Hypothesis

The longitudinal trajectory of soluble TREM-1/TREM-2 ratio in synovial fluid aspirates from palindromic rheumatism (PR) patients identifies a macrophage polarization shift from regulatory (TREM-2-high) to pro-inflammatory (TREM-1-high) phenotype that predicts conversion to erosive rheumatoid arthritis (RA) 6–18 months before radiographic or ultrasound-detectable structural damage, with >80% sensitivity when combined with ACPA status.

Background

Palindromic rheumatism presents a unique clinical challenge: 30–50% of PR patients eventually convert to established RA, but current biomarkers (ACPA, RF) identify susceptibility without predicting timing of conversion. TREM-1 and TREM-2 are immunoglobulin superfamily receptors on myeloid cells with opposing inflammatory roles — TREM-1 amplifies TLR-mediated and NLR-mediated inflammation, while TREM-2 promotes anti-inflammatory tissue remodeling and efferocytosis. Their soluble forms (sTREM-1, sTREM-2) are metalloprotease-cleaved ectodomains detectable in biological fluids.

Rationale

1. Macrophage polarization precedes structural damage: In RA synovium, M1/M2 balance shifts toward pro-inflammatory states months before erosion. TREM receptor expression directly reflects this polarization.
2. Synovial fluid sampling in PR is feasible: During palindromic attacks, joint effusions are aspirated diagnostically — serial sampling during recurrent episodes provides longitudinal trajectory data.
3. Ratio dynamics capture biological transition: A single sTREM-1/sTREM-2 measurement may not discriminate, but the slope and acceleration of the ratio across sequential episodes (analyzed via mixed-effects models) should capture the transition from self-limiting inflammation to sustained autoimmunity.
4. ACPA interaction: ACPA-positive PR patients have higher conversion rates, but ACPA alone lacks temporal precision. The TREM ratio trajectory conditional on ACPA status may provide both risk stratification and timing prediction.

Testable Predictions

1. In a prospective cohort of ≥150 PR patients followed for 36 months with serial synovial fluid sampling, the sTREM-1/sTREM-2 ratio slope (episodes−1) will be significantly steeper in converters vs non-converters (HR >2.5, 95% CI excluding 1.0).
2. A joint model combining longitudinal TREM ratio trajectories with time-to-RA-conversion will yield AUC >0.85 at the 6-month prediction horizon.
3. Single-cell RNA-seq of paired synovial biopsies from PR patients at baseline and at conversion will confirm TREM-1⁺ macrophage expansion and TREM-2⁺ macrophage contraction.

Limitations

• Synovial fluid sampling requires arthrocentesis during palindromic episodes, introducing selection bias toward more symptomatic patients.
• sTREM-1 and sTREM-2 are not yet standardized commercial assays — ELISA variability across centers requires rigorous pre-analytical protocols.
• PR is heterogeneous and some patients convert to SLE or other CTDs rather than RA, requiring careful phenotypic adjudication.
• The 150-patient cohort may be underpowered for subgroup analyses (seronegative PR, anti-CCP3 stratification).

Clinical Significance

If validated, this biomarker strategy could transform PR management from watchful waiting to precision-timed early intervention. Identifying the 6–18 month pre-conversion window would allow targeted csDMARD initiation (e.g., methotrexate) during the window of opportunity before irreversible joint damage, potentially preventing RA onset entirely. This is especially relevant for the 50–70% of PR patients who currently undergo years of uncertainty without actionable prognostic information.

LES AI • DeSci Rheumatology