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1.
Front Immunol ; 12: 734279, 2021.
Article in English | MEDLINE | ID: covidwho-1686469

ABSTRACT

Newly emerging variants of coronavirus 2 (SARS-CoV-2) raise concerns about the spread of the disease, and with the rising case numbers, the Coronavirus disease 2019 (COVID-19) remains a challenging medical emergency towards the end of the year 2021. Swiftly developed novel vaccines aid in the prevention of the spread, and it seems that a specific cure will not be at hand soon. The prognosis of COVID-19 in patients with autoimmune/autoinflammatory rheumatic diseases (AIIRD) is more severe when compared to the otherwise healthy population, and vaccination is essential. Evidence for both the efficacy and safety of COVID-19 vaccination in AIIRD under immunosuppression is accumulating, but the effect of Interleukin-1 on vaccination in general and in AIIRD patients is rarely addressed in the current literature. In light of the current literature, it seems that the level of agreement on the timing of COVID-19 vaccination is moderate in patients using IL-1 blockers, and expert opinions may vary. Generally, it may be recommended that patients under IL-1 blockade can be vaccinated without interrupting the anti-cytokine therapy, especially in patients with ongoing high disease activity to avoid disease relapses. However, in selected cases, after balancing for disease activity and risk of relapses, vaccination may be given seven days after the drug levels have returned to baseline, especially for IL-1 blocking agents with long half-lives such as canakinumab and rilonacept. This may help to ensure an ideal vaccine response in the face of the possibility that AIIRD patients may develop a more pronounced and severe COVID-19 disease course.


Subject(s)
Antirheumatic Agents/adverse effects , COVID-19 Vaccines/immunology , COVID-19/prevention & control , Interleukin-1beta/antagonists & inhibitors , Rheumatic Diseases/drug therapy , SARS-CoV-2/immunology , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , Antirheumatic Agents/therapeutic use , Autoimmune Diseases/drug therapy , Autoimmune Diseases/immunology , Humans , Immunosuppressive Agents/adverse effects , Immunosuppressive Agents/therapeutic use , Recombinant Fusion Proteins/adverse effects , Recombinant Fusion Proteins/therapeutic use , Rheumatic Diseases/immunology , Vaccination
3.
Inflamm Res ; 71(2): 169-182, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1615450

ABSTRACT

Ethyl pyruvate (EP) has potent influence on redox processes, cellular metabolism, and inflammation. It has been intensively studied in numerous animal models of systemic and organ-specific disorders whose pathogenesis involves a strong immune component. Here, basic chemical and biological properties of EP are discussed, with an emphasis on its redox and metabolic activity. Further, its influence on myeloid and T cells is considered, as well as on intracellular signaling beyond its effect on immune cells. Also, the effects of EP on animal models of chronic inflammatory and autoimmune disorders are presented. Finally, a possibility to apply EP as a treatment for such diseases in humans is discussed. Scientific papers cited in this review were identified using the PubMed search engine that relies on the MEDLINE database. The reference list covers the most important findings in the field in the past twenty years.


Subject(s)
Autoimmune Diseases/drug therapy , Inflammation/drug therapy , Pyruvates/therapeutic use , Animals , Disease Models, Animal , Humans , Myeloid Cells/drug effects , Pyruvates/pharmacology , Reactive Oxygen Species/metabolism , Signal Transduction/drug effects , T-Lymphocytes/drug effects
4.
Mod Rheumatol ; 32(2): 444-451, 2022 Feb 28.
Article in English | MEDLINE | ID: covidwho-1596576

ABSTRACT

OBJECTIVES: To examine how the novel coronavirus disease (COVID-19) has changed infectious complications in outpatients with autoimmune diseases. METHODS: We performed a retrospective, record-linked cohort study and questionnaire about lifestyle changes in patients who visited our department in 2019 and 2020. RESULTS: We surveyed 1316 outpatients in 2019 and 1284 in 2020. The most common underlying diseases were rheumatoid arthritis (842 vs. 814) and systemic lupus erythematosus (SLE) (126 vs. 127). No significant difference in median age (66 vs. 67 years), respiratory comorbidities (30.4% vs. 32.0%), or corticosteroid use (42.2% vs. 44.3%) was found between the years. Immunomodulating agents were used more in 2020 (33.1% vs. 39.7%, p < .001). Total number of infections (28.0/100 vs. 19.4/100 person-years), pneumonia (3.6 vs. 1.6), influenza (2.1 vs. 0.1), and nonviral dermatological infections (3.8 vs. 2.1) were significantly lower in 2020. No significant difference was found for herpes zoster (2.2 vs. 1.8), urinary tract infections (3.3 vs. 3.8), or gastrointestinal infections (2.9 vs. 3.0). According to the questionnaire, 75% of the respondents became more conscious about wearing masks and 81% began to use hand sanitizer during the pandemic. CONCLUSION: Under the COVID-19 pandemic, some infectious complications have decreased in outpatients with autoimmune diseases.


