• Hormone Replacement Therapy
• Cyclophosphamide
• Leuprolide Acetate (Lupron)
• Hydroxychloroquine
• Mycophenolate (Cellcept)
• Methotrexate
• Cytoxan
• Advances in Basic Science

Hormone replacement therapy was shown to increase the risk of developing NEW lupus in the Nurses’ Health Study. Because estrogen can stimulate the immune system and increase autoantibody production, there has been concern that HRT might lead to lupus flares. In addition, some SLE patients are hypercoagulable, with antiphospholipid antibodies, and the addition of estrogen in them might increase the risk of thrombosis.

Editorial Comment: Clinical trials are necessary to definitively address this issue. The design of such trials is crucial-the question to be answered is whether HRT is safe. The appropriate study design is an “equivalence” trial. Such trials require larger number of patients than the usual type of trial, “superiority”. For example, if rheumatologists were willing to tolerate a difference in severe flare rates of 6% (in placebo) and 15% (in HRT), then an equivalence trial would require 175 patients per arm.

Dr. Sanchez-Guerrero presented a single-center trial of HRT done in Mexico City. 52 patients were assigned to HRT and 54 to placebo. He reported no difference in severe flares. However, the exact design of his study and the power were not discussed in the abstract. At the actual presentation it remained unclear whether the study had adequate power to address safety. In the United States, the multi–center SELENA trial will definitively address the safety of HRT.

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Most SLE patients have repeated flares or continuous disease activity. Only a lucky minority has long periods of disease quiescence. Cyclophosphamide therapy is the only therapy associated with disease quiescence; it is limited in use to patients with severe organ involvement. When used monthly as an intravenous bolus (the NIH protocol), it has important toxicity, including premature ovarian failure, infections, and likely an increase in later malignancy. At Johns Hopkins Hospital, an open label experience with a different mode of cytoxan administration-high dose immunoblative cytoxan (200 mg/kg) has been gained over the last 5 years in patients with severe lupus refractory to multiple other therapies.

Of the first 14 patients, 43% (an update from the abstract) have remained in long term remission. Of the rest, 50% have a partial response. Some late relapses in partial responders have occurred, at year 3. One complete responder developed Graves disease at year 3.

There have been no deaths and no premature ovarian failure. The long-term experience of the therapy in aplastic anemia is also encouraging-there have not been later malignancies.

Editorial Comment: Currently, Johns Hopkins Hospital has embarked on a randomized trial of high dose cytoxan vs. the NIH protocol in SLE patients who require cytoxan for the first time. Referrals are welcome (telephone #: 410-614-1573).

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The risk of premature ovarian failure with cytoxan in women over the age of 35 is large (50% or more), and even younger women have substantial risk.

At last year’s ACR meeting Dr. Mary Ann Dooley presented the first prospective study of Lupron to protect fertility during cytoxan induction. Basically, Lupron puts the ovaries at rest. The regimen is 3.75mg two weeks before each cytoxan bolus. In the Dooley trial, Lupron was successful in preventing ovarian failure. Surprisingly, the women did not develop symptoms of estrogen deficiency and did not require supplemental estrogen.

In a retrospective case–control study, McCune and colleagues suggested efficacy of Lupron (p=0.06). In contrast to Dooley, supplemental estrogen was given to most patients (it is not clear whether this was triggered by symptoms or not).

Editorial Comment: We do not know if any of the women had contraindications to estrogen (i.e., hypercoagulability) or developed severe flares afterwards.

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Hydroxychloroquine is a mainstay of SLE treatment for cutaneous and musculoskeletal lupus. Our prospective work has shown that patients who remain on hydroxychloroquine are less likely to have later thrombosis. In a randomized withdrawal study, Canadian researchers demonstrated that SLE patients on hydroxychloroquine were less likely to have lupus flares.

Editorial Comment: This abstract furthers our exploration of hydroxychloroquine as “lupus health insurance”. Using the SLICC/ACR Damage Index for lupus we found that plaquenil use is associated with less neuropsychiatric and renal damage. As expected from previous work, it was associated with fewer thromboses (p=0.04) and lower cholesterol (p=.001). These data, obtained from a prospective cohort study, are subject to bias in that hydroxychloroquine was not prescribed randomly. However, the study strongly suggests that SLE patients should remain on hydroxychloroquine, with yearly ophthalmology monitoring for retinopathy.

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A Taiwan-Hong Kong study showed that mycophenolate mofetil ("cellcept") and oral cytoxan worked equally well in diffuse proliferative glomerulonephritis. However, in later follow-up presented at the International Lupus Conference in Barcelona, it appeared that the cytoxan arm was doing better in later follow–up.

Gordon and colleagues presented a prospective study of MMF in 24 SLE patients with nephritis. 86% achieved renal remission and 57% all systems remission. MMF was well tolerated, with no withdrawals. There were three withdrawals for refractory disease that then was controlled with cytoxan.

