Dear editor,
Vaccination against SARS-CoV-2 is effective against severe forms of COVID-19, but there remain concerns about a reduced vaccine response in patients treated by immunosuppressive therapies [1], [2], [3]. We analysed the impact of bDMARDs on the humoral anti-SARS-CoV-2 vaccine response, after a vaccine regimen of 2 or 3 doses of vaccine, of patients followed in day hospitals, treated with an intravenous bDMARD between September 2019 and August 2021. The study was approved by the ethic review board of Strasbourg medical faculty (#CE-2021-103). Serological assessment was performed using various commercially available assays dosing IgG (or total) anti-Spike antibodies, all FDA approved [4]. Patients were considered non-responders if the antibody level detected was inferior to the threshold of positivity of the kit used.
205 patients were included. Characteristics and comparisons of responders and non-responders are summarized in Table 1 .When considering both patients after a vaccination schema of 2 doses, or 1 dose in case of prior COVID-19, and those with 1 booster dose, 34 patients (16.6%) were non-responders (2 [5.9%] treated by IFX, none treated by TCZ, 9 [26.5%] treated by ABA and 23 [67.7%] treated by RTX). In multivariate analysis, the only characteristics that significantly and independently differed between responders and non-responders were last bDMARD and corticosteroid therapy at the time of 1st vaccination. In RTX-treated patients, the delay from last infusion to 1st vaccine dose was significantly shorter in non-responders (median 4.3 IQR [2.9-6.1] months in non-responders versus 8.4 IQR [5.7–14.5] in responders, P = 0.0007). Median survival, i.e. achieving a vaccine response in 50% of rituximab-treated subjects, was achieved after 277 days in patients vaccinated with 2 or 3 doses and 287 days with 2 doses (Fig. 1 ). There was no significant difference in the number of prior cycles of rituximab prior to vaccination among responders or non-responders. In ABA-treated patients, the delay from last infusion to 1st vaccine dose was not different between non-responders and responders.
Table 1.
Patients’ characteristics and comparisons between responders and non-responders.
| All patients (n = 205) | Responders (n = 171) | Non responders (n = 34) | P-value (univariate comparisons between responders and non-responders) | Multivariate P-value (comparisons between responders and non-responders) | |
|---|---|---|---|---|---|
| Age (median [IQR]), in years | 64 [56–71] | 64 [54–70] | 69 [57–75.5] | 0.07 | 0.40 |
| Female sex, n (%) | 148 (72.2) | 125 [73.1) | 23 (67.7) | 0.53 | |
| Inflammatory arthritides, n (%) | 0.16bb | 0.24 | |||
| Rheumatoid Arthritis | 156 (78.0) | 128 (74.9) | 28 (82.4) | 0.51 | |
| Spondyloarthritis | 33 (16.1) | 31 (18.1) | 2 (5.9) | 0.12 | |
| Othersaa | 16 (7.8) | 12 (5.9) | 4 (1.9) | 0.31 | |
| Last bDMARDs at time of vaccination, n (%) |
|
0.0004 | 0.00024 | ||
| Infliximab | 53 (25.9) | 51 (29.8) | 2 (5.9) | ABA/RTX versus IFX/TCZ<0.0001 | |
| Tocilizumab | 25 (12.2) | 25 (14.6) | 0 | ABA/RTX versus IFX/TCZ<0.0001 | |
| Abatacept | 36 (17.6) | 27 (15.8) | 9 (26.5) | ABA/RTX versus IFX/TCZ<0.0001 | |
| Rituximab | 91 (44.4) | 68 (39.8) | 23 (67.7) | ABA/RTX versus IFX/TCZ<0.0001 | |
| Associated treatments ongoing at time of vaccination | |||||
| CsDMARDs, n (%) | 126 (61.5) | 107 (62.6) | 19(55.9) | 0.56 | |
| Methotrexate | 91 (44.4) | 78 (45.6) | 13 (38.2) | 0.46 | |
| Median dose in users (mg/week) [IQR] | 15 [10-17.5] | 13.8 [10-15.6] | 15 [13.8-20] | 0.07 | |
| Otherscc | 31 (15.1) | 24 (14.0) | 7 (20.6) | 0.31 | |
| Immunosppressants, n (%) | |||||
