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Mycophenolate is the mainstay of treatment for many organ and life-threatening manifestations of rheumatic and musculoskeletal diseases (RMD). In contrast to most patients with RMD, those taking mycophenolate have an attenuated humoral response to SARS-CoV-2 mRNA vaccination.1 2 The American College of Rheumatology recently recommended withholding mycophenolate for 1 week after vaccination to enhance immunogenicity in this vulnerable population.3 Thus, we sought to analyse the impact of withholding perivaccination mycophenolate in 24 patients with RMD.
We leveraged our observational prospective cohort of patients with RMD without prior COVID-19 who underwent SARS-CoV-2 vaccination between 17 December 2020 and 13 May 2021.2 Information on demographics, diagnoses, immunosuppressive regimens and management of perivaccination immunosuppression was collected via electronic questionnaire. One month following vaccination, venipuncture samples were obtained and tested on the semiquantitative Roche Elecsys anti-SARS-CoV-2 S enzyme immunoassay which tests for antibodies against the receptor binding domain (RBD) of the SARS-CoV-2 spike protein; a consistent correlate of neutralising antibody.4 We compared the percentage of participants with detectable anti-RBD antibody in the group that withheld mycophenolate (n=24) to the group that continued mycophenolate (n=171) using Fisher’s exact test (online supplemental table 1). Crude and adjusted logistic regression analyses were performed to assess associations between antibody response and the primary variable of withholding mycophenolate, as well as after adjusting for clinical characteristics (age, sex, race, vaccine type (mRNA vs adenovirus vector), use of rituximab and glucocorticoids). Wilcoxon rank-sum test was used to compare anti-RBD titers of the patients who withheld therapy to those who continued therapy. This study was approved by the Johns Hopkins Institutional Review Board (IRB00248540).
We studied 24 patients who withheld mycophenolate (table 1). Most were female (96%) with a median (IQR) age 51 (40-58) years. Overall, 13% received the Janssen/Johnson and Johnson vaccine while the remainder completed two-dose Pfizer/BioNTech or Moderna mRNA series. The most common diagnoses were systemic lupus erythematosus (25%) and myositis (20%). Most participants reported two times per day dosing of mycophenolate, with a median (IQR) total daily dose of 2000 mg (1625–3000 mg). The median (IQR) number of doses held was 20 (8–34). Thirteen participants (54%) withheld before vaccination, nine (38%) withheld both before and after vaccination, while two (8%) withheld after vaccination. Among those who withheld both before and after vaccination, the majority (seven out of nine) held for the same duration before and after, while the remaining two participants held more doses after vaccination.
At a median (IQR) of 32 (28–35) days after vaccination, 22/24 participants who withheld mycophenolate had detectable antibody response compared with 112/171 who continued therapy (92% vs 65%, p=0.01). Those who withheld therapy were more likely to have a positive antibody response (OR 5.8, 95% CI 1.3 to 25.5 p=0.02). In the adjusted logistic regression model, the association between withholding mycophenolate and positive response remained statistically significant (aOR 7.24, 95% CI 1.72 to 44.31 p=0.01) (online supplemental table 2). Since the rare disease assumption was not met, this OR cannot be interpreted as a relative chance of a positive response. Median anti-RBD Ig titers in the withholding group were significantly higher than the group that continued therapy (125 vs 7 U/L, p=0.004) (online supplemental figure 1). Two participants reported flare of their underlying disease requiring treatment in the perivaccination period; these were treated with topical and oral glucocorticoids, respectively.
In this case series, we describe 24 patients with RMD who withheld mycophenolate in the perivaccination period of whom (92%) had a detectable humoral response, which was more frequent and robust than among participants who continued therapy.
The small sample size did not allow for evaluation of optimal duration of withholding therapy. Further limitations of this study include non-randomised design, lack of data on cellular response and limited information on dosing of other immunosuppressive agents.
These early results suggest that a temporary hold in mycophenolate therapy is safe and augments the humoral response to SARS-CoV-2 vaccination in diverse patients with RMD. Given the limited immunogenicity to SARS-CoV-2 vaccination in other immunosuppressed patients,5 the generalisability of these preliminary findings warrants further investigation. Evidence-based, personalised approaches to perivaccination immunosuppression modulation will be key in safely optimising responses to SARS-CoV-2 vaccination for vulnerable populations.
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 organisations for dissemination to their patient communities once published.
Patient consent for publication
Handling editor Josef S Smolen
Twitter @CaoilfhionnMD, @JenLAlejo
Contributors Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work: CMC, TP-YC, BJB, MT, JLA, AM, AAS, WAW, JG-W, DLS, JJP. Drafting the work or revising it critically for important intellectual content: CMC, TP-YC, JAR, BJB, MT, JLA, AM, LC-S, AAS, WAW, JG-W, DLS, JJP. Final approval of the version to be published: CMC, TP-YC, JAR, BJB, JLA, AM, LC-S, AAS, WAW, DLS, JG-W, JJP. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: CMC, TP-YC, JAR, BJB, JLA, LC-S, WAW, JG-W, DLS, JJP.
Funding This work was made possible by the generous support of the Ben Dov family. This work was supported by grant number F32DK124941 (Boyarsky), 5T32DK007713 (Alejo),K01DK101677 (Massie) and K23DK115908 (Garonzik‐Wang) from the National Institute of Diabetes and Digestive and Kidney Diseases, K24AI144954 (Segev) from National Institute of Allergy and Infectious Diseases, K23AR073927 (Paik) from National Institute of Arthritis and Musculoskeletal and Skin Diseases.
Disclaimer 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 organisations imply endorsement by the US Government.
Competing interests DLS, 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-Ingelheim, Mallinckrodt, EMD-Serono, Allogene and ArgenX.
Provenance and peer review Not commissioned; externally peer reviewed.
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