EXPERT OPINION ON BIOLOGICAL THERAPY 2020, VOL. 20, NO. 7, 717–723 https://doi.org/10.1080/14712598.2020.1770222 EDITORIAL Tocilizumab: from the rheumatology practice to the fight against COVID-19, a virus infection with multiple faces Miguel A. González-Gaya,b,c*, José Mayod, Santos Castañedae, José M. Cifriánf and José Hernández-Rodríguez g * a Division of Rheumatology and Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain; bUniversity of Cantabria, Santander, Spain; cCardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; dInfectious Diseases Unit, Galdakao-Usansolo Hospital, Galdakao, Bizkaia, Spain; eRheumatology Division, Hospital de La Princesa, IIS-Princesa, Cátedra UAM- Roche, EPID Future, Universidad Autónoma de Madrid (UAM), Madrid, Spain; fDivision of Pneumology, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain; gVasculitis Research Unit and Clinical Unit of Autoinflammatory Diseases, Department of Autoimmune Diseases, Hospital Clínic of Barcelona, University of Barcelona, Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain ARTICLE HISTORY Received 20 April 2020; Accepted 13 May 2020 KEYWORDS Chimeric antigen receptor (CAR) T cell-induced cytokine release syndrome; coronavirus; COVID-19; inflammation; interleukin-6; macrophage activation syndrome; tocilizumab; anakinra; colchicine 1. Introduction A delayed implication is also recognized by hematologists for In the past two decades, we have witnessed significant problems derived from a hypercoagulative state, and pulmo- advances in the management of autoimmune diseases. The nologists for the acute and chronic consequences of the early widespread use of biologic therapies in patients with severe or and uncontrolled lung involvement. This is a repetitive process refractory autoimmune diseases has improved the prognosis that has sadly occurred (and still occurs) in all the places in of these conditions. Tocilizumab (TCZ), an anti-interleukin 6 a similar way. However, we finally learn that working together receptor (IL-6 R), is one of these biologic agents. Recent stu- altruistically as a local or international network, and also bring- dies indicate that TCZ is an effective treatment in SARS-CoV-2 ing together expert people from different fields in multidisci- infection (COVID-19) patients [1,2]. In the present report, we plinary teams, can make us succeed and defeat this infectious briefly summarized the use of TCZ in rheumatic diseases as and immune-inflammatory pandemic disease caused by well as the recent evidence supporting its use in the treatment a complex virus. for COVID-19 patients experiencing severe complications. This editorial was elaborated by a group of clinicians that 2. The role of tocilizumab in systemic autoimmune included two rheumatologists with experience in the manage- and inflammatory diseases ment of systemic diseases, an internist dedicated to vasculitis and autoinflammatory syndromes, a pneumologist, and an Going back to inflammation, it is already known that interleu- infectious diseases specialist. Based on our vision as clinical kin 6 (IL-6) is a pleiotropic cytokine, which, apart from its role physicians involved in different aspects of COVID-19, we have in the inflammatory and immune responses, influences realized that human beings often learn from our own mis- a variety of systems (Figure 1). This pivotal proinflammatory takes. Unfortunately, we do not tend to learn from others in cytokine promotes the production of acute-phase protein advance for taking early actions against any new potential such as the C-reactive protein (CRP) by the liver. IL-6 also threat when this danger signal is affecting other communities leads to the hepatic production of hepcidin that is responsible or countries may be too far from us (but not any longer in for the development of chronic anemia in inflammatory con- today’s globalized world). In addition, when COVID-19 arrives ditions. The effect of IL-6 on the hypothalamic–pituitary–adre- in our own countries, mainly infectious diseases and intensive nal axis promotes the development of fatigue. Besides effects care specialists rapidly take over the management of the acute on osteoporosis, IL-6 