Editorial Comment: The definitive MMF cytoxan study, sponsored by the FDA, is currently underway in the United States under the direction of Ellen Ginzler, MD, MPH. It compares MMF with monthly IV cytoxan (the NIH protocol). Until the study is completed, MMF may be appropriate induction therapy in patients who do not have rapidly progressive renal failure.

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Several past studies have shown benefit of methotrexate in SLE, especially for cutaneous and joint lupus. In a double-blind randomized controlled trial conducted in Canada, Fortin and colleagues, in the abstract, found a reduction in activity on SLAM (1.15 points, p=0.04) and prednisone dose (3.54 mg, p=0.02) only in the subgroup without damage.

Editorial Comment: Dr. Esdaile, who presented at the ACR meeting, did not consider the results impressive and could not think of any scientific rationale for the subgroup analyses.

No analyses had been done for SLE patients in the trial with skin and joint lupus-if methotrexate has benefit, these are the patients who should be evaluated in subgroup analyses.

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Graham Hughes’ group suggested several years ago that smaller doses of cytoxan, given more frequently, might be as effective (but less toxic) than the NIH protocol. The Euro-Lupus group has now completed a prospective trial, with 43 months median follow-up. No differences were seen. However, the NIH experience suggests that differences in renal outcomes are not evident until 5 years or more.

As expected, infections were actually twice as frequent in the NIH cytoxan arm as in the low dose arm, but it did not reach statistical significance.

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Abstract #264 Dendritic Cells and Type I Interferon in Systemic Lupus Erythematosus.
V Pascual, P Blanco, M Gill, J Banchereau, K Palucka.

In this very interesting abstract, Banchereau and colleagues show that monocytes from SLE patients are highly efficient stimulators of the immune responses, generally a property of dendritic cells (DC). They initially located the activity responsible for this phenotypic alteration of monocytes within SLE serum, and demonstrated that the presence of this property correlated with SLE activity (using the SLEDAI index). The investigators demonstrate conclusively that this effect is mediated by interferon-α (IFN-α), and that DC induction by SLE sera correlated tightly with serum IFN-α levels.

Editorial Comments: These studies provide novel insights into the mechanism of SLE, suggesting that the elaboration of factors that induce the differentiation of monocytes into potent antigen-presenting cells may play an important role in initiating and driving the autoimmune response to self-antigens. The data also suggest that inhibition of this pathway may have therapeutic potential in this disease.

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Abstract #1336 Apoptotic Cell-Pulsed Dendritic Cells Break Tolerance and Accelerate Lupus in NZB/W F1 Mice.
A Bondanza, M Sabbadini, V Zimmermann, G Dell'Antonio, A Tincani, G Balestrieri, A Manfredi, P Rovere.

Many recent studies have suggested that the immune response in systemic autoimmune diseases like SLE are driven by cells which die by the programmed cell death process called apoptosis. Apoptotic cells are generated in many physiological and pathological processes, and are not usually associated with the development of autoimmunity. One of the ways in which apoptotic cells might initiate an autoimmune response is if they are efficiently taken up by a highly potent form of antigen-presenting cell, which is very efficient in initiating a primary immune response. In this abstract, Drs. Rovere, Manfredi and colleagues have addressed whether activated dendritic cells (potent antigen-presenting cells) pulsed with cells dying by apoptosis can accelerate development of an SLE-like phenotype in a mouse model of lupus. They demonstrate that this is indeed the case, and that the generation of an antibody response to beta2-glycoprotein-I may be a very important intermediate in this process.

Editorial Comments: Similar data in non-autoimmune mouse strains was also presented by Dr. Ashany and colleagues at this meeting (abstract 1383). Together, the data suggest that activated DCs may play a role in the initiation and propagation of the autoimmune response to apoptotic cell-derived antigens in SLE and associated diseases. The data also suggests that DC immunization protocols (e.g. for tumor immunization strategies) may carry a risk of inducing systemic autoimmune diseases.

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Abstract #286 Pathogenic Autoantibody Production Controlled by T-bet, A Transcriptional Regulator of B Cell Class Switching.
S Peng, S Szabo, L Glimcher.

Recent data from Glimcher and colleagues have demonstrated that the T-box transcription factor T-bet directly regulates commitment of CD4+ T cells to the Th1 differentiation lineage. In the current studies, the effects of T-bet on B cell class switching and pathogenic autoantibody production in a mouse model of SLE are addressed. Interestingly, T-bet deficient B cells were deficient in their production of several IgG isotypes, and were unable to make IgG2a. Furthermore, enforced expression of T-bet in B cells in vitro initiated IgG2a expression. When the effect of T-bet deficiency was addressed in the MRL/lpr mouse model of SLE, the authors found that the animals were protected from immune complex renal disease. Interestingly, many of the infiltrative inflammatory lesions in skin and liver were unchanged in these T-bet deficient animals. The data thus identify this transcription factor as playing an important, independent role in B cell class switching, and thus in generation of pathogenic autoantibodies.

Editorial Comments: Understanding the basic mechanisms of the pathogenic immune response may provide novel therapeutic targets for this group of diseases.

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