| Aziathioprine | 2 (1.0) | 1 (0.6) | 1 (2.9) | 0.30 | |
| Corticosteroids, n (%) | 25 (12.2) | 19 (11.1) | 6 (17.6) | 0.29 | |
| Median dose (mg/day) [IQR] | 0 [0–0] | 0 [0–0] | 0 [0–2] | 0.035 | 0.016 |
| Median dose in users (mg/day) [IQR] | 5 [4.25–10] | 5 [4–10] | 10 [5–16] | 0.07 | |
| Previous COVID-19 infection, n (%) | 23 (11.2) | 21 (12.3) | 2 (5.9) | 0.38 | |
| Type of vaccine, n (%) | 0.62 | ||||
| Pfizer | 169 (82.4) | 142 (83.0) | 27 (79.4) | 0.62 | |
| Moderna | 14 (68.3) | 11 (6.4) | 3 (8.8) | 0.71 | |
| Astra-Zeneca | 17 (8.3) | 15 (8.8) | 2 (5.9) | 0.74 | |
| Janssen | 5 (2.4) | 3 (1.8) | 2 (5.9) | 0.19 | |
| mRNA vaccine | 183 (89.3) | 153 (89.5) | 30 (88.2) | 0.77 | |
| Viral vector vaccine | 21 (10.2) | 17 (1.0) | 4 (11.8) | 0.76 | |
| Mixed mRNA and viral vector vaccines | 1 (0.5) | 1 (0.6) | 0 | 1.00 | |
| Vaccination scheme, n (%) | |||||
| Complete | 167 (81.5) | 141 (82.5) | 28 (16.8) | 0.47 | |
| Complete + 1 booster dose | 56 (27.3) | 43 (25.1) | 13 (38.2) | 0.14 | |
| Interval between last vaccine shot and serology (median week [IQR]) | 7.4 [4.4–11.3] | 7.4 [4.4–11.6] | 7.5 [4.6–10.9] | 0.90 |
IQR: interquartile range; DMARD: disease modifying anti-rheumatic drug; bDMARD: biological DMARD; cs DMARD: conventional synthetic DMARD.
Non RA–non SPA were represented by connective tissue diseases (n = 5): 2 Sjögren's syndromes, 1 lupus, 1 systemic sclerosis and 1 Mixed connective tissue disease, myositis (n = 3), vasculitis (n = 2), juvenile idiopathic arthritis (n = 2) and other indications (n = 4): 1 sarcoidosis, 1 stiff-person syndrom, 1 Castelman disease and 1 chronic fatigue syndrome.
Comparisons of responders versus responders according to inflammatory arthritides (Rheumatoid arthritis, spondyloarthritis or other).
Other csDMARDS were represented by leflunomide (n = 21), hydroxychloroquine (n = 8) and sulfasalazine (n = 2).
Fig. 1.
Cumulative seropositive rate according to the interval (days) between the last course of rituximab administration and vaccination. A in case of 2 or 3 doses of vaccine; B in case of 2 doses of vaccine.
Limitations of the present study include the heterogenity of diseases, concomitant treatments and vaccine regimens and the absence of information on disease activity.
Our results illustrate the weaker anti-SARS-CoV-2 vaccine response in patient treated with B or T- cell targeting treatments than in those treated with anti-cytokine biologicals (IFX and TCZ). The present study confirms that the time interval between the prevaccination administration of rituximab and vaccination has a significant impact on the vaccine's immunogenicity [5], [6], [7] but 4 months appear to be often insufficient. Indeed, 9 months between last rituximab infusion were necessary to obtain a serological response in only half of the patients.
The role of ABA in the reduced SARS-CoV-2 vaccine response, has not been studied extensively, as that of rituximab [1], [2], [8], [9], despite a reduced vaccine response to other vaccines [10], in agreement with the inhibitory effect of abatacept on T-cell costimulation. In the present study, median delay between last ABA infusion and the first dose of vaccine was longer than recommended (4 weeks) and no difference was shown according to the delay between last infusion and first dose of vaccine.
In conclusion, B- and T-cell targeted therapies were associated with nearly all vaccine non-responses in the present study.
Funding
No acknowledgement and no funding sources.
Disclosure of interest
The authors declare that they have no competing interest.
References
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