Current Evidence on Vaccinations in Pediatric and Adult Patients with Systemic Autoinflammatory Diseases.

Systemic autoinflammatory diseases (SAIDs) are defined by recurrent febrile attacks associated with protean manifestations involving joints, the gastrointestinal tract, skin, and the central nervous system, combined with elevated inflammatory markers, and are caused by a dysregulation of the innate immune system. From a clinical standpoint, the most known SAIDs are familial Mediterranean fever (FMF); cryopyrin-associated periodic syndrome (CAPS); mevalonate kinase deficiency (MKD); and periodic fever, aphthosis, pharyngitis, and adenitis (PFAPA) syndrome. Current guidelines recommend the regular sequential administration of vaccines for all individuals with SAIDs. However, these patients have a much lower vaccination coverage rates in 'real-world' epidemiological studies than the general population. The main purpose of this review was to evaluate the scientific evidence available on both the efficacy and safety of vaccines in patients with SAIDs. From this analysis, neither serious adverse effects nor poorer antibody responses have been observed after vaccination in patients with SAIDs on treatment with biologic agents. More specifically, no new-onset immune-mediated complications have been observed following immunizations. Post-vaccination acute flares were significantly less frequent in FMF patients treated with colchicine alone than in those treated with both colchicine and canakinumab. Conversely, a decreased risk of SARS-CoV-2 infection has been proved for patients with FMF after vaccination with the mRNA-based BNT162b2 vaccine. Canakinumab did not appear to affect the ability to produce antibodies against non-live vaccines in patients with CAPS, especially if administered with a time lag from the vaccination. On the other hand, our analysis has shown that immunization against Streptococcus pneumoniae, specifically with the pneumococcal polysaccharide vaccine, was associated with a higher incidence of adverse reactions in CAPS patients. In addition, disease flares might be elicited by vaccinations in children with MKD, though no adverse events have been noted despite concurrent treatment with either anakinra or canakinumab. PFAPA patients seem to be less responsive to measles, mumps, and rubella-vaccine, but have shown higher antibody response than healthy controls following vaccination against hepatitis A. In consideration of the clinical frailty of both children and adults with SAIDs, all vaccinations remain 'highly' recommended in this category of patients despite the paucity of data available.

Phenotypical and Functional Alteration of γδ T Lymphocytes in COVID-19 Patients: Reversal by Statins.

(1) Background: statins have been considered an attractive class of drugs in the pharmacological setting of COVID-19 due to their pleiotropic properties and their use correlates with decreased mortality in hospitalized COVID-19 patients. Furthermore, it is well known that statins, which block the mevalonate pathway, affect γδ T lymphocyte activation. As γδ T cells participate in the inflammatory process of COVID-19, we have investigated the therapeutical potential of statins as a tool to inhibit γδ T cell pro-inflammatory activities; (2) Methods: we harvested peripheral blood mononuclear cells (PBMCs) from COVID-19 patients with mild clinical manifestations, COVID-19 recovered patients, and healthy controls. We performed ex vivo flow cytometry analysis to study γδ T cell frequency, phenotype, and exhaustion status. PBMCs were treated with Atorvastatin followed by non-specific and specific stimulation, to evaluate the expression of pro-inflammatory cytokines; (3) Results: COVID-19 patients had a lower frequency of circulating Vδ2+ T lymphocytes but showed a pronounced pro-inflammatory profile, which was inhibited by in vitro treatment with statins; (4) Conclusions: the in vitro capacity of statins to inhibit Vδ2+ T lymphocytes in COVID-19 patients highlights a new potential biological function of these drugs and supports their therapeutical use in these patients.

From Sharks to Yeasts: Squalene in the Development of Vaccine Adjuvants.

