Understanding the Role of Interleukin-6 (IL-6) in the Joint and Beyond: A Comprehensive Review of IL-6 Inhibition for the Management of Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic, debilitating autoimmune disorder involving inflammation and progressive destruction of the joints, affecting up to 1% of the population. The majority of patients with RA have one or more comorbid conditions, the most common being cardiovascular disease, osteoporosis, and depression, the presence of which are associated with poorer clinical outcomes and lower healthrelated quality of life. RA pathogenesis is driven by a complex network of proinflammatory cells and cytokines, and of these, interleukin-6 (IL-6) plays a key role in the chronic inflammation associated with RA. Through cell signaling that can be initiated by both membrane-bound and soluble forms of its receptor, IL-6 acts both locally to promote joint inflammation and destruction, and in the circulation to mediate extra-articular manifestations of RA, including pain, fatigue, morning stiffness, anemia, and weight loss. This narrative review describes the role of IL-6 in the pathogenesis of RA, its comorbidities, and extra-articular systemic manifestations, and examines the effects of the IL-6 receptor inhibitors sarilumab and tocilizumab on clinical endpoints of RA, patient-reported outcomes, and common comorbidities and extra-articular manifestations.

The Potential Role of Extracellular Vesicles in COVID-19 Associated Endothelial injury and Pro-inflammation

“…Interleukin-6, known to influence osteoclast and osteoblast activity through RANK/RANKL/OPG interactions has been implicated in the cytokine storm associated with ARDS, septic shock, and COVID-19 disease(15-17). Further, IL-6 is capable of activating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathways, which can lead to robust innate and adaptive immune response and promote cellular crosstalk between immune and stromal cells.…”

Clinical management of patients with rheumatoid arthritis during the COVID-19 pandemic

“…Another clinical challenge is related to the potential atypical presentation of COVID-19 in patients on immunosuppressants. For example, glucocorticoids (GCs) and nonsteroidal anti-inflammatory drugs (NSAIDs) may inhibit a febrile response and IL-6 inhibitors prevent a rise in inflammatory markers [11]. Also, to be considered that symptoms like arthralgia, myalgia, fever, and elevation of inflammatory indexes, may be difficult to distinguish in RA patients between a disease flare and a SARS-CoV-2 infection.…”

Genotypic and Haplotype Analysis of Interleukin-6 and-18 Gene Polymorphisms in Association with Clinicopathological Factors in Breast Cancer

“…IL6 -597G>A polymorphism was reported to be associated with serum IL6 levels and as a susceptibility factor in several diseases such as multiple myeloma [21], rheumatoid arthritis [22], Sepsis [23], cervical cancer [24] and chronic obstructive pulmonary disease [25]. The genotype and allele frequency distribution of IL6 -597G>A polymorphism in controls and breast cancer patients revealed that the AA genotype and A-allele frequency was higher in breast cancer patients compared to controls and has conferred 3.97 and 2.53 folds risk for breast cancer respectively.…”