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1.
Rev Med Virol ; 31(5): 1-13, 2021 09.
Article in English | MEDLINE | ID: covidwho-1574052

ABSTRACT

Anti-tumour necrosis factor (TNF) biologicals, Dexamethasone and rIL-7 are of considerable interest in treating COVID-19 patients who are in danger of, or have become, seriously ill. Yet reducing sepsis mortality by lowering circulating levels of TNF lost favour when positive endpoints in earlier simplistic models could not be reproduced in well-conducted human trials. Newer information with anti-TNF biologicals has encouraged reintroducing this concept for treating COVID-19. Viral models have had encouraging outcomes, as have the effects of anti-TNF biologicals on community-acquired COVID-19 during their long-term use to treat chronic inflammatory states. The positive outcome of a large scale trial of dexamethasone, and its higher potency late in the disease, harmonises well with its capacity to enhance levels of IL-7Rα, the receptor for IL-7, a cytokine that enhances lymphocyte development and is increased during the cytokine storm. Lymphoid germinal centres required for antibody-based immunity can be harmed by TNF, and restored by reducing TNF. Thus the IL-7- enhancing activity of dexamethasone may explain its higher potency when lymphocytes are depleted later in the infection, while employing anti-TNF, for several reasons, is much more logical earlier in the infection. This implies dexamethasone could prove to be synergistic with rIL-7, currently being trialed as a COVID-19 therapeutic. The principles behind these COVID-19 therapies are consistent with the observed chronic hypoxia through reduced mitochondrial function, and also the increased severity of this disease in ApoE4-positive individuals. Many of the debilitating persistent aspects of this disease are predictably susceptible to treatment with perispinal etanercept, since they have cerebral origins.


Subject(s)
COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Dexamethasone/administration & dosage , Interleukin-17/administration & dosage , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Animals , COVID-19/genetics , COVID-19/immunology , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/immunology , Humans , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunology
2.
Biomolecules ; 11(12)2021 12 04.
Article in English | MEDLINE | ID: covidwho-1554985

ABSTRACT

Inflammation involves a complex biological response of the body tissues to damaging stimuli. When dysregulated, inflammation led by biomolecular mediators such as caspase-1 and tumor necrosis factor-alpha (TNF-alpha) can play a detrimental role in the progression of different medical conditions such as cancer, neurological disorders, autoimmune diseases, and cytokine storms caused by viral infections such as COVID-19. Computational approaches can accelerate the search for dual-target drugs able to simultaneously inhibit the aforementioned proteins, enabling the discovery of wide-spectrum anti-inflammatory agents. This work reports the first multicondition model based on quantitative structure-activity relationships and a multilayer perceptron neural network (mtc-QSAR-MLP) for the virtual screening of agency-regulated chemicals as versatile anti-inflammatory therapeutics. The mtc-QSAR-MLP model displayed accuracy higher than 88%, and was interpreted from a physicochemical and structural point of view. When using the mtc-QSAR-MLP model as a virtual screening tool, we could identify several agency-regulated chemicals as dual inhibitors of caspase-1 and TNF-alpha, and the experimental information later retrieved from the scientific literature converged with our computational results. This study supports the capabilities of our mtc-QSAR-MLP model in anti-inflammatory therapy with direct applications to current health issues such as the COVID-19 pandemic.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Caspase Inhibitors/pharmacology , Drug Repositioning/methods , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Anti-Inflammatory Agents/chemistry , COVID-19/drug therapy , Caspase 1/metabolism , Caspase Inhibitors/chemistry , Humans , Inflammation/drug therapy , Molecular Docking Simulation , Quantitative Structure-Activity Relationship , Tumor Necrosis Factor-alpha/metabolism
3.
J Virol ; 95(22): e0127621, 2021 10 27.
Article in English | MEDLINE | ID: covidwho-1494956

