Faculty Bibliography

BACKGROUND: Oral contraceptives are rarely prescribed for women with systemic lupus erythematosus, because of concern about potential negative side effects. In this double-blind, randomized, noninferiority trial, we prospectively evaluated the effect of oral contraceptives on lupus activity in premenopausal women with systemic lupus erythematosus. METHODS: A total of 183 women with inactive (76 percent) or stable active (24 percent) systemic lupus erythematosus at 15 U.S. sites were randomly assigned to receive either oral contraceptives (triphasic ethinyl estradiol at a dose of 35 microg plus norethindrone at a dose of 0.5 to 1 mg for 12 cycles of 28 days each; 91 women) or placebo (92 women) and were evaluated at months 1, 2, 3, 6, 9, and 12. Subjects were excluded if they had moderate or high levels of anticardiolipin antibodies, lupus anticoagulant, or a history of thrombosis. RESULTS: The primary end point, a severe lupus flare, occurred in 7 of 91 subjects receiving oral contraceptives (7.7 percent) as compared with 7 of 92 subjects receiving placebo (7.6 percent). The 12-month rates of severe flare were similar: 0.084 for the group receiving oral contraceptives and 0.087 for the placebo group (P=0.95; upper limit of the one-sided 95 percent confidence interval for this difference, 0.069, which is within the prespecified 9 percent margin for noninferiority). Rates of mild or moderate flares were 1.40 flares per person-year for subjects receiving oral contraceptives and 1.44 flares per person-year for subjects receiving placebo (relative risk, 0.98; P=0.86). In the group that was randomized to receive oral contraceptives, there was one deep venous thrombosis and one clotted graft; in the placebo group, there was one deep venous thrombosis, one ocular thrombosis, one superficial thrombophlebitis, and one death (after cessation of the trial). CONCLUSIONS: Our study indicates that oral contraceptives do not increase the risk of flare among women with systemic lupus erythematosus whose disease is stable

Immunoassay-based anti-nuclear antibody (ANA) screens are increasingly used in the initial evaluation of autoimmune disorders, but these tests offer no 'pattern information' comparable to the information from indirect fluorescence assay-based screens. Thus, there is no indication of 'next steps' when a positive result is obtained. To improve the utility of immunoassay-based ANA screening, we evaluated a new method that combines a multiplex immunoassay with a k nearest neighbor (kNN) algorithm for computer-assisted pattern recognition. We assembled a training set, consisting of 1,152 sera from patients with various rheumatic diseases and non-diseased patients. The clinical sensitivity and specificity of the multiplex method and algorithm were evaluated with a test set that consisted of 173 sera collected at a rheumatology clinic from patients diagnosed by using standard criteria, as well as 152 age- and sex-matched sera from presumably healthy individuals (sera collected at a blood bank). The test set was also evaluated with a HEp-2 cell-based enzyme-linked immunosorbent assay (ELISA). Both the ELISA and multiplex immunoassay results were positive for 94% of the systemic lupus erythematosus (SLE) patients. The kNN algorithm correctly proposed an SLE pattern for 84% of the antibody-positive SLE patients. For patients with no connective tissue disease, the multiplex method found fewer positive results than the ELISA screen, and no disease was proposed by the kNN algorithm for most of these patients. In conclusion, the automated algorithm could identify SLE patterns and may be useful in the identification of patients who would benefit from early referral to a specialist, as well as patients who do not require further evaluation

