Abstract
Abstract
Objectives and design
To further elucidate the effects of rare systemic autoimmune rheumatic diseases (SARD) and their treatment on antibody development after vaccination against SARS-CoV-2, we compared patients with and without immunosuppressive therapy to healthy controls in an observational cohort study.
Participants and setting
We enrolled 52 patients with SARD and 72 healthy subjects in a prospective, observational study at the Medical University of Vienna and measured the humoral response 6 months after two mRNA vaccinations and 2–6 weeks after a third dose.
Results
Patients with vasculitis showed significantly (p=0.02) lower antibody titres 6 months after vaccination (median 247 BAU/mL, IQR [185–437]), as compared with healthy controls (median 514 BAU/mL, [185–437], IQR 323; 928, vasculitis patients: 247, IQR [185; 437], p<0.05). Patients receiving 2–3 immunomodulatory medications showed significantly lower antibody levels. Of note, all patients with SARD, even those without immunomodulatory medication, developed lower antibody levels after the third dose compared with healthy controls (median 22 630, IQR [16 945; 43 200] in HC, 9510 IQR [3866; 14 215] in patients without immunosuppressive treatment (p<0.001), 7780 IQR [2203; 15 645] in patients receiving a single immunomodulatory drug (p<0.0001) and 14 320 IQR [2415; 35 400] in patients receiving combination therapy (p=0.081)).
Conclusions
Patients with SARD displayed lower antibody development after booster vaccination, even if antibody levels after two immunisations were comparable to healthy controls. Our data may be limited due to sample size, but it provides pointers for a more individualised, antibody-titre-oriented approach and earlier booster vaccination in patients with SARD.
Keywords: COVID-19, Rheumatology, Chronic Disease, IMMUNOLOGY
strengths and limitations of this work.
In this study, we measured antibody levels in systemic autoimmune rheumatic diseases patients without therapy before and after three SARS-CoV-2 vaccinations.
The development of antibody levels after booster vaccination is studied here as a follow-up study to depict individual development.
Patients receiving two or three immunomodulatory drugs were compared with patients without therapy, a single immunomodulatory drug or healthy controls.
A strength is the exclusion of patients with SARS-CoV-2 infection, to display the antibody development after vaccination only.
A clear limitation is the low sample size, but this study can be seen as an impulse to plan further studies with a higher number of participants.
Introduction
The SARS-CoV-2 pandemic has presented unprecedented global challenges. SARS-CoV-2 infections can lead to severe infections that may require intensive care treatment and can even induce the development of systemic autoimmune rheumatic diseases (SARD), for example, myositis.1 2 Patients with immunodeficiencies and those under immunosuppressive therapy are particularly prone to develop severe disease.2 Apart from the many challenges due to SARS-CoV-2, positive aspects such as a deeper understanding of vaccinations and their effects on the immune system also need to be highlighted. In this context, particular attention has been paid to the production of antibodies after immunisation.3,8 Many studies elucidated the immune response after the first and second vaccinations and the effect of immunosuppressive agents on this response.7 9 10 By measuring serum levels of antibodies, the function of the adaptive immune system, and thus the immunity of individual patients, can be assessed.3 7 9 In patients receiving B-cell depleting therapy, especially rituximab, the antibody responses were clearly decreased, leading to less protection from severe infections.3,8
Patients with connective tissue diseases (CTD) such as systemic lupus erythematosus (SLE) or rheumatoid arthritis, who receive not only conventional systemic disease-modifying drugs (csDMARDs) but also combination therapy with biological or targeted synthetic DMARDs (bDMARDs or tsDMARDs) had a higher risk for SARS-CoV-2 infections.11 Furthermore, we learnt from various studies that the antibodies and with them, the protection against severe SARS-CoV-2 infections, were not long-lasting and thus required regular booster vaccinations.3,8 Within the scientific community, there is broad agreement on the need for regular immunisations in patients undergoing immunosuppressive treatment.3,8
Whereas numerous publications investigated the impact of immunosuppressive drugs on antibody development after SARS-CoV-2 vaccines, less attention was devoted to the impact of the autoimmune disease itself on antibody titres.12 For a distinct look at the effects of the vaccine itself, we excluded patients who suffered from a COVID-19 infection, verified via measurement of nucleocapsid antibodies.