ABSTRACT

The emergence of life-threatening zoonotic diseases caused by betacoronaviruses, including the ongoing coronavirus disease 19 (COVID-19) pandemic, has highlighted the need for developing preclinical models mirroring respiratory and systemic pathophysiological manifestations seen in infected humans. Here, we showed that C57BL/6J wild-type mice intranasally inoculated with the murine betacoronavirus murine hepatitis coronavirus 3 (MHV-3) develop a robust inflammatory response leading to acute lung injuries, including alveolar edema, hemorrhage, and fibrin thrombi. Although such histopathological changes seemed to resolve as the infection advanced, they efficiently impaired respiratory function, as the infected mice displayed restricted lung distention and increased respiratory frequency and ventilation. Following respiratory manifestation, the MHV-3 infection became systemic, and a high virus burden could be detected in multiple organs along with morphological changes. The systemic manifestation of MHV-3 infection was also marked by a sharp drop in the number of circulating platelets and lymphocytes, besides the augmented concentration of the proinflammatory cytokines interleukin 1 beta (IL-1ß), IL-6, IL-12, gamma interferon (IFN-γ), and tumor necrosis factor (TNF), thereby mirroring some clinical features observed in moderate and severe cases of COVID-19. Importantly, both respiratory and systemic changes triggered by MHV-3 infection were greatly prevented by blocking TNF signaling, either via genetic or pharmacologic approaches. In line with this, TNF blockage also diminished the infection-mediated release of proinflammatory cytokines and virus replication of human epithelial lung cells infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Collectively, results show that MHV-3 respiratory infection leads to a large range of clinical manifestations in mice and may constitute an attractive, lower-cost, biosafety level 2 (BSL2) in vivo platform for evaluating the respiratory and multiorgan involvement of betacoronavirus infections. IMPORTANCE Mouse models have long been used as valuable in vivo platforms to investigate the pathogenesis of viral infections and effective countermeasures. The natural resistance of mice to the novel betacoronavirus SARS-CoV-2, the causative agent of COVID-19, has launched a race toward the characterization of SARS-CoV-2 infection in other animals (e.g., hamsters, cats, ferrets, bats, and monkeys), as well as adaptation of the mouse model, by modifying either the host or the virus. In the present study, we utilized a natural pathogen of mice, MHV, as a prototype to model betacoronavirus-induced acute lung injure and multiorgan involvement under biosafety level 2 conditions. We showed that C57BL/6J mice intranasally inoculated with MHV-3 develops severe disease, which includes acute lung damage and respiratory distress that precede systemic inflammation and death. Accordingly, the proposed animal model may provide a useful tool for studies regarding betacoronavirus respiratory infection and related diseases.


Subject(s)
Coronavirus Infections/pathology , Disease Models, Animal , Lung/pathology , Murine hepatitis virus/pathogenicity , Animals , Cell Line , Containment of Biohazards , Coronavirus Infections/immunology , Coronavirus Infections/virology , Cytokines/metabolism , Humans , Inflammation , Liver/pathology , Liver/virology , Lung/virology , Mice , Murine hepatitis virus/drug effects , Murine hepatitis virus/physiology , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , Signal Transduction/drug effects , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/metabolism , Virus Replication/drug effects
4.
Int J Mol Sci ; 22(18)2021 Sep 13.
Article in English | MEDLINE | ID: covidwho-1409702

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic with high infectivity and mortality has caused severe social and economic impacts worldwide. Growing reports of COVID-19 patients with multi-organ damage indicated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) may also disturb the cardiovascular system. Herein, we used human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iCMs) as the in vitro platform to examine the consequence of SARS-CoV2 infection on iCMs. Differentiated iCMs expressed the primary SARS-CoV2 receptor angiotensin-converting enzyme-II (ACE2) and the transmembrane protease serine type 2 (TMPRSS2) receptor suggesting the susceptibility of iCMs to SARS-CoV2. Following the infection of iCMs with SARS-CoV2, the viral nucleocapsid (N) protein was detected in the host cells, demonstrating the successful infection. Bioinformatics analysis revealed that the SARS-CoV2 infection upregulates several inflammation-related genes, including the proinflammatory cytokine tumor necrosis factor-α (TNF-α). The pretreatment of iCMs with TNF-α for 24 h, significantly increased the expression of ACE2 and TMPRSS2, SASR-CoV2 entry receptors. The TNF-α pretreatment enhanced the entry of GFP-expressing SARS-CoV2 pseudovirus into iCMs, and the neutralization of TNF-α ameliorated the TNF-α-enhanced viral entry. Collectively, SARS-CoV2 elevated TNF-α expression, which in turn enhanced the SARS-CoV2 viral entry. Our findings suggest that, TNF-α may participate in the cytokine storm and aggravate the myocardial damage in COVID-19 patients.


Subject(s)
COVID-19/complications , Cardiovascular Diseases/immunology , Cytokine Release Syndrome/immunology , SARS-CoV-2/immunology , Tumor Necrosis Factor-alpha/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Cardiovascular Diseases/virology , Cell Differentiation , Cell Line , Computational Biology , Coronavirus Nucleocapsid Proteins/metabolism , Cytokine Release Syndrome/pathology , Cytokine Release Syndrome/virology , Humans , Induced Pluripotent Stem Cells , Myocardium/cytology , Myocardium/immunology , Myocardium/pathology , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/virology , Phosphoproteins/metabolism , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Serine Endopeptidases/metabolism , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Up-Regulation/immunology , Virus Internalization/drug effects
5.
Bioorg Chem ; 115: 105265, 2021 10.
Article in English | MEDLINE | ID: covidwho-1356144

