COVID-19, immune system response, hyperinflammation and repurposing antirheumatic drugs

AVANOĞLU GÜLER, Aslıhan; TUFAN, Abdurrahman; CERİNİC, Marco Matucci

doi:10.3906/sag-2004-168

COVID-19, immune system response, hyperinflammation and repurposing antirheumatic drugs

Abdurrahman TUFAN, (Gazi Üniversitesi)

Aslıhan AVANOĞLU GÜLER, (Gazi Üniversitesi)

Marco Matucci CERİNİC (University of Florence)

Turkish Journal of Medical Sciences

6 0

Yıl: 2020 Cilt: 50 Sayı: 3 Sayfa Aralığı: 620 - 632 Metin Dili: İngilizce DOI: 10.3906/sag-2004-168 İndeks Tarihi: 24-04-2020

COVID-19, immune system response, hyperinflammation and repurposing antirheumatic drugs

Öz:

In the Wuhan Province of China, in December 2019, the novel coronavirus 2019 (COVID-19) has caused a severe involvementof the lower respiratory tract leading to an acute respiratory syndrome. Subsequently, coronavirus 2 (SARS-CoV-2) provoked apandemic which is considered a life-threatening disease. The SARS-CoV-2, a family member of betacoronaviruses, possesses singlestrandedpositive-sense RNA with typical structural proteins, involving the envelope, membrane, nucleocapsid and spike proteinsthat are responsible for the viral infectivity, and nonstructural proteins. The effectual host immune response including innate andadaptive immunity against SARS-Cov-2 seems crucial to control and resolve the viral infection. However, the severity and outcomeof the COVID-19 might be associated with the excessive production of proinflammatory cytokines “cytokine storm” leading to anacute respiratory distress syndrome. Regretfully, the exact pathophysiology and treatment, especially for the severe COVID-19, isstill uncertain. The results of preliminary studies have shown that immune-modulatory or immune-suppressive treatments such ashydroxychloroquine, interleukin (IL)-6 and IL-1 antagonists, commonly used in rheumatology, might be considered as treatmentchoices for COVID-19, particularly in severe disease. In this review, to gain better information about appropriate anti-inflammatorytreatments, mostly used in rheumatology for COVID-19, we have focused the attention on the structural features of SARS-CoV-2, thehost immune response against SARS-CoV-2 and its association with the cytokine storm.

Anahtar Kelime:

