Helpful resources for you and your patients with RA

TRANSCRIPT

Inflammatory rheumatic diseases like rheumatoid arthritis, or RA, and polymyalgia rheumatica, or PMR, are systemic autoimmune diseases characterized by persistent inflammation^1-3 which can lead to impaired joint and muscle function, pain, and difficulty performing daily routines.^1,4,5

Pro-inflammatory cytokines, such as Interleukin-6, or IL-6, immune cells, such as T cells and macrophages, tumor necrosis factor alpha, or TNF-alpha, as well as intracellular signaling pathways, such as Janus kinase and signal transducer and activator of transcription, or JAK/STAT, contribute to disease development and progression.^6-12

IL-6 serum levels in particular are elevated in patients with inflammatory rheumatic diseases. They play a central role in the inflammatory pathways that may lead to chronic inflammation, morning stiffness, and systemic manifestations, including pain, and in the case of RA, disease progression.^5,6,13-17

IL-6 is a key cytokine featuring pleiotropic activity. The effects of IL-6 include stimulation of acute phase protein synthesis, such as C-reactive protein, or CRP, serum amyloid A, fibrinogen, and induced hepcidin production by hepatocytes. IL-6 also inhibits the production of albumin. IL-6 plays an important role in immune response by stimulating antibody-producing B cells and influencing effector T-cell development. Dysregulated, continuous IL-6 production may be associated with the development of inflammatory autoimmune diseases.^6,11,14,18

IL-6 exerts its inflammatory effects through activation of certain proinflammatory signaling pathways important to inflammatory rheumatic diseases.⁷

IL-6 primarily activates the JAK/STAT pathway, as well as the mitogen-activated protein kinase, or MAPK, signaling pathway, and the phosphoinositide 3-kinase, or PI3K, signaling pathway.^6,19-22

These signaling features help explain both the overlapping and distinct roles that IL-6 and JAK/STAT play in the pathogenesis of inflammatory rheumatic diseases.^7,19

Persistently elevated levels of IL-6 are a major driver of inflammation in RA and PMR.^{4,11,13,14,18,23,24}

While several cytokines signal only through membrane-bound receptors, IL-6 acts through a dual signaling mechanism involving both a soluble and cell membrane-bound receptors.⁶

The IL-6/IL-6 receptor complexes become activated when they associate with glycoprotein 130, or gp130, a transmembrane receptor expressed in abundance on the surface of most cells.^5,25,26

As a result, elevated levels of IL-6 have widespread effects throughout the body, modulating both adaptive and innate immune responses.^7,27

It is also important to note that systemic inflammation can be associated with activation of an acute phase response, like CRP.^7,11,28

The ability to modulate these effects may be important to control disease activity.^7,11,23

KEVZARA, or sarilumab, is the only fully human monoclonal antibody that inhibits IL-6 receptor signaling.²⁹

KEVZARA targets and binds with high affinity to both soluble and membrane-bound IL-6 receptors, thereby inhibiting IL-6 signaling.^29,30

In this way, KEVZARA helps disrupt the effects of elevated IL-6 levels in adult patients with moderately to severely active RA who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs, or DMARDs, and adult patients with PMR who have had an inadequate response to corticosteroids or who cannot tolerate corticosteroid taper.²⁹

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INDICATIONS

KEVZARA® (sarilumab) is indicated for treatment of:

• adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs).
• adult patients with polymyalgia rheumatica (PMR) who have had an inadequate response to corticosteroids or who cannot tolerate corticosteroid taper.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATION
Do not use KEVZARA in patients with known hypersensitivity to sarilumab or any of the inactive ingredients.