ABSTRACT

In spite of possessing a wide range of pharmacological properties the anti-inflammatory activities of isoquinolin-1(2H)-ones were rarely known or explored earlier. PDE4 inhibitors on the other hand in addition to their usefulness in treating inflammatory diseases have been suggested to attenuate the cytokine storm in COVID-19 especially TNF-α. In our effort, a new class of isoquinolin-1(2H)-ones derivatives containing an aminosulfonyl moiety were designed and explored as potential inhibitors of PDE4. Accordingly, for the first time a CuCl2-catalyzed inexpensive, faster and ligand/additive free approach has been developed for the synthesis of these predesigned isoquinolin-1(2H)-one derivatives via the coupling-cyclization strategy. Thus, the CuCl2-catalyzed reaction of 2-iodobenzamides with appropriate terminal alkynes proceeded with high chemo and regioselectivity affording the desired compounds in 77-84% yield within 1-1.5 h. The methodology also afforded simpler isoquinolin-1(2H)-ones devoid of aminosulfonyl moiety showing a broader generality and scope of this approach. Several of the synthesized compounds especially 3c, 3k and 3s showed impressive inhibition (83-90%) of PDE4B when tested at 10 µM in vitro whereas compounds devoid of aminosulfonyl moiety was found to be less active. In spite of high inhibition showed at 10 µM these compounds did not show proper concertation dependent inhibition below 1 µM that was reflected in their IC50 values e.g. 2.43 ± 0.32, 3.26 ± 0.24 and 3.63 ± 0.80 µM for 3k, 3o and 3s respectively. The anti-inflammatory potential of these compounds was indicated by their TNF-α inhibition (60-50% at 10 µM). The in silico docking studies of these molecules suggested good interactions with PDE4B and selective inhibition of PDE4B by 3k over PDE4D that was supported by in vitro assay results. These observations together with the favorable ADME and safety predicted for 3kin silico not only suggested 3k as an interesting hit molecule for further studies but also reveal the first example of isoquinolin-1(2H)-one based inhibitor of PDE4B.


Subject(s)
Anti-Inflammatory Agents/chemistry , Copper/chemistry , Cyclic Nucleotide Phosphodiesterases, Type 4/chemistry , Isoquinolines/chemistry , Phosphodiesterase 4 Inhibitors/chemistry , Animals , Anti-Inflammatory Agents/chemical synthesis , Catalysis , Cyclization , Enzyme Assays , Humans , Isoquinolines/chemical synthesis , Mice , Molecular Structure , Phosphodiesterase 4 Inhibitors/chemical synthesis , RAW 264.7 Cells , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/antagonists & inhibitors
6.
Front Immunol ; 12: 641295, 2021.
Article in English | MEDLINE | ID: covidwho-1241168

ABSTRACT

Although millions of patients with underlining conditions are treated primarily with anti-TNF-α agents, little is known about the safety of this standard therapy during the coronavirus disease-2019 (COVID-19) pandemic. In this study, we investigated the effect of anti-TNF-α monoclonal antibodies on the cellular entry mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and increasing the risk of COVID-19 development. We focused on the expression of angiotensin-converting enzyme II (ACE2), type II transmembrane serine proteases (TMPRSS2)/TNF-α converting enzyme (TACE) ratio. We also investigated the involvement of Notch-1 signaling and its downstream influence on IL-6, myeloid cell leukemia sequence-1(MCL-1) in the anti-TNF-α mode of action and increased the susceptibility to Mycobacterium avium subspecies paratuberculosis (MAP) infection. Surprisingly, anti-TNF-α downregulated ACE2 expression by 0.46-fold and increased TMPRSS2/TACE ratio by 44% in THP-1 macrophages. Treatment of macrophages with rIL-6 also downregulated ACE2 and increased TMPRSS2/TACE ratio by 54%. Interestingly, anti-TNF-α treatment upregulated Notch-1, IL-6, and MCL-1 by 1.3, 1.2, and 1.9-fold, respectively, and increased viability and burden of MAP infection in macrophages. Blocking Notch signaling doubled ACE2 expression, decreased TMPRSS2/TACE ratio by 38%, and reduced MAP viability by 56%. In a small group of patients, ACE2 level was significantly lower in the plasma from rheumatoid arthritis (RA) patients on anti-TNF-α treatment compared to healthy control. The data in this critical study demonstrated that through Notch-1/IL-6 signaling, anti-TNF-α agents decreased ACE2 expression and shedding through TMPRSS2/TACE modulation and increased the susceptibility to infection. Overall, this study warns against anti-TNF-α therapy in some patients with underlining inflammatory conditions during the COVID-19 pandemic. The findings should impact current guidelines regarding treatment decisions of patients on anti-TNF-α during the COVID-19 pandemic.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/immunology , Macrophages/immunology , Mycobacterium avium/physiology , Receptor, Notch1/metabolism , SARS-CoV-2/physiology , Tuberculosis, Avian/immunology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , ADAM17 Protein/metabolism , Animals , COVID-19/transmission , COVID-19/virology , Disease Susceptibility , Disease Transmission, Infectious , Humans , Interleukin-6/metabolism , Risk , Serine Endopeptidases/metabolism , Signal Transduction , THP-1 Cells
8.
Biomed Pharmacother ; 133: 111037, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-1059801

