Chemo Drug Effective For Autoimmune Disorders
Such As Rheumatoid Arthritis,
Lupus
BALTIMORE, MD ? Dec. 15, 1998 -- Researchers at the Johns Hopkins Oncology Center used high doses of the chemotherapy drug cyclophosphamide alone to control previously untreatable forms of autoimmune disorders such as rheumatoid arthritis, lupus and hemolytic anemia.
Their findings are reported in today's issue of Annals of Internal Medicine. Of eight patients treated in the study with stand-alone high dose cyclophosphamide, five reported complete remissions and two achieved and maintained partial remissions. Four patients treated from six months to more than a year ago remain disease free and two patients, in partial remission, continue to improve after more than a year. In addition, all patients were able to decrease their doses of medication, and three patients have completely discontinued medications for their disease.
These patients had not responded to disease therapies and suffered from recurrent infections, persistent pain and kidney problems. Treatment for severe autoimmune diseases using high-dose cyclophosphamide followed by bone marrow or stem cell transplantation to repopulate the immune system destroyed by the drug treatment is being studied elsewhere.
The new Hopkins research, funded by the National Institutes of Health, suggests that transplants are unnecessary. "Stem cells, the marrow cells that reconstitute the immune system, are resistant to the drug and will repopulate in the marrow, without the need for transplantation," said Robert Brodsky, M.D., assistant professor of oncology and medicine and lead author of the study. "High-dose cyclophosphamide, without stem cell or bone marrow reinfusion, appears to be safer for the patient and avoids reinfusion of diseased immune cells."
Hopkins scientists believe the cyclophosphamide works by reprogramming the immune system. "Immunity is learned not inherited," explained Richard Jones, M.D., associate professor of oncology and director of bone marrow transplantation at the Johns Hopkins Oncology Center. "We acquire immunity through vaccinations and exposure to organisms which teach immune cells to recognise and attack foreign bodies."
In people with autoimmune disorders, the immune system attacks its own tissues and organs and must be re-taught to differentiate between the body's own cells and foreign attackers. "This therapy is analogous to rebooting a computer -- you wipe out the old information, then allow it to re-learn," Jones said. "The immune system that returns should function normally." While the researchers are optimistic about these results, they caution that additional research and a larger number of patients are necessary to confirm these findings. They are now expanding the study to include additional patients with severe autoimmune disorders.
Why would anyone take a medicine that might cause their white blood cell count or platelet count to fall abruptly, leading to increased susceptibility to infections or a tendency to bleed? Why would anyone take a medicine that might, to a small extent, predispose them to develop certain cancers?
People with lupus and other autoimmune diseases take them because these medications can be very helpful, especially in cases where the kidneys or other major organs are involved.
While some of the side effects of Imuran (azathioprine), Cytoxan (cyclophosphamide) and other immunosuppressive and cytotoxic drugs are noted above, they are generally reversible by either reducing the dosage or stopping the medication. Although immunosuppressive drugs can have serious side effects, they can be of great value in the treatment of lupus. They can help to prolong life, preserve kidney function, reduce symptoms, and sometimes may serve to put the disease into remission. These drugs help to reduce symptoms and damage to vital organs, such as the kidney, until a natural remission occurs. They sometimes help to achieve a remission earlier.
Immunosuppressive and cytotoxic drugs are sometimes used in the treatment of systemic lupus erythematosus (SLE) for two major reasons. First, they are potent drugs which help to reduce disease activity in major organs such as the kidney. Second, they may reduce or sometimes eliminate the need for steroids (cortisone derivatives such as prednisone). Steroids used alone to treat major organ involvement must sometimes be given in high doses. This increases the risk of both short-term and long-term side effects, which may sometimes be worse than the disease itself.
Immunosuppressive drugs can be used either in addition to, or instead of, steroids or to lower the amount of steroid needed and often spare the patient the undesirable side effects of steroid therapy.
HOW DO THEY WORK?
Cells in the body divide and grow at varying rates. Examples of rapidly dividing cells include the antibody producing cells of the immune system, blood cells, hair cells, gonadal cells and malignant cells. Cytotoxic (cyto=cell, toxic=damage) drugs work by targeting and damaging cells which grow at a rapid rate. In lupus, the immune system is hyperactive and produces auto-antibodies at a rapid rate of growth. Cytotoxic medicines have their greatest effect against rapidly dividing cells and, therefore, can be beneficial in the treatment of lupus by suppressing the cells involved in the hyperactive immune response. The effect is a reduction in disease activity. There are risks associated with the use of cytotoxic drugs. The immune system may be suppressed too much and cause an increased susceptibility to infections such as shingles and pneumonia. The bone marrow may be suppressed and result in reductions in red blood cells, white blood cells and platelets. Suppression of hair cell growth may lead to a net loss of hair. The cytotoxic effects on gonadal cells may lead to sterility.
