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A Review of Recent Advances Using Tocilizumab in the Treatment of Rheumatic Diseases.

ABSTRACT: Tocilizumab (TCZ) is the first humanized anti-interleukin-6 (IL-6) receptor monoclonal antibody approved for the treatment of patients with rheumatoid arthritis (RA), Castleman's disease, polyarticular and systemic juvenile idiopathic arthritis, and, most recently, giant cell arteritis as well as for the treatment of chimeric antigen receptor T cell therapy-induced cytokine release syndrome. The global clinical development program for TCZ provides a wealth of clinical data on intravenous TCZ, and more recent studies in patients with RA have provided evidence characterizing the role of intravenous TCZ as monotherapy in early disease and led to the introduction of a subcutaneous formulation of TCZ. In addition, recently published open-label extension and observational studies continue to support the long-term efficacy and safety of TCZ in both clinical trial and real-world settings. Given the involvement of IL-6-mediated signaling in inflammatory disorders, TCZ is also being investigated in other immunological diseases. In particular, a phase 2 trial on the safety and efficacy of subcutaneous TCZ in adults with systemic sclerosis shows clinically relevant improvements in skin sclerosis and lung function in these patients. Another anti-IL-6 receptor agent, sarilumab, targeting the IL6 receptor alpha subunit, was recently approved for the treatment of patients with RA, although long-term data for this biologic are not yet published. In this article we review the placement of TCZ in current treatment guidelines; recent clinical trial data, including quality of life in patients with RA; recent updates to the TCZ safety profile; recent investigations of TCZ in other immunological diseases; and the clinical development of other novel IL-6-targeted agents.

SUBMITTER: Rubbert-Roth A

PROVIDER: S-EPMC5935615 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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A Review of Recent Advances Using Tocilizumab in the Treatment of Rheumatic Diseases.

Rubbert-Roth Andrea A Furst Daniel E DE Nebesky Jan Michael JM Jin Angela A Berber Erhan E

Rheumatology and therapy 20180303 1

Tocilizumab (TCZ) is the first humanized anti-interleukin-6 (IL-6) receptor monoclonal antibody approved for the treatment of patients with rheumatoid arthritis (RA), Castleman's disease, polyarticular and systemic juvenile idiopathic arthritis, and, most recently, giant cell arteritis as well as for the treatment of chimeric antigen receptor T cell therapy-induced cytokine release syndrome. The global clinical development program for TCZ provides a wealth of clinical data on intravenous TCZ, an ...[more]

PMID: 29502236

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Project description:Progress in hemophilia therapy has been remarkable in the first 20 years of the third millennium, but the innovation began with the description the fractionation of plasma in 1946. The first concentrates followed the discovery of FVIII in the cryoprecipitate of frozen plasma and FIX in the supernatant in the early 1960s, which led to the initial attempts at replacement therapy. Unfortunately, the lack of screening methods for viral pathogens resulted in people with hemophilia (PWH) receiving concentrates contaminated by hepatitis A virus, hepatitis C virus, and human immunodeficiency virus, as these concentrates were made from large industrial pools of plasma derived from thousands of donors. Fortunately, by 1985, viral screening methods and proper virucidal techniques were developed that made concentrates safe. Increasingly pure products followed the introduction of chromatography steps with monoclonal antibodies in the production process. The problem of immunogenicity of exogenously administered concentrates has not yet had a complete solution. The development of alloantibodies against FVIII in about 25-35% of PWH is the most serious adverse effect of replacement therapy. The next major advance followed the cloning of the F8 gene and later the F9 genes, which paved the way to produce concentrates of factors obtained by the recombinant DNA technology. The injected FVIII and FIX molecules had a relatively short circulating half-life in the plasma of people with hemophilia A and B, approximately 12 and 18 hours, respectively. The ability to prolong the plasma half-life and extend the interval between injections followed the application of methods to conjugate the factor molecule with the fragment crystallizable of IgG1 or albumin or by adding polyethylene glycol, which has led to an increase in the half-life of concentrates, especially for rFIX. The next frontier in hemophilia therapy is the application of durable and potentially curative therapies such as with gene addition therapy. Experiments in hemophilia B have demonstrated durable responses. Unfortunately, the results with gene therapy for hemophilia A have not been as remarkable and the durability must still be demonstrated. Nonetheless, the long-term safety, predictability, durability, and efficacy of gene therapy for hemophilia A and B remain an open question. At present, only healthy adult PWH have been enrolled in gene therapy clinical trials. The application of gene therapy to children and those with pre-existing antibodies against the delivery vector must also be studied before this therapy becomes widespread.

Project description:BackgroundJaundice is a common symptom of inherited or acquired liver diseases or a manifestation of diseases involving red blood cell metabolism. Recent progress has elucidated the molecular mechanisms of bile metabolism, hepatocellular transport, bile ductular development, intestinal bile salt reabsorption, and the regulation of bile acids homeostasis.Main bodyThe major genetic diseases causing jaundice involve disturbances of bile flow. The insufficiency of bile salts in the intestines leads to fat malabsorption and fat-soluble vitamin deficiencies. Accumulation of excessive bile acids and aberrant metabolites results in hepatocellular injury and biliary cirrhosis. Progressive familial intrahepatic cholestasis (PFIC) is the prototype of genetic liver diseases manifesting jaundice in early childhood, progressive liver fibrosis/cirrhosis, and failure to thrive. The first three types of PFICs identified (PFIC1, PFIC2, and PFIC3) represent defects in FIC1 (ATP8B1), BSEP (ABCB11), or MDR3 (ABCB4). In the last 5 years, new genetic disorders, such as TJP2, FXR, and MYO5B defects, have been demonstrated to cause a similar PFIC phenotype. Inborn errors of bile acid metabolism also cause progressive cholestatic liver injuries. Prompt differential diagnosis is important because oral primary bile acid replacement may effectively reverse liver failure and restore liver functions. DCDC2 is a newly identified genetic disorder causing neonatal sclerosing cholangitis. Other cholestatic genetic disorders may have extra-hepatic manifestations, such as developmental disorders causing ductal plate malformation (Alagille syndrome, polycystic liver/kidney diseases), mitochondrial hepatopathy, and endocrine or chromosomal disorders. The diagnosis of genetic liver diseases has evolved from direct sequencing of a single gene to panel-based next generation sequencing. Whole exome sequencing and whole genome sequencing have been actively investigated in research and clinical studies. Current treatment modalities include medical treatment (ursodeoxycholic acid, cholic acid or chenodeoxycholic acid), surgery (partial biliary diversion and liver transplantation), symptomatic treatment for pruritus, and nutritional therapy. New drug development based on gene-specific treatments, such as apical sodium-dependent bile acid transporter (ASBT) inhibitor, for BSEP defects are underway.Short conclusionUnderstanding the complex pathways of jaundice and cholestasis not only enhance insights into liver pathophysiology but also elucidate many causes of genetic liver diseases and promote the development of novel treatments.

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A Review of Recent Advances Using Tocilizumab in the Treatment of Rheumatic Diseases.

Publications

A Review of Recent Advances Using Tocilizumab in the Treatment of Rheumatic Diseases.

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