Home Page - About the Arthritis Center -Hopkins Rheumatology - Myositis Center - Vasculitis Center - Scleroderma Center
| |
 
|
|
| Michelle Petri, M.D.
| ||
|
Abstract 1690 A Multicenter Study of Mycophenolate Mofetil (MMF) vs. Intravenous Cyclophosphamide (IVC) as Induction Therapy for Severe Lupus Nephritis (LN): Preliminary Results The hot topic at the ACR for SLE was the FDA sponsored trial of mycophenolate mofetil (Cellcept) versus monthly IV cyclophosphamide for lupus nephritis (Class III, IV, and V). This trial is the second large MMF clinical trial; Chan et al. performed a trial of MMF versus daily oral cyclophosphamide for diffuse proliferative glomerulonephritis, showing equivalence (Chan TM et al. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group.(N Engl J Med 343(16):1156-62, 2000). The FDA sponsored trial was designed to show equivalence between the two regimens. The MMF was gradually increased in the MMF arm, versus the NIH monthly IV Cytoxan schedule (and the prednisone tapered in both arms). The outcome was a complete response (creatinine, urine protein, urine sediment) at six months. Crossover to the opposite arm was allowed in those not responding at three months. The trial showed not just equivalence, but superiority of MMF over monthly IV cyclophosphamide. Because the outcome was at six months, both the FDA and the Chan trial cannot address long-term renal survival in either regimen. Furthermore, only a minority of patients in both arms achieved a complete response by six months. Fascinating epidemiologic data were gleaned from the trial. The majority of lupus nephritis patients in the trial were Africa-American. There was no difference in response rates by race. Editorial Comment: The FDA trial should not be interpreted as a "one drug fits all" solution to lupus nephritis. There were failures in the Cellcept (MMF) arm. At the Lupus Center at Hopkins, we use a higher starting dose of MMF (1000mg bid for the first month, then 1000mg tid if there is no improvement by month two), than was employed in this trial. We continue to treat patients with rapidly progressive glomerulonephritis with IV Cytoxan. One of the dreaded complications of IV Cytoxan, premature ovarian failure, can now be drastically reduced by giving Lupron 2 weeks before each IV infusion. However, the FDA trial suggests that MMF may be the induction regimen of choice for most lupus nephritis. The next step is to study its benefit in maintenance therapy. | ||
|
Abstract 1712 BLyS Plasma Concentrations Correlate with Disease Activity and Levels of Anti-dsDNA Autoantibodies and Immunoglobulins (IG) in a SLE Patient Observational Study BLyS, or a B Lymphocyte stimulator, is a homotrimer that binds to receptors on B cells, stimulating their development. In murine models of SLE, BLyS is overexpressed, and blocking BLyS leads to better survival. In both rheumatoid arthritis and lupus in humans, serum levels of BLyS are increased over controls. In a multi-center study sponsored by Human Genome Sciences, BLyS levels were determined quarterly for the 1st year and then every six months for the next year. At baseline, BLyS levels correlated with anti-dsDNA levels and the SLEDAI measure of disease activity. In the longitudinal portion of the study, a multiple variable model was constructed to predict changes in SLEDAI. In this model, both the previous level of BLyS and the change in BLyS level predicted a change in the SLEDAI score. The model contained prednisone, race, and site. The study strongly suggests that BLyS plays a role in the pathogenesis of disease activity in SLE. However, the analysis did not include a categorical definition of "flare/no flare" (a "clinically meaningful change" in SLEDAI). There were important baseline differences between the sites in disease activity, prednisone use and dose, and race. In spite of these differences, the model remained true regardless of site or race. Editorial Comment: Phase I trials of an anti-BLyS monoclonal were presented at the ACR meeting. B cells were reduced, anti-dsDNA levels were reduced, without major toxicity, in this initial SLE treatment study. Phase 2/3 studies in SLE are now underway. | ||
|
Estrogen/Cyclic Progesterone Replacement is Associated with an Increased Rate of Mild/Moderate but not Severe Flares in the SLE Patients in the SELENA Trial The results of the NIH-sponsored multi-center trial of hormone replacement therapy versus placebo in postmenopausal women with SLE was presented as a "late breaking abstract". The trial was designed as an equivalence study. The SELENA (Safety of Estrogens in Lupus Erythematosus National Assessment) found no difference in severe flares in the two groups, but total flares were 30% increased (statistically significant) in the HRT arm. SELENA lost some of its relevance after the Women's Health Initiative Study. Initially, it was thought that most postmenopausal women with lupus would be treated with HRT to prevent osteoporosis and atherosclerosis. The WHI found that