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Table of Contents
REVIEW ARTICLE
Year : 2020  |  Volume : 3  |  Issue : 4  |  Page : 344-355

2020 Updates on tocilizumab indications for clinicians managing patients with severe acute respiratory syndrome coronavirus 2


1 Rheumatology Unit, Department of Medicine, King Saud University, Riyadh, Saudi Arabia
2 Rheumatology unit, Department of Medicine, College of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
3 Rheumatology Unit, Department of Medicine, University of Jeddah, Jeddah, Saudi Arabia
4 Department of Clinical Pharmacy, King Saud University Medical City, Riyadh, Saudi Arabia
5 Pediatric Rheumatology Unit, Department of Pediatric, King Abdullah Specialized Children Hospital, Riyadh, Saudi Arabia
6 Infectious Disease Unit, Department of Medicine, King Saud University, Riyadh, Saudi Arabia

Date of Submission03-Jul-2020
Date of Acceptance10-Jul-2020
Date of Web Publication02-Oct-2020

Correspondence Address:
Mohammed A Omair
Rheumatology Unit, Department of Medicine, King Saud University, 38, PO Box 2925, Riyadh 11461
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JNSM.JNSM_85_20

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  Abstract 


In March 2020, the World Health Organization declared coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2, as a global pandemic. The number of infected individuals has grown exponentially, and no vaccine candidate is currently available. Hence, various drugs are being considered for the treatment of patients with COVID-19. Tocilizumab, a novel humanized monoclonal antibody targeting interleukin-6 (IL-6) receptor, has been approved for the treatment of various inflammatory conditions, including moderate-to-severe rheumatoid arthritis, giant cell arteritis, active polyarticular and systemic juvenile idiopathic arthritis in patients aged ≥2 years, and Castleman disease. Given that patients with severe COVID-19 show features of an accentuated immune response and increased release of many proinflammatory cytokines, including IL-6, tocilizumab has been repurposed as a possible COVID-19 therapy. This review provides clinicians managing patients with COVID-19 with an overview of the IL-6 pathway, its blockade by tocilizumab, and the effects of this drug in various inflammatory conditions, including current understanding of its effects in patients with COVID-19. Tocilizumab is listed as an option for treating severe or critical cases of COVID-19 with elevated IL-6 in the 7th edition of the National Health Commission of the People's Republic of China COVID-19 Diagnosis and Treatment Guide. A systematic review of six small observational studies and case reports on the supportive use of tocilizumab in patients with COVID-19 suggested some benefits of the treatment but did not allow solid conclusions; further clinical trials are currently evaluating the impact of adding tocilizumab to the treatment regimen for these patients.

Keywords: Coronavirus disease 2019, interleukin-6, receptor, tocilizumab


How to cite this article:
Omair MA, Hafiz W, Mustafa M, Ghoniam L, Alreshaid A, Almaghlouth I, Barry M. 2020 Updates on tocilizumab indications for clinicians managing patients with severe acute respiratory syndrome coronavirus 2. J Nat Sci Med 2020;3:344-55

How to cite this URL:
Omair MA, Hafiz W, Mustafa M, Ghoniam L, Alreshaid A, Almaghlouth I, Barry M. 2020 Updates on tocilizumab indications for clinicians managing patients with severe acute respiratory syndrome coronavirus 2. J Nat Sci Med [serial online] 2020 [cited 2020 Oct 20];3:344-55. Available from: https://www.jnsmonline.org/text.asp?2020/3/4/344/297123




  Introduction Top


On March 11, 2020, the World Health Organization recognized coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as a global pandemic. By May 28, 2020, it had infected 5,716,271 individuals in 188 countries and had caused 356,124 deaths. The number of cases is projected to grow exponentially worldwide, given the lack of availability of a vaccine candidate in the near future. Moreover, no randomized controlled clinical trial (RCT) data are available for the multiple therapeutic drugs currently being used to treat COVID-19-positive patients. Against this background, tocilizumab has emerged and has been repurposed as a possible therapy for COVID-19.

