ABSTRACT
Background: Disease-specific studies have reported impaired humoral responses after SARS-CoV-2 vaccination in patients with immune-mediated inflammatory disorders (IMIDs) treated with specific immunosuppressants and immunomodulating agents. The objective of this study is to investigate the humoral immune response after SARS-CoV-2 vaccination in patients using immunosuppressive and immunomodulating mono- and combination therapies, focussing on frequently prescribed therapies for inflammatory neuromuscular diseases. Methods: National prospective observational cohort study in selected patients with prevalent IMIDs including neuromuscular disease, and immunosuppressive or immunomodulating monotherapy (n=1273), combination therapies (n=419), patients without immunosuppressants (n=473), and healthy controls (n=174). Anti-RBD IgG responses and neutralisation capacity were monitored following standard vaccination regimens and a three-vaccination regimen in subgroups. Hybrid immune responses, i.e. vaccination after previous SARS-CoV-2 infection, were studied as a proxy for recall responses. Findings: Sera from 1869 participants without and 470 participants with previous SARS-CoV-2 infection were analysed. We included 168 (7 2%) patients with inflammatory neuropathies and myopathies, and 127 (5 4%) patients with myasthenia gravis. Humoral responses did not differ between disorders. Anti-CD20 therapy and mycophenolate mofetil combined with corticosteroids were associated with lower relative risks (RR) for reaching seroconversion following standard vaccination (RR: 0 32 and 0 61 respectively). The monotherapies corticosteroids, purine antagonists, methotrexate, mycophenolate mofetil and IVIg were not associated with a lower RR for reaching seroconversion (RR: 0 97, 0 98, 1 01, 0 86, and 0 99, respectively). Similarly, corticosteroids combined with either methotrexate or purine antagonists was not associated with a lower RR for reaching seroconversion (RR 0 89). A third vaccination increased seroconversion for mycophenolate mofetil combination treatments but not for anti-CD20 therapies. Most immunosuppressant groups showed moderately reduced antibody titres after standard vaccination that, in subgroups, did not increase after a third vaccination, although seroconversion rates and neutralisation capacity were unaffected. In participants with previous SARS-CoV-2 infection, SARS-CoV-2 antibodies were boosted after vaccination, regardless of immunosuppressive treatment. Interpretation: Humoral responses following vaccination are impaired by specific immunosuppressants, most relevant for neuromuscular diseases being anti-CD20 and mycophenolate mofetil combination treatments. After standard vaccination regimens most immunosuppressants show equal seroconversion to controls although antibody titres may be moderately reduced. As neutralisation capacity and recall responses are also preserved in these patients, this is not likely to translate in loss of (short term) protection. Alternatively, in immunosuppressants showing poor humoral responses after standard vaccination regimens such as, a third vaccination resulted in additional seroconversion in mycophenolate mofetil combination treatments whereas the effect for anti-CD20 therapy was limited.
ABSTRACT
Background: Concerns have been raised regarding risks of COVID-19 breakthrough infections in vaccinated patients with immune-mediated infammatory diseases (IMIDs) treated with immunosuppressants, but data on COVID-19 breakthrough infections in these patients are still scarce. Objectives: The primary objective was to compare the incidence and severity of COVID-19 breakthrough infections with the SARS-CoV-2 delta variant between fully vaccinated IMID patients with immunosuppressants, and controls (IMID patients without immunosuppressants and healthy controls). The secondary objective was to explore determinants of breakthrough infections. Methods: In this study we pooled data collected from two large ongoing prospective multi-center cohort studies (Target to-B! [T2B!] study and ARC study). Clinical data were collected between February and December 2021, using digital questionnaires, standardized electronic case record forms and medical files. Post-vaccination serum samples were analyzed for anti-RBD antibodies (T2B! study only) and anti-nucleocapsid antibodies to identify asymptomatic breakthrough infections (ARC study only). Logistic regression analyses were used to assess associations with the incidence of breakthrough infections. Multivariable models were adjusted for age, sex, cardiovascular disease, chronic pulmonary disease, obesity and vaccine type. Results: We included 3207 IMID patients with immunosuppressants and 1810 controls (985 IMID patients without immunosuppressants and 825 healthy controls). The incidence of COVID-19 breakthrough infections was comparable between patients with immunosuppressants (5%) and controls (5%). The absence of SARS-CoV-2 IgG antibodies after COVID-19 vaccination was independently associated with an increased incidence of breakthrough infections (P 0.044). The proportion of asymptomatic COVID-19 breakthrough cases that were additionally identifed serologically in the ARC cohort was comparable between IMID patients with immunosuppressants and controls;66 (10%) of 695 patients vs. 64 (10%) of 647 controls. Hospitalization was required in 8 (5%) of 149 IMID patients with immunosuppressants and 5 (6%) of 86 controls with a COVID-19 breakthrough infection. Hospitalized cases were generally older, and had more comorbidities compared with non-hospitalized cases (Table 1). Hospitalization rates were signifcantly higher among IMID patients treated with anti-CD20 therapy compared to IMID patients using any other immunosuppres-sant (3 [23%] of 13 patients vs. 5 [4%] of 128 patients, P 0.041;Table 1). Conclusion: The incidence of COVID-19 breakthrough infections in IMID patients with immunosuppressants was comparable to controls, and infections were mostly mild. Anti-CD20 therapy might increase patients' susceptibility to severe COVID-19 breakthrough infections, but traditional risk factors also continue to have a critical contribution to the disease course of COVID-19. Therefore, we argue that most patients with IMIDs should not necessarily be seen as a risk group for severe COVID-19, and that integrating other risk factors should become standard practice when discussing treatment options, COVID-19 vaccination, and adherence to infection prevention measures with patients.
