Immunogenicity during the treatment of chronic rheumatic diseases: focus on TH9 lymphocytes

Background Rheumatoid arthritis (RA) is an autoimmune chronic disease characterized by inflammation of peripheral joints with a various degree of systemic involvement. The pathogenesis is partly understood. Adaptive immunity plays indeed a pivotal role in inducing and maintaining the inflammatory process. Several cells belonging to the adaptive immune system have been associated to specific histological synovial patterns and clinical findings; among these, T helper (Th) lymphocytes have been exhaustively studied in RA due to their capability of producing cytokines and chemokines, migrating into articular sites and activating other immune or resident cells. The pool of Th cells comprehends many subsets, each of which plays a precise role in inducing, tuning and repressing the immune response. Over the past twenty years, five distinct Th cell populations, properly named Th1, Th2, Th17, Th22 and Th9 cells, along with a counterpart of T cells with immune-repressive properties (T regulatory cells) have been described and characterized. Th9 cells develop under stimulation with Tissue Growth Factor-beta (TGF-β) and Interleukin-4 (IL-4) either from naïve or primed Th lymphocytes. They prevalently synthetize IL-9, but, in vitro, the production of IL-10, IL-17, IL-21 and IL-22 has been also reported. Th9 lymphocytes seem to be involved in the immunological responses underlying parasitic infections and allergic diseases. Neutralization of IL-9 worsens the symptomatic course of infestations while ameliorating the allergic manifestations. Some authors have demonstrated that Th9 cells take part to the pathogenesis of experimental autoimmune encephalomyelitis, systemic lupus erythematosus, systemic sclerosis, psoriatic arthritis and RA. Th9 lymphocytes are increased in the bloodstream and in the synovial membranes of RA patients, being their percentage directly related to the degree of lymphoid organisation and to the production of autoantibodies, like anti-citrullinated peptide antibodies (ACPAs). However, it is unclear whether Th9 lymphocytes could be involved in the response to the therapy, or in the immunogenicity of biologic agents. Aim Primary objective: to evaluate the prevalence of Th9 lymphocytes in the peripheral blood of RA patients, assigned or not to an immunosuppressant treatment (including conventional drugs and infliximab), and to assess the immunogenicity of infliximab by detecting changes in Th9 percentages following an in vitro stimulation test. Secondary objective: to compare the Th9-related immunogenicity of infliximab originator with that of its biosimilar compound (CT-P13, Remsima®), and to evaluate the influence of demographic and clinical features and concomitant medications on Th9 percentages. Methods We collected peripheral blood mononuclear cells (PBMCs) from 55 consecutive RA outpatients according to ACR/EULAR 2010 criteria and 10 healthy controls. We enrolled 15 subjects affected by RA not treated with immunosuppressive drugs, 20 patients successfully treated with branded infliximab, and 20 patients who discontinued branded infliximab due to adverse events or inefficacy. Allowed drugs included prednisone (< 10 mg/day), methotrexate (< 15 mg/week), sulphasalazine (< 3 g/day), hydroxychloroquine (< 400 mg/day) and, in the group of non responder patients, intravenous (i.v.) abatacept (10 mg/kg every 4 weeks), i.v. tocilizumab (8 mg/kg every 4 weeks), subcutaneous (s.c.) etanercept (50 mg once a week) and s.c. certolizumab pegol (200 mg every other week). The PBMCs were cultured with/without 50 μg/mL infliximab originator (Remicade®) or 50 μg/mL infliximab biosimilar (Remsima®), 50 μg/mL Human IgG1kappa and 50 μg/mL recombinant Human IgG Fc for 18 hours, and the percentage of Th9 cells was assessed by means of flow cytometry. Th9 lymphocytes were firstly identified as IFNγ-, IL-4-, IL-17-, IL-9- secreting CD4+ T cells, and, in a second time, as PU.1+, IRF4+, IL-9+ CD4+ cells. Furthermore, the markers CCR7 and CD45RA were used to distinguish naïve from memory IL-9-producer cells. Results In unstimulated condition, untreated RA patients showed the highest percentages of Th9 lymphocytes, either assessed according to cytokine or transcriptional profile, which was also higher in overall RA patients than in healthy controls. The higher frequency of Th9 cells in RA patients was not associated with higher levels of anti-nuclear autoantibodies or other autoantibody subsets, or with a higher likelihood of experiencing an adverse event or lack of efficacy on infliximab treatment. The percentage of PU.1+, IRF4+ Th9 cells, but not that of IL-9+, IFNγ-, IL-4-, IL- 17- CD4+ cells, increased following the exposure to branded infliximab in the group of non responder RA patients, although these data were not confirmed after biosimilar infliximab exposure. Furthermore, when IL-9 producing T cells were subdivided according to the expression of the markers CD45RA and CCR7, CCR7+, CD45RA- central memory and CCR7-, CD45RA- effector memory IL-9-producer lymphocytes increased in non responder RA patients after branded infliximab exposure, whereas CCR7+, CD45RA+ naïve and CCR7-, CD45+ terminal effector memory Th9 cells, although being more represented in RA patients than in healthy subjects, did not vary after drug stimulation. In line with the previous experiment, the exposure to biosimilar infliximab did not induce an increase in the percentage of memory Th9 cell in non responder patients. Conclusions IL-9 levels are increased in RA patients, in whom this cytokine plays indeed a crucial role. Th9 cells are the major producers of IL-9, and their prevalence is higher in RA patients than in healthy subjects. According to our results, PU.1+, IRF4+ Th9 cells may be involved in orchestrating the immune response against the epitopes of branded infliximab; and this condition could rely on the recall and stimulation of both central and effector memory cells. On the other hand, biosimilar infliximab seems not able to activate these pools of cells. However, no significant difference was noticed in the PU.1+, IRF4+ Th9 cell percentages in Remicade®-responder patients after stimulation test either with biosimilar and branded infliximab, proving that in vitro both the two drugs seem to have a comparable efficacy. Our results carry a novel point of view in the immunogenicity of anti-TNF agents, routinely based on the detection of anti-drug antibodies. However, since actual knowledge is still scarce, these data, highlighting a discrepancy between the Th9- driven immunogenicity of branded and biosimilar infliximab, indeed deserve further investigations