Tocilizumab is a humanized monoclonal antibody targeting the interleukin (IL)-6 receptor. It has been approved for different indications, including moderate-to-severe rheumatoid arthritis (RA), giant cell arteritis (GCA), active polyarticular and systemic juvenile idiopathic arthritis (PJIA and SJIA) in patients ≥2 years of age, and Castleman disease. Features of critically ill patients with COVID-19 suggest the presence of an accentuated immune response and increased release of many proinflammatory cytokines, including IL-6, resulting in adult acute respiratory distress syndrome (ARDS) and multiorgan failure. This hypothesis has spurred RCTs to evaluate the impact of using tocilizumab to the treatment regimen delivered to the patients with severe COVID-19 infection. Consequently, this review aimed to provide a concise overview of the IL-6 pathway and its blockade by tocilizumab to clinicians managing patients with COVID-19.


  Interleukin-6 and Interleukin-6 Receptor Top


IL-6 is a member of the IL-6 family, which consists of polypeptide cytokines with a 4-α-helix structure and a molecular mass of 21-'28 kDa [Figure 1].[1] IL-6 is encoded in the p15-'p21 region of chromosome 7 of the human genome.[2]
Figure 1: Structure of interleukin-6 of the 4 helices and the gp130 and interleukin-6 receptor alpha sites and Oncostatin M (reprinted permission from biochemical journal Heinrich et al. https://doi.org/10.1042/bj20030407)

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IL-6 was discovered in 1986 as an antigen-nonspecific B-cell differentiation factor that was initially named B-cell stimulatory factor 2 (BSF2).[3],[4],[5] IL-6 is a pleotropic cytokine that is produced by various types of immune and nonimmune cells, including T-lymphocytes, B-lymphocytes, fibroblasts, monocytes, and endothelial cells.[6]

IL-6 receptor (IL-6R) belongs to the cytokine receptor class I family and has two components: the α chain that is an 80-kDa IL-6-binding protein and the β chain that is a 130-kDa signal transducer, known as glycoprotein 130 (gp130).[7],[8],[9],[10] IL-6R exists in two forms: a soluble IL-6 receptor (sIL-6R) and a membrane-bound (or transmembrane) IL-6 receptor (mIL-6R) [Figure 2]. IL-6 transsignaling occurs through the sIL-6R, which activates cells that express gp130, whereas classical signaling is limited to the cells that express mIL-6R.[11] IL-6 binds to the IL-6R, leading to homo- or hetero-dimerization of the gp130 subunit and resulting in the creation of the high-affinity IL-6/IL-6R/gp130 complex. This complex has an essential role in the activation of the Janus tyrosine kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. The gp130 subunit contains two motifs, Box 1 and Box 2. The membrane-proximal region containing Box 1 and Box 2 activates JAK. Then, tyrosine phosphorylation in the distal part of gp130 occurs and recruitment of different subtypes of STAT, particularly STAT1 and STAT3 happens. STAT is then tyrosine phosphorylated by JAK.
Figure 2: Displaying the two types of interleukin-6 receptor; (a) membrane interleukin-6 receptor bound functioning through the classic membrane signaling and (b) soluble interleukin-6 receptor functioning through the transsignaling

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  Role of Interleukin-6 in Inflammation Top


IL-6 has many functions in immune regulation, hematopoiesis, inflammation, and oncogenesis. It induces differentiation and proliferation of many T-cell subtypes directly or through augmentation of IL-2R and increases the production of IL-2.[12],[13] IL-6 plays a vital role in the regulation of T-regulatory and Th17 cells. Its blockadein vivo corrects the Th17/T-regulatory cell imbalance.[14] It also enhances differentiation of macrophages, megakaryocytes, osteoclasts/osteoclast-like cell formation, angiogenesis, and demargination of neutrophils.[15],[16],[17],[18],[19],[20],[21],[22] IL-6 increases the release of IL-8, monocyte chemoattractant proteins, and adhesion molecules, all leading to an intense recruitment of different white cells into inflamed cites. In the synovium of patients with RA, IL-6 increases matrix metalloproteinase production, induces fibroblast-like synoviocyte proliferation, and enhances RANKL and ADAMTS-4 expression, all contributing to joint and cartilage destruction.[23],[24],[25],[26] Because of its positive effects on osteoclasts, IL-6 deficiency protects against bone loss in both animal models and human studies.[27],[28] IL-6 levels are also negatively correlated with bone mineral density in RA patients.[29]

