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

Background 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. Methods 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 one or more plasma samples at least 2 years before sarcoidosis diagnosis. Plasma protein levels were measured using the Olink Inflammation panel and expressed in normalised 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. Results We included 152 cases and 341 controls. Mean time between sample and sarcoidosis diagnosis was 13.4 years. 44 proteins were significantly elevated prior to sarcoidosis compared to controls in multivariable-adjusted analyses. The 10 proteins with the lowest p-values were CCL-3, CCL-19, cub domain-containing protein 1, CXCL9, CXCL10, interferon-γ, interleukin-12B, monocyte chemoattractant protein-3, tumour necrosis factor (TNF), and TNF receptor superfamily 9. 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. Conclusion Several inflammatory proteins were elevated in plasma many years before sarcoidosis onset compared to controls, revealing a pre-clinical phase characterised by inflammation.