http://www.reutershealth.com/archive/2002/01/18/eline/links/20020118elin031.html

By Faith Reidenbach

NEW YORK, Jan 18 (Reuters Health) - In a small number of cases, certain arthritis drugs have been associated with serious nervous system problems, according to a recent report from researchers at the US Food and Drug Administration (FDA) and elsewhere in Washington, DC.

They recommend that patients receiving Enbrel (etanercept) or Remicade (infliximab) be monitored by their physicians for neurologic symptoms such as confusion, numbness, changes in vision and difficulty walking.

These symptoms are suggestive of demyelination, or the loss of myelin, the fatty sheath that coats nerve fibers and helps nerves function. A familiar example of a demyelinating disease is multiple sclerosis, in which degeneration of nerve cells results in symptoms ranging from numbness and muscle weakness to paralysis.

If neurologic symptoms appear in a patient taking Enbrel or Remicade, the drug should be discontinued immediately, the researchers advise in a recent issue of Arthritis & Rheumatism. The patient should be referred to a neurologist for a thorough examination, they say.

In interviews with Reuters Health, spokespeople for Enbrel's maker Immunex, and Centocor, the maker of Remicade, emphasized that demyelinating disease is a rare complication of therapy with these two drugs. The companies have known about this complication for over a year, and a warning about it appears on their drug packaging and Web sites.

"Our current knowledge of this would suggest that (demyelinating disease) is a very, very rare complication," Dr. John H. Klippel, medical director of the Arthritis Foundation in Atlanta, Georgia, concurred in an interview with Reuters Health.

"On the other hand, the authors of this study have asked for additional studies to reassure ourselves that it is in fact quite rare, because it has not been systematically studied," he said. "The Arthritis Foundation would certainly agree that additional studies are warranted."

Dr. Niveditha Mohan of Georgetown University Medical Center and colleagues first suspected a possible link between neurologic symptoms and the drugs when a 48-year-old man was referred to them because of confusion and difficulty walking. The man had rheumatoid arthritis and had been taking Enbrel for 4 months.

A brain biopsy revealed some damage to nerve fibers, although no actual loss of myelin was visible when the man underwent an MRI brain scan.

To investigate whether similar cases had ever been reported, the researchers searched an FDA database. They found reports of 17 other patients taking Enbrel and 2 taking Remicade who had developed neurologic symptoms suggestive of demyelination.

Eighteen of those patients had undergone brain MRI. In all of them the scans showed demyelination in one or more areas of the central nervous system, or some other injury to nerve fibers.

The average length of therapy before neurologic symptoms developed was 5 months, the database showed. In all patients, symptoms improved completely or partially after patients stopped using Enbrel or Remicade. When one patient began taking Enbrel again, his symptoms returned.

"Reports to the (FDA) do not necessarily represent causal relationships between adverse events and drugs," the researchers note. "In addition, underreporting of adverse events occurs, and the reports may be missing data. Therefore these reports should be interpreted cautiously."

In correspondence with Immunex, Mohan's group learned that Enbrel was prescribed for 77,152 patients between November 1998 and May 2000. Symptoms suggestive of a demyelinating disorder were reported for only nine patients during this period.

That figure is similar, the researchers point out, to the natural rate of new cases of multiple sclerosis: 4 to 6 cases for every 100,000 people per year. The spokesman for Centocor also noted that the rate of demyelinating disorders associated with Remicade is no higher than the expected rate of MS in the general population.

The research team acknowledges that the patients they studied might have had "a genetic propensity to develop MS." Four of the patients were known to have had MS or an MS-like syndrome before they started taking the arthritis drug.

"Clinicians should consider avoiding (Enbrel, Remicade, and similar drugs) in those patients who have a preexisting diagnosis of MS," Mohan's group recommends.

"I would be a little more emphatic," Klippel told Reuters Health. "Instead of giving consideration to avoiding, I think that the medical community would be of the view that these drugs should not be used in people with known demyelinating diseases like multiple sclerosis."

SOURCE: Arthritis & Rheumatism 2001;44:2862-2869.
 

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