BACKGROUND: Since anecdotal series and small, prospective, controlled trials suggest that mycophenolate mofetil may be effective for treating lupus nephritis, larger trials are desirable. METHODS: We conducted a 24-week randomized, open-label, noninferiority trial comparing oral mycophenolate mofetil (initial dose, 1000 mg per day, increased to 3000 mg per day) with monthly intravenous cyclophosphamide (0.5 g per square meter of body-surface area, increased to 1.0 g per square meter) as induction therapy for active lupus nephritis. A change to the alternative regimen was allowed at 12 weeks in patients who did not have an early response. The study protocol specified adjunctive care and the use and tapering of corticosteroids. The primary end point was complete remission at 24 weeks (normalization of abnormal renal measurements and maintenance of baseline normal measurements). A secondary end point was partial remission at 24 weeks. RESULTS: Of 140 patients recruited, 71 were randomly assigned to receive mycophenolate mofetil and 69 were randomly assigned to receive cyclophosphamide. At 12 weeks, 56 patients receiving mycophenolate mofetil and 42 receiving cyclophosphamide had satisfactory early responses. In the intention-to-treat analysis, 16 of the 71 patients (22.5 percent) receiving mycophenolate mofetil and 4 of the 69 patients receiving cyclophosphamide (5.8 percent) had complete remission, for an absolute difference of 16.7 percentage points (95 percent confidence interval, 5.6 to 27.9 percentage points; P=0.005), meeting the prespecified criteria for noninferiority and demonstrating the superiority of mycophenolate mofetil to cyclophosphamide. Partial remission occurred in 21 of the 71 patients (29.6 percent) and 17 of the 69 patients (24.6 percent), respectively (P=0.51). Three patients assigned to cyclophosphamide died, two during protocol therapy. Fewer severe infections and hospitalizations but more diarrhea occurred among those receiving mycophenolate. CONCLUSIONS: In this 24-week trial, mycophenolate mofetil was more effective than intravenous cyclophosphamide in inducing remission of lupus nephritis and had a more favorable safety profile

Deficiency of dehydroepiandrosterone (DHEA) is associated with lupus erythematosus, diabetes mellitus, Alzheimer disease, and some cancers, but we are not yet ready to conclude that prescribing supplemental DHEA is helpful in these or any other conditions. DHEA shows some promise in observational clinical studies and laboratory experiments, but we still need large-scale human studies to answer key questions. For now, we do not have enough evidence to recommend routine treatment with DHEA. As with other supplements, quality control is always a concern, and different brands may contain different amounts of active ingredient

Although considered a prototypic autoimmune disease, the hallmark of systemic lupus erythematosus (SLE) is its heterogeneity. Accordingly, manifestations can vary widely from person to person, with the potential involvement of virtually any bodily organ. Furthermore, the genetic abnormalities underlying this condition are complicated, with diverse genetic polymorphisms described in different ethnic groups, strongly suggesting that the actual pathology underlying the immunologic disarray might not be the same for each patient. Evolving concepts of genetics and immunity have clarified that patients can carry unique arrays of exacerbating and protective factors. These factors, in conjunction with variable environmental triggers for SLE, probably determine the sequelae that an individual experiences. Therefore, it is not surprising that the clinical manifestations are diverse, the temporal sequence of organ involvement often unpredictable, and that the flares of inflammatory activity that characterize SLE can either remit without consequence or leave permanent damage in their wake. It is widely accepted that the current standard of care for SLE patients is inadequate. Programs to develop and test new drug and/or device therapies have been ongoing since the mid-1990s but have encountered formidable obstacles. With the current burst of drug discovery and the advent of several large international trials of promising new agents, the challenge to overcome these obstacles has never been greater. A burgeoning literature in the past decades nevertheless suggests that despite the complexities of the many immunologic pathways that impact on SLE, characteristic biologic markers are emerging as potential signposts that can characterize patient subgroups, predict prognosis, mark the exacerbations and remissions of SLE flares, and serve as endpoints in the determination of the dosing and timing of immune-modulating treatments. Several of the promising biomarkers are addressed in this chapter