atherosclerosis, dementia, venous thrombosis, and breast cancer were actually increased in HRT. NIH actually stopped enrollment in SELENA after the WHI results were released. Editorial Comment: Practically speaking, long-term HRT will not be recommended in SLE, since the disease itself is associated with atherosclerosis and malignancy. From a clinical perspective, the increase in total flares suggests caution even with short-term use of HRT for vasomotor symptoms in SLE. There are alternative pharmacologic approaches to postmenopausal symptoms, including some antidepressants and gabapentin. The SELENA study, from a science viewpoint, appears to confirm the murine models of SLE, indicating that estrogen is involved in the pathogenesis of disease activity. | ||
|
Post-meeting CME Symposium Understanding Bone Health in Lupus In a CME post meeting symposium, several speakers (Barbara Lukert, MD, Rosalind Ramsey-Goldman, MD, PhD, and Michelle Petri, MD, MPH) explored what is understood about corticosteroid-induced osteoporosis in SLE. Dr. Lukert reviewed the complicated pathogenesis of corticosteroid-induced osteoporosis, emphasizing that the process is much more complicated than effects on calcium absorption and parathyroid hormone. The more important corticosteroid effects are on osteoblast apoptosis and survival and on sex steroid levels. No dose of corticosteroid can be considered safe for bone. Dr. Ramsey-Goldman summarized several studies of risk factors for CIO in SLE, many of which found independent effects of corticosteroid dose and duration. However, there is evidence in SLE that osteoporosis is an inflammatory disease, using metrics such as RANK lygand and osteoprotegrin. DHEA (or its synthetic form, prasterone), has already been studied in 2 SLE trials that addressed osteoporosis. In a Stanford trial of SLE patients with very severe disease on high-dose corticosteroids, there was preservation of bone density in the DHEA group and significant loss in the placebo group (van Vollenhoven RF, et al. A double-blind, placebo-controlled, clinical trial of dehydroepiandrosterone in severe systemic lupus erythematosus. Lupus 8(3):181-7, 1999). In a second multi-center trial of women with active SLE on prednisone, the prasterone group significantly gained bone density at 1 year at lumbar spine and hip, while the placebo group lost. A second multi-center trial of prasterone for corticosteroid-induced osteoporosis in SLE is currently underway. Prasterone, if FDA approved for CIO in SLE, would offer several benefits. Its benefit on symptoms and signs of SLE would be important in and of itself (Petri MA, et al. Effects of prasterone on corticosteroid requirements of women with systemic lupus erythematosus: A double-blind, randomized, placebo-controlled trial. Arthritis Rheum 46:1820-1829, 2002) but also, secondarily, by reducing the inflammatory component of osteoporosis. It would also be available for use in women who currently are not candidates for bisphosphonates, i.e., those planning later pregnancies and those with renal insufficiency. | ||
|
Abstract 1085 Impact of the Intensity and Timing of Lupus Activity on Pregnancy Outcomes Because most SLE patients are premenopausal, pregnancy is often an issue. When patients become pregnant, there is a tendency "to draw back" on therapy. Intensive visits with high risk obstetricians and rheumatologists usually start in the second and third trimester. Editorial Comment: The above paper is important because it summarizes a 19-year prospective study of over 200 pregnant SLE patients seen every 4 to 6 weeks during the pregnancy. Pre-term birth is the most frequent adverse outcome. Disease activity was seen in all three trimesters. Disease activity, regardless of trimester, is a predictor of adverse outcome. The study strongly suggests that control of disease activity is essential throughout the pregnancy. | ||
|
Abstract 900 Statin Toxicity in the Lupus Atherosclerosis Prevention Study The Lupus Atherosclerosis Prevention Study is a two-year intervention of atorvastatin versus placebo, to determine if it is possible to prevent atherosclerosis (measured by coronary calcium or carotid IMT). Baseline data were presented at the meeting. Hypertension and age are the major predictors of carotid IMT - not lipids or inflammation. CRP was one of the best predictors of coronary calcium. This suggests that carotid and coronary atherosclerosis may be different in SLE. Editorial Comment: Although it will be another year before results are available, the safety data so far show more statin toxicity, both increased transaminases and CK, in SLE than expected in the general population. In addition, the adverse events occur throughout the trial, not just in the first three months. The elevations were always reversible by stopping the drug. No patient got both transaminitis and CK elevation. The safety data suggest caution and the need for long-term monitoring if statins are introduced in a SLE patient. | ||
| ((top of page)) (next page)
|
||