Subject(s)
Autoimmune Diseases , COVID-19 , Autoimmune Diseases/complications , Autoimmune Diseases/drug therapy , Autoimmune Diseases/epidemiology , COVID-19/complications , COVID-19/epidemiology , Cohort Studies , Humans , Japan/epidemiology , Outpatients , Pandemics , Retrospective Studies , SARS-CoV-2
5.
J Autoimmun ; 125: 102743, 2021 12.
Article in English | MEDLINE | ID: covidwho-1568811

ABSTRACT

OBJECTIVES: To investigate humoral responses and safety of mRNA SARS-CoV-2 vaccines in systemic autoimmune and autoinflammatory rheumatic disease (SAARD) patients subjected or not to treatment modifications during vaccination. METHODS: A nationwide, multicenter study, including 605 SAARD patients and 116 controls, prospectively evaluated serum anti-SARS-CoV-2 S1-protein IgG antibody titers, side-effects, and disease activity, one month after complete vaccination, in terms of distinct treatment modification strategies (none, partial and extended modifications). Independent risk factors associated with hampered humoral responses were identified by data-driven multivariable logistic regression analysis. RESULTS: Patients with extended treatment modifications responded to vaccines similarly to controls as well as SAARD patients without immunosuppressive therapy (97.56% vs 100%, p = 0.2468 and 97.56% vs 97.46%, p > 0.9999, respectively). In contrast, patients with partial or without therapeutic modifications responded in 87.50% and 84.50%, respectively. Furthermore, SAARD patients with extended treatment modifications developed higher anti-SARS-CoV-2 antibody levels compared to those without or with partial modifications (median:7.90 vs 7.06 vs 7.1, p = 0.0003 and p = 0.0195, respectively). Mycophenolate mofetil (MMF), rituximab (RTX) and methotrexate (MTX) negatively affected anti-SARS-CoV-2 humoral responses. In 10.5% of vaccinated patients, mild clinical deterioration was noted; however, no differences in the incidence of deterioration were observed among the distinct treatment modification SAARD subgroups. Side-effects were generally comparable between SAARD patients and controls. CONCLUSIONS: In SAARD patients, mRNA SARS-CoV-2 vaccines are effective and safe, both in terms of side-effects and disease flares. Treatment with MMF, RTX and/or MTX compromises anti-SARS-CoV-2 antibody responses, which are restored upon extended treatment modifications without affecting disease activity.


Subject(s)
/immunology , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Autoimmune Diseases/immunology , Hereditary Autoinflammatory Diseases/immunology , Rheumatic Diseases/immunology , /adverse effects , Adolescent , Adult , Aged , Aged, 80 and over , Autoimmune Diseases/drug therapy , COVID-19/prevention & control , Female , Greece , Hereditary Autoinflammatory Diseases/drug therapy , Humans , Immunoglobulin G/blood , Male , Methotrexate/adverse effects , Methotrexate/therapeutic use , Middle Aged , Mycophenolic Acid/adverse effects , Mycophenolic Acid/therapeutic use , Prospective Studies , Rheumatic Diseases/drug therapy , Rituximab/adverse effects , Rituximab/therapeutic use , SARS-CoV-2/immunology , Young Adult
6.
BMJ Case Rep ; 14(12)2021 Dec 09.
Article in English | MEDLINE | ID: covidwho-1566338

ABSTRACT

We describe two young cases of reactive haemophagocytic lymphohistiocytosis (HLH) with the resultant stress cardiomyopathy in the setting of underlying autoimmune diseases, systemic lupus erythematosus (SLE) and Still's disease. The initial presentation was similar in both cases with fever, hyperinflammatory response, hypotension (vasoplegia), bicytopenia and hyperferritinemia. Despite standard of care and multiple broad-spectrum antibiotics, both cases remained pyrexic and were ultimately admitted to the intensive therapy unit to treat cardiogenic shock. Echocardiogram of both cases showed low ejection fraction, the cause for which was not found until the final diagnosis of HLH was made. Both cases made a complete clinical and cardiac recovery following the initiation of high-dose glucocorticoids and anakinra.


