Version May 2024
INTRODUCTION — Interleukin (IL) 6 is a potent proinflammatory mediator that is important in immune defense and in immune-mediated disease. Four pharmacologic inhibitors (sometimes termed blockers) of IL-6 are commercially available for clinical use: tocilizumab, sarilumab, and satralizumab, which are all monoclonal antibodies directed against the IL-6 receptor (IL-6R), and siltuximab, a monoclonal antibody specific for IL-6.
General considerations regarding the use of these agents are presented here. The use of these agents for the treatment of specific inflammatory and autoimmune conditions is described in detail separately:
●(See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'IL-6 inhibitor therapies' and "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'Methotrexate plus IL-6 inhibitor/IL-6 inhibitor monotherapy'.)
●(See "Polyarticular juvenile idiopathic arthritis: Treatment", section on 'Tocilizumab'.)
●(See "Systemic juvenile idiopathic arthritis: Treatment", section on 'Interleukin 6 inhibitors'.)
●(See "Treatment of adult-onset Still's disease", section on 'Interleukin 6 inhibition'.)
●(See "Treatment of giant cell arteritis", section on 'Tocilizumab'.)
●(See "HHV-8-negative/idiopathic multicentric Castleman disease", section on 'IL-6 inhibitors'.)
INTERLEUKIN 6 BIOLOGY AND FUNCTION — Interleukin (IL) 6 is a proinflammatory cytokine, originally described as B cell differentiation factor, that mediates pleiotropic functions in immunologic responses during host infection, inflammatory disease, hematopoiesis, and oncogenesis. It can also exhibit antiinflammatory effects [1-3].
The IL-6 receptor (IL-6R) comprises two functional chains, IL-6R alpha (IL-6Ra) and a 130 kD non-ligand-binding chain capable of signal-transduction (glycoprotein 130 [gp130]), which mediate gene activation and a wide range of biologic activities (figure 1) [4,5]. IL-6 binds to both soluble and membrane-bound receptors, using three different but related signaling pathways [2,6,7]. It can signal by binding membrane-bound IL-6Ra/gp130 complexes on target cells (termed classic cis signaling) and can form soluble complexes with non-membrane bound IL-6Ra. Membrane expression of gp130 in the absence of IL-6Ra is widespread and confers upon the expressing cell the capacity to respond to circulating IL-6/IL-6Ra complexes (termed soluble trans-signaling). Trans-presentation of IL-6 by dendritic cell (DC)-bound IL-6Ra to gp130-expressing T cells can also induce a signal (termed trans presentation) [7,8].
IL-6Ra is expressed on a limited number of cell types, including hematopoietic cells and hepatocytes. By contrast, gp130 is expressed ubiquitously on most cells. The classic pathway is thought to induce the acute phase response, protect against infection, and stimulate metabolism and regeneration in liver and intestinal epithelium, while the soluble trans pathway is thought to be more important in stimulating inflammation.
IL-6 regulates the immune response, specifically the proliferation and differentiation of T cells and the terminal differentiation of B cells. IL-6 also activates macrophages and osteoclasts and is a pivotal mediator of the hepatic acute phase response. In concert with tumor necrosis factor (TNF) alpha and IL-1, IL-6 promotes vascular endothelial growth factor (VEGF) and metalloproteinase production [5]. IL-6, together with transforming growth factor (TGF) beta, also has a role in the development of regulatory T cells. IL-6, like IL-1, is important for both systemic and local inflammation that is often associated with symptoms like fever, fatigue, and anorexia, with changes in acute phase proteins in the plasma (eg, C-reactive protein and fibrinogen).
IL-6 has been implicated in the pathogenesis of autoimmune diseases. As an example, in rheumatoid arthritis (RA), IL-6 is expressed in RA synovial tissues and plays an important role in upregulation of endothelial adhesion molecule expression, in osteoclast maturation, and in promoting bone erosion. IL-6 also mediates systemic features of disease, including fatigue, cognitive dysfunction, and metabolic shift.