induces metabolic abnormalities that process with all the weapons available at this time (again, lead to insulin resistance, and it is also implicated in the being unaware of all the medical information from other increased risk of cardiovascular disease associated with affected countries in this regard). Several days or weeks later, chronic inflammatory rheumatic diseases [3]. most physicians dedicated to immunology and autoimmune TCZ is the first recombinant humanized anti-human mono- diseases discover that the disease is of our concern, due to the clonal antibody directed against soluble and membrane- predominant immunology-mediated hyperinflammatory bound interleukin 6 receptors (IL-6 R). TCZ inhibits the binding response as the ultimate cause of death in COVID-19 patients. of IL-6 to its receptors, thus reducing this cytokine’s pro- CONTACT Miguel A. González-Gay miguelaggay@hotmail.com University of Cantabria, Rheumatology, Division and Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, Hospital Universitario Marqués de Valdecilla, IDIVAL, Avenida Cardenal Herrera Oria S/n, Santander 39011, Spain * These authors share senior authorship © 2020 Informa UK Limited, trading as Taylor & Francis Group 718 M. A. GONZÁLEZ-GAY ET AL. Figure 1. Pleiotropic effects of interleukin-6 (IL-6). inflammatory activity by competing with both the soluble and GCA, the most common systemic vasculitis in people older than membrane-bound forms of the IL-6 R [4]. This biologic agent 50 years, using subcutaneous TCZ (162 mg/week) [9], confirmed prevents the interaction of IL-6 with both the IL-6 R and the the promising results shown in a GCA open-label study in which signal transducer glycoprotein 130 complex, which leads to TCZ was given intravenously at a dose of 8 mg/kg intravenously inhibition of both the cis- and trans-signaling cascades invol- every 4 weeks [10]. Additional open-label studies have demon- ving the Janus kinase (JAK)-signal transducer and the activator strated the efficacy of TCZ in severe ocular complications, such as of transcription (JAK-STAT) pathway [5]. uveitis associated with Behçet’s disease and JIA refractory to con- As illustrated in Table 1, the anti-IL-6 R tocilizumab has ventional and biological immunosuppressive drugs, including anti- been labeled by the U.S. Food and Drug Administration TNF agents [11,12]. Although the main monogenic autoinflamma- (FDA) and the European Medicines Agency (EMA) for differ- tory diseases are mostly caused by an uncontrolled increase of IL-1, ent autoimmune and inflammatory conditions, such as rheu- TCZ has shown efficacy in several cases refractory to colchicine, matoid arthritis, systemic and polyarticular juvenile anti-IL-1, and anti-TNF agents [13]. idiopathic arthritis (JIA), giant cell arteritis (GCA), and severe More familiar to rheumatologists and internists is the use of or life-threatening cytokine release syndrome (CRS) second- TCZ in adult-onset Still’s disease (AOSD), particularly in ary to chimeric antigen receptor (CAR) T cell therapy. Of patients who are refractory to conventional therapies and note, CRS is directly caused by the excessive release of present a predominant polyarticular pattern of the disease proinflammatory cytokines during an exaggerated immune [14–16]. AOSD is a rare multisystem inflammatory disease of response [6]. unknown origin that is included within the clinical spectrum of In more detail, TCZ was initially approved for rheumatoid arthri- autoinflammatory disorders [16,17]. It shares many clinical and tis refractory to methotrexate or tumor necrosis factor (TNF) inhibi- laboratory features as well as gene profile activation with tors [7], and systemic onset JIA, at doses of 4–8 mg/kg intravenously systemic onset JIA, for which the usefulness of biologic thera- once every 2 weeks [8]. More recently, a clinical trial in patients with pies is also similar [16]. Table 1. Current indications of tocilizumab. FDA EMA Autoimmune/ administration administration inflammatory condition U.S. Food and Drug Administration (FDA) route European Medicines Agency (EMA) route RA Adults with active RA and inadequate IV or SC Adults with severe RA and inadequate response