Subject(s)
Autoimmune Diseases , Lymphohistiocytosis, Hemophagocytic , Macrophage Activation Syndrome , Takotsubo Cardiomyopathy , Autoimmune Diseases/complications , Autoimmune Diseases/drug therapy , Humans , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Lymphohistiocytosis, Hemophagocytic/complications , Lymphohistiocytosis, Hemophagocytic/drug therapy , Takotsubo Cardiomyopathy/drug therapy
7.
Molecules ; 26(23)2021 Dec 06.
Article in English | MEDLINE | ID: covidwho-1559466

ABSTRACT

Bruton's tyrosine kinase (BTK) represented, in the past ten years, an important target for the development of new therapeutic agents that could be useful for cancer and autoimmune disorders. To date, five compounds, able to block BTK in an irreversible manner, have been launched in the market, whereas many reversible BTK inhibitors (BTKIs), with reduced side effects that are more useful for long-term administration in autoimmune disorders, are under clinical investigation. Despite the presence in the literature of many articles and reviews, studies on BTK function and BTKIs are of great interest for pharmaceutical companies as well as academia. This review is focused on compounds that have appeared in the literature from 2017 that are able to block BTK in an irreversible or reversible manner; also, new promising tunable irreversible inhibitors, as well as PROTAC molecules, have been reported. This summary could improve the knowledge of the chemical diversity of BTKIs and provide information for future studies, particularly from the medicinal chemistry point of view. Data reported here are collected from different databases (Scifinder, Web of Science, Scopus, Google Scholar, and Pubmed) using "BTK" and "BTK inhibitors" as keywords.


Subject(s)
Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Agammaglobulinaemia Tyrosine Kinase/metabolism , Autoimmune Diseases/drug therapy , Autoimmune Diseases/metabolism , Neoplasms/drug therapy , Neoplasms/metabolism , Protein Kinase Inhibitors/therapeutic use , Agammaglobulinaemia Tyrosine Kinase/chemistry , Agammaglobulinaemia Tyrosine Kinase/classification , Animals , B-Lymphocytes/metabolism , Humans , Inhibitory Concentration 50 , Treatment Outcome
8.
Autoimmun Rev ; 21(2): 102994, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1527592

ABSTRACT

Disruption of immune and neuroendocrine system function has been shown to play a key role in COVID-19. Oxytocin is vitally important for the immune and neuroendocrine systems. However, oxytocin dysfunction might occur in COVID-19 leading to autoimmune disease. Intranasal oxytocin may be effective in turning off an overactive immune system. This could be a powerful approach to avoid possible autoimmune diseases after COVID-19.


Subject(s)
Autoimmune Diseases , COVID-19 , Oxytocin/therapeutic use , Administration, Intranasal , Autoimmune Diseases/drug therapy , Autoimmune Diseases/prevention & control , COVID-19/complications , Humans
9.
Arthritis Rheumatol ; 74(1): 33-37, 2022 01.
Article in English | MEDLINE | ID: covidwho-1527417