WARNINGS AND PRECAUTIONS

• Infections. Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving immunosuppressive agents including KEVZARA. Among opportunistic infections, TB, candidiasis, and pneumocystis were reported with KEVZARA. The most frequently observed serious infections with KEVZARA in RA patients included pneumonia and cellulitis.
  • Hold treatment with KEVZARA if a patient develops a serious infection or an opportunistic infection.
  • Patients with latent TB should be treated with standard antimycobacterial therapy before initiating KEVZARA. Consider anti-TB therapy prior to initiation of KEVZARA in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but having risk factors for TB infection.
  • Consider the risks and benefits of treatment prior to initiating KEVZARA in patients who have: chronic or recurrent infection, a history of serious or opportunistic infections, underlying conditions that may predispose them to infection, been exposed to TB, or lived in or traveled to areas of endemic TB or endemic mycoses.
  • Viral reactivation has been reported with immunosuppressive biologic therapies. Cases of herpes zoster were observed in clinical studies with KEVZARA.
• Laboratory Abnormalities. Treatment with KEVZARA was associated with decreases in absolute neutrophil counts (including neutropenia), and platelet counts; and increases in transaminase levels and lipid parameters (LDL, HDL cholesterol, and/or triglycerides). Increased frequency and magnitude of these elevations were observed when potentially hepatotoxic drugs (e.g., MTX) were used in combination with KEVZARA. Assess neutrophil count, platelet count, and ALT/AST levels prior to initiation with KEVZARA. Monitor these parameters 4 to 8 weeks after start of therapy and every 3 months thereafter. Assess lipid parameters 4 to 8 weeks after start of therapy, then at 6 month intervals.
• Gastrointestinal Perforation. GI perforation risk may be increased with concurrent diverticulitis or concomitant use of NSAIDs or corticosteroids. Gastrointestinal perforations have been reported in clinical studies, primarily as complications of diverticulitis. Promptly evaluate patients presenting with new onset abdominal symptoms.
• Immunosuppression. Treatment with immunosuppressants may result in an increased risk of malignancies. The impact of treatment with KEVZARA on the development of malignancies is not known but malignancies have been reported in clinical studies.
• Hypersensitivity Reactions. Hypersensitivity reactions have been reported in association with KEVZARA. Hypersensitivity reactions that required treatment discontinuation were reported in 0.3% of patients in controlled RA trials. Injection site rash, rash, and urticaria were the most frequent hypersensitivity reactions. Advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction. If anaphylaxis or other hypersensitivity reaction occurs, stop administration of KEVZARA immediately. Do not administer KEVZARA to patients with known hypersensitivity to sarilumab.
• Active Hepatic Disease and Hepatic Impairment. Treatment with KEVZARA is not recommended in patients with active hepatic disease or hepatic impairment, as treatment with KEVZARA was associated with transaminase elevations.
• Live Vaccines. Avoid concurrent use of live vaccines during treatment with KEVZARA due to potentially increased risk of infections. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving KEVZARA. Prior to initiating treatment, it is recommended that all patients be brought up to date with all immunizations in agreement with current immunization guidelines.

ADVERSE REACTIONS

• For Rheumatoid Arthritis: The most common serious adverse reactions were infections. The most frequently observed serious infections included pneumonia and cellulitis. The most common adverse reactions (occurred in at least 3% of patients treated with KEVZARA + DMARDs) are neutropenia, increased ALT, injection site erythema, upper respiratory infections, and urinary tract infections.
• For Polymyalgia Rheumatica: Serious adverse reactions of neutropenia occurred in 2 patients (3.4%) in the KEVZARA group compared to none in the placebo group. The proportion of patients with serious infections was similar in the KEVZARA group (5.1%) compared to the placebo group (5.2%). The common adverse reactions occurring in ≥5% of patients treated with KEVZARA were neutropenia, leukopenia, constipation, rash pruritic, myalgia, fatigue, and injection site pruritus.

DRUG INTERACTIONS

• Exercise caution when KEVZARA is co-administered with CYP substrates with a narrow therapeutic index (e.g. warfarin or theophylline), or with CYP3A4 substrates (e.g. oral contraceptives or statins) as there may be a reduction in exposure which may reduce the activity of the CYP3A4 substrate.
• Elevated interleukin-6 (IL-6) concentration may down-regulate CYP activity such as in patients with RA and hence increase drug levels compared to subjects without RA. Blockade of IL-6 signaling by IL-6Rα antagonists such as KEVZARA might reverse the inhibitory effect of IL-6 and restore CYP activity, leading to altered drug concentrations.

USE IN SPECIFIC POPULATIONS

• KEVZARA should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Because monoclonal antibodies could be excreted in small amounts in human milk, the benefits of breastfeeding and the potential adverse effects on the breastfed child should be considered along with the mother’s clinical need for KEVZARA.
• Use caution when treating the elderly.

Advise patients to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Please click here to see full Prescribing Information, including Boxed WARNING.