to IV or SC response to DMARDs methotrexate, or with moderate to severe active RA not responding to DMARDs or TNF blockers Systemic JIA Patients ≥ 2 years with active disease IV Patients ≥ 1 year with poor response to NSAIDs and GC IV Polyarticular JIA Patients ≥ 2 years with active disease IV Patients ≥ 2 years with active disease, not responding IV or SC to methotrexate GCA Adult patients SC Adult patients SC CRS due to CAR-T cell Adults and pediatric patients ≥2 years IV Adults and pediatric patients ≥2 years with IV therapy with CAR T cell-induced severe or life-threatening CAR T cell-induced severe or life- CRS threatening CRS Abbreviations: CAR = Chimeric antigen receptor; CRS = Cytokine release syndrome; DMARDs = Disease modifying anti-rheumatic drugs; GC = Glucocorticoids; GCA = Giant cell arteritis; IV = Intravenous; JIA = Juvenile idiopathic arthritis; NSAIDs = Non-steroidal anti-inflammatory drugs; RA = Rheumatoid arthritis; SC = Subcutaneous; TNF = Tumor necrosis factor. EXPERT OPINION ON BIOLOGICAL THERAPY 719 Around 15–20% of patients with AOSD develop some life- forms of COVID-19. However, some authors have postulated threatening events, being the macrophage activation syn- that low doses of tacrolimus in kidney transplant patients may drome (MAS), a secondary form of hemophagocytic lympho- attenuate the hyperinflammatory reaction leading to severe histiocytosis (HLH), the most feared complication leading to COVID-19 [23]. In a similar way, baseline immunosuppression high mortality rate [16]. It may occur as the first manifestation with cytotoxic drugs (e.g. methotrexate, azathioprine, cyclos- or during the disease course, usually associated with infec- porine, mycophenolate mofetil, tacrolimus, etc.) or biologic tions, drugs, or disease relapses [16,18,19]. In AOSD and other agents (anti-IL-6, anti-IL-1, anti-TNF, JAK inhibitors, or B-cell autoimmune diseases, MAS is characterized by high non- depleting agents), or even previous immunomodulatory treat- remitting fever, central nervous system dysfunction, involve- ment (e.g. hydroxychloroquine or colchicine), might play ment of the heart (as myocarditis or pericarditis) and lung (as a protective role in the development of the exaggerated acute respiratory distress syndrome), pancytopenia, coagulo- immune-mediated inflammatory response associated with pathy, abnormally increased triglycerides, or hyperferritinemia SARS-CoV-2 infection in patients with autoimmune or autoin- (generally >5,000 mg/L) [16,19,20]. TCZ onset after adequate flammatory diseases. nonselective immunosuppressive therapy, such as pulses of As in some preliminary reports [1,2], the real-word experi- methylprednisolone or a prednisone-based combination of ence in COVID-19 patients with TCZ, mostly given in an early immunosuppressants, can be an effective treatment for inflammatory phase, has shown a rapid resolution of fever and AOSD-associated MAS [18]. improvement of respiratory function and chest imaging changes, as well as the progressive reduction of inflammatory parameters such as CRP and ferritin. Our own experience also 3. The role of tocilizumab and other supports these observations with the use of this biologic anti-inflammatory/immunosuppressive agents in agent in severe COVID-19 patients. COVID-19 Patients with COVID-19 present with features mimicking auto- immune diseases, such as fever, arthralgia, acute interstitial 4. Our expert opinion in recognizing and treating pneumonia, myocarditis, leukopenia, lymphopenia, thrombo- COVID-19 cytopenia, coagulopathy, and biological inflammatory changes derived from a cytokine storm, similar to HLH or From its occurrence in China first and Italy afterward, until the MAS associated with autoimmune or inflammatory conditions experience of having to deal with urgent solutions in our own [1,2,16,21,22]. country, we have learned how to recognize the different COVID-19 patients may suffer severe complications, includ- phases (or ‘faces’) of COVID-19, and also how to manage ing acute respiratory distress syndrome and death, which is them. After the initial viral phase (‘face 1’) with variable symp- finally provoked by an increased alveolar exudate and