PRETREATMENT TESTING — We perform the following testing and evaluation before initiating treatment with an interleukin (IL) 6 inhibitor:
●Patients are at risk for cytopenias, dyslipidemias, and abnormalities in liver function (see 'Adverse effects' below). Baseline laboratory studies typically include a complete blood count with differential and platelet count; liver function tests, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST), bilirubin, and alkaline phosphatase; and a lipid panel, including total cholesterol, low-density lipoprotein, high-density lipoprotein, and triglycerides. Additional testing may be required for assessment of disease activity, which varies depending upon the disorder being treated. Testing varies with region in some cases (eg, alkaline phosphatase is not typically performed in Germany for these patients).
●Females of reproductive age should be screened for pregnancy and counseled appropriately with respect to reproductive risk. Additional information regarding risk during pregnancy and breastfeeding is provided separately, including in the respective drug information topics for each agent. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Tocilizumab'.)
●Screening for latent tuberculosis, hepatitis B (including testing for hepatitis B virus [HBV] surface antigen and HBV core antibody), and hepatitis C virus is generally performed prior to initiating treatment. (See 'Infection' below and "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)" and "Tuberculosis infection (latent tuberculosis) in children" and "Hepatitis B virus: Screening and diagnosis in adults" and "Screening and diagnosis of chronic hepatitis C virus infection".)
In patients with rheumatoid arthritis (RA), giant cell arteritis (GCA), and systemic sclerosis with interstitial lung disease (SSc with ILD), IL-6 inhibitors, including tocilizumab and sarilumab, are usually avoided in those with absolute neutrophil counts <2000/mm3, platelet counts <100,000/mm3, or ALT or AST levels >1.5 times the upper limit of normal. Patients with cytopenias or abnormal liver testing who do receive these drugs should be closely monitored. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'IL-6 inhibitor therapies'.)
Treatment with IL-6 inhibitors is generally avoided in patients with prior diverticulitis, active hepatic disease or hepatic impairment, or in patients with RA or GCA whose baseline ALT or AST is >1.5 times the upper limit of normal. In patients in whom there is an urgent indication for use, such as resistant GCA, consultation with a gastroenterologist or a hepatologist is advised.
Patients with severe or life-threatening cytokine release syndrome (CRS) may exhibit cytopenias or elevated liver transaminases due to the underlying disease state and/or its treatment. Thus, relative risks and benefits should be evaluated on an individual basis in such patients. (See "Cytokine release syndrome (CRS)", section on 'Laboratory'.)
STRUCTURE AND MECHANISM OF ACTION OF SPECIFIC AGENTS
●Tocilizumab – Tocilizumab is a humanized immunoglobulin G subclass 1 (IgG1) monoclonal antibody to the interleukin (IL) 6 receptor (IL-6R). The antibody is made by grafting the complementarity determining regions of a mouse anti-human IL-6R monoclonal antibody onto human IgG1. Tocilizumab binds to both the membrane-bound and soluble forms of human IL-6R, thereby inhibiting the binding of the native cytokine to its receptor and interfering with the cytokine's effects.
●Sarilumab – Sarilumab is a fully human recombinant IgG1 monoclonal antibody that is directed against the membrane-bound and soluble forms of the IL-6R. As with tocilizumab, sarilumab inhibits the binding of the native cytokine to its receptor and interferes with the cytokine's effects.
●Siltuximab – Siltuximab is a chimeric anti-IL-6 monoclonal antibody that directly inhibits IL-6.
●Satralizumab – Satralizumab is a humanized monoclonal antibody that binds IL-6Rs, thereby suppressing inflammation mediated by IL-6 signaling pathways.
●Investigational agents – Several agents that also inhibit IL-6 have been investigated for various disorders but are not available for clinical use. These include the anti-IL-6 antibodies, clazakizumab [9-11], and olokizumab [11-16].
