COVID-19 Global Rheumatology Alliance

Gianfrancesco, M

Graef, ER

Kim, AH

Konig, MF

Langguth, D

Liew, JW

Machado, PM

Robinson, PC

Scheetz, MH

Simard, J

Yazdany, J

English

UCL Discovery

1 Baseline use of hydroxychloroquine in systemic lupus erythematosus does not preclude 2 SARS-CoV-2 infection and severe COVID-1934 Maximilian F Konig1*, Alfred HJ Kim2-4, Marc H Scheetz5-7, Elizabeth R Graef8, Jean W Liew9, 5 Julia F Simard10, Pedro M Machado11-13, Milena A Gianfrancesco14, Jinoos Yazdany14, Daman 6 Langguth15, Philip C Robinson16*, On behalf of the COVID-19 Global Rheumatology Alliance78 1Division of Rheumatology, Department of Medicine, The Johns Hopkins University School of 9 Medicine, Baltimore, MD, USA10 2Division of Rheumatology, Department of Medicine, Washington University School of Medicine, 11 Saint Louis, MO, USA12 3Division of Immunobiology, Department of Pathology and Immunology, Washington13 University School of Medicine, Saint Louis, Missouri, USA14 4Andrew M. and Jane M. Bursky Center of Human Immunology and Immunotherapy Programs, 15 Washington University School of Medicine, Saint Louis, Missouri, USA16 5Midwestern University, Departments of Pharmacy Practice and Pharmacology, Chicago 17 College of Pharmacy, and College of Graduate Studies, Downers Grove, IL, USA18 6Midwestern University Pharmacometrics Center of Excellence, Downers Grove, IL, USA19 7Northwestern Memorial Hospital, Department of Pharmacy, Chicago, IL, USA 20 8Division of Rheumatology and Clinical Immunology, Beth Israel Deaconess Medical Center, 21 Harvard Medical School, Boston, MA, USA22 9Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA, 23 USA24 10Department of Epidemiology & Population Health; and Department of Medicine, Division of 25 Immunology & Rheumatology, Stanford School of Medicine, Stanford, CA, USA 12345678910111213141516171819202122232425262728293031323334353637383940414243444546474849505152535455565758596026 11Centre for Rheumatology & Department of Neuromuscular Diseases, University College 27 London, London, UK28 12Department of Rheumatology & Queen Square Centre for Neuromuscular Diseases, 29 University College London Hospitals NHS Foundation Trust, London, UK30 13Department of Rheumatology, Northwick Park Hospital, London North West University 31 Healthcare NHS trust, London, UK32 14Division of Rheumatology, Department of Medicine, University of California San Francisco, 33 San Francisco, CA, USA34 15Department of Immunology, Sullivan and Nicolaides Pathology, Brisbane, Australia35 16University of Queensland Faculty of Medicine, Brisbane, Australia3637 *Correspondence to: 38 Maximilian F Konig, MD, Division of Rheumatology, The Johns Hopkins University School of 39 Medicine, Baltimore, MD, USA (konig@jhmi.edu); Philip C Robinson, MBChB, PhD, University 40 of Queensland Faculty of Medicine, Brisbane, QLD, Australia (philip.robinson@uq.edu.au)414243 The use of hydroxychloroquine (HCQ) in the prophylaxis and treatment of Coronavirus disease 44 2019 (COVID-19) has received significant attention by politicians and media figures. This has 45 occurred despite limited data supporting its efficacy in COVID-19 as well as considerable concern 46 about its safety when used at high doses (>400 mg daily) and in combination with other QT 47 interval-prolonging drugs [1–4]. 4849 An inaccurate narrative has emerged in recent weeks that patients with systemic lupus 50 erythematosus (SLE) who are taking HCQ as a baseline therapy are less affected by or do not 51 develop COVID-19 [5–7]. This assumption has been challenged by Monti et al. [8], referencing Page 3 of 1812345678910111213141516171819202122232425262728293031323334353637383940414243444546474849505152535455565758596052 data from the COVID-19 Global Rheumatology Alliance registry on patients with rheumatic 53 disease which previously identified 19/110 (17%) patients with SLE [9]. A case series of 17 54 patients with lupus or antiphospholipid syndrome who developed COVID-19 on a median HCQ 55 dose of 400 mg daily (median HCQ blood level of 648 ng/mL) has since become available [10]. 