Immune-system injuries prompt suits over arthritis drugs.

In September 2003, Aventis SA introduced its drug Arava to patients in Japan. The Franco-German pharmaceutical company's treatment for rheumatoid arthritis (RA) had been available in the United States and Europe for five years, and despite a labeling change and reports of severe infections in patients taking the drug, Japanese health officials approved its use without requiring the manufacturer to conduct a clinical trial in their country. Instead, they required Aventis to monitor the first 3,000 patients who took the drug.

In January, the company announced that 16 people in Japan had developed interstitial pneumonia while taking Arava--and 5 of them had died. It also said that more than 80 people worldwide had developed the chronic lung infection and that doctors should no longer prescribe the medication to patients with respiratory problems.

Arava is only one of several drugs developed to treat rheumatoid arthritis that are attracting the attention of the FDA and plaintiff attorneys because of severe infections in patients taking them. Lawyers and clients across the country are assessing the risks associated with these drugs and questioning whether the drug companies' warnings are adequate.

"Many patients say, look, I had arthritis, but the drug made me worse, and I spent months in the hospital for tuberculosis. Is that enough to make the drug defective?" said Christine Brandt of Birmingham, Alabama, who represents several clients injured by these drugs. "What is the responsibility of the doctors? And were they given enough information to make a good decision and help the patient make a good decision?"

Rheumatoid arthritis is an autoimmune disorder. In a patient with the disease, the body's immune system attacks the tissue in the joints, causing inflammation and tissue damage. The disease can also affect a patient's skin, eyes, lungs, heart, blood, nerves, and kidneys. The cause is unknown, but doctors suspect that genetic, environmental, and hormonal factors may trigger the disease.

There is no known cure. Doctors have had some success treating milder symptoms with generalized anti-inflammatory drugs and topical pain relievers, but for many patients such treatment is not enough. Drug researchers are testing more intensive treatments, trying to stop the immune-system attack that causes the inflammation.

This line of research holds promise for treating other diseases, as well. Inflammation is a critical part of the immune system's battle against infection, but the system has a delicate balance. According to a recent article in Time, many researchers now believe that a host of serious diseases--including heart attacks, colon cancer, and Alzheimer's--may be caused by out-of-control inflammation. Medications that control the inflammation causing disorders like RA could revolutionize the way doctors treat many chronic diseases. (Christine Gorman & Alice Park, The Fires Within, TIME, Feb. 23, 2004, at 38.)

So far, though, the new RA drugs--including Arava, Remicade, and Enbrel--have had the risks of devastating side effects, Arava (leflunomide), a disease-modifying antirheumatic drug (DMARD), was approved by the FDA in September 1998. DMARDs work by stopping the underlying process that causes inflammation. Arava, taken in pill form, specifically stops the development of immune cells.

In contrast, Remicade (infliximab) and Enbrel (etanercept) are "biologic response modifiers." Unlike DMARDs, which affect the entire immune system, biologics focus on a specific component. Remicade and Enbrel inhibit tumor necrosis factor (TNF), a protein that regulates the immune system. Remicade, manufactured by Centocor, Inc. (a subsidiary of Johnson & Johnson), was originally approved in early 1998 to treat Crohn's disease, and subsequently approved in August of that year to treat RA. Remicade is administered by intravenous infusion in a doctor's office. Enbrel, made by Immunex and co-marketed by Wyeth-Ayerst Laboratories (later purchased by Amgen Inc.), was approved in November 1998 to treat RA and is given by injection.

Record of risk

Studies have shown that these three drugs, when used alone or with other medications, effectively treat RA in many patients who do not respond to other medications, but suppressing the immune system may lead to bigger problems for some users. All three drugs have been linked to severe infections, including sepsis, and development of serious diseases, including lymphoma, tuberculosis (TB), congestive heart failure, multiple sclerosis (MS), and lupus.

In May 1999, the FDA reported six deaths and 24 hospitalizations linked to Enbrel. Immunex sent a letter to health care professionals warning of an increased risk of serious infection, including sepsis. The company also revised the drug's label, advising doctors not to prescribe Enbrel for patients with infections and to closely monitor all patients taking the drug.

