For years, the pain and inflammation of arthritis have been treated with varying success, using medications, local steroid injections, and joint replacement. Seldom did the therapies make the pain go away completely or for very long, nor did they affect the underlying joint damage. Just ask Jo Ellen Gluscevich, who has tried more drugs and treatments than she can remember, to no avail.
“It seems I’ve tried them all,” says the 50-year-old from Frederick, Md., who was diagnosed with rheumatoid arthritis 10 years ago. “Every year continues to be a challenge for me medically.”
But now there are some new treatments available, and patients should consult with their doctors to determine which are the most appropriate for their conditions.
When taken regularly and at high doses, traditional nonsteroidal anti-inflammatory drugs (NSAIDs) used for pain relief can cause gastrointestinal (GI) bleeding or ulcers. But a new type of NSAID, cyclooxygenase-2 inhibitors, better known as COX-2 inhibitors, has joined the old standbys and helps suppress arthritis with less stomach irritation.
Cyclooxygenases are enzymes needed for the synthesis of hormone-like substances called prostaglandins. There are two types of cyclooxygenases: the COX-2 enzyme that mediates inflammation and pain, and the COX-1 enzyme that helps maintain other physiological functions in the body. Traditional NSAIDs inhibit both enzymes. The new NSAIDs, however, block mostly the COX-2 enzyme, offering a new treatment option for people who have had difficulty tolerating the old NSAIDs.
“COX-2 inhibitors are just as effective in treating osteoarthritis as other NSAIDs,” says Maria Villalba, M.D., a medical officer with FDA’s Center for Drug Evaluation and Research. “And they have similar renal effects, liver effects and the potential for allergic reactions. But they seem to have a better GI safety profile than traditional NSAIDs.”
FDA approved the first COX-2 inhibitor, Celebrex (celecoxib), in December 1998 to treat rheumatoid arthritis and osteoarthritis. Vioxx (refecoxib) became the second COX-2 inhibitor to receive approval, in May 1999, but only for the treatment of osteoarthritis, dysmenorrhea (pain with menstrual periods), and the relief of acute pain in adults, such as that caused by dental surgery.
Both drugs, taken orally, were found to substantially lower the risk of stomach and upper intestinal ulcers detected by endoscopy in clinical trials, compared with other NSAIDs. Additional studies are needed to determine whether Celebrex and Vioxx actually cause fewer serious stomach problems, including GI ulceration, bleeding and perforation. Until such studies are done, FDA is requiring the drugs’ labeling to include the standard warning about the GI risks that are associated with NSAIDs.
Two non-drug alternatives for the treatment of pain in osteoarthritis of the knee were approved by the Center for Devices and Radiological Health in 1997 for patients who have failed to respond adequately to simple analgesics, such as acetaminophen, and to conservative nonpharmacologic therapy. Hyalgan and Synvisc are viscous solutions composed of hyaluronan (hyaluronic acid, a lubricant found naturally in the joints), and are injected directly into the knee joint. Both are believed to increase the quality of synovial fluid, although the mechanism of action for these products is not well understood. The most common side effects reported from these treatments–injection site pain and knee pain and/or swelling–were found to be temporary. For patients who cannot tolerate oral medications and who are not candidates for surgical knee replacement, these treatments may be an ideal option.
In recent years, the typical treatments for rheumatoid arthritis relied on combination NSAIDs, such as ibuprofen and aspirin. These drugs reduce swelling and alleviate pain but do little to change the course of the disease. Another class of treatments relied on disease-modifying, antirheumatic drugs (DMARDs), such as methotrexate and sulfasalazine. DMARDs work to slow inflammation and can, in many cases, alter the course of the disease. Because of their adverse effects, most doctors reserved these more powerful drugs for patients who failed to respond to other therapies. Now, many physicians are using DMARDs early and aggressively in the hope of slowing disease progression and preventing damage to joints and internal organs.
The most recently approved treatment regimen for rheumatoid arthritis is one that combines the genetically engineered biological drug Remicade (infliximab) with the drug methotrexate. (Not all patients with rheumatoid arthritis can tolerate or respond to methotrexate alone, a standard treatment for the disease.) Remicade is the second in a new class of drugs known as biologic response modifiers, which bind to and block the action of a naturally occurring protein called tumor necrosis factor (TNF), believed to play a role in joint inflammation and damage. Elevated levels of TNF are found in the synovial fluid of rheumatoid arthritis patients.
Remicade, which is administered intravenously by a health-care professional in a two-hour outpatient procedure, was approved by FDA in November 1999 to reduce the signs and symptoms in patients who have not experienced significant relief from methotrexate alone.
Enbrel (etanercept) is the first biologic response modifier to receive FDA approval for patients with moderate to severe rheumatoid arthritis. Taken twice weekly by injection, Enbrel was shown to decrease pain and morning stiffness and improve joint swelling and tenderness.
Jeffrey N. Siegel, M.D., a medical officer with FDA’s Center for Biologics Evaluation and Research, says that Enbrel is an exciting breakthrough because it helps a majority of patients who have not responded to any of the other commonly used therapies. Although it is injected, the treatment can be administered at home. In addition, Enbrel has been shown to be effective for children with the juvenile form of rheumatoid arthritis. In clinical trials, Enbrel was generally well tolerated, and one of the most common side effects was an injection site reaction.
Both Remicade and Enbrel show promise in treating rheumatoid arthritis, although the long-term risks and benefits of these drugs are unknown.
Arava (leflunomide) is the first oral treatment approved for slowing the progression of rheumatoid arthritis. Although its effects are similar to those of methotrexate, this drug works by a different chemical mechanism, blocking an enzyme in certain lymphocytes (a type of white blood cell that is part of the immune system) and thereby retarding the progression of the disease.
Arava is not a cure, however, and studies have suggested that the drug may cause birth defects. Therefore, its labeling carries a special warning for pregnant women, women of childbearing age, and those who want to become pregnant.
The first non-drug alternative for adult patients with moderate to severe rheumatoid arthritis and longstanding disease who have failed or cannot tolerate DMARDs was approved by FDA in March 1999. The Prosorba column, which was initially approved in 1987 to treat an immune blood disorder, is a single-use medical device, about the size of a coffee mug, containing a material that binds antibodies and antigen-antibody complexes.
In a two-hour process performed in a hospital or specialized treatment center, a patient’s blood is removed and passed through a machine that separates the blood cells from the plasma (the liquid portion of the blood). The plasma is then passed through the Prosorba column, recombined with the blood cells, and returned to the patient. Although this filtering process is believed to remove proteins that may inadvertently attack the joint cells, the mechanism of action of the Prosorba column is not well understood. The treatment is once a week for 12 weeks. The most common side effects include joint pain and/or swelling, fatigue, hypotension (low blood pressure), and anemia.
“For those patients who have failed or are intolerant to DMARDs, including Arava and the anti-TNF agents,” says Sahar M. Dawisha, M.D., a medical officer in FDA’s Center for Devices and Radiological Health, “the Prosorba column may be an additional treatment option.”
Source: Food and Drug Administration