Materials and methods
Patients
We prospectively enrolled 52 patients from the rheumatology outpatient clinic of the Medical University of Vienna suffering from SARD: systemic sclerosis (SSc), dermatomyositis and polymyositis (DM/PM), large-vessel vasculitis (LVV), antineutrophil cytoplasmic antibody-associated vasculitis (AAV), polymyalgia rheumatica (PMR), SLE, Sjögren’s disease (SD), mixed connective tissue disease (MCTD) and undifferentiated connective tissue disease (UCTD). We grouped patients into two disease clusters (1) vasculitis (LVV, antineutrophil cytoplasmic AAV, PMR or eosinophilic granulomatosis with polyangiitis (EGPA)) and (2) CTD (SSc, DM/PM, SLE, Sjögren’s disease (SD), MCTD, UCTD, common variable immunodeficiency (CVID), sarcoidosis and adult-onset Sill’s disease). The exact numbers of patients are shown in table 1. Patients declining their participation in the study received standard of care treatment in our outpatient clinic as usual and regular antibody measurements to verify antibody response to vaccination. 72 healthy subjects without a rheumatic disease and without immunosuppressive therapy served as a healthy control group (HC). Patients were recruited while visiting our outpatient clinic, whereas HCs were asked for participation while visiting official vaccination centres in Vienna. This study is a follow-up study of a previous work from our working group,9 but 16 patients were lost to follow-up, 3 showed SARS-CoV-2 infection and 1 received apheresis and was therefore excluded from the study. Patients who showed a medical history of COVID-19 infection were not included in the study. To verify this status, nucleocapsid antibodies were analysed in the serum of every patient, and patients with positive nucleocapsid antibodies were actively excluded. Furthermore, patients receiving B-cell-depleting therapy with rituximab were excluded from the study. Compared with our previously published manuscript (Mandl P. et al9), 3 patients developed a SARS-CoV-2 infection and showed positive nucleocapsid antibodies, and 1 patient received apheresis, which would lead to false results in antibody levels and was thus excluded. The rest of the missing patients (n:16) were lost to follow-up. Breakthrough infections after the end of the study or further follow-ups other than those stated here were not assessed in this study. Patients and healthy controls received two doses of mRNA vaccines. Antibodies targeting the SARS-CoV-2 receptor-binding domain (RBD) and B-cell count (only total B-cell count according to routine clinical practice was assessed, without further immunophenotyping via FACS (fluorescence-activated cell sorting)) were quantified 6 months (median days 182, IQR [159–216]), after the second vaccination and 2–6 weeks (median days 31, IQR [28–44]) after the third vaccination. B-cells were assessed during clinical routine on a BD Canto II flow cytometer. The gating of lymphocytes was performed using forward scatter (FSC) and side scatter (SSC). Furthermore, CD3+ T cells were excluded, and all CD19+ B-cells were analysed. For data evaluation, the FACS Diva software was used. All patients received mRNA vaccinations. Serum samples were stored on further processing at the Biobank of the Medical University of Vienna according to guidelines of the International Standards Organization (ISO) 9001:2015.13
Table 1. Study subject demographics.
