key: cord-0778431-gn1lkctx
authors: van der Togt, Céleste J T; Ten Cate, David F; den Broeder, Nathan; Rahamat-Langendoen, Janette; van den Bemt, Bart J F; den Broeder, Alfons A
title: Humoral response to Coronavirus Disease-19 vaccines is dependent on dosage and timing of rituximab in patients with rheumatoid arthritis
date: 2022-04-04
journal: Rheumatology (Oxford)
DOI: 10.1093/rheumatology/keac206
sha: 3853e9a3e616b42920d6726e6880723b4c0406ab
doc_id: 778431
cord_uid: gn1lkctx

OBJECTIVES: Humoral response to vaccines in rheumatoid arthritis (RA) patients treated with rituximab (RTX) in standard dosages (≥1000mg) is decreased. Ultralow dosages (500 or 200 mg) may have better response. Also, timing after latest RTX infusion may be an important variable. We aimed to investigate the influence of RTX dosage and timing on response to COVID-19 vaccination in RA patients. METHODS: A single-centre observational study (n = 196) investigated the humoral response, measured by total Ig anti-COVID-19 assay (positive response ≥1.1), 2–6 weeks after complete COVID-19 vaccination. A multivariable logistic regression model was built to study the effect of RTX dosage and time between latest rituximab and vaccination on response, adjusting for age and methotrexate use. RESULTS: After two-dose vaccination, the response rate was significantly better for patients receiving 200 mg (n = 31, 45%) rituximab compared with 1000 mg (n = 98, 26%; OR 3.07, 95% CI 1.14–8.27,) and for each additional month between latest rituximab and vaccination (OR 1.67, 1.39–2.01). CONCLUSION: Both increased time between latest rituximab infusion and complete vaccination and 200 mg as latest dose were associated with a better response to COVID-19 vaccination and should be considered when trying to increase vaccine response after rituximab in RA patients. TRIAL REGISTRATION: Netherlands Trial Register, https://www.trialregister.nl/, NL9342

Since the beginning of 2020, SARS CoV-2 virus rapidly spread around the world, causing widespread coronavirus disease-19 (COVID-19) infections. Although the risk of severe SARS-CoV-2 is not increased for patients with rheumatoid arthritis (RA) in general, [1] RA patients treated with rituximab (RTX) do have an increased risk. [2] Treatment with rituximab also impairs humoral response to both COVID-19 [3] [4] [5] [6] and non-COVID-19 vaccines. [7] Thus, for optimal prevention of COVID-19 in this patient group, increasing vaccine response is of utmost importance. Two factors could conceptually influence vaccine response in patients treated with RTX: RTX dose and vaccination timing. The effect of RTX on severity of infection and vaccination response has been shown for standard doses only (1000-2000 mg per cycle). However, data from a randomised controlled study shows that ultra-low dose rituximab, 500 or 200 mg per cycle, has similar efficacy, and halves infection risk. [8] Therefore, it would be of interest to investigate humoral response to COVID-19 vaccines after these ultra-low doses. Recent studies on COVID-19 vaccination with small RTX populations suggest an association between longer time since latest RTX infusion at first vaccination and better humoral response. [3, 4, 9] Again, these studies only described patients receiving full dose RTX, indicating the importance of data on ultra-low dosed rituximab. The Dutch nationwide COVID-19 vaccination effort started in the spring of 2021. This provided us the opportunity to study the effects of RTX dose and relative timing of vaccination on humoral response to COVID-19 vaccination in our large cohort of RA patients using regular and ultra-low dose RTX.

All RA patients aged ≥16 years of the Sint Maartenskliniek (Nijmegen, the Netherlands) were invited to participate in the cohort, if 1) they received at least one dose of rituximab (200 mg, 500 mg, or 1000 mg) in the year prior to their first dose of COVID-19 vaccination and 2) COVID-19 vaccination was performed according to the registered dose and interval. The RTX dose was based on the treating physician's discretion. At the time of the study, the Dutch national vaccine programme included four vaccines against COVID-19, of which three two-dose regimens: BNT162b2 (Comirnaty; Pfizer-BioNtech), ChAdOx1 nCoV-19 (Vaxzevria; AstraZeneca) and CX-024414 (Spikevax; Moderna), and one single-dose: Ad.26.COV2.S (COVID-19 vaccine Janssen).

[10] If a COVID-19 infection had occurred in the six months prior to first vaccination, the Dutch government also approved one dose of a two-dose vaccine as fully vaccinated. [11] This study has been approved by the ethics committee (CMO Arnhem-Nijmegen, 2021-7406) and the competent authority (CCMO, NL76709.091.21). The study protocol was registered in the Netherlands Trial Register (NL9342) before start. All participants provided written informed consent.