Before elucidation of the multiple roles of IL-6, it was also known as a hepatocyte stimulating factor as it stimulated the production of positive acute-phase proteins (APPs), including C-reactive protein (CRP), fibrinogen, α1-antitrypsin, antichymotrypsin, and serum amyloid A. However, it suppressed the production of negative APPs, such as albumin and transferrin.[30],[31],[32] Hepcidin, a peptide produced by the liver, plays a major role in iron regulation. Anemia of chronic illness is believed to be partly due to the overproduction of hepcidin, which inhibits iron release from macrophages and decreases iron absorption from the intestines.[33] In addition, IL-6 levels were found to be elevated in the bone marrow of RA patients, leading to inhibition of erythroid cells.[34],[35],[36]

IL-6 has also an anti-inflammatory effect through the suppression of tumor necrosis factor (TNF)-α and IL-1.[25] IL-6 inhibits the proliferation of fibroblastic synovial cells and exerts a negative feedback on TNF-α-induced synovial growth.[37] Furthermore, IL-6 is believed to play a vital role in directing the transition from innate immunity to acquired immunity [Figure 3].
Figure 3: The therapeutic effect of blocking interleukin-6 in patients with rheumatic diseases

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  Mechanism of Action of Tocilizumab Top


Tocilizumab is a genetically engineered humanized monoclonal antibody. It competitively inhibits the binding of IL-6 to both s- and mIL-6Rs, thereby inhibiting IL-6 signaling. Tocilizumab is approved by the US Food and Drug Administration (US FDA) for the treatment of patients with active RA in whom disease-modifying antirheumatic drugs (DMARDs) have failed, as well as for the treatment of GCA. Moreover, it has been approved for both PJIA and SJIA in patients ≥2 years of age. In 2017, the US FDA expanded the approval of tocilizumab to use in both adults and pediatric ≥2 years of age, with chimeric antigen receptor (CAR) T-cell-induced severe or life-threatening cytokine-release syndrome (CRS) associated with hematological malignancies.[38] Tocilizumab is available in intravenous (IV) and subcutaneous dosage forms. Dosing recommendations differ based on the diagnosis, route of administration, and patient's weight [Table 1].
Table 1: Approved doses for tocilizumab in different indications

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Pharmacodynamics

Tocilizumab binds to IL-6R in a dose-dependent manner, saturating the receptor at a concentration of approximately 0.1 mg/mL. Complete competitive inhibition of binding of IL-6 to its receptor is observed at a tocilizumab concentration of approximately 4 mg/mL.[39]

Pharmacokinetics

Tocilizumab has a nonlinear pharmacokinetic profile, based on preclinical and human clinical studies. Dose-'response curves demonstrated that as the dose is increased, the maximum concentration is increased in approximate proportion, whereas the area under the receiver operating characteristic curve increases disproportionately. Therefore, doses greater than 800 mg are unlikely to increase clinical efficacy and are not recommended in the package insert.[39]

Tocilizumab's pharmacokinetic parameters are not affected by age, sex, race, alcohol intake, mild renal dysfunction, or concomitant administration of medications, such as methotrexate (MTX), nonsteroidal anti-inflammatory drugs, or steroids.

In patients with RA, the volume distribution at steady state is 6.4 L. The excretion in breast milk is still not known, and caution should be taken when prescribed to lactating patients. No pharmacokinetic studies in patients with moderate-to-severe renal impairment or in patients with hepatic dysfunction have been reported to provide recommendations on dosing adjustment in these patients. The small values for the volume of distribution indicate a low tissue penetration of tocilizumab, comparable to that of other IgG molecules.

The total clearance of tocilizumab is concentration dependent and is described as biphasic, with linear and nonlinear clearance pathways. Nonlinear clearance plays a leading role at low tocilizumab concentrations and depends on IL-6R saturation. At higher tocilizumab concentrations, and as the nonlinear clearance pathway becomes saturated, drug elimination is mainly determined by linear clearance. In addition, body weight has a major impact on IV tocilizumab's clearance and volume parameters, and exposure of drug is inversely correlated with body weight. At a 10 mg/kg single dose in RA patients, the mean clearance was 0.29 ± 0.10 mL/h/kg, the mean apparent terminal t1/2 was 151 ± 59 h (6.3 days), and the steady state volume of distribution was 60 mL/kg. These values were comparable to those in healthy subjects receiving the same dose.[40]

Cytokines, such as IL-6, downregulate the cytochrome P450 (CYP450) system enzymes in the liver during infection and inflammation. Blocking of IL-6 signaling with tocilizumab may restore CYP450 actions, leading to higher metabolism of CYP450 substrates. IL-6 inhibits the action of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 enzymes. Hence, caution should be applied when using tocilizumab concomitantly with CYP450 substrates with a narrow therapeutic index, such as warfarin, cyclosporine, or phenytoin. Due to the long half-life of tocilizumab, monitoring of such interactions may be needed for several weeks after discontinuation of therapy.