| SARD (n=52) | HC (n=72) | |
|---|---|---|
| Age median (IQR) | 52 (IQR 41; 60) | 56 (IQR 45; 63) |
| Female n (%) | 45 (86.5) | 46 (63.9) |
| Systemic lupus erythematosus, n (%) | 17 (32.7) | |
| Systemic sclerosis, n (%) | 11 (21.2) | |
| Vasculitides, n (%)* | 12 (23.1) | |
| Other connective tissue diseases, n (%)† | 9 (17.3) | |
| Miscellaneous, n (%)‡ | 3 (5.8) | |
| csDMARD or b/tsDMARD monotherapy, n (%) | 21 (40.4) | |
| csDMARD and/or b/tsDMARD combination therapy, n (%) | 13 (25) | |
| No therapy, n (%) | 18 (34.6) | |
| Methotrexate (monotherapy or combination), n (%) | 9 (17.3) | |
| Mycophenolate (monotherapy or combination), n (%) |
11 (21.2) | |
| Hydroxychloroquine (monotherapy or combination), n (%) |
16 (30.8) | |
| Azathioprine (monotherapy or combination), n (%) | 7 (13.5) | |
| Belimumab (monotherapy or combination), n (%) | 3 (5.8) | |
| Tocilizumab (monotherapy or combination), n (%) | 3 (5.8) | |
| Tacrolimus (monotherapy or combination), n (%) | 1 (1.9) | |
| Glucocorticoid dose, mean (SD) at first vaccination | 2.5 (±9.4) | |
| Glucocorticoid dose, mean (SD) at second vaccination | 2.2 (±9.2) |
Antineutrophil cytoplasmic antibody-associated vasculitis (n=2), large-vessel vasculitis (n=3), polymyalgia rheumatica (n=7), osinophilic granulomatosis with polyangiitis (n=1).
Dermatomyositis/polymyositis (n=2), mixed connective tissue disease (n=2), primary Sjögren’s disease (n=3) and undifferentiated connective tissue disease (n=2).
CVID (n=1), sarcoidosis (n=1), adult-onset Still’s disease (n=1).
HC, healthy control group; SARD, systemic autoimmune rheumatic diseases.
Antibody testing
Antibodies were measured quantitatively with an immunoassay determining the antibodies against the RBD of the spike (S) protein of the SARS-CoV-2 virus (Elecsys Anti-SARS-CoV-2 S immunoassay).14 The antibody levels were determined within a range of 0.4 and 2500 binding antibody units (BAU/mL). Levels above 2500 were diluted 1:10 or 1:100. For exclusion purposes, nucleocapsid-specific antibodies were measured using qualitative immunoassays (Elecsys Anti-SARS-CoV-2 assay).15 Calibration is performed regularly to avoid batch effects and ensure proper function. Both tests were performed at the Department for Laboratory Medicine of the Medical University of Vienna and measured on a Cobas e801 analyser (Roche Diagnostics, Switzerland). (Detailed information can be found at https://diagnostics.roche.com/global/en/products/lab/elecsys-anti-sars-cov-2-cps-000273.html)
Statistical analysis
Patients suffering from a SARD were allocated into a vasculitis or CTD group and compared with the HCs. Normality of anti-SARS-CoV-2 antibody levels was assessed using the Kolmogorov-Smirnov test and was found to be non-normally distributed. Therefore, a Wilcoxon non-parametric test was used to assess the significance of anti-SARS-CoV-2 antibody levels in different populations. When multiple tests were performed, multiple hypothesis correction was applied according to Benjamini-Hochberg. Due to the non-linear distribution of data, correlation was assessed via Spearman’s rank correlation coefficient. Multiple comparison correction was done with the Benjamini-Hochberg procedure. Data are shown as either mean and SD or median with IQR.
We performed analyses on the two largest groups of patients, which could be identified in the SARD cohort, those with either LVV, AAV or PMR (vasculitis group) and those with various forms of CTD (CTD group).
In addition, patients were grouped into different categories according to the applied medication. The first group ‘none’ did not receive any immunosuppressive agents. The second group ‘mono’ received a single csDMARD or a single bDMARD, or tsDMARD. The third group ‘combination’ consisted of patients receiving two csDMARDs, a csDMARD with a b/tsDMARD or a csDMARD and glucocorticoids.
As our cohort is not gender or age-matched, we performed a multivariable linear regression model to further specify the role of age, gender, glucocorticoids and therapy on the antibody levels.
Patient and public involvement
None.
Results
This analysis includes 52 patients and compares the antibody levels to 72 healthy controls. Demographic parameters, disease entities and medication are shown in table 1. Disease entities in the two disease groups: vasculitis (n: 12) and CTD (n: 40) are shown with their individual diagnosis and respective antibody levels in online supplemental figure 1.
