Version July 2025
INTRODUCTION —
Interleukin 6 (IL-6) is a potent proinflammatory mediator that is important in immune defense and in immune-mediated disease. Multiple pharmacologic inhibitors (sometimes termed blockers) of IL-6 are commercially available for clinical use, including monoclonal antibodies directed against the IL-6 receptor (IL-6R; eg, tocilizumab, sarilumab, and satralizumab) as well as monoclonal antibodies specific for IL-6 (eg, siltuximab and olokizumab).
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 "Polyarticular juvenile idiopathic arthritis: Treatment and prognosis", section on 'IL-6 inhibitors'.)
●(See "Adult-onset Still's disease: Treatment".)
●(See "Treatment of giant cell arteritis", section on 'Tocilizumab'.)
●(See "Treatment of polymyalgia rheumatica", section on 'Indications and rationale'.)
INTERLEUKIN 6 BIOLOGY AND FUNCTION —
Interleukin 6 (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 which activate three different but related signaling pathways [2,6,7]. It can bind 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 triggering both systemic and local inflammation, resulting in symptoms like fever, fatigue, and anorexia and increasing the levels of 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.
SPECIFIC AGENTS
Structure and mechanism of action — Tocilizumab, sarilumab, and satralizumab all bind to the interleukin 6 receptor (IL-6R), while siltuximab and olokizumab directly bind to IL-6 itself. It is not known whether there are particular advantages to targeting IL-6 itself rather than the receptor [2]. Additional information on specific agents is provided below:
●Tocilizumab and biosimilars – 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. Several biosimilars of tocilizumab are available or in development [9-11].
●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.
●Olokizumab – Olokizumab is a humanized monoclonal antibody against IL-6 that is approved for medical use in certain countries (eg, Russia, Kazakhstan, Belarus, Kyrgyzstan, and Azerbaijan).
●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 [12-14], levilimab, and vobarilizumab [15].
Route of administration — Tocilizumab can be administered subcutaneously or intravenously, while siltuximab is only administered intravenously and satralizumab and sarilumab are only administered subcutaneously. These agents also differ by dosing intervals. As an example, for rheumatoid arthritis (RA), tocilizumab is given every one to two weeks subcutaneously or every four weeks intravenously, whereas sarilumab is given every two weeks subcutaneously.
PRETREATMENT EVALUATION
Pretreatment testing — We perform the following testing and evaluation before initiating treatment with an interleukin (IL-6) inhibitor:
●Baseline laboratory testing – 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).
●Screening for latent infections – 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" and "Overview of infections associated with immunomodulatory (biologic) agents".)
●Reproductive health counseling – 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'.)
Contraindications and precautions — IL-6 inhibitors should not be given in combination with other biologic agents or if there is concern for a serious active infection. In addition, we generally avoid treatment with IL-6 in patients with prior diverticulitis, active hepatic disease, or hepatic impairment, or in patients with RA or giant cell arteritis (GCA) whose baseline ALT or AST is >1.5 times the upper limit of normal. If there is an urgent indication for IL-6 inhibitor use (eg, resistant GCA) in a patient with these conditions, we advise consultation with a gastroenterologist or a hepatologist.
IL-6 inhibitors (eg, tocilizumab and sarilumab) are also usually avoided when there is significant neutropenia (ie, absolute neutrophil counts <2000/mm3) and/or thrombocytopenia (ie, platelet counts <100,000/mm3) in patients with certain conditions, including rheumatoid arthritis (RA), GCA, and systemic sclerosis (SSc) with interstitial lung disease (ILD). Patients with cytopenias 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'.)
Patients with severe or life-threatening cytokine release syndrome 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'.)
Preventive vaccinations — Patients who anticipate starting IL-6 inhibitors should receive any indicated prophylactic vaccinations (eg, pneumococcal vaccination) if possible prior to starting therapy, as summarized in the table (table 1) and discussed in detail elsewhere. Live or live-attenuated vaccines are generally not recommended during treatment. (See "Immunizations in autoimmune inflammatory rheumatic disease in adults".)
ADVERSE EFFECTS
Range of adverse effects — The most commonly reported adverse events associated with interleukin 6 receptors (IL-6Rs)/IL-6 inhibitors in clinical trials 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 has not been reported [16]. The risk of tuberculosis reactivation and of primary infection appears to be very low [17], 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 [18]; they may be more common in children. With intravenous administration, infusion reactions can occur, but anaphylaxis is rare [18,19]. 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 [20,21]. Loss of efficacy was not observed in the analysis of multiple trials involving nearly 9000 patients [21].
The safety of tocilizumab has been characterized in multiple randomized trials, systematic reviews, and meta-analyses, particularly for treatment of RA [16,22-28]. 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 [29-32], and clazakizumab.
Infection — An increased rate of infections, including mycobacterial and other opportunistic infections, is reported in patients treated with IL-6R/IL-6 inhibitors [23,25]. As an example, in a 2011 meta-analysis of randomized trials, the rate of infection in patients with rheumatoid arthritis (RA) was increased in those receiving tocilizumab plus methotrexate compared with those receiving placebo plus methotrexate (odds ratio [OR] 1.3, 95% CI 1.1-1.6) [16]. This increase in risk of infections appears similar to that found with other biologic disease-modifying antirheumatic drugs (DMARDs) based on clinical trials and an integrated safety analysis of patients receiving an IL-6R inhibitor in combination with a conventional DMARD or as monotherapy [6,23,33-36]. The risk of serious infection is greater in patients on concomitant immunosuppressive therapy. Most patients recover with appropriate treatment. Key studies examining specific types of infections include the following:
●Serious infections – The reported serious infection rate in patients with RA treated with tocilizumab ranges from 3.7 to 5.7 per 100 patient-years [24,26,27]. 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 (sJIA) [37]. Few serious infections have been reported in patients treated with siltuximab and sarilumab [38-41]. (See "Overview of infections associated with immunomodulatory (biologic) agents".)