ADVERSE EFFECTS
Range of adverse effects — The most commonly reported adverse events associated with interleukin (IL) 6 receptors (IL-6Rs)/IL-6 inhibitors are nasopharyngitis, headache, upper respiratory tract infection, gastritis, rash, arthralgia, extremity pain, fatigue, and nausea. Infections are the most frequent serious adverse events reported. Gastrointestinal perforation can occur in adults. Laboratory abnormalities include neutropenia, thrombocytopenia, dyslipidemia, and elevated liver enzymes. A significant increase in the rates of malignancy, autoimmunity, tuberculosis reactivation, or hepatitis have not been reported [17]. The risk of tuberculosis reactivation and of primary infection appears to be very low [18], although some trials excluded patients with latent tuberculosis.
Injection site reactions have been reported in approximately 10 percent of adults receiving tocilizumab by subcutaneous injection [19]; they may be more common in children. With intravenous administration, infusion reactions can occur, but anaphylaxis is rare [19,20]. Antidrug antibodies against tocilizumab occur in 0 to 16 percent of patients with rheumatoid arthritis (RA) and 1 to 8 percent of patients with juvenile idiopathic arthritis [21,22]. Loss of efficacy was not observed in the analysis of multiple trials involving nearly 9000 patients [22].
The safety of tocilizumab has been characterized in multiple randomized trials, systematic reviews, and meta-analyses, particularly for treatment of RA [17,23-29]. The adverse effects of other IL-6 inhibitors are thought to be similar, although there is less experience with sarilumab, as well as siltuximab, satralizumab, sirukumab [30-33], and clazakizumab.
Infection — In clinical trials and an integrated safety analysis of patients receiving an IL-6R inhibitor in combination with a conventional disease-modifying antirheumatic drug (DMARD) or as monotherapy, the risk of infections was found to be increased compared with placebo but in line with other biologic DMARDs [6,24,34-37].
An increased rate of infections, including mycobacterial and other opportunistic infections, is reported in patients treated with IL-6R/IL-6 inhibitors [24,26]. Most patients recover with appropriate treatment. The risk of serious infection is greater in patients on concomitant immunosuppressive therapy.
The reported serious infection rate in patients with RA treated with tocilizumab ranges from 3.7 to 5.7 per 100 patient-years [25,27,28]. Most infections are bacterial in nature, including pneumonia, bronchitis, cellulitis, and sepsis, although atypical mycobacterial infections, Pneumocystis jirovecii pneumonia, and herpes zoster infections occur as well. Risk factors include advanced age, long disease duration, concomitant therapy (such as glucocorticoids and methotrexate), and respiratory comorbidities. Higher rates of infections, including sinopulmonary infections, septic arthritis, varicella, and gastroenteritis, were also reported in a trial of tocilizumab in children with systemic juvenile idiopathic arthritis [38].
A 2011 meta-analysis of safety data in patients with RA on tocilizumab found that opportunistic infections developed at a rate of 0.23 episodes per 100 patient-years [26]. Such infections included active tuberculosis, nontuberculous mycobacteria, invasive candidiasis, P. jirovecii pneumonia, and cryptococcosis, especially with higher doses of tocilizumab. Another 2011 meta-analysis of randomized trials in patients with RA found that the rate of infection was increased in patients receiving tocilizumab plus methotrexate compared with placebo plus methotrexate (odds ratio [OR] 1.3, 95% CI 1.1-1.6) [17].
In patients with coronavirus disease 2019 (COVID-19), several observational studies found an association between treatment with tocilizumab and increased rates of fungal infections, particularly Candida and Aspergillus, and bacterial infections in patients with severe disease [39-41]. However, many of the patients in these studies were critically ill, and they also received glucocorticoids, sometimes in high doses, as well as other immunosuppressive agents. In addition, a meta-analysis of 10 observational studies of patients with COVID-19 did not show a clear association between tocilizumab and increased secondary infections [42]. Furthermore, this finding was not confirmed in several randomized trials, in which fewer serious infections were seen in patients hospitalized with COVID-19 who were receiving tocilizumab compared with placebo [43-45]. Despite lack of a clearcut signal for increased risk of fungal and bacterial infections in patients with COVID-19 treated with tocilizumab, clinicians should still monitor these patients closely for serious infections, particularly those with severe disease who have received other immunosuppressive agents.
