# Cytokines, chemokines and antibodies against histone-3/4 citrullinated peptides in rheumatoid arthritis patients with pulmonary fibrosis

## TL;DR

This study finds that specific antibodies and cytokines in RA patients at diagnosis are linked to later development of pulmonary fibrosis, suggesting potential early detection markers.

## Contribution

Identifies anti-citrullinated histone antibodies and elevated cytokines as novel biomarkers for predicting pulmonary fibrosis in rheumatoid arthritis.

## Key findings

- Anti-CitH3(114–135) antibodies were more frequent and elevated in RA patients with pulmonary fibrosis.
- Combining anti-CitH3 and anti-CitH4 antibodies increased the odds ratio for PF development.
- Elevated levels of IL1α, IL1ß, TNFα, VEGFA, and MIPα were associated with PF in RA patients.

## Abstract

Rheumatoid arthritis (RA) associated interstitial lung disease (ILD) is the most common pulmonary manifestations of RA, with a progressive course and a poor survival. An early detection and better treatment is essential to improve outcome. We evaluated 16 analytes that could be relevant for the development of RA ILD.

In an inception cohort of 1118 early RA patients, pulmonary fibrosis (PF) were identified in 60 patients after a mean follow-up of 5.3 years using high resolution computer tomography (HRCT). As controls, 124 early RA patients without PF and 94 matched population controls without known rheumatic disease were studied. Analysis of antibodies against histones 3 and 4 derived citrullinated peptides (CitH3/H4), and cytokines/chemokines levels were performed in plasma samples collected at RA diagnosis using in-house ELISA and Luminex analysis.

Anti-CitH3(114–135) antibodies were the only antibody with increased frequency and levels in patients with PF versus without PF. The highest OR for PF development were found when combining positivity for anti-CitH3(114–135) and -CitH4(31–50) antibodies, OR 2.26. Levels of IL1α, IL1ß, TNFα, VEGFA and MIPα remained significantly elevated in patients with PF compared without PF, after adjustments and Bonferroni corrections. Several of the cytokines/chemokines correlated significantly with the histone antibodies in patients without PF. Partial least squares discriminant analysis including antibodies against citrullinated histon peptides and cytokines/chemokines identified significantly in PF in non-smokers.

Antibodies against CitH3 peptides and several of the analysed cytokines/chemokines in samples collected at diagnosis were associated with subsequent delevopment of PF in patients with RA.

The online version contains supplementary material available at 10.1186/s13075-025-03603-x.