ABSTRACT
Background: In line with other reports, our group showed that patients treated with rituximab had signifcant impaired antibody response compared to patients treated with other biologic and targeted and synthetic disease modifying anti-rheumatic drugs (csDMARD). Objectives: To investigate predictors of response to COVID-19 vaccination (2 doses of mRNA vaccines, 2 doses of virus vector vaccines or combinations of these) in patients with infammatory rheumatic diseases (IRD) treated with ritux-imab and controls. Methods: Antibody levels to three antigens: Spike protein full length, Spike S1 and Nucleocapsid C-terminal fragment (to confrm previous COVID-19 infection) were measured in sera collected before vaccination and 2-12 weeks after the second vaccine using a multiplex bead-based serology assay. The antigen-specifc cut-off was defned as the median fuorescence intensity signal plus 6x standard deviations across 12 pre-pandemic controls. A good vaccine response was defned as having antibodies over the cut-off level for both spike antigens. Proportion (%) responders was compared between patients and controls (Chi2 test). Patients with IRD receiving last rituximab treatment within a mean (range) 193 (23-501) days before frst vaccination participated. Individuals without IRD served as a control group. Predictors of a good vaccine response were explored using multivariate logistic regression analysis adjusted for age, sex, disease duration, diagnosis (systemic vasculitis/RA/JIA/other), concomitant csDMARD, rituximab dose and prednisolone dose. Hazard ratio (chanse) of a good antibody response in relation to time between the last rituximab treatment and vaccination was studied by Kaplan-Meier survival analysis. Results: In total, 145 patients receiving rituximab and 61 controls were inclyded. Of these, 82 received rituximab as monotherapy (67% women;mean age 66 years, mean disease duration 13 years;33% had RA/JIA and 60% vasculi-tis) and 63 received rituximab+csDMARD (62% women;mean age 66 years;mean disease duration 17 years;76% had RA/JIA and 10 % vasculitis). Controls (n=61) were 74% women and mean age 49 years. Compared to controls, rituximab patients had lower antibody levels for both spike proteins (p<0.001). Proportion (%) responders among patients receiving rituximab as monotherapy (40.2%) and rituximab+DMARDs (25.4%) was signifcantly lower than in controls (98.4%) (p<0.001, Chi2). Higher age, concomitant csDMARD at vaccination and shorter time from last rituximab treatment predicted impaired antibody response (multivariate logistic regression model) (Table 1). Longer time between the last rituximab course and vaccination was associated with better antibody response (Figure 1). Conclusion: Patients with IRD getting vaccinated with two doses of COVID19 vaccine during the treatment with rituximab have the ability to develop antibody response although the response is impaired. For each month passed after the last rituximab course, the chance of good antibody response increases with 30%. Younger patients receiving rituximab as monotherapy and vaccinated preferably several months after the last rituximab treatment have the highest chance of achieving a good antibody response.
ABSTRACT
Background: Initial studies on the immunogenicity of COVID-19 vaccines in patients with immune-mediated infammatory rheumatic diseases (IRD) reported diminished antibody response in general, and particularly when treated with rituximab or abatacept (1). Additional data are needed, especially for patients with IRD and immunomodulatory treatments. Objectives: To elucidate the antibody response after two doses of COVID-19 vaccine in patients with IRD treated with biologic or targeted synthetic disease modifying anti-rheumatic drugs (b/ts DMARDs) as monotherapy or combined with conventional synthetic DMARDS (csDMARDs). Methods: Antibodies against two antigens representing Spike full length protein and Spike S1 and a Nucleocapsid C-terminal fragment (used to confrm previously COVID-19 infection) were measured in serum obtained before and after the second vaccination using a multiplex bead-based serology assay (2). Patients with IRD receiving immunomodulating treatment, followed at a rheumatology department and healthy individuals (controls) were recruited from five Swedish regions. Antibody positivity was classifed as the signal passing an antigen specifc cutoff based on the mean intensity signal of 12 selected negative pre-pandemic controls plus 6SD for Spike/S1 and 12SD for Nucleocapsid-C. Good vaccine response was defned as having antibodies over cut-off level for both spike antigens. Percentage of responders in each treatment group was compared to controls (Chi2 test). Predictors of antibody response were determined using logistic regression analysis. Results: In total, 414 patients (320 RA/JIA/psoriatic arthritis/axial spondylar-thritis, 60 systemic vasculitis and 32 other IRD) and 61 controls participated. Patients receiving rituximab (n=145;65% female;mean age 65years), abatacept (n=21;77% female;mean age 66 years), IL6 inhibitors (n=77;74% female;mean age 64years), JAK-inhibitors (n=58;75% female, mean age 53years), TNF-inhib-itors (n=68;66% female;mean age 44years;), IL17 inhibitors (n=42;54% female;mean age 44years) and controls (n=61;74% female, mean age 49years) were studied. Patients receiving IL6 inhibitor (81.0%), abatacept (43.8%) or rituximab (33.8%) had a signifcantly lower antibody response rate compared to controls (98.4%), further pronounced if combined with csDMARD (p<0.001) (Figure 1). In the adjusted logistic regression analysis, higher age, rituximab, abatacept, concomitant csDMARD but not IL6 inhibitors, concomitant prednisolone, or a vascu-litis diagnosis, remained signifcant predictors of antibody response (Table 1). All vaccines were well tolerated. 14 (3.4%) patients reported an increased activity in their IRD following vaccination. Conclusion: In this nationwide study including IRD patients receiving b/ts DMARDs a decreased immunogenicity of COVID-19 vaccines was observed in patients receiving rituximab, abatacept and to some extent IL-6 inhibitors. Concomitant csDMARD gave further attenuation. Patients on rituximab and abata-cept should be prioritized for booster doses of COVID19 vaccine.