The enemy from within
|Systemic lupus erythematosus is a complex disease that requires more research and publicity.
With symptoms ranging from skin rashes, achy joints, and chronic fatigue to serious neurological and renal problems, systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease. Almost 2 million Americanspredominantly women of child bearing agesuffer from lupus, more than those who suffer from multiple sclerosis and cystic fibrosis combined.
As in any autoimmune disorder, SLE hinders the immune systems ability to differentiate between foreign antigens and native cells, thus inciting the production of autoantibodies programmed to attack and damage particular organs. In lupus, the targets are unpredictable and potentially wide-ranging; and they may include the skin, bones, blood, brain, heart, and kidney.
In a very real sense, said U.S. Surgeon General David Satcher in an address to the Lupus National Town Hall Meeting held last May, lupus transforms your body to the enemy from within.
How this occurs is a focus of current research. Topics that are under investigation include the hyperresponsiveness of antibody-producing B cells and the malfunctions of antigen-detecting T cells. Abnormal complement proteins, which are supposed to help break up and remove antibodyantigen complexes, also are often associated with SLE and can lead to deposits of the immune complexes on tissue and subsequent organ inflammation.
Know thine enemy
As an illustration of a common diagnostic problem in SLE, consider the role of antinuclear antibodies (ANAs). These molecules, which are directed against the bodys cell nuclei, are present in almost all cases of lupus, but they are also important elements of many other disorders.
According to Michelle Petri, a physician and leading SLE researcher at Johns Hopkins University (Baltimore), The most common problem is misdiagnosis of lupus in a woman with a positive ANA and chronic fatigue. . . . Most of these patients do not have lupus but have a chronic pain condition called fibromyalgia.
Some autoantibodies, such as those directed against double-stranded DNA (dsDNA) and the nonhistone nuclear Sm protein, are specific to the disease but occur in only a small fraction of lupus sufferers. Therefore, to make an effective diagnosis, the American College of Rheumatology criteria and ancillary symptoms must be considered along with a patients complete medical history.
Lines of defense
One component of lupus treatment is to target the symptoms. For example, non steroidal anti-inflammatory drugs and acetaminophen are widely used against joint pain, antimalarial medicines such as hydroxychloroquine (Plaquenil) are prescribed for joint and skin symptoms, and anticoagulants are often necessary for patients at risk of thrombosis (blood clots).
A second component of treatment attacks the problem at the source, that is, the immune system. Corticosteroids such as prednisonehormones that generally suppress the immune system and reduce inflammationare commonly prescribed for lupus. They can minimize symptoms, but the potential side effects are many, including higher risk of infection, weight gain, acne, osteoporosis, high blood pressure, cataracts, and the onset of diabetes. Serious forms of SLE often require the more powerful immunosuppressing cytotoxic agents, such as cyclophosphamide (Cytoxan). While these drugs can debilitate the immune system, wiping out the autoimmune activity, they also leave the body open to infection and can lead to anemia, low white blood cell count, gonadal failure, and some forms of cancer.
These treatment combinations, together with a healthy lifestyle that includes the avoidance of known SLE triggers such as UV light, have been somewhat successful in controlling severe aspects of SLE. Although lupus is a potentially fatal disorder, usually because of end-stage renal failure or aggressive infection, 8090% of sufferers live at least 10 years after diagnosis, and many have a normal lifespan. This prognosis is greatly improved from what it was 50 years ago.
However, [the] health status of lupus patients, says Petri, tends to be poorperhaps as bad as AIDS patients. Disabling fatigue and debilitating side effects, and the fact that some patients fail to repond to immunomodulating treatment, necessitate the search for new therapies.
Molding these issues into an understanding of the root cause of lupus is a grand goal, but for now less toxic therapies that can diminish at least some lupus activity are sought. Finding a new therapy is not easy, however; no new SLE-specific treatment has been approved in about 40 years.
A product that almost reached market was Aslera, a synthetic version of the mild male hormone dehydroepiandrosterone (DHEA), which, according to Petri, had been studied in clinical trials for lupus for the past seven years. A New Drug Application for the use of Aslera in women with SLE was submitted to the FDA in September 2000.
The major claims of the application included less reliance on and a reduction in bone loss compared with prednisone, and less frequent flare-ups. Last June, however, the product received a not approvable letter from the FDA because of concerns about the interpretation of some of the efficacy and safety data submitted for the product.
We were very disappointed that the FDA did not approve DHEA, says Petri, and hope that this can be resolved through the appeal process.
Another direction that researchers are taking is to develop biologics that are more distinctly targeted to specific aspects of the immune system, thus minimizing drug toxicity. One T-cell signaling component in which abnormal regulation has been observed in SLE is the CD40 ligand. Two monoclonal antibodies in the pipeline target this protein, but clinical trials for both have been halted, one because of safety issues and the other because of insufficient efficacy.
Other potential treatments are still moving forward through the pipeline. For example, LJP-394 was designed to block B-cell production of anti-dsDNA antibodies (often associated with kidney involvement) as a means of treating lupus nephritis, which affects about half of SLE patients and is a major cause of lupus mortality. With the use of a newly designed blood assay, physicians were able to test the drugautoantibody binding strength. For those patients in the Phase II/III trials that exhibited high affinity (80% of participants), LJP-394 reduced anti-dsDNA autoantibodies, lowered the frequency of renal flare-ups, and lessened the need for steroids and cytotoxics.
In many cases, with the right treatment and a practical lifestyle, lupus can be a manageable disease, but only if patients make educated decisions about their care and behavior. Without a well-informed public, early detection will be difficult and the push for needed research dollars will not be strong.
David Filmore is an assistant editor of Modern Drug Discovery. Send your comments or questions regarding this article to email@example.com or the Editorial Office by fax at 202-776-8166 or by post at 1155 16th Street, NW; Washington, DC 20036.