Konular: Cerrahi

Belge Türü: Makale Makale Türü: Derleme Erişim Türü: Erişime Açık

1. Rothan HA, Byrareddy SN. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. Journal of autoimmunity 2020:102433. doi: 10.1016/j.jaut.2020.102433
2. Zhou P, Yang X-L, Wang X-G, Hu B, Zhang L et al. Discovery of a novel coronavirus associated with the recent pneumonia outbreak in humans and its potential bat origin. BioRxiv 2020: 2020.2001.2022.914952. doi: 10.1101/2020.01.22.914952
3. Xu Z, Shi L, Wang Y, Zhang J, Huang L et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. The Lancet Respiratory Medicine 2020. doi: 10.1016/s2213-2600(20)30076-x
4. Wang D, Hu B, Hu C, Zhu F, Liu X et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirusinfected pneumonia in Wuhan, China. Jama 2020. doi: 10.1001/jama.2020.1585
5. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ et al. Clinical characteristics of coronavirus disease 2019 in China. The New England Journal of Medicine. 2020. doi: 10.1056/ NEJMoa2002032
6. Wan S, Yi Q, Fan S, Lv J, Zhang X et al. Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP). MedRxiv 2020. doi: 10.1101/2020.02.10.20021832
7. Yang Y, Shen C, Li J, Yuan J, Yang M et al. Exuberant elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 infection is associated with disease severity and fatal outcome. MedRxiv 2020. doi: 10.1101/2020.03.02.20029975
8. Woo PC, Huang Y, Lau SK, Yuen KY. Coronavirus genomics and bioinformatics analysis. Viruses 2010; 2 (8): 1804-1820. doi: 10.3390/v2081803
9. Forni D, Cagliani R, Clerici M, Sironi M. Molecular Evolution of Human Coronavirus Genomes. Trends in Microbiology 2017; 25 (1): 35-48. doi: 10.1016/j.tim.2016.09.001
10. Ashour HM, Elkhatib WF, Rahman MM, Elshabrawy HA. Insights into the recent 2019 novel coronavirus (SARS-CoV-2) in light of past human coronavirus outbreaks. Pathogens (Basel, Switzerland) 2020; 9 (3). doi: 0.3390/pathogens9030186
11. Tang X, Wu C, Li X, Song Y, Yao X et al. On the origin and continuing evolution of SARS-CoV-2. National Science Review 2020. doi: 10.1093/nsr/nwaa036
12. Ziebuhr J, Snijder EJ, Gorbalenya AE. Virus-encoded proteinases and proteolytic processing in the Nidovirales. The Journal of General Virology. 2000; 81 (Pt 4): 853-879. doi: 10.1099/0022-1317-81-4-853
13. Baez-Santos YM, St John SE, Mesecar AD. The SARScoronavirus papain-like protease: structure, function and inhibition by designed antiviral compounds. Antiviral Research 2015; 115: 21-38. doi: 10.1016/j.antiviral.2014.12.015
14. Masters PS. The molecular biology of coronaviruses. Advances in Virus Research 2006; 66: 193-292. doi: 10.1016/s0065- 3527(06)66005-3
15. Hussain S, Pan J, Chen Y, Yang Y, Xu J et al. Identification of novel subgenomic RNAs and noncanonical transcription initiation signals of severe acute respiratory syndrome coronavirus. Journal of Virology 2005; 79 (9): 5288-5295. doi: 10.1128/jvi.79.9.5288-5295.2005
16. Chang C-k, Sue S-C, Yu T-h, Hsieh C-M, Tsai C-K et al. Modular organization of SARS coronavirus nucleocapsid protein. Journal of Biomedical Science 2006; 13 (1): 59-72.
17. Hurst KR, Koetzner CA, Masters PS. Identification of in vivointeracting domains of the murine coronavirus nucleocapsid protein. Journal of Virology 2009; 83 (14): 7221-7234.
18. Lu X, Pan J, Tao J, Guo D. SARS-CoV nucleocapsid protein antagonizes IFN-beta response by targeting initial step of IFNbeta induction pathway, and its C-terminal region is critical for the antagonism. Virus Genes 2011; 42 (1): 37-45. doi: 10.1007/ s11262-010-0544-x
19. Ujike M, Taguchi F. Incorporation of spike and membrane glycoproteins into coronavirus virions. Viruses 2015; 7 (4): 1700-1725. doi: 10.3390/v7041700
20. Neuman BW, Kiss G, Kunding AH, Bhella D, Baksh MF et al. A structural analysis of M protein in coronavirus assembly and morphology. Journal of Structural Biology 2011; 174 (1): 11- 22. doi: 10.1016/j.jsb.2010.11.021
21. Schoeman D, Fielding BC. Coronavirus envelope protein: current knowledge. Virology Journal 2019; 16 (1): 69. doi: 10.1186/s12985-019-1182-0
22. Nieto-Torres JL, DeDiego ML, Verdiá-Báguena C, Jimenez- Guardeño JM, Regla-Nava JA et al. Severe acute respiratory syndrome coronavirus envelope protein ion channel activity promotes virus fitness and pathogenesis. PLoS Pathogens 2014; 10 (5): e1004077. doi: 10.1371/journal.ppat.1004077
23. Kumar S, Maurya VK, Prasad AK, Bhatt MLB, Saxena SK. Structural, glycosylation and antigenic variation between 2019 novel coronavirus (2019-nCoV) and SARS coronavirus (SARS-CoV). VirusDisease 2020; 31 (1): 13-21. doi: 10.1007/ s13337-020-00571-5
24. Morse JS, Lalonde T, Xu S, Liu WR. Learning from the past: possible urgent prevention and treatment options for severe acute respiratory infections caused by 2019-nCoV. ChemBioChem: a European Journal of Chemical Biology 2020; 21 (5): 730-738. doi: 10.1002/cbic.202000047
25. Xia S, Zhu Y, Liu M, Lan Q, Xu W et al. Fusion mechanism of 2019-nCoV and fusion inhibitors targeting HR1 domain in spike protein. Cellular & Molecular Immunology 2020. doi: 10.1038/s41423-020-0374-2
26. Bosch BJ, de Haan CA, Smits SL, Rottier PJ. Spike protein assembly into the coronavirion: exploring the limits of its sequence requirements. Virology 2005; 334 (2): 306-318.
