Observational Study Medicine ® OPEN Sarilumab (IL-6R antagonist) in critically ill patients with cytokine release syndrome by SARS-CoV2 ∗ Hèctor Corominas, MD, PhDa, , Ivan Castellví, MD, PhDa, César Diaz-Torné, MD, PhDa, Laia Matas, MD, PhDb, David de la Rosa, MD, PhDc, Maria Antònia Mangues, Phar, PhDd, Patricia Moya, MD, PhDa, Virginia Pomar, MD, PhDe, Natividad Benito, MD, PhDe, Ester Moga, MD, PhDf, Nerea Hernandez-de Sosa, MD, PhDb, Jordi Casademont, MD, PhDb, Pere Domingo, MD, PhDe Abstract Blocking IL-6 pathways with sarilumab, a fully human anti–IL-6R antagonist may potentially curb the inflammatory storm of SARS- CoV2. In the present emergency scenario, we used “off-label” sarilumab in 5 elderly patients in life-threatening condition not candidates to further active measures. We suggest that sarilumab can modulate severe COVID-19-associated Cytokine Release Syndrome. Abbreviations: CRP = C-reactive protein, CRS = cytokine release syndrome, SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2. Keywords: covid-19, critically ill, sarilumab, SARS-Cov-2 infection 1. Introduction Editor: Jianli Tao. Facing the second wave of this COVID-19 outbreak, the spread This study was part of a fully supported research grant (COV20/00070) from of positive cases worldwide has brought a landscape of fear and ISCIII Spain. respect with a maddening increase of cases over 122,036,229 and The authors have no conflicts of interests to disclose. 2,694,915 deaths at March 15th.[1–3] However, several trials are The datasets generated during and/or analyzed during the current study are not ongoing to consider biological therapy as an alternative for publicly available, but are available from the corresponding author on reasonable unresponsive and life-threatening cases of cytokine release request. The datasets generated during and/or analyzed during the current study syndrome (CRS).[4–7] are available from the corresponding author on reasonable request. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. All data generated or analyzed during this study are included in this published article [and its supplementary information files]. The data that 2. Objective support the findings of this study are available from a third party, but restrictions apply to the availability of these data, which were used under license for the We recently hypothesized that blocking IL-6 pathways with current study, and so are not publicly available. Data are available from the (sarilumab/(Kevzara), a fully human anti–IL-6R antagonist mono- authors upon reasonable request and with permission of the third party. The clonal antibody that binds membrane bound and soluble human IL- datasets generated during and/or analyzed during the current study are publicly 6R with high affinity, may potentially curb the inflammatory available. storm.[8,9] In the present emergency, according to our hospital a Servei de Reumatologia, b Servei de Medicina Interna, c Servei de Pneumologia, guidelines we used “off-label” sarilumab in cases of critically d Servei de Farmàcia Hospitalària, e Unitat de Malalties Infeccioses, f Servei Immunologia, Hospital de la Santa Creu i Sant Pau, Barcelona, Universitat advanced CRS, considering the higher 10-fold increase affinity for Autònoma de Barcelona (UAB), Barcelona, Catalonia, Spain. the receptor that sarilumab presents over tocilizumab.[10,11] ∗ Correspondence: Hèctor Corominas, Servei de Reumatologia i Malalties Autoimmunes Sistèmiques, Hospital Universitari de la Santa Creu i Sant Pau, 3. Methods Barcelona, Universitat Autònoma de Barcelona (UAB), Mas Casanovas, 90, Barcelona 08025, Catalonia, Spain (e-mail: Hcorominas@santpau.cat). In this retrospective, single-centre observational report, we Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc. describe a case-series of 5 patients with severe, progressive and This is an open access article distributed under the terms of the Creative life-threatening severe acute respiratory syndrome coronavirus 2 Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided (SARS-CoV-2) (COVID-19) infection. All patients or their legal it is properly cited. The work cannot be used commercially without permission representatives gave oral informed consent. An expert committee from the journal. prescribed the therapy according to more than one of the How to cite this article: Corominas H, Castellví I, Diaz-Torné C, Matas L, de la following criteria: Rosa D, Mangues MA, Moya P, Pomar V, Benito N, Moga E, Sosa Nd, Casademont J, Domingo P. Sarilumab (IL-6R antagonist) in critically ill patients 1. Age-adjusted Charlson Comorbidity Index scores <4,[12] with cytokine release syndrome by SARS-CoV2. Medicine 2021;100:19(e25923). 