Type of vaccine and immunosuppressive therapy but not diagnosis critically influence antibody response after COVID-19 vaccination in patients with rheumatic disease

Objective: The development of sufficient COVID-19 vaccines has been a big breakthrough in fighting the global SARS-CoV-2 pandemic. However, vaccination effectiveness can be reduced in patients with autoimmune rheumatic diseases (AIRD). The aim of this study was to identify factors that lead to a diminished humoral vaccination response in patients with AIRD. Methods: Vaccination response was measured with a surrogate virus neutralisation test and by testing for antibodies directed against the receptor-binding-domain (RBD) of SARS-CoV-2 in 308 fully vaccinated patients with AIRD. In addition, 296 immunocompetent participants were investigated as a control group. Statistical adjusted analysis included covariates with a possible influence on antibody response. Results: Patients with AIRD showed lower antibody responses compared with immunocompetent individuals (median neutralising capacity 90.8% vs 96.5%, p<0.001; median anti-RBD-IgG 5.6 S/CO vs 6.7 S/CO, p<0.001). Lower antibody response was significantly influenced by type of immunosuppressive therapy, but not by rheumatic diagnosis, with patients under rituximab therapy developing the lowest antibody levels. Patients receiving mycophenolate, methotrexate or janus kinase inhibitors also showed reduced vaccination responses. Additional negative influencing factors were vaccination with AZD1222, old age and shorter intervals between the first two vaccinations. Conclusion: Certain immunosuppressive therapies are associated with lower antibody responses after vaccination. Additional factors such as vaccine type, age and vaccination interval should be taken into account. We recommend antibody testing in at-risk patients with AIRD and emphasise the importance of booster vaccinations in these patients

Incidence and characteristics of reversible and new diffusion-weighted magnetic resonance imaging hyperintensities in the first week after ischemic stroke

Einleitung und Zielsetzung: Die diffusionsgewichtete Magnetresonanztomographie (DWI) ist sensibler in der Aufdeckung ischämischer Hirnläsionen als die klinisch-neurologische Untersuchung. Obwohl DWI-Hyperintensitäten üblicherweise als irreversibel geschädigtes Infarktgewebe angesehen werden, konnte in Einzelfällen eine frühe komplette Rückbildung gezeigt werden. Durch eine systematische Untersuchung der Inzidenz und der Charakteristika des Neuauftretens und der frühen Rückbildung von DWI-Hyperintensitäten soll diese Arbeit zu einem besseren Verständnis der Rezidivrate, Pathophysiologie und des zeitlichen Verlaufs der bildgebenden Korrelate innerhalb der ersten Woche nach ischämischem Schlaganfall beitragen. Methodik: Bei Patienten mit einem akuten ischämischen Schlaganfall wurden an drei Zeitpunkten innerhalb der ersten Erkrankungswoche magnetresonanztomographische Untersuchungen durchgeführt. Die auf den DWI-Bildern sichtbaren akuten Hirnläsionen wurden jeweils geblindet gegenüber den klinischen Informationen und unabhängig von den zeitlich früheren oder späteren Bildbefunden manuell markiert. Auf koregistrierten Bildern wurden daraufhin mithilfe der Markierungen neu auftretende sowie vollständig reversible DWI-Läsionen identifiziert und mit klinischen, bildgebungsbasierten und laborchemischen Risikofaktoren korreliert. Ergebnisse: Bei mehr als einem Viertel der Patienten traten innerhalb der ersten Woche nach Schlaganfall neue zusätzliche ischämische Hirnläsionen auf. Klinisch manifeste Schlaganfallrezidive zeigten sich bei 3 % der Patienten. Bei einem Viertel der Patienten bildeten sich einzelne initial sichtbare Hyperintensitäten vollständig zurück. Die Rückbildung war auf kleine Läsionen beschränkt. Sowohl neue als auch reversible Läsionen waren signifikant mit multiplem Infarktmuster und symptomatischen Karotisstenosen assoziiert. Thrombolysetherapie war insbesondere mit neuen Läsionen innerhalb der ersten 24 Stunden assoziiert und Rekanalisation war insbesondere mit neuen Läsionen innerhalb des initialen Perfusionsdefizits assoziiert. Bei mehr als der Hälfte der Patienten mit reversiblen Läsionen fanden sich auch zusätzliche neue Läsionen in der ersten Woche. Schlussfolgerungen: In der ersten Woche nach ischämischem Schlaganfall zeigen serielle DWI-Untersuchungen viele neue Läsionen, die der klinisch-neurologischen Untersuchung entgehen. Der Zeitpunkt des Auftretens und das initial bestehende Perfusionsdefizit können dabei helfen, tatsächliche Rezidivereignisse von Verlaufsereignissen des Indexinfarktes im Rahmen von Thrombolyse und Rekanalisation abzugrenzen. Die frühe komplette Rückbildung von DWI-Hyperintensitäten ist kein seltenes Phänomen, sie ist jedoch auf einzelne kleine Läsionen beschränkt. Neue sowie reversible Läsionen sind möglicherweise Ausdruck eines mehrzeitigen embolischen Infarktgeschehens.Background and Purpose: Diffusion-weighted magnetic resonance imaging (DWI) is more sensitive in detecting ischemic brain lesions than the neurologic examination. Usually, DWI hyperintensities are regarded as irreversibly damaged infarct tissue. In some cases however, a complete early reversal of hyperintensities has been reported. In this study, incidence and characteristics of new as well as reversible hyperintensities in the first week were systematically investigated to extend the current knowledge on recurrence rates, pathophysiology and the time course of hyperintensities after ischemic stroke. Methods: Patients with an acute ischemic stroke underwent magnetic resonance imaging at three time points within the first week of stroke. DWI hyperintensities were manually delineated by raters blinded to clinical information and without knowledge of the findings of the other time points. Then, images of the three time points were coregistered. New as well as fully reversible DWI lesions were identified using the delineated regions of interest on coregistered images and correlated with risk factors derived from the clinical evaluation, imaging and laboratory results. Results: New ischemic lesions were found in more than a fourth of the patients in the first week after stroke. Clinical stroke recurrence was seen in 3 % of the patients. Individual initial hyperintensities reversed completely in a fourth of the patients. Reversal was limited to small lesions. New as well as reversible lesions were significantly associated with multiple initial infarcts and symptomatic carotid stenosis. Thrombolytic therapy was especially associated with new lesions in the first 24 hours and recanalization was especially associated with new lesions inside the area of initial hypoperfusion. In more than half of the patients with reversible lesions, new additional lesions were also found in the first week. Conclusions: Follow-up DWI measurements reveal many new lesions in the first week after ischemic stroke that are not detected by neurologic examination. The time point of occurrence and the initial perfusion deficit can help to differentiate true recurrent events from those related to thrombolysis and recanalization. Complete reversal of DWI hyperintensities is not a rare phenomenon, but it is limited to small individual lesions. New as well as reversible lesions may indicate ongoing recurrent embolism