ABSTRACT

COVID-19 is a global pandemic, with over 50 million confirmed cases and 1.2 million deaths as of November 11, 2020. No therapies or vaccines so far are recommended to treat or prevent the new coronavirus. A novel traditional Chinese medicine formula, Taiwan Chingguan Yihau (NRICM101), has been administered to patients with COVID-19 in Taiwan since April 2020. Its clinical outcomes and pharmacology have been evaluated. Among 33 patients with confirmed COVID-19 admitted in two medical centers, those (n = 12) who were older, sicker, with more co-existing conditions and showing no improvement after 21 days of hospitalization were given NRICM101. They achieved 3 consecutive negative results within a median of 9 days and reported no adverse events. Pharmacological assays demonstrated the effects of the formula in inhibiting the spike protein/ACE2 interaction, 3CL protease activity, viral plaque formation, and production of cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α. This bedside-to-bench study suggests that NRICM101 may disrupt disease progression through its antiviral and anti-inflammatory properties, offering promise as a multi-target agent for the prevention and treatment of COVID-19.


Subject(s)
Antiviral Agents/therapeutic use , Drugs, Chinese Herbal/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/drug effects , Coronavirus 3C Proteases/drug effects , Drug Compounding , Drugs, Chinese Herbal/adverse effects , Drugs, Chinese Herbal/pharmacology , Female , Humans , Interleukin-6/antagonists & inhibitors , Male , Medicine, Chinese Traditional , Middle Aged , Negative Results , Spike Glycoprotein, Coronavirus/drug effects , Treatment Outcome , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Viral Plaque Assay , Young Adult
9.
Aging (Albany NY) ; 13(2): 1571-1590, 2021 01 19.
Article in English | MEDLINE | ID: covidwho-1040203

ABSTRACT

The main aspects of severe COVID-19 disease pathogenesis include hyper-induction of proinflammatory cytokines, also known as 'cytokine storm', that precedes acute respiratory distress syndrome (ARDS) and often leads to death. COVID-19 patients often suffer from lung fibrosis, a serious and untreatable condition. There remains no effective treatment for these complications. Out of all cytokines, TNFα and IL-6 play crucial roles in cytokine storm pathogenesis and are likely responsible for the escalation in disease severity. These cytokines also partake in the molecular pathogenesis of fibrosis. Therefore, new approaches are urgently needed, that can efficiently and swiftly downregulate TNFα, IL-6, and the inflammatory cytokine cascade, in order to curb inflammation and prevent fibrosis, and lead to disease remission. Cannabis sativa has been proposed to modulate gene expression and inflammation and is under investigation for several potential therapeutic applications against autoinflammatory diseases and cancer. Here, we hypothesized that the extracts of novel C. sativa cultivars may be used to downregulate the expression of pro-inflammatory cytokines and pathways involved in inflammation and fibrosis. Initially, to analyze the anti-inflammatory effects of novel C. sativa cultivars, we used a well-established full thickness human 3D skin artificial EpiDermFTTM tissue model, whereby tissues were exposed to UV to induce inflammation and then treated with extracts of seven new cannabis cultivars. We noted that out of seven studied extracts of novel C. sativa cultivars, three (#4, #8 and #14) were the most effective, causing profound and concerted down-regulation of COX2, TNFα, IL-6, CCL2, and other cytokines and pathways related to inflammation and fibrosis. These data were further confirmed in the WI-38 lung fibroblast cell line model. Most importantly, one of the tested extracts had no effect at all, and one exerted effect that may be deleterious, signifying that careful cannabis cultivar selection must be based on thorough pre-clinical studies. The observed pronounced inhibition of TNFα and IL-6 is the most important finding, because these molecules are currently considered to be the main targets in COVID-19 cytokine storm and ARDS pathogenesis. Novel anti-TNFα and anti-IL-6 cannabis extracts can be useful additions to the current anti-inflammatory regimens to treat COVID-19, as well as various rheumatological diseases and conditions, and 'inflammaging' - the inflammatory underpinning of aging and frailty.


