For years, the pain and inflammation of arthritis have been treated with pretty much the same combination of medications, rest, moderate exercise or activity, and pain management. Most of the time, existing medications do a reasonably good job of controlling arthritis — depending, that is, on the exact nature of the arthritis and on the timeliness with which it is diagnosed. For example, 60 percent to 70 percent of all cases of rheumatoid arthritis are managed successfully with current medication, especially when it is diagnosed early. However, for many arthritis sufferers, life seems like a continuous battle to keep the arthritis and the pain under control. And even when the symptoms are kept at bay, the side effects caused by the medications can be troubling.
Today, nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly used anti-arthritis agents, and aspirin is the most common form of NSAID. Since the late 1800s, when the Bayer Company in Germany synthesized the pain reliever, acetylsalicylic acid, or aspirin, this class of medications has been used to treat just about any type of pain and inflammation. Later, other forms of NSAIDs were developed, ranging from over-the-counter ibuprofen (for example, Advil, Motrin IB and Nuprin) and naproxen (Aleve) to more powerful agents obtained only through prescription. Yet aspirin and other NSAIDs, when taken regularly and at high dosages, can cause serious side effects.
Although NSAIDs have been used to relieve pain and inflammation for 100 years, and although they continue to be the backbone of arthritis treatment, it wasn't until the late 1970s and early 1980s that we began to understand the dynamics of inflammation and the way in which aspirin works to control it. Sir John Vane, an English pharmacologist, discovered that any type of trauma generates the release of prostaglandins, substances that are responsible for the fundamental features of inflammation: pain, swelling, heat and redness. He then went on to delineate the mechanism by which aspirin relieves inflammation; it blocks the cyclooxygenase or COX enzyme, which aids in the production of prostaglandins. (In 1982, Sir Vane received the Nobel Prize for Physiology or Medicine for this work.)
However, this very same enzyme protects the stomach lining from irritation. And it has other housekeeping functions throughout the body as well. Therefore, the fact that aspirin and other NSAIDs achieve their effect by blocking the enzyme means that there can be significant side effects. Once this enzyme is inhibited, it increases the chances of side effects, including upset stomach, bleeding ulcers and the tendency to retain fluids. Aspirin also has an anticoagulant effect, that is, it inhibits the blood's ability to clot; therefore, people who take aspirin or most other NSAIDs may bruise or bleed easily.
Other anti-arthritis agents can also have troublesome side effects. Unless you have arthritis, it may strike you as curious that people would risk such side effects just to reduce a bit of inflammation. When we think of inflammation, we tend to discount it as merely an irritating symptom. In fact, inflammation perpetuates as well as signals injury. Inflammation at the joints, in the muscles, in the connective tissues and the like not only announces the presence of an arthritic condition, but over time, it can also render the condition chronic, intensely painful, crippling and very hard to treat. Perhaps that's why people with arthritis are willing to take high dosages of drugs that promise some relief even though they may bring on troublesome and, at times, serious side effects. Little wonder, too, that people with arthritis spend billions of dollars on diets, dietary supplements, devices and other alternative treatments in the hopes of alleviating the pain and inflammation.
Since World War II, medical research has turned its eye to the study of chronic diseases, such as those of the heart and kidneys, cancer, arthritis and neurologic disorders, as well as health problems associated with aging and childhood. Sir Vane's discovery two decades ago was just one of many that signaled an explosion in the field of scientific research.
Much of the new research seeks to develop a more precise understanding of how the body works, specifically the molecular and immunologic mechanisms of disease. As scientists are able to specify the particulars of human biology, they may be able to translate this knowledge into safer and more effective treatments for patients with rheumatic diseases.
Recently, for example, it was discovered that there are two kinds of COX enzymes involved in inflammation: COX-1 is responsible for keeping the stomach, platelets (cells that help prevent excessive bleeding), kidneys and other tissues working properly, and COX-2 that is produced in response to trauma and infection. It is the COX-2 enzyme that generates the high level of prostaglandins related to inflammation in the joints of arthritis patients. Out of this discovery comes a new class of arthritis drugs that can inhibit inflammation and pain while reducing the risk of serious side effects. These COX-2 inhibitors zero in on COX-2 enzyme that is activated only when there is inflammation. This is in contrast to NSAIDs, which block the action of both COX-2 and COX-1 enzymes.
Celecoxib (Celebrex), rofecoxib (Vioxx) and valdecoxib (Bextra) were the first COX-2 inhibitors approved by the Food and Drug Administration. Although COX-2 inhibitors seem best suited for patients with the highest risk of ulcers or bleeding, their high cost and concern about other side effects have tempered enthusiasm for these agents.
(Alert: Two of the COX-2 inhibitors have been withdrawn from the market due to concerns about their cardiovascular safety — valdecoxib [Bextra] on April 7, 2005 and rofecoxib [Vioxx] in September 2004.)
Another category of arthritis drugs is evolving out of the 20-year-old biotechnology industry: inhibitors of tumor necrosis factor (TNF) including adalimumab (Humira), etanercept (Enbrel) and infliximab (Remicade). An inflammation factor, TNF is involved in the body's immune response. By blocking TNF, these drugs are thought to counteract the inflammation present in the joints of patients with autoimmune disorders such as rheumatoid arthritis. This approach has proven useful in other systemic rheumatic diseases as well. These new agents may be especially effective for people whose arthritis has not responded to conventional treatment; in fact, clinical tests have demonstrated that patients treated with TNF blockers may improve more quickly than with older agents and reduce the rate of joint damage over time.
Other so-called "biologic agents" target different chemicals involved in inflammation, including interleukin-1 (IL-1); anakinra (Kineret) is an example of a newly approved agent for rheumatoid arthritis that inhibits the action of IL-1. It is likely that additional medications targeting TNF, IL-1 and other important mediators of inflammation will be developed to combat different forms of arthritis. Whether they will be safe and effective over time and will improve quality of life at an acceptable cost remains to be seen. Thus far, all of the approved forms of the biologic agents for arthritis are injected (into a vein or under the skin); eventually, oral forms may be developed.
Another area of study involves looking into ways of restraining the body's autoimmune response before it is triggered. One approach is to devise a vaccine to stimulate or suppress certain parts of the immune system, which may, in turn, lead to improvement in autoimmune disorders. Yet another approach has centered on genetics and genetic engineering to predict the development of disease, predict response to therapy and even alter genes to improve therapy of (or even prevent) these disorders.
Despite the spirit of optimism surrounding these lines of research, there are some sobering caveats. For one, the body's immune response is complex and, at the present time, any effort to suppress the immune system often leaves a person more vulnerable to infection. Even if these new approaches prove effective, a person may have to take them for life, sometimes coupled with other arthritis medications.
As research scientists get closer to finding what exactly causes the body to attack itself in the first place and identify the genetic markers that predispose a person to an autoimmune disorder, the course and treatment of arthritis — not to mention that of other diseases, such as cancer, allergy, diabetes and heart disease — may be changed dramatically. Moreover, because not everyone who is genetically predisposed develops the disease, scientists are looking into what triggers the disease in one person but not another.
In the future, a physician may be able to look at your genetic make-up, anticipate possible internal and external triggers, recommend life-style changes and adjustments, and customize treatment for your particular disease. In the meantime, the new therapies coming down the pike promise more effective ways of managing arthritis, and more effective management can spell the difference between centering your life around illness and leading a normal life.