A flat dose of subcutaneous tocilizumab of 162 mg is used, regardless of the patient's weight, different from the weight-based dosing of the IV form. The pharmacokinetics of the subcutaneous formulation of tocilizumab is best defined by a two-compartment model, with linear elimination and first-order absorption. To maintain a comparable clinical response to the IV administration, subcutaneous tocilizumab is given every week in obese patients (>100 kg).[41]


  Required Screening Tests Before Initiation of Tocilizumab Top


Routine laboratory tests, such as a complete blood count, liver function test (LFT), and creatinine and urine analysis, are the standard of care. Viral hepatitis screening and screening for latent tuberculosis with chest X-rays and tuberculin skin tests or interferon-gamma release assays are essential to prevent reactivation, even in tuberculosis-nonendemic areas.


  Safety of Tocilizumab Top


An integrated analysis of 4.6 years of exposure, including all RCTs with their long-term extensions, was the largest safety report on tocilizumab, involving 4009 patients with 12,293 patient-years (PY). On average, 16% of patients withdrew from tocilizumab because of adverse events, with the majority discontinuing treatment within the 1st year. The rate of withdrawal owing to adverse events was 10.2/100 PY.[42]

Liver function test abnormalities

Raised LFT values are the most commonly encountered laboratory abnormality in patients receiving tocilizumab. Routine monitoring is advised, particularly in the first 12 weeks of therapy. A 3-fold increase in ALT and AST was observed in 10.8% and 3.4% of patients, respectively. Eighty percent of patients' values return to normal after 5 weeks of treatment, while ≥5-fold increase in ALT and AST values is observed in only 2.9% and 0.9% of patients, respectively. This increase in LFT values led to discontinuation of tocilizumab treatment in 2.5% of patients.[43]

Cytopenia

The most important CBC abnormality observed in patients on tocilizumab is mild neutropenia, with 4.8% of patients reaching neutrophil levels of 500-'1000 × 109/L, while <1% of patients reach a level below 500 × 109/L, mandating discontinuation. Similarly, <1% of patients developed thrombocytopenia, with platelet counts of 50-'25 × 109/L, while another 1% developed platelet levels < 25 × 109/L, mandating treatment discontinuation.

Effect on lipid profile

Increased lipid parameters were observed in patients using tocilizumab during the first 6 weeks, with subsequent stabilization. This increase was greater than that seen in patients on a TNF inhibitor (TNFi).[44]

Infection

Tocilizumab has been associated with a serious infection rate of 4.5/100 PY. This risk is higher than that of conventional DMARDs and is similar to all other biologics and small molecules.[45] Most involved bacterial infections, such as pneumonia. In rare cases, invasive fungal infection can occur.

Gastrointestinal perforation

Gastrointestinal perforation is another rare complication seen in patients using tocilizumab, occurring at a rate of 0.2/100 PY. Patients with a history of diverticular disease or previous perforation need to be counseled before tocilizumab initiation.


  Rheumatoid Arthritis Top


RA is the most common indication for tocilizumab use. The efficacy of tocilizumab in RA management was assessed in many pivotal RCTs. The tocilizumab program enrolled patients who had active disease, manifested by ≥8 tender and ≥6 swollen joints, and high disease activity, evaluated by composite measures, such as Disease Activity Score at 28 joints (DAS28) and the American College of Rheumatology (ACR) 20%, 50%, and 70% response rates at study inclusion.

In the AMBITION study, IV tocilizumab monotherapy was administered every 4 weeks as monotherapy,[46] while in the LITHE,[47] OPTION,[48] and RADIATE[49] studies, IV tocilizumab every 4 weeks was combined with MTX as compared with placebo plus MTX. In the TOWARD study,[50] IV tocilizumab was administered every 4 weeks in combination with other DMARDs, as compared with placebo and other DMARDs. All studies proved superiority of IV tocilizumab (8 mg/kg) in view of statistically significantly higher ACR 20%, 50%, and 70% response rates and greater reduction in the DAS28 score at 24 weeks as compared with controls.