27. Dong N, Yang X, Ye L, Chen K, Chan EW-C et al. Genomic and protein structure modelling analysis depicts the origin and infectivity of 2019-nCoV, a new coronavirus which caused a pneumonia outbreak in Wuhan, China. BioRxiv 2020. doi: 10.1101/2020.01.20.913368
28. Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh C-L et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 2020; 367 (6483): 1260-1263. doi: 10.1126/science.abb2507
29. Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020. doi: 10.1016/j.cell.2020.02.052
30. Ou X, Liu Y, Lei X, Li P, Mi D et al. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nature Communications 2020; 11 (1): 1620. doi: 10.1038/s41467-020-15562-9
31. Ivashkiv LB, Donlin LT. Regulation of type I interferon responses. Nature Reviews Immunology 2014; 14 (1): 36-49. doi: 10.1038/nri3581
32. Li G, Fan Y, Lai Y, Han T, Li Z et al. Coronavirus infections and immune responses. Journal of Medical Virology 2020; 92 (4): 424-432.
33. George MR. Hemophagocytic lymphohistiocytosis: review of etiologies and management. Journal of Blood Medicine 2014; 5: 69-86. doi: 10.2147/jbm.s46255
34. Ramos-Casals M, Brito-Zeron P, Lopez-Guillermo A, Khamashta MA, Bosch X. Adult haemophagocytic syndrome. Lancet (London, England) 2014; 383 (9927): 1503-1516. doi: 10.1016/s0140-6736(13)61048-x
35. McGonagle D, Sharif K, O’Regan A, Bridgewood C. Interleukin-6 use in COVID-19 pneumonia related macrophage activation syndrome. Autoimmunity Reviews 2020: 102537. doi: 10.1016/j.autrev.2020.102537
36. Huang C, Wang Y, Li X, Ren L, Zhao J et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet (London, England) 2020; 395 (10223): 497-506. doi: 10.1016/s0140-6736(20)30183-5
37. Qin C, Zhou L, Hu Z, Zhang S, Yang S et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clinical Infectious Diseases:an official publication of the Infectious Diseases Society of America 2020. doi: 10.1093/ cid/ciaa248
38. Chen L, Liu HG, Liu W, Liu J, Liu K et al. [Analysis of clinical features of 29 patients with 2019 novel coronavirus pneumonia]. Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese Journal of Tuberculosis and Respiratory Diseases 2020; 43 (3): 203-208 (in Chinese). doi: 10.3760/cma.j.issn.1001-0939.2020.03.013
39. Wang F, Nie J, Wang H, Zhao Q, Xiong Y et al. Characteristics of peripheral lymphocyte subset alteration in COVID-19 pneumonia. The Journal of Infectious Diseases 2020. doi: 10.1093/infdis/jiaa150
40. Crayne CB, Albeituni S, Nichols KE, Cron RQ. The immunology of macrophage activation syndrome. Frontiers in Immunology 2019; 10: 119. doi: 10.3389/fimmu.2019.00119
41. Wang W, He J, Lie p, Huang l, Wu S et al. The definition and risks of cytokine release syndrome-like in 11 COVID- 19-infected pneumonia critically ill patients: disease characteristics and retrospective analysis. MedRxiv 2020. doi: 10.1101/2020.02.26.20026989
42. Zinkernagel RM. Immunology taught by viruses. Science 1996; 271 (5246): 173-178. doi: 10.1126/science.271.5246.173
43. Li T, Qiu Z, Zhang L, Han Y, He W et al. Significant changes of peripheral T lymphocyte subsets in patients with severe acute respiratory syndrome. The Journal of Infectious Diseases 2004; 189 (4): 648-651. doi: 10.1086/381535
44. Cecere TE, Todd SM, Leroith T. Regulatory T cells in arterivirus and coronavirus infections: do they protect against disease or enhance it? Viruses 2012; 4 (5): 833-846. doi: 10.3390/ v4050833
45. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell 2008; 133 (5): 775-787. doi: 10.1016/j.cell.2008.05.009
46. Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3+ regulatory T cells in the human immune system. Nature Reviews Immunology 2010; 10 (7): 490-500. doi: 10.1038/ nri2785
47. Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 1999; 401 (6754): 708-712. doi: 10.1038/44385
48. Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet 2020; 395 (10223): 473-475. doi: 10.1016/s0140- 6736(20)30317-2
49. Arabi YM, Fowler R, Hayden FG. Critical care management of adults with community-acquired severe respiratory viral infection. Intensive Care Medicine 2020; 46 (2): 315-328. doi: 10.1007/s00134-020-05943-5
50. Peiris JS, Chu CM, Cheng VC, Chan KS, Hung IF et al. Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study. Lancet (London, England) 2003; 361 (9371): 1767-1772. doi: 10.1016/s0140-6736(03)13412-5
51. Zha L, Li S, Pan L, Tefsen B, Li Y et al. Corticosteroid treatment of patients with coronavirus disease 2019 (COVID-19). The Medical Journal of Australia 2020. doi: 10.5694/mja2.50577
52. Zhou W, Liu Y, Tian D, Wang C, Wang S et al. Potential benefits of precise corticosteroids therapy for severe 2019-nCoV pneumonia. Signal Transduction and Targeted Therapy 2020; 5: 18. doi: 10.1038/s41392-020-0127-9
53. Lu X, Chen T, Wang Y, Wang J, Zhang B et al. Adjuvant corticosteroid therapy for critically ill patients with COVID-19. MedRxiv 2020. doi: 10.1101/2020.04.07.20056390
54. Xu K, Chen Y, Yuan J, Yi P, Ding C et al. Factors associated with prolonged viral RNA shedding in patients with COVID-19. Clinical Infectious Diseases: an official publication of the Infectious Diseases Society of America 2020. doi: 10.1093/cid/ ciaa351