Subject(s)
COVID-19 , Cannabis , Cytokine Release Syndrome , Interleukin-6/antagonists & inhibitors , Plant Extracts/pharmacology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Anti-Inflammatory Agents/pharmacology , COVID-19/complications , Cannabinoids/pharmacology , Cell Line , Fibroblasts/drug effects , Humans , Inflammation/virology , SARS-CoV-2 , Skin/drug effects , Tissue Culture Techniques
10.
J Alzheimers Dis ; 79(3): 931-948, 2021.
Article in English | MEDLINE | ID: covidwho-1033235

ABSTRACT

Proinflammatory cytokines such as tumor necrosis factor (TNF), with its now appreciated key roles in neurophysiology as well as neuropathophysiology, are sufficiently well-documented to be useful tools for enquiry into the natural history of neurodegenerative diseases. We review the broader literature on TNF to rationalize why abruptly-acquired neurodegenerative states do not exhibit the remorseless clinical progression seen in those states with gradual onsets. We propose that the three typically non-worsening neurodegenerative syndromes, post-stroke, post-traumatic brain injury (TBI), and post cardiac arrest, usually become and remain static because of excess cerebral TNF induced by the initial dramatic peak keeping microglia chronically activated through an autocrine loop of microglial activation through excess cerebral TNF. The existence of this autocrine loop rationalizes post-damage repair with perispinal etanercept and proposes a treatment for cerebral aspects of COVID-19 chronicity. Another insufficiently considered aspect of cerebral proinflammatory cytokines is the fitness of the endogenous cerebral anti-TNF system provided by norepinephrine (NE), generated and distributed throughout the brain from the locus coeruleus (LC). We propose that an intact LC, and therefore an intact NE-mediated endogenous anti-cerebral TNF system, plus the DAMP (damage or danger-associated molecular pattern) input having diminished, is what allows post-stroke, post-TBI, and post cardiac arrest patients a strong long-term survival advantage over Alzheimer's disease and Parkinson's disease sufferers. In contrast, Alzheimer's disease and Parkinson's disease patients remorselessly worsen, being handicapped by sustained, accumulating, DAMP and PAMP (pathogen-associated molecular patterns) input, as well as loss of the LC-origin, NE-mediated, endogenous anti-cerebral TNF system. Adrenergic receptor agonists may counter this.


Subject(s)
Brain Injuries/physiopathology , Neurodegenerative Diseases/physiopathology , Stroke/physiopathology , Tumor Necrosis Factor-alpha/physiology , Alzheimer Disease/diagnosis , Alzheimer Disease/physiopathology , Alzheimer Disease/therapy , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Brain/physiopathology , Brain Injuries/diagnosis , Brain Injuries/therapy , COVID-19/diagnosis , COVID-19/physiopathology , COVID-19/therapy , Disease Progression , Etanercept/therapeutic use , Heart Arrest/diagnosis , Heart Arrest/physiopathology , Heart Arrest/therapy , Humans , Locus Coeruleus/physiopathology , Neurodegenerative Diseases/diagnosis , Neurodegenerative Diseases/therapy , Norepinephrine/physiology , Parkinson Disease/diagnosis , Parkinson Disease/physiopathology , Parkinson Disease/therapy , Risk Factors , SARS-CoV-2 , Stroke/diagnosis , Stroke/therapy , Survivors , Tumor Necrosis Factor-alpha/antagonists & inhibitors
11.
Dermatol Ther ; 33(5): e13687, 2020 09.
Article in English | MEDLINE | ID: covidwho-1006125

ABSTRACT

Coronavirus disease 2019 (COVID-19) is responsible for at least 2 546 527 cases and 175 812 deaths as of April 21, 2020. Psoriasis and atopic dermatitis (AD) are common, chronic, inflammatory skin conditions, with immune dysregulation as a shared mechanism; therefore, mainstays of treatment include systemic immunomodulating therapies. It is unknown whether these therapies are associated with increased COVID-19 susceptibility or worse outcomes in infected patients. In this review, we discuss overall infection risks of nonbiologic and biologic systemic medications for psoriasis and AD and provide therapeutic recommendations. In summary, in patients with active infection, systemic conventional medications, the Janus kinase inhibitor tofacitinib, and biologics for psoriasis should be temporarily held until there is more data; in uninfected patients switching to safer alternatives should be considered. Interleukin (IL)-17, IL-12/23, and IL-23 inhibitors are associated with low infection risk, with IL-17 and IL-23 favored over IL-12/23 inhibitors. Pivotal trials and postmarketing data also suggest that IL-17 and IL-23 blockers are safer than tumor necrosis factor alpha blockers. Apremilast, acitretin, and dupilumab have favorable safety data and may be safely initiated and continued in uninfected patients. Without definitive COVID-19 data, these recommendations may be useful in guiding treatment of psoriasis and AD patients during the COVID-19 pandemic.