ABSTRACT

OBJECTIVE: B cell depletion is an established therapeutic principle in a wide range of autoimmune diseases. However, B cells are also critical for inducing protective immunity after infection and vaccination. We undertook this study to assess humoral and cellular immune responses after infection with or vaccination against SARS-CoV-2 in patients with B cell depletion and controls who are B cell-competent. METHODS: Antibody responses (tested using enzyme-linked immunosorbent assay) and T cell responses (tested using interferon-γ enzyme-linked immunospot assay) against the SARS-CoV-2 spike S1 and nucleocapsid proteins were assessed in a limited number of previously infected (n = 6) and vaccinated (n = 8) autoimmune disease patients with B cell depletion, as well as previously infected (n = 30) and vaccinated (n = 30) healthy controls. RESULTS: As expected, B cell and T cell responses to the nucleocapsid protein were observed only after infection, while respective responses to SARS-CoV-2 spike S1 were found after both infection and vaccination. A SARS-CoV-2 antibody response was observed in all vaccinated controls (30 of 30 [100%]) but in none of the vaccinated patients with B cell depletion (0 of 8). In contrast, after SARS-CoV-2 infection, both the patients with B cell depletion (spike S1, 5 of 6 [83%]; nucleocapsid, 3 of 6 [50%]) and healthy controls (spike S1, 28 of 30 [93%]; nucleocapsid, 28 of 30 [93%]) developed antibodies. T cell responses against the spike S1 and nucleocapsid proteins were found in both infected and vaccinated patients with B cell depletion and in the controls. CONCLUSION: These data show that B cell depletion completely blocks humoral but not T cell SARS-CoV-2 vaccination response. Furthermore, limited humoral immune responses are found after SARS-CoV-2 infection in patients with B cell depletion.


Subject(s)
Autoimmune Diseases/immunology , B-Lymphocytes/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , Lymphocyte Depletion/adverse effects , SARS-CoV-2/immunology , Autoimmune Diseases/drug therapy , Autoimmune Diseases/virology , COVID-19/prevention & control , Humans , Immunity, Cellular/immunology , Immunity, Humoral/immunology
10.
Eur J Med Chem ; 229: 114002, 2022 Feb 05.
Article in English | MEDLINE | ID: covidwho-1517139

ABSTRACT

Compounds targeting the inflammasome-caspase-1 pathway could be of use for the treatment of inflammation and inflammatory diseases. Previous caspase-1 inhibitors were in great majority covalent inhibitors and failed in clinical trials. Using a mixed modelling, computational screening, synthesis and in vitro testing approach, we identified a novel class of non-covalent caspase-1 non cytotoxic inhibitors which are able to inhibit IL-1ß release in activated macrophages in the low µM range, in line with the best activities observed for the known covalent inhibitors. Our compounds could form the basis of further optimization towards potent drugs for the treatment of inflammation and inflammatory disorders including also dysregulated inflammation in Covid 19.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Autoimmune Diseases/drug therapy , Caspase 1/drug effects , Inflammasomes/drug effects , Inflammation/drug therapy , Serpins/chemical synthesis , Serpins/pharmacology , Tetrazoles/chemical synthesis , Tetrazoles/therapeutic use , Viral Proteins/chemical synthesis , Viral Proteins/pharmacology , COVID-19 , Cell Division/drug effects , Drug Design , Drug Evaluation, Preclinical , Humans , Interleukin-1beta/metabolism , Macrophages/drug effects , Macrophages/metabolism , Tetrazoles/pharmacology , U937 Cells
11.
Reumatol Clin (Engl Ed) ; 17(9): 491-493, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1510266

ABSTRACT

SARS-COV-2 infection has spread worldwide since it originated in December 2019, in Wuhan, China. The pandemic has largely demonstrated the resilience of the world's health systems and is the greatest health emergency since World War II. There is no single therapeutic approach to the treatment of COVID-19 and the associated immune disorder. The lack of randomised clinical trials (RCTs) has led different countries to tackle the disease based on case series, or from results of observational studies with off-label drugs. We as rheumatologists in general, and specifically rheumatology fellows, have been on the front line of the pandemic, modifying our activities and altering our training itinerary. We have attended patients, we have learned about the management of the disease and from our previous experience with drugs for arthritis and giant cell arteritis, we have used these drugs to treat COVID-19.


Subject(s)
Antiviral Agents/therapeutic use , Biological Factors/therapeutic use , COVID-19/drug therapy , Immunosuppressive Agents/therapeutic use , Physician's Role , Rheumatologists , Autoimmune Diseases/complications , Autoimmune Diseases/drug therapy , Autoimmune Diseases/immunology , COVID-19/complications , COVID-19/epidemiology , COVID-19/immunology , Drug Therapy, Combination , Education, Medical, Graduate , Fellowships and Scholarships , Global Health , Humans , Immunocompromised Host , Opportunistic Infections/complications , Opportunistic Infections/drug therapy , Opportunistic Infections/immunology , Patient Care Team/organization & administration , Practice Patterns, Physicians' , Rheumatic Diseases/complications , Rheumatic Diseases/drug therapy , Rheumatic Diseases/immunology , Rheumatologists/education , Rheumatologists/organization & administration , Rheumatology/education , Rheumatology/methods , Rheumatology/organization & administration , Spain/epidemiology
12.
Biomolecules ; 11(11)2021 11 03.
Article in English | MEDLINE | ID: covidwho-1502359

