Interleukin-6 Receptor Inhibitors for the Treatment of Rheumatoid Arthritis
Rheumatoid arthritis (RA) is one of the most common inflammatory autoimmune rheumatic diseases, with a global prevalence of 0.24% according to the Global Burden of Disease 2010 study.1 However, the incidence and prevalence of this condition vary substantially among geographic areas.1,2 A US study reported a higher annual RA incidence in women compared with men.2 Furthermore, a moderate increase in the incidence of RA in women was reported during 1995-2007.2
Although RA is associated with significant morbidity, the increasing number of effective drugs and modes of action has improved the disease outcome. Currently, several US Food and Drug Administration (FDA)-approved therapies are available for RA: synthetic disease-modifying antirheumatic drugs (DMARDs) — which include conventional synthetic DMARDs (csDMARDs), targeted synthetic DMARDs (tsDMARDS) such as Janus kinase (JAK) inhibitors, and biological DMARDs (bDMARDs) such as tumor necrosis factor (TNF)-α inhibitors — interleukin (IL)-6 receptor antagonists, a T-cell costimulation blocker (abatacept), and an anti-CD20 B-cell-depleting monoclonal antibody (rituximab).
The Role of IL-6 in RA
Although the pathophysiology of RA is complex, there is no doubt that inflammation plays a major role in the associated damage to the articular cartilage. 5 Numerous proinflammatory cytokines are involved in the disease process, and studies have suggested that IL-6 also has a significant impact on the development of RA.5
The pleiotropic cytokine IL-6 mediates a wide range of immunologic responses during host infection and inflammatory disease.5 Prompt and transient synthesis of IL-6 in response to infections and tissue injury is beneficial and contributes to host defense, but persistent dysregulated expression of IL-6 may be involved in the pathogenesis of various chronic inflammatory and autoimmune diseases, including RA.6
Studies have suggested that in patients with RA, dysregulation of IL-6 production occurs in the synovial cells, and the pleiotropic mediator can cause persistent synovial inflammation and associated damage to the articular cartilage and underlying bone.6
More than 2 decades ago, Straub et al reported that a decrease in IL-6 is a potential prognostic marker for clinical outcome in patients with RA treated with DMARDs.7
IL-6 Receptor Antagonists in RA
Although the 2020 American College of Rheumatology guidelines for the management of RA are pending publication, the European League Against Rheumatism (EULAR) recently released updated recommendations for the management of RA with synthetic and biological DMARDs. 8
There is a consensus that csDMARDs are the mainstay of RA treatment, and the 2019 update of the EULAR recommendations supported the use of methotrexate as the first-line DMARD.8 If there is insufficient response to the initial csDMARD or if the patient is not suitable for these medications, bDMARDs or tsDMARDs should be considered.
Inhibitors of IL-6 action can target either the IL-6 ligand itself or the IL-6 receptor.
Currently, tocilizumab (Actemra®) and sarilumab (Kevzara®) are IL-6 receptor antagonists that have been approved by the US Food and Drug Administration (FDA).9,10 Sirukumab, a human monoclonal antibody that targets the IL-6 cytokine rather than the IL-6 receptor, was rejected for approval by the FDA due to safety concerns, as data suggested an imbalance in deaths among the trial patients taking the drug.11
Tocilizumab
Tocilizumab is a humanized monoclonal antibody targeting the IL-6 receptor that was approved by the FDA in 2010 as an intravenous formulation for the treatment of RA; it was later approved as a subcutaneous formulation.