Relevant demographics and RA disease characteristics were obtained at study inclusion (Supplementary Data S1, available at Rheumatology online). Also, we recorded relevant treatment characteristics including concomitant csDMARD use, prednisolone use, current b/tsDMARD, cumulative RTX dose, and dosage and date of the latest RTX administration. Details on a previous COVID-19 infection (including date of positive test) and COVID-19 vaccination (type and dates) were 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60 provided by the participant. For humoral response assessment, blood samples were drawn two to six weeks after the second COVID-19 vaccination. [3, 12] 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60 p=0.11). In the participants with a previous COVID-19 infection, response rate was 46% (7/15) for participants who received two-dose vaccination, and 40% for one-dose (2/5).

The multivariable model including time between latest rituximab infusion and first vaccination, age, concomitant csDMARD use, and prednisolone use confirmed the association between vaccination response and low dose RTX (200mg group vs 1000mg (OR 3.07 [95% CI 1.55 to 8.27, p=0.03]). The time between most recent infusion and first vaccination was positively associated with higher chance of vaccination response in the multivariable model (per month OR 1.67, 95% CI 1.39 to 2.01, p<0.0001, see Figure 1 ).

This study is the first to show that 200mg RTX in RA patients is associated with a significantly better humoral response to COVID-19 vaccines than higher dosages (500 mg and 1000 mg) of RTX. Also, timing the vaccination longer after the RTX infusion yields significantly better vaccination response, confirming data in the literature. [3, 4, 9] Although this study is the largest cohort investigating humoral response to COVID-19 vaccines in RA patients using (ultra-low dose) RTX, this study has some limitations. First, a relatively small number of patients received 200mg. Nonetheless, statistically significant factors were identified. Another limitation may be the lack of a comparison group of RA patients with other DMARDs. However, COVID-19 vaccination response in patients with other DMARDs and has been extensively investigated in other studies and the focus of the study was different RTX dosages, not co-DMARDs. [3, 5] Third, total IgG levels were not measured during this study and therefore the relationship between these levels and humoral response could not be investigated. Fourth, this study was only conducted in RA patients so cannot easily be extrapolated to other populations treated with rituximab. Last, because of study feasibility, only one surrogate vaccination response outcome was investigated, namely humoral response, and not T-cell response nor clinical vaccine efficacy. A clear cut off in amount of protective antibodies measured by commercial assays is yet unclear, however the assay used in this study has been clinically validated, [13, 15] . Besides, T-cell response is associated with humoral response. [9] Therefore, we think that the differences in vaccination response could indeed translate to differences in clinical vaccine efficacy.

Based on our findings, two recommendations can be formulated. First, COVID-19 vaccination should be timed as late as possible after the latest rituximab infusion, preferably more than one rituximab cycle (6 months). Second, RTX should be dosed as low as possible, preferably 200 mg. The safety and feasibility of this dosage is supported by high quality evidence. [8, 16] Some important questions remain, including the effects of a third booster vaccination in patients who did not show response to the first vaccination, and the optimal timing for RTX retreatment after the vaccination. Also, it would be important to see whether these differences between dose and timing on vaccination response can be extrapolated to COVID-19 infection risk and infection outcome. Last, it would be of interest to investigate how long vaccination response lasts.

In conclusion, COVID-19 vaccination response can be improved in RTX-treated RA patients by adjusting the dose and time between rituximab treatment and vaccination. 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58 59 60 13 (6) 0 (0) 4 (6) 9 (9) Prior documented COVID infection 20 (10) 2 (6) 8 (12) 10 (10) Either displayed as number (percentage), median (interquartile range) † or mean ± standard deviation ‡ . # Includes 1 patient treated with 2x 1000mg. 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60 

Risk and clinical outcomes of COVID-19 in patients with rheumatic diseases compared with the general population: a systematic review and meta-analysis

COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases treated with rituximab: a cohort study

Immunogenicity and safety of the BNT162b2 mRNA COVID-19 vaccine in adult patients with autoimmune inflammatory rheumatic diseases and in the general population: a multicentre study

but not other antirheumatic therapies, is associated with impaired serological response to SARS-CoV-2 vaccination in patients with rheumatic diseases

Antibody development after COVID-19 vaccination in patients with autoimmune diseases in the Netherlands: a substudy of data from two prospective cohort studies

Correspondence on "SARS-CoV-2 vaccination in rituximab-treated patients: evidence for impaired humoral but inducible cellular immune response

Effect of methotrexate, anti-tumor necrosis factor α, and rituximab on the immune response to influenza and pneumococcal vaccines in patients with rheumatoid arthritis: a systematic review and meta-analysis

Ultra-low doses of rituximab for continued treatment of rheumatoid arthritis (REDO study): a randomised controlled non-inferiority trial

Humoral and cellular responses to mRNA vaccines against SARS-CoV-2 in patients with a history of CD20 B-cell-depleting therapy (RituxiVac): an investigator-initiated, single-centre, open-label study

Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates

Comparison of eight commercial, high-throughput, automated or ELISA assays detecting SARS-CoV-2 IgG or total antibody

An evaluation of COVID-19 serological assays informs future diagnostics and exposure assessment

We thank Kasper Jolink and the staff of the rheumatology outpatient clinic of the Sint Maartenskliniek for performing additional blood sampling for this study, and Paul Daemen for performing the assays.