My doctor wants to start me on Enbrel… what are the risks?

Enbrel (etanercept) is a biologic drug.  Biologic drugs are protein-based medications that have been synthesized in a lab to perform a biologic function.  Enbrel is a biologic that blocks the effects of tumor necrosis factor-alpha.  Tumor necrosis factor (TNF) is a protein messenger produced by immune cells.  It promotes and perpetuates inflammation in rheumatoid arthritis (RA).

In addition to Enbrel, there are two other inhibitors of TNF available.  They are Remicade (infliximab) and Humira (adalimumab). All three drugs neutralize and eliminate excess amounts of TNF from the circulation and from areas of inflammation. These cytokine inhibitors have proven effective when other medicines such as disease modifying anti-rheumatic drugs (DMARDS) like methotrexate have failed to control symptoms or halt joint damage.

They are effective in improving symptomatic and x-ray outcomes and have been found safe, even when administered early in the disease process. However, as these drugs are used more extensively, there are growing concerns about the safety of biologic therapies.

Infection.

Since TNF also helps maintain normal immune function, blocking this cytokine may predispose to infection, malignancy, or other autoimmune states. To date, the most frequently reported adverse events (AEs) are related to the drug's administration -- mild rash, local pain or swelling at administration sites, and hypersensitivity reactions.

Data from the clinical trials for all 3 currently available TNF inhibitors did not show an overall increase in TNF inhibitor-related serious infection rates compared to the placebo control group.

However, several studies have examined drug safety in patients with other underlying diseases and conditions (elderly age, diabetes, chronic lung and kidney disease, chronic osteomyelitis, etc.).  This group mirrors the type of patient seen in real life clinical practice.

Results from some of these studies did show an increased risk for infection. In addition, rheumatoid arthritis itself may increase the risk of infection. This combination of risk factors probably increases the risk for infection even more.

Data since FDA approval has also shown higher incidences of other types of unusual infections such as tuberculosis, atypical mycobacteria, histoplasmosis, aspergillosis, and others

These infections appear to be more aggressive and tend to occur in areas of the body outside of the lung. Of greater concern is that infection risk is significantly greater when biologics are given in combination. For instance, the incidence of serious infections was considerably increased when TNF blockers were given along with with Kineret (anakinra) or Orencia (abatacept), and the combination of biologics failed to demonstrate any added benefit over a single drug given alone. Therefore, combination biologic therapy should not be used n patients with RA.

Malignancy.

In addition to infection, there have been concerns that the TNF inhibitor may lead to a greater risk for malignancy, particularly lymphoma, because TNF is an important component of the immune system. Several studies have revealed that patients with RA have an activity-related increased rate of non-Hodgkin's lymphoma compared to that in the normal population. In other words, the worse the RA, the higher likelihood of developing lymphoma.

In some studies there has been reported a slightly higher incidence of lymphoma in patients receiving anti-TNF drugs versus patients with RA who don’t.  However, there may be a selection bias. Patients at highest risk for lymphoma (eg, those with higher disease activity) are more likely to receive anti-TNF therapy.

Liver and blood problems.

Large clinical studies have also demonstrated evidence of blood count abnormalities and liver enzyme elevations. These abnormalities are difficult to interpret because other factors such as concurrent diseases and concomitant use of medications (eg, non-steroidal anti-inflammatory drugs, methotrexate, and leflunomide) may also cause these effects.

Given the potential for blood and liver toxicity, regular laboratory monitoring should be considered for patients receiving TNF inhibitors. More reports are emerging regarding rapidly progressive liver failure in patients with chronic hepatitis B virus infection. Reactivation of the hepatitis B virus following immunosuppression when fatal hepatitis has occurred has been seen in transplant and cancer studies.  Pretreatment blood testing for chronic viral hepatitis (HBV and hepatitis C virus) is recommended. Prophylaxis with lamivudine or other effective antiviral drugs should be considered in patients who are hepatitis B surface antigen (HBsAg)-positive and who will be placed on TNF inhibitor therapy.

Congestive heart failure.

Use of TNF inhibitors in patients with moderate to severe congestive heart failure has been discouraged because of the potential for worsening of heart function. TNF may play a role in the progression of heart failure.

Caution should be taken when using TNF inhibitors in patients with unstable cardiac dysfunction.

Other risks.

Demyelinating diseases, lupus-like syndromes, and abnormal antibody production have been reported in association with these drugs. The cases are rare, and the impact of these drugs in patients with other underlying autoimmune conditions such as multiple sclerosis, systemic lupus erythematosus is still unclear.

So… while anti-TNF drugs have revolutionized our ability to treat RA and have allowed us to put significant numbers of patients with RA into remission, they should be used by experienced rheumatologists. Patient information is critical as well.