Anti-SARS-CoV-2 mRNA vaccination among patients living with SLE in Sweden: coverage progression and clinical effectiveness.
Creators: name: Arkema, Elizabeth
name: Mageau, Arthur
Publisher: name: Open Science Framework
Year: 2023
Subjects: subject: Public Health
subject: Medicine and Health Sciences
subject: Clinical Epidemiology
subject: Rheumatology
subject: Medical Specialties
subject: Internal Medicine

description: Project title: Anti-SARS-CoV-2 mRNA vaccination among patients living with SLE in Sweden: coverage progression and clinical effectiveness. Protocol authors: Arthur Mageau &amp; Elizabeth V. Arkema Date: 2023-02-09 Updated: 2023-04-18 1. BACKGROUND Patients living with systematic lupus erythematosus (SLE) raise a particular concern in the COVID-19 pandemic in particular because of their immunosuppression and their comorbidities. A previous study showed that SLE was independently associated with a poor prognosis after a COVID-19 associated organ failure (1). Therefore, anti-SARS-CoV-2 vaccination was quickly recommended in the SLE population (2). Unfortunately, several immunological reports showed that the ability of SLE patients to produce a humoral response following vaccination was lower than the general population, even for patients without immunosuppressive treatments (3,4). However, the humoral response measured by the concentration of vaccine-induced anti-Spike (anti-S) antibodies, which has been the most studied, is only a surrogate marker of the vaccine effectiveness. Thus, some studies showed that immunocompromised patients could have a T-cell-driven vaccine response even without a humoral response (5). Unfortunately, real-world data assessing the effectiveness of the vaccination using clinical outcomes in this population are currently lacking. Furthermore, the impact of the different kind of immunosuppression has not been studied at a large scale and with long-term follow-up. A better understanding of the vaccination effectiveness and of the factors associated with a decreased effectiveness could help to improve the vaccination guidelines in this population. 2. RESEARCH QUESTIONS Our overall aim is to determine whether, to which extent and among which patients, anti-SARS-CoV2 mRNA vaccination clinical effectiveness is affected by SLE. Specifically, we aim to answer the following questions: 1- Was the progression of the vaccination coverage similar between SLE patients and general population ? 2- Do vaccinated SLE patients have an increased risk of hospitalization for COVID-19 compared to vaccinated people without SLE from the general population? 3- Among patients living with SLE, does the risk of COVID-19 hospitalization vary by immunosuppressive treatment? 1. METHODS Study design Matched cohort study. Study population We will define two study populations: one for the description of the vaccination coverage (aim 1) and one for the assessment of vaccine effectiveness (aims 2 &amp; 3). Study populations will be comprised of exposed and unexposed individuals, defined below, using information from the nationwide Swedish registers. These registers can be linked using the personal identification number to identify exposure, outcome and other variables. The population will be restricted to individuals ≥ 18 y.o living in Sweden at the start of the vaccination campaign (January 1st 2021). Study population 1: Description of the vaccination coverage progression (aim 1) Exposed individuals: - The exposure is SLE, defined as having two ICD M32 codes (excluding M32.0, drug-induced lupus) with at least 1 specialist visit before January 2021 (also ≥ 18 y.o, living in Sweden as of Jan 2021). Our objective is to include the whole SLE population for this descriptive part. Non-exposed individuals: Ten population controls selected at random from the Total Population Register (TPR) were matched to each unique individual with SLE on year of birth, sex, county of residence and living in Sweden at the time the matched case was first identified with SLE (index date). We will include all the matched controls ≥ 18 y.o living in Sweden at the start of the vaccination campaign (January 1st 2021). Study population 2: Vaccine effectiveness assessment (aims 2 &amp; 3) We will aim to include COVID-19 naïve individuals with and without SLE vaccinated by mRNA vaccines in order to have the most homogeneous exposed group. Exposed individuals: The exposure is prevalent SLE, defined as having two ICD M32 codes (excluding M32.0, drug-induced lupus) with at least 1 specialist visit before January 2021. - Still alive and still living in Sweden at the time of their 2nd vaccine dose - Age ≥ 18 y.o at the time of their 2nd vaccine dose - Who received two-doses of anti-SARS-CoV2 mRNA vaccines in 2021. - Without any COVID-19 diagnosis code in the national patient register before the 2nd vaccine dose. - With more than 10 days and less than 90 days between the two injections. This delay will be defined as an inclusion