Few serious infections have been reported in patients treated with siltuximab [46].
Hematologic — Neutropenia and thrombocytopenia have been reported and may require dose adjustment or drug discontinuation [29,38] according to recommendations in the summary of product characteristics (SPC) issued by the European Medicines Agency (EMA). Leukopenia, lymphopenia, and polycythemia have also been reported [46]. Whether the neutropenia is clinically relevant or is due to a margination of neutrophils to the vessel walls is still not clear.
Gastrointestinal
●Dyslipidemia – IL-6 inhibitors may cause dyslipidemia [23,38,46]. In a systematic review, patients receiving tocilizumab were more likely to experience an elevation in the ratios of low-density lipoprotein to high-density lipoprotein cholesterol (20 versus 12 percent, relative risk [RR] 1.7, 95% CI 1.2-2.2) and of total to high-density lipoprotein cholesterol (12 versus 7 percent, RR 1.7, 95% CI 1.2-2.6) [23]. Dyslipidemia should be managed according to available guidelines. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)
●Elevated liver enzymes – Significant liver enzyme (aminotransferase) elevations have been reported [38] and may require dose adjustment or drug discontinuation. Serious liver disease is rare.
●Gastrointestinal symptoms and gastrointestinal tract perforation – Gastrointestinal symptoms are more common in patients on IL-6 inhibitors and are usually mild (eg, nausea, abdominal pain) [24,46]. However, gastrointestinal tract perforations have been reported, especially in older patients, particularly those on glucocorticoids, and in patients with a history of diverticulitis, which is a contraindication to the use of tocilizumab [29,47]. Patients should be instructed that these disorders may occur and that clinical manifestations may be blunted without a significant elevation of inflammatory laboratory parameters such as C-reactive protein. Some experts provide patients a note to inform clinicians in emergency departments about IL-6 blocking treatment and its potential effect on the clinical presentation in such instances.
EFFECTS ON ACUTE PHASE REACTANTS — Interleukin (IL) 6 inhibitors are antiinflammatory and suppress fever and acute phase reactants, such as C-reactive protein and ferritin. Masking of the signs and symptoms of acute inflammation can delay the diagnosis of infection, make it more difficult to diagnosis macrophage activation syndrome (MAS) in patients with systemic juvenile idiopathic arthritis, and can lead to overestimation of the clinical response to IL-6 inhibition if the composite disease activity score used gives relatively greater weight to levels of acute phase reactants. (See "HHV-8-negative/idiopathic multicentric Castleman disease", section on 'IL-6 inhibitors' and "Assessment of rheumatoid arthritis disease activity and physical function" and "Systemic juvenile idiopathic arthritis: Treatment", section on 'Biologic disease-modifying antirheumatic drug (DMARD) therapy' and "Systemic juvenile idiopathic arthritis: Course, prognosis, and complications", section on 'Diagnosis'.)
MONITORING AND RESTRICTIONS — Interleukin (IL) 6 inhibitors should not be given in combination with other biologic agents. Active infection should be excluded prior to every dose, and treatment should be delayed for patients with active infection until resolved. In addition, live or live-attenuated vaccines are not recommended during treatment. Patients should also be monitored for new onset of gastrointestinal symptoms that may suggest diverticulitis or gastrointestinal perforation and for signs and symptoms of central nervous system demyelinating disorders [6]. (See "General principles and overview of management of rheumatoid arthritis in adults", section on 'Drug monitoring and prevention of drug toxicity' and "Immunizations in autoimmune inflammatory rheumatic disease in adults" and "Neuromyelitis optica spectrum disorder (NMOSD): Treatment and prognosis", section on 'Attack prevention'.)
Recommended laboratory monitoring in patients on IL-6 inhibitors:
●Rheumatoid arthritis (RA) in adults – Testing typically includes complete blood count with differential (neutrophils) and liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and bilirubin) every month until stable, then every three months. Testing varies in some regions (eg, alkaline phosphate is typically not performed in Germany). Lipids should be obtained every six months. (See "General principles and overview of management of rheumatoid arthritis in adults", section on 'Drug monitoring and prevention of drug toxicity'.)