In October 2000, Wyeth-Ayerst Laboratories sent another "dear doctor" letter warning that MS and other central nervous system disorders may be associated with the drug. And in February 2002, researchers at Rush Medical College in Chicago reported that Enbrel may cause lupus.

Despite these warnings, the FDA has continued to approve Enbrel for other indications, including treatment of psoriatic arthritis--a form associated with the skin disease psoriasis--in August 2003.

Remicade has a similar track record. In August 2001, Centocor announced that it would add a "black box" warning to the drug's label, advising of the increased risk of developing TB while taking the drug.

In early October 2001, the company wrote to health care professionals explaining the increased risk of TB and "other serious opportunistic infections." The letter said that 84 cases of TB, including 4 deaths, had been associated with the drug and advised doctors to test patients for latent TB infections before prescribing it.

Two weeks later, an other dear-doctor letter warned that Remicade should not be prescribed for patients with congestive heart failure because the drug may worsen the condition and increase the risk of death.

Aventis changed Arava's label in June 2003 to indicate a risk of serious infections. The company sent a dear-doctor letter four months later, warning that "serious hepatic in jury, including cases with fatal outcome," had been reported. In addition to the January 2004 announcement of deaths in Japan, European health officials have reported more than 200 cases of liver problems, including at least 9 deaths, associated with the drug.

Litigation emerges

In fall 2001, the FDA launched an investigation into the safety of Remicade, Enbrel, and Arava. The agency's arthritis drug advisory committee met in March 2003 to discuss its progress. The FDA would not comment for this story, as the investigation is ongoing.

Plaintiff attorneys are not waiting for the FDA to act. Although at press time no lawsuit against a manufacturer bad yet been settled or tried, more than a dozen law firms are filing or investigating claims. The lawsuits allege that the pharmaceutical companies failed to adequately warn doctors and patients of the serious side effects associated with these medications.

"The question is whether these drugs confer a benefit that is not significantly outweighed by the risk," said Brandt, "and also whether the company adequately warned about the nature of potential injuries, so that the patient with arthritis doesn't wake up with tuberculosis or multiple sclerosis and say, 'If I had known that I actually might spend months in the hospital for TB or end up with MS along with my other problems, I would have certainly made a different choice.'"

The litigation is more complicated than many other pharmaceutical products liability cases, said attorney Cindi Anne Solomon of Mount Pleasant, South Carolina. "This isn't a Rezulin case, where the product causes mainly one disease, in that case liver damage," she said. Rather, the drugs have caused a multitude of problems.

Solomon--with cocounsel at Weitz and Luxembourg in New Jersey--has filed 21 suits in state court in Middlesex, New Jersey, dealing with Remicade and Enbrel. The cases involve myriad medical problems associated with the drugs, including TB, sepsis, MS, lupus, and death. The defendants are the manufacturers and marketers of the drugs--for Remicade, Centocor Inc., Johnson & Johnson, and Ortho-McNeil Pharmaceutical, Inc.; for Enbrel, Amgen Inc., Immunex Corp., Immunex Manufacturing, Wyeth, and Wyeth Pharmaceuticals, Inc. (See, e.g., Mire v. Amgen, Inc., No. L-4063-03 (N.J., Middlesex County Super. Ct. filed May 30, 2003); Funk v. Centocor, Inc., No. MID-L-7645-03 (N.J., Middlesex County Super. Ct. filed Oct. 22, 2003).)

Last year, the parents of a woman who died from heart failure after taking Remicade for Crohn's disease filed suit in Louisiana. (Lyons v. Centocor, Inc., No. CV-03-1643 (La., Calcasieu Parish Dist. Ct. filed Sept. 3, 2003).) They have also sued the doctor who administered the drug for failing to properly monitor their daughter during infusion and for not responding to her symptoms of heart failure.

Plaintiff advocates say they recognize that patients necessarily assume some risks when they are treated for serious illnesses, but these cases ask, how much is too much?

"Drugs do not have to be perfect," said Brandt. "Side effects happen, even serious ones. All the drug companies have to do is make a drug with a reasonable risk/benefit analysis, adequately warn about the seriousness of the side effects, and instruct their sales reps to tell the truth to the doctors. You would be surprised how often that does not happen."