ABSTRACT

Immune cells, including dendritic cells, macrophages, and T and B cells, express the vitamin D receptor and 1α-hydroxylase. In vitro studies have shown that 1,25-dihydroxyvitamin D, the active form of vitamin D, has an anti-inflammatory effect. Recent epidemiological evidence has indicated a significant association between vitamin D deficiency and an increased incidence, or aggravation, of infectious diseases and inflammatory autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis. However, the impact of vitamin D on treatment and prevention, particularly in infectious diseases such as the 2019 coronavirus disease (COVID-19), remains controversial. Here, we review recent evidence associated with the relationship between vitamin D and inflammatory diseases and describe the underlying immunomodulatory effect of vitamin D.


Subject(s)
COVID-19/drug therapy , COVID-19/prevention & control , Immune System/drug effects , Inflammation/drug therapy , Vitamin D/therapeutic use , Animals , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/prevention & control , Autoimmune Diseases/drug therapy , B-Lymphocytes/immunology , Dendritic Cells/immunology , Disease Models, Animal , Humans , Influenza, Human/drug therapy , Influenza, Human/prevention & control , Lupus Erythematosus, Systemic/drug therapy , Lupus Erythematosus, Systemic/prevention & control , Macrophages/immunology , Mice , Monocytes/immunology , Multiple Sclerosis/drug therapy , Multiple Sclerosis/prevention & control , Receptors, Calcitriol/genetics , Receptors, Calcitriol/physiology , T-Lymphocytes/immunology , Vitamin D Deficiency/complications
13.
Front Immunol ; 12: 732992, 2021.
Article in English | MEDLINE | ID: covidwho-1497075

ABSTRACT

Chronic inflammatory disorders (CID), such as autoimmune diseases, are characterized by overactivation of the immune system and loss of immune tolerance. T helper 17 (Th17) cells are strongly associated with the pathogenesis of multiple CID, including psoriasis, rheumatoid arthritis, and inflammatory bowel disease. In line with the increasingly recognized contribution of innate immune cells to the modulation of dendritic cell (DC) function and DC-driven adaptive immune responses, we recently showed that neutrophils are required for DC-driven Th17 cell differentiation from human naive T cells. Consequently, recruitment of neutrophils to inflamed tissues and lymph nodes likely creates a highly inflammatory loop through the induction of Th17 cells that should be intercepted to attenuate disease progression. Tolerogenic therapy via DCs, the central orchestrators of the adaptive immune response, is a promising strategy for the treatment of CID. Tolerogenic DCs could restore immune tolerance by driving the development of regulatory T cells (Tregs) in the periphery. In this review, we discuss the effects of the tolerogenic adjuvants vitamin D3 (VD3), corticosteroids (CS), and retinoic acid (RA) on both DCs and neutrophils and their potential interplay. We briefly summarize how neutrophils shape DC-driven T-cell development in general. We propose that, for optimization of tolerogenic DC therapy for the treatment of CID, both DCs for tolerance induction and the neutrophil inflammatory loop should be targeted while preserving the potential Treg-enhancing effects of neutrophils.


Subject(s)
Adjuvants, Immunologic/therapeutic use , Autoimmune Diseases/drug therapy , Autoimmunity/drug effects , Dendritic Cells/drug effects , Immune Tolerance/drug effects , Inflammation/drug therapy , Neutrophils/drug effects , Th17 Cells/drug effects , Animals , Autoimmune Diseases/immunology , Autoimmune Diseases/metabolism , Dendritic Cells/immunology , Dendritic Cells/metabolism , Humans , Inflammation/immunology , Inflammation/metabolism , Neutrophils/immunology , Neutrophils/metabolism , Th17 Cells/immunology , Th17 Cells/metabolism
14.
Immunology ; 164(4): 722-736, 2021 12.
Article in English | MEDLINE | ID: covidwho-1494730

