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| Michelle Petri, M.D.
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Abstract 1103 Inhibition of Complement Activation: A Novel Mechanism for the Protective Effects of Heparin in Antiphospholipid Antibody-Induced Pregnancy Loss. A paradigm shift has occurred in the antiphospholipid world due to work in a murine model of antiphospholipid syndrome (APS). In this model, presented by Dr. Salmon in the Dubois Lecture, and by Dr. Girardi in the plenary session, complement activation has been proven to be a necessary step in the pathogenesis of APS pregnancy loss. In a murine APS model, mice who are complement deficient or who are given an inhibitor (Crry) of complement activation do not suffer pregnancy loss. Editorial Comment: Since the landmark clinical trial of Cowchock et al (Cowchock FS, Reece EA, Balaban D, Branch DW, Plouffe L. Repeated fetal losses associated with antiphospholipid antibodies: a collaborative randomized trial comparing prednisone with low-dose heparin treatment. Am. J. Obstet. Gynecol. 1992;166:1318-1323), heparin and aspirin have been the preferred therapy to prevent APS pregnancy loss. The work of Dr. Salmon and colleagues now challenges the concept that heparin helps because it is an anticoagulant. They have proven that only heparins which are anti-inflammatory (i.e., block complement activation) prevent APS pregnancy loss. This research needs to be extended to women with APS; an observational study, PROMISSE is underway. Complement activation may not be the sole answer in APS pregnancy (because heparin, in a review of many studies, prevents only about 50% of pregnancy losses), but it is likely to be a major player and a potential new target of novel therapies. | ||
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Abstract 1125: A Phase I trial of Rituximab (Anti-CD20) for Treatment of Systemic Lupus Erythematosus
Abstract 1126: B Lymphocyte Depletion in the Treatment of Systemic Lupus Erythematosus A major theme of the ACR meeting was taking a B cell approach to the treatment of SLE. There are several approaches, but the most preliminary data are available for anti-CD20, rituximab, which is FDA-approved for lymphoma. It depletes B cells, but not plasma cells. Rituximab improves abnormalities in B cell homeostasis (naive lymphopenia, expansion of CD27 neg IgD neg population, and circulating lymphoblasts) and tolerance. The frequency of auto-reactive VH4.34 memory B cells also decreased 1 year post-treatment. Several dosing regimens have been tried. John Looney and colleagues (Arthritis and Rheumatism 2004) did a dose-finding study and did report benefit of the lymphoma dosing regimen 375 mg/m2 weekly for 4 weeks. David Isenberg and colleagues, in contrast, have used a regimen developed for rheumatoid arthritis, in which rituximab and cyclophosphamide are given and then repeated in 2 weeks. To avoid serious infections, other immunosuppressive drugs are stopped and prednisone is tapered, as possible. Clinical benefit was demonstrated in most patients in the Isenberg series, with reduction in a disease activity measure called BILAG. Because cyclophosphamide was also given, the improvement may not be due to rituximab alone. In the Albert study, cyclophosphamide was not given, the regimen being rituximab 375 mg/m2 weekly for four weeks. Six of eight patients had a response. Two out of six had a long-term response (6-14 months). There were no consistent changes in complement, autoantibody titers and immunoglobulin levels. The response of anti-dsDNA in most series was variable, with an anti-dsDNA decrease in the Anolik series only found in those with effective B cell depletion. Editorial Comment: Early data suggest that autoantibodies rebound before lupus flare. It appears likely that re-treatment - perhaps every 6 months - may be required in some patients. Major infusion reactions were not a problem in the Isenberg and Albert series (likely because of pre-treatment), but are possible with rituximab. | ||
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Several groups have found a pattern of over 100 genes that are activated in SLE patients but not in controls. Over 75% of SLE patients have this pattern, characterized by genes regulated by interferon-alpha. In newly diagnosed pediatric lupus patients, Pascual and colleagues have found the interferon signature to associate with lupus nephritis. In adult lupus, the interferon signature is not associated with proteinuria, likely reflecting that these patients are on immunosuppressive therapy. There are other subsets of SLE signatures with clinical relevance, including ribosomal, inflammatory, and mitochondrial oxidative stress signatures. Editorial Comment: Follow-up clinical data are available in the SLE patients. Further gene expression profiling will determine if changes occur in relation to: 1) changes in disease activity; or 2) changes in treatment. | ||