Improvement in patient-reported outcomes was evident in multiple RCTs assessing patient function, quality of life, fatigue, and sleep quality in RA patients treated with tocilizumab compared with control (adalimumab monotherapy, conventional DMARDs, MTX, or placebo). The ADACTA trial[51] was the first head-to-head comparison between two biologics as monotherapy. The trial used IV tocilizumab monotherapy every 4 weeks, as compared with adalimumab (the current market leader) monotherapy subcutaneously every 2 weeks. At week 24, patients on tocilizumab had a more significant improvement in all composite measures, including one that did not include an acute-phase reactant component (Clinical Disease Activity Index) [Figure 4].
Figure 4: Timeline of landmark clinical trials and Food and Drug Authority approval of different drug formula and indications of tocilizumab in rheumatology

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  Giant Cell Arteritis Top


GCA is an idiopathic systemic vasculitis that involves the aorta, its major branches, and other large vessels. It occurs after the age of 50 years and affects females more frequently than males. Clinical features include new-onset temporal headache, jaw claudication, a variety of ocular manifestations, and constitutional symptoms. Erythrocyte sedimentation rate and CRP levels are typically elevated, and temporal artery biopsy is required to confirm the presence of vasculitis and granuloma.[52]

IL-6 production by GCA granuloma cells has long been documented, and the level of this cytokine is elevated in patients with GCA.[53] These observations suggest a possible role of IL-6 inhibition in the treatment of GCA. The GIACTA trial was a randomized, multicenter, double-blind, placebo-controlled Phase III superiority study that was conducted to assess the efficacy and safety of tocilizumab in GCA patients.[54] Two hundred and fifty-one GCA patients were enrolled in an initial 52-week blinded period followed by a 104-week open-label extension. Two subcutaneous doses of tocilizumab (162 mg every week and 162 mg every other week) with background prednisone were compared with two different placebo-controlled groups. The primary efficacy end point was the percentages of patients with sustained prednisone-free remission at week 52.

Sustained remission at 52 weeks was achieved by 56% of the weekly tocilizumab group and 53% of the every-other-week tocilizumab group, as compared with 14% of the 26-week tapered prednisone and placebo group and 18% of the 52-week tapered prednisone and placebo group. Further, the tocilizumab groups had a significantly lower cumulative prednisone dose as compared to both placebo groups. Finally, a lower risk of flare was observed in the tocilizumab groups (P = 0.01). Serious adverse events were more common in the placebo group and mostly involved infection.


  Adult-Onset Still's Disease Top


Adult-onset Still's disease (AOSD) has similar features of SJIA in the adult population. This includes, fever, arthritis, rashes, elevated ferritin, and CRP.

Tocilizumab efficacy and safety have been demonstrated in a small RCT from Japan[56] and in several case reports[57],[58],[59],[60],[61],[62],[63],[64],[65],[66],[67] and one case series.[68] The patients included in these studies were refractory to corticosteroids, DMARDs, TNFis, and anakinra.

In 2013, a systematic review of 35 patients with AOSD who were treated with tocilizumab revealed that 94% of patients had been resistant to other immunosuppressive therapies.[69] Significant improvement in joint symptoms was noted in 86% of the patients, while 28 of 35 patients noted a remarkable response in their systemic manifestations, and 80% were able to taper their glucocorticoid doses. Disease relapse was seen in four patients and was attributed to dose reduction or treatment discontinuation. Adverse reactions included development of macrophage activation syndrome, secondary to cytomegalovirus reactivation in two patients, one of whom also had clostridium bacteremia.

