This article provides a comprehensive review of the impact of B-cell-directed therapy on severe acute respiratory syndrome coronavirus 2 vaccine immunity, focusing on its implications in autoimmune inflammatory rheumatic diseases (AIIRD). Rituximab (RTX) is the primary B-cell-depleting drug that has been studied in AIIRD and is the focus of this review. We review the pivotal role of B cells in vaccine response and propose strategies to manage and predict vaccine responses in B-cell-depleted individuals. We highlight the need to strategize patients into distinct groups when predicting vaccine responses and developing guidelines to ensure optimal outcomes for RTX-treated patients.
Key points
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Treatment with rituximab (RTX) poses challenges for vaccine responses against severe acute respiratory syndrome coronavirus 2.
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It is optimal to vaccinate against coronavirus disease 2019 before initiation of RTX to ensure a robust antibody response.
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An interval of 9 months and above after the latest RTX treatment before administering a booster vaccine is associated with an increased antibody response.
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Stratifying patients into distinct groups (RTX-before, RTX-surround, and RTX-after) when predicting vaccine responses is helpful for providing optimal recommendations.
Introduction
Targeting CD20 has transformed the management of various B-cell-mediated autoimmune inflammatory rheumatic diseases (AIIRD). Despite its therapeutic benefits, concerns persist regarding its potential to compromise vaccine responses. This article provides a comprehensive review of the impact of rituximab (RTX) on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine immunity, elucidates the critical role of B cells in vaccine response, and proposes strategies to manage and predict vaccine responses in individuals undergoing B-cell depletion.
When the coronavirus disease 2019 (COVID-19) pandemic emerged, the rheumatology community had a less proactive approach to vaccination. Vaccination guidelines were available, and the European Alliance of Associations for Rheumatology (EULAR) had just published their updated guideline when the pandemic struck. These guidelines recommended administering influenza and pneumococcal vaccines before RTX treatment. In instances where B-cell depletion had commenced before vaccination, the EULAR recommended vaccination during a period termed “the following time window.” This window was defined as occurring at least 6 months post administration of RTX and at least 4 weeks preceding the subsequent course of therapy.
The pandemic served as an invaluable lesson, emphasizing the critical importance of timing vaccinations in relation to the initiation of B-cell-depleting treatment.
Rituximab, B cells, and CD20
B-cell depletion for AIIRD predominantly involves targeting the CD20-expressing B cells with monoclonal antibodies (mAb). B cells can be targeted by an increasing number and variety of CD20-depleting monoclonal antibodies, including murine (tositumomab and ibritumomab); chimeric (rituximab); humanized (ocrelizumab, obinutuzumab, veltuzumab), and human (ofatumumab) antibodies. While various antibodies against CD20 have been developed, RTX has been the most frequently used in rheumatology practice. Therefore, for the purpose of this article, RTX will be used.
CD20 is a cell surface antigen expressed on B cells, from the early pre-B-cell stage to the mature B-cell stage ( Fig. 1 ). CD20 levels are heterogeneously expressed both in the subpopulations of cells and also in individual patients. It is not known whether RTX binds more effectively to specific subtypes of CD20-expressing B cells, and there is variability in the degree of peripheral B-cell depletion. It is crucial to highlight that more advanced B cells, including plasma cells, are often spared from RTX treatment, preserving their function in antibody production (see Fig. 1 ).
From the previous investigations, we know that RTX does not deplete all B cells, which is one of the potential reasons that patients relapse. We also know that repopulation occurs around 8 months after treatment, varying significantly in individuals from 5 to 13 months ( Fig. 2 A ). Key factors found to delay B-cell repopulation include patient-specific attributes such as age (especially those over 60 years), impaired kidney function, and certain diseases like antineutrophil cytoplasmic antibody–associated vasculitis and solid organ transplants. Additionally, therapy-related factors such as coimmunosuppression with corticosteroids and azathioprine significantly slowed down B-cell recovery. These effects were dose-dependent, particularly with corticosteroids and AZA, extending the time needed for B cells to repopulate significantly.
Severe acute respiratory syndrome coronavirus 2 messenger ribonucleic acid vaccine response
The emergence of the COVID-19 pandemic underscored the urgent need for effective vaccination strategies to curb the spread of the virus and mitigate its impact on public health. As COVID-19 vaccines became available in early 2021, their effectiveness was unknown for patients with AIIRD as they were largely excluded from COVID-19 phase III vaccine trials. ,
In healthy individuals, messenger ribonucleic acid (mRNA) vaccines elicited a vigorous and enduring memory B cell (MBC) response, further enhanced after administering the second dose of the first vaccine series. , This augmentation closely paralleled the baseline quantity of preexisting SARS-CoV-2 MBCs, underscoring their crucial involvement in facilitating a prompt immune reaction upon subsequent encounters with SARS-CoV-2 antigens.