Tocilizumab is indicated for adult patients with moderately to severely active RA who have had an inadequate response to a csDMARD. It can be given in combination with a csDMARD or as monotherapy. Tocilizumab also received FDA approval for the treatment of giant cell arteritis, polyarticular or systemic juvenile idiopathic arthritis, and cytokine release syndrome associated with chimeric antigen receptor T cells. 9
In the United States, the recommended intravenous dosage of tocilizumab is 4 mg/kg every 4 weeks, followed by an increase to 8 mg/kg every 4 weeks based on clinical response. Tocilizumab at a dose of 8 mg/kg was found to be more effective than a dose of 4 mg/kg.12 Recommended adult subcutaneous dosage depends on weight: patients weighing <100 kg should be treated at a dosage of 162 mg every 2 weeks, followed by an increase in dosing frequency to a weekly dosage, based on clinical response; patients weighing ≥100 mg should be treated at a dosage of 162 mg every week.9 The MUSASHI study compared subcutaneous vs intravenous tocilizumab monotherapy in patients with RA with previous DMARD failure, reporting the subcutaneous formulation was noninferior to the intravenous infusion.13 The SUMMACTA study (ClinicalTrails.gov Identifier: NCT01194414) supported comparable efficacy of weekly tocilizumab 162 mg subcutaneous and tocilizumab 8 mg/kg intravenous when given in combination with DMARDs.14
Several studies have supported the favorable efficacy of tocilizumab in patients with RA, including DMARD-naive patients and those with an inadequate response to treatment with csDMARDs or TNF inhibitors. Tocilizumab was found to be effective both as monotherapy and in combination with csDMARD in patients with RA.
Monotherapy. The AMBITION study (ClinicalTrials.gov Identifier: NCT00109408) supported improved efficacy of tocilizumab monotherapy over methotrexate monotherapy in patients who responded to treatment with methotrexate or bDMARDs, with rapid improvement in RA signs and symptoms.15 The SAMURAI (ClinicalTrials.gov Identifier: NCT00144508) and SATORI (ClinicalTrials.gov Identifier: NCT00144521) studies have also supported the superiority of tocilizumab monotherapy over methotrexate.16,17
The ACT-RAY study (ClinicalTrials.gov Identifier: NCT00810199) reported that in patients with previous DMARD failure, the combination of tocilizumab with methotrexate was not superior to tocilizumab monotherapy; hence, there was no benefit for an add-on strategy over the switch to tocilizumab monotherapy in patients with an inadequate response to methotrexate.18 Similarly, the FUNCTION (ClinicalTrials.gov Identifier: NCT01007435) and the U-ACT-Early (ClinicalTrials.gov Identifier: NCT01034137) studies showed no added benefit with the combination of methotrexate with tocilizumab over tocilizumab monotherapy for csDMARD-naive patients with early RA.19,20
Patients with early or newly diagnosed RA are potential candidates for tocilizumab, as the FUNCTION and the U-ACT-Early studies have shown that tocilizumab is more effective than methotrexate in patients with early RA, with higher remission rates and better protection from structural joint damage.19,20
In the ADACTA study (ClinicalTrials.gov Identifier: NCT01119859), patients who were intolerant of methotrexate or for whom methotrexate was inappropriate were randomly assigned to receive adalimumab or tocilizumab. Results of the study showed superiority of tocilizumab over adalimumab monotherapy for reduction of signs and symptoms of RA.21 Tocilizumab monotherapy was also found to provide radiographic benefit compared with csDMARD monotherapy.16,22
Combination Therapy. Several studies have supported the efficacy of combination treatment with tocilizumab and csDMARDs in patients with previous DMARD failure.23-26 In addition, in patients with previous failure of TNF inhibitors, the combination of tocilizumab with methotrexate was found to be effective.27
In recent EULAR recommendations for the management of RA, the task force stressed that although in clinical practice many patients are taking bDMARD monotherapy, combination therapy may be more effective for all bDMARDs and tsDMARDs, and combination therapy is advantageous with respect to immunogenicity for all bDMARDs.8
Sarilumab
Sarilumab is a fully human monoclonal antibody against the IL-6 receptor that was approved by the FDA in 2017 for the treatment of adults with moderately to severely active RA who had an inadequate response or intolerance to a csDMARD.
Sarilumab can be used as monotherapy or in combination with another csDMARD. However, due to the possibility of increased immunosuppression and increased risk of infection, it is recommended to avoid using sarilumab with bDMARDs.
The recommended dosage of the subcutaneous injection is 200 mg once every 2 weeks. The dosage may need to be reduced to 150 mg once every 2 weeks to help manage neutropenia, thrombocytopenia, and/or elevated liver transaminases.
