Patients with rheumatoid arthritis (RA) have systemic inflammation characterized by a distinct pattern of circulating cytokines and chemokines. Example: Joint destruction in RA patients is associated with elevated levels of proinflammatory cytokines, as well as CD16+ monocytes in the synovial fluid. Circulating cytokines and altered extracellular vesicles can affect adipose, skeletal muscle, liver and vascular endothelium. Previous studies have shown that, in vitro, extracellular vesicles immune complexes can cause neutrophils to upregulate production of leukotriene B4.
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Recent research demonstrates that extracellular vesicles from seropositive RA patients can activate mononuclear phagocytes in vitro. Catalina Burbano, PhD, a researcher at the Universidad de Antioquia, Colombia, and colleagues found extracellular vesicles from seropositive patients could also induce in vitro proinflammatory cytokines that replicated the inflammatory response observed in these patients at the systemic level. The results, published online in Scientific Reports, suggest extracellular vesicles may contribute to the greater disease severity typically seen in patients with seropositive RA.1
The investigators examined RA patients, finding they had distinct profiles of circulating components, such as cytokines, extracellular vesicles and monocyte subsets, based on their antibody status. Seropositive patients had altered counts and receptor expression of intermediate monocytes, as well as extracellular vesicles immune complexes+ and extracellular vesicles citrullinated peptides+. Seropositive patients also had increased levels of proinflammatory cytokines interleukin (IL) 1β, IL-6 and tumor necrosis factor-alpha, relative to seronegative patients and healthy controls. The researchers found this systemic inflammatory profile was unrelated to disease activity.
“Our results suggest systemic inflammatory process does not always coincide with articular inflammation, as shown by the weak association between circulating cytokines and DAS28 [disease activity score 28],” write the authors in their discussion. “This [finding] suggests classifying the disease as active based only on the articular commitment of DAS28 is insufficient to determine individuals with systemic and non-joint inflammation. In addition, we observed not all patients with high DAS28 exhibited high levels of circulating inflammatory cytokines.”
The researchers discovered that circulating and synovial fluid extracellular vesicles from patients with RA were highly heterogeneous in size and larger than those from healthy controls. They also found platelets were the most frequent source of extracellular vesicles in RA patients. When researchers examined the extracellular vesicles of seropositive patients and compared them with those of seronegative patients, they found seropositive patients had higher frequencies of circulating extracellular vesicles that were positive for IgG, IgM, CD41a and citrulline. However, the investigators did not see similar alterations in seronegative patients whose inflammation profile was more similar to healthy controls. When the researchers compared seropositive patients with healthy controls, they saw a significant decrease in extracellular vesicles CD14+.
Lara C. Pullen, PhD, is a medical writer based in the Chicago area.
- Burbano C, Rojas M, Muñoz-Vahos C, et al. Extracellular vesicles are associated with the systemic inflammation of patients with seropositive rheumatoid arthritis. Sci Rep. 2018 Dec 17;8(1):17917.