2. Interstitial pneumonia with severe respiratory failure (score = Received: 17 December 2020 / Received in final form: 8 April 2021 / Accepted: 2), 12 April 2021 3. rapid respiratory worsening requiring noninvasive or invasive http://dx.doi.org/10.1097/MD.0000000000025923 ventilation (score ≥3 on the COVID respiratory severity scale), 1 Corominas et al. Medicine (2021) 100:19 Medicine the presence of severe systemic inflammatory response criteria Discharged home 22 Discharged home 19 Death 2 days. after after sarilumab Death 6days after FiO2(21%) 9 days was fully present: high levels of D-dimer (>1500 ng/mL) or Limphocytes days after days after sarilumab sarilumab sarilumab sarilumab progressively increasing D-dimer or alternatively high levels of IL-6 (>40 pg/mL). General exclusion criteria for IL-6R antagonist therapy were: AST/ALT values greater than 5 times the upper limit of 1,35 1,76 0,57 0,45 1,98 c normality, neutrophils <500 cells/mm, platelets <50000 cells/ mmc, documented sepsis by pathogens other than SARS-CoV-2, 0,90 0,89 0,47 0,71 1,72 b AF = atrial fibrillation, CKD = chronic kidney disease, COPD = chronic obstructive pulmonary disease, DLP = dyslipidemia, DM = diabetes mellitus, ETI = endotracheal intubation, HTN = hypertension, NIV = non invasive ventilation. presence of comorbidity that can lead, according to clinical (pg/mL) judgment, to a poor prognosis, complicated diverticulitis or 0,37 0,97 0,64 1,29 IL-6 a intestinal perforation, or ongoing skin infection (uncontrolled pyodermitis with antibiotic treatment). The use of IL-6R was Outcome (x109/L) approved in strict compliance with the Hospital Ethics Commit- 124,9 65,2 98,7 380 – tee with the given code (IRS-TOC-2020–01). 31975 2036 1546 515 c 4. Results Our 5 SARS-CoV-2 elderly patients, 3 men and 2 women, 83275 2272 302 856 b (median age: 72–2, [range: 62–79], with good quality of life age adjusted Charlson <4) previous to the outbreak, when first D-Dimer (ng/mL) 774 727 admitted to hospital received hydroxychloroquine plus azithro- a mycin. When they presented radiological progression, increased oxygen needs, and/or worsening of biological parameters, they 3394 348 461 c were considered candidates to sarilumab. Four of them were on noninvasive ventilation (NIV), and 1 was 2529 442 319 581 on invasive mechanical ventilation. An average median peak of b the blood markers present before receiving sarilumab: CRP: Ferritin (mg/L) 3771 1198 302 326 a 247,6 (mg/dL) (range: 123–480), LDH: 467 (U/L) (range: 309– 766), creatine phosphokinase: 135 (U/L) (range: 44–179), 151 27 Ferritin: 967,7 (mg/L) (range: 319–2529), IL-6: 167,2 (pg/mL) c (range: 65,2–380), with an average decrease in lymphocyte 159 179 160 44 b count: 0,93 (x109/L) (0,47–1,7) significantly improved after a single dose of sarilumab 200 mg sc. Clinical and serological (U/L) CPK 424 869 46 a variables of improvement are seen in Table 1. Two patients died; one with previous chronic obstructive pulmonary disease and 247 292 435 713 221 c obesity, and the other with high chronic kidney disease grade. Hydrochloroquine 400 mg/12h (1d) followed by 200 mg/12h (4 more days) plus azithromycin 500 mg/d (3 days). 