SARS-CoV-2 mRNA vaccination elicited high immunogenicity in immunocompetent people in the original vaccine trials,1,2 though recent studies have shown blunted immunogenicity in patients with rheumatic and musculoskeletal diseases (RMD) after a single dose and case reports of non-response after two doses.3,4 We previously detailed antibody response in patients with RMD following the first dose of SARS-CoV-2 mRNA vaccination and herein report response and factors associated with response to two-dose vaccination in a larger cohort.
As previously reported,3 patients ≥18 years old with RMD were recruited to participate in this prospective, observational cohort via social media outreach to national RMD organizations between 12/7/2020–3/16/2021. Demographics, diagnoses, and therapeutic regimens were collected via participant report through the Research Electronic Data Capture (REDCap) tool. One month after D2, participants underwent SARS-CoV-2 antibody testing on the semi-quantitative Roche Elecsys® anti-SARS-CoV-2 S enzyme immunoassay which measures total antibody (IgM, IgG) to the SARS-CoV-2 S-receptor binding domain (RBD) protein,5 the target of the mRNA vaccines. Results range from <0.4 to >250 U/mL with a positive response defined as >0.79 U/mL. Associations were evaluated using Fisher’s exact and Wilcoxon rank sum tests. Participants provided informed consent.
We studied 404 patients who received two doses of the SARS-CoV-2 mRNA vaccine (Supplemental Table 1). The median (IQR) age was 44 (36, 57), 96% were female, 9% were non-white, 49% received the Pfizer/BioNTech vaccine and 51% received Moderna, 4% had a pre-vaccination history of COVID-19 diagnosis, and no participant reported post-vaccination COVID-19 diagnosis. Most common diagnoses included inflammatory arthritis (45%) and systemic lupus erythematosus (22%). The most frequently prescribed medications were hydroxychloroquine (42%) and glucocorticoids (29%); 51% were on combination therapy. Participants completed anti-RBD testing at a median of 29 days after D2.
Anti-SARS-CoV-2 RBD antibodies were positive in 378/404 (94%) participants (95% CI 91–96%) (Supplemental Table 1). Median anti-RBD titer was above the upper limit of the assay (>250 U/mL), while lower median titers were observed in participants on regimens including mycophenolate (8 U/mL) and rituximab (<0.4 U/mL) (Figure 1, Supplemental Table 2). Tumor necrosis factor (TNF) inhibitor use was associated with a positive antibody response (100% positive, p<0.001), while regimens including mycophenolate (73% positive, p<0.001), rituximab (26% positive, p<0.001), or glucocorticoids (82% positive, p<0.001), and a diagnosis of myositis (79% positive, p=0.01) were associated with a negative response. Of note, 4/5 (80%) negative responders with myositis and 18/21 (86%) negative responders on glucocorticoids were on regimens including mycophenolate or rituximab; all 8 on glucocorticoid monotherapy had an anti-RBD titer >250 U/mL.
Figure 1.
Anti-SARS-CoV-2 RBD antibody titer overall (n=403*) and by medications associated with a negative antibody response: mycophenolate included in regimen (n=41), rituximab included in regimen (n=19), glucocorticoid included in regimen (n=116), and glucocorticoid monotherapy (n=8) in patients with RMD after two-dose SARS-CoV-2 mRNA vaccination. Results range from <0.4 to >250 U/mL with positive antibody defined as an anti-SARS-CoV-2 RBD antibody titer >0.79 U/mL by the manufacturer; blue data points indicate median titer.
* 1 titer value was missing from the total N (404).
In this study of humoral response to two-dose SARS-CoV-2 mRNA vaccination in patients with RMD, the vast majority of participants developed anti-RBD antibodies. Among negative responders, most were on regimens containing mycophenolate or rituximab. Glucocorticoid use was also associated with a negative response, though all of these individuals were on concomitant lymphocyte-depleting therapy. Compared to patients with RMD following D1 (74% seroconversion),3 this study showed increased seroconversion following two-dose vaccination (94% seroconversion). Similarly, seroconversion for those on mycophenolate-based regimens was 73% after two doses compared to 27% after D1, while the response for those on rituximab remained poor (33% seroconversion after D1, 26% seroconversion after D2). Despite a blunted humoral response in participants on these regimens, the rate of seroconversion was comparable to those seen in the original vaccine trials and current studies on patients with RMD.1,2,6
Limitations of this study include a younger, generally female, racially homogenous population and limited information on immunomodulatory timing and dosage. Additionally, we did not evaluate for asymptomatic COVID-19 infection and disease activity was not assessed.
While certain lymphocyte-depleting therapies were associated with failure to develop a humoral response, reassuringly, the majority of patients with RMD on a variety of immunosuppressive regimens had a robust humoral response to SARS-CoV-2 mRNA vaccination.
Supplementary Material
ACKNOWLEDGEMENTS
We also acknowledge the following individuals for their assistance with this study: Allan B. Massie PhD, Robin K. Avery MD, Michael T. Ou BS, Ross S. Greenberg BS, and Iulia Barber BS.
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 National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAIM). 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
- D1
Dose 1
- D2
Dose 2
- IL
Interleukin
- JAK
Janus kinase
- RBD
S-receptor binding domain
- RMD
Rheumatic and musculoskeletal diseases
- TNF
Tumor necrosis factor
Footnotes
PATIENT AND PUBLIC INVOLVEMENT
Patients were not involved in the design, conduct, or dissemination of the study, though this study was motivated by questions frequently posed by patients. The study has a public website (https://vaccineresponse.org/) and email account where we welcomed participants and the public to contact the research team. Results of the study will be shared with national RMD organizations for dissemination to their patient communities once published.
DISCLOSURES
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. Lisa Christopher-Stine has the following financial disclosures: consultant fees from Janssen, Boehringer-ngelheim, Mallinckrodt, EMD-Serono, Allogene, and ArgenX.
The other authors of this manuscript have no financial disclosures or conflicts of interest to disclose as described by Annals of the Rheumatic Diseases.
ETHICS APPROVAL
This study was approved by the Johns Hopkins School of Medicine Institutional Review Board (IRB00248540).
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