ACPA Status May Shape Early Rheumatoid Arthritis Progression in Arthralgia Patients, Reveals Research
Netherlands: New research suggests that patients with clinically suspect arthralgia (CSA), a precursor stage of rheumatoid arthritis (RA), follow different symptom and disease progression pathways depending on their anti-citrullinated protein antibody (ACPA) status. In a longitudinal study of 173 CSA patients, ACPA-positive individuals demonstrated distinct trajectories compared with ACPA-negative patients, indicating that the biological differences associated with RA may emerge well before the disease can be formally diagnosed.
The findings, published in the Annals of the Rheumatic Diseases, come from a study led by Mitra Hosseini Malekroudi from the Department of Rheumatology at Leiden University Medical Center, the Netherlands, and colleagues. The researchers investigated whether the progression from initial symptoms to the development of rheumatoid arthritis differs between patients who are ACPA-positive and those who are ACPA-negative.
Rheumatoid arthritis is categorized into ACPA-positive and ACPA-negative forms, which differ in their genetic and environmental risk factors. However, it remains unclear whether they also follow distinct pathways during the symptomatic phase before RA develops.
The study analyzed 173 patients with clinically suspect arthralgia who later developed RA, including 86 ACPA-positive and 87 ACPA-negative individuals. Researchers compared disease timelines and tracked inflammatory changes using clinical symptoms, C-reactive protein levels, and MRI findings.
The study led to the following findings:
- ACPA-positive patients had a longer interval between symptom onset and presentation with clinically suspect arthralgia.
- After reaching the CSA stage, ACPA-positive patients progressed to rheumatoid arthritis more rapidly than ACPA-negative patients.
- ACPA-negative patients experienced more severe morning stiffness from symptom onset and throughout the symptomatic pre-RA phase.
- Hand pain at symptom onset was more pronounced in ACPA-negative patients.
- ACPA-negative patients had a greater number of tender hand joints at CSA presentation and during follow-up before RA development.
- ACPA-positive patients showed a faster increase in inflammatory activity during the year preceding RA diagnosis.
- C-reactive protein levels rose more rapidly in ACPA-positive patients than in ACPA-negative patients.
- MRI assessments revealed a greater increase in subclinical joint inflammation among ACPA-positive patients.
- The increase in inflammation in ACPA-positive patients was particularly prominent in the forefoot region.
The findings indicate that ACPA-positive and ACPA-negative RA have distinct biological pathways during the preclinical phase. ACPA-negative disease is marked by greater symptoms and hand involvement, whereas ACPA-positive disease is characterized by a faster rise in systemic and subclinical inflammation before RA develops.
The researchers concluded that differences in disease progression, symptom severity, and inflammatory patterns suggest distinct underlying mechanisms in the two RA subtypes. These findings highlight the potential need for ACPA-specific prevention strategies to delay or prevent the onset of rheumatoid arthritis.
Reference:
Malekroudi, M. H., Claassen, S., Van Steenbergen, H. W., Van Mulligen, E., & Van der Helm-van Mil, A. H. (2026). Progression from symptom onset to rheumatoid arthritis: Is the trajectory similar in anticitrullinated protein antibody-positive and -negative disease? A comparative longitudinal study. Annals of the Rheumatic Diseases. https://doi.org/10.1016/j.ard.2026.04.011
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