ABSTRACT

Bruton's tyrosine kinase (BTK) is a TEC kinase with a multifaceted role in B-cell biology and function, highlighted by its position as a critical component of the B-cell receptor signalling pathway. Due to its role as a therapeutic target in several haematological malignancies including chronic lymphocytic leukaemia, BTK has been gaining tremendous momentum in recent years. Within the immune system, BTK plays a part in numerous pathways and cells beyond B cells (i.e. T cells, macrophages). Not surprisingly, BTK has been elucidated to be a driving factor not only in lymphoproliferative disorders but also in autoimmune diseases and response to infection. To extort this role, BTK inhibitors such as ibrutinib have been developed to target BTK in other diseases. However, due to rising levels of resistance, the urgency to develop new inhibitors with alternative modes of targeting BTK is high. To meet this demand, an expanding list of BTK inhibitors is currently being trialled. In this review, we synopsize recent discoveries regarding BTK and its role within different immune cells and pathways. Additionally, we discuss the broad significance and relevance of BTK for various diseases ranging from haematology and rheumatology to the COVID-19 pandemic. Overall, BTK signalling and its targetable nature have emerged as immensely important for a wide range of clinical applications. The development of novel, more specific and less toxic BTK inhibitors could be revolutionary for a significant number of diseases with yet unmet treatment needs.


Subject(s)
Agammaglobulinaemia Tyrosine Kinase/metabolism , B-Lymphocytes/enzymology , Immune System/enzymology , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Animals , Autoimmune Diseases/drug therapy , Autoimmune Diseases/enzymology , Autoimmune Diseases/immunology , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , COVID-19/drug therapy , COVID-19/enzymology , COVID-19/immunology , Humans , Immune System/drug effects , Immune System/immunology , Lymphoproliferative Disorders/drug therapy , Lymphoproliferative Disorders/enzymology , Lymphoproliferative Disorders/immunology , Molecular Targeted Therapy , Protein Kinase Inhibitors/therapeutic use , Receptors, Antigen, B-Cell/metabolism , Receptors, Chemokine/metabolism , Signal Transduction , Toll-Like Receptors/metabolism
15.
Biomolecules ; 11(10)2021 09 28.
Article in English | MEDLINE | ID: covidwho-1480575

ABSTRACT

BACKGROUND: Acute myocarditis often progresses to heart failure because there is no effective, etiology-targeted therapy of this disease. Simvastatin has been shown to be cardioprotective by decreasing matrix metalloproteinases' (MMPs) activity. The study was designed to determine whether simvastatin inhibits MMPs activity, decreases the severity of inflammation and contractile dysfunction of the heart in experimental autoimmune myocarditis (EAM). METHODS: Simvastatin (3 or 30 mg/kg/day) was given to experimental rats with EAM by gastric gavage for 21 days. Then transthoracic echocardiography was performed, MMPs activity and troponin I level were determined and tissue samples were assessed under a light and transmission electron microscope. RESULTS: Hearts treated with simvastatin did not show left ventricular enlargement. As a result of EAM, there was an enhanced activation of MMP-9, which was significantly reduced in the high-dose simvastatin group compared to the low-dose group. It was accompanied by prevention of myofilaments degradation and reduction of severity of inflammation. CONCLUSIONS: The cardioprotective effects of simvastatin in the acute phase of EAM are, at least in part, due to its ability to decrease MMP-9 activity and subsequent decline in myofilaments degradation and suppression of inflammation. These effects were achieved in doses equivalent to therapeutic doses in humans.


Subject(s)
Inflammation/drug therapy , Metalloproteases/genetics , Myocarditis/drug therapy , Simvastatin/pharmacology , Animals , Autoimmune Diseases/drug therapy , Autoimmune Diseases/genetics , Autoimmune Diseases/immunology , Cardiotonic Agents/pharmacology , Echocardiography , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Inflammation/genetics , Inflammation/immunology , Inflammation/pathology , Metalloproteases/antagonists & inhibitors , Models, Animal , Myocarditis/genetics , Myocarditis/immunology , Myocarditis/pathology , Rats , Ventricular Dysfunction, Left/drug therapy , Ventricular Dysfunction, Left/pathology , Ventricular Dysfunction, Left/prevention & control
16.
Immunology ; 164(4): 722-736, 2021 12.
Article in English | MEDLINE | ID: covidwho-1429802

