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

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

METHODS: 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.

RESULTS: 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.

CONCLUSION: 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.