Monoclonal anti–TNF-alpha-antibodies associated with increased risk of herpes zoster

Tumor necrosis factor (TNF, cachexin or cachectin and formally known as tumor necrosis factor-alpha) is a cytokine involved in systemic inflammation and is a member of a group of cytokines that stimulate the acute phase reaction. TNF induces apoptotic cell death, inflammation, and inhibits tumorogenesis and viral replication.


Tumor necrosis factor (TNF superfamily). Image source: Wikipedia, Protein Data Bank (PDB: 1TNF), public domain.

TNF inhibitors

TNF inhibition can be achieved with a monoclonal antibody such as infliximab (Remicade) or adalimumab (Humira), or with a circulating receptor fusion protein such as etanercept (Enbrel). The global market for TNF inhibitors in 2007 was $10 billion.

Infliximab (brand name Remicade) is a chimeric monoclonal antibody. Tthe term "chimeric" refers to the use of both mouse (murine) and human components of the drug i.e. murine binding Fab domains and human constant Fc domains. Remicade is administered by intravenous infusion, typically at 6-8 week intervals, and at a clinic or hospital. It cannot be administered orally (like all antibodies) because the digestive system would destroy the drug.

Etanercept (Enbrel) is a recombinant-DNA drug made by combining two proteins (a fusion protein). It links human soluble TNF receptor to the Fc component of human immunoglobulin G1 (IgG1). Etanercept is not a monoclonal antibody, it is a fusion proteton, thefefore, different from infliximab (Remicade) and adalimumab (Humira).

Etanercept (Enbrel) is a large dimeric molecule (see above), with a molecular weight of 150 kDa, that binds to TNFα. Monomeric version did not have sufficient biologic activity.

Etanercept is made from the combination of two naturally occurring TNF receptors linked to an Fc portion of an IgG1. The effect is an artificially engineered dimeric fusion protein.

Enbrel is injected subcutaneously, typically by the patient at home, using pre-filled 50 mg/ml syringes in late 2004 or a single-use 50 mg autoinjector "pen" was brought to market in 2006.

Adalimumab. Image source: Wikipedia, public domain.

Adalimumab (brand name Humira) is the third TNF inhibitor, after infliximab and etanercept, to be approved in the United States.

Like infliximab and etanercept, adalimumab binds to TNFα, preventing it from activating TNF receptors. Adalimumab (Humira) was constructed fully from a human monoclonal antibody, while infliximab is a mouse-human chimeric antibody. Etanercept is a TNF receptor-IgG fusion protein.

Humira brand name is an abbreviation of "Human Monoclonal Antibody in Rheumatoid Arthritis." Adalimumab is marketed in both preloaded 0.8 ml syringes and preloaded pen devices (Humira Pen), both injected subcutaneously, typically by the patient at home.

Monoclonal anti–TNF-alpha-antibodies associated with increased risk of herpes zoster

The risk of bacterial infection is increased in patients treated with drugs that inhibit tumor necrosis factor-alpha (TNF-alpha). Little is known about the reactivation of latent viral infections during treatment with TNF-alpha inhibitors.

The study authors examined whether TNF-alpha inhibitors together as a class, or separately as either monoclonal anti–TNF- antibodies (adalimumab, infliximab) or a fusion protein (etanercept), are related to higher rates of herpes zoster in patients with rheumatoid arthritis.

Among 5040 patients in Germany receiving TNF- inhibitors or conventional DMARDs, 86 episodes of herpes zoster occurred in 82 patients:

- 39 occurrences could be attributed to treatment with anti–TNF- antibodies
- 23 to etanercept
- 24 to conventional DMARDs (used as controls)

A significantly increased risk was observed for treatment with the monoclonal antibodies although this risk was lower than the threshold for clinical significance. No significant associations were found for etanercept use or for anti–TNF-alpha treatment as a class.

The authors concluded that treatment with monoclonal anti–TNF-alpha antibodies may be associated with increased risk of herpes zoster.

The news outlets reported that the monoclonal anti–TNF- antibodies Humira, Kineret, and Remicade each increased shingles risk by 80%. Enbrel did not.

References:
Risk of Herpes Zoster in Patients With Rheumatoid Arthritis Treated With Anti–TNF- Agents. Anja Strangfeld, MD; Joachim Listing, PhD; Peter Herzer, MD; Anke Liebhaber, MD; Karin Rockwitz, MD; Constanze Richter, MD; Angela Zink, PhD. JAMA. 2009;301(7):737-744.
Tumor necrosis factor-alpha, from Wikipedia, the free encyclopedia.
Infliximab, from Wikipedia, the free encyclopedia.
Adalimumab, from Wikipedia, the free encyclopedia.