-
Increased B cell growth
Overgrowth of B cells and plasma cells
-
Increased VEGF
-
Increased TH2 cells
-
Systemic symptoms
-
Increased size of lymph nodes, lymphoma, myeloma
-
Formation of blood vessels
Increased blood supply to tumor
-
Autoimmune reactions
Increased autoantibodies to organs
-
Inflammatory response
Increased ESR, CRP, IgG, anemia, DVT
IL-6: An Important Signaling Molecule That Can Become Dysregulated
Interleukin-6 (IL-6) is a cytokine that is typically produced because of an infection or tissue damage. The tightly regulated synthesis of IL-6 leads to the production of acute phase proteins such as C-reactive protein (CRP), fibrinogen, and hepcidin in the liver that act as emergency stress signals to protect the body.1IL-6 Is a Key Part of Immune Response
IL-6 plays an important homeostatic role as part of the body’s immune system by regulating B cells and T cells. It triggers B cells to produce antibodies in the germinal centers within the lymph nodes. IL-6 preferentially promotes the differentiation of immature T cells toward TH2 effector cells and away from regulatory T cells (Treg). This imbalance in T-cell distribution has been noted in the development of autoimmune and inflammatory diseases.1,2
During an inflammatory response, IL-6 stimulates hepatocytes to produce acute phase proteins that contribute to the body’s natural defenses. Inside the bone marrow, IL-6 plays an important role in the formation of platelet cells and the activation of hematopoietic cells. With the help of key cell signaling mediators, IL‑6 also promotes bone homeostasis and angiogenesis.1
Stimulatory effects of IL-6 can lead to collagen production by dermal fibroblasts, as well as growth of myeloma cells and mesangial cells. IL-6 is also a critical regulator of energy metabolism in the liver and the skeletal muscle, and it supports insulin to eliminate free glucose.1,3
Adapted from Tanaka and Kishimoto, 2014.1
A Cytokine Storm Associated With Elevated IL-6 May Lead to iMCD
A cytokine storm is characterized by perpetual activation of lymphocytes and macrophages, resulting in the secretion of large quantities of multiple cytokines. One of the key mediators of cytokine storms is IL-6. Overproduction of IL-6 can trigger autoimmunity and chronic inflammation that can result in tissue damage and have long-term, harmful effects on health.4
Increased IL-6 signaling is the established driver of iMCD. In patients with iMCD, IL-6 levels are highly elevated during flare-ups and correlate with the intensity of symptoms observed in patients.4
Dysregulated IL-6 can increase the growth of B cells, vascular endothelial growth factor (VEGF) signaling and angiogenesis, production of helper T cells (TH), and synthesis of acute phase proteins that can lead to various systemic symptoms of iMCD. An IL-6–driven cytokine storm may lead to systemic inflammation, multicentric lymphadenopathy, cytopenia, and potentially fatal multiple organ dysfunction.5,6
The following graphic highlights the biological effects of increased IL-6 on various cell types.6
Did you know?
A cytokine storm may result from the dysregulated overproduction of cytokines such as IL-6 and may have severe or life-threatening consequences.7
Abbreviations: DVT, deep vein thrombosis; ESR, erythrocyte sedimentation rate; IgG, immunoglobulin G; TH2, type 2 helper T cells.
References:
Tanaka T, Kishimoto T. The biology and medical implications of interleukin-6. Cancer Immunol Res. 2014;2(4):288-294.
Stebegg M, Kumar SD, Silva-Cayetano A, Fonseca VR, Linterman MA, Graca L. Regulation of the germinal center response. Front Immunol. 2018;9:2469.
Garbers C, Heink S, Korn T, Rose-John S. Interleukin-6: designing specific therapeutics for a complex cytokine. Nat Rev Drug Discov. 2018;17(6):395-412.
England JT, Abdulla A, Biggs CM, et al. Weathering the COVID-19 storm: lessons from hematologic cytokine syndromes. Blood Rev. Published online May 15, 2020. doi:10.1016/j.blre.2020.100707
Fajgenbaum DC. Novel insights and therapeutic approaches in idiopathic multicentric Castleman disease. Blood. 2018;132(22):2323-2330.
van Rhee F, Stone K, Szmania S, Barlogie B, Singh Z. Castleman disease in the 21st century: an update on diagnosis, assessment, and therapy. Clin Adv Hematol Oncol. 2010;8(7):486-498.
Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR, Katze MG. Into the eye of the cytokine storm. Microbiol Mol Biol Rev. 2012;76(1):16-32.
Important Safety Information
Indications and Usage
SYLVANT® (siltuximab) is indicated for the treatment of patients with multicentric Castleman’s disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative.
Limitations of Use
SYLVANT was not studied in patients with MCD who are HIV positive or HHV-8 positive because SYLVANT did not bind to virally produced IL-6 in a nonclinical study.
Contraindications
Severe hypersensitivity reaction to siltuximab or any of the excipients in SYLVANT.
Warnings and Precautions
Concurrent Active Severe Infections
Do not administer SYLVANT to patients with severe infections until the infection resolves. SYLVANT may mask signs and symptoms of acute inflammation including suppression of fever and of acute Phase reactants such as C-reactive protein (CRP). Monitor patients receiving SYLVANT closely for infections. Institute prompt anti-infective therapy and do not administer further SYLVANT until the infection resolves.