●Opportunistic infections – A 2011 meta-analysis of safety data in patients with RA treated with tocilizumab found that opportunistic infections developed at a rate of 0.23 episodes per 100 patient-years [25]. Such infections included active tuberculosis, nontuberculous mycobacteria, invasive candidiasis, P. jirovecii pneumonia, and cryptococcosis, especially with higher doses of tocilizumab. (See "Overview of infections associated with immunomodulatory (biologic) agents".)
●COVID-19 – Patients taking immunosuppression are at higher risk for developing coronavirus disease 2019 (COVID-19) infection, which is discussed in detail elsewhere (see "COVID-19: Care of adult patients with systemic rheumatic disease"). Patients who develop COVID-19 while taking tocilizumab should be monitored closely for the development of serious superimposed bacterial or fungal infections, especially when there is severe disease or use of other immunosuppressive agents. However, despite observational reports of an association between tocilizumab use and an increased rate of fungal and bacterial infections in patients with COVID-19 [42-44], a subsequent meta-analysis of 10 observational studies [45] and several randomized trials comparing tocilizumab with placebo [46-48] have not identified similar risks. (See "Overview of infections associated with immunomodulatory (biologic) agents".)
Hematologic — Neutropenia and thrombocytopenia have been reported and may require dose adjustment or drug discontinuation [28,37] 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 [38]. It is still not clear whether the neutropenia is clinically relevant or due to a margination of neutrophils to the vessel walls.
Gastrointestinal
●Dyslipidemia – IL-6 inhibitors may cause dyslipidemia [22,37,38]. 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) [22]. 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 [37] 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) [23,38]. 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 [28,49]. 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. We provide patients taking IL-6 inhibitors with a note to inform clinicians in emergency situations about IL-6 blocking treatment and its potential effect on the clinical presentation in such instances.
MONITORING
Clinical monitoring for complications — Active infection should be excluded prior to every dose of interleukin 6 (IL-6) inhibitors, and treatment should be delayed for patients with a significant active infection (eg, ones that cause fever or require antibiotics) until resolved. 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].
Routine laboratory testing — For adults taking an IL-6 inhibitor, we check a complete blood count (CBC) with differential and liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and bilirubin) at regular intervals, typically monthly for the first six months of therapy and then every three months. In addition, we obtain a lipid panel every six months. Testing varies in some regions (eg, alkaline phosphate is typically not performed in Germany).
Laboratory monitoring for children is similar; however, we obtain a lipid panel after a month of therapy before extending to every six months, and we only check bilirubin and alkaline phosphatase as clinically indicated.
Effects on acute phase reactants — IL-6 inhibitors are antiinflammatory and suppress fever and acute phase reactants, such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and ferritin. Masking of the signs and symptoms of acute inflammation can delay the diagnosis of infection and make it more difficult to diagnose certain disease complications, such as macrophage activation syndrome (MAS) in patients with systemic juvenile idiopathic arthritis (sJIA). (See "Systemic juvenile idiopathic arthritis: Complications", section on 'Evaluation and diagnostic testing'.)
Use of IL-6 inhibitors can also lead to overestimation of the clinical response to therapy in conditions that follow ESR and CRP to monitor disease activity, such as rheumatoid arthritis (RA), polymyalgia rheumatica (PMR), and giant cell arteritis (GCA). (See "Assessment of rheumatoid arthritis disease activity and physical function" and "Treatment of giant cell arteritis", section on 'Routine monitoring of disease activity'.)
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".)
SUMMARY
●Interleukin 6 biology and function – Interleukin 6 (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 as an important pathogenic mediator in autoimmune diseases. IL-6 binds to both soluble and membrane-bound forms of its receptor. (See 'Interleukin 6 biology and function' above.)
●Specific agents – 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 'Specific agents' above.)
●Pretreatment evaluation
•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.)
•Contraindications and precautions – IL-6 inhibitors should not be given in combination with other biologic agents or if there is concern for a serious active infection. We generally avoid using IL-6 inhibitors in patients with prior diverticulitis, active hepatic disease, or hepatic impairment. In addition, we avoid using IL-6 inhibitors if there is significant neutropenia and/or thrombocytopenia in patients with certain conditions, including rheumatoid arthritis (RA), giant cell arteritis (GCA), and systemic sclerosis (SSc) with interstitial lung disease (ILD). (See 'Contraindications and precautions' above.)
●Adverse effects – Pharmacologic inhibition of IL-6 is generally well tolerated. The most common non-serious adverse events are nasopharyngitis, headache, upper respiratory tract infection, gastritis, rash, arthralgia, extremity pain, fatigue, and nausea. Infections are the most frequent serious adverse event. 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.)
●Monitoring
•Clinical and laboratory monitoring – Patients should be monitored for signs or symptoms of infection and gastrointestinal or central nervous system complications. Laboratory monitoring includes blood counts, liver function tests, and lipid levels. (See 'Monitoring' above.)
•Effects on acute phase reactants – IL-6 inhibitors suppress fever and acute phase reactants, such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and ferritin. This pharmacologic effect may mask signs and symptoms of acute inflammation and delay the diagnosis of infection, certain medication-related adverse effects (eg, gastrointestinal perforation), or certain disease complications (eg, macrophage activation syndrome [MAS] in systemic juvenile idiopathic arthritis [sJIA]). (See 'Effects on acute phase reactants' above.)
