Absence of Humoral Response After Two-Dose SARS-CoV-2 Messenger RNA Vaccination in Patients With Rheumatic and Musculoskeletal Diseases: A Case Series
Authors: Caoilfhionn M. Connolly, Brian J. Boyarsky, Jake A. Ruddy, William A. Werbel, Lisa Christopher-Stine, Jacqueline M. Garonzik-Wang, Dorry L. Segev, Julie J. Paik
Journal: Annals of Internal Medicine (2021)

Letters25 May 2021Absence of Humoral Response After Two-Dose SARS-CoV-2 Messenger RNA Vaccination in Patients With Rheumatic and Musculoskeletal Diseases: A Case SeriesFREECaoilfhionn M. Connolly, MD, MSc, Brian J. Boyarsky, MD, PhD, Jake A. Ruddy, BS, William A. Werbel, MD, Lisa Christopher-Stine, MD, MPH, Jacqueline M. Garonzik-Wang, MD, PhD, Dorry L. Segev, MD, PhD†, and Julie J. Paik, MD, MHS†Caoilfhionn M. Connolly, MD, MScJohns Hopkins University School of Medicine, Baltimore, MarylandSearch for more papers by this author, Brian J. Boyarsky, MD, PhDJohns Hopkins University School of Medicine, Baltimore, MarylandSearch for more papers by this author, Jake A. Ruddy, BSJohns Hopkins University School of Medicine, Baltimore, MarylandSearch for more papers by this author, William A. Werbel, MDJohns Hopkins University School of Medicine, Baltimore, MarylandSearch for more papers by this author, Lisa Christopher-Stine, MD, MPHJohns Hopkins University School of Medicine, Baltimore, MarylandSearch for more papers by this author, Jacqueline M. Garonzik-Wang, MD, PhDJohns Hopkins University School of Medicine, Baltimore, MarylandSearch for more papers by this author, Dorry L. Segev, MD, PhD†Johns Hopkins University School of Medicine, Baltimore, MarylandSearch for more papers by this author, and Julie J. Paik, MD, MHS†Johns Hopkins University School of Medicine, Baltimore, MarylandSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M21-1451 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Background: Patients with rheumatic and musculoskeletal diseases (RMDs) are at increased risk for SARS-CoV-2 infection because of both the immunomodulatory effects of their underlying diseases and treatment with immunosuppressive agents. Early data have suggested limited immunogenicity of SARS-CoV-2 messenger RNA (mRNA) vaccines in immunocompromised patients (1), and although most patients with RMDs developed a robust response to the first dose of the mRNA vaccine (2), an important subset of patients did not mount an appreciable humoral response. Thus, we sought to analyze a subset of 20 patients with RMDs who did not develop a detectable antibody response 1 month after completion of 2-dose mRNA vaccination against SARS-CoV-2.Objective: To evaluate the clinical characteristics of patients with RMDs and absence of a humoral vaccine response.Case Report: Patients aged 18 years or older with RMDs were recruited to participate in this prospective cohort assessing SARS-CoV-2 vaccine response through a digital campaign between 7 December 2020 and 11 March 2021. Demographic characteristics, diagnoses, and immunosuppressive regimens were collected. One month after the second dose, venipuncture samples were obtained and tested on the semiquantitative Elecsys anti–SARS-CoV-2 S enzyme immunoassay (Roche), which tests for antibodies against the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein—a consistent correlate of neutralizing antibody (3). Twenty participants with undetectable anti-RBD antibodies were included in this case series. This study was approved by the Johns Hopkins Institutional Review Board.Twenty participants did not have detectable anti-RBD antibodies (<0.4 U/mL) at a median of 30 days (interquartile range, 28 to 36 days) after the second dose of the SARS-CoV-2 mRNA vaccine (Table). Most were female (95%) and White (90%), and the median age was 46 years (interquartile range, 37 to 51 years). Sixty percent received the Pfizer-BioNTech and 40% received the Moderna mRNA vaccine series. The most common diagnosis was systemic lupus erythematosus (50%), followed by myositis (25%) and vasculitis (15%). The final 2 participants reported