309 528 398 766 334 Among both we observed the highest CRP: 480 (mg/dl), ferritin b level: 3394 (mg/L), D-Dimer: 83275 (ng/mL), IL-6: 380 (pg/mL) (U/L) LDH 293 608 287 331 and the lowest lymphocyte count: 0,45 (x109/L). In the follow-up a 3 patients fully recovered and were discharged home with 208 18 15 25 c improvement in the control chest X-Ray. 153 330 152 480 123 b 5. Discussion (mg/dl) CRP 221 143 400 68 76 Sarilumab, is a fully human anti–IL-6R antagonist monoclonal a antibody that binds membrane bound and soluble human IL-6R ETI/NIV with high affinity to treat adult patients with moderately to NIV NIV NIV NIV ETI severely active rheumatoid arthritis who have had an inadequate response or intolerance to 1 or more disease-modifying prednisolone 250 mgc hydroxychloroquine∗∗ antirheumatic drugs.[10] Sarilumab, Inhibits IL-6-mediated hydroxychloroquine hydroxychloroquine hydroxychloroquine hydroxychloroquine plus azithromycinb plus azithromycinb plus azithromycinb plus azithromycinb a plus azithromycinb, lopinavir/ritonavir signaling pathway which involves ubiquitous signal-transducing treatments glycoprotein 130 (gp130) and the Signal Transducer and Activator of Transcription-3, only in the presence of IL-6. IL-6 Other also stimulates diverse cellular responses such as proliferation, differentiation, survival, and apoptosis and can activate HTN, COPD, AF, hepatic fibrosis HTN, DMII, AF Comorbidities hepatocytes to release acute-phase proteins, including C-reactive HTN, DMII, HTN, DMII HTN, DLP CKDIIIa, Obesity protein (CRP) and serum amyloid.[9] Scarce existing evidence supports its use in the case of CRS, and has only been described in Before sarilumab. 4 previous reports in COVID-19.[13–17] After sarilumab. At admission. Table 1 Those 5 patients were in life-threatening critical condition not P1: W, 76y P2: W, 71y P4: W, 79y P3: M, 78y P5: M, 62y XXXX. candidates to further active measures, neither to tocilizumab therapy because of comorbidities, limited access or temporary lack ∗∗ b a c 2 Corominas et al. Medicine (2021) 100:19 www.md-journal.com of stock. Therefore, sarilumab treatment was then started. Three Moya, Virginia Pomar, Natividad Benito, Nerea Hernandez out of 5 patients fully recovered and were later discharged home. de Sosa, Jordi Casademont, Pere Domingo. We may argue the role that NIV and invasive ventilation played, but considering the worsening of those not treated with References sarilumab, we assume the importance of the blockade of IL-6R. Interestingly, all blood active phase reactants improved after 24 [1] Bouadma L, Lescure FX, Lucet JC, et al. Severe SARS-CoV-2 infections: practical considerations and management strategy for intensivists. hour. The crux of matter was the patients were treated late Intensive Care Med 2020;46:579–82. enough to avoid invasive ventilation measures. Thus, since they [2] Lescure FX, Bouadma L, Nguyen D, et al. Clinical and virological data of had an ominous clinical picture, advanced age and a late stage of the first cases of COVID-19 in Europe: a case series. Lancet Infect Dis the disease, our belief is that sarilumab therapy helped to reverse 2020;S1473-3099(20)30200-0. doi:10.1016/S1473-3099(20)30200-0. [3] Fu B, Xu X, Wei H. Why tocilizumab could be an effective treatment for their CRS loop. severe COVID-19? J Transl Med 2020;18:164Published 2020 Apr 14. Currently, the optimal treatment for SARS CoV-2 pneumonia doi:10.1186/s12967-020-02339-3. has not been defined yet. In a context of international emergency, [4] Cao B, Wang Y, Wen D, et al. A trial of lopinavir-ritonavir in adults we believed sarilumab therapy was a rationale option to minimize hospitalized with severe covid-19. N Engl J Med 2020;NEJMoa2001282. or reverse CRS in these critically ill patients. Ideally, we could doi:10.1056/NEJMoa2001282. [5] Russell CD, Millar JE, Baillie JK. Clinical evidence does not support have treated these patients sooner, but the emergency situation corticosteroid treatment for 2019-nCoV lung injury. Lancet 2020; and the lack of recommendations for treating elderly patients 395:473–5. prompted us to use sarilumab. Hopefully, in the near future we [6] Arabi YM, Mandourah Y, Al-Hameed F, et al. Corticosteroid therapy expect to have randomized controlled trials (23 studies registered for critically Ill patients with Middle East Respiratory Syndrome. Am J Respir Crit Care Med 2018;197:757–67. in NCT, including ours) and data from observational studies [7] Corominas H, Castellví I, Pomar V, et