RMD Open
p=0.03), but not with IL-6 inhibitors (611.5±272.7, p=0.79) or anti-TNF (543.6±298, p=0.61). Compared with monotherapy with anti-TNFs, significant lower antibody titres were observed when combined MTX plus anti-TNF therapy was used (543.6±298 vs 356±246, p=0.03). Mean- while, combination of MTX with either BMB or RTX did not worsen the effects of the isolated drugs. Interestingly, higher seroconversion rates in patients under hydroxy- chloroquine were found when compared with IMRD ISP+ ( β =0.22, p=0.01). Cellular responses When analysing T-cell responses, we again observed the lowest responses in abatacept-treated patients (10% CD4- responders of 10 patients, p=0.03 and p=0.003 compared with the rest of IMRD ISP+ or IMRD ISP−, respectively). Eighty per cent of 21 patients on monotherapy with MTX, 70% of 10 patients with MFM and 42% of 7 patients with AZA showed a complete cellular response. Quantitative values of CD4 and CD8 immune responses of patients on different treatments are shown in online supplemental material 4. Compared with monotherapy, combined ther- apies of MTX with either RTX or BMB did not significantly worsen cellular responses to vaccination. Abatacept was associated with lower cellular immunogenicity compared with patients with IMRD ISP− ( β =−0.25, IC 95% –0.79 to −0.29, p=0.003) and the rest of patients with IMRD ISP+ ( β =−0.33, IC 95% –0.59 to −0.25, p=0.03). However, RTX ( β =−0.08, 95% IC −0.47 to 0.3, p=0.08), MTX ( β =−0.4, 95% IC –0.9 to 0.13, p=0.56) and BMB ( β =−0.33, 95% IC −0.29 to 0.96, p=0.47) were not associated with lower cellular immunogenicity compared with patients with IMRD ISP− but associated when compared with healthy controls. Regarding anti-TNF and IL-6 inhibitor thera- pies, either in monotherapy or combined with MTX, we found similar T-cell responses than in the rest of patients with IMRD ISP−. Treatment with hydroxychloroquine was associated with higher cellular immunogenicity in comparison with IMRD ISP+ ( β =0.21, 95% IC 0.12 to 0.86, p=0.03). It must be stressed that CD4 T-cell and CD8 T-cell responses were often present in serological
non-responders under any treatment: RTX (50%), BMB (63%), RTX+MTX (50%), BMB+RTX (60%). Across all patients and treatments, CD4 T-cell and CD8 T-cell responses were positively correlated ( β =0.73, p<0.001). Multivariate analysis To control for possible confounding variables, we performed stepwise multivariate regression analysis adjusting for age, gender, disease duration, treatments and glucocorticoid and MTX cumulative dose (table 3). A negative correlation between IgG anti-spike levels and age >65, disease duration >10 years, abatacept, MTX cumulative dose and glucocorticoid cumulative dose was found. Moreover, a positive correlation with antimalarial treatment was also found. Regarding cellular responses (CD4 and CD8), only a negative correlation with abata- cept was maintained. DISCUSSION We report the results on the effectiveness of SARS-CoV-2 vaccine focusing on humoral and cellular responses after two doses of BNT162b2 or mRNA-1273 in patients with IMRD, and determine the influence of immunosup- pressive and biological therapies in the vaccine’s immu- nogenicity. It is, to our knowledge, one of the very first studies to analyse immunogenicity to mRNA vaccines in immunosuppressed patients with rheumatic diseases simultaneously assessing serological, CD4 T-cell and CD8 T-cell responses. We considered two pre-determined hypotheses: that potential decreased vaccine’s immunogenicity might be due to an underlying IMRD-intrinsic dysregulation of the immune response and/or to immunosuppressive/immu- nomodulatory therapies. Results show that although the entire IMRD population elicited reduced vaccine’s immunogenicity as compared with healthy population, immunosuppressive treatment rather than diagnosis further reduced immunogenicity (online supplemental material 3). Drugs directed to cell surface proteins or that modify T or B-lymphocytes metabolism, but not blockade
Table 3 Multivariant analysis
Cumulative glucocorticoid dose
Cumulative methotrexate dose
Disease duration >10 years
Age >65 years
Abatacept
HCQ
Seronversion
β −0.1 p=0.04 β −0.13 p=0.001 β −0.1 p=0.03 β −0.08 p=0.02
β 0.22 p=0.01 β 0.27 p=0.01 β 0.10 p=0.24 β 0.20 p=0.12
β −0.26 p=0.44 β −0.25 p=0.004 β −0.04 p=0.61 β −0.1 p=0.43
β −0.19 p=0.03 β −0.29 p=0.001 β −0.03 p=0.64 β −0.02 p=0.24
β −0.27 p=0.002 β −0.19 p=0.02 β −0.05 p=0.56 β −0.1 p=0.56
β −0.10 p=0.22 β −0.14 p=0.04 β −0.14 p=0.11 β −0.1 p=0.15
IgG anti-spike levels
CD4 T-cell response CD8 T-cell response
HCQ, hydroxychloroquine.
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Sieiro Santos C, et al . RMD Open 2022; 8 :e001898. doi:10.1136/rmdopen-2021-001898
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