Background/Purpose: Patients with underlying immune-mediated inflammatory diseases (IMIDs), such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), have a higher susceptibility to severe COVID19 and adverse IMID outcomes. While there is growing evidence of SARS-CoV-2 infection triggering preexisting arthritic conditions, the mechanism underlying this phenomenon remains ill-defined. Indeed, the SARS-CoV-2 accessory protein, ORF8, shares similarities with the human inflammatory cytokine IL-17. In light of the potential association between inflammatory arthritis and ORF8-mediated IL-17 signaling, our objectives are to (i) characterize immune alterations, and (ii) determine the role of ORF8 in COVID19-mediated disease exacerbation in patients with preexisting IMIDs.

Methods: Using a retrospective Cleveland Clinic COVID19 biobank cohort, we obtained 74 plasma specimens collected from four groups of patients: (i) Healthy (COVID^NegIMID^Neg; n=20); (ii) IMID only (COVID^NegIMID^Pos; n=20); (iii) COVID19 only (COVID^Pos IMID^Neg; n=20) and (iv) COVID19+IMID (COVID^Pos IMID^Pos; n=14). All COVID^Pos samples were obtained within 10-17 days post-COVID19 diagnosis. We employed aptamer-based SomaScan technology to profile 1500 protein biomarkers in plasma, focusing on the levels of circulating plasma ORF8. Next, primary human osteoblast (OBs) cells derived from a healthy control and an RA patient, were treated with 20ng/ml of ORF8 protein for 2 and 4 days. Supernatants and cells were collected at each time point to evaluate inflammatory (IL-17A, IL-17F, CCL2, IL-6) and bone-resorption (RANKL:OPG, CTSK, PTH1R, TPP1) markers by ELISA and real-time PCR analyses, respectively.

Results: Comparative analysis of four patient groups revealed 154 specific biomarkers associated with COVID19+IMID patients. Specifically, 74 upregulated plasma proteins were found to be indicative of augmented bone resorption process, with elevated levels of the inflammatory IL-17F and bone resorptive biomarkers – RANKL: OPG, CTSK, PTH1R and TPP1. Immunoglobulin was predicted as an upstream regulator of both the IMID only and COVID19+IMID groups, suggestive of autoimmune-dominant IMID condition. Indeed, among both groups of patients with IMIDs (n=34), RA and SLE were most commonly reported, with 15% of the IMID only patients and 17% of COVID19+IMID patients diagnosed for each condition. High circulating ORF8 levels were detected in COVID19+IMID patients, but not seen in the COVID19 only group. Intriguingly, treatment of RA OBs with ORF8 resulted in significantly higher expression of inflammatory markers (IL-17A, IL-17F, CCL2, IL-6) and bone resorption markers: (RANKL: OPG) compared to healthyOB controls, suggesting IL-17-driven inflammation and bone resorption.

Conclusion: We identified an augmented IL-17-mediated inflammatory bone resorption in COVID-19 patients with preexisting IMIDs, which is uniquely driven by SARS-CoV-2 ORF8. The predicted immune pathways identified here provide insights into unique biomarkers and potential therapeutic targets for COVID19-mediated inflammatory “flares” in IMID patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/exacerbation-of-immune-mediated-inflammatory-diseases-in-covid19-sequelae/