References: 1. Aletaha D, Neogi T, Silman AT, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569-2581. 2. Bartoloni E, Pucci G, Alunno A, Gerli R, Schillaci G. Polymyalgia rheumatica. In: Nussinovitch U, ed. The Heart in Rheumatic, Autoimmune and Inflammatory Diseases. Academic Press; 2017:213-231. 3. Prior JA, Muller S, Helliwell T, et al. The association of pain and stiffness with fatigue in incident polymyalgia rheumatica: baseline results from the polymyalgia rheumatica cohort study. Prim Health Care Res Dev. 2019;20(e46):1-6. doi:10.1017/S1463423619000082. 4. González-Gay MA, Matteson EL, Castañeda S. Polymyalgia rheumatica. Lancet. 2017;390:1700-1712. 5. Acharya S, Musa R. Polymyalgia Rheumatica. NCBI Bookshelf. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022. 6. Dayer J-M, Choy E. Therapeutic targets in rheumatoid arthritis: the interleukin-6 receptor. Rheumatology (Oxford). 2010;49(1):15-24. 7. Choy E. Understanding the dynamics: pathways involved in the pathogenesis of rheumatoid arthritis. Rheumatology (Oxford). 2012;51(suppl 5):v3-v11. 8. Schwartz DM, Bonelli M, Gadina M, O’Shea JJ. Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases. Nat Rev Rheumatol. 2016;12(1):25-36. 9. Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol. 2014;6(10):a016295. doi: 10.1101/cshperspect.a016295. 10. González-Gay MA, Pina T, Prieto-Peña D, Calderon-Goercke M, Blanco R, Castañeda S. Drug therapies for polymyalgia rheumatica: a pharmacotherapeutic update. Expert Opin Pharmacother. 2018;19(11):1235-1244. 11. Tanaka T, Narazaki M. Interleukin-6 inhibition in inflammatory diseases: results achieved and tasks to accomplish. J Scleroderma Relat Disord. 2017;2(2_suppl):S20-S28. 12. Toussirot E, Régent A, Devauchelle-Pensec V, Saraux A, Puéchal X. Interleukin-6: a promising target for the treatment of polymyalgia rheumatica or giant cell arteritis? RMD Open. 2016;2(2):e000305. doi:10.1136/rmdopen-2016-000305. 13. Jiemy WF, Zhang A, Boots AMH, et al. Expression of interleukin-6 in synovial tissue of patients with polymyalgia rheumatica. Ann Rheum Dis. 2022;0:1-2. doi:10.1136/ard-2022-222873. 14. Alegria GC, Boukhlal S, Cornec D, Devauchelle-Pensec V. The pathophysiology of polymyalgia rheumatica, small pieces of a big puzzle. Autoimmun Rev. 2020;19(11):102670. doi:10.1016/j.autrev.2020.102670. 15. Gibbs JE, Ray DW. The role of the circadian clock in rheumatoid arthritis. Arthritis Res Ther. 2013;15(205):1-10. 16. Grygiel-Górniak B, Puszczewicz M. Fatigue and interleukin-6—a multi-faceted relationship. Reumatologia. 2015;53(4):207-212. 17. Lundberg IE, Sharma A, Turesson C, Mohammed AJ. An update on polymyalgia rheumatica. J Intern Med. 2022;292(5):717-732. 18. Rose-John S, Scheller J, Elson G, Jones SA. Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer. J Leukoc Biol. 2006;80(2):227-236. 19. Woś I, Tabarkiewicz J. Effect of interleukin-6, -17, -21, -22, and -23 and STAT3 on signal transduction pathways and their inhibition in autoimmune arthritis. Immunol Res. 2021;69(1):26-42. 20. Heinrich PC, Behrmann I, Haan S, Hermanns HM, Müller-Newen G, Schaper F. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J. 2003;374(Pt 1):1-20. doi: 10.1042/BJ20030407. 21. Cahill CM, Rogers JT. Interleukin (IL) 1ß induction of IL-6 is mediated by a novel phosphatidylinositol 3-kinase-dependent AKT/IϰB kinase α pathway targeting activator protein-1. J Biol Chem. 2008;283(38):25900-25912. 22. Zegeye MM, Lindkvist M, Fälker K, et al. Activation of the JAK/STAT3 and PI3K/AKT pathways are crucial for IL-6 trans-signaling-mediated pro-inflammatory response in human vascular endothelial cells. Cell Commun Signal. 2018;16(1):55. doi:10.1186/s12964-018-0268-4. 23. Srirangan S, Choy EH. The role of interleukin 6 in the pathophysiology of rheumatoid arthritis. Ther Adv Musculoskelet Dis. 2010;2(5):247-256. 24. Salvarani C, Cantini F, Niccoli L, et al. Acute-phase reactants and the risk of relapse/recurrence in polymyalgia rheumatica: a prospective followup study. Arthritis Rheum. 2005;53(1):33-38. 25. Witte T. Methotrexate as combination partner of TNF inhibitors and tocilizumab. What is reasonable from an immunological viewpoint? Clin Rheumatol. 2015;34(4):629-634. doi:10.1007/s10067-015-2861-x. 26. Boettger MK, Leuchtweis J, Kümmel D, Gajda M, Braüer R, Schaible H-G. Differential effects of locally and systemically administered soluble glycoprotein 130 on pain and inflammation in experimental arthritis. Arthritis Res Ther. 2010;12(4):R140. doi:10.1186/ar3079. 27. Gierut A, Perlman H, Pope RM. Innate immunity and rheumatoid arthritis. Rheum Dis Clin North Am. 2010;36(2):271-296. 28. Black AP, Bhayani H, Ryder CA, Pugh MT, Gardner-Medwin JM, Southwood TR. An association between the acute phase response and patterns of antigen induced T cell proliferation in juvenile idiopathic arthritis. Arthritis Res Ther. 2003;5(5):R277-R284. doi:10.1186/ar791. 29. KEVZARA [prescribing information]. Bridgewater, NJ: Sanofi/Regeneron Pharmaceuticals, Inc. 30. Genovese MC, Fleischmann R, Kivitz AJ, et al. Sarilumab plus methotrexate in patients with active rheumatoid arthritis and inadequate response to methotrexate: results of a phase III study. Arthritis Rheumatol. 2015;67(6):1424-1437.