Sjögren syndrome and sarcoidosis. Most participants were receiving multiple immunosuppressive agents (90%); maintenance corticosteroids were a part of 16 participant regimens (80%), with a median dose of 5 mg (range, 2.5 to 55 mg). Rituximab (55%) was the most commonly prescribed biologic agent, whereas mycophenolate (50%) was the most frequently reported disease-modifying antirheumatic drug. The median timing of rituximab infusion before dose 1 was 14 weeks (interquartile range, 7 to 19 weeks). Only 2 participants (10%) were not receiving rituximab or mycophenolate; rather, they were treated with belimumab and a combination of azathioprine and tacrolimus, respectively. Three participants (15%) reported use of intravenous immunoglobulin. There were no reported diagnoses of COVID-19 during follow-up.Table Clinical Characteristics of Participants With RMD and Absence of Humoral Response 1 Month After 2-Dose SARS-CoV-2 Messenger RNA VaccinationDiscussion: In this case series, we describe the clinical characteristics of 20 patients with RMDs who did not develop detectable anti-RBD antibodies 1 month after SARS-CoV-2 mRNA vaccination. Systemic lupus erythematosus was the most common diagnosis. Rituximab and mycophenolate were the most commonly prescribed disease-modifying therapies. Although rituximab and methotrexate have been shown to reduce humoral response to both influenza and pneumococcal vaccines (4), impairment of vaccine response by other conventional disease-modifying antirheumatic drugs has not been shown. However, mycophenolate has recently been associated with a diminished humoral response to the first dose of SARS-CoV-2 mRNA vaccination in transplant recipients and patients with RMDs (1, 2).A unifying factor among patients in this case series was the use of either a B-lymphocyte–depleting agent or medication that affects lymphocytes. This supports the critical role of B-cell immunocompetence in generating appropriate response to vaccine antigen and contrasts with the robust anti-RBD responses seen in other patients with RMDs (2). Of note, participants reported rituximab infusion at a median of 14 weeks before the first vaccine dose. Rituximab has been associated with worse outcomes in patients with RMDs and SARS-CoV-2 infection (5), and thus it is of further concern that these patients may not derive protection from vaccination.Limitations of this study include its lack of external validity given homogeneity in age and sex of the case series as well as its nonrandomized design.Additional research is required to further characterize the humoral and cellular responses to SARS-CoV-2 vaccination in patients with RMDs. Optimization of vaccine response in patients receiving B-cell–modulating agents may require perivaccination adjustment in dosing and timing of these agents. Patients receiving these medications should be aware of the potential for suboptimal vaccine response and the need for ongoing vigilance in observing nonpharmacologic preventive measures.References1. Boyarsky BJ, Werbel WA, Avery RK, et al. Immunogenicity of a single dose of SARS-CoV-2 messenger RNA vaccine in solid organ transplant recipients. JAMA. 2021. [PMID: 33720292] doi:10.1001/jama.2021.4385 CrossrefGoogle Scholar2. Boyarsky BJ, Ruddy JA, Connolly CM, et al. Antibody response to a single dose of SARS-CoV-2 mRNA vaccine in patients with rheumatic and musculoskeletal diseases [Letter]. Ann Rheum Dis. 2021. [PMID: 33757968] doi:10.1136/annrheumdis-2021-220289 CrossrefGoogle Scholar3. Higgins V, Fabros A, Kulasingam V. Quantitative measurement of anti-SARS-CoV-2 antibodies: analytical and clinical evaluation. J Clin Microbiol. 2021;59. [PMID: 33483360] doi:10.1128/JCM.03149-20 CrossrefMedlineGoogle Scholar4. Bingham CO 3rd, Looney RJ, Deodhar A, et al. Immunization responses in rheumatoid arthritis patients treated with rituximab: results from a controlled clinical trial. Arthritis Rheum. 