//Background//---
The
main manifestation of SARS-CoV-2 is related to immunological symptom. The
inflammatory immune responses by interleukin-6, tumor necrosis factor α, other cytokine, which are called “cytokine
storm”, are emerged especially in the patient with the
risk factor such as aging, cancer, obesity, male, diabetes, renal dysfunction
and so on(2). Therefore, to provide effective therapy in unknown infective
disease, these immune responses need to be controlled by the (repurpose) drug
in addition to immediate reduction of viral road. Tofacitinib is one of the
chemotherapeutic options.
(Tofacitinib:
pharmacological effect)
Selective inhibitor: JAK1, 2, 3 ⇒ Blocking cellular trafficking via cytokine binding to receptor
Modulate interferon, IL-6 by type 1 and type
17 helper T cells(3-5)
Tofacitinib
may ameliorate the immune response related to inflammation-driven lung injury,
which is major manifestation of SARS-CoV-2, via multiple pathways.
Patrícia
O. Guimarães et al. investigates efficacy of Tofacitinib in the clinical trial (NCT04469114.)(1).
//Characteristics of the patient at
baseline(1)(See Table 1)//---
* Tofacitinib group(Placebo group)
N=144(145)
A total of 289 patients underwent randomization at 15 sites in
Brazil.
Mean age: 55(57)
(Median time to randomization)
-from symptom onset 10 days(9)
-from COVID-19 diagnosis 5
days(4)
⇒After viral road is sufficiently decreased??(10 days from symptom
onset(7:See Fig.3))
(Score on NIAID ordinal scale)
4: 34 persons-23.6%(37-25.5%)
hospitalize
5: 91 persons-63.2%(90-62.1%)
supplemental oxygen
6: 19 persons-13.2%(18-12.4%)
high-flow supplemental oxygen
⇒most patients are moderate-severe symptoms at baseline.
One of participant criteria
is to have evidence of SARS-CoV-2 pneumonia on radiographic imaging
(The other treatments)
Glucocorticoid: 114
persons-79.2%(113-77.9%)
Prophylactic anticoagulation:
113 persons-78.5%(112-77.2%)
//Administration condition(1)//---
Oral tofacitinib at a dose of
10mg twice daily to 14 days or until hospital discharge
//Tofacitinib for placebo:
Efficacy outcome(1)(See Table 2)//---
Death or respiratory failure through day 28:
0.63(0.41-0.97:95% CI)
(*)Dexamethasone / Death at day 28:
0.83(0.75-0.93:95% CI)(6)
⇒Tofacitinib may be superior to Dexamethasone in some clinical
conditions.
(Longitudinal observation of NIAID ordinal
scale)
*Tofacitinib
group(Placebo) at day 14-28
1:
110-129(96-119) /no-hospitalization with no limitation on activity
2:
11-5(15-10) /not hospitalization with limitation on activity
3:
1-0(2-1) /hospitalization with no ongoing medical care
4:
5-0(6-2) /ongoing medical care
5: 7-4(6-1) /supplemental
oxygen
6: 1-1(6-0) /high-flow
supplemental oxygen
7:
7-1(9-4) /ECMO
8:
2-4(5-8) /Death
3-8
at 28 days /10 persons (16 persons) /ongoing hospitalization
No
death persons in Tofacitinib group after 7 days
4
days after treatment is critical between Tofacitinib and placebo.
(See Figure 2)
//Conclusion(1)//---
Tofacitinib leads to a lower risk of death or
respiratory failure through day 28 than placebo for the patient with
moderate-severe symptom. Therefore, Tofacitinib could be one of the
chemotherapeutic options in the hospital. In Brazil, Remdesivir (Anti-viral
drug) is not available. Therefore, we need to investigate the clinical efficacy
Tofacitinib plus Remdesivir.
//Support(1)//---
Supported by Pfizer.
(Reference)
(1)
Patrícia O. Guimarães, M.D., Ph.D., Daniel Quirk, M.D., M.P.H., Remo
H. Furtado, M.D., Ph.D., Lilia N. Maia, M.D., Ph.D., José F. Saraiva, M.D.,
Ph.D., Murillo O. Antunes, M.D., Ph.D., Roberto Kalil Filho, M.D., Ph.D.,
Vagner M. Junior, M.D., Alexandre M. Soeiro, M.D., Alexandre P. Tognon, M.D.,
Ph.D., Viviane C. Veiga, M.D., Ph.D., Priscilla A. Martins, M.D., Diogo D.F.
