Introduction:
Interleukins (IL) are immune system modulators that play essential roles in the activation and differentiation of immune cells. They are involved in immune cell proliferation, maturation, migration, and adhesion. Furthermore, they have pro-inflammatory and anti-inflammatory properties. T and B lymphocytes (white blood cells involved in immunity), fibroblasts (connective tissue cells), and macrophages (immune cells) produce IL-6. The primary effects of IL-6 include B-lymphocyte differentiation and acute phase protein stimulation (circulating blood proteins released in response to inflammation). Hence, IL-6 is produced secondary to infections and tissue injuries. As a result, it contributes to the body's defense through acute inflammation, blood cell formation, and immune reactions. Although precise mechanisms control its expression, dysregulation (overexpression) of IL-6 plays a pathological role in chronic (prolonged) inflammation and autoimmunity (immunity against self). Hence, IL-6 immunotherapy has been successful in various clinical applications and produced excellent results.
What Is the Role of IL-6 Immunotherapy?
IL-6 overexpression was first discovered in a patient with cardiac myxoma (heart tumor) with fever, polyarthritis (arthritis in many joints), and elevated C-reactive protein (CRP; an inflammatory protein) levels. The myxoma tissue was stained with anti-IL-6 antibodies, suggesting that continuous production of IL-6 from the tissue can contribute to chronic inflammation and autoimmunity.
Various studies show that increased IL-6 production occurs in the synovial cells (cells lining the synovial membrane) of rheumatoid arthritis (RA), myeloma cells, lymph nodes of Castleman disease, malignant cells in cancers, and blood cells or tissues of various autoimmune and chronic inflammatory diseases.
Additionally, research shows that IL-6 blockade is preventive or leads to therapeutic suppression of disease development. These findings reveal that targeting IL-6 might be a novel treatment strategy for various diseases. As a result, it led to the development of Tocilizumab, a humanized anti-IL-6 monoclonal antibody (artificially created) that blocks IL-6-mediated signals by inhibiting IL-6.
What Are the Diseases for Which IL-6 Immunotherapy Is Indicated?
Different studies suggest that Tocilizumab is a new drug for many chronic immune-mediated diseases. It is approved for Castleman’s disease and rheumatological (joint) disorders, such as rheumatoid arthritis and juvenile idiopathic arthritis.
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Castleman Disease: Castleman disease (CD) is a lymphoproliferative (uncontrolled white blood cell production) disorder with various subtypes depending on its cause, disease mechanism, and clinical presentation. It can affect lymph nodes of the neck, chest, abdomen, and pelvis. In CD, IL-6 is abnormally produced by B cells in the lymph nodes. A clinical trial of Tocilizumab was done on seven patients with CD. These patients presented with severe inflammatory symptoms such as high fever, anemia, and hypoalbuminemia (low albumin levels). Tocilizumab administration alleviated the clinical symptoms and normalized CRP levels. It further improved anemia and serum albumin. The efficacy of Tocilizumab was confirmed in another clinical trial in 28 patients with CD in Japan. The results led to its approval in Japan in 2005. Siltuximab, another antibody to IL-6, was approved by the United States Food and Drug Administration (US FDA) in 2014 for multicentric CD (affecting multiple lymph nodes).
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Rheumatoid Arthritis (RA): RA is an autoimmune inflammatory disease that mainly attacks many joints. The first trial of Tocilizumab for RA was done in 45 patients who received a single intravenous (IV) dose of Tocilizumab or placebo (an inert substance). A significant difference in symptoms was observed after Tocilizumab. About 60 percent of patients attained improvement in pain and joint swelling. Further, worldwide clinical trials verified its efficacy for disease suppression and joint destruction with a good safety profile. Hence, Tocilizumab is currently approved for RA in more than 130 countries. Also, Tocilizumab is the only drug that has proved to be more efficacious as monotherapy than Methotrexate (MTX; a widely used RA drug). MTX is used in conjunction with other drugs for RA. However, Tocilizumab monotherapy is better than MTX alone or in combination. Therefore, the most effective antirheumatic (against joint) drug available is Tocilizumab.
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Juvenile Idiopathic Arthritis (JIA): The most common chronic arthritis affecting children is JIA. JIA encompasses arthritis (joint inflammation), which can cause joint pain, swelling, heat, stiffness, and functional disability. A six-week clinical trial was performed on 56 children with JIA. Tocilizumab treatment resulted in about 70 percent improvement in the children. A global trial in 112 children with active JIA has also shown that Tocilizumab is highly effective for the suppression of disease activity. IL-6 immunotherapy is also used in other acute and chronic immune-mediated diseases. These include autoimmune diseases, chronic inflammatory diseases, atherosclerosis, diabetes mellitus, bone diseases, cancers, and psychological diseases. Also, accumulated evidence suggests that Tocilizumab is highly promising for the treatment of systemic sclerosis (SSc; a rare disease that leads to skin tightening and hardening), neuromyelitis optica (NMO; an autoimmune disease in which the spinal cord and the eye nerves are affected), large-vessel vasculitis (inflammation of the large blood vessels), and polymyalgia rheumatica (PMR; an inflammatory disorder that causes muscle pain and stiffness). IL-6 immunotherapy is associated with side effects such as pancreatitis (pancreas inflammation), stomach and intestinal issues, and hyperlipidemia (increased blood lipid levels). Hence, adverse event monitoring should always be done, followed by the latest safety information.
What Are the Acute Life-Threatening Conditions in Which IL-6 Immunotherapy Is Helpful?
In addition to the potential indications, Tocilizumab can serve as rescue therapy for acute life-threatening conditions such as cytokine storm and myocardial infarction (MI).
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Cytokine Storm: A cytokine storm is a fatal immune reaction with highly elevated levels of various cytokines (immune mediators) caused by immune cell activation, such as T cells, macrophages, or histiocytes, in response to infections, injuries, and autoimmune reactions. Tocilizumab therapy can suppress these cytokines irrespective of the underlying disease. Hence, IL-6 blockade can become a novel therapeutic approach for many severe systemic inflammatory diseases presenting with “cytokine storm.” making it an attractive target.
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Myocardial Infarction (MI): MI precipitates from a decreased or cessation of blood flow to the myocardium (heart muscles). IL-6 contributes to atherosclerosis (plaque development). In a trial of 117 patients with MI, Tocilizumab showed good efficacy. The trial findings indicate that Tocilizumab can protect against inflammation and myocardial damage.
Conclusion:
Considerable research has led to translating the biology of IL-6 to autoimmune and inflammatory diseases. Tocilizumab has become a first-line biologic agent for moderate-to-severe rheumatoid arthritis. Furthermore, it is the only approved first-line biologic for juvenile idiopathic arthritis and Castleman disease. It is anticipated that IL-6 immunotherapy will be further used for the treatment of various intractable diseases. However, clinical evaluations regarding the same are essential. Hence, the journey of the therapeutic potential of IL-6 immunotherapy has just started.
