ACR Convergence 2024: Rheumatoid Arthritis – Diagnosis, Manifestations, & Outcomes I: Breathe: RA-ILD

Peripheral Biomarker Signatures and a Genetic Risk Score Improve the Identification of RA-ILD Beyond Clinical Risk Factors

Speaker: Dr. Austin Wheeler, University of Nebraska Medical Center

Key Highlights:

Clinical Relevance of RA-ILD:

Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a severe complication affecting 5–10% of RA patients clinically, with up to 40% prevalence detected using high-resolution CT. It is the second leading cause of death in RA patients, highlighting the urgent need for better risk identification tools. Current risk factors include older age, male sex, smoking, high disease activity, and seropositivity for RF or anti-CCP antibodies.

Genetic Contributions to RA-ILD:

The MUC5b promoter variant is the strongest genetic risk factor for RA-ILD, validated across multiple cohorts. A composite genetic risk score integrating five single nucleotide polymorphisms (SNPs), including MUC5b, modestly improved prediction accuracy compared to MUC5b alone.

Dr. Wheeler explained the study in detail.

Results:

Predictive Models: Four models were tested for predicting RA-ILD:

The integrated model outperformed all others, demonstrating the value of combining data types for enhanced prediction accuracy.

Key Observations:

Challenges and Limitations:

The study faced several challenges and limitations, including the need for validation in non-VA cohorts to ensure the generalizability of its findings. The high cost of biomarker measurement presents a significant barrier to widespread clinical application, limiting its practicality. Additionally, reliance on clinical care-based diagnoses for RA-ILD may underestimate the prevalence of subclinical cases, highlighting the need for more systematic screening approaches.

Dr. Wheeler concluded that peripheral biomarker signatures, combined with genetic and clinical data, significantly improve RA-ILD prediction. These findings pave the way for personalised risk stratification approaches, though external validation and model refinement are crucial for clinical adoption.

Associations of Rheumatoid Arthritis Polygenic Risk with Age at Onset, Serostatus, and Interstitial Lung Disease

Speaker: Dr. Gregory McDermott, Brigham and Women’s Hospital, Harvard Medical School

Key Highlights:

Background and Objectives:

Dr. Gregory McDermott presented data from the Mass General Brigham Biobank, with over 1,52,000 patients which integrates over 120 RA-associated loci and the HLA shared epitope into an RA GRS. The study explored associations between the RA GRS and key disease phenotypes, including age at onset, serostatus, and RA-ILD, to refine the understanding of genetic contributions to RA.

Methods and Cohort Details:

The cohort comprised 1,680 RA cases and 22,185 non-RA controls from over 152,000 biobank participants. GRS calculations incorporated trans-ethnic GWAS data, with logistic regression and Cox models analyzing associations. Covariates included age, sex, smoking status, and genetic ancestry.

Key Results:

Strengths and Limitations:

Dr. McDermott concluded that the RA GRS effectively predicts earlier disease onset and seropositive status but does not significantly enhance RA-ILD risk prediction. These findings underscore the importance of genetic risk stratification in RA while highlighting the need for RA-ILD-specific models to address extra-articular disease.

Neutrophil Activation as a Novel Marker of Lung Disease in Rheumatoid Arthritis

Speaker: Dr. Jia Shi, University of Washington and Peking Union Medical College Hospital

Key Highlights:

Rheumatoid arthritis (RA) frequently leads to interstitial lung disease (ILD), a major contributor to patient morbidity and mortality. Neutrophils, while well-studied for their role in joint destruction, are increasingly recognized as key mediators of lung inflammation. Dr. Jia Shi’s study aimed to elucidate the mechanisms of neutrophil activation in RA-ILD and explore their implications for disease monitoring and treatment.

Neutrophil Activation in RA-ILD:

Functional Correlations with Pulmonary Health:

These markers were closely associated with disease severity, highlighting their clinical utility as biomarkers.

Mechanistic Insights: fMet and FPR1 Pathway: fMet activates neutrophils by binding to the FPR1 receptor.

Mitochondrial Dysfunction and Chronic Inflammation:

Oxidative stress and inflammatory cytokines (e.g., TNF-α) promote mitochondrial damage, leading to fMet release and sustained inflammation in RA-ILD. This highlights mitochondria as potential contributors to the disease's inflammatory milieu.

Therapeutic Implications:

Conclusion

Dr. Shi’s work highlights the role of neutrophil activation in RA-ILD pathogenesis and its correlation with lung function impairment. Biomarkers like calprotectin and fMet show promise for disease monitoring, while FPR1 inhibition represents a novel treatment avenue. Further research into mitochondrial dysfunction and targeted therapies could transform care for RA-ILD patients.

Disease Activity is Strongly Associated with RA-related Lung Disease and Interstitial Lung Disease in Early RA: Results from a Multicenter, Prospective Cohort Study

Speaker: Dr. Gregory McDermott, Brigham and Women’s Hospital, Harvard Medical School

Key Highlights:

RA is linked to a spectrum of lung diseases, including RA-ILD, bronchiectasis, and emphysema, which contribute significantly to morbidity and mortality. Early RA presents a critical period for identifying and managing these complications. This multicenter study evaluated:

Study Methods:

Results:

Conclusion:

Early RA patients face a significant burden of lung disease, with RA-ILD being the most prevalent. Screening strategies incorporating simple clinical parameters like age, sex, and disease activity effectively identify high-risk patients, offering opportunities for early intervention. Future research on fibrotic and progressive RA-ILD subtypes is essential to optimize patient outcomes.

