ABSTRACT
BackgroundTreatment with Rituximab (RTX) in patients with rheumatic diseases (RD) has presented a challenge during the COVID-19 pandemic, as RTX leads to markedly reduced and often undetectable antibody responses after COVID-19 vaccination (1).ObjectivesTo investigate the effect of COVID-19 mRNA revaccination (two doses) on the antibody response in patients with RD who were initial vaccine non-responders. Further, to examine if B-cell levels or T-cell responses before revaccination predicted seroconversion.MethodsFrom a RD cohort (COPANARD) vaccinated with the standard two-dose COVID-19 vaccinations, we enrolled cases without detectable antibody responses (n=17) and controls with detectable antibody response (n=29). Blood donors (n=32) were included as additional controls. Samples were collected before and six weeks after completed revaccination. Total antibodies (abs) and specific IgG, IgA, and IgM against SARS-CoV-2 spike protein, SARS-CoV-2 neutralizing abs, and SARS-CoV-2 reacting CD4+ and CD8+ T-cells were measured before and after revaccination. B-cells (CD19+CD45+) were quantified before revaccination. This study was funded by the Danish Rheumatism Association.ResultsPatient demographics are given in Table 1. Forty-seven percent of cases had detectable total SARS-CoV-2 abs and neutralizing abs after revaccination. However, antibody levels were significantly lower than in controls and blood donors (p<0.008), Figure 1A+B. Revaccination induced an antibody class switch in cases with a decrease in detectable IgM abs (Baseline 11/17, Followup 3/17) and increase in IgG. No significant difference was observed in T-cell responses before and after revaccination between the three groups, Figure 1C. The proportion of cases with detectable CD4+ T cells increased from 69% to 88% (p=0.25), and for CD8+ T cells, the proportion decreased from 88% to 82% (p=1.00). Only 29% of cases had measurable B-cells compared to 100% of controls and blood donors, Figure 1D. Fifty percent of revaccinated cases who seroconverted had measurable B-cells before revaccination, Figure 1D.Univariate logistic regression analysis was performed to analyze if active RTX treatment, the presence of B-cells, or a positive T-cell response prior to revaccination predicted seroconversion of total SARS-CoV-2-abs in the patient cohort. We did not find a significant explanatory effect of either variable in the univariate logistic models, data not shown.Table 1.DemographicsCases Revaccination, n=17Controls Boost, n=29Female sex, no(%)1482%2172%Age, median (IQR)6549 - 706762 - 72Disease duration, years1510 - 18229 - 31Rheumatoid Arthritis/SLE13/410/19None DMARD529%828%Prednisone424%13%Methotrexate741%1241%Hydroxychloroquine212%414%None biologic treatment424%931%Rituximab1271%0TNF-inhibitors16%724%JAK-inhibitors0621%IL-6-inhibitors, Abatacept, Benlysta0724%Previous rituximab treatmentAny rituximab treatment1694%13%RTX within the last 15 months, no1488%0Cumulative total dose, mg134-242Time from RTX to revaccination, months95-1249Figure 1.ConclusionIn conclusion, forty-seven percent of initial non-responders were able to seroconvert after two-dose revaccination. However, plasma concentrations of the antibodies against SARS-COV-2 and the levels of neutralizing capacity remained significantly lower than in immunocompetent blood donors. B-cell levels or T-cell responses before revaccination did not predict seroconversion. Our study suggests that patients with RDs who did not mount a detectable serological response to a COVID-19 mRNA vaccine have a T cell response similar to immunocompetent controls. Future studies should establish the antibody levels that identify RD patients without sufficient protection against SARS-CoV-2 infection.References[1]Troldborg A, et al. Time Since Rituximab Treatment Is Essential for Developing a Humoral Response to COVID-19 mRNA Vaccines in Patients With Rheumatic Diseases. J Rheumatol. 2022.AcknowledgementsThe Danish Rheumatism Association [grant number R203-A7217]. We acknowledge all patients and blood donors contributing to the stud for their invaluable participation. The authors would like to thank Sif Kaas Nielsen and Mads Engelhardt Knudsen, the Laboratory of Molecular Medicine at Rigshospitalet, for their excellent technical assistance in analyzing the samples.Disclosure of InterestsNone Declared.