Initial reports including AIIRD patients emerged and provided encouraging data indicating comparable antibody generation and immunogenicity for the majority of AIIRD patients when compared to results from initial phase III trials However, certain treatments such as glucocorticoids, methotrexate, mycophenolate mofetil, abatacept, and, notably, RTX were associated with significantly diminished antibody responses. , , The effect of Janus Kinases inhibition remains unclear with diverging reports. , Sulfasalazine, leflunomide, belimumab, interleukin (IL)-17, IL-12/23, IL-6, and IL-1 inhibitors do not appear to have significant impacts on vaccine response.
Effect of rituximab on antibody response after primary vaccination in autoimmune inflammatory rheumatic diseases
There is strong evidence that RTX-induced B-cell depletion before primary COVID-19 vaccination leads to blunted antibody response in AIIRD patients. , , ,
The administration of RTX before vaccination has been associated with diminished immune responses to various vaccines, including those targeting influenza, pneumococcus, and hepatitis B.
Data on COVID-19 vaccination in AIIRD patients reported seroconversion (=detectable antibodies in the blood) in 24% to 65%, , , , , , , with the 2 largest populations reporting seroconversion in 39% (n = 201) and 43% (n = 110) of the RTX-treated AIIRD patients. Similarly, antibody levels were attenuated compared to both non-RTX-treated AIIRD patients and controls. Subject to different assays used, RTX treatment exposure was associated with antibody levels of 12% to 30% compared to non-RTX-treated AIIRD patients. , , Although a blunted antibody response was observed, the vaccines induced a sufficient cellular response. , Jyssum and colleagues reported CD4+ and CD8 + T-cell responses in 53% and 74% of patients, respectively, after 2 vaccine doses. Following a third dose, all patients assessed exhibited both CD4+ and CD8 + T-cell responses.
Typically, the proportion of patients achieving seroconversion increased to about 50% to 60% when booster vaccinations were administered. Our group examined the difference between a booster vaccination (1 dose) or a new primary vaccination course (2 doses with 3 weeks apart) in RTX-treated patients with no measurable antibodies after the primary vaccination. There was no significant effect on seroconversion as 32% to 38% of the patients seroconverted, but patients receiving 2 doses achieved significantly higher antibody titers. A Norwegian study also reported significantly increased antibody concentrations between the third and fourth booster vaccines.
Effect of Previous Rituximab Treatment on Clinical Outcome of Coronavirus Disease 2019
Early suspicions suggested that individuals treated with RTX might experience a more severe COVID-19 course due to a weakened adaptive immune response, which is crucial for combating viral infections. Studies showed that outcomes in COVID-19 patients previously treated with RTX vary, with many experiencing severe symptoms and complications, including increased rates for hospitalization, treatment in the intensive care unit, and mechanical ventilation. Additionally, the time between the last RTX infusion and the onset of COVID-19 symptoms was significantly shorter in patients who developed severe COVID-19 than in those with moderate or mild forms. The early studies before the Omicron variant emerged reported a markedly increased mortality ranging from 8% to 32%. , Later studies revealed a more favorable disease course for the Omicron variant in AIIRD patients. However, hospitalization rates remained consistently higher in those treated with RTX than in those on other or no immunosuppressants and healthy controls. , Furthermore, RTX treatment has been associated with repeat COVID-19 infection risk, but reassuringly, there were no deaths, and the hospitalization rate was low among those with repeat COVID-19 infection. The low incidence of deaths may also be attributed to the emergence of treatments during the pandemic, including antivirals, postexposure mAbs therapeutic mAbs, and preexposure mAbs.
Approaches to predict and enhance vaccine response
The negative impact of RTX on vaccines’ immunogenicity has been demonstrated for many vaccines before the arrival of COVID-19 vaccines. The ongoing discussion revolves around identifying factors correlating with protection post vaccination against SARS-CoV-2. There is a widespread consensus that neutralizing antibodies serve as a dependable indicator of immunity against virus variants. , However, the precise threshold for a protective SARS-CoV-2 IgG titer remains elusive.