criterion in order to avoid selecting people with very unusual vaccination scheme that might reflect pre-exposure to SARS-CoV-2 or errors in the register. Non-exposed individuals: Ten population controls selected at random from the Total Population Register (TPR) were matched to each unique individual with SLE on year of birth, sex, county of residence and living in Sweden at the time the matched case was first identified with SLE (index date). Among these controls we will include individuals: - Who received two-doses of anti-SARS-CoV2 mRNA vaccines in 2021 - Still alive and still living in Sweden at the time of their 2nd vaccine dose - Age ≥ 18 y.o at the time of their 2nd vaccine dose - Without any COVID-19 diagnosis code before the 2nd vaccine dose - With more than 10 days and less than 90 days between the two injections Among these patients we will define subpopulations according to the disease-modifying treatments that they received and according to their comorbidities. We will define the use of an oral treatment if a patient had two dispensations of the same drug during the year before inclusion (i.e. January 1st 2021 for vaccination coverage description and date of first dose for vaccine effectiveness assessment). For treatment given by infusion (belimumab, rituximab and cyclophosphamide) we will define the use if a patient had one infusion during the last 6 months before inclusion. .Comorbidities (history of end-stage renal disease, renal transplantation, chronic kidney disease, obesity, diabetes, hypertension…) will be defined using ICD codes, procedures codes and treatments as proxy. Outcomes Aim 1 : The main outcome for aim 1 will be first vaccine injection. The objective is to present an overview of the progression of the vaccination coverage in SLE patients living in Sweden. The progression of the vaccination coverage in the matched general population will be also presented, as a reference. Aim 2 &amp; 3: The main outcome will be a first hospitalization with COVID-19 (defined as ICD-10 codes U07.1 or U07.2) as main diagnosis for the hospitalization. Deaths related to COVID-19 (with U07.1 or U07.2 codes reported as primary or underlying cause of death in the death-register) will be a secondary outcome. In sensitivity analyses, we will change the definition of the primary outcome to include only hospitalization with U07.1 (virus identified) ICD-10 code, with COVID-19 related ICD-10 codes such as dyspnea or sepsis or with ICU admission. Other variables - Age (TPR) - Sex (TPR) - Country of birth (TPR) - Education level (TPR) - Region of living (TPR) - Number of children (TPR) - Civil status (TPR) - Treatment (PDR+NPR). We will define the use of a treatment if a patient had two dispensations of the same drug during the year before inclusion (i.e. January 1st 2021 for vaccination campaign description and date of first dose for vaccine effectiveness assessment). o Immunosuppressants: we will consider the use of mycophenolic acid (ATC code L04AA06), methotrexate (L04AX03), oral corticosteroids (H02AB07), and azathioprine (L04AX01) in the PDR. o Hydroxychloroquine (ATC code P01BA02) in the PDR o For biologics (rituximab [L01FA01], belimumab [L04AA26]) and cyclophosphamide [L01AA01] we will define the use if a patient had one infusion during the last 6 months before inclusion. - Comorbidities (NPR + PDR) will be defined as any history of these and without any time window. o High blood pressure (ICD-code I10) o Chronic kidney disease (ICD-codes N183,N184,N185) o Obesity (ICD code E66) o Diabetes (ICD codes E10,E11,E12,E13,E14,O24 and/or use of antidiabetic drugs (ATC codes beginning with A10). - Time since first SLE diagnosis (NPR) Follow-up For the description of the vaccination coverage, the follow-up period will be the year 2021 (January 1st -December 31st). For vaccine effectiveness assessment, start of follow-up will be defined as the date of the second dose of the anti-SARS-CoV-2 mRNA vaccine. End of follow-up will be the date of the first in-hospital admission for COVID-19, death, emigration, 3rd vaccine dose or 12 months-post time 0, whichever comes first. We will censor individuals at 3rd vaccine dose because our main interest is the clinical effectiveness of the first two doses and because the time between the 2nd and the 3rd dose may vary a lot between patients. We will define a global censoring 12 months after second dose if none of the listed events occurred because we consider that the effect of the vaccine is not supposed to last longer than 12 months (the strains changed, the vaccine was less effective against Omicron, and the immune response would be greatly diminished, if not gone). Statistical Analysis Aim1: To describe the vaccination campaign course, we will calculate and plot a cumulative incidence function using first vaccine injection as outcome of interest and death or emigration as competing events. We will describe the characteristics of the SLE population remaining