Background The interplay between humoral and cellular response after vaccination against SARS-CoV-2 in patients (pts.) with autoimmune inflammatory rheumatic diseases (AIRD) remains unknown.

Objectives To investigate the impact of different immunosuppressive therapies on the development of humoral and cellular immune responses to full 2-dose SARS-CoV-2 vaccination in AIRD pts. with stable low disease activity.

Methods The immune reactivity to COVID-19 vaccination was investigated in a prospectively recruited AIRD cohort with rheumatoid arthritis, axial spondyloarthritis or psoriatic arthritis which received a therapy with IL-17i, TNFi, JAKi or MTX (alone or in combination). Almost all patients received mRNA-based vaccine, only 4 patients had a heterologous scheme. Anti-spike(S) antibodies(ab.) and sera neutralizing capacity (neutralization dilution 50; ND50) were measured 4 weeks after the first (prime+4w) and 4 weeks after the second vaccination (boost+4w). Vaccine-specific cellular immunity was evaluated by quantifying expression of activation markers on T cells as well as their production of key cytokines, at prime+4w and boost+4w.

Results Overall, a total of 92 pts. were included in the final cohort. 31 (33.7%) pts. were on TNFi, 24 (26.1%) on IL-17i, 24 (26.1%) on JAKi, each group encompassing pts. receiving drug inhibitors alone or in combination with MTX.13 (14.1%) were treated with MTX alone. The median time between the vaccination and blood sampling was 31 [IQR: 28-34] days after prime+4w and 28 [IRQ: 28-28] days after boost+4w. Although at prime+4w only 34/90 (37.8%) of pts. presented neutralizing ab., the majority (86/91, 94.5%), developed them at boost+4w. The highest neutralization titer developed the pts. on IL-17i both at prime+4w (74 [IQR: 13-91]) and boost+4w (798 [IQR: 511-1344]), while no statistically significant differences were found in the neutralization titer at boost+4w for the TNFi, JAKi, and MTX groups: 207 ND50 [IQR: 120-576], 319 [IQR: 133-461] and 749 [IQR: 264-1920], respectively. 81/90 (90.0%) pts. developed IgG ab. against SARS-CoV-2 S-protein at prime+4w and 91/92 (98.9%) at boost+4w. Pts. receiving IL-17i developed higher ab. titers (8295 U/mL [IQR: 4586-11,237]) compared to the other three groups: JAKi (4405 U/mL [IQR: 1436-7265], TNFi (2313 [IQR: 1156-3630] U/mL) and MTX (2010 U/mL [IQR: 693-9254]). Neutralization capacity correlated well with the titer of anti-S ab. at both timepoints. Co-administration of biologic/tsDMARDs and MTX led to lower titers compared to biologic/tsDMARDs monotherapy. All therapies left frequencies of CD154⁺CD137⁺ CD4⁺ T cells and CD137⁺ CD8⁺ T cells at prime+4w and boost+4w unchanged. Polyfunctionality and T cell cytokine profiles across therapies did not significantly vary at boost+4w.

Conclusion Even after insufficient seroconversion for neutralizing capacity and ab. response against SARS-CoV-2 S-proteins between pts. of different mod of action agents, particularly for MTX and JAKi after first vaccination, a second vaccination covered almost all pts. regardless of DMARDs therapy, with better outcomes in those on IL-17i. T cell immunity revealed similar frequencies of activated T cells in all modes of action after the second vaccination.

Acknowledgements We thank all the patients who participated in this study. We thank the study nurses Gordana Brnos and Silke Kunkel for their support in the implementation of the study. We thank Toralf Roch, Sarah Skrzypczyk, Jan Zapka, Julia Kurek and Eva Kohut for their technical assistance

Disclosure of Interests None declared