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Plasma mtDNA as a possible contributor to and biomarker of inflammation in rheumatoid arthritis

Julia Lehmann^1,2, Stavros Giaglis¹, Diego Kyburz^1,2

¹Laboratory for Experimental Rheumatology, Department of Biomedicine, University of Basel, Basel, Switzerland.

Arthritis Research & Therapy

|May 7, 2024

Abstract

Objectives:

Neutrophil extracellular trap formation and cell-free DNA (cfDNA) contribute to the inflammation in rheumatoid arthritis (RA), but it is unknown if mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) is more abundant in the circulation. It is unclear if DNA concentration measurements may assist in clinical decision-making.

Methods:

This single-center prospective observational study collected plasma from consecutive RA patients and healthy blood donors. Platelets were removed, and mtDNA and nDNA copy numbers were quantified by polymerase chain reaction (PCR).

Results:

One hundred six RA patients and 85 healthy controls (HC) were recruited. Circulating median mtDNA copy numbers were increased 19.4-fold in the plasma of patients with RA (median 1.1 x10⁸ copies/mL) compared to HC (median 5.4 x10⁶ copies/mL, p<0.0001). Receiver operating characteristics (ROC) curve analysis of mtDNA copy numbers identified RA patients with high sensitivity (92.5%) and specificity (89.4%) with an area under the curve (AUC) of 0.97, p <0.0001 and a positive likelihood ratio of 8.7. Demographic, serological (rheumatoid factor (RF) positivity, anti-citrullinated protein antibodies (ACPA) positivity) and treatment factors were not associated with DNA concentrations. mtDNA plasma concentrations, however, correlated significantly with disease activity score-28- erythrocyte sedimentation rate (DAS28-ESR) and increased numerically with increasing DAS28-ESR and clinical disease activity index (CDAI) activity. MtDNA copy numbers also discriminated RA in remission (DAS28 <2.6) from HC (p<0.0001). Also, a correlation was observed between mtDNA and the ESR (p = 0.006, R= 0.29). Similar analyses showed no significance for nDNA.

Conclusion:

In contrast to nDNA, mtDNA is significantly elevated in the plasma of RA patients compared with HC. Regardless of RA activity, the abundance of circulating mtDNA is a sensitive discriminator between RA patients and HC. Further validation of the diagnostic value of mtDNA testing is required.

Insights

Mitochondrial DNA (mtDNA) is significantly elevated in rheumatoid arthritis (RA) patients compared to healthy individuals. Circulating mtDNA levels effectively distinguish RA patients, regardless of disease activity, suggesting potential diagnostic value.

Area of Science:

Immunology
Genetics
Rheumatology

Background:

Neutrophil extracellular traps and cell-free DNA (cfDNA) are implicated in rheumatoid arthritis (RA) inflammation.
The relative abundance of circulating mitochondrial DNA (mtDNA) versus nuclear DNA (nDNA) in RA is not well understood.
The clinical utility of DNA concentration measurements in RA management requires investigation.

Purpose of the Study:

To compare circulating mtDNA and nDNA levels in RA patients versus healthy controls (HC).
To assess the diagnostic potential of plasma DNA concentrations for RA identification.
To explore the correlation between circulating mtDNA levels and RA disease activity.

Main Methods:

Prospective observational study involving RA patients and HC.
Plasma samples were collected, and platelets were removed.
Quantification of mtDNA and nDNA copy numbers using polymerase chain reaction (PCR).

Main Results:

Circulating mtDNA copy numbers were 19.4-fold higher in RA patients (1.1 x10^8 copies/mL) than HC (5.4 x10^6 copies/mL).
mtDNA copy number analysis demonstrated high sensitivity (92.5%) and specificity (89.4%) for RA detection (AUC=0.97).
mtDNA levels correlated with disease activity scores (DAS28-ESR, CDAI) and erythrocyte sedimentation rate (ESR), while nDNA showed no significant difference.

Conclusions:

Mitochondrial DNA (mtDNA), but not nDNA, is significantly elevated in RA patient plasma.
Circulating mtDNA serves as a sensitive biomarker distinguishing RA patients from HC, irrespective of disease activity.
Further research is needed to validate the diagnostic utility of mtDNA testing in RA.

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