General Info, SLE:
Background
Systemic lupus erythematosus (SLE) is a chronic, autoimmune, inflammatory disease that may affect the skin and joints, as well as internal organs, such as the heart, lungs, kidneys, spleen, nervous system and serous membranes lining the lungs, heart and abdominal cavity. Approximately 65% of patients develop SLE between 16 and 55 years of age, and it is 8 to 10 times more common in women than in men (American College of Rheumatology Ad Hoc Committee, 1999).
Although the etiology of lupus is unknown, hormonal influences seem to play a key role in disease development and progression. Beyond the increased incidence in women, several studies have noted that alterations in estrogen and androgen metabolism occur in patients with lupus. Decreased levels of androgens (androstenedione, dehydroepiandrosterone [DHEA], DHEA-S, and testosterone) have been observed in female lupus patients, especially in those with active disease (Lahita, 1987; Jungers, 1983).
Patients with mild to moderate symptoms are usually managed with administration of analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs) and sunscreens. However, NSAIDs may reduce glomerular filtration rates and renal blood flow, cause gastrointestinal bleeding and can be associated with hepatotoxicity. If symptoms are not well controlled by these therapies, the patient's treatment may be augmented by the addition of an antimalarial drug, such as hydroxychloroquine (Plaquenil), although chloroquine and quinacrine are used less frequently. Toxicities with these agents include retinopathy with hydroxychloroquine and chloroquine, aplastic anemia with quinacrine, skin pigmentation changes, as well as development of peripheral neuropathy and myopathy with hydroxychloroquine only.
Most lupus patients do not respond to conservative therapy and require glucocorticoids for control of disease activity. In the Johns Hopkins Lupus Cohort, comprising of 539 patients, 89% had used prednisone, 21% of whom had been treated on one or more occasions with doses over 60 mg/day for at least 2 months. Most patients had used prednisone at doses above 10 mg/day (Zonana-Nacach, 2000).
Despite the fact that they are the mainstay of treatment for most lupus patients, glucocorticoids are well-known to be associated with significant toxicity including ischemic cardiovascular disease, serious infection, hyperglycemia, hypertension, osteoporosis, muscle wasting, avascular necrosis of bone, and cataracts (Zonana-Nacach, 2000). Female SLE patients are at a 5-fold risk of osteoporotic fractures (Ramsey-Goldman, 1999), and a 1.6-fold risk of ischemic necrosis (Zonana-Nacach, 2000). Patients dying early from lupus succumb to complications of lupus and/or infection while those dying after 5 years of disease often succumb to atherosclerotic complications, which may be related in part to chronic corticosteroid therapy (Urowitz, 1999, 2000).
Flares occur commonly among SLE patients. In the Johns Hopkins Lupus Cohort, the incidence of flare was 0.65 per patient-year of follow-up with the median time from first study visit to a flare being 12 months (Petri, 1991). While most flares involve "minor" organ systems, i.e. constitutional (fatigue) musculoskeletal, and cutaneous, it is of interest that in the Hopkins cohort, prednisone dose was increased in 39.7% of the flares (Petri, 1991). Furthermore, of 261 patients, 56.3% were hospitalized over a 2 year period from 1989 to 1990 (Petri, 1992). Prednisone dose over 10 mg/day was one of the risk factors for infection requiring hospitalization (P=0.04), as was use of immunosuppressive drugs (P=0.003).
Thus, an extremely important goal in the treatment of SLE is to reduce glucocorticoids to the lowest dose required to maintain suppression of SLE activity. However, during glucocorticoid taper, patients may experience symptoms of steroid withdrawal (e.g., joint pain, malaise) and the underlying disease may flare, thus perpetuating the need for treatment with glucocorticoids to control flare in this disease.
More aggressive management is often warranted in the treatment of lupus. In the Johns Hopkins lupus cohort alone, 34% of patients were using cytotoxic drugs (Zonana-Nacach, 2000). Immunosuppressive agents such as azathioprine (Imuran) and cyclophosphamide (Cytoxan) are used for patients with life-threatening or major organ system involvement. Toxicities associated with administration of azathioprine include leukopenia, hepatitis, pancreatitis, nausea and vomiting, and infections. Cyclophosphamide can result in urinary bladder toxicity, sterility, teratogenic effects, infections, and cancer.
Progression of SLE is highly variable and is difficult to predict from one individual to another. Lupus remains a serious disease with a 10-year mortality rate of approximately 10 to 20% (Uramoto, 1999).
(From the FDA AC briefing on Aslera.)
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