Optimal time for COVID-19 vaccination in rituximab-treated dermatologic patients

Abstract

BackgroundBy depleting circulating B lymphocytes, rituximab time-dependently suppresses coronavirus disease 2019 (COVID-19) vaccines’ humoral immunogenicity for a prolonged period. The optimal time to vaccinate rituximab-exposed immune-mediated dermatologic disease (IMDD) patients is currently unclear.ObjectiveTo estimate the vaccination timeframe that equalized the occurrence of humoral immunogenicity outcomes between rituximab-exposed and rituximab-naïve IMDD patients.MethodsThis retrospective cohort study recruited rituximab-exposed and age-matched rituximab-naïve subjects tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific immunity post-vaccination. Baseline clinical and immunological data (i.e., immunoglobulin levels, lymphocyte immunophenotyping) and SARS-CoV-2-specific immunity levels were extracted. The outcomes compared were the percentages of subjects who produced neutralizing antibodies (seroconversion rates, SR) and SARS-CoV-2-specific IgG levels among seroconverters. The outcomes were first analyzed using multiple regressions adjusted for the effects of corticosteroid use, steroid-spearing agents, and pre-vaccination immunological status (i.e., IgM levels, the percentages of the total, naïve, and memory B lymphocytes) to identify rituximab-related immunogenicity outcomes. The rituximab-related outcome differences with a 95% confidence interval (CI) between groups were calculated, starting by including every subject and then narrowing down to those with longer rituximab-to-vaccination intervals (≥3, ≥6, ≥9, ≥12 months). The desirable cut-off performances were <25% outcome inferiority observed among rituximab-exposed subgroups compared to rituximab-naïve subjects, and the positive likelihood ratio (LR+) for the corresponding outcomes ≥2.FindingsForty-five rituximab-exposed and 90 rituximab-naive subjects were included. The regression analysis demonstrated a negative association between rituximab exposure status and SR but not with SARS-CoV-2-specific IgG levels. Nine-month rituximab-to-vaccination cut-off fulfilled our prespecified diagnostic performance (SR difference between rituximab-exposed and rituximab-naïve group [95%CI]: -2.6 [-23.3, 18.1], LR+: 2.6) and coincided with the repopulation of naïve B lymphocytes in these patients.ConclusionsNine months of rituximab-to-vaccination interval maximize the immunological benefits of COVID-19 vaccines while avoiding unnecessary delay in vaccination and rituximab treatment for IMDD patients.

COVID-19 Vaccination and Immunosuppressive Therapy in Immune-Mediated Inflammatory Diseases

“…In this context, the data on the cellular response to the COVID-19 vaccine in patients with IMIDs treated with rituximab are especially relevant, given the foreseeable negative effect on the humoral response due to its mechanism of action. As expected, a negative association between seroconversion rates to the COVID-19 vaccine and rituximab has been confirmed, identifying the interval between the last RTX infusion and the first vaccination, the number of peripheral B-cells and the immunoglobulin quantity among the related factors [50,51], while the cellular response seems to be preserved [52]. Intervals of 6 to 9 months between the last rituximab administration and COVID-19 vaccination appear to improve the humoral response, although pharmacokinetic studies suggest that the presence of B cells and/or rituximab in the blood predict seroconversion better than time since last infusion [50,51,53].…”

“…As expected, a negative association between seroconversion rates to the COVID-19 vaccine and rituximab has been confirmed, identifying the interval between the last RTX infusion and the first vaccination, the number of peripheral B-cells and the immunoglobulin quantity among the related factors [50,51], while the cellular response seems to be preserved [52]. Intervals of 6 to 9 months between the last rituximab administration and COVID-19 vaccination appear to improve the humoral response, although pharmacokinetic studies suggest that the presence of B cells and/or rituximab in the blood predict seroconversion better than time since last infusion [50,51,53]. The evidence points to the special need to individualize the COVID-19 vaccination strategy in patients with IMIDs being treated with rituximab, although it does not seem advisable to delay primary immunization in cases in which it is not advisable to delay treatment due to the activity of the disease [54].…”

Immunogenicity, Effectiveness, and Safety of COVID-19 Vaccines among Patients with Immune-Mediated Dermatological Diseases: A Systematic Review and Meta-analysis

“…An effective strategy for COVID-19 vaccination in immunosuppressed IMDD individuals involves establishing an appropriate interval between immunosuppressant administration and vaccination ( 51 ). Additional doses, including both primary and booster doses of COVID-19 vaccines, are also crucial, as they have the potential to enhance SARS-CoV-2-specific immunity and delay breakthrough COVID-19 infections, respectively ( 52 ).…”

Impact of Immunomodulatory Therapy on COVID-19 Vaccine Response in Patients with Autoimmune Inflammatory Rheumatic Diseases

“…The ACR currently recommends completing the vaccination series approximately 4 weeks prior to the next rituximab dose based on the data on influenza vaccination responses after rituximab [ 27 ]. Additionally, a retrospective cohort study comparing rituximab-exposed and rituximab-naïve patients with immune-mediated dermatologic disease suggested that a nine-month interval between rituximab administration and vaccination optimises immunogenicity while avoiding unnecessary delay in treatment [ 48 ].…”