Subject(s)
COVID-19/epidemiology , Dermatitis, Atopic/drug therapy , Psoriasis/drug therapy , SARS-CoV-2 , Humans , Immunologic Factors/adverse effects , Interleukin-17/antagonists & inhibitors , Interleukin-23/antagonists & inhibitors , Janus Kinase Inhibitors/adverse effects , Tumor Necrosis Factor-alpha/antagonists & inhibitors
13.
Eur Cytokine Netw ; 31(3): 81-93, 2020 Sep 01.
Article in English | MEDLINE | ID: covidwho-999892

ABSTRACT

Coronavirus disease (COVID-19) reached pandemic proportions at the beginning of 2020 and continues to be a worldwide concern. End organ damage and acute respiratory distress syndrome are the leading causes of death in severely or critically ill patients. The elevated cytokine levels in severe patients in comparison with mildly affected patients suggest that cytokine release syndrome (CRS) occurs in the severe form of the disease. In this paper, the significant role of pro-inflammatory cytokines, including IL-1, IL-6, and TNF-alpha, and their mechanism of action in the CRS cascade is explained. Potential therapeutic approaches involving anti-IL-6 and anti-TNF-alpha antibodies to fight COVID-19 and reduce mortality rate in severe cases are also discussed.


Subject(s)
Antibodies/therapeutic use , COVID-19 , Cytokine Release Syndrome , Interleukin-6/antagonists & inhibitors , Pandemics , SARS-CoV-2/metabolism , Tumor Necrosis Factor-alpha/antagonists & inhibitors , COVID-19/blood , COVID-19/complications , COVID-19/drug therapy , COVID-19/mortality , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/mortality , Humans , Interleukin-6/blood , Tumor Necrosis Factor-alpha/blood
14.
Gastroenterology ; 160(3): 809-822.e7, 2021 02.
Article in English | MEDLINE | ID: covidwho-990009

ABSTRACT

BACKGROUND AND AIMS: The host receptor for severe acute respiratory syndrome coronavirus 2, angiotensin-converting enzyme 2 (ACE2), is highly expressed in small bowel (SB). Our aim was to identify factors influencing intestinal ACE2 expression in Crohn's disease (CD), ulcerative colitis (UC), and non-inflammatory bowel disease (IBD) controls. METHODS: Using bulk RNA sequencing or microarray transcriptomics from tissue samples (4 SB and 2 colonic cohorts; n = 495; n = 387 UC; n = 94 non-IBD), we analyzed the relationship between ACE2 with demographics and disease activity and prognosis. We examined the outcome of anti-tumor necrosis factor and anti-interleukin-12/interleukin-23 treatment on SB and colonic ACE2 expression in 3 clinical trials. Univariate and multivariate regression models were fitted. RESULTS: ACE2 levels were consistently reduced in SB CD and elevated in colonic UC compared with non-IBD controls. Elevated SB ACE2 was also associated with demographic features (age and elevated body mass index) associated with poor coronavirus disease 2019 outcomes. Within CD, SB ACE2 was reduced in patients subsequently developing complicated disease. Within UC, colonic ACE2 was elevated in active disease and in patients subsequently requiring anti-tumor necrosis factor rescue therapy. SB and colonic ACE2 expression in active CD and UC were restored by anti-cytokine therapy, most notably in responders. CONCLUSIONS: Reduced SB but elevated colonic ACE2 levels in IBD are associated with inflammation and severe disease, but normalized after anti-cytokine therapy, suggesting compartmentalization of ACE2-related biology in SB and colonic inflammation. The restoration of ACE2 expression with anti-cytokine therapy might be important in the context of severe acute respiratory syndrome coronavirus 2 infection and potentially explain reports of reduced morbidity from coronavirus disease 2019 in IBD patients treated with anti-cytokines.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Anti-Inflammatory Agents/therapeutic use , Colitis, Ulcerative/drug therapy , Crohn Disease/drug therapy , Intestines/drug effects , Tumor Necrosis Factor Inhibitors/therapeutic use , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adolescent , Adult , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/genetics , Anti-Inflammatory Agents/adverse effects , COVID-19/enzymology , COVID-19/immunology , COVID-19/virology , Case-Control Studies , Child , Child, Preschool , Colitis, Ulcerative/enzymology , Colitis, Ulcerative/genetics , Colitis, Ulcerative/immunology , Crohn Disease/enzymology , Crohn Disease/genetics , Crohn Disease/immunology , Databases, Genetic , Female , Gene Expression Regulation, Enzymologic , Host-Pathogen Interactions , Humans , Intestines/enzymology , Intestines/immunology , Male , Middle Aged , North America , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Virus/metabolism , SARS-CoV-2/enzymology , SARS-CoV-2/immunology , Severity of Illness Index , Treatment Outcome , Tumor Necrosis Factor Inhibitors/adverse effects , Tumor Necrosis Factor-alpha/metabolism , Young Adult
15.
Expert Opin Biol Ther ; 21(2): 271-277, 2021 02.
Article in English | MEDLINE | ID: covidwho-939506

