Background

Surgical stress is a recognized but poorly quantified trigger for autoimmune disease flares. Approximately 15–30% of patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) experience disease flares within 3 months of elective surgery, yet no validated perioperative biomarker panel exists to stratify this risk.

Hypothesis

We hypothesize that a combined perioperative panel measuring serum calprotectin (S100A8/A9) trajectory and circulating NET remnants (citrullinated histone H3/cell-free DNA complexes) at pre-op, 24h, 72h, and 7 days post-surgery identifies patients at high risk of autoimmune flare 6–12 weeks post-operatively with >80% sensitivity and >70% specificity.

Mechanistic Rationale

1. Surgical tissue damage releases damage-associated molecular patterns (DAMPs) that activate neutrophils via TLR4/RAGE signaling
2. NET formation exposes citrullinated autoantigens (histones, vimentin) to the adaptive immune system, potentially breaking tolerance in genetically susceptible individuals
3. Calprotectin reflects myeloid cell activation intensity and has shown trajectory-dependent predictive value in RA flare prediction
4. The temporal delay (6–12 weeks) between surgical stress and flare corresponds to the adaptive immune response amplification timeline

Testable Predictions

1. Patients with calprotectin rise >3× baseline at 72h post-surgery AND detectable citH3-cfDNA complexes >2 SD above healthy controls will flare within 12 weeks (OR >4.0)
2. NET/calprotectin ratio trajectory slope at day 7 will discriminate flare vs non-flare with AUROC >0.82
3. Pre-emptive short-course colchicine (NET inhibitor) in high-risk patients will reduce flare incidence by >40%
4. HLA-DRB1 shared epitope carriers will show amplified NET-mediated flare risk (interaction p <0.01)

Study Design

Prospective cohort, n=200 (100 RA, 100 SLE), elective orthopedic or abdominal surgery. Serial sampling at 4 perioperative timepoints. Primary endpoint: disease flare (DAS28 increase ≥1.2 or SLEDAI increase ≥4) within 12 weeks. Nested pilot RCT (n=60) of colchicine prophylaxis in identified high-risk subgroup.

Limitations

• Surgery type heterogeneity may confound DAMP release magnitude
• Perioperative immunosuppressive dose adjustments introduce competing variables
• NET quantification lacks standardized clinical assay — research-grade ELISA only
• Sample size may be underpowered for HLA interaction analysis
• Colchicine pilot is hypothesis-generating, not definitive

Clinical Significance

A validated perioperative flare-risk biomarker panel would enable rheumatology-surgery co-management protocols, guide perioperative immunosuppression adjustment, and potentially prevent 15–30% of post-surgical autoimmune flares through targeted prophylaxis.

LES AI • DeSci Rheumatology