damage toms, ranging from asymptomatic or paucisymptomatic forms secondary to an abnormal local immune-inflammatory to overt clinical situations with fever, coughing, ageusia, anos- response. Based on the experience with TCZ in CAR-T cell- mia, and upper respiratory airway involvement, some patients associated CRS and autoimmune diseases-related MAS develop an immunologic and hyperinflammatory phase (‘face [6,16,18–20], and the presence of a cytokine storm syndrome 2’), which is manifested with biological changes of a cytokine potentially causing fatal lung tissue damage, also responding storm (macrophage activation-like) syndrome, usually accom- to TCZ in patients with severe COVID-19 [1,2], TCZ and other panied by a quick respiratory deterioration due to a bilateral anti-IL-6 agents (such as siltuximab and sarilumab) are being pneumonitis. A hypercoagulative status (‘face 3’) may be pre- investigated in ongoing COVID-19 clinical trials in different sent in critically ill patients during the inflammatory phase, countries. and mild to life-threatening thrombotic complications are With regard to anti-IL-1 therapy, anakinra has also shown quite frequent. Inflammatory pneumonitis and lung fibrotic benefit in patients with autoimmune diseases-associated MAS, changes (‘face 4’) have been also described in patients who both subcutaneously [18,19] and intravenously [16]. In severe have suffered from an acute and uncontrolled lung involve- COVID-19, some cases have similarly responded to the sole ment. Finally (by now), dermatologic (mainly with pseudo- administration of anakinra at high doses by intravenous infu- chilblain and vesicular lesions) and coronary inflammatory sion (at 10 mg/kg/day during a mean of 9 days) [21] or by the changes, probably related to immune-mediated vasculitic-like subcutaneous route (at 100 mg/6 hours during 14 days) [22]. lesions, may be developed by young patients in a delayed In addition, different clinical trials with intravenous anakinra phase (‘face 5’). are ongoing at this moment. In the same sense, several clinical Although the exact role of an effective antiviral therapy and trials using colchicine (as an inhibitor of inflammatory cell the best moment for its administration have to be determined migration, also with anti-IL-1 properties) for treating COVID- yet, most of the clinical studies in real life have identified that 19 patients are also being tested. a delay in applying the correct anti-inflammatory treatment The role of conventional immunosuppressive agents in may influence negatively in the outcome of COVID-19 treating or preventing severe forms of COVID-19 is being patients. However, these hypotheses have also to be unveiled analyzed. It is noticeable that patients with conditions char- in the near future after knowing the results of different clinical acterized by drug-induced immunosuppression, such as those trials. In the meantime and with the only aim of saving lives, with autoimmune diseases or transplant recipients, were con- many (urgent) clinical guidelines and standardized working sidered a priori to be at a higher risk for developing severe protocols for managing admitted patients with COVID-19 720 M. A. GONZÁLEZ-GAY ET AL. have been similarly used with a real low level of evidence presence of hypoxemia due to a bilateral pneumonia, usually during the outbreak. associated to increased inflammatory markers, especially CRP While the first-line therapy in all patients with COVID-19 and ferritin), the prompt use of glucocorticoids at high doses has been based in hydroxychloroquine/chloroquine, azithro- and/or intravenous TCZ (ideally at 8 mg/kg) has become the mycin, and lopinavir/ritonavir combinations, without showing treatment of choice in real life. In this regard, the first retro- clear benefit in most clinical studies [24–26], and while remde- spective and observational studies using glucocorticoids [28] sivir is still pending to be validated as a clear option [27], in and tocilizumab in severe COVID-19 have shown promising patients with a moderate to severe disease (defined by the results [1,2]. Figure 2A. Treatment protocol for COVID-19 – Part I. (1) Remdesivir (from Gilead