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Published in: Arthritis Research & Therapy 1/2021

Open Access 01-12-2021 | Coronavirus | Research article

Does methotrexate influence COVID-19 infection? Case series and mechanistic data

Authors: Fabian Schälter, Kerstin Dürholz, Laura Bucci, Gerd Burmester, Roberto Caporali, Camille Figuereido, Jaime Fogagnolo Cobra, Bernhard Manger, Mario M. Zaiss, Georg Schett

Published in: Arthritis Research & Therapy | Issue 1/2021

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Abstract

Background

To investigate whether methotrexate treatment may affect the susceptibility to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Methods

Clinical assessment of symptoms, SARS-CoV-2 RNA, and anti-SARS-CoV-2 IgG in an initial case series of four families and confirmatory case series of seven families, within which one family member developed coronavirus disease 19 (COVID-19) and exposed another family member receiving methotrexate treatment; experimental part with methotrexate treatment of mice and organoids followed by the assessment of mRNA and protein expression of the SARS-CoV-2 receptor angiotensin-converting enzyme (ACE)-2.

Results

In the initial case series, three of four women on a joint ski trip developed COVID-19, while the fourth woman, under treatment with methotrexate, remained virus-free. Two of the three diseased women infected their husbands, while the third husband treated with methotrexate remained virus-free. In addition, 7 other families were identified in a follow-up case series, in which one member developed COVID-19, while the other, receiving methotrexate, remained healthy. Experimentally, when mice were treated with methotrexate, ACE2 expression significantly decreased in the lung, in the intestinal epithelium, and in intestinal organoids.