Rheumatic Diseases and Biosimilars: Evidence about Switch from Originators to Biosimilars in the Real Life

Biosimilars are broadly available for the treatment of several diseases including inflammatory arthritis. Thanks to biosimilars it has been possible to treat a greater number of rheumatic patients who previously were undertreated due to the high cost of originators, in several countries. There are a lot of data from double blind, randomized, controlled clinical trials, especially on TNF inhibitors (TNFi), concerning the maintenance of clinical efficacy after switching from originators to biosimilars; therefore, such a transition is increasingly encouraged both in the US and Europe mainly for economic reasons. However, despite the considerable saving, such shifts to biosimilar drugs are still being debated, principally over their ethical implications. Since the drugs are similar but not identical, the main issues are related to the possibility to compare the adverse events and/or the lack of efficacy and, to date, the variability in effectiveness for a single patient remains an unpredictable datum before effecting the switch. Despite encouraging data about the maintenance of efficacy and safety after the switch, there are many reports of discontinuation due both lack of efficacy or and adverse events. In this chapter we aim at showing the disease activity trend and the safety after the transition to TNF-i biosimilars in patients with rheumatic diseases in real life.

Racial differences in systemic sclerosis disease presentation: a European Scleroderma Trials and Research group study

Objectives. Racial factors play a significant role in SSc. We evaluated differences in SSc presentations between white patients (WP), Asian patients (AP) and black patients (BP) and analysed the effects of geographical locations.Methods. SSc characteristics of patients from the EUSTAR cohort were cross-sectionally compared across racial groups using survival and multiple logistic regression analyses.Results. The study included 9162 WP, 341 AP and 181 BP. AP developed the first non-RP feature faster than WP but slower than BP. AP were less frequently anti-centromere (ACA; odds ratio (OR) = 0.4, P &lt; 0.001) and more frequently anti-topoisomerase-I autoantibodies (ATA) positive (OR = 1.2, P = 0.068), while BP were less likely to be ACA and ATA positive than were WP [OR(ACA) = 0.3, P &lt; 0.001; OR(ATA) = 0.5, P = 0.020]. AP had less often (OR = 0.7, P = 0.06) and BP more often (OR = 2.7, P &lt; 0.001) diffuse skin involvement than had WP.AP and BP were more likely to have pulmonary hypertension [OR(AP) = 2.6, P &lt; 0.001; OR(BP) = 2.7, P = 0.03 vs WP] and a reduced forced vital capacity [OR(AP) = 2.5, P &lt; 0.001; OR(BP) = 2.4, P &lt; 0.004] than were WP. AP more often had an impaired diffusing capacity of the lung than had BP and WP [OR(AP vs BP) = 1.9, P = 0.038; OR(AP vs WP) = 2.4, P &lt; 0.001]. After RP onset, AP and BP had a higher hazard to die than had WP [hazard ratio (HR) (AP) = 1.6, P = 0.011; HR(BP) = 2.1, P &lt; 0.001].Conclusion. Compared with WP, and mostly independent of geographical location, AP have a faster and earlier disease onset with high prevalences of ATA, pulmonary hypertension and forced vital capacity impairment and higher mortality. BP had the fastest disease onset, a high prevalence of diffuse skin involvement and nominally the highest mortality

Immunogenicity during the treatment of chronic rheumatic diseases: focus on TH9 lymphocytes

