Dual RF, ACPA positivity linked to manifestations of rheumatoid arthritis

Patients with rheumatoid arthritis (RA) who are positive for both anticyclic citrullinated peptide antibody (ACPA) and rheumatoid factor (RF) have lower remission rate, higher baseline erythrocyte sedimentation rate (ESR), and need more corticosteroid and disease-modifying antirheumatic drugs (DMARDs) than those with single positivity or double negativity, according to a Singapore study.

"Our findings indicate that identifying this subset of patients who are at risk for more aggressive disease is important, and hence, we suggest the consideration of both RF and ACPA in patients newly diagnosed with RA,” the researchers said.

A total of 731 patients were identified from a prospective multi-ethnic RA cohort. They were then categorized into the following groups: ACPA-positive, RF-positive, doubly positive, and doubly negative.

The researchers compared the demographics, Disease Activity Score-28, Health Assessment Questionnaire score, quality of life using the Short Form-36, and the use of prednisolone and DMARDS among the patient groups.

Of the patients, 491 (67.2 percent) were ACPA+RF+, 54 (7.4 percent) were ACPA+RA-, 82 (11.2 percent) were ACPA-RF+, and 104 (14.2 percent) were ACPA-RA-. The mean disease duration prior to study entry did not differ across the four groups. Those with older age of onset were less likely to be positive for both ACPA and RF. [Singapore Med J 2025;66:486-491]

Fewer patients who were ACPA+RA+ achieved remission compared with those in the other groups (p<0.05). At study entry, ESR rate was higher in the ACPA+RA+ group (40.4 vs 30.6–30.9 mm/h; p<0.05) than other cohorts, as was the number of prednisolone and DMARDs used when compared with the doubly negative group.

Notably, no differences were noted in the functional study and quality of life across cohorts.

Pathogenesis

“RF and ACPA play a pathogenic role in RA and are already present in the preclinical stage,” the researchers said. [Arthritis Rheum 2009;60:1923-1931; Curr Rheumatol Rep 2014;16:419]

Patients with double positivity show significantly increased inflammatory cytokine levels, more advanced preclinical disease state, and more rapid progression from preclinical to clinical RA. [Clin Immunol 2018;195:119-126]

In addition, ACPA can identify patients with early arthritis or palindromic rheumatism who will evolve to RA. [Clin Rheumatol 2007;26:538-545; J Rheumatol 2006;33:1240-1242]

An earlier study also suggested that “RF acts as a potentiator of ACPA-mediated inflammation in RA, augmenting the ability of the ACPA-immune complex to promote macrophage cytokine production.” [Arthritis Rheumatol 2014;66:813-821]

“At the gene level, there are distinct transcriptome profiles apparent in RA patients who are ACPA+,” the researchers said. “The upregulated genes in these profiles are related to inflammation, Wnt signalling, and type I interferon pathways.” [PLoS One 2018;13:e0194205]

In a previous study, Frisell and colleagues found that ACPA+RA was more heritable than ACPA-RA (50 percent vs 20 percent). [Arthritis Rheum 2013;65:2773-2782]

"Seeing the interplay of ACPA positivity along with RF status in heritability of the disease, it is worthwhile considering both ACPA and RF statuses when assessing the family history of RA,” the researchers said. 

Furthermore, clinical trial data suggested that high levels of RF and ACPA at baseline are associated with poorer response to treatment among patients. [Arthritis Res Ther 2017;19:194]

"These, together with our study findings, suggest that RF and ACPA may act synergistically on the manifestations of RA,” the researchers said.