Association Between Follistatin-Related Protein 1 and the Functional Status of Patients With Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) represents a group of systemic vasculitides affecting small vessels, characterized by necrotizing inflammation and minimal immune complex deposition. AAV encompasses three subtypes: microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic GPA (EGPA). The clinical assessment of AAV relies on indices such as the Birmingham Vasculitis Activity Score (BVAS) for disease activity, the Five-Factor Score (FFS) for prognosis, the Vasculitis Damage Index (VDI) for organ damage, and the Short-Form 36-item Health Survey (SF-36) to evaluate physical and mental health-related quality of life. Despite their utility, these indices require significant patient or physician input, underscoring the need for biomarkers that offer objective and efficient insights into disease status.
Follistatin-related protein 1 (FSTL1), a glycoprotein with dual pro- and anti-inflammatory roles, has emerged as a potential candidate. In inflammatory diseases like rheumatoid arthritis, FSTL1 promotes inflammation via pathways involving nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPK). Conversely, in cardiac ischemia-reperfusion injury, FSTL1 demonstrates protective effects. This study investigates whether serum FSTL1 levels correlate with AAV-specific indices, particularly functional status measured by SF-36, providing a novel biomarker for disease monitoring.
Study Design and Methods
This cross-sectional analysis included 74 AAV patients from a prospective Korean cohort. Patients were diagnosed according to established criteria and excluded if they had infections, malignancies, or coexisting systemic vasculitides. Clinical data, ANCA profiles, and disease indices (BVAS, FFS, VDI, SF-36) were recorded. Serum FSTL1 concentrations were measured using enzyme-linked immunosorbent assay (ELISA), with a sensitivity of <10 pg/mL and low intra-/inter-assay variability. Functional impairment was defined as the lowest tertile of SF-36 physical (PCS ≤38.4) and mental component scores (MCS ≤46.8). Statistical analyses included Spearman correlations, multivariable linear regression, and receiver operating characteristic (ROC) curves to identify FSTL1 cutoffs predictive of impaired functional status.
Key Findings
Demographic and Clinical Characteristics
The cohort had a median age of 62.5 years, with 55.4% female participants. MPA was the most common subtype (47.3%), followed by GPA (32.4%) and EGPA (20.3%). MPO-ANCA positivity was observed in 59.5%, while 8.1% had PR3-ANCA. The lungs (58.1%), kidneys (52.7%), and ear-nose-throat (44.6%) were frequently affected. Median SF-36 PCS and MCS scores were 50.8 and 54.2, respectively. Median serum FSTL1 was 879.1 pg/mL.
Correlation Analyses
Serum FSTL1 demonstrated significant negative correlations with SF-36 PCS (r = −0.374, P = 0.001) and MCS (r = −0.377, P = 0.001), indicating higher FSTL1 levels corresponded to worse physical and mental health. A weak positive correlation with C-reactive protein (CRP; r = 0.307, P = 0.008) suggested a link to systemic inflammation. Notably, FSTL1 did not correlate with BVAS, FFS, or VDI, highlighting its distinct association with functional status rather than disease activity or chronic damage.
Regression Analyses
In multivariable models adjusting for covariates:
- SF-36 PCS: Higher BVAS (β = −0.255), CRP (β = −0.430), and FSTL1 (β = −0.266) independently predicted worse physical function (all P < 0.05).
- SF-36 MCS: Similarly, BVAS (β = −0.234), CRP (β = −0.229), and FSTL1 (β = −0.296) were independently associated with impaired mental health (P < 0.05).
Predictive Value of FSTL1
ROC analysis identified serum FSTL1 thresholds predictive of low SF-36 scores:
- SF-36 PCS: A cutoff of ≥779.8 pg/mL yielded 72.7% sensitivity and 75.5% specificity (AUC 0.727). Patients above this threshold had a 7.6-fold increased risk of physical impairment (95% CI: 2.0–28.7).
- SF-36 MCS: A cutoff of ≥841.6 pg/mL provided 71.4% sensitivity and 71.7% specificity (AUC 0.754), with a 6.2-fold higher risk of mental health deficits (95% CI: 2.0–19.4).
Mechanistic Insights and Clinical Implications
FSTL1’s dual inflammatory roles may explain its unique association with functional status. While its pro-inflammatory effects (via NF-κB and MAPK pathways) could drive chronic inflammation impacting quality of life, anti-inflammatory actions (e.g., transforming growth factor-β modulation) might mitigate acute activity, explaining the lack of correlation with BVAS. The link to CRP suggests FSTL1 partly reflects systemic inflammation but is not a direct marker of acute flares.
Clinically, FSTL1’s predictive value for SF-36 scores offers utility in patients unable to complete self-reported surveys, such as those with cognitive impairment or critical illness. This biomarker could complement existing tools, enhancing holistic assessments of therapeutic outcomes.
Limitations and Future Directions
The study’s cross-sectional design precludes causal inferences, and the modest sample size limits generalizability. Longitudinal studies are needed to explore dynamic FSTL1 changes during disease progression and therapy. Including cytokine profiles (e.g., IL-6, TNF-α) could clarify mechanistic pathways. Additionally, validating cutoffs in diverse populations and AAV subtypes is essential for clinical translation.
Conclusion
Serum FSTL1 independently predicts impaired physical and mental health in AAV patients, offering a novel biomarker for functional status assessment. Its integration into clinical practice could improve monitoring and personalize care, particularly for patients with limited capacity for self-reporting.
doi: 10.1097/CM9.0000000000001454
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