Background Rheumatoid arthritis (RA) is an autoimmune chronic disease characterized by inflammation of peripheral joints with a various degree of systemic involvement. The pathogenesis is partly understood. Adaptive immunity plays indeed a pivotal role in inducing and maintaining the inflammatory process. Several cells belonging to the adaptive immune system have been associated to specific histological synovial patterns and clinical findings; among these, T helper (Th) lymphocytes have been exhaustively studied in RA due to their capability of producing cytokines and chemokines, migrating into articular sites and activating other immune or resident cells. The pool of Th cells comprehends many subsets, each of which plays a precise role in inducing, tuning and repressing the immune response. Over the past twenty years, five distinct Th cell populations, properly named Th1, Th2, Th17, Th22 and Th9 cells, along with a counterpart of T cells with immune-repressive properties (T regulatory cells) have been described and characterized. Th9 cells develop under stimulation with Tissue Growth Factor-beta (TGF-β) and Interleukin-4 (IL-4) either from naïve or primed Th lymphocytes. They prevalently synthetize IL-9, but, in vitro, the production of IL-10, IL-17, IL-21 and IL-22 has been also reported. Th9 lymphocytes seem to be involved in the immunological responses underlying parasitic infections and allergic diseases. Neutralization of IL-9 worsens the symptomatic course of infestations while ameliorating the allergic manifestations. Some authors have demonstrated that Th9 cells take part to the pathogenesis of experimental autoimmune encephalomyelitis, systemic lupus erythematosus, systemic sclerosis, psoriatic arthritis and RA. Th9 lymphocytes are increased in the bloodstream and in the synovial membranes of RA patients, being their percentage directly related to the degree of lymphoid organisation and to the production of autoantibodies, like anti-citrullinated peptide antibodies (ACPAs). However, it is unclear whether Th9 lymphocytes could be involved in the response to the therapy, or in the immunogenicity of biologic agents. Aim Primary objective: to evaluate the prevalence of Th9 lymphocytes in the peripheral blood of RA patients, assigned or not to an immunosuppressant treatment (including conventional drugs and infliximab), and to assess the immunogenicity of infliximab by detecting changes in Th9 percentages following an in vitro stimulation test. Secondary objective: to compare the Th9-related immunogenicity of infliximab originator with that of its biosimilar compound (CT-P13, Remsima®), and to evaluate the influence of demographic and clinical features and concomitant medications on Th9 percentages. Methods We collected peripheral blood mononuclear cells (PBMCs) from 55 consecutive RA outpatients according to ACR/EULAR 2010 criteria and 10 healthy controls. We enrolled 15 subjects affected by RA not treated with immunosuppressive drugs, 20 patients successfully treated with branded infliximab, and 20 patients who discontinued branded infliximab due to adverse events or inefficacy. Allowed drugs included prednisone (< 10 mg/day), methotrexate (< 15 mg/week), sulphasalazine (< 3 g/day), hydroxychloroquine (< 400 mg/day) and, in the group of non responder patients, intravenous (i.v.) abatacept (10 mg/kg every 4 weeks), i.v. tocilizumab (8 mg/kg every 4 weeks), subcutaneous (s.c.) etanercept (50 mg once a week) and s.c. certolizumab pegol (200 mg every other week). The PBMCs were cultured with/without 50 μg/mL infliximab originator (Remicade®) or 50 μg/mL infliximab biosimilar (Remsima®), 50 μg/mL Human IgG1kappa and 50 μg/mL recombinant Human IgG Fc for 18 hours, and the percentage of Th9 cells was assessed by means of flow cytometry. Th9 lymphocytes were firstly identified as IFNγ-, IL-4-, IL-17-, IL-9- secreting CD4+ T cells, and, in a second time, as PU.1+, IRF4+, IL-9+ CD4+ cells. Furthermore, the markers CCR7 and CD45RA were used to distinguish naïve from memory IL-9-producer cells. Results In unstimulated condition, untreated RA patients showed the highest percentages of Th9 lymphocytes, either assessed according to cytokine or transcriptional profile, which was also higher in overall RA patients than in healthy controls. The higher frequency of Th9 cells in RA patients was not associated with