Sarilumab has greater affinity for the human IL-6 receptor than tocilizumab and it has a prolonged half-life, but the overall efficacy and safety of tocilizumab and sarilumab seem to be comparable.28
The MOBILITY study (ClinicalTrials.gov Identifier: NCT01061736) investigated the efficacy and safety of sarilumab in combination with methotrexate for the treatment of patients with moderately to severely active RA who had inadequate response to methotrexate. Sarilumab in both approved doses in combination with methotrexate was well tolerated and provided significant clinical and radiographic improvement.29 The TARGET study (ClinicalTrials.gov Identifier: NCT01709578) investigated the outcomes of sarilumab with csDMARDs in patients with moderately to severely active RA who had an inadequate response to or were intolerant of a TNF-α inhibitor. Both doses of sarilumab in combination with csDMARDs were associated with clinical improvement.30 In both studies, a greater proportion of patients treated with sarilumab plus csDMARD compared with placebo achieved low level of disease activity and higher response rates.
The MONARCH study (ClinicalTrials.gov Identifier: NCT02332590), which was a comparable study to ADACTA, compared sarilumab with subcutaneous adalimumab. This study demonstrated superiority of sarilumab monotherapy to adalimumab monotherapy in patients with active RA who have had an inadequate response or were intolerant of methotrexate.
Post hoc analyses of the MOBILITY and MONARCH studies reported that patients with elevated IL-6 levels at baseline had greater clinical response to sarilumab compared with patients with normal IL-6 levels.5 Hence, higher levels of IL-6 at baseline may predict better response to sarilumab treatment and identify potential candidates for IL-6 receptor antagonist therapy.
In addition to the impact of tocilizumab and sarilumab on joint symptoms and structural damage, both medications may improve extra-articular symptoms including fatigue, morning stiffness, and anemia, and improve glucose metabolism.5
Warnings and Precautions
Tocilizumab and sarilumab have a boxed warning about the risk for developing serious infections that may lead to hospitalization or death. Reported infections included active tuberculosis; invasive fungal infections; and bacterial, viral, and other infections due to opportunistic pathogens. Most patients who developed infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. The recommendation is to monitor patients and interrupt treatment with the IL-6 receptor antagonist if a serious infection develops until the infection is controlled.9,10 Prior to initiating tocilizumab or sarilumab, it is recommended to complete testing for latent tuberculosis and consider treatment if results are positive.9,10
Tocilizumab and sarilumab initiation is not recommend in patients with absolute neutrophil count <2000/mm3, platelet count <150,000/mm3, or liver transaminases >1.5 times the upper limit of normal.9,10
Tocilizumab and sarilumab are both contraindicated in patients with known hypersensitivity to the medication. The medications should be used with caution in patients at risk for gastrointestinal perforation. Laboratory monitoring is recommended due to potential changes in neutrophils, platelets, lipids, and liver function tests.9,10
Refer to the full Prescribing Information for additional details about Actemra® and Kevzara®.
References
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2. Myasoedova E, Crowson CS, Kremers HM, Therneau TM, Gabriel SE. Is the incidence of rheumatoid arthritis rising? Results from Olmsted County, Minnesota, 1955-2007. Arthritis Rheum. 2010;62(6):1576-1582. doi:10.1002/art.27425
3. Lo, J, Chan L, Flynn S. A systematic review of the incidence, prevalence, costs, and activity and work limitations of amputation, osteoarthritis, rheumatoid arthritis, back pain, multiple sclerosis, spinal cord injury, stroke, and traumatic brain injury in the United States: a 2019 update. Arch Phys Med Rehabil. 2020; S0003-9993(20)30216-1. doi:10.1016/j.apmr.2020.04.001
4. Institute for Health Metrics and Evaluation. GBD Results Tool. http://ghdx.healthdata.org/gbd-results-tool. Accessed September 9, 2020.
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9. Actemra. Prescribing information. Genentech, Inc. May 2020. Accessed August 31, 2020. https://www.gene.com/download/pdf/actemra_prescribing.pdf.
10. Kevzara. Prescribing information. Sanofi and Regeneron Pharmaceuticals, Inc. April 2018. Accessed August 31, 2020. http://products.sanofi.us/Kevzara/Kevzara.pdf
11. AAC (Arthritis Advisory Committee, FDA). Summary Minutes of the Arthritis Advisory Committee Meeting August 2. Silver Spring, MD: Food and Drug Administration; 2017. August 2017. Accessed August 31, 2020. https://www.fda.gov/media/107409/download.
