The immune response to the SARS-CoV-2 mRNA vaccines in patients with rheumatic and musculoskeletal diseases (RMD) is undefined because these individuals were largely excluded from phase 1–3 studies. To better understand the immune response to vaccination in this patient population, we studied the antibody response in patients with RMD who underwent the first dose of SARS-CoV-2 mRNA vaccination.
Participants with RMD across the US were recruited to participate in this prospective cohort via social media. Those with prior SARS-CoV-2 were excluded. We collected demographics, RMD diagnoses, and immunomodulatory regimens, and tested for SARS-CoV-2 antibodies at baseline and prior to the second vaccine dose. Antibody testing was conducted on the semi-quantitative Roche Elecsys® anti-SARS-CoV-2 S enzyme immunoassay (EIA) which tests for antibodies against the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. [1] We evaluated the association between demographic/clinical characteristics and positive antibody response using Fisher’s exact test and Wilcoxon rank sum test.
We studied 123 participants who received their first SARS-CoV-2 vaccination dose between January 8, 2021 and February 12, 2021; 52% underwent BNT162b2, and 48% underwent mRNA-1273 (Table 1). The most common reported RMD diagnoses were inflammatory arthritis (28%), systemic lupus erythematosus (SLE) (20%), Sjogren’s syndrome (13%), and overlap conditions (29%). Whereas 28% reported not taking immunomodulatory agents, the remainder reported regimens including non- biologic disease modifying anti-rheumatic drugs (DMARDs) (19%), biologic DMARDs (14%), and combination therapy (37%).
Table 1.
Demographic and Clinical Characteristics of Study Participants, Stratified by Immune Response to the First Dose of SARS-CoV-2 mRNA Vaccine
| Overall (n=123) | Detectable antibody (n=91) | Undetectable antibody (n=32) | p-value1 | |
|---|---|---|---|---|
| Age, median (IQR) | 50 (41, 61) | 46 (37, 61) | 57 (43, 68) | 0.06 |
| Female sex, no. (%) | 117 (95) | 87 (96) | 30 (94) | 0.7 |
| Non-white, no. (%) | 12 (10) | 11 (12) | 1 (3) | 0.2 |
| Diagnosis, no. (%) | ||||
| Inflammatory arthritis2 | 34 (28) | 29 (32) | 5 (16) | 0.5 |
| Systemic lupus erythematous | 24 (20) | 16 (18) | 8 (25) | |
| Sjogren’s syndrome | 16 (13) | 12 (13) | 4 (12) | |
| Myositis | 7 (6) | 4 (4) | 3 (9) | |
| Vasculitis | 2 (2) | 1 (1) | 1 (3) | |
| Overlap3 | 35 (29) | 25 (27) | 10 (31) | |
| Other | 5 (4) | 4 (4) | 1 (3) | |
| Therapy, no. (%) | ||||
| None | 34 (28) | 28 (31) | 6 (19) | 0.5 |
| Non-biologic DMARD4 | 23 (19) | 16 (18) | 7 (22) | |
| Biologic DMARD5 | 17 (14) | 11 (12) | 6 (19) | |
| Corticosteroid-monotherapy6 | 4 (3) | 4 (4) | 0 (0) | |
| Combination therapy | 45 (37) | 32 (35) | 13 (41) |
Comparing the detectable antibody group to the undetectable antibody group.
Rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, reactive arthritis and inflammatory bowel disease associated arthritis
Overlap denotes a combination of 2 or more of the above conditions, also includes systemic sclerosis
Azathioprine, hydroxychloroquine, leflunomide, methotrexate, mycophenolate, sulfasalazine, tacrolimus
Adalimumab, certolizumab, etanercept, infliximab, tocilizumab, ustekinumab, ixekizumab, belimumab, rituximab, tofacitinib, abatacept
Prednisone and prednisone equivalents
At a median (IQR) of 22 (18–26) days after the first vaccine dose, 74% (binomial exact 95% confidence interval 65–81%) had a detectable anti-RBD antibody response (Supplemental Table 1). Younger participants appeared more likely to develop an antibody response (p=0.06). No differences were detected between disease groups or overall immunomodulatory therapy categories. However, those on regimens including mycophenolate or rituximab were less likely to develop an antibody response (p=0.001 and p=0.04, respectively) (Table 2). Nearly all patients (94%) on anti-tumor necrosis factor inhibitor (TNF) therapy had detectable antibodies.
Table 2.
