Rheumatoid Arthritis Drugs Linked to Increased Shingles Risk

Rheumatoid arthritis (RA) patients routinely receive immunosuppressive drugs to treat their symptoms and slow the progression of their joint disease. These treatments have long been known to increase the risk of numerous types of infections and cancers.

A recent study published in the Annals of the Rheumatic Diseases (Annals) strongly suggests that RA patients treated with tumor necrosis factor (TNF) blockers, a class of very potent immunosuppressive drugs most commonly used to treat RA, also have an increased risk of developing the viral skin infection shingles. The study also showed that this risk appears to peak at approximately one year after starting the drugs.

Patients prescribed these drugs should be aware of the risk of shingles and associated complications. In addition, patients age 50 or older should strongly consider vaccination with the shingles vaccine, ZOSTAVAX, to protect against this risk prior to starting such RA therapy.

Overview of TNF blockers

TNF blockers are a family of biologic drugs that interfere with the naturally occurring, hormone-like substance TNF, which plays a central role in immune system function. These drugs are considered disease-modifying anti-rheumatic drugs (DMARDs). In contrast to anti-inflammatory drugs such as nonsteroidal anti-inflammatory drugs, DMARDs not only relieve symptoms but also may slow or even modify the rheumatic disease process itself.

Five TNF blockers are available in the U.S. (see table), administered by injection at intervals ranging from one to eight weeks between doses. In many patients, these drugs can cause a dramatic improvement in symptoms by blocking the action of a TNF, believed to play a role in joint inflammation and damage. Elevated levels of TNF are found in the joint fluid of RA patients.

Until recently, most doctors reserved the use of DMARDs for the most severe RA patients who failed to respond to other therapies. Now, many physicians use DMARDs earlier and more aggressively in the hope of slowing disease progression and damage to joints. One of the oldest, still widely prescribed DMARDs, methotrexate (TREXALL), is often recommended as the first DMARD to be used for patients with moderate to severe RA. Patients failing to adequately respond to methotrexate typically are switched to more aggressive treatment with TNF blockers.

As with many drugs with dramatic benefits, TNF blockers also can pose serious risks because they interfere with the body’s immune mechanisms for fighting infectious diseases and destroying cancer cells. Thus, the Food and Drug Administration (FDA) has required information about increased risks of infections (such as tuberculosis) and cancers (such as lymphoma) to be included in black-box warnings on the labels for these drugs, as well as in FDA-approved Medication Guides that are to be provided to patients.

TNF Blockers Available in the U.S.

* Do Not Use for Seven Years
** Limited Use

Overview of shingles

Shingles is also known as herpes zoster and is caused by the varicella-zoster virus, the same virus that causes chicken pox. (Chicken pox was a once-common infection in the U.S. prior to the development of the children’s varicella-zoster vaccine.)

After a person recovers from chicken pox, small amounts of the varicella-zoster virus remain dormant within spinal sensory nerves for life. Shingles may occur later in life when the dormant virus reactivates and spreads from one or more nerves to the skin. The infection is characterized by a rash that initially appears as groups of multiple red bumps and evolves into small blisters and pustules. The lesions generally appear in a narrow band on one side of the body. Known as a dermatome, this band is the area of skin connected to the sensory nerve in which the dormant varicella-zoster virus reactivated.

Besides the rash, pain is the most common symptom of a shingles infection. In approximately three-quarters of cases, the pain begins days to weeks before the appearance of the rash. This pain, which may be constant or intermittent, occurs in the same areas of skin affected by the subsequent rash. A minority of shingles patients also experience headaches, fever, malaise and fatigue.

A common complication of shingles, occurring in approximately 10 to 15 percent of cases, is post-herpetic neuralgia, which causes chronic, often severe pain in the same area of skin that had the rash. The risk of developing post-herpetic neuralgia increases with age, and patients over age 60 are at greatest risk of this complication. Patients who are immunosuppressed also are at higher risk of developing post-herpetic neuralgia.

Other complications of shingles include blindness due to shingles infection in areas of skin around the eyes that can spread to the cornea, meningitis, encephalitis (brain infection) and secondary bacterial infection of the skin pustules.

