IMMUNE RESPONSE to SARS-COV-2 INFECTION in PATIENTS with RHEUMATIC MUSCULOSKELETAL DISEASES: The MAINSTREAM STUDY

ABSTRACT

Background: Rheumatic musculoskeletal diseases (RMD) are pathological conditions characterized by an impaired immunological system that is determinant both in the pathogenesis and in the inadequate response to infections. The use of disease-modifying anti-rheumatic drugs (DMARDs), which include conventional synthetic (cs) or biologic and targeted synthetic (b/ts) DMARDs, contribute to compromise immunological reactivity. Objectives: To analyze the immune response to SARS-CoV-2 in patients with rheumatoid arthritis (RA) or spondyloarthritis (SpA) receiving treatment with DMARDs and to investigate the effect of the different classes of drugs on humoral and cellular response. Methods: Patients were tested for anti-SARS-CoV-2 IgG, IgM and IgA antibodies to nucleoprotein (N) and receptor-binding domain (RBD) through ELISA and neutralization assays. Then, we performed a fow cytometry analysis of monocytes, NK cells, B and T lymphocytes from PBMCs of serologically positive patients. We also included a cohort of non-RMD individuals recovered from COVID-19 as a reference group of non-immunosuppressed subjects. A frst recruitment occurred in May-June 2020 (T1) and a second recruitment, 3-4 months after (T2), allowed to evaluate the persistence of the antibody response over time and to investigate the cellular immune response to SARS-CoV-2 in RMD patients having resolved the infection. Results: During T1, 358 patients with RA (n=200) or SpA (n=158) were recruited. Mean age was 52.8, 64% were female. All patients were treated with DMARDs, 299 with b/tsDMARDs and 59 received csDMARDs alone. One third was also receiving corticosteroids (CS). At T2, 36 subjects were recruited. We found a seroprevalence rate of 18.4%, which did not signifcantly differ between RA and SpA groups, and between patients treated with b/ts-DMARD or csDMARDs, either alone or in combination with CS (Table 1). Antibody levels of RMD patients were lower than non-RMD individuals (Figure 1), with CTLA4-Ig-treated patients having the lowest IgG levels. This difference was less marked in symptomatic RMD patients. 72% of seropositive patients elicited neutralizing sera. Despite an overall decrease in anti-RBD and anti-N titers, more than two-third of patients maintained antibodies titers above positivity threshold at T2. Concerning cellular response, we found that CD8+ T-cells frequency was overall comparable between RMD and non-RMD convalescents, and did not differ in b-or cs-DMARD treated ones. Conversely, CD4+ T-cell frequencies were signifcantly lower in RMD patients, especially those treated with anti-IL6R and CTLA4-Ig. B-cell subpopulations (class-switched, memory, and IgG+ memory B-cells) had sustained frequencies in anti-TNFα treated patients, while they had a trend of reduction in patients treated with anti-IL6R and CTLA4-Ig. Conclusion: Our data provide a comprehensive picture of the humoral and cellular immune responses to SARS-CoV-2 infection in RMD patients. We showed that DMARDs treatments did not alter a successful antibody response to the virus and did not hamper the antibody neutralizing ability. However, the magnitude of antibody response was slightly reduced compared to non-RMD individuals, especially in patients receiving CTLA4-Ig. We did not observe marked differences in the B-and T-cell populations between RMD patients compared to non-RMD individuals. However, in patients receiving anti-TNFα we found a higher relative abundance of effector adaptive population compared to other bDMARDs.