55. Al-Bari MA. Chloroquine analogues in drug discovery: new directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases. The Journal of Antimicrobial Chemotherapy 2015; 70 (6): 1608- 1621. doi: 10.1093/jac/dkv018
56. Costedoat-Chalumeau N, Hulot JS, Amoura Z, Leroux G, Lechat P et al. Heart conduction disorders related to antimalarials toxicity: an analysis of electrocardiograms in 85 patients treated with hydroxychloroquine for connective tissue diseases. Rheumatology (Oxford, England) 2007; 46 (5): 808- 810. doi: 10.1093/rheumatology/kel402
57. Varan O, Kucuk H, Tufan A. Myasthenia gravis due to hydroxychloroquine. Reumatismo 2015; 67 (3): 849. doi: 10.4081/reumatismo.2015.849
58. Tonnesmann E, Kandolf R, Lewalter T. Chloroquine cardiomyopathy - a review of the literature. Immunopharmacology and Immunotoxicology 2013; 35 (3): 434-442. doi: 10.3109/08923973.2013.780078
59. Chhonker YS, Sleightholm RL, Li J, Oupicky D, Murry DJ. Simultaneous quantitation of hydroxychloroquine and its metabolites in mouse blood and tissues using LC-ESI-MS/ MS: an application for pharmacokinetic studies. Journal of Chromatography B, Analytical Technologies in the Biomedical and Life Sciences. 2018; 1072: 320-327. doi: 10.1016/j. jchromb.2017.11.026
60. D’Alessandro S, Scaccabarozzi D, Signorini L, Perego F, Ilboudo DP et al. The use of antimalarial drugs against viral infection. Microorganisms 2020; 8 (1). doi: 10.3390/ microorganisms8010085
61. Vincent MJ, Bergeron E, Benjannet S, Erickson BR, Rollin PE et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virology Journal 2005; 2: 69. doi: 10.1186/1743-422x-2-69
62. Wang H, Jiang C. Influenza A virus H5N1 entry into host cells is through clathrin-dependent endocytosis. Science in China Series C, Life Sciences 2009; 52 (5): 464-469. doi: 10.1007/ s11427-009-0061-0
63. Yang ZY, Huang Y, Ganesh L, Leung K, Kong WP et al. pH-dependent entry of severe acute respiratory syndrome coronavirus is mediated by the spike glycoprotein and enhanced by dendritic cell transfer through DC-SIGN. Journal of Virology 2004; 78 (11): 5642-5650. doi: 10.1128/ jvi.78.11.5642-5650.2004
64. Symington BE. Fibronectin receptor modulates cyclindependent kinase activity. The Journal of Biological Chemistry 1992; 267 (36): 25744-25747.
65. Schrezenmeier E, Dorner T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nature Reviews Rheumatology 2020; 16 (3): 155-166. doi: 10.1038/s41584-020-0372-x
66. Aruoma OI, Halliwell B. The iron-binding and hydroxyl radical scavenging action of anti-inflammatory drugs. Xenobiotica 1988; 18 (4): 459-470. doi: 10.3109/00498258809041682
67. Wang M, Cao R, Zhang L, Yang X, Liu J et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research 2020; 30 (3): 269-271. doi: 10.1038/s41422-020-0282-0
68. Yao X, Ye F, Zhang M, Cui C, Huang B et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe aAcute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clinical Infectious Diseases: an official publication of the Infectious Diseases Society of America 2020. doi: 10.1093/cid/ciaa237
69. Gao J, Tian Z, Yang X. Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Bioscience Trends 2020; 14 (1): 72-73. doi: 10.5582/bst.2020.01047
70. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. International Journal of Antimicrobial Agents 2020: 105949. doi: 10.1016/j.ijantimicag.2020.105949
71. Tang W, Cao Z, Han M, Wang Z, Chen J et al. Hydroxychloroquine in patients with COVID-19: an open-label, randomized, controlled trial. MedRxiv 2020. doi:10.1101/2020.04.10.20060558
72. Mahevas M, Tran V-T, Roumier M, Chabrol A, Paule R et al. No evidence of clinical efficacy of hydroxychloroquine in patients hospitalized for COVID-19 infection with oxygen requirement: results of a study using routinely collected data to emulate a target trial. MedRxiv 2020. doi: 10.1101/2020.04.10.20060699
73. Tan YW, Yam WK, Sun J, Chu JJH. An evaluation of Chloroquine as a broad-acting antiviral against hand, foot and mouth disease. Antiviral Research 2018; 149: 143-149. doi: 10.1016/j.antiviral.2017.11.017
74. Arumugham VB, Rayi A. Intravenous Immunoglobulin (IVIG). StatPearls. Treasure Island (FL): StatPearls PublishingStatPearls Publishing LLC.; 2020.
75. Ferro F, Elefante E, Baldini C, Bartoloni E, Puxeddu I et al. COVID-19: the new challenge for rheumatologists. Clinical and Experimental Rheumatology 2020; 38 (2): 175-180.
76. Cao W, Liu X, Bai T, Fan H, Hong K et al. High-dose intravenous immunoglobulin as a therapeutic option for deteriorating patients with coronavirus disease 2019. Open Forum Infectious Diseases. 2020; 7 (3): ofaa102. doi: 10.1093/ ofid/ofaa102
77. Uciechowski P, Dempke WCM. Interleukin-6: A masterplayer in the cytokine network. Oncology 2020; 98 (3): 131-137. doi: 10.1159/000505099
78. FDA (2010). Actemra® (tocilizumab) injection, for intravenous or subcutaneous use: highlights of prescribing information [online]. Website https://www.accessdata.fda.gov/drugsatfda_ docs/label/2017/125276s114lbl.pdf [accessed 16 April 2020].
79. Liao Y, Wang X, Huang M, Tam JP, Liu DX. Regulation of the p38 mitogen-activated protein kinase and dual-specificity phosphatase 1 feedback loop modulates the induction of interleukin 6 and 8 in cells infected with coronavirus infectious bronchitis virus. Virology 2011; 420 (2): 106-116. doi: 10.1016/j.virol.2011.09.003