Antibody levels 6 months after the second vaccination
Antibodies targeting the RBD domain of the S protein were measured 6 months after two doses of mRNA vaccinations and compared with healthy controls. We compared patients with vasculitis and CTD and found a significant difference between antibody titres (healthy controls: median 514 BAU/mL, IQR 323; 928, vasculitis patients: 247 BAU/mL, IQR 185; 437, p=0.02 and CTD patients: 517 BAU/mL, IQR 91; 934, p=0.35) (figure 1). Different antibody levels between SARD subgroups compared with HCs were shown in a descriptive manner in online supplemental figure 1.
Figure 1. SARS-CoV-2 receptor-binding domain (RBD) antibody levels measured 6 months after the second vaccination in healthy controls (HC) and patients with vasculitis or connective tissue disease (CTD).
We found no difference between the antibody levels of healthy subjects and SARD patients receiving no immunosuppressive therapy or those on monotherapy. The median antibody levels were 514 BAU/mL, IQR [323; 928] in healthy controls, 749 BAU/mL, (IQR 279; 1664) in patients with no immunosuppressants (p=0.35), 432 BAU/mL, [IQR 209; 775] in patients with a single immunosuppressive drug (any) and 96 BAU/mL in those taking a csDMARD and b/tsDMARD or glucocorticoids (combination therapy, IQR [7; 288] p=0.14). However, we could observe a significant decrease in SARS-CoV-2 RBD titres in patients treated with combination therapy (p=0.00087; figure 2).
Figure 2. SARS-CoV-2 receptor-binding domain (RBD) antibody levels measured 6 months after the second vaccination of healthy control subjects (HC); patients receiving no immunosuppressive therapy (none); patients receiving a single conventional systemic disease-modifying drug (csDMARD) or biological or targeted synthetic DMARD b/tsDMARD (mono); and patients receiving combination therapy of csDMARD, b/tsDMARD and/or glucocorticoids (combination).
We depicted the differences in antibody levels 6 months after the second vaccination in the different disease subgroups. As the number of patients in each subset is too low for reasonable statistical analysis, we present the data descriptively (online supplemental figure 5). The highest antibody levels could be found in the myositis group (median 1321 BAU/mL, [IQR 1104; 1539]), followed by Sjögren’s disease 880 BAU/mL [IQR 820; 1471], then the UCTD group 656 BAU/mL, [IQR 587; 725], while the group with SSc displayed antibody levels of median 617 BAU/mL, [IQR 90; 1076]. Patients with MCTD had a median of 419 BAU/mL, [IQR 405; 432], the patient with sarcoidosis showed a median titre of 312 BAU/mL, [IQR 312; 312], and lastly, patients with SLE had a low median antibody level of 137 BAU/mL, [IQR 14; 520].
Factors associated with antibody development
To detect possible correlations relevant for the lower titres in patients receiving combination therapies, CD19+ B-cells as total B-cell count were quantified at the time of SARS-CoV-2 antibody measurement, without further immunophenotyping as described above, and compared between healthy controls and patients. We could show a weak correlation between B-cells and antibody titres (R=0.41; p<0.05) (online supplemental figure 2). Age, another important factor influencing antibody development, was acknowledged by choosing patients and HCs of similar age (median 52 years, IQR [41; 60] vs 56 years, IQR [45; 63]). Glucocorticoid dose, which is another very important factor in antibody development, was rather low in our disease cohort (median 2.75 mg IQR [1.31; 5]). Finally, we investigated antibody levels 6 months after the second vaccination and found a non-significant correlation with glucocorticoid dose (R: −0.031; p=0.92) (online supplemental figure 3).
Moreover, to determine the effect of age, sex and glucocorticoid therapy on the antibody titres, we performed a multivariate regression model (online supplemental figure 6). A significant effect of age on antibody levels 6 months after the second vaccination could be detected in the multivariate linear regression analysis −10.6 (97.5% CI [−17.5; −3.8] p=0.003). No significant difference could be observed regarding sex 30.6 (CI [−188.6; 249.9] p=0.783) or glucocorticoid dose in our cohort −3.8 (CI [−17.0; 9.4] p=0.570). We observed an effect of immunosuppressive therapy on antibody development: healthy controls and patients receiving no therapy 376.1 (CI [90.1; 662.1] p=0.010), patients under monotherapy −122.7 (CI [−378.1; 132.6] p=0.343) and patients receiving combination therapy −348.0 (CI [−676.0; −20.0] p=0.038).
