Characteristics of participants

Demographic, clinical, and biochemical characteristics of the 204 participants included in the MASH study were stratified according to the group classification and presented in Table 2. Overall, 84 (41.2%) of the participants were male, the mean age was 33.2 years (range 19–45), and 22% were HLA-B27 positive. In addition, 36 (17.6%) of the participants were daily smokers and 70 (34.3%) practiced moderate physical activity. Patients with axSpA exhibited higher inflammatory back pain, Spondyloarthritis Research Consortium of Canada (SPARCC) sacroiliac joint inflammation and structural scores compared to the rest of the groups, and 12 patients had a medical history of arthritis, 6 of enthesitis, 9 of uveitis, 1 of psoriasis, and 4 of inflammatory bowel disease.

Table 2 Demographic, clinical, and biochemical characteristics of the different groups of study participants

Demographic description

ECM turnover is enhanced in patients with axSpA compared to women with pelvic postpartum pain, patients with disc herniation, and healthy controls

Patients with axSpA expressed significantly higher levels of MMP-degraded type I, IV, and VI collagen (C1M, C4M and C6M; p < 0.0001, p < 0.05, p < 0.0001, respectively), MMP-driven citrullinated vimentin degradation (VICM, p < 0.05), type IV collagen formation (PRO-C4, p < 0.0001), and degradation/formation ratio of type VI collagen (C6M/PRO-C6, p < 0.0001) compared to women with buttock/pelvic postpartum pain when adjusting for confounders age, gender and body mass index (BMI) (Table 3). Patients with axSpA also presented significantly higher levels of C1M, C4M, VICM, and degradation/formation ratio of type III collagen (C3M/PRO-C3; p < 0.05, p ≤ 0.01, p ≤ 0.01, p < 0.05, respectively) when compared to patients with disc herniation (Table 3). Furthermore, when compared to healthy controls, patients with axSpA showed significantly higher levels of the same biomarkers as when compared to women with pelvic postpartum pain (C1M, C4M, C6M, VICM, PRO-C4, C3M/PRO-C3; p < 0.0001, p < 0.0001, p < 0.0001, p < 0.01, p < 0.0001, p < 0.01, respectively) and significant decreased levels of type III collagen formation (PRO-C3, p ≤ 0.01). Similar significant differences were observed when further adjusting for the participants’ physical activity (from light to most heavy) or their smoking status (from daily smoker to never smoked) (Table 3). C-reactive protein metabolite (CRPM) and type III collagen degradation (C3M) levels were higher in patients with axSpA compared to healthy subjects when further adjusting for their smoking status (p < 0.05 in both) and type IV degradation/formation ratio (C4M/PRO-C4) was significantly lower in patients with axSpA compared to patients with disc herniation (p < 0.05). However, when further adjusting for MRI inflammation score, no significant differences were found in C4M or VICM among patients with axSpA vs. women with pelvic postpartum pain, vs. patients with disc herniation or vs. healthy controls (Table 3). No significant differences were observed in biomarkers of type II and VI collagen formation (PRO-C2 and PRO-C6, respectively), type II collagen degradation (C2M and T2CM) or type II degradation/formation ratio (C2M/PRO-C2), type X collagen degradation (C10C and COL10NC), nor MMP-cleaved prolargin (PROM) among the three comparisons in any of the adjusted models (Table 3).

Table 3 Comparison of serum-tested biomarkers levels between groups

We also explored for differences between patients with axSpA and each of the initial seven groups (Supplementary Figure S1). Similar differences were observed within the same biomarkers as described above. C1M, C3M, C4M C6M, CRPM, PRO-C4, and VICM showed significantly higher levels in patients with axSpA than in the runners’ group (p < 0.01 for all except VICM (p < 0.05)), and the C3M/PRO-C3 ratio was also significantly increased (p < 0.001). C1M, C6M, PRO-C4, and VICM showed significantly increased levels in the axSpA group compared to the healthy men group. PRO-C4 also showed higher levels in the axSpA group compared to the cleaning staff group and the women with pelvic postpartum pain group (p < 0.001, p < 0.01, respectively). C6M/PRO-C6 ratio showed significantly higher levels in the group of patients with axSpA compared to the women with pelvic postpartum pain (p < 0.01). Neither C2M, T2CM, PRO-C2, C2M/PRO-C2, C4M/PRO-C4, nor PROM showed any significant differences between the axSpA group and each of the other groups; see Figure S1.

ECM remodeling biomarkers are not strongly associated with clinical assessment of disease activity or severity of axSpA