●Giant cell arteritis (GCA) – GCA is monitored in a similar fashion to RA.
●Juvenile idiopathic arthritis (polyarticular and systemic) – Testing should include neutrophil and platelet counts, liver enzyme (AST/ALT) levels, and lipid levels at least monthly until stable and then every three months (six months for lipid levels). (See "Systemic juvenile idiopathic arthritis: Treatment", section on 'In patients on tocilizumab'.)
ADDITIONAL DISTINCTIONS BETWEEN AGENTS
●Route of administration – Tocilizumab can be administered subcutaneously or intravenously, siltuximab is only administered intravenously, and satralizumab and sarilumab are only administered subcutaneously. For additional information, refer to the drug interactions program included within UpToDate. These agents also differ by dosing intervals. As an example, for rheumatoid arthritis (RA), tocilizumab is given weekly (European Medicines Agency [EMA]) or every two weeks subcutaneously or every four weeks intravenously, whereas sarilumab is given every two weeks subcutaneously.
●Mechanistic distinctions – Tocilizumab, sarilumab, and satralizumab all bind to the interleukin (IL) 6 receptor (IL-6R), while siltuximab directly binds to IL-6 itself. It is not known whether there are particular advantages to targeting IL-6 itself rather than the receptor [2].
DISCONTINUING INTERLEUKIN 6 INHIBITION — In patients treated for rheumatoid arthritis (RA), discontinuation of tocilizumab, like most other biologic disease-modifying antirheumatic drugs (DMARDs), leads to a subsequent flare in most patients, even in those with low disease activity or remission [48-50]. Resumption of therapy improves disease control in the majority of patients.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Rheumatoid arthritis" and "Society guideline links: Juvenile idiopathic arthritis" and "Society guideline links: Side effects of anti-inflammatory and anti-rheumatic drugs".)
SUMMARY
●Mechanisms of action – Interleukin (IL) 6 is a proinflammatory cytokine that mediates pleiotropic functions in immunologic responses during host infection, inflammatory disease, hematopoiesis, and oncogenesis. It can also exhibit antiinflammatory effects and has been implicated in autoimmune diseases. IL-6 binds to both soluble and membrane-bound forms of its receptor. (See 'Interleukin 6 biology and function' above.)
●Pretreatment testing – Baseline laboratory studies should include a complete blood count, differential, and platelet count; liver function tests; and a lipid panel. Patients should also be screened for latent tuberculosis and hepatitis B and C. Females of reproductive age should be screened for pregnancy. (See 'Pretreatment testing' above.)
●Types of agents available – Several agents are available for pharmacologic inhibition of IL-6, including the anti-IL-6 receptor (IL-6R) monoclonal antibodies tocilizumab, sarilumab, and satralizumab and the anti-IL-6 monoclonal antibody siltuximab. (See 'Structure and mechanism of action of specific agents' above.)
●Adverse effects – Pharmacologic inhibition of IL-6 is generally well tolerated. The most commonly reported adverse events associated with IL-6 inhibitors are nasopharyngitis, headache, upper respiratory tract infection, gastritis, rash, arthralgia, extremity pain, fatigue, and nausea. Infections are the most frequent serious adverse events reported. Gastrointestinal perforation can occur in adults. Injection site and infusion reactions may occur. Laboratory abnormalities include neutropenia, thrombocytopenia, dyslipidemia, and elevated liver enzymes. (See 'Adverse effects' above.)
●Effects on acute phase reactants – IL-6 inhibitors suppress fever and acute phase reactants, such as C-reactive protein and ferritin. (See 'Effects on acute phase reactants' above.)
●Precautions – IL-6 inhibitors should not be given in combination with other biologic agents, and active infection should be excluded prior to every dose. Live or live-attenuated vaccines are not recommended during treatment. (See 'Adverse effects' above.)
●Monitoring – Patients should be monitored for signs or symptoms of gastrointestinal or central nervous system complications. Laboratory monitoring includes blood counts, liver function tests, and lipid levels. (See 'Adverse effects' above.)
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