Third vaccination and its effect on antibody levels
Antibody levels for the individual diseases are shown in online supplemental figure 4. After the third vaccination, both the vasculitis group, as well as the CTD group displayed significantly lower antibody levels compared with healthy controls (HC median 22 630 BAU/mL, IQR [16 945; 43 200], vasculitis 3897 BAU/mL, IQR [2916; 7075 p=0.0000036, CTD 13410 BAU/mL, IQR [2878; 16 820] p=0.00013; figure 3). Surprisingly, after the third vaccination, we found lower antibody levels not only in patients on combination therapy but also those receiving monotherapy or even those not receiving any immunosuppressive therapy: median 22 630 BAU/mL, IQR [16 945; 43 200] in HC, 9510 IQR [3866; 14 215] BAU/mL, in patients without immunosuppressive treatment (p=0.00023), 7780 BAU/mL, IQR [2203; 15 645] in patients receiving a single immunosuppressive drug (p=0.000012) and 14 320 BAU/mL, IQR [2415; 35 400] in patients receiving combination therapy (p=0.081) (figure 4)
Figure 3. SARS-CoV-2 receptor-binding domain (RBD) antibody levels measured after the third vaccination in healthy control subjects (HC) and patients with vasculitis or connective tissue disease (CTD).
Figure 4. SARS-CoV-2 receptor-binding domain (RBD) antibody levels measured after the third vaccination of healthy control subjects (HC); patients receiving no immunosuppressive therapy (none); patients receiving a single conventional systemic disease-modifying drug (csDMARD) or biological or targeted synthetic DMARD b/tsDMARD (mono); and patients receiving combination therapy of csDMARD, b/tsDMARD and/or glucocorticoids (combination).
Discussion
In our study, we could show that patients with a SARD diagnosis, even without immunosuppressive therapy, displayed lower antibody titres after a third mRNA vaccination. As patients without medication affecting the immune system and HCs started with comparable antibody levels 6 months after the second vaccination, this was a surprising finding and may suggest an influence of the altered immune system on the antibody response in SARD patients. This is of special interest, as patients with autoimmune disease have a higher risk for infection and a severe disease course.2 These results highlight the need for titre determination and a more personalised vaccination strategy for SARD patients, even in those not receiving immunosuppressive treatment.
Our findings go hand in hand with those of previous studies, confirming reduced antibody development in SARD patients undergoing immunosuppressive therapy.12 Patients receiving combination therapy, in particular, demonstrated lower antibody response after the third booster vaccination. As we excluded patients receiving B-cell depleting therapy, we can rule out B-cells as being the sole culprits behind this observation. Furthermore, to minimise the effect of antibody elevation after previous illness, we excluded patients with previous SARS-CoV-2 infection. Finally, we consider it highly unlikely that the observed effect is mediated by glucocorticoids, given the low dose of these medications used in the cohort.
Our study is not without limitations. In addition to the small sample size, our cohort encompasses a heterogeneous group of entities, yet these diseases nevertheless share common features, such as systemic inflammation, multiorgan involvement and autoimmune features, which justify their inclusion into a single cohort. Indeed, our findings might be affected by additional confounding factors such as differences in disease activity, concomitant medication or comorbidities.
