POS0081 ASSOCIATIONS OF CIRCULATING INFLAMMATORY CYTOKINES WITH LONG COVID AMONG PATIENTS WITH SYSTEMIC AUTOIMMUNE RHEUMATIC DISEASES
Authors: J. A. Sparks, X. Wang, P. Y. Lee, K. Brodeur, M. Lin, N. Patel, Y. Kawano, A. Schiff, A. King, J. Hanberg, S. Srivatsan, E. Kowalski, C. Johnson, K. Vanni, Z. Williams, G. Qian, C. Bolden, K. Mueller, K. Bade, A. Saavedra, R. Venkat, Z. S. Wallace
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> While the incidence of severe acute COVID-19 has decreased, post-acute sequelae of COVID-19, or 'long COVID,' is common and associated with lower quality of life and morbidity. Long COVID is likely multifactorial, but may be in part driven by systemic inflammation and immune dysregulation. Patients with systemic autoimmune rheumatic diseases (SARDs) may be at risk for long COVID due to underlying altered immunity, immunosuppressive drug use, and propensity for systemic inflammation. Thus, identifying inflammatory biomarkers for long COVID may be helpful to identify biologic pathways and develop treatments and diagnostic tests. <h3>Objectives:</h3> We aimed to examine whether circulating inflammatory cytokines after COVID-19 were associated with presence of long COVID among patients with SARDs. <h3>Methods:</h3> We investigated biomarkers of inflammation and long COVID using RheumCARD, a prospective study of people with prevalent SARDs with (cases) and without (comparators) a history of COVID-19 from a large healthcare system in the US. Cases are recruited ≥28 days following onset of acute COVID-19 to answer surveys and provide blood samples (March 2021 to July 2023). We measured circulating cytokines in serum using the proximity extension assay (Olink Target 48 cytokine panel). If patients were on a DMARD targeted to a cytokine (e.g., TNF), their data was excluded. The primary outcome was long COVID defined according to US CDC criteria as persisting for ≥28 days. The primary analysis compared those with vs without long COVID among SARDs after COVID-19. We compared median cytokine levels between groups using Wilcoxon rank sum tests. We compared those with vs. without long COVID for cytokine levels using linear regression, adjusting for age, sex, vaccine status, and SARS-CoV-2 variant. We performed subgroup analyses among those with inflammatory arthritis, pre-Omicron variants, Omicron variants, remission/low disease activity, moderate/high disease activity as well as a more stringent definition of long COVID (≥90 days of persistent symptoms). We also analyzed comparators, SARDs who never had COVID-19 before sample collection. <h3>Results:</h3> We analyzed a total of 201 cases (prevalent SARDs after COVID-19; mean age 56 years, 81% female) and 47 comparators (SARDs without COVID-19; mean age 62 years, 75% female). The most common SARD type among cases was inflammatory arthritis (60%), followed by connective tissue disease (22%, Table 1). Considering SARD treatment, 63 (31%) were only on conventional synthetic DMARDs, and 53 (26%) were on TNF inhibitors. A total of 54 (27%) cases were unvaccinated at COVID-19 onset, and 76 (38%) had pre-Omicron SARS-CoV-2 variants. Among cases, 78 (39%) reported COVID-19 symptoms persisting for ≥28 days and were classified as long COVID for the primary outcome; 44 (22%) had symptoms for ≥90 days. IL18 levels were lower among those with long COVID (199 pg/mL) vs without long COVID (221 pg/mL; p=0.001). In the multivariable analysis, long COVID cases had lower IL-18 levels than those without long COVID (β -55 pg/mL, SE 17, p=0.0011, Table 2). There were also associations of lower levels of CSF2 and CCL7 as well as higher levels of IL-2 with long COVID. IL-18 levels were consistently lower in those with vs without long COVID in all additional analyses: inflammatory arthritis (p=0.021), remission/low disease activity (p=0.02), moderate/high disease activity (p=0.015), pre-Omicron variants (p=0.004), Omicron variants (p=0.06), long COVID defined as ≥90 days of persistent symptoms (p=0.004), and vs comparators (p=0.011). <h3>Conclusion:</h3> In this prospective study performed among SARDs after COVID-19, lower IL-18 levels were associated with long COVID. This finding was robust across all analyses examined and not explained by vaccination or viral variants. IL-18 is produced by inflammasome activation and induces cell-mediated immunity following infection, implicating a blunted immune response, rather than exuberant hyperinflammation, as a potential mechanism for long COVID among patients with SARDs. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> Jeffrey A. Sparks AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, Pfizer, ReCor, Sobi, and UCB, Bristol Myers Squibb and Boehringer Ingelheim, Xiaosong Wang: None declared, Pui.Y Lee: None declared, Kailey Brodeur: None declared, Miao Lin: None declared, Naomi Patel FVC, Yumeko Kawano: None declared, Abigail Schiff: None declared, Andrew King: None declared, Jennifer Hanberg: None declared, Shruthi Srivatsan: None declared, Emily Kowalski: None declared, Colebrook Johnson: None declared, Kathleen Vanni: None declared, Zachary Williams: None declared, Grace Qian: None declared, Caleb Bolden: None declared, Kevin Mueller: None declared, Katarina Bade: None declared, Alene Saavedra: None declared, Rathnam Venkat: None declared, Zachary S. Wallace Viela Bio, Zenas BioPharma, Horizon Therapeutics, Sanofi, MedPace, BioCryst, Amgen, PPD, Shionogi, Otsuka/Visterra, BMS, Sanofi, Amgen, Bristol-Myers Squibb and Principia/Sanofi.