higher levels of anti-nuclear autoantibodies or other autoantibody subsets, or with a higher likelihood of experiencing an adverse event or lack of efficacy on infliximab treatment. The percentage of PU.1+, IRF4+ Th9 cells, but not that of IL-9+, IFNγ-, IL-4-, IL- 17- CD4+ cells, increased following the exposure to branded infliximab in the group of non responder RA patients, although these data were not confirmed after biosimilar infliximab exposure. Furthermore, when IL-9 producing T cells were subdivided according to the expression of the markers CD45RA and CCR7, CCR7+, CD45RA- central memory and CCR7-, CD45RA- effector memory IL-9-producer lymphocytes increased in non responder RA patients after branded infliximab exposure, whereas CCR7+, CD45RA+ naïve and CCR7-, CD45+ terminal effector memory Th9 cells, although being more represented in RA patients than in healthy subjects, did not vary after drug stimulation. In line with the previous experiment, the exposure to biosimilar infliximab did not induce an increase in the percentage of memory Th9 cell in non responder patients. Conclusions IL-9 levels are increased in RA patients, in whom this cytokine plays indeed a crucial role. Th9 cells are the major producers of IL-9, and their prevalence is higher in RA patients than in healthy subjects. According to our results, PU.1+, IRF4+ Th9 cells may be involved in orchestrating the immune response against the epitopes of branded infliximab; and this condition could rely on the recall and stimulation of both central and effector memory cells. On the other hand, biosimilar infliximab seems not able to activate these pools of cells. However, no significant difference was noticed in the PU.1+, IRF4+ Th9 cell percentages in Remicade®-responder patients after stimulation test either with biosimilar and branded infliximab, proving that in vitro both the two drugs seem to have a comparable efficacy. Our results carry a novel point of view in the immunogenicity of anti-TNF agents, routinely based on the detection of anti-drug antibodies. However, since actual knowledge is still scarce, these data, highlighting a discrepancy between the Th9- driven immunogenicity of branded and biosimilar infliximab, indeed deserve further investigations.Introduzione L’artrite reumatoide (AR) è una patologia cronica autoimmune con interessamento delle articolazioni diartrodiali. I meccanismi patogenetici alla base della malattia sono ancora poco chiari. Diverse cellule del sistema immunitario contribuiscono all’innesco e al mantenimento del processo infiammatorio. Tra di esse, i linfociti T helper (Th) svolgono un importante ruolo nella produzione di citochine, chemochine, nel reclutamento di cellule dal torrente circolatorio e nell’attivazione di cellule residenti. Tra i linfociti Th, le cellule Th9, che si sviluppano sotto l’azione combinata del Tissue Growth Factor-beta (TGF-β) e dell’interleuchina 4 (IL-4) a partite da cellule Th naive e Th2, sintetizzano IL-9 e, in minime quantità, IL-10, IL-17, IL-21 e IL-22, e sembrerebbero essere coinvolte nelle risposte immunitarie in corso di infestazioni parassitarie e allergie. Recentemente è stato dimostrato che queste cellule sono anche coinvolte nella patogenesi di patologie autoimmuni, come il lupus eritematoso sistemico, la sclerosi sistemica, l’artrite psoriasica e l’AR. In particolare, in corso di AR, i linfociti Th9 potrebbero dirigere la formazione dei centri linfoidi nel tessuto sinoviale e favorire la produzione di autoanticorpi come gli anticorpi anti-peptide ciclico citrullinato (ACPAs). Non è invece noto il ruolo di tali cellule nella risposta al trattamento con farmaci biologici e nei processi di immunogenicità. Scopo Obiettivo primario: valutare la prevalenza dei linfociti Th9 nel sangue periferico di pazienti con AR, in trattamento o meno con farmaci immunosoppressori (DMARDs convenzionali, steroidi o infliximab) e valutare l’immunogenicità di infliximab relativamente alle risposte Th9 dopo test di stimolazione in vitro, confrontando un gruppo di pazienti con AR responder a infliximab (Remicade®) con un gruppo di pazienti con AR non responder al farmaco. Obiettivo secondario: confrontare, con un test in vitro, l’immunogenicità Th9-correlata di infliximab originator Remicade® con quella del suo biosimilare (CT-P13, Remsima®). Valutare l’influenza delle variabili