Given these limitations, clearly more studies are needed before clear recommendations can be made on the ideal time point of antibody measurement. We hope that our study increases awareness to seek earlier antibody measurement, not only after 1 year, but possibly even 6 months after vaccination, and thus gives new impetus for future studies aiming to gather more knowledge about humoral response in patients with SARD with and without immunomodulatory treatment. SARDs are regarded as rare diseases and affect less than 1% of the population in general; therefore, the benefit of routine antibody measurements may outweigh the costs, as infections are commonly seen in these patients and may lead to a decline in quality of life. Yet, further cost/benefit calculations need to be performed. Since our study indeed included only patients on mRNA vaccines, we cannot know for sure whether the results are applicable to other vaccine types. However, findings from studies such as that of Yu et al16 have shown that there is a difference between mRNA and recombinant protein vaccines in that the former induces higher cellular immune responses; thus, one may postulate that waning of antibody levels due to disease might be even greater in patients with SARD vaccinated with recombinant protein vaccines.
As an individualised approach, but under emphasis of the above-mentioned limitations in our study, one scenario could involve testing antibodies 6 months after vaccination, especially in patients receiving a combination therapy of immunomodulating drugs. In Austria, booster vaccination is usually scheduled after 1 year, yet earlier antibody testing after 6 months may be useful to gauge protection from severe infection in individual patients. In case antibody levels are exceptionally low, earlier booster vaccination may be recommended to improve antibody levels.
From the literature, we know that patients under B-cell depleting therapy have the highest risk of failing to develop or developing low antibody levels.17 18 So, according to the EULAR recommendations, patients with B-cell depleting therapy should postpone the next treatment regimen, if directly before or directly following a vaccination for adequate antibody development, in stable disease.19 Another B-cell affecting drug that is known to lower the humoral response in SARD patients is mycophenolate mofetil.20 Patients receiving bDMARDs, such as interleukin-6 inhibitors, Janus-kinase inhibitors or tumour necrosis factor-α (TNF-α) inhibitors, also display lower antibody development,21 whereas those receiving interleukin-17 inhibitors showed higher antibody titres compared with other bDMARDs.21 In addition, patients under methotrexate are very prone to low adaptive immune system reaction.22 Thus, the combination of, for example, TNF inhibitors and methotrexate may lead to significant decrease in humoral response.23 Patients receiving hydroxychloroquine also develop lower but adequate antibody levels; however, a combination with different DMARDs decreases the humoral response.24 To sum up, the above-described studies and also our results may imply that patients receiving a combination of immunomodulatory treatments should be tested for antibody levels after SARS-CoV-2 vaccination and may benefit from earlier booster vaccination. Last but not least, age is a factor in humoral response, as underlined by the results of our study and should factor into decisions on the timing of antibody testing and vaccination.
Furthermore, we have to emphasise that our sample size is too low to give verified recommendations, and the reader may see this as a personal opinion.
We excluded patients with infection and acknowledge that this is a limitation and indeed excludes likely a large percentage of patients; however, it would have been difficult to interpret antibody responses in patients who had previous infections and also received vaccines. As protective vaccination is recommended for patients with SARD and especially under immunosuppressive therapy, we are only starting to understand the processes behind antibody development and persistence in this vulnerable patient group, due to the SARS-CoV-2 pandemic. This study should serve to gain some insights into antibody development purely driven by vaccination.
Concerning subgroup analysis of SARD patients, we have to emphasise the limitation of a low number of participants in our study. However, according to our descriptive analysis, we may hypothesise that screening of SLE patients, MCTD and sarcoidosis may be reasonable. Yet, further studies with a higher sample size are necessary before formulating any recommendations in this regard.
Finally, we hope that the insight gained from our study can be applied to other vaccines in patients with autoimmune disease, who are immunocompromised and thus need additional protection against serious infections. The more information we gather on the use of vaccinations, the better we can treat our patients at an individualised and patient-centred level.
Supplementary material
Acknowledgements
We thank all the patients who participated. We thank Sylvia Taxer and Zoltan Vass for their support.
Footnotes
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Prepublication history and additional supplemental material for this paper are available online. To view these files, please visit the journal online (https://doi.org/10.1136/bmjopen-2024-094948).
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient consent for publication: Not applicable.
Ethics approval: This study involves human participants and was approved by Ethics Committee of the Medical University of Vienna: 1291/2021; 559/2005; and 1073/2021. Participants gave informed consent to participate in the study before taking part.
Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Data availability statement
Data are available upon reasonable request.
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