The role of IL-6 in rheumatoid arthritis comorbidity and implications for therapy

Immune-mediated inflammatory diseases (IMIDs) are complex conditions commonly associated with alterations in cytokine biology. In rheumatoid arthritis (RA), the systemic activities of cytokines, such as interleukin (IL)-6, have led to the clinical introduction of targeted medicines that greatly improve patient outcomes. However, the beneficial effects of these therapies extend beyond improvements in joint pathology and often affect a range of RA-associated comorbidities that influence a patient's quality of life. For IL-6, these include impacts on cardiovascular risk, metabolic diseases, neuropsychiatric conditions, pain, fatigue, and altered tissue homeostasis. Reviewing the involvement of classical IL-6R signalling and IL-6 trans-signalling in these processes, we will examine the mechanistic basis for these comorbidities and consider the implications for therapy in RA and related IMIDs.