By Nathan Wei

Rheumatoid arthritis is a chronic, progressive, systemic disease that affects more than 2.1 million Americans.

Because it is a systemic disease it affects more than just the joints.

Other organ systems that may be adversely affected include the eyes, lungs, central and peripheral nervous system, skin, heart, and blood.

Long term complications of rheumatoid arthritis include early death from heart attack and stroke, the development of lymphoma, and disability.

Early aggressive therapy with slow-acting disease modifying drugs (DMARDS) such as sulfasalazine (Azulfidine), methotrexate, hydroxychloroquine (Plaquenil), leflunomide (Arava), and azathioprine (Imuran) have shown that many of these potential systemic problems can be mitigated. Yet, until recently, remission was an elusive target.

With the advent of newer biologic therapies, the possibility- and probability of remission has increased several-fold.

The first biologic drugs are the tumor necrosis factor (TNF) inhibitors. These drugs block the effect of a protein messenger that is responsible for much of the inflammation and destruction that occurs in RA.

The three TNF inhibitors (etanercept [Enbrel], infliximab [Remicade], and adalimumab [Humira]) were demonstrated to have significant clinical benefits in randomized trials that resulted in their US Food and Drug Administration (FDA) approval.

Patients enrolled in these trials had severe RA disease, as reflected by more than 20 swollen and 30 tender joints and baseline scores measuring their ability to perform activities of daily living consistent with extremely poor functioning.

Improvement in signs and symptoms as measured by American College of Rheumatology (ACR) response were similar for all 3 therapies. Responses are graded as being a 20 per cent response (ACR 20), a 50 per cent response (ACR 50), and a 70 per cent response (ACR 70).

The higher the response, the better the drug works on RA. All three TNF inhibitors performed about the same, ie., (ACR20 ~60%, ACR50 ~40%, and ACR70 ~20%).

Patients having either early or long-standing RA demonstrated significant response. In addition to improvement in signs and symptoms, dramatic reduction in x-ray progression was noted as well as improvement in health-related quality of life and physical function and disability. This is not surprising since x-ray progression is intimately correlated with both reduction in functionality as well as the eventual development of disability.

Subsequent studies comparing TNF inhibitors in combination with MTX vs MTX alone, or in the case of etanercept and adalimumab an additional comparison with TNF inhibitor single drug use, demonstrated greater effectiveness when used in combination with MTX.

In all three studies, the number of patients achieving remission as defined by a scoring system known as the Disease Activity Score (DAS) 28 was twice that seen in the single drug group and approached 40%. These studies clearly showed that TNF inhibitors in combination with MTX was the most effective regimen available for RA patients.

But, what about side effects?

While there were early concerns about the development of increased risk for B-cell non-Hodgkin’s lymphoma in patients treated with these drugs, there has not been a definite link between TNF inhibitors and lymphoma.

Studies before the advent of biologic drugs demonstrated that RA disease severity was associated with increased lymphoma risk; however, several studies involving RA patients who have since been treated with TNF inhibitors demonstrated no increase in lymphoma incidence compared with RA patients on MTX.

No studies have demonstrated an increase in solid tumor malignancy in patients treated with TNF inhibitors, except for reports of non-melanoma skin cancers.

Nonetheless, what is not known is the risk for cancer in patients with previous malignancy who are receiving TNF inhibitors.

Experience culled from clinical trials as well as real life data has shown that adverse events, such as upper respiratory infections, are increased with TNF inhibitor treatment. Some studies have indicated that there is an increased risk for serious infection with these drugs as well.

Currently, the feeling is that patients receiving biologic therapies are at risk for serious infection, and this is an issue to be discussed with patients prior to the initiation of these therapies.

Reactivation of latent TB has been clearly associated with TNF inhibitor utilization. The use of effective screening for TB prior to initiating TNF inhibitors has reduced the frequency of TB reactivation.

Other types of infection such as Listeria, histoplasmosis, and coccidiomycosis, have been reported in patients receiving TNF inhibitors.

Injection site reactions or infusion reactions have been reported and treatment needs to be cut back or stopped if these reactions persist.

TNF-inhibitor treatment is contraindicated in patients with class III-IV congestive heart failure. These drugs can make the heart failure worse.

Patients with neurologic conditions in which there is demyelination such as multiple sclerosis are not considered to be good candidates for TNF inhibitor therapy. Rare reports of patients developing a demyelinating condition have been noted.

Liver failure has been seen in patients on TNF inhibitors. TNF inhibitors are contraindicated in patients with acute or chronic hepatitis B, but data from uncontrolled case series have suggested that TNF inhibitors may be safely used in hepatitis C patients.

About the Author: Nathan Wei, MD FACP FACR is a rheumatologist and Director of the Arthritis and Osteoporosis Center of Maryland. He is a Clinical Assistant Professor of Medicine at the University of Maryland School of Medicine. For more info:

Arthritis Treatment

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