Vaccinations
Do not administer live vaccines to patients receiving SYLVANT because IL-6 inhibition may interfere with the normal immune response to new antigens.
Infusion Related Reactions and Hypersensitivity
Stop the infusion of SYLVANT if the patient develops signs of anaphylaxis. Discontinue further therapy with SYLVANT.
Stop the infusion if the patient develops a mild to moderate infusion reaction. If the reaction resolves, the SYLVANT infusion may be restarted at a lower infusion rate. Consider medicating with antihistamines, acetaminophen, and corticosteroids. Discontinue SYLVANT if the patient does not tolerate the infusion following these interventions.
Administer SYLVANT in a setting that provides resuscitation equipment, medication, and personnel trained to provide resuscitation.
Gastrointestinal (GI) Perforation
Gastrointestinal (GI) perforation has been reported in clinical trials although not in MCD trials. Use with caution in patients who may be at increased risk for GI perforation. Promptly evaluate patients presenting with symptoms that may be associated or suggestive of GI perforation.
Adverse Reactions
The most common adverse reactions (>10% compared to placebo) in the MCD clinical trial were pruritus, increased weight, rash, hyperuricemia, and upper respiratory tract infections.
Drug Interactions
Cytochrome P450 Substrates
Upon initiation or discontinuation of SYLVANT, in patients being treated with CYP450 substrates with a narrow therapeutic index, perform therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) as needed and adjust dose. The effect of SYLVANT on CYP450 enzyme activity can persist for several weeks after stopping therapy. Exercise caution when SYLVANT is co-administered with CYP3A4 substrate drugs where a decrease in effectiveness would be undesirable (e.g., oral contraceptives, lovastatin, atorvastatin).
Dosage and Administration
Perform hematology laboratory tests prior to each dose of SYLVANT therapy for the first 12 months and every 3 dosing cycles thereafter. If treatment criteria outlined in the Prescribing Information are not met, consider delaying treatment with SYLVANT. Do not reduce dose.
Do not administer SYLVANT to patients with severe infections until the infection resolves.
Discontinue SYLVANT in patients with severe infusion related reactions, anaphylaxis, severe allergic reactions, or cytokine release syndromes. Do not reinstitute treatment.
Please see full Prescribing Information for additional important safety information.
Important Safety Information
Indications and Usage
SYLVANT® (siltuximab) is indicated for the treatment of patients with multicentric Castleman’s disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative.
Limitations of Use
SYLVANT was not studied in patients with MCD who are HIV positive or HHV-8 positive because SYLVANT did not bind to virally produced IL-6 in a nonclinical study.
Contraindications
Severe hypersensitivity reaction to siltuximab or any of the excipients in SYLVANT.
Warnings and Precautions
Concurrent Active Severe Infections
Do not administer SYLVANT to patients with severe infections until the infection resolves. SYLVANT may mask signs and symptoms of acute inflammation including suppression of fever and of acute Phase reactants such as C-reactive protein (CRP). Monitor patients receiving SYLVANT closely for infections. Institute prompt anti-infective therapy and do not administer further SYLVANT until the infection resolves.
Vaccinations
Do not administer live vaccines to patients receiving SYLVANT because IL-6 inhibition may interfere with the normal immune response to new antigens.
Infusion Related Reactions and Hypersensitivity
Stop the infusion of SYLVANT if the patient develops signs of anaphylaxis. Discontinue further therapy with SYLVANT.
Stop the infusion if the patient develops a mild to moderate infusion reaction. If the reaction resolves, the SYLVANT infusion may be restarted at a lower infusion rate. Consider medicating with antihistamines, acetaminophen, and corticosteroids. Discontinue SYLVANT if the patient does not tolerate the infusion following these interventions.
Administer SYLVANT in a setting that provides resuscitation equipment, medication, and personnel trained to provide resuscitation.
Gastrointestinal (GI) Perforation
Gastrointestinal (GI) perforation has been reported in clinical trials although not in MCD trials. Use with caution in patients who may be at increased risk for GI perforation. Promptly evaluate patients presenting with symptoms that may be associated or suggestive of GI perforation.
Adverse Reactions
The most common adverse reactions (>10% compared to placebo) in the MCD clinical trial were pruritus, increased weight, rash, hyperuricemia, and upper respiratory tract infections.
Drug Interactions
Cytochrome P450 Substrates
Upon initiation or discontinuation of SYLVANT, in patients being treated with CYP450 substrates with a narrow therapeutic index, perform therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) as needed and adjust dose. The effect of SYLVANT on CYP450 enzyme activity can persist for several weeks after stopping therapy. Exercise caution when SYLVANT is co-administered with CYP3A4 substrate drugs where a decrease in effectiveness would be undesirable (e.g., oral contraceptives, lovastatin, atorvastatin).
Dosage and Administration
Perform hematology laboratory tests prior to each dose of SYLVANT therapy for the first 12 months and every 3 dosing cycles thereafter. If treatment criteria outlined in the Prescribing Information are not met, consider delaying treatment with SYLVANT. Do not reduce dose.
Do not administer SYLVANT to patients with severe infections until the infection resolves.
Discontinue SYLVANT in patients with severe infusion related reactions, anaphylaxis, severe allergic reactions, or cytokine release syndromes. Do not reinstitute treatment.
Please see full Prescribing Information for additional important safety information.
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