Serum Adipokines and Interstitial Lung Disease in a Prospective Rheumatoid Arthritis Cohort

Speaker: Anna Haggart, University of Nebraska Medical Center

Key Highlights:

Adipokines in RA-ILD:

Anna Haggart started her presentation by talking about Adipokines, such as adiponectin, FGF21, and leptin, which are hormones involved in regulating energy, metabolism, and inflammation. While their roles have been studied in cardiovascular diseases and idiopathic pulmonary fibrosis (IPF), their significance in RA-associated interstitial lung disease (RA-ILD) has been less clear. This study evaluated the relationship between serum adipokine levels and RA-ILD risk, as well as their association with survival outcomes in patients with RA-ILD.

Key Findings on RA-ILD Risk:

The study found no significant associations between adiponectin, FGF21, or leptin levels and the risk of either prevalent or incident RA-ILD. Despite their established links to systemic inflammation and other comorbidities, these adipokines did not appear to serve as predictors of RA-ILD development. This suggests that their role in RA-ILD may not be as direct as in other inflammatory conditions or organ-specific fibrotic diseases.

FGF21 and Survival Outcomes:

FGF21 emerged as a significant prognostic biomarker in RA-ILD. Elevated serum FGF21 levels were associated with a twofold increase in mortality risk (hazard ratio: 2.37) in patients with RA-ILD. Kaplan-Meier survival curves revealed that patients with higher FGF21 levels had significantly lower survival rates compared to those with lower levels. In contrast, adiponectin and leptin did not show any association with survival outcomes. These findings highlight FGF21’s potential role in disease progression or underlying metabolic dysfunction affecting RA-ILD prognosis.

Clinical Implications of FGF21:

FGF21’s link to poorer survival in RA-ILD aligns with its hypothesized role in metabolic dysfunction and possibly fibrogenesis. Although its exact mechanism remains unclear, it may reflect broader systemic processes contributing to inflammation and organ damage. The findings suggest that monitoring FGF21 levels could help identify RA-ILD patients at higher risk of adverse outcomes, offering a potential avenue for personalized care and management strategies.

Strengths and Limitations:

The study's large, well-characterized cohort and extensive follow-up were significant strengths, allowing for robust data analysis adjusted for multiple confounders, such as BMI and disease activity. However, the predominantly male cohort limited generalizability to broader RA populations. Additionally, the reliance on single time-point adipokine measurements and routine clinical detection methods may have underestimated subclinical ILD or overlooked longitudinal trends in biomarker changes.

Anna Haggart concluded that while serum adipokines such as adiponectin, FGF21, and leptin were not associated with the risk of developing RA-ILD, FGF21 emerged as a significant prognostic marker for survival in patients with RA-ILD. Elevated FGF21 levels were linked to a twofold increase in mortality risk, suggesting its potential utility in identifying patients at higher risk of poor outcomes. However, she emphasized the need for further research to clarify whether FGF21 reflects fibrotic processes, metabolic dysfunction, or broader systemic inflammation.

Serologic and Clinical Predictors of Progressive Pulmonary Fibrosis in Rheumatoid Arthritis-associated Interstitial Lung Disease Progression: A Prospective Longitudinal Cohort

Speaker: Dr. Sung Hae Chang, Brigham and Women’s Hospital and Harvard Medical School

Key Highlights:

Progressive pulmonary fibrosis (PPF) is a major complication that significantly worsens outcomes in patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). This study aimed to identify clinical, serologic, and ILD-specific factors that could predict disease progression in RA-ILD, with a particular emphasis on RA-specific characteristics. By focusing on these predictors, the study sought to improve the early identification of patients at risk for PPF, ultimately optimizing management strategies and potentially improving patient outcomes.

Study Design:

Key Results:

Strengths and Limitations

Conclusion:

Dr. Sung Hae Chang concluded that a combination of traditional ILD risk factors, RA-specific disease characteristics, and pulmonary damage biomarkers provides a robust approach for predicting progressive pulmonary fibrosis (PPF) in RA-ILD. Factors such as the UIP pattern, ILD extent >10%, reduced DLCO, high RA disease activity, and elevated anti-CCP titers were identified as significant predictors. The addition of biomarkers like KL-6 and SPD enhanced the predictive accuracy, with a combined model achieving an AUC of 0.75.

Dr. Chang emphasized the need for external validation of the predictive model in diverse populations and recommended further studies to evaluate the potential impact of DMARDs and antifibrotic therapies on disease progression. Incorporating broader biomarkers and respiratory symptom data could refine predictive tools and improve clinical outcomes for RA-ILD patients.

Abstracts: 0799-0804, American College of Rheumatology Convergence 2024, November 14–19, Washington, D.C