Inflammatory and total immunoglobulin biomarker domains in systemic sclerosis vasculopathy: a phenotype-based...

To characterize inflammatory and total immunoglobulin-domain profiles across clinically defined vasculopathy phenotypes in SSc using a phenotype-oriented framework.

In this retrospective cross-sectional study, 314 patients with SSc fulfilling the 2013 ACR/EULAR criteria were classified into four vasculopathy phenotypes: no DU/gangrene/clinically diagnosed PAH/SRC-defined overt vasculopathy ("none"), peripheral only, visceral only, and mixed. Inflammatory and total immunoglobulin-domain scores were prespecified as the mean of standardised ESR and hs-CRP, and IgG and IgA, respectively. Associations between domain scores and phenotypes were evaluated using adjusted multinomial logistic regression, with prespecified binary and sensitivity analyses used as supportive analyses.

Omnibus comparisons across the four phenotypes, ESR, hs-CRP, CAR, and IgG remained significant after FDR correction, whereas albumin, IgA, and ACA showed nominal differences only. Descriptively, ESR and hs-CRP were higher in visceral-involvement phenotypes, IgG was highest in the visceral-only group, and IgA was highest in the mixed group. In adjusted multinomial models, each 1-SD increase in the inflammatory domain score was associated with visceral-only phenotype versus none (OR 1.49, 95% CI 1.06-2.10, p = 0.021) and mixed phenotype versus none (OR 1.60, 95% CI 1.03-2.47, p = 0.035) in the single-domain model, while each 1-SD increase in the total immunoglobulin-domain score was associated with visceral-only phenotype versus none (OR 1.43, 95% CI 1.02-2.02, p = 0.039). These multinomial associations did not remain robust after FDR correction and were attenuated in the joint-domain model. In the prespecified supportive binary analyses, the clearest associations were observed for visceral involvement versus none: inflammatory domain OR 1.59 (95% CI 1.19-2.14) and total immunoglobulin-domain OR 1.53 (95% CI 1.14-2.06). Sensitivity analyses showed no material direction reversal but indicated attenuation after extended adjustment.

Circulating inflammatory and total immunoglobulin-domain scores showed a directionally consistent association with clinically defined, predominantly clinically diagnosed PAH-weighted visceral vascular involvement in this inpatient SSc cohort. These exploratory cross-sectional findings require confirmation in prospectively phenotyped cohorts. Key Points • We classified systemic sclerosis vasculopathy into clinically defined phenotypes based on structural peripheral ischaemic damage and clinically diagnosed PAH/SRC-defined visceral vascular involvement. • Circulating inflammatory and total immunoglobulin-domain enrichment was more evident in clinically defined, predominantly PAH-weighted visceral-involvement phenotypes than in peripheral-only disease. • Peripheral-only phenotype, defined narrowly by structural ischaemic damage endpoints, showed limited domain-level enrichment after adjustment. • Attenuation in joint-domain models suggests partial overlap between systemic inflammatory burden and total immunoglobulin-related signals.