Tolerance of COVID-19 vaccination in patients with systemic lupus erythematosus: the international VACOLUP study.

131 vaccine candidates have been evaluated for SARS-CoV-2 in more than 380 trials, eventually leading to 20 vaccine approvals and more than 1·8 billion people vaccinated worldwide as of July 1, 2021. There is a paucity of data regarding the safety of COVID-19 vaccines in patients with rheumatic and musculoskeletal diseases such as systemic lupus erythematosus (SLE), because patients with SLE have largely been excluded from vaccine trials.3, 4, 5 Furthermore, the use of mRNA vaccines has raised substantial concerns about the tolerance of these new vaccine technologies in patients with SLE, as toll-like receptor stimulation by nucleic acids might increase the risk of flare. These uncertainties have been shown to be major determinants of reduced vaccination willingness in patients with rheumatic and musculoskeletal diseases. Therefore, the primary objective of the international vaccination against COVID in systemic lupus (VACOLUP) study was to assess the tolerance of COVID-19 vaccines in patients with SLE, including the risk of incident flare, from the patients' perspective.

VACOLUP was a cross-sectional study based on a 43-question web-based survey, which took place between March 22, 2021, and May 17, 2021. The study was approved by the ethics review board of Strasbourg medical faculty (#CE-2020-29) and respondents gave their written informed consent to participate in this research via a dedicated question at the beginning of the online questionnaire. The study targeted patients with a self-reported medically confirmed diagnosis of SLE. The primary outcome was the occurrence of side-effects, including flare. The VACOLUP questionnaire and detailed methods are shown in the appendix (pp 1–2, 7–17).

The study included 696 participants (669 [96%] women and 27 [4%] men) from 30 countries, with a median age of 42 years (IQR 34–51). Detailed patient characteristics are shown in the appendix (p 5). The type of COVID-19 vaccine administered and the occurrence of side-effects after vaccination (as self-reported by patients) are summarised in the table . All patients received at least one dose of vaccine and 343 (49%) patients received a second dose (appendix p 3). The most common vaccines were Pfizer-BioNTech (399 [57%] participants), Sinovac (156 [22%] participants), AstraZeneca (73 [10%] participants), and Moderna (57 [8%] participants; table; appendix p 6).

Table

COVID-19 vaccination and consequences

		Patients (n=696)
Vaccination
	First dose	696 (100%)
	First and second dose	343 (49%)
Vaccine received
	Pfizer-BioNTech	399 (57%)
	Sinovac	156 (22%)
	AstraZeneca	73 (10%)
	Moderna	57 (8%)
	Other*	11 (2%)
Side-effects after first vaccine dose		316 (45%)
Timing of onset of side-effects after first dose, days		0 (0–1)
Side-effects after second vaccine dose		181/343 (53%)
Timing of onset of side-effects after second dose, days		0 (0–1)
Consultations or admissions to hospital for side-effects (first and second doses together)
	Medical consultation	81/1039 (8%)
	Emergency consultation	14/1039 (1%)
	Admission to hospital	5/1039 (<1%)
SLE flare after vaccination		21 (3%)
SLE flare manifestations
	Fever (temperature >38°C or 100·4°F)	10/21 (48%)
	Cutaneous (skin) flare (medically confirmed)	12/21 (57%)
	Musculoskeletal symptoms (joint, arthritis, arthralgia, or myalgia; medically confirmed)	19/21 (90%)
	Pleuritis or pleurisy (medically confirmed)	1/21 (5%)
	Pericarditis (medically confirmed)	1/21 (5%)
	Renal involvement (medically confirmed)	2/21 (10%)
	Neuro-psychiatric manifestations (medically confirmed)	0
	Cytopenia (anaemia, thrombocytopenia, or leukocytopenia; medically confirmed)	8/21 (38%)
	Low complement (medically confirmed)	5/21 (24%)
	Increase in anti-dsDNA antibody titre (medically confirmed)	7/21 (33%)
	Fatigue	18/21 (86%)
Consequences of SLE flare
	Change in SLE treatment	15/21 (71%)
	Medical consultation	21/21 (100%)
	Admission to hospital	4/21 (19%)
COVID-19 after vaccination		0

Data are n (%), median (IQR), or n/N (%).

Other vaccines were Cansino (one patient), Curevac (one patient), Janssen (five patients), Sinopharm (two patients), Sputnik V (one patient), and unknown (one patient). SLE=systemic lupus erythematosus.

