Arthritis Under Arrest

By MICHAEL D. LEMONICK

For most victims arthritis simply means pain and stiffness in the joints--sometimes moderate, sometimes severe, usually responsive to treatment with one of a number of drugs. Pain can be just the beginning, though, for the more than 2 million Americans who suffer from the variant of the disease known as rheumatoid arthritis. This unfortunate minority may experience not just discomfort but also joint deformities, fatigue, nodules of tissue under the skin and inside internal organs and, in rare cases, inflammation of the membranes surrounding the heart and lungs.

Unfortunately, even the most powerful existing medications, like Methotrexate, either carry unacceptable side effects or are ineffective against rheumatoid arthritis, or both. Clinicians are understandably a bit giddy, therefore, at the news that after more than a decade of no progress, not just one but a number of new treatments are all at once streaming out of research labs.

Last week, for example, an FDA advisory panel recommended that the agency approve a new drug called Enbrel. The week before, the full FDA had given the nod to another anti-rheumatoid arthritis drug called Arava. Next month the agency will assess a promising blood-filtration device that clears the body of arthritis-promoting substances the same way kidney dialysis cleans the blood of toxins. Within a few months the FDA will also consider a new class of anti-inflammatories called COX-2 inhibitors (a.k.a. "super aspirin") that will attack arthritis pain. Says Steven Abramson, an FDA adviser and chief of rheumatology at New York University's Hospital for Joint Diseases: "This is the most exciting time I've witnessed."

The excitement began with a growing understanding of how rheumatoid arthritis works. Unlike its more common cousin, osteoarthritis, which causes pain in more than 20 million mostly older Americans through simple deterioration of joint cartilage, rheumatoid arthritis is a complex disease involving an immune system gone awry.

Most experts believe the trigger for rheumatoid arthritis is an ordinary infection in a joint, to which the immune system mounts an ordinary response. Then, for some unknown reason, the white blood cells that are fighting invading microbes attack the joint itself--specifically the synovial sac, which acts as both a cushion that keeps bones from banging together and a source of lubricating fluid. Even as the white cells attack, they send out signals, in the form of hormones called cytokines, that rally more troops to their aid. Meanwhile, the besieged synovial cells secrete prostaglandins, which cause inflammation. All this makes the joint redden and become sore.

Armed with this knowledge, says Edward Keystone, director of advanced therapeutics in arthritis at Mount Sinai Hospital in Toronto, "we're targeting every element of this disease from start to finish." The new drug Arava, for example, created by the Kansas City, Mo., firm Hoechst Marion Roussel, stops white cells from reproducing. Enbrel, a genetically engineered medication from Seattle-based Immunex, works by sopping up a tumor-killing cytokine called tumor necrosis factor before it can issue its call for reinforcements. The COX-2 inhibitors target prostaglandin production, limiting pain and inflammation. And the blood-filtration device, invented at Cypress Bioscience of San Diego, strips the blood of proteins that tell white cells (erroneously) what tissues to attack--a treatment so effective in clinical trials that the FDA review-and-approval process has been put on a faster track.

While none of these treatments cure the disease, many slow its relentless progress, usually with fewer side effects than existing drugs have. That doesn't mean problems won't eventually show up in long-term users. "There is always a concern," says Michael Schiff of the Denver Arthritis Clinic, "that when you interfere with the immune system, you could get serious infections or malignancies."

A more immediate problem is cost. Even at wholesale, Arava carries a price tag of about $3,000 for a year's treatment, and Enbrel could go for up to $10,000. Blood filtration might come in as high as $25,000. "It's expensive," admits Chad Deal of Case Western Reserve School of Medicine, who participated in clinical trials of the blood-filtration system. "But the 10% to 20% of patients who aren't responding to other treatments are miserable, and their joints are still eroding." Given the alternative--and, with any luck, given reasonable insurance coverage--it's easy to guess what choice the patients will make.

--Reported by Dick Thompson/Washington

With reporting by Dick Thompson/Washington