- Many patients who develop rheumatoid arthritis (RA) have anti‑citrullinated protein antibodies (ACPA) while early symptoms are present but before full‑blown RA can be diagnosed.
- Those who are ACPA‑positive and later develop full RA tend to exhibit distinct symptom patterns and disease courses compared with ACPA‑negative patients; however, it was unclear whether the same distinctions exist during the pre‑RA phase, known as clinically suspect arthralgia (CSA), which had not been studied.
- In a longitudinal cohort of 173 CSA patients, researchers documented varying disease‑progression trajectories according to ACPA status.
Patients with clinically suspect arthralgia (CSA)—a frequent precursor to rheumatoid arthritis (RA)—exhibited differing symptom patterns and disease trajectories based on their ACPA test results, the investigators reported.
Over a follow‑up period of at least two years involving 173 CSA patients, those who tested ACPA‑positive progressed to full‑blown inflammatory arthritis (IA)—the broader category that encompasses RA—more rapidly than ACPA‑negative participants. Conversely, ACPA‑positive individuals reported less morning stiffness and pain at symptom onset, according to Annette van der Helm‑van Mil, MD, PhD, of Leiden University, and co‑authors.
Inflammation locations also varied by ACPA status, the authors reported in *Annals of the Rheumatic Diseases*. Positive serology correlated with heightened inflammation in the feet, while ACPA‑negative patients displayed greater hand involvement.
The researchers noted that these distinctions likely reflect underlying inflammatory mechanisms and indicate that preventive strategies for ACPA‑positive and ACPA‑negative RA may need to be differentiated.
ACPA can be identified years before symptoms emerge, and the transition from CSA to full RA may span many additional years—or may never progress to RA. In established RA, symptom presentation, treatment response, and bone erosion rates can also differ by ACPA status; however, the role of serology during the early symptomatic phase—before the condition fulfills formal RA criteria—remains insufficiently examined.
For this investigation, van der Helm‑van Mil and colleagues synthesized data from two CSA cohorts: participants from a prospective observational study at Leiden and the placebo arm of the landmark TREAT‑EARLIER trial, which evaluated whether methotrexate could postpone or prevent progression to full RA (reported in 2022). Notably, in the TREAT‑EARLIER cohort, ACPA‑positive participants experienced greater methotrexate benefit than ACPA‑negative patients, suggesting that serology may dictate distinct disease trajectories in the absence of disease‑targeted therapy.
Patients from both cohorts were monitored closely for two years, with subsequent assessments at clinicians’ discretion (extending to five years for the TREAT‑EARLIER subgroup; the Leiden cohort has no predetermined endpoint). The final sample comprised equal numbers of ACPA‑positive and ACPA‑negative individuals, with mean ages of 49 and 46 years respectively, and comprising 72 % women in each group.
- Symptom onset preceded formal CSA diagnosis in both groups, but the latency differed by serology: ACPA‑positive patients experienced a longer interval between symptom onset and CSA diagnosis (median 24 versus 16 weeks; P = 0.006). In contrast, the interval from CSA to IA diagnosis was shorter for ACPA‑positive participants (median 12 weeks) than for ACPA‑negative participants (median 21 weeks; P = 0.014).
At the point of symptom onset, 79 % of ACPA‑negative participants reported that pain and stiffness were primarily localized to small joints, compared with 62 % of ACPA‑positive participants. Conversely, 69 % of ACPA‑negative patients identified hand involvement as predominant, versus 52 % of ACPA‑positive patients. ACPA‑negative individuals also experienced morning stiffness more frequently (70 % versus 54 %, P = 0.024) and rated its severity higher by one point on an 11‑point scale. Moreover, ACPA‑negative patients exhibited a greater number of tender joints (median 5 versus 3; P < 0.001).
Far from indicating milder CSA disease, ACPA‑positive patients displayed a more rapid acceleration of C‑reactive protein (CRP), a key systemic inflammation marker. CRP rose from an average of ~2.5 mg/dL at 24 months before clinically apparent IA to nearly 10 mg/dL at the time of IA onset; in contrast, ACPA‑negative patients began with higher CRP but increased by only about 1 mg/dL, reaching just over 7 mg/dL. MRI‑based inflammation showed comparable trends: ACPA‑positive patients started with lower MRI scores but demonstrated faster incremental rises over time.
The authors did not elaborate extensively on clinical implications, but they noted that, given the TREAT‑EARLIER finding that methotrexate delays RA progression more effectively in ACPA‑positive patients, preventive interventions for CSA may need to be stratified according to serology.
Study limitations include differences in monitoring protocols—particularly MRI scheduling—between the Leiden and TREAT‑EARLIER cohorts. Additionally, initial symptom reports were retrospective self‑assessments. Biomarker data beyond CRP were not collected, making it unclear whether other inflammatory markers varied by ACPA status.