demografiche, cliniche e farmacologiche sulla variazione delle percentuali linfocitarie Th9. Metodi: Abbiamo arruolato 55 pazienti affetti da AR secondo i criteri ACR/EULAR 2010 e 10 controlli sani. I pazienti con AR erano suddivisi in un gruppo di 15 pazienti naive a terapie immunosoppressive, inclusi gli steroidi; un gruppo di 20 pazienti in trattamento con farmaci convenzionali, steroidi e infliximab (Remicade®) con buona risposta clinica e un gruppo di 20 pazienti che avevano fallito in passato la terapia con Remicade® per eventi avversi o inefficacia e che praticavano altre terapie biologiche (abatacept 10 mg/kg e.v. ogni 4 settimane in 13 casi; tocilizumab 8 mg/kg e.v. ogni 4 settimane in 5 casi; etanercept 50 mg a settimana s.c. in un caso e certolizumab pegol 200 mg ogni 2 settimane s.c. in un caso) oltre a DMARDs e steroidi. Era consentito l’uso di prednisone (< 10 mg/die), methotrexate (< 15 mg/settimana), sulfasalazina (< 3g/die), idrossiclorochina (< 400 mg/die). Dopo firma del consenso informato, le cellule mononucleate ottenute da sangue periferico (PBMCs) di ciascun soggetto sono state poste in coltura con aggiunta o meno di 50 μg/ml di infliximab originator (Remicade®) o 50 μg/ml di infliximab biosimilare (Remsima®), 50 μg/ml di IgG1kappa umane e 50 μg/ml di IgG Fc umane per 18 ore. La percentuale di linfociti Th9 cells è stata valutata per mezzo di indagini citofluorimetriche. I linfociti Th9 sono stati inizialmente identificati come cellule T CD4+ producenti IL-9 ma non esprimenti interferon-gamma (IFNγ), IL-4 e IL-17; e secondariamente come cellule T CD4+ PU.1+, IRF4+ e IL-9+. Sono state valutate inoltre le percentuali dei linfociti Th9 in accordo ai marcatori CCR7 e CD45RA al fine di distinguere le cellule naive dal pool delle cellule di memoria. Risultati Al basale, le percentuali di linfociti Th9, sia valutate in base al profilo citochinico che ai fattori trascrizionali, erano significativamente più alte nel gruppo di pazienti con AR rispetto ai controlli, e tra i pazienti, nel gruppo dei non trattati. Le percentuali di cellule Th9 non erano tuttavia significativamente correlate con lo sviluppo di eventi avversi o inefficacia, né con la comparsa di autoanticorpi non specifici per l’AR (es. anticorpi anti-nucleo). Dopo stimolazione con infliximab originator, la percentuale di linfociti Th9 PU.1+, IRF4+ ma non di quella dei linfociti IL-9+, IFNγ-, IL-4-, IL-17- aumentava significativamente rispetto al basale solo nel gruppo dei non responder. Questo evento non è stato registrato invece dopo stimolazione con infliximab biosimilare. Inoltre, quando i linfociti Th9 sono stati suddivisi in accordo all’espressione delle molecole CD45RA e CCR7, le cellule CCR7+ e CD45RA- (central memory) e quelle CCR7- e CD45RA- (effector memory) aumentavano significativamente rispetto al basale nel gruppo dei non responder dopo stimolazione con infliximab originator ma non biosimilare; al contrario nessuna variazione è stata registrata nelle percentuali dei linfociti CCR7+ e CD45RA+ (naive) nè in quella dei linfociti CCR7- e CD45+ (terminal effector memory). Conclusioni I nostri dati dimostrano che la percentuale di linfociti Th9, che rappresentano i maggiori produttori di IL-9, è maggiore nei pazienti con AR rispetto ai controlli sani. L’IL-9 potrebbe infatti giocare un ruolo fondamentale nel processo patogenetico della malattia. Inoltre, i nostri risultati dimostrano che i linfociti Th9, valutati attraverso i fattori trascrizionali PU.1 e IRF4, potrebbero essere implicati nella risposta immunitaria contro gli epitopi di infliximab originator, attraverso fenomeni di recalling di cellule di memoria. Al contrario, nonostante diversi studi abbiano dimostrato una sostanziale comparabilità dal punto di vista biomolecolare e quindi del profilo di immunogenicità relativo alla produzione di anticorpi anti-farmaco tra infliximab originator e biosimilare, dopo stimolazione in vitro con Remsima® non abbiamo osservato variazioni nelle percentuali delle cellule Th9 rispetto al basale nel gruppo dei non responder. Il nostro lavoro si è incentrato su una diversa prospettiva immunologica nell’ambito dell’immunogenicità di un farmaco biologico anti-TNF, valutando anche la presunta sovrapponibilità del farmaco originator al suo biosimilare. Tuttavia, la conoscenza attuale sull’argomento è ancora scarsa e merita ulteriori ricerche