Conclusion

These clinical and experimental data indicate that methotrexate has certain protective effects on SARS-CoV-2 infection via downregulating ACE2.
Literature
1.
go back to reference Hoffmann M, Kleine-Weber H, Schroeder S, Krueger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181:271–80.CrossRef Hoffmann M, Kleine-Weber H, Schroeder S, Krueger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181:271–80.CrossRef
2.
go back to reference Huang C, Wang J, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497–506.CrossRef Huang C, Wang J, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497–506.CrossRef
3.
go back to reference Chen K, Bi J, Su Y, Chappell MC, Rose JC. Sex-specific changes in renal angiotensin-converting enzyme and angiotensin-converting enzyme 2 gene expression and enzyme activity at birth and over the first year of life. Reprod Sci. 2016;23:200–10.CrossRef Chen K, Bi J, Su Y, Chappell MC, Rose JC. Sex-specific changes in renal angiotensin-converting enzyme and angiotensin-converting enzyme 2 gene expression and enzyme activity at birth and over the first year of life. Reprod Sci. 2016;23:200–10.CrossRef
4.
go back to reference Bernardi S, Toffoli B, Zennaro C, Tikellis C, Monticone S, Losurdo P, et al. High-salt diet increases glomerular ACE/ACE2 ratio leading to oxidative stress and kidney damage. Nephrol Dial Transplant. 2012;27:1793–800.CrossRef Bernardi S, Toffoli B, Zennaro C, Tikellis C, Monticone S, Losurdo P, et al. High-salt diet increases glomerular ACE/ACE2 ratio leading to oxidative stress and kidney damage. Nephrol Dial Transplant. 2012;27:1793–800.CrossRef
5.
go back to reference Liu Y, Zhao L, Zhang Q, Zhang L, Ren G. Effect of long-term smoking on expression of serum ACE and ACE2 as well as its significance. J Taishan Med Coll. 2019;40:258–60. Liu Y, Zhao L, Zhang Q, Zhang L, Ren G. Effect of long-term smoking on expression of serum ACE and ACE2 as well as its significance. J Taishan Med Coll. 2019;40:258–60.
7.
go back to reference Simon D, Tascilar K, Kroenke G, Kleyer A, Zaiss MM, Heppt F, et al. Patients with immune-mediated inflammatory diseases receiving cytokine inhibitors have low prevalence of SARS-CoV-2 seroconversion. Nat Commun. 2020;11:3774.CrossRef Simon D, Tascilar K, Kroenke G, Kleyer A, Zaiss MM, Heppt F, et al. Patients with immune-mediated inflammatory diseases receiving cytokine inhibitors have low prevalence of SARS-CoV-2 seroconversion. Nat Commun. 2020;11:3774.CrossRef
8.
go back to reference Tajik N, Frech M, Schulz O, Schälter F, Lucas S, Azizov V, et al. Targeting zonulin and intestinal epithelial tight barrier function to prevent onset of arthritis. Nat Commun. 2020;11:1995.CrossRef Tajik N, Frech M, Schulz O, Schälter F, Lucas S, Azizov V, et al. Targeting zonulin and intestinal epithelial tight barrier function to prevent onset of arthritis. Nat Commun. 2020;11:1995.CrossRef
9.
go back to reference Leeb B, et al. Methotrexate serum-level determinations during low-dose therapy of rheumatoid and psoriatic arthritis. Int J Clin Pharmacol Res. 1989;9:209–15.PubMed Leeb B, et al. Methotrexate serum-level determinations during low-dose therapy of rheumatoid and psoriatic arthritis. Int J Clin Pharmacol Res. 1989;9:209–15.PubMed
10.
go back to reference Weinblatt ME. Methotrexate: who would have predicted its importance in rheumatoid arthritis? Arthritis Res Ther. 2018;20:103.CrossRef Weinblatt ME. Methotrexate: who would have predicted its importance in rheumatoid arthritis? Arthritis Res Ther. 2018;20:103.CrossRef
11.
go back to reference Cronstein BN, Aune TM. Methotrexate and its mechanisms of action in inflammatory arthritis. Nat Rev Rheumatol. 2020;16:145–54.CrossRef Cronstein BN, Aune TM. Methotrexate and its mechanisms of action in inflammatory arthritis. Nat Rev Rheumatol. 2020;16:145–54.CrossRef
12.
go back to reference Kremer J. Towards a better understanding of methotrexate. Arthritis Rheumatol. 2004;50:1370–82.CrossRef Kremer J. Towards a better understanding of methotrexate. Arthritis Rheumatol. 2004;50:1370–82.CrossRef
13.
go back to reference Friebe D, Yang T, Schmidt T, Borg N, Steckel B, Ding Z, Schrader J. Purinergic signaling on leukocytes infiltrating the LPS-injured lung. PLoS One. 2014;9:e95382.CrossRef Friebe D, Yang T, Schmidt T, Borg N, Steckel B, Ding Z, Schrader J. Purinergic signaling on leukocytes infiltrating the LPS-injured lung. PLoS One. 2014;9:e95382.CrossRef
14.
go back to reference Ali RA, Gandhi AA, Meng H, Yalavarthi S, Vreede AP, Estes SK, et al. Adenosine receptor agonism protects against NETosis and thrombosis in antiphospholipid syndrome. Nat Commun. 2019;10:1916.CrossRef Ali RA, Gandhi AA, Meng H, Yalavarthi S, Vreede AP, Estes SK, et al. Adenosine receptor agonism protects against NETosis and thrombosis in antiphospholipid syndrome. Nat Commun. 2019;10:1916.CrossRef
15.
go back to reference Leppkes M, Knopf J, Naschberger E, Lindemann A, Singh J, Herrmann I, et al. Vascular occlusion y neutrophil extracellular taps in COVID-19. EBioMedicine. 2020;58:102925. Leppkes M, Knopf J, Naschberger E, Lindemann A, Singh J, Herrmann I, et al. Vascular occlusion y neutrophil extracellular taps in COVID-19. EBioMedicine. 2020;58:102925.
16.
go back to reference Patel VB, Zhong JC, Grant MB, Oudit GY. Role of the ACE2/angiotensin 1-7 Axis of the renin-angiotensin system in heart failure. Circ Res. 2016;118:1313–26.CrossRef Patel VB, Zhong JC, Grant MB, Oudit GY. Role of the ACE2/angiotensin 1-7 Axis of the renin-angiotensin system in heart failure. Circ Res. 2016;118:1313–26.CrossRef
17.
go back to reference Haberman R, Axelrad J, Chen A, Castillo R, Yan D, Izmirly P, et al. Covid-19 in immune-mediated inflammatory diseases — case series from New York. N Engl J Med. 2020;58:102925. Haberman R, Axelrad J, Chen A, Castillo R, Yan D, Izmirly P, et al. Covid-19 in immune-mediated inflammatory diseases — case series from New York. N Engl J Med. 2020;58:102925.
18.
go back to reference Haberman RH, Castillo R, Chen A, Yan D, Ramirez D, Sekar V, et al. COVID-19 in patients with inflammatory arthritis: a prospective study on the effects of comorbidities and DMARDs on clinical outcomes. Arthritis Rheumatol. 2020. Haberman RH, Castillo R, Chen A, Yan D, Ramirez D, Sekar V, et al. COVID-19 in patients with inflammatory arthritis: a prospective study on the effects of comorbidities and DMARDs on clinical outcomes. Arthritis Rheumatol. 2020.
19.
go back to reference Gianfrancesco M, Hyrich K, Al-Adely S, Carmona L, Danila MI, Gossec L, et al. Characteristics associated with hospitalization for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry. Ann Rheum Dis. 2020. Gianfrancesco M, Hyrich K, Al-Adely S, Carmona L, Danila MI, Gossec L, et al. Characteristics associated with hospitalization for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry. Ann Rheum Dis. 2020.
20.
go back to reference Li W, Greenough TC, Moore MJ, Vasilieva N, Somasundaran M, Sullivan JL, et al. Efficient replication of severe acute respiratory syndrome coronavirus in mouse cells is limited by murine angiotensin converting enzyme 2. J Virol. 2004;78:11429–33.CrossRef Li W, Greenough TC, Moore MJ, Vasilieva N, Somasundaran M, Sullivan JL, et al. Efficient replication of severe acute respiratory syndrome coronavirus in mouse cells is limited by murine angiotensin converting enzyme 2. J Virol. 2004;78:11429–33.CrossRef
21.
go back to reference Schett G, Sticherling M, Neurath MF. COVID-19: risk for cytokine targeting in chronic inflammatory diseases? Nat Rev Immunol. 2020;20:271–2.CrossRef Schett G, Sticherling M, Neurath MF. COVID-19: risk for cytokine targeting in chronic inflammatory diseases? Nat Rev Immunol. 2020;20:271–2.CrossRef
Metadata
Title
Does methotrexate influence COVID-19 infection? Case series and mechanistic data
Authors
Fabian Schälter
Kerstin Dürholz
Laura Bucci
Gerd Burmester
Roberto Caporali
Camille Figuereido
Jaime Fogagnolo Cobra
Bernhard Manger
Mario M. Zaiss
Georg Schett
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 1/2021
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/s13075-021-02464-4

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