2010;62:64-74. [PMID: 20039397] doi:10.1002/art.25034 CrossrefMedlineGoogle Scholar5. Strangfeld A, Schäfer M, Gianfrancesco MA, et al; COVID-19 Global Rheumatology Alliance. Factors associated with COVID-19-related death in people with rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance physician-reported registry. Ann Rheum Dis. 2021. [PMID: 33504483] doi:10.1136/annrheumdis-2020-219498 CrossrefGoogle Scholar Comments 0 Comments Sign In to Submit A Comment Jeffrey Hsu, BS, Yuan-Ti Lee, MD, PhD, James Cheng-Chung Wei, MD, PhDChung Shan Medical University Hospital16 June 2021 Additional patient characteristics, controls, and assays to address SARS-CoV-2 vaccine immunogenicity concerns in rheumatic and musculoskeletal disease patients We commend Connolly and colleagues for reporting this case series regarding an issue of much-needed attention—rheumatic and musculoskeletal disease patients who cannot adequately generate antibodies against SARS-CoV-2, post-vaccination, amid antirheumatic agent treatments (1). However, we would like to highlight a few concerns in the study, apart from the reported limitations. For one, we believe it is necessary for the authors to report pertinent patient characteristics and comorbidities that could impact antibody production, such as hypertension or common kidney diseases (2). We also believe it is necessary for the case series to expand their study participant inclusion criteria to include patients with detectable anti-SARS-CoV-2 antibodies after treatment with antirheumatic agents. Two studies in Germany have shown that the majority of rheumatic disease patients can produce anti-SARS-CoV-2 antibodies post-SARS-CoV-2 mRNA vaccination even in the presence of immunosuppressive treatments (3, 4), albeit antibody production may be “delayed and reduced” (4). The limited number of patients reported to have impaired humoral responses post-vaccination were indeed treated with B-lymphocyte depleting agents—confirming the results from Connolly et al. Therefore, we find it even more prudent for Connolly and researchers to expand their patient inclusion criteria for the study; these additions will help increase the generalizability and impact of the study by providing some level of internal control for confounding variables, allowing for easier comparisons with published literature, and potentially addressing an important concern regarding the vaccine immunogenicity of B-lymphocyte-depleting agent-treated patients. Finally, while we recognize that the authors suggest the lack of a humoral response may be attributed to the use of B-lymphocyte-depleting agents, we believe it to be critical to include, especially for future cases, basic flow cytometry data for CD19+ or CD20+ B-lymphocytes at the time antibody detection assays were collected. We believe this data will help corroborate the presence of viable circulating B-lymphocytes and the efficacy of B-lymphocyte depleting-agents at the time of antibody detection. A recent study has demonstrated that SARS-CoV-2-vaccinated rheumatic disease patients with detectable circulating B-lymphocytes had the capacity to generate a slight humoral response, despite treatment with rituximab (5). This study further confirms the importance of validating the presence of circulating B-lymphocytes—if viable circulating B-lymphocytes were to be detected in any of the 20 study participants in the study, it could suggest an additional mechanism for the absent humoral response worth probing, such as a glucocorticoid-dependent mechanism. References: Connolly CM, Boyarsky BJ, Ruddy JA, Werbel WA, Christopher-Stine L, et al. Absence of Humoral Response After Two-Dose SARS-CoV-2 Messenger RNA Vaccination in Patients With Rheumatic and Musculoskeletal Diseases: A Case Series. Ann Intern Med. 2021. [Epub ahead of print] Kwetkat A, Heppner HJ. Comorbidities in the Elderly and Their Possible Influence on Vaccine Response. Interdiscip Top Gerontol Geriatr. 