ABSTRACT
Background: Many countries are promoting booster SARS-CoV-2 vaccination campaigns as the COVID-19 pandemic continues. Incremental short-term adverse events after two SARS-CoV-2 vaccinations have been reported in healthy individuals.1,2 However, data on incremental short-term adverse events in patients with various immune-mediated infammatory diseases (IMIDs) after repeated SARS-CoV-2 vaccination is scarce. Objectives: We report risk factors for short-term adverse events in IMID patients after SARS-CoV-2 vaccination. Methods: Self-reported daily questionnaires on adverse events in the frst seven days after SARS-CoV-2 vaccination were obtained from individuals participating in an ongoing prospective multi-arm multicenter cohort study on SARS-CoV-2 vaccination in patients with various IMIDs in the Netherlands (T2B! immunity after SARS-CoV-2). Clinically relevant adverse events were defned as systemic adverse advents lasting longer than two days or hindering daily activities. Adjusted relative risks for developing clinically relevant adverse events were calculated using a logistic mixed-effects model. Results: Data of 2081 patients and 178 healthy controls were obtained. Infammatory bowel disease (N:480), Multiple sclerosis (N:343) and Rheumatoid arthritis (N:266) were the largest disease groups. Adjusted relative risks for relevant adverse events are presented in Figure 1. Third vaccination was not associated with increased risk on adverse events when compared to a second vaccination (aRR: 0.93 95% CI: 0.84-1.02). Patients with IMIDs were at increased risk for developing adverse events after vaccination when compared to controls (aRR: 1.16 95% CI: 1.01-1.34). Female sex (aRR 1.43 95% CI: 1.32-1.56), age below 50 (aRR 1.14 95% CI: 1.06-1.23) and a preceding SARS-CoV-2 infection (aRR: 1.14 95% CI: 1.01-1.29) were also associated with increased risk of adverse events following vaccination. Allergic reactions and hospital admission were uncommon (0.67% and 0.19% respectively);7.4% and 6.8% of patients reported adverse events impacting daily life on day seven after second and third vaccination, respectively. Data on increase in disease activity of the IMID following vaccination are currently being investigated. Conclusion: A third SARS-CoV-2 vaccination was not associated with an increased risk on short-term clinically relevant adverse events when compared to a second vaccination. Although patients with IMIDs may be slightly more at risk to develop adverse events after SARS-CoV-2 vaccination, most adverse events were transient and disappeared within seven days. This message should reassure IMID patients who are hesitant on booster vaccination. Data on potential IMID fare-ups after vaccination will follow.
ABSTRACT
Background The aim of this study was to investigate the effect of various immunosuppressants on the humoral immune responses after vaccination against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs). Methods The Target to B! SARS-CoV-2 study is a multicentre study, taking place in 7 Dutch academic hospitals. Patients with the following IMIDs were recruited: Crohn’s disease (CD), ulcerative colitis (UC), auto-immune hepatitis, rheumatic (e.g. rheumatoid arthritis), neurological (e.g. multiple sclerosis) and dermatological IMIDs (e.g. atopic dermatitis). Patients were recruited based on immunosuppressants (table 1) and previous SARS-CoV-2 infection. The control group consisted of healthy subjects and IMID patients without immunosuppressants. SARS-CoV-2 receptor binding domain (RBD) antibodies were measured 28 days after completed SARS-CoV-2 vaccination. Seroconversion was defined as anti-RBD IgG >4 AU/mL. In this , we focus on therapies relevant for inflammatory bowel diseases (IBD) and present results for these treatments from patients with IBD, but also other IMIDs. Results Numbers of recruited patients with each immunosuppressant are shown in table 1. Amongst these patients, 312 patients had CD and 176 UC, the rest was diagnosed with another IMID. Seroconversion was reduced in patients receiving sphingosine 1-phosphate (S1P) modulators (all multiple sclerosis patients) while seroconversion was similar to controls in the other treatment groups. However, use of Anti-tumour necrosis factor (TNF), methotrexate, janus kinase (JAK) inhibitor monotherapy and all combination therapies (except for corticosteroids combined with other immunosuppressants) were associated with reduced Sars-CoV-2 antibody titres. Patients with a previous SARS-CoV-2 infection had higher median antibody titres after second vaccination than those without a previous SARS-CoV-2 infection. The type of IMID did not affect seroconversion rates. Conclusion No immunosuppressant, registered for IBD, reduced the rates of seroconversion after vaccination against SARS-CoV-2. Some immunosuppressants were associated with lower antibody titres. However, the clinical relevance of lower antibody titres remains unknown. S1P modulators, had a clear negative impact on the humoral response against SARS-CoV-2 after vaccination. This might be relevant in the future as this therapy is currently being approved for UC. Disease aetiology did not impair immunity against SARS-CoV-2 immunity after vaccination. Disclaimer: Absolute numbers of antibody titres and rates of seroconversion will be reported at the conference and are not reported in this as this might negatively impact the current submission process.