Side-effects were reported by 316 (45%) patients after the first vaccine dose and by 181 (53%) of 343 patients after the second vaccine dose, with no difference according to gender (308 [46%] of 669 female participants vs eight [30%] of 27 male participants; p=0·11), age (median 41 years, IQR 34–50 in patients with side-effects vs 43, 35–52 in those without side-effects; p=0·079), or vaccine type (204 [45%] of 456 participants who received mRNA vaccines vs 111 [46%] of 239 participants who received vaccines with other modes of action; p=0·69; the participant with unknown vaccine type was excluded). Patients who received both vaccine doses and reported side-effects after the first dose were more likely to report side-effects after the second dose than those who did not (109 [81%] of 135 patients vs 72 [35%] of 205 participants; relative risk [RR] 2·30, 95% CI 1·88–2·82; p<0·0001). Occurrence of side-effects by country and vaccine type is shown in the appendix (p 6).

The type and intensity of side-effects reported by patients with SLE are shown in the appendix (p 4). The symptoms were of minor or moderate intensity (ie, without an effect on the ability to do daily tasks) in 2232 (83%) of 2683 cases.

21 (3%) of 696 patients reported a medically confirmed SLE flare (table), typically with predominant musculoskeletal symptoms (19 [90%] patients) and fatigue (18 [86%] patients), after a median of 3 days (IQR 0–29) after COVID-19 vaccination. These flares led to a change in SLE treatment in 15 (71%) of 21 cases and to admission to hospital in four (19%) cases. Having a flare during the past year before vaccination was associated with an increased risk of SLE flare after COVID-19 vaccination (RR 5·52, 95% CI 2·17–14·03; p<0·0001). We found no significant association between side-effects or occurrence of a SLE flare and SLE medications or previous SLE disease manifestations.

To our knowledge, the VACOLUP study is the first large-scale study of tolerance of COVID-19 vaccines in patients with SLE. An important finding of the study is that side-effects after COVID-19 vaccination in patients with SLE are common (around 50%) but do not impair daily functioning in most cases. We found no difference in the occurrence of side-effects after receipt of mRNA vaccines compared with vaccines with other modes of action, which is an important and reassuring finding. Finally, the number of medically confirmed flares reported after COVID-19 vaccination was low. The short median time between vaccination and flare onset suggests that it might be difficult to distinguish actual SLE flares from common and expected post-vaccine side-effects, and therefore the 3% figure could be an overestimation of the actual flare rate. Vaccination is recommended for patients with rheumatic and musculoskeletal diseases according to the American College of Rheumatology, irrespective of disease activity and severity, except for those with severe and life-threatening illness (eg, a patient receiving treatment in the intensive care unit for any condition). The main limitation of our study is the self-reported and subjective nature of the outcomes. We tried to mitigate this by asking patients to report only medically confirmed flares. Another limitation is the absence of a control group. However, Furer and colleagues reported that the prevalence of mild adverse events was similar in patients with autoimmune rheumatic and musculoskeletal disease and controls.

In conclusion, the VACOLUP study suggests that COVID-19 vaccination appears well tolerated in patients with SLE, with only a minimal risk of flare, if any, including after the mRNA vaccines. Willingness to get vaccinated against COVID-19 in patients with autoimmune diseases is limited by the fear of side-effects and the paucity of available data. Therefore, disseminating these reassuring data might prove crucial to increasing vaccine coverage in patients with SLE.

RF has received consultancy fees from Pfizer and Janssen (unrelated to the VACOLUP study). MP has received consultancy fees from GSK and Pfizer (unrelated to the VACOLUP study). MFU-G reports grants from Janssen and Pfizer, and support for attending meetings and/or travel from Pfizer and Abbvie (unrelated to the VACOLUP study). LA has received consultancy fees from Pfizer and AstraZeneca (unrelated to the VACOLUP study). All other authors declare no competing interests. RF and LA verified all the data in the study. We wish to acknowledge the crucial role of the following patient associations: LupusEurope (@LupusEurope), Agrupación Lupus Chile (@Lupus_Chile), Lupus UK, Lupus France, AFL+, and Gruppo LES Italiano, in the dissemination of the survey. RF, LK, MD, and LA conceived the study. RF and LA curated the data. All authors did the investigation. RF, LK, MD, and LA devised the methodology. RF and LA wrote the original draft of the manuscript. All authors reviewed and edited the manuscript.