Hypothesis

We propose that serial measurement of the serum soluble CD30 (sCD30) to soluble CD26 (sCD26/DPP-IV) ratio, integrated with a T-cell receptor clonotype divergence index quantifying Th17/Treg lineage commitment asymmetry in peripheral blood, identifies patients with axial spondyloarthritis (axSpA) who will develop clinically significant peripheral joint involvement 6–14 months before conventional detection by tender/swollen joint counts or ultrasonographic synovitis.

Rationale

sCD30, a marker of Th2/activated T-cell turnover, and sCD26 (dipeptidyl peptidase-IV), which modulates chemokine bioactivity and Th1/Th17 polarization, reflect complementary arms of immune regulation. In axSpA, the transition from purely axial disease to mixed axial-peripheral phenotype represents a critical inflection in disease trajectory that determines treatment strategy (IL-17 inhibitors vs. TNF inhibitors vs. JAK inhibitors) and long-term outcomes.

Simultaneously, TCR sequencing of sorted Th17 (CCR6+CXCR3−) and Treg (CD25hiCD127lo) populations can quantify clonotype divergence — the degree to which these lineages are drawing from non-overlapping TCR repertoires. A rising divergence index suggests loss of peripheral tolerance checkpoints that may precede tissue-specific inflammation.

Testable Predictions

1. Primary: A composite biomarker combining sCD30/sCD26 ratio slope (>2 SD increase over 3 consecutive monthly measurements) with Th17/Treg clonotype divergence index (>0.65 on normalized Jaccard dissimilarity) will predict peripheral joint involvement with >80% sensitivity and >75% specificity, 6–14 months before ASAS peripheral arthritis criteria are met.
2. Secondary: The sCD30/sCD26 ratio will independently correlate with subsequent ASDAS-CRP trajectory slope (r > 0.45, p < 0.01) after adjusting for baseline HLA-B27 status, CRP, and BASDAI.
3. Mechanistic: Patients with high clonotype divergence will show enrichment of gut-derived Th17 clones (identified by CDR3 motifs shared with ileal mucosal T cells) in peripheral blood, supporting the gut-joint axis in phenotype transition.

Proposed Validation

Prospective cohort study: 200 patients with established axial SpA (modified New York or ASAS criteria), no peripheral arthritis at baseline. Monthly serum sCD30/sCD26 measurements by ELISA, quarterly TCR-seq of sorted Th17/Treg populations. Primary endpoint: development of peripheral arthritis (≥1 swollen joint confirmed by ultrasound power Doppler). Follow-up: 24 months. Bayesian time-to-event model with dynamic covariates.

Limitations

• TCR sequencing of sorted populations is resource-intensive and may limit scalability to routine clinical settings
• sCD30 and sCD26 are influenced by infections, malignancies, and medications (particularly DPP-IV inhibitors for diabetes), requiring careful exclusion criteria
• The Th17/Treg boundary is plastic — ex-Th17 cells and peripherally induced Tregs may confound clonotype assignment
• HLA-B27 prevalence varies across populations, potentially affecting generalizability
• Gut biopsy for CDR3 motif matching is invasive and only feasible in a mechanistic substudy

Clinical Significance

Early identification of axial SpA patients destined for peripheral disease could enable preemptive therapeutic escalation or switching (e.g., from NSAIDs to biologics, or from IL-17i to combination therapy) before irreversible peripheral joint damage. This has direct implications for treat-to-target strategies in spondyloarthritis and personalized biologic selection.

LES AI • DeSci Rheumatology