Lupus, vaccinations and COVID-19: What we know now.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the virus causing Coronavirus disease 2019 (COVID-19), has had a huge impact on health services, with a high mortality associated with complications including pneumonia and acute respiratory distress syndrome. Patients with systemic lupus erythematosus (SLE) are at increased risk of viral infections, and recent data suggests they may be at an increased risk of poor outcomes with COVID-19. This may be particularly true for those on rituximab or high dose steroids. A huge international effort from the scientific community has so far resulted in the temporary authorisation of three vaccines which offer protection against SARS-CoV-2, with over 30 other vaccines being evaluated in ongoing trials. Although there has historically been concern that vaccines may trigger disease flares of SLE, there is little convincing evidence to show this. In general lupus patients appear to gain good protection from vaccination, although there may be reduced efficacy in those with high disease activity or those on immunosuppressive therapies, such as rituximab or high dose steroids. Recent concerns have been raised regarding rare clotting events with the AstraZeneca/Oxford vaccine and it is currently unknown whether this risk is higher for those patients with secondary antiphospholipid syndrome. With the possibility of annual COVID vaccination programmes in the future, prospective data collection and registries looking at the effect of vaccination on SLE disease control, the incidence of COVID-19 in SLE patients and severity of COVID-19 disease course would all be useful. As mass vaccination programmes begin to roll out across the world, we assess the evidence of the use of vaccines in SLE patients and in particular vaccines targeting SARS-CoV-2.

Changing trends in mortality in systemic lupus erythematosus? An analysis of SLE inpatient mortality at University Hospital Coventry and Warwickshire NHS Trust from 2007 to 2016.

The aim of this study was to determine the causes of mortality in patients with systemic lupus erythematosus (SLE) at the University Hospital Coventry and Warwickshire (UHCW) NHS Trust over a 10 year period. This was a retrospective study of patients who had died in UHCW NHS Trust between 2007 and 2016, where SLE or lupus was mentioned on the death certificate. Ethics approval was obtained from the Research and Development. We identified 22 patients out of 1979 admissions with SLE who had died during the period between 2007 and 2016, 7 of these patients were under 50 years of age. The leading cause of death was infection with pneumococcus being associated with two deaths. Active disease was associated with younger age at death. Median age at death was 58.5 years, with median duration of disease of 14.5 years. Constitutional and mucocutaneous features were the most common items scoring on disease activity, seen in 68.2% and 45.45%, respectively. We identified three patients with biopsy proven lupus nephritis and one patient with CNS lupus. Surprisingly, none of the patients died because of vascular problems. The study suggests a changing trend in SLE mortality with none of the deaths in this cohort being due to cardiovascular or cerebrovascular disease. Infection continues to be the biggest reason for mortality in this cohort and greater emphasis is needed on vaccination for preventable infections like pneumococcus.

NMDA receptor hypofunction phase couples independent γ-oscillations in the rat visual cortex.

Hallucinations, a hallmark of psychosis, can be induced by the psychotomimetic N-methyl-D-aspartic acid (NMDA) receptor antagonists, ketamine and phencyclidine (PCP), and are associated with hypersynchronization in the γ-frequency band, but it is unknown how reduced interneuron activation associated with NMDA receptor hypofunction can cause hypersynchronization or distorted perception. Low-frequency γ-oscillations (LFγ) and high-frequency γ-oscillations (HFγ) serve different aspects of perception. In this study, we test whether ketamine and PCP affect the interactions between HFγ and LFγ in the rat visual cortex in vitro. In slices of the rat visual cortex, kainate and carbachol induced LFγ (∼ 34 Hz at 32°C) in layer V and HFγ (∼ 54 Hz) in layer III of the same cortical column. In controls, HFγ and LFγ were independent, and pyramidal neurons recorded in layer III were entrained by HFγ, but not by LFγ. Sub-anesthetic concentrations of ketamine selectively decelerated HFγ by 22 Hz (EC(50)=2.7 µM), to match the frequency of LFγ in layer V. This caused phase coupling of the two γ-oscillations, increased spatial coherence in layer III, and entrained the firing of layer III pyramidal neurons by LFγ in layer V. PCP similarly decelerated HFγ by 22 Hz (EC(50)=0.16 µM), causing cross-layer phase coupling of γ-oscillations. Selective NMDA receptor antagonism, selective NR2B subunit-containing receptor antagonism, and reduced D-serine levels caused a similar selective deceleration of HFγ, whereas increasing NMDA receptor activation through exogenous NMDA, D-serine, or mGluR group 1 agonism selectively accelerated HFγ. The NMDA receptor hypofunction-induced phase coupling of the normally independent γ-generating networks is likely to cause abnormal cross-layer interactions, which may distort perceptions due to aberrant matching of top-down information with bottom-up information. If decelerated HFγ and subsequent cross-layer synchronization also underlie pathological psychosis, acceleration of HFγ could be the target for improved antipsychotic therapy.

High-frequency gamma oscillations coexist with low-frequency gamma oscillations in the rat visual cortex in vitro.

Synchronization of neuronal activity in the visual cortex at low (30-70 Hz) and high gamma band frequencies (> 70 Hz) has been associated with distinct visual processes, but mechanisms underlying high-frequency gamma oscillations remain unknown. In rat visual cortex slices, kainate and carbachol induce high-frequency gamma oscillations (fast-gamma; peak frequency approximately 80 Hz at 37 degrees C) that can coexist with low-frequency gamma oscillations (slow-gamma; peak frequency approximately 50 Hz at 37 degrees C) in the same column. Current-source density analysis showed that fast-gamma was associated with rhythmic current sink-source sequences in layer III and slow-gamma with rhythmic current sink-source sequences in layer V. Fast-gamma and slow-gamma were not phase-locked. Slow-gamma power fluctuations were unrelated to fast-gamma power fluctuations, but were modulated by the phase of theta (3-8 Hz) oscillations generated in the deep layers. Fast-gamma was spatially less coherent than slow-gamma. Fast-gamma and slow-gamma were dependent on gamma-aminobutyric acid (GABA)(A) receptors, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and gap-junctions, their frequencies were reduced by thiopental and were weakly dependent on cycle amplitude. Fast-gamma and slow-gamma power were differentially modulated by thiopental and adenosine A(1) receptor blockade, and their frequencies were differentially modulated by N-methyl-D-aspartate (NMDA) receptors, GluK1 subunit-containing receptors and persistent sodium currents. Our data indicate that fast-gamma and slow-gamma both depend on and are paced by recurrent inhibition, but have distinct pharmacological modulation profiles. The independent co-existence of fast-gamma and slow-gamma allows parallel processing of distinct aspects of vision and visual perception. The visual cortex slice provides a novel in vitro model to study cortical high-frequency gamma oscillations.