Moia, Pharm.D., Bruna S. Sampaio, B.Sc., Silvia R.L. Assis, M.S., Ronaldo V.P.
Soares, Pharm.D., Luciana P.A. Piano, Ph.D., Kleber Castilho, M.B.A., Roberta G.R.A.P.
Momesso, Ph.D., Frederico Monfardini, M.Sc., Helio P. Guimarães, M.D., Ph.D.,
Dario Ponce de Leon, M.D., Majori Dulcine, M.D., Marcia R.T. Pinheiro, M.D.,
Levent M. Gunay, M.D., J. Jasper Deuring, Ph.D., Luiz V. Rizzo, M.D., Ph.D.,
Tamas Koncz, M.D., Ph.D., and Otavio Berwanger, M.D., Ph.D. for the STOP-COVID
Trial Investigators*
Tofacitinib in Patients Hospitalized with Covid-19 Pneumonia
The New England Journal of Medicine June 16, 2021
---
Author Affiliations
From the Hospital Israelita Albert Einstein (P.O.G., R.H.F.,
D.D.F.M., B.S.S., S.R.L.A., R.V.P.S., L.P.A.P., K.C., R.G.R.A.P.M., F.M.,
H.P.G., L.V.R., O.B.), the Heart Institute, InCor, University of São Paulo
Medical School (R.H.F., R.K.F., V.M.J.), BP Mirante–A Beneficência Portuguesa
de São Paulo (A.M.S.), BP–A Beneficência Portuguesa de São Paulo (V.C.V.), and
Pfizer (M.D., M.R.T.P.), São Paulo, Centro Integrado de Pesquisa, Hospital de
Base, São José do Rio Preto Medical School, São José do Rio Preto (L.N.M.),
Pontifícia Universidade Católica de Campinas, Campinas (J.F.S.), Hospital
Universitário São Francisco de Assis na Providência de Deus and Irmandade do
Senhor Bom Jesus dos Passos da Santa Casa de Misericórida de Bragança Paulista,
Bragança Paulista (M.O.A.), Hospital São Vicente de Paulo, Passo Fundo
(A.P.T.), and Hospital Estadual Jayme dos Santos Neves, Vila Velha (P.A.M.) —
all in Brazil; Pfizer, Collegeville, PA (D.Q.); Pfizer, Lima, Peru (D.P.L.);
Pfizer, Istanbul, Turkey (L.M.G.); Pfizer, Rotterdam, the Netherlands (J.J.D.);
and Pfizer, New York (T.K.).
(2)
Fajgenbaum DC, June
CH.
Cytokine storm.
N Engl J Med 2020; 383: 2255-73.
(3)
Maeshima K, Yamaoka K, Kubo S, et al.
The JAK inhibitor tofacitinib regulates synovitis through inhibition
of interferon-γ and interleukin-17 production by human
CD4+ T cells.
Arthritis Rheum 2012; 64: 1790-8.
(4)
Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ.
COVID-19: consider cytokine storm syndromes and
immunosuppression.
Lancet 2020; 395: 1033-4.
(5)
Boor PPC, de Ruiter PE, Asmawidjaja PS, Lubberts E, van der Laan
LJW, Kwek-keboom J.
JAK-inhibitor
tofacitinib suppresses interferon
alfa production by plasmacytoid dendritic cells and inhibits
arthrogenic and antiviral effects of interferon alfa.
Transl Res 2017; 188: 67-79.