80. Zhou Y, Fu B, Zheng X, Wang D, Zhao C et al. Aberrant pathogenic GM-CSF+ T cells and inflammatory CD14+ CD16+ monocytes in severe pulmonary syndrome patients of a new coronavirus. BioRxiv 2020.
81. Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Seminars in Immunopathology 2017; 39 (5): 529-539. doi: 10.1007/s00281-017-0629-x
82. Mihai C, Dobrota R, Schroder M, Garaiman A, Jordan S et al. COVID-19 in a patient with systemic sclerosis treated with tocilizumab for SSc-ILD. Annals of the Rheumatic Diseases 2020. doi: 10.1136/annrheumdis-2020-217442
83. A TV, Haikarainen T, Raivola J, Silvennoinen O. Selective JAKinibs: prospects in inflammatory and autoimmune diseases. BioDrugs 2019; 33 (1): 15-32. doi: 10.1007/s40259- 019-00333-w
84. Fragoulis GE, McInnes IB, Siebert S. JAK-inhibitors. New players in the field of immune-mediated diseases, beyond rheumatoid arthritis. Rheumatology (Oxford, England) 2019; 58 (Suppl 1): i43-i54. doi: 10.1093/rheumatology/key276
85. Richardson P, Griffin I, Tucker C, Smith D, Oechsle O et al. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet (London, England) 2020; 395 (10223): e30-e31. doi: 10.1016/s0140-6736(20)30304-4
86. Chen IY, Moriyama M, Chang MF, Ichinohe T. Severe acute respiratory syndrome coronavirus viroporin 3a activates the NLRP3 inflammasome. Frontiers in Microbiology 2019; 10: 50. doi: 10.3389/fmicb.2019.00050
87. Nieto-Torres JL, Verdia-Baguena C, Jimenez-Guardeno JM, Regla-Nava JA, Castano-Rodriguez C et al. Severe acute respiratory syndrome coronavirus E protein transports calcium ions and activates the NLRP3 inflammasome. Virology 2015; 485: 330-339. doi: 10.1016/j.virol.2015.08.010
88. Conti P, Gallenga CE, Tete G, Caraffa A, Ronconi G et al. How to reduce the likelihood of coronavirus-19 (CoV-19 or SARSCoV- 2) infection and lung inflammation mediated by IL-1. Journal of Biological Regulators and Homeostatic Agents 2020; 34 (2). doi: 10.23812/Editorial-Conti-2
89. FDA (2001). Kineret® (anakinra) for injection, for subcutaneous use: highlights of prescribıng information [online]. Website https://www.accessdata.fda.gov/drugsatfda_ docs/label/2012/103950s5136lbl.pdf [accessed 10 April 2020].
90. Opal SM, Fisher CJ, Jr., Dhainaut JF, Vincent JL, Brase R et al. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebocontrolled, multicenter trial. Critical Care Medicine 1997; 25 (7): 1115-1124. doi: 10.1097/00003246-199707000-00010
91. Shakoory B, Carcillo JA, Chatham WW, Amdur RL, Zhao H et al. Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation ayndrome: reanalysis of a prior phase III trial. Critical Care Medicine 2016; 44 (2): 275-281. doi: 10.1097/ ccm.0000000000001402
92. Tardif JC, Kouz S, Waters DD, Bertrand OF, Diaz R et al. Efficacy and safety of low-dose colchicine after myocardial infarction. The New England Journal of Medicine 2019; 381 (26): 2497-2505. doi: 10.1056/NEJMoa1912388
93. Deftereos SG, Siasos G, Giannopoulos G, Vrachatis DA, Angelidis C et al. The GReek study in the Effects of Colchicine in COvid-19 complications prevention (GRECCO-19 study): rationale and study design. Hellenic Journal of Cardiology 2020. doi: 10.1016/j.hjc.2020.03.002
94. Haga S, Yamamoto N, Nakai-Murakami C, Osawa Y, Tokunaga K et al. Modulation of TNF-alpha-converting enzyme by the spike protein of SARS-CoV and ACE2 induces TNF-alpha production and facilitates viral entry. Proceedings of the National Academy of Sciences of the United States of America 2008; 105 (22): 7809-7814. doi: 10.1073/pnas.0711241105
95. Feldmann M, Maini RN, Woody JN, Holgate ST, Winter G et al. Trials of anti-tumour necrosis factor therapy for COVID-19 are urgently needed. The Lancet 2020. doi: 10.1016/S0140- 6736(20)30858-8
96. Wu D, Yang XO. TH17 responses in cytokine storm of COVID-19: An emerging target of JAK2 inhibitor Fedratinib. Journal of Microbiology, Immunology, and Infection 2020. doi: 10.1016/j.jmii.2020.03.005
97. Crotti C, Biggioggero M, Becciolini A, Agape E, Favalli EG. Mavrilimumab: a unique insight and update on the current status in the treatment of rheumatoid arthritis. Expert Opinion on Investigational Drugs 2019; 28 (7): 573-581. doi: 10.1080/13543784.2019.1631795
98. Russell B, Moss C, George G, Santaolalla A, Cope A et al. Associations between immune-suppressive and stimulating drugs and novel COVID-19–a systematic review of current evidence. Ecancermedicalscience 2020; 14: 1022. doi: 10.3332/ ecancer.2020.1022
99. Al Ghamdi M, Alghamdi KM, Ghandoora Y, Alzahrani A, Salah F et al. Treatment outcomes for patients with Middle Eastern respiratory syndrome coronavirus (MERS CoV) infection at a coronavirus referral center in the Kingdom of Saudi Arabia. BMC Infectious Diseases 2016; 16: 174. doi: 10.1186/s12879- 016-1492-4
100. Sodhi M, Etminan M. Safety of Ibuprofen in Patients with COVID-19: causal or confounded? Chest 2020. doi: 10.1016/j. chest.2020.03.040
101. Amici C, Di Caro A, Ciucci A, Chiappa L, Castilletti C et al. Indomethacin has a potent antiviral activity against SARS coronavirus. Antiviral Therapy 2006; 11 (8): 1021-1030.

