Inflammatory plasma protein levels are elevated years before sarcoidosis diagnosis: a nested case-control study in Sweden

Sarcoidosis is an immune-mediated inflammatory disease whose natural development is not well understood. We aimed to determine if inflammatory plasma protein levels are elevated before sarcoidosis diagnosis compared to controls. Furthermore, we investigated which proteins are increased and how long before diagnosis they are increased. Cases with sarcoidosis and controls matched 2:1 on sex, birthdate, subcohort and sample date were identified in the Northern Sweden Health and Disease Study to perform a nested case-control study. Cases were validated and included if they provided ≥1 plasma sample ≥2 years before sarcoidosis diagnosis. Plasma protein levels were measured using the Olink Inflammation panel and expressed in Normalized Protein eXpression values. Unconditional logistic regression models adjusted for age, sex, subcohort and time since sampling were used to estimate log odds ratios with 95% confidence intervals for each protein overall and by time to diagnosis. p-values were adjusted for multiple comparisons using the Benjamini-Hochberg method. We included 152 cases and 341 controls. Mean time between sample and sarcoidosis diagnosis was 13.4 years. Forty-four proteins were significantly elevated prior to sarcoidosis compared to controls in multivariable-adjusted analyses. The ten proteins with the lowest p-values were CCL3, CCL19, CDCP1, CXCL9, CXCL10, IFNγ, IL-12B, MCP-3, TNF, and TNFRSF9. Fewer proteins were associated with sarcoidosis in samples taken longer before diagnosis. Restricting to samples taken ≥10 years prior to sarcoidosis diagnosis, 27 proteins remained statistically significant. Several inflammatory proteins were elevated in plasma many years before sarcoidosis onset compared to controls, revealing a preclinical phase characterised by inflammation.