ABSTRACT
Background: Reports of an impaired humoral response after COVID-19 vaccination in patients treated with rituximab (RTX) have raised particular concern for patients with infammatory rheumatic diseases (IRD) receiving RTX (1). This calls for strategies to enhance a humoral response in RTX-treated patients. At present, there is no data on whether it is best to increase the humoral response with a third vaccine dose (a booster) or with a third and fourth dose (re-vaccination). Objectives: In IRD patients treated with RTX, without a detectable humoral response after the frst vaccination course (two shots), we aimed to investigate the difference of either a booster vaccine (dose 3) or a new re-vaccination course (dose 3 + 4) on the serological response of the COVID-19 mRNA vaccines. Methods: We included 84 patients with IRD treated with RTX, all without measurable total SARS-CoV-2 antibodies after a full primary COVID-19 vaccination course (2 doses three weeks apart). All patients were offered a new re-vaccination course with the mRNA vaccine not used primarily (Pfzer/Biontec or Moderna). A small number of patients declined the revaccination, and recieved a booster with the mRNA vaccine used initially. Serum total antibodies were measured before and six weeks after the last dose against recombinant SARS-CoV-2 spike S1 protein (VITROS). In addition, CD19+ B-cells were measured at inclussion. Results: Patient characteristics are in Table 1. The median age was 64 years;68% were female with a disease duration of 5 years. Sixty-nine out of 84 were re-vaccinated (3 + 4 dose). Details previous exposure to RTX are given in Table 1. CD19+ B-cells were measurable in 12/81 at inclusion. We found a combined seroconversion rate of 33% six weeks after the last shot. There was no statistical difference between the booster (38,5%) and the re-vaccination group (32,3%), p=0.67 (Pearson's chi-squared). IRD patients with a humoral response in the re-vaccination group had signifcantly higher levels of total SARS-CoV-2 antibodies (median(IQR) 306(49-464) AU/ml) compared to the booster group (14(4-15) AU/ml) p=0.02, Figure 1A. In multiple logistic regression model, we found that levels of CD19+ B-cells were the only variable able to predict a humoral response, Figure 1B. However, only 39% of the patients with a humoral response to vaccination had measurable CD19+ B-cells before vaccination. We found no effect of age, sex, diagnosis, treatment, and RTX exposure on the chance of seroconversion in multiple logistic regression models when corrected for CD19+ B-cells. Conclusion: We found that re-vaccination (dose 3 + 4) with COVID-19 mRNA vaccines favored a high humoral response in patients with IRD treated with RTX, who did not have a detectable humoral response after the frst two vaccine doses, compared to a booster shot (dose 3). A detectable humoral response after re-vaccination was seen in more than half of the patients with no measurable CD19+ B-cells before vaccination. Presence of circulating CD19+ B-cells are a signifcant predictor of humoral response to mRNA COVID-19 vaccination.
ABSTRACT
Background: Vaccine trials of the SARS-CoV-2 mRNA vaccines were encouraging but excluded most patients with rheumatic diseases (RD) and patients treated with immunosuppressive therapy. However, reports of a more severe COVID-19 disease course in patients with RDs prompted strategies for expediting vaccination of RD patients in most countries. In addition to the impact experienced by most people of the pandemic, patients with RDs were adversely impacted by the potential risk of severe COVID-19 due to their disease and immunosuppressive treatment. Fear of COVID-19 led to disproportionate anxiety, self-isolation, and shielding behavior for many RD patients at the beginning of the pandemic. Objectives: We investigated antibody levels in serum against SARS-CoV-2 after a two-dose vaccination with an mRNA vaccine in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Further, we examined the association between reactogenicity and immunogenicity and how vaccination influenced patient behavior concerning fear of COVID-19 and shielding. Methods: Patients with SLE or RA from the COPANARD (Corona PANdemic Autoimmune Rheumatic Disease)1 cohort received two doses of an mRNA vaccine between January and August 2021 and had total antibodies against SARS-CoV-2 measured before vaccination and 2 and 9 weeks after the second vaccination. In addition, patients answered an electronic questionnaire before and eight weeks after vaccination concerning behavior, anxiety, and symptoms of depression (PHQ-9). Results: Three-hundred-and-three patients and 44 blood donors (healthy controls) were included. Signifcantly fewer patients (90%) had measurable antibodies against SARS-CoV-2 compared to blood donors (100%) after the second vaccination (p<0.001) (Figure 1). Treatment with Rituximab was the strongest predictor of unfavorable vaccine response, as only 27% were seropositive after vaccination. We found a negative effect of prednisone and methotrexate but no effect of age, comorbidity, or pausing medication on seroconversion. Patients experienced signifcant improvement after vaccination in 10 out of 12 questions regarding behavior and fear of COVID-19, but no change was observed in symptoms of depression (p=0.62) or anxiety (p=0.46). Conclusion: The majority of patients with SLE or RA had a measurable sero-logical response to the COVID-19 mRNA vaccine after two doses. Treatment with Rituximab was the strongest predictor of no seroconversion. Our fndings warrant encouragement of vaccination against COVID-19 for patients with RD, as most patients benefts with both a serological immune response and reduced isolation and shielding behavior.
