RA May Be a Causal Driver of Idiopathic Pulmonary Fibrosis

TOPLINE: 

Rheumatoid arthritis (RA) was causally linked to the development of idiopathic pulmonary fibrosis, with shared plasma factors CC motif chemokine ligand 2 (CCL2) and CXC motif chemokine ligand 2 (CXCL2) identified as potential diagnostic biomarkers.

METHODOLOGY:

• Idiopathic pulmonary fibrosis shares inflammatory and fibrotic features with RA, but the causal relationship is unknown. Researchers conducted a bidirectional Mendelian randomization analysis using genome-wide association study data from European cohorts to explore causality between the two conditions.
• They analyzed the data of 14,361 patients with RA and 42,923 control individuals as well as data from 1028 patients with idiopathic pulmonary fibrosis and 196,986 control individuals.
• Significant single nucleotide polymorphisms were selected as instrumental variables, and the inverse variance weighted method was used for analysis, supplemented by Mendelian randomization-Egger, weighted median, and sensitivity tests.
• Transcriptomic and single-cell RNA sequencing data from patients with RA vs control individuals were analyzed to identify shared genetic features.

TAKEAWAY:

• Mendelian randomization analysis indicated that RA increases the risk for idiopathic pulmonary fibrosis (inverse variance weighted method: odds ratio, 1.156; P = .002). However, the reverse analysis found no effect of idiopathic pulmonary fibrosis on RA.
• CCL2 and CXCL2 were identified as key shared biomarkers in transcriptomic analysis.
• Biomarker validation in 40 individuals with RA vs 40 controls showed higher levels of CCL2 and CXCL2 in the plasma of patients with RA (P < .05 for both), with area under the curve values from the receiver operating characteristic analysis indicating diagnostic potential.

IN PRACTICE:

“RA causally contributes to [idiopathic pulmonary fibrosis], with CCL2 and CXCL2 as shared biomarkers exhibiting diagnostic potential. Elevated in RA-specific cell types and linked to inflammation, they offer insights into disease mechanisms and early detection strategies for RA-associated idiopathic pulmonary fibrosis,” the authors concluded.

SOURCE:

The study was led by Xixi Pan, Taizhou Hospital of Zhejiang Province affiliated with Wenzhou Medical University in Linhai, China. It was published online on July 25, 2025, in Med Research.

LIMITATIONS: 

The study’s findings might only apply to groups similar to those in the genome-wide association study datasets, with some possible overlap in samples and remaining confounding factors. Using publicly available datasets may limit how detailed the phenotypic characterization is. The small validation group may be underpowered to detect small effects, and the absence of epigenetic analysis and functional tests restricts understanding of the underlying mechanisms.

DISCLOSURES:

The study was supported by grants from the Joint TCM Science & Technology Projects of National Demonstration Zones for Comprehensive TCM Reform, Zhejiang Provincial Natural Science Foundation, General Scientific Research Project of the Zhejiang Provincial Department of Education, and others. The authors declared having no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.