Interaction between Long Noncoding RNAs and Syncytin-1/Syncytin-2 Genes and Transcripts: How Noncoding RNAs May Affect Pregnancy in Patients with Systemic Lupus Erythematosus

Background: Patients with systemic lupus erythematosus (SLE) often suffer from obstetric complications not necessarily associated with the antiphospholipid syndrome. These events may potentially result from the reduced placental synthesis of the fusogenic proteins syncytin-1 and syncytin-2, observed in women with pregnancy-related disorders. SLE patients have an aberrant noncoding (nc)RNA signature that may in turn dysregulate the expression of syncytin-1 and syncytin-2 during placentation. The aim of this research is to computationally evaluate and characterize the interaction between syncytin-1 and syncytin-2 genes and human ncRNAs and to discuss the potential implications for SLE pregnancy adverse outcomes. Methods: The FASTA sequences of the syncytin-1 and syncytin-2 genes were used as inputs to the Ensembl.org library to find any alignments with human ncRNA genes and their transcripts, which were characterized for their tissue expression, regulatory activity on adjacent genes, biological pathways, and potential association with human disease. Results: BLASTN analysis revealed a total of 100 hits with human long ncRNAs (lncRNAs) for the syncytin-1 and syncytin-2 genes, with median alignment scores of 151 and 66.7, respectively. Only lncRNAs TP53TG1, TTTY14, and ENSG00000273328 were reported to be expressed in placental tissue. Dysregulated expression of lncRNAs TP53TG1, LINC01239, and LINC01320 found in this analysis has previously been described in SLE patients as well as in women with a high-risk pregnancy. In addition, some of the genes adjacent to lncRNAs aligned with syncytin-1 or syncytin-2 in a regulatory region might increase the risk of pregnancy complications or SLE. Conclusions: This is the first computational study showing alignments between syncytin-1 and syncytin-2 genes and human lncRNAs. Whether this mechanism affects syncytiotrophoblast morphogenesis in SLE females is unknown and requires further investigation

Impaired VEGF-A-Mediated Neurovascular Crosstalk Induced by SARS-CoV-2 Spike Protein: A Potential Hypothesis Explaining Long COVID-19 Symptoms and COVID-19 Vaccine Side Effects?

