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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. • IL-6 is a key mediator linking joint inflammation to systemic comorbidities in RA, including cardiovascular, metabolic, and neuropsychiatric conditions. • Biological therapies targeting IL-6 signalling improve both joint inflammation and comorbidities, though ~40% of patients fail to respond. • The alternate modes of IL-6 signalling offer different approaches to targeting this cytokine in inflammation while preserving homeostatic IL-6 functions. • Predictive biomarkers, long-term outcome studies, and mechanistic patient-derived evidence are critical research priorities for improving personalised treatment in RA.
Monaco et al. (Sat,) studied this question.