unvaccinated in September 2021 with simple descriptive statistics and compare them to those SLE patients who get vaccinated. Aim 2: Vaccine effectiveness will be studied with a time-to-event analysis using a marginal Cox proportional hazard model that considers the matching between exposed and non-exposed patients. We will use inverse probability censoring weighted (IPCW) to take the censoring mechanism into account. We will also calculate unadjusted and adjusted incidence rates. The model will be adjusted for age, sex, health administrative region and household composition. Household composition will be defined using a three-level variable : ‘"Living alone" / “"Living with partner, without child"/ "Living with child(ren), with or without partner". This will be derived from civil status and child aged younger than 18. The main result will be the HR associated with SLE diagnosis compared to non-SLE comparators and 95% confidence intervals. Aim 3: We will divide the whole study population in three groups : 1-general population (excluding individuals under immunosuppressive drug), 2-SLE patients without immunosuppressive drug and 3-SLE patients under immunosuppressive treatment. Hydroxychloroquine will not be considered as an immunosuppressive drug. We will plot the survival without COVID-19-related hospitalization in these three groups using Kaplan-Meier method. Then, we will run one/several standard Cox regression model(s) to calculate the hazard ratio associated to SLE with or without immunosuppressive treatment, using general population as reference. We will use main comorbidities and variables listed in aim 2 as covariates. Finally, we will describe more precisely which immunosuppressive drugs are used by patients that experienced the main outcome. Because we will probably have very low numbers of patients in each category, we will not perform any statistical test here. PRELIMINARY RESULTS We have observed that, according to our inclusion criteria, 7 429 SLE patients and 64 568 matched controls were ≥ 18 y.o and living in Sweden at January 1st 2021. Below is plotted the cumulative incidence function of their time to first vaccine dose : 2. ETHICAL APPROVAL Ethics Review Board DNR 2021-01148 3. LIMITATIONS/CHALLENGES/QUESTIONS The COVID ICD-10 codes might not always be accurate. Some patients may have a previous COVID-19 infection without any indication of it in the Patient Register because we do not have testing data nor primary care data. We are capturing ICD codes for COVID-19 from hospital care, which misses less severe infection. It is a strength to examine the more severe outcome, which the vaccine was developed to address. We assumed that the only reason that drove the decision to admit was the immediate severity of the patient, but patients with SLE might be more likely to be hospitalized with COVID-19 than people without SLE (differential misclassification of the outcome). The collection of the immunosuppressive treatment might not reflect the state of immunosuppression at time of vaccination and during the follow-up. We could lack power. Some comorbidities like obesity and diabetes could be badly reported in the register. We have no access to the type different strains of SARS-CoV-2 involved in the COVID-19 episode. 4. TIME PLAN February -March-April 2023: run the analyses April – May 2023: write the manuscript, receive co-author feedback, present results at KEP, submit an abstract to ACR (due June) June 2023: Submission of the manuscript 5. FUNDING AM is funded by a PhD fellowship of the Fondation pour la Recherche Médicale. 6. REFERENCES 1. Mageau A, Papo T, Ruckly S, Strukov A, van Gysel D, Sacre K, et al. Survival after COVID-19-associated organ failure among inpatients with systemic lupus erythematosus in France: a nationwide study. Ann Rheum Dis. avr 2022;81(4):569‑74. 2. Landewé RBM, Kroon FPB, Alunno A, Najm A, Bijlsma JW, Burmester GRR, et al. EULAR recommendations for the management and vaccination of people with rheumatic and musculoskeletal diseases in the context of SARS-CoV-2: the November 2021 update. Ann Rheum Dis. 1 déc 2022;81(12):1628‑39. 3. Mageau A, Ferré VM, Goulenok T, Charpentier C, Delory N, Francois C, et al. Severely impaired humoral response against SARS-CoV-2 variants of concern following two doses of BNT162b2 vaccine in patients with systemic lupus erythematosus (SLE). Ann Rheum Dis. 8 avr 2022;annrheumdis-2022-222498. 4. Moyon Q, Sterlin D, Miyara M, Anna F, Mathian A, Lhote R, et al. BNT162b2 vaccine-induced humoral and cellular responses against SARS-CoV-2 variants in systemic lupus erythematosus. Ann Rheum Dis. 4 oct 2021;annrheumdis-2021-221097. 5. Bitoun S, Henry J, Desjardins D, Vauloup-Fellous C, Dib N, Belkhir R, et al. Rituximab Impairs B Cell Response But Not T Cell Response to COVID-19 Vaccine in Autoimmune Diseases. Arthritis Rheumatol [Internet]. [cité 1 avr 2022];n/a(n/a). Disponible sur: http://onlinelibrary.wiley.com/doi/abs/10.1002/art.42058