2020;43:73-85 Geisen UM, Berner DK, Tran F, Sümbül M, Vullriede L, et al. Immunogenicity and safety of anti-SARS-CoV-2 mRNA vaccines in patients with chronic inflammatory conditions and immunosuppressive therapy in a monocentric cohort. Ann Rheum Dis. 2021;24:annrheumdis-2021-220272. [Epub ahead of print] Simon D, Tascilar K, Fagni F, Krönke G, Kleyer A, et al. SARS-CoV-2 vaccination responses in untreated, conventionally treated and anticytokine-treated patients with immune-mediated inflammatory diseases. Ann Rheum Dis. 2021;6:annrheumdis-2021-220461. [Epub ahead of print] Bonelli MM, Mrak D, Perkmann T, Haslacher H, Aletaha D. SARS-CoV-2 vaccination in rituximab-treated patients: evidence for impaired humoral but inducible cellular immune response. Ann Rheum Dis. 2021;6:annrheumdis-2021-220408. [Epub ahead of print] Author, Article, and Disclosure InformationAuthors: Caoilfhionn M. Connolly, MD, MSc; Brian J. Boyarsky, MD, PhD; Jake A. Ruddy, BS; William A. Werbel, MD; Lisa Christopher-Stine, MD, MPH; Jacqueline M. Garonzik-Wang, MD, PhD; Dorry L. Segev, MD, PhD†; Julie J. Paik, MD, MHS†Affiliations: Johns Hopkins University School of Medicine, Baltimore, Maryland* Drs. Connolly and Boyarsky contributed equally to this work.† Drs. Segev and Paik are co–senior authors.Disclaimer: The analyses described here are the responsibility of the authors alone and do not necessarily reflect the views or policies of the U.S. Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government.Acknowledgment: The authors thank the following individuals for their assistance with this study: Allan B. Massie, PhD; Robin K. Avery, MD, PhD; Michael T. Ou, BS; and Jennifer D. Motter, MHS.Financial Support: By the Ben-Dov family and by grants F32DK124941 (Dr. Boyarsky) and K23DK115908 (Dr. Garonzik-Wang) from the National Institute of Diabetes and Digestive and Kidney Diseases, grant K24AI144954 (Dr. Segev) from the National Institute of Allergy and Infectious Diseases, and grant K23AR073927 (Dr. Paik) from the National Institute of Arthritis and Musculoskeletal and Skin Diseases.Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M21-1451.Corresponding Author: Dorry L. Segev, MD, PhD, Johns Hopkins University School of Medicine, 2000 East Monument Street, Baltimore, MD 21205; e-mail, dorry@jhmi.edu.This article was published at Annals.org on 25 May 2021. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byAssociations of HLA Polymorphisms with Anti-SARS-CoV-2 Spike and Neutralizing Antibody Titers in Japanese Rheumatoid Arthritis Patients Vaccinated with BNT162b2Equity Considerations in COVID‐19 Vaccination Studies of Individuals With Autoimmune Inflammatory Rheumatic DiseasesInter-individual variation in objective measure of reactogenicity following COVID-19 vaccination via smartwatches and fitness bandsLow Positivity Rate of Anti–SARS-CoV-2 IgG in Unvaccinated Patients With Rheumatic Diseases Treated With RituximabThe Third Dose Is the Charm: Effective Cellular and Humoral Immune Responses to Third COVID-19 Vaccine Doses in Immunosuppressed NonrespondersAn update on the considerations for patients with rheumatic disease being treated with rituximab during the COVID-19 pandemic and the potential drug treatment strategiesAdverse events and humoral response after two doses of severe acute respiratory coronavirus virus 2 (SARS-CoV-2) mRNA vaccine in the hospital personnel of a cardiopulmonary tertiary-care centerPharmacokinetics and Efficacy of Human Hyperimmune Intravenous Immunoglobulin Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Adult Syrian HamstersImmunogenicity, breakthrough infection, and underlying disease flare after SARS-CoV-2 vaccination among individuals with systemic autoimmune rheumatic diseasesHumoral and cellular responses to spike of δ SARS-CoV-2 variant in vaccinated patients with immune-mediated inflammatory diseasesAnti-SARS-CoV-2 Spike Antibody Titers and Neutralizing Antibodies in Vaccinated Rheumatoid Arthritis PatientsAbsent or suboptimal response to booster dose of COVID-19 vaccine in patients with autoimmune systemic diseasesFactors associated with poor antibody response to third-dose SARS-CoV-2 vaccination in patients with rheumatic and musculoskeletal diseasesRandomised trials