ABSTRACT

Background: The susceptibility of patients with chronic plaque psoriasis and the risks or benefits related to the use of biological therapies for COVID-19 are unknown. Few data about prevalence, clinical course and outcomes of COVID-19 among psoriatic patients were reported. The aims of this study were 1) to assess the prevalence and severity of COVID-19 in psoriatic patients treated with biologic agents during the first phase of the emergency (22 February to 22 April 2020) in Italy, and 2) to report the clinical outcomes of patients who have been exposed to individuals with confirmed SARS-CoV-2 infection. Methods: Patients with moderate-to-severe chronic plaque psoriasis, aged ≥18 years and undergoing treatment with biologic agents as of 22 February 2020, were eligible to be included in PSO-BIO-COVID study. Demographic and clinical characteristics of patients using any biologic for psoriasis treatment between 22 February and 22 April 2020 were registered. Results: A total of 12,807 psoriatic patients were included in the PSO-BIO-COVID study. In this cohort 26 patients (0.2%) had a swab confirmation of SARS-CoV-2 infection. Eleven patients required hospitalization and two died. Conclusion: The incidence of COVID-19 observed in our cohort of psoriatic patients (0.2%) is similar to that seen in the general population (0.31%) in Italy. However, the course of the disease was mild in most patients. Biological therapies may likely lessen 'cytokine storm' of COVID-19, which sometimes lead to multiple organ failure, ARDS, and death.


Subject(s)
Biological Products/therapeutic use , Biological Therapy/methods , COVID-19/epidemiology , Psoriasis/drug therapy , Adult , Aged , Aged, 80 and over , Biological Products/pharmacology , COVID-19/diagnosis , Chronic Disease , Cohort Studies , Female , Humans , Incidence , Interleukin-17/antagonists & inhibitors , Italy/epidemiology , Male , Middle Aged , Pandemics , Psoriasis/diagnosis , Psoriasis/epidemiology , Receptors, Interleukin/antagonists & inhibitors , Risk Assessment/methods , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Young Adult
16.
Pan Afr Med J ; 35(Suppl 2): 134, 2020.
Article in French | MEDLINE | ID: covidwho-926732

ABSTRACT

Hydroxychloroquine is an agent used as a treatment but also considered as a prophylaxis for SARS-CoV-2 infection. We report the case of a patient who developed COVID-19 while on hydroxychloroquine for mixed connectivitis associated with spondyloarthritis. Although more work is needed before any conclusions can be drawn, this raises questions about the protective role of this drug against infection. Are they really protected against COVID-19 or will they develop pauci-symptomatic forms?


Subject(s)
Antirheumatic Agents/therapeutic use , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Etanercept/therapeutic use , Hydroxychloroquine/therapeutic use , Mixed Connective Tissue Disease/drug therapy , Pneumonia, Viral/drug therapy , Skin Diseases, Viral/etiology , Spondylarthropathies/drug therapy , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Urticaria/etiology , Antirheumatic Agents/adverse effects , COVID-19 , Coronavirus Infections/complications , Disease Susceptibility , Etanercept/adverse effects , Humans , Male , Mixed Connective Tissue Disease/complications , Pandemics , Pneumonia, Viral/complications , SARS-CoV-2 , Spondylarthropathies/complications , Tumor Necrosis Factor-alpha/adverse effects , Young Adult
18.
Exp Biol Med (Maywood) ; 246(4): 406-413, 2021 02.
Article in English | MEDLINE | ID: covidwho-835740

ABSTRACT

The appearance of excessive inflammatory activity is associated with onset of many disease states. Such non-productive responses are often the basis of the mortality consequent to incurring numerous disorders. The current outbreak of coronavirus disease 2019 caused by the virus "severe acute respiratory syndrome coronavirus 2" is a striking reflection of the inadequacy of current medical science to adequately address this issue. The usefulness of a range of materials of botanical origin in the attenuation of both chronic and acute inflammatory responses to various disease stressors is described. The properties of preparations of plant-based origin often parallel those of synthesized pharmacologics, but differ from them in some key respects. These differences can lead to more traditional preparations having distinct therapeutic advantages but also a number of specific shortcomings. The strengths and weaknesses of these materials are objectively contrasted with that of a more orthodox pharmacological approach. Each of these emphases in style has specific advantages and they should not be considered as competitors, but rather as accomplices in combating adverse states involving derangement of immune function.