Several factors, such as age, type of vaccine, current treatments, previous vaccines, timing of vaccines, and number of booster doses, may influence the likelihood of a favorable vaccine response in individuals receiving RTX ( Fig. 3 ). Thus, predicting vaccine response in RTX-treated individuals requires a multidimensional approach integrating clinical, immunologic, and molecular factors.
Of clinical factors influencing vaccine response in healthy individuals, we know that age, time since last vaccination, and the type of vaccination can negatively impact the serologic response to SARS-CoV-2. For example, older age is associated with immunosenescence, where the immune system’s ability to respond to vaccination weakens, leading to lower antibody production. Longer intervals since the last vaccine dose can result in waning immunity, reducing the overall antibody response. Additionally, mRNA vaccine platforms induce a more robust antibody production than viral vector vaccines. On the other hand, prior COVID-19 infection, which can result in hybrid immunity, and receiving a higher number of vaccine doses are associated with a stronger serologic response in AIIRD patients as these factors enhance the immune system’s memory and ability to mount a more effective response upon vaccination.
The impact of gender on vaccine response has been extensively investigated. Studies on hepatitis A and B, seasonal influenza, Haemophilus influenzae type A, yellow fever, and measles consistently show that women exhibit a greater serologic response. , Men generally demonstrate a higher antibody response to tetanus and diphtheria vaccines than women. , Regarding the COVID-19 vaccine, gender appears to have minimal impact on antibody levels.
Correlations between vaccine-induced symptoms and antibody levels have been reported in some studies; however, the results are conflicting. , , , Our research did not observe a correlation between reactogenicity and immunogenicity.
Evidence existed pre COVID-19 that withholding methotrexate treatment one or 2 weeks after administering seasonal influenza vaccines can significantly increase antibody levels post vaccination. Recently 2 randomized controlled trials have shown similar results in AIIRD patients, with increased antibody levels after primary vaccination with an inactivated CVOID-19 vaccine and after booster dose with an mRNA vaccine. Furthermore, a case series reported that withholding mycophenolate improved antibody response to primary COVID-19 vaccine. This is in line with the American College of Rheumatology recommendation (ACR) that conventional synthetic disease-modifying antirheumatic drugs such as methotrexate should be withheld “for 1 to 2 weeks (as disease activity allows) after each COVID-19 vaccine dose”. Although, as RTX was an exclusion criterion in both the trials, the effect size of methotrexate withholding is unknown when combined with RTX treatment. However, the decision to withhold methotrexate must be balanced against the risk of disease flare-ups as a higher incidence of mild disease flare-ups was reported in the group that paused methotrexate.
Our previous research revealed 2 pivotal factors strongly shaping the serologic response to COVID-19 vaccination in RTX-treated patients: the duration since their last RTX treatment and the presence of measurable B cells. ,
The kinetics of B-cell repopulation is highly variable. Although we noted that the presence of peripheral B cells correlated with a higher chance of serologic vaccine response in initial nonresponders treated with RTX, we also observed instances where patients lacking detectable B cells still achieved a serologic response. However, detectable levels of B cells signify immune system recovery, a process influenced by time, and are linked to an increased probability of mounting a serologic vaccine response. One study investigated the minimal B-cell count necessary for seroconversion to anti-S1 IgG in patients treated with RTX. It determined this count to be 10 B cells per microliter in peripheral circulation, which equates to 0.4% of the lymphocytes.
The timing of RTX treatment in relation to COVID-19 vaccination is essential. Optimal protection is given when patients are vaccinated before initiating RTX ( Fig. 4 , “RTX after”). When this is not possible, vaccination after the B-cell recovery phase may enhance responsiveness. The B-cell recovery refers to the process through which B cells gradually repopulate and restore their function after being depleted by RTX treatment. Expanding on our previous studies, we determined the ideal timing after initiating RTX treatment to attain a detectable serologic response to be slightly under 9 months post RTX, which has been corroborated in a dermatologic cohort of RTX-treated patients.
Related posts:
The Impact of Coronavirus Disease 2019 on Patients Living with Rheumatic Diseases
The Burden of Post-Acute Sequelae of Coronavirus Disease 2019 in Individuals with Rheumatic Diseases
Flares of Systemic Autoimmune Rheumatic Disease Following Coronavirus Disease 2019 Vaccination
Lessons on Telemedicine in Rheumatology
Review of Immunologic Manifestations of COVID-19 Infection and Vaccination
Coronavirus Disease-2019 in the Immunocompromised Host
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