The shingles vaccine, ZOSTAVAX, reduces the risk of having shingles by about 50 percent — as well as reducing the risk of major complications, including post-herpetic neuralgia by two-thirds, if a shingles infection does occur — without serious side effects. This vaccine, approved for use in adults age 50 and older, is different than the one given to children to prevent chicken pox. ZOSTAVAX includes live varicella-zoster virus that has been modified so that it can no longer cause active infection. In people anticipating immunosuppression, the vaccine should be given at least 14 days to one month prior to starting immunosuppressant therapy.

Overview of the Annals study

Beginning in 2001, the British Society for Rheumatology (BSR) initiated the BSR Biologics Register (BSRBR) to prospectively evaluate the long-term clinical outcomes, including the incidence of rare and unexpected adverse events, of RA patients treated across the U.K. with TNF blockers and other similar biologic drug therapies.

BSRBR recruitment of RA patients treated with either etanercept (ENBREL) or infliximab (REMICADE) started in 2001, and recruitment of patients prescribed adalimumab (HUMIRA) began in 2003. The planned subject enrollment for each patient group was 4,000, which has been attained for all three drugs.

The BSRBR also included a prospectively enrolled comparison control group of active RA patients who were not treated with TNF blockers or other similar biologic drugs, but instead received nonbiological DMARDs, such as methotrexate.

Patients previously treated with any TNF blocker or other biologic drugs were excluded from the study.

At the time of initial enrollment in the registry, all patients provided a complete medical history and underwent a baseline physical exam. Patients and their physicians completed follow-up medical questionnaires every six months for three years. Patients also maintained a diary to record hospitalizations, adverse events and new prescriptions for three years.

Results of the Annals study

For the recent Annals study, data on new skin infections, including shingles, were analyzed for 11,881 RA patients taking TNF blockers and 3,673 control patients.

There were 275 cases of shingles in patients receiving TNF blockers (incidence rate of 1.6 infections per 100 patient-years, which is an estimate of the number of infections that would occur if 100 RA patients were each treated for one year with these drugs) and 45 cases in the control group patients (incidence rate of 0.8 infections per 100 patient-years). Twenty shingles infections (7 percent) in TNF-blocker patients were classified as severe, whereas only one case of shingles (2 percent) in a control patient was severe. Six of the severe infections in the TNF-blocker patients as well as the one severe infection in the control-group patient involved the eye.

After controlling for multiple confounding factors (including age; sex; severity and duration of RA; disability scores; baseline steroid use; smoking status; other diseases, such as diabetes and emphysema; and year of entry into the study), patients treated with any of the three TNF blockers were 70 percent more likely to contract shingles than control patients. The researchers estimated that for every 128 patients treated for one year with a TNF blocker, one additional case of shingles occurred.

RA patients treated with infliximab had the highest risk of shingles, with a 2.2-fold greater incidence than control patients. The risk in etanercept patients was 1.7-fold higher, and adalimumab-treated patients had the lowest risk (1.5-fold higher incidence compared with those in the control groups).

Finally, an analysis of the risk of shingles over time revealed that the level of risk peaked at one year of treatment and then gradually decreased.

What You Can Do

If you are an RA patient age 50 or older in whom treatment with a TNF blocker is being considered, you should discuss with your physician whether you should receive the shingles vaccine prior to initiation of the drug. Low-dose steroids or methotrexate, both frequently prescribed to RA patients prior to TNF blockers, are not contraindicated to the shingles vaccine. If the vaccine is to be given, it should be administered two to four weeks prior to starting any TNF blocker.

Regardless of whether you receive the shingles vaccine prior to starting a TNF blocker, you should be alert for signs of the shingles rash. If you develop shingles, see your health care provider immediately to discuss whether an antiviral drug active against the varicella-zoster virus should be initiated. This is particularly important if shingles develops on the face near the eye, because such treatment is needed to prevent eye infection and possible blindness.

For any shingles rash, you should monitor the affected areas for signs of secondary bacterial infection, such as spreading areas of redness, warmth and tenderness. If these signs develop, you should contact your physician promptly to determine whether you need antibiotics for a bacterial skin infection on top of the shingles.