Squalene is a natural linear triterpene that can be found in high amounts in certain fish liver oils, especially from deep-sea sharks, and to a lesser extent in a wide variety of vegeTable oils. It is currently used for numerous vaccine and drug delivery emulsions due to its stability-enhancing properties and biocompatibility. Squalene-based vaccine adjuvants, such as MF59 (Novartis), AS03 (GlaxoSmithKline Biologicals), or AF03 (Sanofi) are included in seasonal vaccines against influenza viruses and are presently being considered for inclusion in several vaccines against SARS-CoV-2 and future pandemic threats. However, harvesting sharks for this purpose raises serious ecological concerns that the exceptional demand of the pandemic has exacerbated. In this line, the use of plants to obtain phytosqualene has been seen as a more sustainable alternative, yet the lower yields and the need for huge investments in infrastructures and equipment makes this solution economically ineffective. More recently, the enormous advances in the field of synthetic biology provided innovative approaches to make squalene production more sustainable, flexible, and cheaper by using genetically modified microbes to produce pharmaceutical-grade squalene. Here, we review the biological mechanisms by which squalene-based vaccine adjuvants boost the immune response, and further compare the existing sources of squalene and their environmental impact. We propose that genetically engineered microbes are a sustainable alternative to produce squalene at industrial scale, which are likely to become the sole source of pharmaceutical-grade squalene in the foreseeable future.

Efficacy, safety and tolerance of anakinra in paediatric rheumatology and periodic fever clinics: Real life experience

Introduction: Interleukin 1 (IL-1) induced proinflammatory signals were discovered as a causative aetiology in a spectrum of diseases. Efficacy and safety of the recombinant IL-1 receptor antagonist anakinra across autoinflammatory and autoimmune diseases has been demonstrated in many studies. Despite the recommended dosage in patients above 8 months and weighing more than 10 kg, use of higher doses or earlier onset of therapy have been occasionally reported. Objectives: To an institutional review of data on efficacy, safety and tolerance of anakinra in patients with autoinflammatory diseases (AID). Methods: A single-centre retrospective review of electronic records of patients treated with anakinra between August 2007 and May 2021. Results: A total of 47 patients (30 children, 17 adults) were identified. The median follow-up was 35 months (range 1-165 months). Patients have been treated for diagnosis of systemic juvenile idiopathic arthritis (sJIA) (n = 18;38%), cryopyrinopathy (CAPS) (n = 10;21%), mevalonate-kinase deficiency (MKD) (n = 7;15%), undifferentiated AID (uAID) (n = 6;13%), PIMS-TS (n = 3;6%), NLRC4-GOF (n = 1, 2%), PAPA syndrome (n = 1;2%) and polyarticular JIA (n = 1, 2%). The most frequent indication for starting anakinra was macrophage activation syndrome (MAS) (n = 20;42,5%) which occurred in patients with sJIA (n=14, 70%), uAID (n=3, 15%), PIMS (n=1, 5%), NLRC4-GOF (n=1, 5%) or polyarticular JIA (n=1, 5%). Fourteen patients with sJIA (78%) received anakinra due to macrophage activation syndrome. MAS was the first manifestation of sJIA in 6 patients (33%). Recommended dosing of anakinra (1-4 mg/kg/day) was exceeded in 44,6% of patients (n=21) with the following dose range: 4-6 mg/kg (n = 8;38%), 6-9,9mg/kg (n = 4;19%), ≥10 mg/kg (n = 9;43%). Paediatric cohort received anakinra in very wide dosing range of 1,4 -26,1 mg/kg (average 5,59 mg/kg, median 4,15 mg/kg). The highest dose (10-26mg/kg) was required by patients with uAID (n=1, 8 days of age), sJIA/MAS (n=2, 3 and 5 years of age), CINCA (n=1, 4 years of age) and NLRC4-GOF (n=1, 4 weeks of age). The median dose of anakinra in adult patients was 1,6 mg/kg (range 0,9-7,7mg/kg). In severely sick patients the daily dose was divided into 2-4 intravenous applications, one patient received continuous anakinra i.v. infusion. Rapid therapeutic effect (within 24-48 hours from starting anakinra) was observed in all patients. The most frequent recorded adverse effects were already well-known injection-site reaction in 25,5% (n = 12) of patients which disappeared within one month in all of them. Persistent eosinophilia (highest values 3,6 and 2,3x10 ∗9 cells) was documented in 2 sJIA patients. Mild asymptomatic neutropenia (ANC min 0,8 x10 ∗9/L) and transient liver transaminase elevation (up to 3-times ULN) both occurred in 4,2% (n = 2) of patients each. Conclusion: Use of anakinra in a wide dosing range was reported. Our observation illustrates the need as well as safety of higher anakinra dosing in younger age groups including 2 newborns. No serious adverse effects that would require discontinuation or termination of anakinra were observed at all dosing regimens.