ABSTRACT

Bruton's tyrosine kinase (BTK) is a TEC kinase with a multifaceted role in B-cell biology and function, highlighted by its position as a critical component of the B-cell receptor signalling pathway. Due to its role as a therapeutic target in several haematological malignancies including chronic lymphocytic leukaemia, BTK has been gaining tremendous momentum in recent years. Within the immune system, BTK plays a part in numerous pathways and cells beyond B cells (i.e. T cells, macrophages). Not surprisingly, BTK has been elucidated to be a driving factor not only in lymphoproliferative disorders but also in autoimmune diseases and response to infection. To extort this role, BTK inhibitors such as ibrutinib have been developed to target BTK in other diseases. However, due to rising levels of resistance, the urgency to develop new inhibitors with alternative modes of targeting BTK is high. To meet this demand, an expanding list of BTK inhibitors is currently being trialled. In this review, we synopsize recent discoveries regarding BTK and its role within different immune cells and pathways. Additionally, we discuss the broad significance and relevance of BTK for various diseases ranging from haematology and rheumatology to the COVID-19 pandemic. Overall, BTK signalling and its targetable nature have emerged as immensely important for a wide range of clinical applications. The development of novel, more specific and less toxic BTK inhibitors could be revolutionary for a significant number of diseases with yet unmet treatment needs.


Subject(s)
Agammaglobulinaemia Tyrosine Kinase/metabolism , B-Lymphocytes/enzymology , Immune System/enzymology , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Animals , Autoimmune Diseases/drug therapy , Autoimmune Diseases/enzymology , Autoimmune Diseases/immunology , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , COVID-19/drug therapy , COVID-19/enzymology , COVID-19/immunology , Humans , Immune System/drug effects , Immune System/immunology , Lymphoproliferative Disorders/drug therapy , Lymphoproliferative Disorders/enzymology , Lymphoproliferative Disorders/immunology , Molecular Targeted Therapy , Protein Kinase Inhibitors/therapeutic use , Receptors, Antigen, B-Cell/metabolism , Receptors, Chemokine/metabolism , Signal Transduction , Toll-Like Receptors/metabolism
18.
Curr Pharm Des ; 27(41): 4245-4252, 2021.
Article in English | MEDLINE | ID: covidwho-1394670

ABSTRACT

BACKGROUND: The Covid-19 pandemic may have a deleterious impact on patients with autoimmune systemic diseases (ASD) due to their deep immune-system alterations. OBJECTIVE: This study aims to investigate the prevalence of symptomatic Covid-19 and its correlations with both organ involvement and ongoing treatments in a large series of Italian ASD patients during the first wave of pandemic. METHODS: Our multicenter telephone 6-week survey included 3,029 unselected ASD patients enrolled at 36 tertiary referral centers of northern, central, and southern Italian macro-areas with different diffusion of the pandemic. Symptomatic SARS-CoV-2 infection was classified as definite Covid-19 (presence of symptoms plus positive oral/nasopharyngeal swabs) or highly suspected Covid-19 (highly suggestive symptoms, in the absence of a swab testing). RESULTS: A significantly higher prevalence of definite plus highly suspected Covid-19 compared to the Italian general population was detected in the whole ASD series (p=.000), as well as in patients from the three macro-areas (p=.000 in all). Statistically higher prevalence of Covid-19 was also found in connective tissue diseases compared to chronic arthritis subgroup (p=.000) and in ASD patients with pre-existing interstitial lung involvement (p=.000). Patients treated with either conventional disease-modifying anti-rheumatic drugs (DMARDs) and/or biological DMARDs showed a significantly lower prevalence of Covid-19 (p=.000 in both). Finally, scleroderma patients undergoing low-dose aspirin showed a significantly lower rate of Covid-19 compared to those without (p=0.003). CONCLUSION: The higher prevalence of Covid-19 in ASD patients, along with the significant correlations with important clinical features and therapeutic regimens, suggests the need to develop targeted prevention/management strategies during the current pandemic wave.