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15. Jones G, Sebba A, Gu J, et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis. 2010;69(1):88-96. doi:10.1136/ard.2008.105197
16. Yamamoto K, Kawai S, Takeuchi T, Murata N, Van Der Heijde D, Kishimoto T. Study of Active controlled Monotherapy Used for Rheumatoid Arthritis, an IL-6 Inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab. Ann Rheum Dis. 2007;66:1162-1167. doi:10.1136/ard.2006.068064
17. Nishimoto N, Miyasaka N, Yamamoto K, et al. Study of active controlled tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate (SATORI): significant reduction in disease activity and serum vascular endothelial growth factor by IL-6 receptor inhibition. Mod Rheumatol. 2009;19:12-19. doi:10.1007/s10165-008-0125-1
18. Dougados M, Kissel K, Sheeran T, et al. Adding tocilizumab or switching to tocilizumab monotherapy in methotrexate inadequate responders: 24-week symptomatic and structural results of a 2-year randomised controlled strategy trial in rheumatoid arthritis (ACT-RAY). Ann Rheum Dis. 2013;72(1):43-50. doi: 10.1136/annrheumdis-2011-201282
19. Burmester GR, Rigby WF, Vollenhoven RF Van, et al. Tocilizumab in early progressive rheumatoid arthritis: FUNCTION, a randomised controlled trial. Ann Rheum Dis. 2016;75(6):1081-1091. doi:10.1136/annrheumdis-2015-207628
20. Heurkens AHM, Teitsma XM, Tekstra J, Marijnissen ACA, Lafeber FPJ, Jacobs JWG. Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early): a multicentre, randomised, double-blind, double-dummy, strategy trial. Lancet. 2016;388(10042):343-355. doi:10.1016/S0140-6736(16)30363-4
21. Gabay C, Emery P, Van Vollenhoven R, et al. Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial. Lancet. 2013;381(9877):1541-1550. doi:10.1016/S0140-6736(13)60250-0
22. Kremer JM, Blanco R, Brzosko M, et al. Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate: Results from the double‐blind treatment phase of a randomized placebo‐controlled trial of tocilizumab safety and prevention of structural joint damage at one year. Arthritis Rheum. 2011;63(3):609-621. doi:10.1002/art.30158
23. Smolen JS, Beaulieu A, Rubbert-Roth A, et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet. 2008;371(9617):987-997. doi:10.1016/S0140-6736(08)60453-5
24. Yazici Y, Curtis JR, Ince A, et al. Efficacy of tocilizumab in patients with moderate to severe active rheumatoid arthritis and a previous inadequate response to disease-modifying antirheumatic drugs: the ROSE study. Ann Rheum Dis. 2012;71(2):198-205. doi:10.1136/ard.2010.148700
25. Genovese MC, McKay JD, Nasonov EL, et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum. 2008;58(10):2968-2980. doi:10.1002/art.23940
26. Nishimoto N, Yoshizaki K, Miyasaka N, et al. Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheumatol. 2004;50(6):1761-1769. doi:10.1002/art.20303
27. Strand V, Burmester GR, Ogale S, Devenport J, John A, Emery P. Improvements in health-related quality of life after treatment with tocilizumab in patients with rheumatoid arthritis refractory to tumour necrosis factor inhibitors: results from the 24-week randomized controlled RADIATE study. Rheumatology. 2012;51(10):1860-1869. doi:10.1093/rheumatology/kes131
28. Ogata A, Kato Y, Higa S, Yoshizaki K. IL-6 inhibitor for the treatment of rheumatoid arthritis: A comprehensive review. Mod Rheumatol. 2019;29(2):258-267. doi:10.1080/14397595.2018.1546357
29. Genovese MC, Fleischmann R, Kivitz AJ, et al. Sarilumab plus methotrexate in patients with active rheumatoid arthritis and inadequate response to methotrexate. Arthritis Rheumatol. 2015;67(6):1424-1437. doi:10.1002/art.39093
30. Fleischmann R, van Adelsberg J, Lin Y, et al. Sarilumab and nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis and inadequate response or intolerance to tumor necrosis factor inhibitors. Arthritis Rheumatol. 2018;69(2):277-290. doi:10.1002/art.39944
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Reviewed September 2020