(6)
The RECOVERY Collaborative Group*
Dexamethasone in Hospitalized Patients with Covid-19
The New England Journal of Medicine 2021; 384:693-704
---
Author Affiliations
From the Nuffield Department of Medicine (P.H.), Nuffield Department
of Population Health (J.R.E., M.M., J.L.B., L.L., N.S., E.J., R.H., M.J.L.),
and MRC Population Health Research Unit (J.R.E., N.S., R.H., M.J.L.),
University of Oxford, the Oxford University Hospitals NHS Foundation Trust
(K.J.), and National Institute for Health Research (NIHR) Oxford Biomedical
Research Centre (M.J.L.), Oxford, the Respiratory Medicine Department,
Nottingham University Hospitals NHS Trust (W.S.L.), and the School of Medicine,
University of Nottingham (A.M.), Nottingham, the Institute for Lung Health,
Leicester NIHR Biomedical Research Centre, University of Leicester, Leicester
(C.B.), the Regional Infectious Diseases Unit, North Manchester General
Hospital and University of Manchester (A.U.), and the University of Manchester
and Manchester University NHS Foundation Trust (T.F.), Manchester, the Research
and Development Department, Northampton General Hospital, Northampton (E.E.),
the Department of Respiratory Medicine, North Tees and Hartlepool NHS
Foundation Trust, Stockton-on-Tees (B.P.), University Hospitals Birmingham NHS
Foundation Trust and Institute of Microbiology and Infection, University of
Birmingham, Birmingham (C.G.), the Centre for Clinical Infection, James Cook
University Hospital, Middlesbrough (D.C.), the North West Anglia NHS Foundation
Trust, Peterborough (K. Rege), the Department of Research and Development,
Cardiff and Vale University Health Board, Cardiff (C.F.), the School of Life
Course Sciences, King’s College London (L.C.C.), and
the Intensive Care National Audit and Research Centre (K. Rowan), London, the
NIHR Southampton Clinical Research Facility and Biomedical Research Centre,
University Hospital Southampton NHS Foundation Trust and University of
Southampton, Southampton (S.N.F.), the Department of Mathematics and
Statistics, Lancaster University, Lancaster (T.J.), the MRC Biostatistics Unit,
University of Cambridge, Cambridge (T.J.), and Roslin Institute, University of
Edinburgh, Edinburgh (J.K.B.) — all in the United Kingdom.
(7)
Jingyou Yu, Lisa H. Tostanoski, Noe B.
Mercado, Katherine McMahan, Jinyan Liu, Catherine Jacob-Dolan, Abishek
Chandrashekar, Caroline Atyeo, David R. Martinez, Tochi Anioke, Esther A.
Bondzie, Aiquan Chang, Sarah Gardner, Victoria M. Giffin, David L. Hope, Felix
Nampanya, Joseph Nkolola, Shivani Patel, Owen Sanborn, Daniel Sellers, Huahua
Wan, Tammy Hayes, Katherine Bauer, Laurent Pessaint, Daniel Valentin, Zack
Flinchbaugh, Renita Brown, Anthony Cook, Deandre Bueno-Wilkerson, Elyse Teow,
Hanne Andersen, Mark G. Lewis, Amanda J. Martinot, Ralph S. Baric, Galit Alter,
Frank Wegmann, Roland Zahn, Hanneke Schuitemaker & Dan H. Barouch
Protective efficacy of Ad26.COV2.S against
SARS-CoV-2 B.1.351 in macaques
Nature (2021)
---
Author information
Author notes
These authors contributed equally: Jingyou
Yu, Lisa H. Tostanoski, Noe B. Mercado, Katherine McMahan, Jinyan Liu,
Catherine Jacob-Dolan, Abishek Chandrashekar
Affiliations
Center for Virology and Vaccine Research,
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
Jingyou Yu, Lisa H. Tostanoski, Noe B.
Mercado, Katherine McMahan, Jinyan Liu, Catherine Jacob-Dolan, Abishek
Chandrashekar, Tochi Anioke, Esther A. Bondzie, Aiquan Chang, Sarah Gardner, Victoria
M. Giffin, David L. Hope, Felix Nampanya, Joseph Nkolola, Shivani Patel, Owen
Sanborn, Daniel Sellers, Huahua Wan & Dan H. Barouch
Harvard Medical School, Boston, MA, USA
Catherine Jacob-Dolan, Caroline Atyeo,
Aiquan Chang & Dan H. Barouch
Ragon Institute of MGH, MIT and Harvard,
Cambridge, MA, USA
Caroline Atyeo, Galit Alter & Dan H.
Barouch
University of North Carolina at Chapel
Hill, Chapel Hill, NC, USA
David R. Martinez & Ralph S. Baric
Tufts University Cummings School of
Veterinary Medicine, North Grafton, MA, USA
Tammy Hayes, Katherine Bauer & Amanda
J. Martinot
Bioqual, Rockville, MD, 20852, USA
Laurent Pessaint, Daniel Valentin, Zack
Flinchbaugh, Renita Brown, Anthony Cook, Deandre Bueno-Wilkerson, Elyse Teow,
Hanne Andersen & Mark G. Lewis
Janssen Vaccines & Prevention, Leiden,
The Netherlands
Frank Wegmann, Roland Zahn & Hanneke
Schuitemaker
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