al. Effectiveness and safety of (IIBSP-COV-2020–28) to support clinical decisions. intravenous tocilizumab to treat COVID-19-associated hyperinflamma- In summary, we suggest that sarilumab can be useful in a global tory syndrome: covizumab-6 observational cohort. Clin Immunol context of IL-6R antagonist indication, as an alternative to 2021;223:108631doi: 10.1016/j.clim.2020.108631. tocilizumab or other therapies targeted to modulate mild to [8] Corominas H, Castellví I, Domingo P, et al. Facing the SARS-CoV-2 (COVID-19) outbreak with IL- 6R antagonists. Eur J Rheumatol severe COVID-19-associated CRS. 2020;10.5152/eurjrheum.2020.20061. [9] Huizinga TW, Fleischmann RM, Jasson M, et al. Sarilumab, a fully human monoclonal antibody against IL-6Ra in patients with rheumatoid Author contributions arthritis and an inadequate response to methotrexate: efficacy and safety Conceptualization: Hèctor Corominas, Ivan Castellví, César results from the randomised SARIL-RA-MOBILITY Part A trial. Ann Rheum Dis 2014;73:1626–34. Diaz-Torné, Laia Matas, Natividad Benito, Nerea Hernandez de [10] Kim GW, Lee NR, Pi RH, et al. IL-6 inhibitors for treatment of Sosa, Jordi Casademont, Pere Domingo. rheumatoid arthritis: past, present, and future. Arch Pharm Res 2015; Data curation: Hèctor Corominas, Ivan Castellví, Nerea 38:575–84. Hernandez de Sosa. [11] Rafique A, Martin J, Blome M, et al. Evaluation of the binding kinetics Formal analysis: Hèctor Corominas, Ivan Castellví, César Diaz- and functional bioassay activity of sarilumab and tocilizumab to the human IL-6 receptor (il-6r) alpha. Ann Rheum Dis 2013;72:A797. Torné, Laia Matas, David de la Rosa, Pere Domingo. [12] Dessai SB, Fasal R, Dipin J, et al. Age-adjusted charlson comorbidity Funding acquisition: César Diaz-Torné. index and 30-day morbidity in pelvic surgeries. South Asian J Cancer Investigation: Hèctor Corominas, Ivan Castellví. 2018;7:240–3. Methodology: Hèctor Corominas, Ivan Castellví, Laia Matas, [13] Zhou Z, Price CC. Overview on the use of IL-6 agents in the treatment of patients with cytokine release syndrome (CRS) and pneumonitis related David de la Rosa, Virginia Pomar, Natividad Benito, Ester to COVID-19 disease. Expert Opin Investig Drugs 2020;1–6. Moga, Nerea Hernandez de Sosa, Pere Domingo. [14] Della-Torre , Campochiaro E, Cavalli C, et al. Dagna L; SARI-RAF Study Project administration: Ivan Castellví, Laia Matas, Nerea Group; SARI-RAF Study Group members. Interleukin-6 blockade with Hernandez de Sosa. sarilumab in severe COVID-19 pneumonia with systemic hyper- Resources: Hèctor Corominas, Ester Moga. inflammation: an open-label cohort study. Ann Rheum Dis 2020;79: 1277–85. Supervision: Hèctor Corominas, Ivan Castellví, César Diaz- [15] Khiali S, Rezagholizadeh A, Entezari-Maleki T. A comprehensive review Torné, Laia Matas, David de la Rosa, Maria Antònia on sarilumab in COVID-19. Expert Opin Biol Ther 2020;1–12. doi: Mangues, Patricia Moya, Jordi Casademont. 10.1080/14712598.2021.1847269. Validation: Hèctor Corominas, César Diaz-Torné, Laia Matas, [16] Caballero Bermejo AF, Ruiz-Antorán B, Fernández Cruz A, et al. Puerta de Hierro COVID-19 Study Group. Sarilumab versus standard of care David de la Rosa, Maria Antònia Mangues, Patricia Moya, for the early treatment of COVID-19 pneumonia in hospitalized Virginia Pomar, Jordi Casademont, Pere Domingo. patients: SARTRE: a structured summary of a study protocol for a Visualization: Hèctor Corominas, Ivan Castellví, Maria Antònia randomised controlled trial. Trials 2020;21:794doi: 10.1186/s13063- Mangues, Patricia Moya, Virginia Pomar, Natividad Benito, 020-04633-3. Jordi Casademont, Pere Domingo. [17] Garcia-Vicuña R, Abad-Santos F, González-Alvaro I, et al. Subcutaneous Sarilumab in hospitalised patients with moderate-severe COVID-19 Writing – original draft: Hèctor Corominas. infection compared to the standard of care (SARCOVID): a structured Writing – review & editing: Hèctor Corominas, Ivan Castellví, summary of a study protocol for a randomised controlled trial. Trials César Diaz-Torné, Laia Matas, David de la Rosa, Patricia 2020;21:772doi: 10.1186/s13063-020-04588-5. 3