Systemic Lupus Erythematosus
Stem Cell Transplantation
Cyclophosphamide
Leflunomide
GL701 (Prasterone, Dehydroepiandrosterone) Mycophenolate Mofetil
Anti-Malarial
Inhibition of T cell Costimulation
Stem Cell Transplantation
Abstract #1999 Haemopoietic Stem Cell Transplantation for Severe Autoimmune Disease - An Update of Results and Planned Trials
A Tyndall
Twenty SLE patients have been treated with stem cell. Although follow-up is short, progression and relapses have already been seen. Mortality overall in the registry is 9%. There is concern that mobilization of stem cells can itself be dangerous (G-CSF has been associated with SLE flares). Some patients improved with just high-dose cyclophosphamide and did not proceed to stem cell transplant.
Editorial Comment: This is consistent with our findings (Abstract #1050, below) that high-dose cyclophosphamide alone can lead to long-term remissions in SLE. NIH trials are underway to evaluate stem cell transplantation in the U.S.
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Abstract #1050 High-Dose Immunoblative Cyclophosphamide Open-Label Trial: Complete Responders and Durability of Response
M Petri, R Jones, R Brodsky. Maryland.
High-dose cyclophosphamide (200mg/kg) leads to several weeks of aplasia, but the patients own stem cells survive and re-populate the marrow (thus, stem cell "rescue" is not needed). This report details the course of 13 SLE patients with severely active disease despite multiple previous immunosuppressive regimens. Fifty-four percent went into complete remission - some of the remaining had partial responses. Complete remissions, in some cases, have lasted for three years (and counting). There has been no mortality.
Editorial Comment: High-dose cytoxan is cheaper and easier than stem cell transplant, and may be equally efficacious. At Johns Hopkins Hospital, a trial comparing high-dose cyclophosphamide with NIH monthly cytoxan (for patients receiving cytoxan for the first time) is currently underway.
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Leflunomide
Abstract #1049 A Pilot Study of Leflunomide in SLE
P Petera, B Manger, K Manger, J Smolen, J Kalden. Austria and Germany.
Eleven SLE patients received ARAVA, 100mg daily for 3 days, followed by 20mg daily. Only 4 patients completed the trial. A similar safety profile to that known in rheumatoid arthritis (elevated liver function tests, diarrhea, rare rash, rare alopecia) was observed. Some improvement was seen in ECLAM, a measure of disease activity, but it failed to reach statistical significance. This early pilot suggests that ARAVA should be further studied in SLE, as we are now doing at Hopkins. Our trial has only enrolled patients with recalcitrant arthritis. Early results show a profound improvement in a subset (about 25%) of SLE patients.
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GL701
Abstract #1048 GL701 (Prasterone, Dehydroepiandrosterone) Significantly Reduces Flares in Female Patients with Mild to Moderate SLE
D Chang, J Lan, H Lin, S Luo. Taiwan.
Prasterone (DHEA) is a mild androgen with immunomodulatory effects in SLE. In a previous U.S. study, it was shown to be prednisone-sparing in SLE patients with active disease (Petri et al.). In this study of 119 Taiwanese women, 200mg of prasterone (versus placebo) led to a significant reduction in SLE flares and improvement in the patient VAS. Although there were reductions in two clinical disease indices, SLEDAI and SLAM, with prasterone, these failed to achieve statistical significance.
Abstract #1230 GL701 (Prasterone, Dehydroepiandrosterone) Improves SLE
P Mease, J Merrill, R Lahita, M Petri, E Ginzler, R Katz, O Gluck, K Schwartz, M Gurwith.
In the report of this multi-center trial of prasterone 200mg versus placebo, significantly more women on prasterone achieved response, defined by an index including two disease activity indices (SLAM, SLEDAI), patient VAS, Krupp fatigue severity score, and no clinical deterioration (58% versus 46%, p = 0.018). The effect is even more marked in SLE with active disease (66% versus 49%, p = 0.005). There was also a significant increase in bone mineral density, equivalent to that seen with bisphosphonates in steroid-induced osteoporosis. As expected with a mild androgen, some acne and hirsutism were seen, but rarely severe. Prasterone will be presented to the FDA Arthritis Advisory Committee on February 2001.
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Mycophenolate Mofetil
Abstract #1047 Tolerability of Mycophenolate Mofetil (MMF) in Patients with SLE
M Riskalla, R Fatica, E Somers, W McCune. Michigan.
A recent Hong Kong trial of mycophenolate (Cellcept) suggested that it might be equally efficacious to cytoxan for lupus nephritis. This study, of general SLE, followed 24 patients given Cellcept. Forty percent could not take the target dose of 2000mg.
Editorial Comment: This is very different from our experience, where withdrawals due to severe diarrhea are rare. Improvement was seen (at 3 month analysis) in overall activity (measured by SLEDAI), in reduction of prednisone dose, and in improvement in serology (namely C3). We have previously reported that significant improvement can be seen at 1 month. Cellcept is rapidly becoming one of the preferred immunosuppressive drugs in SLE, but there is controversy about its tolerability at the higher doses needed to achieve response in severe SLE.
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Anti–Malarial
Abstract #1233 The Use of Antimalarial Treatment in Lupus Pregnancy and Lactation
A Al-Herz, M Schulzer, J Esdaile. Canada.
Using a physician questionnaire, the authors found surprising disagreement in the use of Plaquenil during pregnancy. Although safety data were published by Ann Parke and colleagues in 1986, and a randomized clinical trial (with follow-up of the children) was presented by R. Levy et al. at a past ACR meeting, only 18% of physicians "always" continued Plaquenil during pregnancy. Because Plaquenil is stored in tissue, stopping it at the time pregnancy is recognized has never made sense, because there will be continued fetal exposure during the first trimester. However, its safety and utility in pregnancy need to be emphasized if practice patterns are to be altered.
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T cell Costimulation
Abstract #1228 Treatment of SLE by Inhibition of T cell Costimulation
K Kalunian, J Davis, J Merrill, M Petri, J Buyon, E Ginzler, R Furie, M Totoritis, D Wofsy.
Anti-CD40 ligand blocks a second co-stimulatory pathway between T and B cells. This approach had great promise in SLE, with the idea being to stop inflammation at an early stage. Two companies - Biogen and IDEC - did clinical trials of anti-CD40 ligand in SLE. Biogens product was withdrawn because of an unexpected side effect of thrombosis. In this study of IDECs monoclonal, no benefit was seen. This may reflect the need to use a higher dose.
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Abstract #175 Increased Soluble CD95 Concentrations in Patients with Severe SLE, But Not Their First73150;Degree Relatives M van der Linden, T van Lopik, L Aarden, R Westendorp, and T Huizinga. The Netherlands.
(report by Antony Rosen, M.D.)
There has been much controversy about whether levels of soluble Fas (sCD95) are increased in patients with SLE, and the specificity of this observation. Huizinga and colleagues add clarity to this area by demonstrating that the levels of sCD95 are significantly elevated in the serum of patients with severe SLE (renal and/or CNS disease treated with cytoxan), but not in patients with milder SLE, chronic cutaneous LE, controls, or first-degree relatives of patients with SLE. Interestingly, levels of sCD95 were significantly correlated with organ damage, as measured by the SLICC-ACR Damage index (r=0.47, p<0.01).
Editorial Comment:These data highlight the predictive value of sCD95 levels for organ damage in SLE, and suggest that the process that generates these elevated levels is important pathogenetically.