Proceedings of the 27th European Paediatric Rheumatology Congress (PReS 2021) : Virtual. 19-21 September 2021

The proceedings contain 431 papers. The topics discussed include: long-term efficacy and safety of canakinumab in patients with mevalonate kinase deficiency: results from the randomized phase 3 cluster trial;long-term safety of canakinumab in patients with autoinflammatory periodic fever syndromes - interim analysis of the reliance registry;NLRP3 splice variants inactivate caps phenotype in vitro;OAS1 GOF causes a novel autoinflammatory disease characterized by persistently elevated ifn signature, hypogammaglobulinemia, and alveolar proteinosis;while looking for one, you may find another: tin soldiers and the search for undiagnosed individuals with fibrodysplasia ossificans progressiva (FOP);nailfold capillaroscopy: a sensitive method for evaluating microvascular involvement in children with SARS-COV-2 infection;and outcomes of COVID-19 infection among children and young people with pre-existing rheumatic and musculoskeletal diseases.

Dysregulation of the mevalonate pathway during SARS-CoV-2 infection: An in silico study.

SARS-CoV-2 triggers a dysregulated innate immune system activation. As the mevalonate pathway (MVP) prevents the activation of inflammasomes and cytokine release and regulates endosomal transport, compromised signaling could be associated with the pathobiology of COVID-19. Prior transcriptomic studies of host cells in response to SARS-CoV-2 infection have not reported to date the effects of SARS-CoV-2 on the MVP. In this study, we accessed public data sets to report in silico investigations into gene expression. In addition, we proposed candidate genes that are thought to have a direct association with the pathogenesis of COVID-19, and which may be dependent on signals derived from the MVP. Our results revealed dysregulation of genes involved in the MVP. These results were not found when investigating the gene expression data from host cells infected with H3N2 influenza virus, H1N1 influenza virus, or respiratory syncytial virus. Our manually curated gene set showed significant gene expression variability in A549 cells infected with SARS-CoV-2, as per Blanco-Melo et al. data set (GSE147507). In light of the present findings, SARS-CoV-2 could hijack the MVP, leading to hyperinflammatory responses. Prompt reconstitution of this pathway with available agents should be considered in future studies.

Lipid homeostasis and mevalonate pathway in COVID-19: Basic concepts and potential therapeutic targets.

Despite encouraging progresses achieved in the management of viral diseases, efficient strategies to counteract infections are still required. The current global challenge highlighted the need to develop a rapid and cost-effective strategy to counteract the SARS-CoV-2 pandemic. Lipid metabolism plays a crucial role in viral infections. Viruses can use the host lipid machinery to support their life cycle and to impair the host immune response. The altered expression of mevalonate pathway-related genes, induced by several viruses, assures survival and spread in host tissue. In some infections, statins, HMG-CoA-reductase inhibitors, reduce cholesterol in the plasma membrane of permissive cells resulting in lower viral titers and failure to internalize the virus. Statins can also counteract viral infections through their immunomodulatory, anti-inflammatory and anti-thrombotic effects. Beyond statins, interfering with the mevalonate pathway could have an adjuvant effect in therapies aimed at mitigating endothelial dysfunction and deregulated inflammation in viral infection. In this review we depicted the historical and current evidence highlighting how lipid homeostasis and mevalonate pathway targeting represents a valid approach to rapidly neutralize viruses, focusing our attention to their potential use as effective targets to hinder SARS-CoV-2 morbidity and mortality. Pros and cons of statins and Mevalonate-pathway inhibitors have been also dissected.