APA	TUFAN A, AVANOĞLU GÜLER A, CERİNİC M (2020). COVID-19, immune system response, hyperinflammation and repurposing antirheumatic drugs. , 620 - 632. 10.3906/sag-2004-168
Chicago	TUFAN Abdurrahman,AVANOĞLU GÜLER Aslıhan,CERİNİC Marco Matucci COVID-19, immune system response, hyperinflammation and repurposing antirheumatic drugs. (2020): 620 - 632. 10.3906/sag-2004-168
MLA	TUFAN Abdurrahman,AVANOĞLU GÜLER Aslıhan,CERİNİC Marco Matucci COVID-19, immune system response, hyperinflammation and repurposing antirheumatic drugs. , 2020, ss.620 - 632. 10.3906/sag-2004-168
AMA	TUFAN A,AVANOĞLU GÜLER A,CERİNİC M COVID-19, immune system response, hyperinflammation and repurposing antirheumatic drugs. . 2020; 620 - 632. 10.3906/sag-2004-168
Vancouver	TUFAN A,AVANOĞLU GÜLER A,CERİNİC M COVID-19, immune system response, hyperinflammation and repurposing antirheumatic drugs. . 2020; 620 - 632. 10.3906/sag-2004-168
IEEE	TUFAN A,AVANOĞLU GÜLER A,CERİNİC M "COVID-19, immune system response, hyperinflammation and repurposing antirheumatic drugs." , ss.620 - 632, 2020. 10.3906/sag-2004-168
ISNAD	TUFAN, Abdurrahman vd. "COVID-19, immune system response, hyperinflammation and repurposing antirheumatic drugs". (2020), 620-632. https://doi.org/10.3906/sag-2004-168