Subject(s)
COVID-19/drug therapy , Phytochemicals/therapeutic use , Plant Preparations/therapeutic use , SARS-CoV-2/drug effects , Cytokines/antagonists & inhibitors , Humans , Inflammation/drug therapy , NF-kappa B/antagonists & inhibitors , Nitric Oxide Synthase Type II/antagonists & inhibitors , Tumor Necrosis Factor-alpha/antagonists & inhibitors
19.
Front Immunol ; 11: 1844, 2020.
Article in English | MEDLINE | ID: covidwho-742725

ABSTRACT

With the onset of the global pandemic in 2020 of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), there has been increasing research activity around certain disease-modifying drugs that are used for the management of inflammatory disorders such as rheumatoid arthritis, spondyloarthrosis, psoriatic arthritis, systemic lupus erythematosus, and inflammatory bowel disease for managing coronavirus symptoms. In the conditions mentioned, many people are on long-term treatment with agents including hydroxychloroquine, tumor necrosis factor alpha (TNFα) inhibitor drugs, other biologic agents such as monoclonal antibodies to IL-6 and Janus kinase inhibitors including baricitinib and tofacitinib, which are used to control inflammatory responses in their respective auto-immune condition. There is emerging data that immunomodulatory drugs could be protective at reducing certain features of SARS-CoV-2 and improving recovery. In addition, it is important to understand if subjects being treated with the immunomodulatory agents described have a less severe SARS-CoV-2 infection, as they are deemed some protection from their immunomodulatory treatment, or if they develop infections similar to non-immunocompromised patients. There is a huge unmet clinical need to advise patients responsibly about whether they should remain on their immunomodulatory treatment or not in light of Covid-19 infection. In this article we will discuss potential treatment options for SARS-CoV-2 using immunomodulatory drugs and at what stage of the condition they may be beneficial. Viable treatment options during the global coronavirus pandemic are a much-needed and an intensely active area of research.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Immunomodulation/drug effects , Pneumonia, Viral/drug therapy , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19 , Colchicine/therapeutic use , Cytokine Release Syndrome/drug therapy , Cytokines/blood , Female , Humans , Hydroxychloroquine/therapeutic use , Janus Kinase Inhibitors/therapeutic use , Middle Aged , Pandemics , Risk Factors , SARS-CoV-2 , Tumor Necrosis Factor-alpha/antagonists & inhibitors
20.
Expert Opin Biol Ther ; 21(2): 219-228, 2021 02.
Article in English | MEDLINE | ID: covidwho-735642

ABSTRACT

INTRODUCTION: SARS-CoV-2 is a novel coronavirus that was first isolated from a group of patients hospitalized with pneumonia in China at the end of 2019, and, in February 2020, the syndrome it caused was named coronavirus disease 2019 (COVID-19) by the World Health Organization. In the absence of specific antiviral treatments capable of neutralizing the etiological agent, one therapeutic approach is to control the cytokine storm responsible for the most severe forms of the disease. The characteristic cytokine profile of severely affected patients is increased levels of interleukin (IL)-1ß, IL-2, IL-6, IL-7, IL-8, and tumor necrosis factor alpha (TNF-α). AREAS COVERED: This article discusses the pathogenesis of COVID-19 as a rationale for using the biological and targeted synthetic drugs used in rheumatology (anti-TNF, anti-IL-1 and anti-IL-6 agents and baricitinib) to treat the disease, and provides key information concerning their potential benefits and adverse effects. EXPERT OPINION: Interleukin inhibition seems to be a promising means of treating COVID-19 patients when respiratory function declines (or even earlier) if there are laboratory data indicating the presence of a cytokine storm because the interleukins are key drivers of inflammation. However, it is important to consider the risks and benefits of biological agents carefully, and critically analyze the evidence concerning their use in COVID-19 patients.


Subject(s)
Antirheumatic Agents/therapeutic use , COVID-19/drug therapy , Cytokines/antagonists & inhibitors , Rheumatology/methods , SARS-CoV-2/drug effects , Antirheumatic Agents/pharmacology , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Azetidines/pharmacology , Azetidines/therapeutic use , COVID-19/epidemiology , COVID-19/metabolism , China/epidemiology , Clinical Trials as Topic/methods , Cytokines/metabolism , Humans , Immunosuppressive Agents/pharmacology , Immunosuppressive Agents/therapeutic use , Purines/pharmacology , Purines/therapeutic use , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , SARS-CoV-2/metabolism , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Treatment Outcome , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/metabolism
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