Tocilizumab, sold under the brand name Actemra among others, is an immunosuppressive drug, used for the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis, giant cell arteritis, cytokine release syndrome, COVID‑19, and systemic sclerosis-associated interstitial lung disease (SSc-ILD). It is a recombinant humanized monoclonal antibody of the immunoglobulin IgG1 subclass against the interleukin-6 receptor (IL-6R). Interleukin 6 (IL-6) is a cytokine that plays an important role in immune response and is implicated in the pathogenesis of many diseases, such as autoimmune diseases, multiple myeloma and prostate cancer. Tocilizumab was jointly developed by Osaka University and Chugai, and was licensed in 2003 by Hoffmann-La Roche. Tocilizumab was approved for medical use in the European Union in January 2009, and in the United States in January 2010.
Medical uses In the United States, tocilizumab is indicated for the treatment of rheumatoid arthritis, giant cell arteritis, systemic sclerosis-associated interstitial lung disease, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, cytokine release syndrome, and COVID‑19. In the European Union, tocilizumab is indicated for the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis, juvenile idiopathic polyarthritis, giant cell arteritis, cytokine release syndrome, and COVID‑19.
Rheumatoid arthritis Tocilizumab is used for the treatment of moderate to severe rheumatoid arthritis, applied in combination with methotrexate, if other drugs like disease-modifying antirheumatic drugs (DMARDs) and TNF alpha blockers have proven to be ineffective or were not tolerated. It can be used as a monotherapy for patients who do not tolerate methotrexate. The drug slows down the progression of the disease and can improve physical function of patients.
Systemic juvenile idiopathic arthritis The treatment of systemic juvenile idiopathic arthritis is similar to rheumatoid arthritis treatment: tocilizumab is combined with methotrexate unless the latter is not tolerated. General safety and effectiveness is established for children of two years and older. In 2011, the US Food and Drug Administration (FDA) approved tocilizumab for the treatment of active systemic juvenile idiopathic arthritis.
Castleman's disease In Japan, tocilizumab is also approved for the treatment of Castleman's disease, a rare benign tumor of B cells.
Giant cell arteritis In May 2017, the FDA approved tocilizumab for giant cell arteritis.
Cytokine release syndrome On 30 August 2017, the FDA approved tocilizumab for cytokine release syndrome, a side effect of CAR-T cell therapies.
COVID-19 As early as March 2020, at the height of the pandemic in Italy, Paolo Antonio Ascierto, an Italian oncologist, researched alongside his colleagues the use of the arthritis drug tocilizumab to treat severe COVID-19 pneumonia, seeing some results. The results were recognized nationally and prompted national calls for treatment protocols surrounding the research. Ascierto was heard in an official hearing at the Italian Chamber of Deputies, presenting data suggesting tocilizumab reduced COVID-19 mortality by approximately 22% in clinical use, underscoring its potential benefit. Paolo was at the center of the development of multicenter evaluations of tocilizumab against COVID-19 pneumonia during the whole year, being essential to it. In 2021 his research of the usage of tocilizumab against COVID-19 was evaluated by the European Medicines Agency and the European Union, where Ascierto was called to as to support such thesis. In June 2021, the US Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for tocilizumab for the treatment of COVID‑19 in hospitalized people aged two years of age and older who are receiving systemic corticosteroids and require supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). The FDA approved tocilizumab for those indications in December 2022.
Adverse effects The most common adverse effects observed in clinical trials were upper respiratory tract infections (more than 10% of patients), nasopharyngitis (common cold), headache, and high blood pressure (at least 5%). The enzyme alanine transaminase was also elevated in at least 5% of patients, but in most cases without symptoms. Elevated total cholesterol levels were common. Among the less common side effects were dizziness, various infections, as well as reactions of the skin and mucosae like mild rashes, gastritis and mouth ulcer. Rare but severe reactions were gastrointestinal perforations (0.26% in six months) and anaphylaxis (0.2%).
Interactions There are no certain interactions with other drugs. The blood plasma levels of simvastatin were reduced by 57% after a single dose of tocilizumab, but it is not known whether this is clinically relevant. A possible mechanism is that the elevated IL-6 levels of patients with rheumatoid arthritis suppress the biosynthesis of various cytochrome P450 enzymes, notably CYP1A2, CYP2C9, CYP2C19 and CYP3A4. Tocilizumab lowers IL-6 and thus normalises cytochrome levels, increasing the metabolization of simvastatin (and possibly other cytochrome metabolised drugs).
Mechanism of action Besides other functions, interleukin 6 (IL-6) is involved in the development of immunological and inflammatory reactions. Some autoimmune diseases like rheumatoid arthritis are associated with abnormally high IL-6 levels. Tocilizumab binds soluble as well as membrane bound interleukin-6 receptors, hindering IL-6 from exerting its pro-inflammatory effects. It has been noted that the membrane bound form and soluble form of the IL-6 receptor may have different effects in the pathogenesis of rheumatoid arthritis with the soluble form being more implicated in disease progression.
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