Sciences): loading dose of 200 mg i. v. on day 1, then 100 mg i.v. for the following 9 days. Only antiviral likely active, trials currently ongoing. (2) Hydroxychloroquine (DOLQUINE®): 200 mg per tablet; 2 tablets (400 mg)/12 hours the first 24 hours, and subsequently, 1 tablet (200 mg)/12 hours; duration of treatment 7–14 days. (3) Colchicine (COLCHICINA SEID®): 0.5 mg per tablet; 1 tablet (0.5 mg)/12 h for 3 days, followed by 0.5 mg/day during a total of 7 days. (4) Methylprednisolone (URBASON®): 250 mg i.v./day x 3 days. (5) Tocilizumab (RoACTEMRA®): if possible, an i.v. dose of 8 mg/Kg. However, due to a shortage of stock, a dose per patient was authorized, of 600 mg (if weight ≥75 Kg) or 400 mg (if weight <75 Kg). * Additional dose of tocilizumab if available or a similar anti-IL6 agent (e.g. sarilumab, siltuximab) or anakinra (according to doses in Part II – Figure 2B). ** Specified in the following section (ICU) EXPERT OPINION ON BIOLOGICAL THERAPY 721 Herein, we intend to show the collaborative and multidis- and a single infusion of TCZ (600 mg in patients ≥75 Kg, ciplinary protocol for managing COVID-19 at Hospital limited by the Spanish Ministry of Health) was given with the Galdakao (Bizkaia, Spain), elaborated with the participation of intention of avoiding patient transfer to the Intensive Care all the authors (Figures 2A and 2B). The protocol was adjusted Unit (ICU) or, if ICU was required, these drugs were still admi- several times during the entire outbreak period, and the last nistered to avoid invasive ventilation. In non-responsive cases, version at this time (20 April 2020) has been included. For mild anakinra was subcutaneously administered at doses of COVID-19 cases, a combination of hydroxychloroquine and 100 mg/6 hours for 3 days, followed by daily reductions of colchicine (with remdesivir, if available) was used. For moder- 100 mg until maintain 100 mg/day during a total of 7 days. In ate to severe cases, depending on the respiratory severity our hands, this scheme of management yielded good results (FiO2 requirement ≥40%) and levels of ferritin (≥1,500 ng/ in hospital wards and also in ICU (data not published, still mL) and/or CRP (≥3 mg/dL), the prompt administration (dur- under analysis). ing the first 7 to 14 days of the beginning of the symptoms) of In conclusion, while conventional biologic markers (ferritin, intravenous methylprednisolone (250 mg/day during 3 days) CRP, etc.) or cytokine measurements (circulating levels of IL-6, Figure 2B. Treatment protocol for COVID-19 – Part II. Adapted with permission from the updated protocol proposed on 20 April 2020, by Dr. Mayo at Hospital Galdakao, Bizkaia, Spain (anticoagulation recommendations not included). 722 M. A. GONZÁLEZ-GAY ET AL. IL-1 receptor-antagonist, among others) have to be deter- •• Excellent review on the role of IL-6 in the mechanisms associated mined as prognostic factors for COVID-19 in still required with inflammation in rheumatoid arthritis. It describes in an elegant way the inflammatory pathways activated by IL-6. rigorous studies, and while the results of still pending clinical 4. Sebba A. Tocilizumab: the first interleukin-6-receptor inhibitor. Am trials will shed the ultimate light on the accurate management J Health Syst Pharm. 2008;65:1413–1418. of COVID-19, at this moment, we strongly support a proactive • In this report the author provided useful information on the and early management with the administration of glucocorti- pharmacology, pharmacokinetics, clinical efficacy, safety, and coids and anti-IL-6 or anti-IL-1 agents in critically ill patients, or role of tocilizumab in rheumatoid arthritis 5. Johnson DE, O’Keefe RA, Grandis JR. Targeting the IL-6/JAK/STAT3 in those with a rapidly progressive disease in the context of signalling axis in cancer. Nat Rev Clin Oncol. 2018;15:234–248. a hyperinflammatory state. By doing so, the progression to the •• Review on the role of IL-6/JAK/STAT3 signalling in the tumor different phases and faces of COVID-19 will be probably mini- microenvironment and the status of preclinical and clinical mized or avoided. Indeed, to achieve these goals faster and investigations of agents targeting this pathway. The authors better, we believe we have worked together, in multidisciplin- also discussed the potential of combining IL-6/JAK/STAT3 inhi- bitors with therapeutic agents directed against immune-check- ary teams, from the beginning. point inhibitor. 