Tocilizumab was also effective as monotherapy or when corticosteroids could not be used.[70] It was successful in managing serious AOSD-related complications, such as thrombotic thrombocytopenic purpura, aseptic meningitis, and macrophage activation syndrome.[63],[64],[71]


  Systemic Juvenile Idiopathic Arthritis Top


SJIA is a subcategory of juvenile idiopathic arthritis (JIA). JIA is a group of heterogeneous diseases involving chronic inflammatory arthritis of unknown cause and lasting for more than 6 weeks, with onset below 16 years of age. JIA is subdivided into seven relatively homogenous groups that include oligoarticular (affecting four or fewer joints), polyarticular (affecting more than four joints), either rheumatoid factor-positive or -negative, systemic, psoriatic, enthesitis-related, and undifferentiated arthritis. SJIA is a very distinctive subtype and is characterized by fever and arthritis associated with at least one of the following: rash, generalized lymphadenopathy, serositis, and hepatomegaly or/and splenomegaly.[72]

Serum and synovial levels of IL-6 have been found to correlate with the presence of spiking fever.[73],[74] Tocilizumab received FDA approval in 2011 for the treatment of SJIA after the promising results of two Phase II dose-escalating trials,[75],[76] and two Phase III studies, which showed the efficacy of tocilizumab. In the first study, 56 Japanese children were included in 3-phase RCT with a withdrawal design. The first phase was an open-label phase of 6-week duration followed by a double-blind randomized phase of 12-week duration and ended by an open-label and open-label extension phase of at least 48 weeks. Of the patients who were included in the double-blind phase, 4 (17%) of 23 patients in the placebo group maintained an ACR Pedi 30 response (a similar composite measure to the previously described ACR, used in JIA patients) and a CRP concentration of <15 mg/L, compared with 16 (80%) of 20 in the tocilizumab group (P < 0.0001). At the end of the open-label extension Phase IV, 7 (98%), 45 (94%), and 43 (90%) of patients achieved ACR Pedi 30, 50, and 70 responses, respectively.[40] In the second multicenter Phase III trial of patients who had active SJIA for at least 6 months and an inadequate response to nonsteroidal anti-inflammatory drugs and glucocorticoids, 112 children were enrolled (37 controls, 75 on tocilizumab, at a dose of 8 mg/kg for those weighing ≥30 kg or a dose of 12 mg/kg for those weighing <30 kg). The children received randomized treatment for 12 weeks, followed by a long-term open-label phase. ACR Pedi 30, 70, and 90 responses were achieved in 85%, 71%, and 37% of the tocilizumab group versus 24%, 8%, and 5% in the control group.[77]

Subcutaneous tocilizumab received FDA approval for the treatment of active SJIA in patients ≥2 years, with a dose of 162 mg every 2 weeks for those weighing <30 kg and a dose of 162 mg every week for those weighing ≥30 kg.


  Polyarticular Juvenile Idiopathic Arthritis Top


The efficacy of tocilizumab at the 8 mg/kg dosing was shown in an open-label Phase III study, in 19 children with PJIA (2 with oligoarticular onset), in whom MTX therapy failed. The study was divided into two phases, an initial 12-week phase, followed by a 48-week extension phase. At 48 weeks, 100%, 94.1%, 88.2%, and 64.7% achieved ACR Pedi 30, 50, 70, and 90 response rates. Rheumatoid factor tested positive in 9 (47%) patients.

Brunner et al. performed an RCT with a withdrawal design on tocilizumab in PJIA patients, using three phases: a 16-week open-label period (Phase I), followed by a double-blinded withdrawal period (Phase II) for patients who responded to tocilizumab in Phase I, as well as an open-label extension period (Phase III). All patients (188 patients at enrolment) received tocilizumab. In the second phase of the study, patients were randomly assigned to receive either placebo or to continue active therapy until week 40; patients were withdrawn from the study if they did not achieve ACR Pedi 30 by the end of Phase I. Overall, 89.4% attained ACR Pedi 30 by the end of Phase I, at week 16. The primary end point was JIA flare at the end of part 2, at week 40 of the study, with 48.1% of the patients in the placebo group developing flare, as compared with only 25.6% in the tocilizumab group.

Tocilizumab has also been used off label in pediatric patients with Takayasu's arteritis, autoimmune encephalitis, and JIA-associated refractory uveitis, with promising results.[78]


  Chimeric Antigen Receptor T-Cell-Induced Severe or Life-Threatening Cytokine-Release Syndrome Top


CRS has been identified as an adverse event of CAR T-cell therapies. It is characterized by initial features such as fever, fatigue, and headache. Patients can progress and develop more serious manifestations, including tachycardia hypotension, encephalopathy, coagulopathy, and capillary leak, all leading to multiorgan dysfunction and death.[79] CRS results from the effect of cytokines released by the CAR T-cell once it is engaged with the target malignant cells. Serum levels of cytokines, particularly IL-6, are elevated, and the severity of symptoms correlates with the serum cytokine concentrations and the duration of exposure to inflammatory cytokines.[80] The US FDA has approved tocilizumab for the treatment of CAR T-cell-induced severe or life-threatening CRS for children ≥2 years of age.