Participant Immunomodulatory Therapy1, Stratified by Humoral Immune Response to the First Dose of SARS-CoV-2 mRNA Vaccine
| Detectable antibody (n=91) | Undetectable antibody (n=32) | p-value | |
|---|---|---|---|
| Medication, no. (%) | |||
| Non-biologic | |||
| Azathioprine | 9 (10) | 4 (12) | 0.7 |
| Hydroxychloroquine | 27 (30) | 10 (31) | 0.9 |
| Mycophenolate2 | 3 (3) | 8 (25) | 0.001 |
| Sulfasalazine | 4 (4) | 1 (3) | 0.9 |
| Tacrolimus | 0 (0) | 2 (6) | 0.07 |
| Leflunomide | 2 (2) | 2 (6) | 0.3 |
| Methotrexate | 10 (11) | 3 (9) | 0.9 |
| Biologic | |||
| Abatacept | 3 (3) | 3 (9) | 0.5 |
| Belimumab | 5 (5) | 5 (16) | 0.1 |
| Interleukin inhibitor3 | 6 (7) | 0 (0) | 0.3 |
| Rituximab | 2 (2) | 4 (12) | 0.04 |
| TNF inhibitor4 | 16 (18) | 1 (3) | 0.07 |
| Tofacitinib | 2 (2) | 1 (3) | 0.9 |
Since participants could report more than one medication, the total N in this table is greater than the stated cohort size.
Mycophenolic acid or mycophenolate mofetil
Interleukin inhibitors: tocilizumab, ustekinumab, and ixekizumab
TNF inhibitors: Adalimumab certolizumab, etanercept, and infliximab
In this study of the immune response to the first dose of the SARS-CoV-2 mRNA vaccine in patients with RMD, the majority of participants developed detectable anti-SARS-CoV-2 RBD antibodies, however patients on regimens including mycophenolate or rituximab were less likely to develop an antibody response. Overall, there were no major differences by diagnosis or being on immunomodulatory therapy (versus not being on therapy), though consistent with prior studies, younger patients were more likely to develop antibody responses. Nearly all patients on anti-TNF therapy developed detectable antibody. These associations warrant further investigation.
Rituximab and methotrexate have been shown to reduce humoral responses to influenza and pneumococcal vaccines [2, 3]. We found that patients on rituximab were less likely to develop antibody response, yet methotrexate did not negatively impact antibody development. Additionally, we found that patients on mycophenolate were less likely to develop antibody response to mRNA vaccination, consistent with observed experience of influenza vaccination in the renal transplant population and reduced response to HPV vaccination in patients with SLE [4].
Limitations of this study include a small, non-randomized sample, limited information on immunomodulatory dosage and timing, lack of serial measurements, and use of an EIA designed to detect antibody response after natural infection. Furthermore, these are data on the first-dose response to a two-dose series.
Nearly half of patients with RMD have expressed hesitancy or unwillingness to receive a SARS-CoV-2 mRNA vaccine due to a paucity of data [5], however this report can provide reassurance to patients and their providers. We did, however, observe that certain lymphocyte-modulating therapies were associated with poorer humoral vaccine response; potential exploratory strategies to increase immunogenicity in this subgroup may involve adjustment in immunomodulatory therapy, dosage or timing around vaccination.
Supplementary Material
ACKNOWLEDGEMENTS
FUNDING/GRANT/AWARD INFORMATION
This research was made possible with generous support of the Ben-Dov family. This work was supported by grant number F32DK124941 (Boyarsky), and K23DK115908 (Garonzik-Wang) from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), K24AI144954 (Segev) from National Institute of Allergy and Infectious Diseases (NIAID), K23AR073927 (Paik) from NIAMS, and by a grant from the Transplantation and Immunology Research Network of the American Society of Transplantation (Werbel). The analyses described here are the responsibility of the authors alone and do not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government.
ABBREVIATIONS
- RMD
rheumatic and musculoskeletal diseases
- SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
- COVID-19
Coronavirus disease 2019
- EIA
enzyme immunoassay
- RBD
receptor binding domain
- SLE
systemic lupus erythematosus
- DMARD
disease modifying anti-rheumatic drug
- TNF
tumor necrosis factor
Footnotes
COMPETING INTERESTS
Dorry L. Segev, MD PhD has the following financial disclosures: consulting and speaking honoraria from Sanofi, Novartis, CSL Behring, Jazz Pharmaceuticals, Veloxis, Mallincrodt, Thermo Fisher Scientific. The other authors of this manuscript have no financial disclosures or conflicts of interest to disclose as described by Annals of Rheumatic Diseases.
ETHICAL APPROVAL INFORMATION
This study was approved by the Johns Hopkins School of Medicine Institutional Review Board (IRB00248540).
DATA SHARING STATEMENT
All data relevant to the study are included in the article or uploaded as supplementary information.
PATIENT AND PUBLIC INVOLVEMENT
Patients or the public WERE NOT involved in the design, or conduct, or reporting, or dissemination plans of our research
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