6. Le RQ, Li L, Yuan W, et al. FDA Approval Summary: tocilizumab for Treatment of Chimeric Antigen Receptor T Cell-Induced Severe or Funding Life-Threatening Cytokine Release Syndrome. Oncologist. This paper is not funded. 2018;23:943–947. •• Tocilizumab proved to be useful for the treatment of severe or life-threatening chimeric antigen receptor T cell-induced cyto- kine release syndrome. Declaration of interest 7. Biggioggero M, Crotti C, Becciolini A, et al. Tocilizumab in the MA Gonzalez-Gay has received grants/research supports from Abbvie, treatment of rheumatoid arthritis: an evidence-based review and MSD, Jansen and Roche, and had consultation fees/participation in com- patient selection. Drug Des Devel Ther. 2018;13:57–70. pany sponsored speaker´s bureau from Abbvie, Pfizer, Roche, Sanofi, Lilly, •• Outstanding review article on tocilizumab and its efficacy in MSD and Novartis. S Castañeda has received grants/research supports the management of rheumatoid arthritis. from MSD and Pfizer, consultation fees/participation in company spon- 8. Yokota S, Itoh Y, Morio T, et al. Tocilizumab in systemic juvenile sored speaker´s bureau from Amgen, MSD, Lilly, Sobi and Pfizer. idiopathic arthritis in a real-world clinical setting: results from J Hernández-Rodríguez has participated in Sobi, Novartis and Roche 1 year of postmarketing surveillance follow-up of 417 patients in sponsored educational activities and has received consultation fees from Japan. Ann Rheum Dis. 2016;75:1654–1660. Sobi. J Cifrián participated in Boehringer Ingelheim, MSD and Roche • Study showing the efficacy of tocilizumab in systemic juvenile sponsored educational activities. The authors have no other relevant idiopathic arthritis, a chronic inflammatory disease that in affiliations or financial conflict with the subject matter or materials dis- some cases may be associated with the development of cussed in the manuscript apart from those disclosed. The remaining a macrophage activation syndrome. authors have nothing to declare. 9. Stone JH, Tuckwell K, Dimonaco S, et al. Trial of Tocilizumab in Giant-Cell Arteritis. N Engl J Med. 2017;377:317–328. •• A randomized controlled trial confirming the efficacy of tocili- zumab in giant cell arteritis, the most common vasculitis in Reviewer disclosures people 50 years and older from Western countries. Peer reviewers on this manuscript have no relevant financial relationships 10. Loricera J, Blanco R, Hernández JL, et al. Tocilizumab in giant cell or otherwise to disclose. arteritis: multicenter open-label study of 22 patients. Semin Arthritis Rheum. 2015;44:717–723. • Data supporting the efficacy of tocilizumab in real-world giant ORCID cell arteritis patients. In this open-label study tocilizumab led to clinical improvement in most cases. Significant reduction of José Hernández-Rodríguez http://orcid.org/0000-0002-2357-2015 acute phase proteins and prednisone dose was also achieved. 11. Atienza-Mateo B, Calvo-Río V, Beltrán E, et al. 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Current therapeutic options severe COVID-19 requiring ventilatory support who were trea- for the main monogenic autoinflammatory diseases and PFAPA ted with intravenous tocilizumab, obtaining rapid, sustained, syndrome: evidence-based approach and proposal of a practical and significant clinical improvement. guide. Front Immunol. 2020;11:865. 3. Srirangan S, Choy EH. The role of interleukin 6 in the pathophysiology •• Exhaustive review focused on conventional and biologic thera- of rheumatoid arthritis. Ther Adv Musculoskelet Dis. 2010;2:247–256. pies available (including colchicine, anakinra and tocilizumab) EXPERT OPINION ON BIOLOGICAL THERAPY 723 for the main monogenic autoinflammatory diseases and •• Interesting series of 29 patients with severe COVID-19 in PFAPA syndrome. whom anakinra at high doses (10 mg/kg/day intravenously) 14. 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