56 As of April 17, 2020, we have now identified 80 patients with SLE and COVID-19 in the global 57 physician-reported registry. Patients were predominantly female (72/80, 90%) and less than 65 58 years of age (69/80, 86%). Importantly, 64% (51/80) of SLE patients were taking an antimalarial 59 (HCQ or chloroquine) prior to infection with SARS-CoV-2 (30% as monotherapy). Notably, 21.1% 60 (121/573) of all reported patients with rheumatic disease in the registry were treated with an 61 antimalarial prior to onset of COVID-19, yet 49.6% (60/121) required hospitalization. In patients 62 with SLE, frequency of hospitalization with COVID-19 did not differ between individuals using an 63 antimalarial vs non-users (55% [16/29] vs 57% [29/51], p=ns; chi-squared test). In lupus patients, 64 escalation to maximum level of care (non-invasive ventilation, invasive ventilation, or ECMO) was 65 required regardless of HCQ use (Table 1). Thus, patients with lupus – even if they are using an 66 antimalarial such as HCQ as baseline therapy – can develop SARS-CoV-2 infection and severe 67 COVID-19 at similar frequency as lupus patients not on antimalarials.6869 Table 1. Coronavirus disease 2019 severity in patients with SLE by antimalarial use 70AllSLE(n=80)AntimalarialYes(n=51)AntimalarialNo(n=29)Hospitalized 45 (56%) 29 (57%) 16 (55%)Level of Care*Did not require supplemental oxygen 48 (60%) 33 (65%) 15 (52%)123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960Required supplemental oxygen, non-invasive or invasive ventilation or ECMO30 (38%) 17 (33%) 13 (45%)71 *Information unknown for 2 cases727374 There are currently >40 ongoing clinical trials examining HCQ in the prophylaxis or treatment of 75 SARS-CoV-2 infection which employ highly variable strategies with regards to dosing (total oral 76 loading dose 400-1400 mg), duration, and time of initiation [11]. However, dosing considerations 77 of HCQ in COVID-19 may be critical to understand why patients with lupus may not be protected 78 from SARS-CoV-2 infection. 7980 Similar to in-vitro studies indicating activity of antimalarial 4-aminoquinoline derivatives against 81 SARS-CoV-1 and MERS-CoV [12,13], a putative role for HCQ in the treatment of COVID-19 has 82 been suggested by its antiviral effect in cell culture systems [14,15]. Given the assumptions made 83 when moving from a cell-based model to a complex in vivo system, in vitro potency cannot be 84 expected to translate into in vivo efficacy [16], as observed for chloroquine in a mouse model of 85 SARS-CoV-1 infection [17]. To date, no in vivo exposure response data are available for HCQ in 86 COVID-19. Few data are available to extrapolate what drug concentrations must be achieved to 87 observe in vivo efficacy, and in which compartment (e.g. whole blood vs. epithelial lining fluid vs. 88 lung parenchyma). Even for influenza and approved antiviral drugs (oseltamivir), the direct 89 relationship between drug concentration and in vivo activity is uncertain [18,19]. Current in vitro 90 data suggests that the concentration of HCQ at which 50% of the maximal activity against SARS-91 CoV-2 is obtained (EC50) is 0.72-4.51 μM (i.e. ~242-1,515 ng/mL) [14,15], similar to the EC50 92 observed in SARS-CoV-1 and MERS-CoV [13]. Ninety percent inhibition of SARS-CoV-2 (EC90) 93 with HCQ was achieved at ~5-15 μM (~1,679-5,038 ng/mL), while clearance required ~20 μM 94 (~6,717 ng/mL) [14,15]. Importantly, both EC50 and EC90 concentrations may be insufficient to Page 5 of 1812345678910111213141516171819202122232425262728293031323334353637383940414243444546474849505152535455565758596095 improve clinical outcomes. Instead, the concentration of