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Background: Concerns about Rituximab (RTX) treatment and potentially inadequate vaccine response were aired early in the pandemic, and initial data seem to support this concern (1). So far, studies regarding rheumatic patients and the COVID-19 vaccines have included a relatively small number of patients receiving rituximab. Objectives: We aimed to investigate if patients with rheumatic diseases treated with RTX raise a serological response towards the COVID-19 mRNA vaccines and to elucidate the influence of time since the last dose RTX before vaccination on this response. Methods: We included 201 patients followed at the Department of Rheumatology, Aarhus University Hospital. All had been treated with RTX in the period 2017-2021, and had fnished a two-dose COVID-19 mRNA vaccination. All patients and 44 blood donors had total antibodies against SARS-CoV2 spike protein measured. Univariate and multivariate logistic regression were used. Results: Patients were predominantly female (67%) with a median age of 62 years. The most frequent diagnosis was ANCA-associated vasculitis (32%), rheumatoid arthritis (31%), and myositis (14%), and 97% had the Pfzer/Biontic vaccine. Median number of RTX infusions were 5 (IQR 2-8), with a cumulative dose of 4g (2-8), and 72% had received RTX within the last 15 months. Prednisone was used by 43%, followed by methotrexate (25%), hydroxychloroquine (11%) and azathioprine (10%). We observed a time-dependent increase in antibody response as the interval from the last RTX treatment to vaccination increased (Table 1). Only 17.3% of patients developed a detectable antibody response after receiving their vaccination 6 months or less after their previous RTX treatment (Figure 1). Positive antibody response increased to 66.7% in patients who had RTX 9-12 months before vaccination. Neither cumulative treatment time nor cumulative RTX dose seemed to influence the serological response to the vaccine (Table 1). Thus, even in patients who have received RTX for a substantial time, expanding time-since-last-RTX treatment could prove benefcial for increasing the chance of a serological response. We further found that 'months between last Rtx and vaccination', prednisone and azathioprine treatment were alle negatively associated with antibody response in a multivariate logistic regression analysis(Table 1). All blood donors (100%) had detectable antibodies after vaccination. Conclusion: In conclusion, patients with rheumatic diseases treated with RTX have a severely impaired serological response towards the COVID-19 mRNA vaccine. This is especially true if the interval between RTX treatment and vaccination is less than 9 months. For the majority of RTX treated patients, the recommended six months since last RTX is insufficient to develop a humoral response to COVID-19 mRNA vaccines. Our data suggest that the current recommendations of a 6 months interval should be revised.
ABSTRACT
Background: The coronavirus disease 2019 (COVID-19) pandemic has complicated the management of chronic rheumatic diseases (CRD). Patients with CRDs are immunocompromised and generally prone to infection. The fear of COVID-19 and the degree of the self-imposed shielding strategy implemented by many patients introduced new challenges for the patients. Although recommendations have been developed to manage patients with CRDs by, i.e., EULAR, strong evidence is still lacking to guide treatment decisions. Objectives: This study aimed to assess the seroprevalence of SARS-CoV-2 antibodies in patients with CRDs and healthy controls during the first wave of the pandemic. We further evaluated the effect of the pandemic on patient behavior regarding medication, exercise, pain, and experienced disease activity. Finally, we investigated the self-perceived consequences of the pandemic and lock-down on anxiety and depression in patients with CRDs compared with healthy controls. Methods: More than 900 participants were included in the study: 405 patients with rheumatoid arthritis or systemic lupus erythematosus and 513 blood donors. All participants had SARS-CoV-2 antibodies measured (Wantai SARS-CoV-2 total antibody ELISA;sensitivity 96.7%, specificity 99.5%) and answered a questionnaire concerning behavior, anxiety, and symptoms of depression (PHQ-9). The participants with CRD were further asked about physical activity, adherence to medication, and disease-related symptoms. Results: CRD patients had a sixfold lower seroprevalence of SARS-CoV-2 antibodies compared to controls (p=0.03) (Figure 1). Almost 60% of patients were unable to exercise as usual, leading to increased pain in 34%, and experience of increased disease activity in 27%. Approximately 10% of patients reduced or discontinued their immunosuppressive treatments at their own initiative. Symptoms of moderate depression were present in 19% of patients compared to 6,8% of controls (p<0.001). Conclusion: Low seroprevalence in patients with CRDs indicates successful mitigation of exposure to SARS-CoV-2. However, this appears to occur at the expense of physical activity and adherence to immunosuppressive treatment. Our results raise an important concern regarding the consequences of isolation for patients with CRDs. The result of physical isolation is a risk of severe mental health issues, physical inactivity, self-medication, increased pain, and increased disease activity. The long-term consequences of recommendations for patients with CRDs should be taken into account when tackling the continuing pandemic.