Subject(s)
Autoimmune Diseases , COVID-19 , Rheumatic Diseases , Autoimmune Diseases/drug therapy , Autoimmune Diseases/epidemiology , Humans , Lung , Pandemics , Rheumatic Diseases/drug therapy , Rheumatic Diseases/epidemiology , SARS-CoV-2
19.
Ann Rheum Dis ; 80(10): 1345-1350, 2021 10.
Article in English | MEDLINE | ID: covidwho-1394067

ABSTRACT

OBJECTIVES: Evidence suggests that B cell-depleting therapy with rituximab (RTX) affects humoral immune response after vaccination. It remains unclear whether RTX-treated patients can develop a humoral and T-cell-mediated immune response against SARS-CoV-2 after immunisation. METHODS: Patients under RTX treatment (n=74) were vaccinated twice with either mRNA-1273 or BNT162b2. Antibodies were quantified using the Elecsys Anti-SARS-CoV-2 S immunoassay against the receptor-binding domain (RBD) of the spike protein and neutralisation tests. SARS-CoV-2-specific T-cell responses were quantified by IFN-γ enzyme-linked immunosorbent spot assays. Prepandemic healthy individuals (n=5), as well as healthy individuals (n=10) vaccinated with BNT162b2, served as controls. RESULTS: All healthy controls developed antibodies against the SARS-CoV-2 RBD of the spike protein, but only 39% of the patients under RTX treatment seroconverted. Antibodies against SARS-CoV-2 RBD significantly correlated with neutralising antibodies (τ=0.74, p<0.001). Patients without detectable CD19+ peripheral B cells (n=36) did not develop specific antibodies, except for one patient. Circulating B cells correlated with the levels of antibodies (τ=0.4, p<0.001). However, even patients with a low number of B cells (<1%) mounted detectable SARS-CoV-2-specific antibody responses. SARS-CoV-2-specific T cells were detected in 58% of the patients, independent of a humoral immune response. CONCLUSIONS: The data suggest that vaccination can induce SARS-CoV-2-specific antibodies in RTX-treated patients, once peripheral B cells at least partially repopulate. Moreover, SARS-CoV-2-specific T cells that evolved in more than half of the vaccinated patients may exert protective effects independent of humoral immune responses.


Subject(s)
Antirheumatic Agents/therapeutic use , COVID-19 Vaccines/immunology , COVID-19/prevention & control , Immunocompromised Host/immunology , Immunogenicity, Vaccine/immunology , Rituximab/therapeutic use , Adult , Aged , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , Autoimmune Diseases/drug therapy , Autoimmune Diseases/immunology , B-Lymphocytes/immunology , Female , Humans , Immunity, Cellular/immunology , Immunity, Humoral/immunology , Immunogenicity, Vaccine/drug effects , Male , Middle Aged , SARS-CoV-2 , T-Lymphocytes/immunology
20.
Front Immunol ; 11: 631743, 2020.
Article in English | MEDLINE | ID: covidwho-1389175

ABSTRACT

The concept of trained immunity has recently emerged as a mechanism contributing to several immune mediated inflammatory conditions. Trained immunity is defined by the immunological memory developed in innate immune cells after a primary non-specific stimulus that, in turn, promotes a heightened inflammatory response upon a secondary challenge. The most characteristic changes associated to this process involve the rewiring of cell metabolism and epigenetic reprogramming. Under physiological conditions, the role of trained immune cells ensures a prompt response. This action is limited by effective resolution of inflammation and tissue repair in order to restore homeostasis. However, unrestrained activation of innate immune cells contributes to the development of chronic inflammation and tissue destruction through the secretion of inflammatory cytokines, proteases and growth factors. Therefore, interventions aimed at reversing the changes induced by trained immunity provide potential therapeutic approaches to treat inflammatory and autoimmune diseases like rheumatoid arthritis (RA). We review cellular approaches that target metabolism and the epigenetic reprogramming of dendritic cells, macrophages, natural killer cells, and other trained cells in the context of autoimmune inflammatory diseases.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Autoimmune Diseases/drug therapy , Autoimmunity/drug effects , Biological Products/therapeutic use , Immune System/drug effects , Inflammation/drug therapy , Animals , Autoimmune Diseases/genetics , Autoimmune Diseases/immunology , Autoimmune Diseases/metabolism , COVID-19/drug therapy , COVID-19/immunology , Energy Metabolism/drug effects , Epigenesis, Genetic/drug effects , Humans , Immune System/immunology , Immune System/metabolism , Immunity, Innate/drug effects , Immunologic Memory/drug effects , Inflammation/genetics , Inflammation/immunology , Inflammation/metabolism , Signal Transduction
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