In patients with axSpA, PRO-C3 and C3M/PRO-C3 mild–moderately correlated with age (Spearman’s ρ ≥ ±0.35, p < 0.05-p < 0.001, Table 4). C1M, C3M, C4M, C6M, PRO-C4, and C3M/PRO-C3 moderate–highly correlated with CRP (ρ ≥ 0,5; all p < 0.001, Table 4), while COL10NC, VICM, CRPM, and C6M/PRO-C6 presented a mild-moderate correlation (ρ ≥ ±0.35; p < 0.05-p < 0.01, Table 4). C3M, PRO-C3, and C3M/PRO-C3 mild–moderately correlated with symptom duration of the disease (ρ > ±0.34; p < 0.05-p < 0.001, Table 4). Pain visual analog scale (VAS) mildly correlated with PRO-C6 and C6M/PRO-C6 (ρ ≥ ±0.35; p < 0.05, Table 4). Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) presented a mild correlation with PRO-C3 (ρ = − 0.31; p < 0.01), whereas Bath Ankylosing Spondylitis Metrology Index (BASMI) showed a mild to moderate correlation with C6M and C6M/PRO-C6 (ρ ≥ 0.37; p < 0.05 and p < 0.001, Table 4). The SPARCC MRI SI joint inflammation score was mildly correlated with C10C (ρ = − 0.32; p < 0.05). From the MRI SI Joint Structural Scores (SSS), erosion presented a mild correlation with C10C, and C6M/PRO-C6 (ρ ≥ ±0.3; p < 0.01) and a moderate to high correlation with PRO-C6 (ρ = 0.55; p < 0.001). SSS Backfill score presented a mild to moderate correlation with T2CM, C10C, and PRO-C4 (all ρ > ±0.32; p < 0.05), whereas SSS ankylosis score was mild-moderately correlated with C3M, C4M, C6M, PROM, C3M/PRO-C3, C4M/PRO-C4, and C6M/PRO-C6 (all ρ > ±0.34; p < 0.05-p < 0.01).

Table 4 Correlations of the biomarkers with clinical variables in patients with axSpA

C1M, T2CM C3M, C4M, C6M, COL10NC, PROM, VICM, CRPM, PRO-C3, PRO-C4, PRO-C6 C3M/PRO-C3, C4M/PRO-C4, and C6M/PRO-C6 were not correlated with BMI, VAS patient global, BASDAI, BASFI, swollen joint count (SJC), tender joint count (TJC), SPARCC SSS fat score, and SSS erosion score (Table 4). C2M, PRO-C2, and C2M/PRO-C2 did not show any correlation with any of the clinical variables.

We further examined the correlation between ECM metabolites and clinical parameters in the women with pelvic postpartum pain and in the patients with disc herniation (Table S1, Table S2). From the clinical variables, we could include age, BMI, CRP, symptom duration, BASMI, and SPARCC SI joint inflammation score. In women with postpartum pain, C6M, PRO-C4, and the ratio C4M/PRO-C4 presented a mild correlation with BMI (ρ ≥ ±0.33; p < 0.05-p < 0.01). C4M, C6M, and PROM were mildly correlated with CRP (ρ ≥ 0.31; p < 0.05), whereas PRO-C4 presented a moderate correlation (ρ = 0.47, p < 0.01). COL10NC, PRO-C6, CRPM, and the ratio C6M/PRO-C6 presented a mild-moderate correlation with symptom duration (ρ ≥ ±0.33; p < 0.05-p < 0.01). C10C, PRO-C4, and C4M/PRO-C4 were mild–moderately correlated with BASMI (ρ ≥ ±0.3; p < 0.05-p < 0.01), and only C3M presented a mild correlation with inflammation score (ρ> 0.3; p < 0.05). C3M, C6M, PRO-C4, PRO-C6, CRPM, C10C, COL10NC, C4M/PRO-C4, and C6M/PRO-C6 did not show any relevant correlation with age (Table S1). C1M, C2M, T2CM, VICM, PRO-C2, PRO-C3, C2M/PRO-C2, and C3M/PRO-C3 did not present any relevant correlation with the clinical parameters.

In patients with disc herniation, C4M presented a moderate correlation with age (ρ = 0.47; p < 0.001), whereas CRPM and the ratio C4M/PRO-C4 presented a mild correlation (ρ ≥ 0.31; p < 0.001). CRPM also presented a mild correlation with BMI (ρ = 0.37; p < 0.05). C1M and PROM showed a mild correlation with CRP (ρ ≥ ±0.33, p < 0.01), whereas PRO-C4 and C3M/PRO-C3 showed a moderate correlation (ρ ≥ ±045, p < 0.01-p < 0.001). PRO-C4 mildly correlated with symptom duration (ρ = − 0.32; p < 0.05), whereas PRO-C6 showed a moderate correlation (ρ = − 0.58; p < 0.05). C2M mildly correlated with BASMI (ρ > 0.31; all p < 0.01), and together with PRO-C3, it showed a mild to moderate correlation with SPARCC SI joint inflammation score (ρ ≥ − 0.35; p < 0.05-p < 0.01). C1M, C2M, T2CM, COL10NC, VICM, PRO-C2, C2M/PRO-C2, and C6M/PRO-C6 did not present any relevant correlation with the clinical parameters.

Diagnostic utility of biomarker levels for axial spondyloarthritis

CRP presented the highest AUC in axSpA vs. women with postpartum pain (AUC = 0.80, Table 5). CRP was also the best metabolite for the identification of axSpA from disc herniation patients and healthy controls. The AUC from axSpA vs. disc herniation patients was 0.71 and vs. healthy controls was 0.83 (Table 5). Moreover, for identifying axSpA from women with pelvic postpartum pain, inflammation biomarkers VICM and PROM as well as PRO-C4 had higher AUC than the rest of tested biomarkers (Table 5). To discriminate between axSpA and healthy subjects, PRO-C4, C6M, and C1M presented the second, third, and fourth highest AUC after CRP. However, the rest of biomarkers presented weak AUCs for differentiating patients with axSpA from women with pelvic postpartum pain, patients with disc herniation and control subjects (AUC < 0.73, Table 5).

Table 5 Diagnostic value of biomarker levels for axSpA

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