Interleukin-6 and related proteins as biomarkers in systemic sclerosis

The search for biomarkers in systemic sclerosis (SSc) is driven by a goal to stratify patients, identify potential subgroups for treatment, and help assess response to therapy. Emerging evidence indicates that interleukin-6 (IL-6) and some family members are key biomarkers involved in SSc pathogenesis and therefore suitable targets for therapy. Recent studies evaluating IL-6 and its canonical Janus kinase/signal transducers and activators of transcription downstream pathways in modulating fibrotic response and immune cell function suggest a pivotal role for IL-6 in SSc pathogenesis. Although the significance and effect of local tissue expression of IL-6 and its family members are less well established, high levels of circulating IL-6 may identify subgroups of patients with earlystage disease, particularly those at risk for progressive lung fibrosis. In addition, higher disease activity may portend poor prognostic outcome in terms of survival and skin disease. Longitudinal assessment of serum levels of IL-6 and its signaling associates may prove valuable in monitoring response to treatment. As an IL-6–dependent surrogate marker, C-reactive protein may assist cohort enrichment if targeted treatment for IL-6 demonstrates efficacy, especially in subgroups with high IL-6 levels. Although IL-6 appears to be a key factor in the hierarchy of the complex network of disease-associated molecules, the systemic or autocrine/paracrine manner in which IL-6 asserts its profibrotic effects—particularly its interaction with other key pathogenic factors in SSc—is unknown. Ongoing clinical trials will help to delineate the mechanisms of IL-6 in SSc pathogenesis and inform on the role of these biomarkers