  Castleman Disease Top


Tocilizumab is approved in Japan for the treatment of Castleman disease after a pilot study, which involved seven patients, and a multicenter Phase I trial, which involved 28 patients, as well as numerous case reports. It was found to be effective in improving a wide range of disease manifestations, including autoimmune hemolytic anemia, hepatosplenomegaly, pulmonary hypertension, lung lesions, cardiomyopathy, renal manifestations, and IgA nephropathy with cutaneous nodule.[81],[82]


  Benefits of Tocilizumab in Patients With Systemic Sclerosis-Associated Interstitial Lung Disease Top


Several uncontrolled studies have demonstrated good efficacy of tocilizumab in autoimmune-associated interstitial lung disease (ILD), including conditions such as Castleman disease, RA, and Sjögren's syndrome.[83],[84],[85],[86] Systemic sclerosis (SSc) is considered an autoimmune disease with predominant fibrotic features, such as skin thickening/tightness, and a very high rate of ILD. IL-6 stimulates fibroblasts to produce collagen, which underlies the main aspect of SSc pathogenesis.[87] The FaSScinate study, a Phase II RCT, has shown that tocilizumab improves the skin score and lung function of patients with SSc with a disease duration of ≤5 years, indicating that IL-6 blockade halts fibrosis and is a promising agent in a disease with limited options, such as SSc.[88]


  Covid-19 Pathogenesis Top


SARS-CoV-2 is a positive-sense, single-stranded RNA virus that belongs to the genus Betacoronavirus.[89] Its spike protein binds to angiotensin-converting enzyme 2 (ACE2), which is a cell surface protein that is highly expressed in the lungs, heart, and kidneys.[90] Its genome is more than 80% similar to that of SARS-CoV-1 and 50% to that of MERS-CoV.[91] These three coronaviruses are known to cause ARDS; the ARDS caused by MERS-CoV has the highest case-fatality rate.[92] Studies to date suggest that most patients infected with SARS-CoV-2 remain asymptomatic or develop mild symptoms, but a small proportion between 15% and 20% of patients develop severe respiratory distress syndrome or septic shock. Pneumonia associated with COVID-19 is marked by the hyperactivation of effector T-cells and excessive production of inflammatory cytokines, particularly IL-6, which causes a cytokine storm, also known as CRS. This causes capillary leakage, increased vascular permeability, and coagulopathy, which causes further dissemination of the SARS-CoV-2 and ultimately death. Hence, the use of an IL-6 blocker may be useful.[93] It has also been speculated that patients taking such therapy may even be protected against SARS-CoV-2 pneumonia (5), and because of its efficacy in CRS, it has been proposed that tocilizumab should be used to treat severe cases.

Early diagnosis of CRS in patients with COVID-19 and prompt initiation of immunomodulatory therapy would be needed if such treatment is to be effective. Screening of patients with COVID-19 by means of the H-score (a diagnostic score for hemophagocytic lymphohistiocytosis)[94] may help identify patients with CRS and may have clinical application.[95] Treatment with tocilizumab is included as one of the treatment options for severe or critical cases of COVID-19 with elevated IL-6 in the 7th ed.ition of the National Health Commission of the People's Republic of China COVID-19 Diagnosis and Treatment Guide.[96] The recommended dose in this guide is 4-'8 mg/kg or 400 mg standard dose IV once, with the option to repeat a dose in 12 h (not to exceed a total dose of 800 mg). A systematic review published on six studies that included small observational studies and case reports on the supportive use of tocilizumab in patients with COVID-19 suggested some benefits of the treatment but did not allow solid conclusions.[97]