Pausing methotrexate prevents impairment of Omicron BA.1 and BA.2 neutralisation after COVID-19 booster vaccination

Objective The level of neutralising capacity against Omicron BA.1 and BA.2 after third COVID-19 vaccination in patients on paused or continuous methotrexate (MTX) therapy is unclear. Methods In this observational cohort study, neutralising serum activity against SARS-CoV-2 wild-type (Wu01) and variant of concern Omicron BA.1 and BA.2 were assessed by pseudovirus neutralisation assay before, 4 and 12 weeks after mRNA booster immunisation in 50 rheumatic patients on MTX, 26 of whom paused the medication. 44 non-immunosuppressed persons (NIP) served as control group. Results While the neutralising serum activity against SARS-CoV-2 Wu01 and Omicron variants increased 67-73 fold in the NIP after booster vaccination, the serum activity in patients receiving MTX increased only 20-23 fold. Patients who continued MTX treatment during vaccination had significantly lower neutralisation against all variants at weeks 4 and 12 compared with patients who paused MTX and the control group, except for BA.2 at week 12. Patients who paused MTX reached comparably high neutralising capacities as NIP, except for Wu01 at week 12. The duration of the MTX pause after-not before-was associated with a significantly higher neutralisation capacity against all three variants, with an optimal duration at 10 days after vaccination. Conclusion Patients pausing MTX after COVID-19 booster showed a similar vaccine response to NIP. Patients who continued MTX demonstrated an impaired response indicating a potentially beneficial second booster vaccination. Our data also suggest that a 1 week MTX break is sufficient if the last administration of MTX occurs 1-3 days before vaccination

Characteristics and outcomes of SARS-CoV-2 breakthrough infections among double-vaccinated and triple-vaccinated patients with inflammatory rheumatic diseases

Objective To analyse the clinical profile of SARS-CoV-2 breakthrough infections in at least double-vaccinated patients with inflammatory rheumatic diseases (IRDs).Methods Data from the physician-reported German COVID-19-IRD registry collected between February 2021 and July 2022 were analysed. SARS-CoV-2 cases were stratified according to patients’ vaccination status as being not vaccinated, double-vaccinated or triple-vaccinated prior to SARS-CoV-2 infection and descriptively compared. Independent associations between demographic and disease features and outcome of breakthrough infections were estimated by multivariable logistic regression.Results In total, 2314 cases were included in the analysis (unvaccinated n=923, double-vaccinated n=551, triple-vaccinated n=803, quadruple-vaccinated n=37). SARS-CoV-2 infections occurred after a median of 151 (range 14–347) days in patients being double-vaccinated, and after 88 (range 14–270) days in those with a third vaccination. Hospitalisation was required in 15% of unvaccinated, 8% of double-vaccinated and 3% of triple-vaccinated/quadruple-vaccinated patients (p&lt;0.001). Mortality was 2% in unvaccinated, 1.8% in the double-vaccinated and 0.6% in triple-vaccinated patients. Compared with unvaccinated patients, double-vaccinated (OR 0.43, 95% CI 0.29 to 0.62) and triple-vaccinated (OR 0.13, 95% CI 0.08 to 0.21) patients showed a significant lower risk of COVID-19-related hospitalisation. Using multivariable analysis, the third vaccination was significantly associated with a lower risk for COVID-19-related death (OR 0.26; 95% CI 0.01 to 0.73).Conclusions Our cross-sectional data of COVID-19 infections in patients with IRD showed a significant reduction of hospitalisation due to infection in double-vaccinated or triple-vaccinated patients compared with those without vaccination and even a significant reduction of COVID-19-related deaths in triple-vaccinated patients. These data strongly support the beneficial effect of COVID-19 vaccination in patients with IRD.Trial registration number EuDRACT 2020-001958-21