IMURAN
Imuran is less potent and less effective than Cytoxan, but it has far fewer side effects. Its use may cause the white blood cell count, platelet count, or red blood cell count to decrease, and it might increase the risk of developing lymphoma (a cancer involving the lymph glands, liver and spleen). However, it is well tolerated in most cases. Blood tests to determine the white blood cell, platelet and red blood cell count should be taken regularly in patients receiving Imuran. Adjustments in dosage are made if the tests indicate a serious decrease in the blood count. Imuran is also used to treat lupoid hepatitis, rheumatoid arthritis and other autoimmune disorders, and to reduce the amount of steroids given.
CYTOXAN
Cytoxan may cause many side effects, but it is well tolerated by most patients. Like Imuran, it may cause an upset stomach and its use may cause the white blood cell count, platelet count, or red blood cell count to decrease. Blood tests to determine the white blood cell, platelet and red blood cell count should be taken each month in patients receiving Cytoxan. If the blood count is seriously decreased, the dosage is adjusted and the blood counts will generally return toward normal.
Patients receiving treatment with Cytoxan have an increased risk of developing malignancies including leukemia, bladder cancer, and other tumors. Cytoxan may also cause temporary or permanent sterility in both women and men, preventing them from having children. It may also cause damage to a developing fetus if a woman gets pregnant unintentionally while being treated with the drug. Use of Cytoxan may cause bleeding from the bladder, but this usually can be prevented by drinking large amounts of water. Cytoxan also predisposes a patient to develop shingles, which is a painful, blistering skin condition. It can cause hair loss. Like Imuran, use of Cytoxan may predispose a patient to develop unusual infections, particularly when it is used in combination with high doses of steroids.
A typical daily dose of Imuran or Cytoxan is 125 to 150 milligrams (mg) a day given orally. A low dose is 75 mg or less. Cytoxan should be taken in the morning with fluid and should not be taken at night, when fluid intake is low.
Cytoxan and Imuran are not used together except in certain experimental conditions. Cytoxan (but not Imuran) can be given at a much higher dose intravenously on a monthly basis. This may be quite effective for severe kidney disease and may help to avoid some of the side effects that occur with daily oral dosages of this drug.
RELATED DRUGS
Other cytotoxic drugs related to cyclophosphamide (Cytoxan) are chlorambucil (Leukeran) and nitrogen mustard (Mustargen). Leukeran has similar side effects to Cytoxan. As previously stated, lupus patients taking cyclophosphamide (Cytoxan), azathioprine (Imuran), chlorambucil (Leukeran) or nitrogen mustard (Mustargen) need to have their blood counts monitored each month. In response to the lab tests and side effects, drug dosage is adjusted to prevent or reverse any serious toxicity.
Methotrexate is usually given orally once a week, although it may also be given by injection. The dosage is generally 7.5 to 20 milligrams per week. Methotrexate is well tolerated by most patients. Its use in lupus has not been thoroughly tested, but it is given quite commonly for rheumatoid arthritis and has been shown to produce improvement of joint pain and stiffness. It does not predispose a patient to develop malignancies. However, liver disease and lung reactions can occasionally occur with the use of methotrexate and it can be sun sensitizing. Dosage may need to be decreased if kidney disease is present. Blood counts should also be taken each month in patients receiving this drug and dosage modified if side effects are detected.
CONCLUSION
While cytotoxic medications are not needed and should not be used in cases of mild lupus, these medications can be very helpful in cases where the kidneys or other major organs are involved, or in cases where the lupus is quite active and symptomatic. Sometimes a kidney biopsy or other tissue biopsy is necessary before deciding whether to use these medications. Even in more serious cases of major organ involvement, they should not be used indefinitely without good reason. Therefore, it is important to assess the beneficial effects as well as the risks involved in cytotoxic drug therapy. Doctors use the term "risk-benefit ratio" to describe the comparison of side effects to beneficial effects of medications. While these drugs are not FDA-approved, they are commonly used and accepted as standard practice. People with lupus should discuss the risk-benefit ratio of these medications with their physician.