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The multi-center collaborative clinical trial Safety fo Estrogen in Lupus: National Assessment presented the results of the double-blind randomized controlled clinical trial of oral contraceptives in SLE. Before this trial, OCPs were not routinely given to women with SLE. This was based on the murine NZB/NZW model in which estrogen accelerates lupus and androgens protect. Data in women tended to support this model. There are case reports of OCPs being used just before the onset of lupus. A prospective cohort study, the Nurses Health Study, showed an increased risk of SLE with prior OCP use. Case-control studies differed, but one showed a large rate of flare in women with renal lupus who took OCPs. Women with SLE who have moderate to high titer anticardiolipin should not take OCPs, which might increase the risk of hypercoagulability. Women with prior thrombosis should not take OCPs, regardless of antiphospholipid status. The study also excluded women with other contraindications, such as severe migraines and liver disease. Women were enrolled with inactive (SLEDAI < 4) and stable active (SLEDAI > 4 but < 12) disease, and randomized to OCP vs placebo for 1 year. Assessments were made at 1 month and then 3, 6, 9 and 12 months. There was no difference in the severe flare, mild/moderate flare or total flare rate between the group. There was no difference in the number of thromboses; one death occurred post trial in the placebo group. Editorial Comment: This trial opens the possibility of using OCPs in women with SLE who match the inclusion/exclusion criteria of the trial. OCPs are the preferred means of contraception in young women, and have additional health benefits in terms of treating irregular menses, endometriosis, and ovarian cysts. | ||
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Studies done in individual institutions have differed in whether SLE increases the risk of cancer. Our study at Hopkins, for example, did NOT find an increased risk. The multi-center collaboration of Bernatsky and colleagues (9,846 SLE patients; mean follow-up 8 years) has now reported a significant increase in cancer (SIR 2) risk in SLE. One of the most impressive increases is in non-Hodgkins lymphoma (SIR 3.7), but lung (SIR 1.4) and hepatobiliary (SIR 2.6) also stand out. Editorial Comment:SLE or co-morbid factors (smoking, secondary Sjogrens) or treatment (immunosuppressives) may play a role. Secondary Sjogrens syndrome can occur in SLE without the presence of anti-Ro and/or anti-La, such that searching databases for the presence of these autoantibodies might not be sufficient. If Sjogrens syndrome is the explanation for the increase in lymphoma, then analyses will need to look at whether hydroxychloroquine use is protective (some studies suggested that hydroxychloroquine could reduce immunoglobulin levels in Sjogrens syndrome). Epstein-Barr virus is one of the putative environmental risk factors for SLE. Unfortunately, existing datasets do not have information on EB viral antibody titers nor on evidence of activation of EB. Therefore, one of the most interesting, and potentially most important, hypotheses regarding the increased lymphoma risk cannot be examined. Editorial Comment:However, these results clearly mandate following guidelines for cancer prevention and surveillance in patients with SLE. | ||
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and Abstract 1579: Prevention of Avascular Necrosis of Bone in Systemic Lupus Erythematosus:APLLE Trial Osteonecrosis (or avascular necrosis) is a corticosteroid-induced damage that has a threshold: usually exposure at 20 mg of prednisone or more is required. The onset of ON may occur years after the exposure, however. The actual pathogenesis of ON is not clear, but may involve hyperlipidemia and/or hypercoagulability. In the LUMINA cohort, LDL level (0.007), anti-phospholipid antibodies (p=0.061) and African-American race (p=0.052) were associated with ON in univariate models. In a multiple variable analysis, gender (p=0.037), disease duration (0.002), triglyceride level (p=0.009), LDL (p=0.023), mean glucocorticoid (0.005) were statistically significant. Hydroxychloroquine use was protective (OR 0.305, p=0.014). Because patients who take hydroxychloroquine have cutaneous and arthritis manifestations of lupus, it is possible that this subset is less likely to develop ON. Editorial Comment: Prevention of osteonecrosis is essential. Several approaches have been suggested, including hydroxychloroquine (which helps both hyperlipidemia and hypercoagulability), statins, and bisphosphonate. The APLLE Trial is a double-blind placebo-controlled trial of atorvastatin 40 mg vs placebo in SLE patients requiring prednisone > 0.75 mg/kg/day. At MRI follow-up at 9 months, 435 had new AVN. In the APLLE Trial, Belmont and colleagues found that atorvastatin was well tolerated. | ||
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Abstract 397: Obesity, a Modifiable Risk Factor, is a Major Determinant of Quality of Life, Functional Capacity and Inflammatory Markers in Systemic Lupus Erythematosus (SLE) | ||
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