HCQ required to eliminate SARS-CoV-2 96 may be a more meaningful target [20]. Such concentrations of HCQ (i.e. ~6,700 ng/mL), however, 97 are not safely achievable in whole blood, and little is known about the concomitant concentrations 98 obtainable in lung parenchymal cells in humans (assuming this represents a critical site for 99 antiviral activity in COVID-19). Without an understanding of effective HCQ concentrations in target 100 tissues, effective therapeutic doses remain difficult to predict by simulation. For dosing strategies 101 to be informed, an intricate understanding of HCQ transfer constants between the blood and the 102 lung tissue is required.103104 HCQ used in the treatment of SLE is typically prescribed at doses of 5.0-6.5 mg/kg, with a 105 maximum dose of 400 mg daily. The majority of patients with SLE on chronic HCQ treatment do 106 not achieve whole blood concentrations of 5-15 μM (~1,679-5,038 ng/mL) [21,10], corresponding 107 to the EC90 for SARS-CoV-2 [14,15]. While pulmonary drug concentrations in mice are known to 108 reach much higher levels than in blood, these HCQ concentrations may be required to achieve 109 meaningful antiviral activity in blood. The difficulty of achieving potentially meaningful blood 110 concentrations at HCQ doses typically prescribed in SLE may have important implications for trial 111 design in COVID-19, and needs to be considered when interpreting outcomes of these studies. 112 Notably, results from an open-label, randomized, controlled trial using doses as high as HCQ 113 1200 mg for three days (followed by a maintenance dose of 800 mg daily for 2-3 weeks) did not 114 suggest efficacy of HCQ in suppressing viral replication [22]. These efficacy data, and the 115 irrefutable clinical data collected through the COVID-19 Global Rheumatology Alliance registry, 116 establishes that lupus patients on baseline therapy with HCQ are not universally protected from 117 COVID-19.118119 Acknowledgement: M.F.K. was supported by the National Institute of Arthritis and 120 Musculoskeletal and Skin Diseases of the National Institutes of Health under Award no. 123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960121 T32AR048522, and received personal fees from Bristol-Myers Squibb and Celltrion, unrelated to 122 this manuscript. A.H.J.K. was supported by grants from NIH/NIAMS and Rheumatology Research 123 Foundation, and personal fees from Exagen Diagnostics, Inc. and GlaxoSmithKline, unrelated to 124 this manuscript. P.M.M. is supported by the National Institute for Health Research (NIHR) 125 University College London Hospitals (UCLH) Biomedical Research Centre (BRC), and received 126 consulting or speaker’s fees from Abbvie, Eli Lilly, Novartis, and UCB Pharma. J.Y. received 127 personal fees from Astra Zeneca and Eli Lilly, unrelated to this manuscript. P.R. reports personal 128 fees from Abbvie, Pfizer, UCB Pharma, Novartis, Eli Lilly, and Janssen, and non-financial support 129 from Roche. The views expressed here are those of the authors and participating members of the 130 COVID-19 Global Rheumatology Alliance, and do not necessarily represent the views of the 131 American College of Rheumatology, the European League Against Rheumatism, or any other 132 organization. 133134 References135 1 Kim AHJ, Sparks JA, Liew JW, et al. A Rush to Judgment? Rapid Reporting and 136 Dissemination of Results and Its Consequences Regarding the Use of Hydroxychloroquine 137 for COVID-19. 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Baseline use of hydroxychloroquine in systemic lupus erythematosus does not preclude SARS-CoV-2 infection and severe COVID-19.

https://discovery.ucl.ac.uk/10098285/1/HCQ%20Paper.pdf

Baseline use of hydroxychloroquine in systemic lupus erythematosus does not preclude SARS-CoV-2 infection and severe COVID-19.

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