Long coronavirus disease-19 (COVID-19) is a newly discovered syndrome characterized by multiple organ manifestations that persist for weeks to months, following the recovery from acute disease. Occasionally, neurological and cardiovascular side effects mimicking long COVID-19 have been reported in recipients of COVID-19 vaccines. Hypothetically, the clinical similarity could be due to a shared pathogenic role of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike (S) protein produced by the virus or used for immunization. The S protein can bind to neuropilin (NRP)-1, which normally functions as a coreceptor for the vascular endothelial growth factor (VEGF)-A. By antagonizing the docking of VEGF-A to NRP-1, the S protein could disrupt physiological pathways involved in angiogenesis and nociception. One consequence could be the increase in unbound forms of VEGF-A that could bind to other receptors. SARS-CoV-2-infected individuals may exhibit increased plasma levels of VEGF-A during both acute illness and convalescence, which could be responsible for diffuse microvascular and neurological damage. A few studies suggest that serum VEGF-A may also be a potential biomarker for long COVID-19, whereas evidence for COVID-19 vaccines is lacking and merits further investigation

Retroviruses in the pathogenesis of systemic lupus erythematosus: Are they potential therapeutic targets?

The pathogenesis of systemic lupus erythematosus (SLE) is characterised by the hyper-activation of immunologic pathways related to the antiviral response. Exogenous and endogenous retroviruses, by integrating their DNA templates in the host cell genome, may epigenetically control the transcription of genes involved in the immune response. Furthermore, their nucleic acids or neo-synthesized proteins could stimulate the sensor molecules placed upstream the inflammatory cascade. Exogenous retroviruses, like human immunodeficiency virus, have been associated to SLE-like manifestations or to a fair SLE diagnosis. In addition, there is some evidence confirming a pathogenic role of human endogenous retroviruses in SLE. In line with these data, the use of antiretroviral agents could represent an attractive opportunity in the future therapeutic algorithms of this disease, but studies are still missing

Lipid rafts as viral entry routes and immune platforms: A double-edged sword in SARS-CoV-2 infection?

Lipid rafts are nanoscopic compartments of cell membranes that serve a variety of biological functions. They play a crucial role in viral infections, as enveloped viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can exploit rafts to enter or quit target cells. On the other hand, lipid rafts contribute to the formation of immune synapses and their proper functioning is a prerequisite for adequate immune response and viral clearance. In this narrative review we dissect the panorama focusing on this singular aspect of cell biology in the context of SARS-CoV-2 infection and therapy. A lipid raft-mediated mechanism can be hypothesized for many drugs recommended or considered for the treatment of SARS-CoV-2 infection, such as glucocorticoids, antimalarials, immunosuppressants and antiviral agents. Furthermore, the additional use of lipid-lowering agents, like statins, may affect the lipid composition of membrane rafts and thus influence the processes occurring in these compartments. The combination of drugs acting on lipid rafts may be successful in the treatment of more severe forms of the disease and should be reserved for further investigation

What are the dangers of biological therapy discontinuation or dose reduction strategies when treating rheumatoid arthritis?

Introduction: Treatment with biological DMARDs (bDMARDs) has meant that remission or low disease activity (LDA) is now a realistic goal for patients with rheumatoid arthritis (RA). However, as in the case of all long-term therapies, potential side-effects give rise to concern. The main reasons for withdrawing or tapering bDMARDs are safety and the sustainability of national healthcare systems. Given these data our review has been focused on important question: whether conventional, including steroids, or bDMARDs can be reduced or even stopped in patients with stable established RA or early RA. Areas covered: The studies included in the evaluation had to be RCTs, observational studies, systematic reviews evaluating the withdrawing or tapering bDMARDs in RA patients who have been on long-term treatment and have achieved remission or LDA. A search was made in the MEDLINE and EMBASE databases from 1980 to May 2016. Expert commentary: There is curently no standardised way of identifying the patients for whom reducing bDMARD therapy is appropriate. Clinical experience and data from de-escalation studies suggest that patients with RA in sustained remission are the best target population for studying drug-tapering regimens, and that LDA should not be considered an adequate indication for bDMARD de-escalation because it could hide a persistent amount of inflammation