Background/Purpose: Neutrophil activation is associated with inflammation and autoimmunity, including rheumatoid arthritis (RA), where neutrophil infiltration into joints participates in tissue destruction and development of arthritis. In RA, neutrophils may undergo a programmed form of necrosis, NETosis, upon which neutrophil extracellular traps (NETs) are extruded. Due to their inflammatory capacity in vitro, as well as containing key autoantigens such as citrullinated histones and vimentin, NETs have been suggested to be an important contributor in the pathogenesis of RA. However, the clinical utility, and in particular the prognostic capacity, of neutrophil biomarkers has not been carefully addressed.

Methods: Markers of neutrophil activation (S100A8/A9) and NETosis were analyzed by ELISA in healthy controls (HC, n=24, and n=100) and RA patients from two independent cross-sectional cohorts (n=101 and n=93), as well as one longitudinal inception RA cohort (n=250) followed for a median of 8.3 years (4.4-19.8 years). The first cohort focused on disease activity measures, whereas the other cohorts were designed to study outcome measures.

Results: Levels of S100A8/A9 and NETs were markedly elevated in all three RA cohorts as compared to healthy individuals (p<0.0001). Both markers, particularly S100A8/A9, were associated with clinical markers of disease activity, including CDAI (r=0.52, p<0.0001) and the presence of swollen joints (r=0.50, p<0.0001). Patients who met the 1958 criteria for probable or definite RA but did not fulfill the 1987 ACR criteria (n=32), had significantly lower levels of circulating NETs as compared to individuals fulfilling the 1987 ACR criteria for RA (n=250, p<0.0001), and were indistinguishable from healthy individuals (p=0.16). Levels of NETs showed high specificity for patients fulfilling the 1987 ACR criteria for RA, as compared to healthy individuals (90%), as well as compared to symptomatic individuals not fulfilling the 1987 ACR criteria (94%), indicating a potential diagnostic utility of the test. Using the inception cohort, levels of NETs and S100A8/A9 were able to predict future development of extra articular nodules (OR=2.8, p<0.05, and OR=3.4, p<0.01, respectively). Furthermore, S100A8/A9 levels could predict future joint space narrowing (OR=4.4, p<0.0001) and erosive disease (OR=5.5, p<0.0001). A small number (12.5%) of newly diagnosed RA patients had noticeable erosive changes when recruited. Excluding these individuals from the analysis further strengthened the results with S100A8/A9 predicting joint space narrowing (OR=8.8, p=0.003) and the development of erosive disease (OR=5.7, p<0.0001).

Conclusion: Our results demonstrate a clear contribution of neutrophils in RA pathogenesis. Neutrophil-derived biomarkers may be able to monitor and predict disease activity and severity in RA patients. Thus, therapies targeting exaggerated neutrophil activation are anticipated to be beneficial in RA. Finally, monitoring of neutrophil biomarkers may allow for early preventive treatment avoiding long-term disabling disease in RA, including extra articular manifestations and erosive changes.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/neutrophil-activation-is-associated-with-disease-activity-and-predicts-development-of-erosive-disease-and-extra-articular-manifestations-in-rheumatoid-arthritis/