Elevated Serum Biomarkers Predict Rheumatoid Arthritis Diagnosis Within 6 Months

Have Any New Predictive Biomarkers Been Identified?
Have Any New Predictive Biomarkers Been Identified?
Researchers sought to identify a panel of serum biomarkers that could identify imminent cases of rheumatoid arthritis prior to diagnosis.

Serum testing for elevated concentrations of specific cytokine biomarkers predicted rheumatoid arthritis (RA) diagnosis up to 6 months before actual diagnosis in individuals classified as healthy or already diagnosed with reactive arthritis (ReA), according to study findings published in Arthritis & Rheumatology.

Researchers conducted a case-control study that compared 307 active military personnel diagnosed with RA or ReA with 76 healthy control participants to identify serum biomarkers predictive of RA prior to diagnosis. The study occurred in 2 phases: phase 1 established prediction models for RA diagnosis and phase 2 validated the model.

The researchers collected serum samples at 4 timepoints labeled A through D, with sample A being closest to time of diagnosis. Following the initial collection, they analyzed the serum for the presence of anti-citrullinated protein antibodies (ACPA) to separate the patients into ACPA seropositive and seronegative RA groups.

They evaluated serum samples included in phase 1 at all 4 timepoints for soluble programmed cell death protein-1 (sPD-1) levels and other analytes including interferon-induced lymphocyte chemoattractants, such as CXCL10, CXCl11, and CXCL13, and acute phase proteins such as C reactive protein (CRP) and serum amyloid A (SAA).

The researchers observed elevated serum concentrations of sPD-1, CRP, and SAA in ACPA seropositive individuals up to several years in advance, but closest to the time of RA diagnosis.

In healthy control participants, sPD-1 levels remained constant, while sPD-1 levels increased significantly in patients just prior to RA diagnosis. In contrast, patients with ReA demonstrated a slight decrease in sPD-1 levels just after diagnosis.

Compared with healthy control participants, study patients closer to time of RA diagnosis demonstrated elevated levels of CRP, SAA, CXCL10, CXCL11, and CXCL13. Compared with the ReA group, those closest to RA diagnosis also demonstrated higher levels of CRP, CXCL10, and CXCL13.

In phase 2, the researchers confirmed a 69% sensitivity for a model assessing 8 analytes to predict seropositive RA diagnosis, whereas it failed to predict seronegative RA cases. Elevated sPD-1 levels predicted RA diagnosis up to 6 months in advance with greater than 89% specificity compared with ReA.

Limitations of the study included lack of generalizability outside of active military personnel and the possible influence of intense military training on inflammatory processes.

The study authors concluded, “[W]e have demonstrated that imminent diagnosis of RA could be classified with high specificity compared to [healthy control] subjects and ReA cases based on a panel of cytokines measured in serum samples collected within 6 months before actual diagnosis. The predictive power diminishes dramatically when evaluating serum samples from timepoints further from diagnosis.”


Loza MJ, Nagpal S, Cole S, et al. Serological biomarkers of progression towards diagnosis of rheumatoid arthritis in active component military personnel. Arthritis Rheumatol. Published online June 7, 2022. doi:10.1002/art.42260