The pharmacological class of TNF alpha inhibitors includes etanercept (Enbrel) infliximab (Remicade) and adalimumab (HUMIRA), among others (see below). These drugs share mechanisms of action and therapeutic uses (rheumatologic diseases, bowel inflammatory disease and psoriasis).

The first approved TNF alpha blocker was etanercept (Enbrel) in May 1998. Then came infliximab (Remicade) in November 1999, while adalimumab (HUMIRA) was approved in December 2002.

TNF alpha, a key cytokine for the development of the inflammatory response

An excerpt from the excellent “ Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy” by D. Golan , A.H. Tashjian , E. J. Armstrong and A.  W Armstrong

Tumor necrosis factor-α (TNF-α) is a cytokine central to many aspects of the inflammatory response. Macrophages, mast cells, and activated T_H cells (especially T_H1 cells) secrete TNF-α. TNF-α stimulates macrophages to produce cytotoxic metabolites, thereby increasing phagocytic killing activity.

TNF-α has been implicated in numerous autoimmune diseases. Rheumatoid arthritis, psoriasis, and Crohn’s disease are three disorders in which inhibition of TNF-α has demonstrated therapeutic efficacy. Rheumatoid arthritis illustrates the central role of TNF-α in the pathophysiology of autoimmune diseases. Although the initial stimulus for joint inflammation is still debated, it is thought that macrophages in a diseased joint secrete TNF-α, which activates endothelial cells, other monocytes, and synovial fibroblasts. Activated endothelial cells up-regulate adhesion molecule expression, resulting in recruitment of inflammatory cells to the joint. Monocyte activation has a positive feedback effect on T-cell and synovial fibroblast activation. Activated synovial fibroblasts secrete interleukins, which recruit additional inflammatory cells. With time, the synovium hypertrophies and forms a pannus that leads to destruction of bone and cartilage in the joint, causing the characteristic deformity and pain of rheumatoid arthritis.

Anti TNF agents molecular characteristics

Etanercept (Enbrel): Soluble TNF receptor fusion protein. As you can see in the image, etanercept molecule consists of 2 extracellular domains of human soluble TNF receptor p75 that binds to TNF and a Fc fragment of human IgG that serves as a stabilizer.

Infliximab (Remicade): chimeric human-mouse anti-TNF alpha  . This drug is 25% murinal (mouse) derived and 75% human. The binding epitope for TNF is of murine origin while the IgG fragment is of human origin.

Adalimumab (HUMIRA- Human Monoclonal Antibody in Rheumatoid Arthritis-): fully human anti-tumor necrosis factor alpha monoclonal antibody produced by phage-display technology.

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The TNF alpha inhibitors share therapeutic uses

This chart shows the latest (May 2009) information on the FDA approved uses of  three selected TNF alpha blockers.

Source: FDA.gov

Newer TNF alpha blockers

Certolizumab pegol (Cimzia): pegylated humanized Fab’ fragment that binds tumor necrosis factor alpha. FDA approved it in April 2008  for the treatment of Crohn’s disease.

Golimumab (Simponi). Approved in April 2009 for: moderate-to-severe rheumatoid arthritis, active psoriatic arthritis, and active ankylosing spondylitis.

TNF blockers adverse effects: risks of tuberculosis reactivation and invasive fungal infections

TNF inhibitors have a number of known side effects, mainly related to their immunosuppressant activity.

Since TNF is a important cytokine when fighting against tuberculosis, these drugs can reactivate a latent tuberculosis infection.

The official FDA presentation below discusses adverse effects associated with TNF blockers: infections (tuberculosis, histoplasmosis and other invasive fungal infections) , congestive heart failure, neurologic events, malignancies and autoimmunity.

Download PPT file

This is a FDA patient safety alert video, warning about the risk of serious fungal infections in patients receiving TNF alpha inhibitors.

Also, the UK’s National Institute for Health and Clinical Excellence (NICE) issued in February 2009 an update of the rheumatoid arthritis clinical guideline.