We searched the ClinicalTrials.gov and Chinese Clinical Trial Registry websites on April 15, 2020 and found 19 ongoing registered clinical trials for the use of tocilizumab in patients with COVID-19. Of those, 4, 13, and 2 are Phase III, II, and observational trials. [Table 2] describes the title, phase, sample size, and primary outcomes of these studies. Six trials are evaluating the effects of tocilizumab either as a monotherapy or part of a combination regimen, including hydroxychloroquine/azithromycin, anakinra, favipiravir, the lysosomotropic oral agent GNS561 (a chloroquine analog)/nivolumab, mefloquine, and dalargin. The following primary outcomes were selected cure rate/clinical recovery (4 studies), mortality/survival (3 studies), admission to intensive care unit/requirement of mechanical ventilation (3 studies), and improvement of oxygen saturation (3 studies). The results of these and other studies, once available, will ultimately shed light on the true efficacy of tocilizumab against SARS-CoV-2.
Table 2: Clinical trials registered evaluating tocilizumab in patients with coronavirus disease 2019 infection

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  Tocilizumab and the Risk of Pulmonary Toxicity Top


As patients with COVID-19 commonly experience pulmonary deterioration, it is important to understand that tocilizumab has been associated with the development or deterioration of preexisting ILD and other noninfectious pulmonary complications, particularly in RA-related reports. This is, in part, related to the variation in definition of the study population, misclassification of RA patients without ILD, particularly when chest X-ray is used for case definition, selection bias, or channeling bias.

Given that patients with preexisting ILD are usually excluded from RA RCTs, the effect of tocilizumab on the lung needs to be assessed through registries and anecdotal reports.[98] This is further confounded by the underlying disease and concomitant MTX use. Nishimoto et al. reported a case of an allergic pneumonitis patient who had received three doses of IV tocilizumab in a RCT of 164 Japanese patients.[99] Similarly, in the OPTION study, one patient who received tocilizumab was diagnosed with ILD after 9 weeks.[48] In the Satori study, comparing MTX versus tocilizumab, Nishimoto et al. reported one case of pneumonia in each group. Ikegawa et al. reported the case of an RA patient who developed organizing pneumonia after 3 days of starting tocilizumab, against a background of MTX treatment. They concluded that tocilizumab caused the development of organizing pneumonia, given that the patient had been treated with MTX for 2 years before the incident, and there was a significant resolution of symptoms and radiological changes after tocilizumab was discontinued, without the need for initiating corticosteroids.[100] In 2010, Kawashiri et al. reported the first RA patient to die from severe ILD exacerbation after tocilizumab treatment for 10 months.[101] Curtis et al. assessed the MarketScan databases between 2010 and 2012 and found that there was no difference in the incidence of ILD or its complications between TNFi and biologics with other mechanisms of action, including tocilizumab. This was confounded by the fact that patients in the described database typically cycle between TNFis before using a drug with a different mechanism of action; hence, their disease duration is longer and their condition is more refractory to treatment.[102] Akiyama et al. identified several risk factors that may increase the risk of ILD in 395 patients receiving tocilizumab who are aged ≥60 years (odds ratio [OR] 4.5, 95% confidence interval [CI] 2.2–9.4, P < 0.0001), have positive smoking status (OR 2.9, 95% CI 1.5–5.5, P = 0.002), and have high rheumatoid factor levels (OR 2.8, 95% CI 1.4–5.5, P = 0.002).


  Conclusions Top


Tocilizumab is a drug with an innovative mechanism of action that might has potential benefits in patients with COVID-19 infection and manifestations related to uncontrolled cytokine release. Its safety and effectiveness profile in patients with different chronic inflammatory disorders has been well established in the last decade. Pivotal clinical trials testing its use in patients with COVID-19 is awaiting.

Acknowledgment

The authors would like to thank Editage (www.editage.com) for the English language editing services provided.

Financial support and sponsorship

Nil.

Conflicts of interest

Mohammed A. Omair has received speaker's fees/grants from Abbvie, Actelion, Amgen, Brystol Myers Squibb, Glaxo-Smith-Kline, Hekma, Janssen, New Bridge, Novartis, Pfizer, and Roche.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

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  In this article
Abstract
Introduction
Interleukin-6 an...
Role of Interleu...
Mechanism of Act...
Required Screeni...
Safety of Tocili...
Rheumatoid Arthritis
Giant Cell Arteritis
Adult-Onset Stil...
Systemic Juvenil...
Polyarticular Ju...
Chimeric Antigen...
Castleman Disease
Benefits of Toci...
Covid-19 Pathoge...
Tocilizumab and ...
Conclusions
References
Article Figures
Article Tables

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