (41.1% of dcSSc cases) than lcSSc or overlap subsets.
Anti-Centromere (ACA)
ACA-positive patients exhibited milder fibrosis and distinct demographics:
- Milder Skin Involvement: Median mRSS was 3.0 (IQR: 2.0–8.0) vs. 7.0 (IQR: 3.0–14.5) in ACA-negative patients (P=0.005).
- Lower ILD Risk: ACA positivity correlated with reduced ILD prevalence (P<0.0001).
- Female Predominance: ACA-positive patients were predominantly female (P=0.04).
- Disease Subset: Strong association with lcSSc (42.4% of lcSSc cases) vs. dcSSc or overlap (P<0.0001).
Anti-RNA Polymerase III (ARA)
ARA-positive patients presented with later disease onset (mean 56.0 ± 13.4 years vs. 45.9 ± 15.0 in ARA-negative patients; P=0.04). However, no significant correlations were found with renal crisis, contrasting previous reports linking ARA to SRC.
Anti-nRNP
Anti-nRNP positivity was associated with overlap syndromes (5.6% of overlap cases; P=0.0003 vs. dcSSc, P=0.001 vs. lcSSc) and milder skin fibrosis (median mRSS 2.0 vs. 7.0; P=0.009).
SSc-AAbs (–) Patients
Antibody-negative patients displayed a paradoxical trend toward severe skin involvement, with higher proportions of dcSSc vs. lcSSc (P=0.009). This suggests potential undiscovered AAbs driving fibrosis in seronegative subgroups.
Non-Correlations and Limitations
No significant associations were observed between AAbs and RP duration, digital ulcers, puffy fingers, telangiectasia, PAH, or SRC. The study’s cross-sectional design and limited sample size for rare AAbs (e.g., anti-fibrillarin) precluded robust analysis of their clinical relevance. Additionally, the low frequency of ARA-positive patients (n=11) may explain the absence of expected correlations with SRC.
Implications for Clinical Practice and Research
This study underscores the prognostic value of ATA and ACA in risk-stratifying SSc patients. ATA positivity should prompt vigilant monitoring for ILD and aggressive skin fibrosis, while ACA positivity may indicate a milder course. The heightened fibrotic burden in SSc-AAbs (–) patients highlights the need for expanded serological panels to capture novel antibodies. Future multicenter studies with longitudinal follow-up are warranted to validate these findings and explore mechanistic links between AAbs and disease endotypes.
doi.org/10.1097/CM9.0000000000001935
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