of COVID-19 vaccines in Africa – charting the path forwardComparison of SARS-CoV-2 Antibody Response After 2-Dose mRNA-1273 vs BNT162b2 Vaccines in Incrementally Immunosuppressed PatientsB Cell Reconstitution Is Strongly Associated With COVID ‐19 Vaccine Responsiveness in Rheumatic Disease Patients Who Received Treatment With RituximabHumoral response following SARS-CoV-2 vaccination: not all immunosuppressants are created equalSARS-CoV-2 antibody testing for transplant recipients: A tool to personalize protection versus COVID-19Efficacy of inactivated vaccines in patients treated with immunosuppressive drug therapyAntibody durability 6 months after two doses of SARS-CoV-2 mRNA vaccines in patients with rheumatic and musculoskeletal diseaseCOVID-19 in people with rheumatic diseases: risks, outcomes, treatment considerationsCytokine autoantibodies in SARS-CoV-2 prepandemic and intrapandemic samples from an SLE cohortMandating COVID-19 vaccination prior to kidney transplantation in the United States: No solutions, only decisionsBooster-dose SARS-CoV-2 vaccination in patients with autoimmune disease: a case seriesTemporary hold of mycophenolate augments humoral response to SARS-CoV-2 vaccination in patients with rheumatic and musculoskeletal diseases: a case seriesHumoral and cellular immunogenicity to a second dose of COVID-19 vaccine BNT162b2 in people receiving methotrexate or targeted immunosuppression: a longitudinal cohort study5 reasons to encourage anti-SARS-CoV-2 vaccination in patients with rheumatic diseasesImpaired immunogenicity to COVID-19 vaccines in autoimmune systemic diseases. High prevalence of non-response in different patients’ subgroupsSARS-CoV-2 seroprevalence, seroconversion and neutralizing antibodies in a systemic lupus erythematosus cohort and comparison to controlsEffect of Immunosuppression on the Immunogenicity of mRNA Vaccines to SARS-CoV-2 A Prospective Cohort StudyParakkal Deepak, MBBS, MS, Wooseob Kim, PhD, Michael A. Paley, MD, PhD, Monica Yang, MD, Alexander B. Carvidi, BA, Emanuel G. Demissie, BS, Alia A. El-Qunni, BS, Alem Haile, BS, Katherine Huang, BA, Baylee Kinnett, BS, Mariel J. Liebeskind, BA, Zhuoming Liu, PhD, Lily E. McMorrow, BA, Diana Paez, BS, Niti Pawar, BA, Dana C. Perantie, MPH, Rebecca E. Schriefer, BA, Shannon E. Sides, BA, Mahima Thapa, BS, Maté Gergely, MD, Suha Abushamma, MD, Sewuese Akuse, MBBS, MPH, Michael Klebert, PhD, RN, ANP-BC, Lynne Mitchell, MA, MS, Darren Nix, Jonathan Graf, MD, Kimberly E. Taylor, PhD, MPH, Salim Chahin, MD, MSCE, Matthew A. Ciorba, MD, Patricia Katz, PhD, Mehrdad Matloubian, MD, PhD, Jane A. O’Halloran, MD, PhD, Rachel M. Presti, MD, PhD, Gregory F. Wu, MD, PhD, Sean P.J. Whelan, PhD, William J. Buchser, PhD, Lianne S. Gensler, MD, Mary C. Nakamura, MD, Ali H. Ellebedy, PhD, and Alfred H.J. Kim, MD, PhDImpact of rituximab on humoral response to COVID-19 booster vaccine and antibody kinetics in patients with anti–neutrophil cytoplasmic antibody vasculitisA Rapid and Simple Multiparameter Assay to Quantify Spike-Specific CD4 and CD8 T Cells after SARS-CoV-2 Vaccination: A Preliminary ReportIn Vivo Electroporation of Plasmid DNA: A Promising Strategy for Rapid, Inexpensive, and Flexible Delivery of Anti-Viral Monoclonal AntibodiesHigh antibody response to two-dose SARS-CoV-2 messenger RNA vaccination in patients with rheumatic and musculoskeletal diseasesCorrespondence on “SARS-CoV-2 vaccination in rituximab-treated patients: evidence for impaired humoral but inducible cellular immune response” by Bonelli et alPresence of specific T cell response after SARS-CoV-2 vaccination in rheumatoid arthritis patients receiving rituximab September 2021Volume 174, Issue 9 Page: 1332-1334 Keywords Case series COVID-19 Disclosure Disease modifying antirheumatic drugs Immunosuppressives Interquartile range Lupus erythematosus Messenger RNA Muscular dystrophies Vaccines ePublished: 25 May 2021 Issue Published: September 2021 Copyright & PermissionsCopyright © 2021 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...