APA	TUFAN A, AVANOĞLU GÜLER A, CERİNİC M (2020). COVID-19, immune system response, hyperinflammation and repurposing antirheumatic drugs. Turkish Journal of Medical Sciences, 50(3), 620 - 632. 10.3906/sag-2004-168
Chicago	TUFAN Abdurrahman,AVANOĞLU GÜLER Aslıhan,CERİNİC Marco Matucci COVID-19, immune system response, hyperinflammation and repurposing antirheumatic drugs. Turkish Journal of Medical Sciences 50, no.3 (2020): 620 - 632. 10.3906/sag-2004-168
MLA	TUFAN Abdurrahman,AVANOĞLU GÜLER Aslıhan,CERİNİC Marco Matucci COVID-19, immune system response, hyperinflammation and repurposing antirheumatic drugs. Turkish Journal of Medical Sciences, vol.50, no.3, 2020, ss.620 - 632. 10.3906/sag-2004-168
AMA	TUFAN A,AVANOĞLU GÜLER A,CERİNİC M COVID-19, immune system response, hyperinflammation and repurposing antirheumatic drugs. Turkish Journal of Medical Sciences. 2020; 50(3): 620 - 632. 10.3906/sag-2004-168
Vancouver	TUFAN A,AVANOĞLU GÜLER A,CERİNİC M COVID-19, immune system response, hyperinflammation and repurposing antirheumatic drugs. Turkish Journal of Medical Sciences. 2020; 50(3): 620 - 632. 10.3906/sag-2004-168
IEEE	TUFAN A,AVANOĞLU GÜLER A,CERİNİC M "COVID-19, immune system response, hyperinflammation and repurposing antirheumatic drugs." Turkish Journal of Medical Sciences, 50, ss.620 - 632, 2020. 10.3906/sag-2004-168
ISNAD	TUFAN, Abdurrahman vd. "COVID-19, immune system response, hyperinflammation and repurposing antirheumatic drugs". Turkish Journal of Medical Sciences 50/3 (2020), 620-632. https://doi.org/10.3906/sag-2004-168