BACKGROUND: There is concern that exogenous female hormones may worsen disease activity in women with systemic lupus erythematosus (SLE). OBJECTIVE: To evaluate the effect of hormone replacement therapy (HRT) on disease activity in postmenopausal women with SLE. DESIGN: Randomized, double-blind, placebo-controlled noninferiority trial conducted from March 1996 to June 2002. SETTING: 16 university-affiliated rheumatology clinics or practices in 11 U.S. states. PATIENTS: 351 menopausal patients (mean age, 50 years) with inactive (81.5%) or stable-active (18.5%) SLE. Interventions: 12 months of treatment with active drug (0.625 mg of conjugated estrogen daily, plus 5 mg of medroxyprogesterone for 12 days per month) or placebo. The 12-month follow-up rate was 82% for the HRT group and 87% for the placebo group. MEASUREMENTS: The primary end point was occurrence of a severe flare as defined by Safety of Estrogens in Lupus Erythematosus, National Assessment-Systemic Lupus Erythematosus Disease Activity Index composite. RESULTS: Severe flare was rare in both treatment groups: The 12-month severe flare rate was 0.081 for the HRT group and 0.049 for the placebo group, yielding an estimated difference of 0.033 (P = 0.23). The upper limit of the 1-sided 95% CI for the treatment difference was 0.078, within the prespecified margin of 9% for noninferiority. Mild to moderate flares were significantly increased in the HRT group: 1.14 flares/person-year for HRT and 0.86 flare/person-year for placebo (relative risk, 1.34; P = 0.01). The probability of any type of flare by 12 months was 0.64 for the HRT group and 0.51 for the placebo group (P = 0.01). In the HRT group, there were 1 death, 1 stroke, 2 cases of deep venous thrombosis, and 1 case of thrombosis in an arteriovenous graft; in the placebo group, 1 patient developed deep venous thrombosis. LIMITATIONS: Findings are not generalizable to women with high-titer anticardiolipin antibodies, lupus anticoagulant, or previous thrombosis. CONCLUSIONS: Adding a short course of HRT is associated with a small risk for increasing the natural flare rate of lupus. Most of these flares are mild to moderate. The benefits of HRT can be balanced against the risk for flare because HRT did not significantly increase the risk for severe flare compared with placebo

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease, characterised by flares of rampant inflammation that can threaten, in an unpredictable manner, almost any organ in the body. Current standard of care is largely empiric, involving the use of corticosteroids and toxic immune suppressive agents that are widely acknowledged to have unacceptable side effects for long-term use. Recently, there have been significant advances in understanding the nature of some fundamental immune imbalances underlying the complicated clinical manifestations of SLE. Nevertheless attempts to develop and test more targeted, and potentially safer immune-modulating drugs for lupus have encountered significant obstacles, due to the lack of validated biological markers for disease flare and remission, and difficulties in the clinical assessment of the heterogeneous patients. In support of renewed interest in drug development for lupus, large collaborative groups have formed, and efforts are underway to develop objective biomarkers for SLE as well as to improve the standardisation and reproducibility of clinical outcome measures in multi-centre trials

The major impediment to drug development for systemic lupus erythematosus (SLE) is its heterogeneity. The unpredictable manner in which lupus targets different organs at varying intensity makes the study of new drugs and the optimization of their administration extremely difficult. With the advent of novel, targeted biologic agents for SLE, it can be hoped that more strategic, lupus-relevant immune modulation will lead to safer and more effective treatments. Two alternative new approaches to lupus treatment are reviewed. The first involves selective inhibition of a single protein (BLyS), which may play a central role in host defense and in the pathogenesis of SLE. Although this approach is finely targeted to the inhibition of a single protein which is known to be upregulated in SLE patients, the positioning of BLyS at a critical hub in the immune response suggests that more global adverse repercussions on immunity might still occur. The second strategy is the use of peptides designed to specifically induce tolerance in limited autoreactive immune responses. Immune repercussions might, at least in theory, be almost nonexistent with this kind of approach. Concerns that limited induction of tolerance might have equally limited impact on the complex immune disorder of SLE are not borne out in preliminary murine data. Specific development programs are ongoing using both of these strategies and have recently entered human trials.

It is now widely accepted that the current standard of care for systemic lupus erythematosus (SLE) patients is inadequate. There has not been a new medication approved for this disease in thirty years. Attempts to develop and test new drugs have been ongoing since the mid-1990s, but have encountered formidable obstacles. Current models for lupus pathogenesis have provided a theoretical framework for understanding how heterogeneous genetic defects might combine in various ways to increase susceptibility to SLE in different individuals, and could have important implications for new drug development. With the current burst of drug discovery and increased public awareness of SLE, the impetus to overcome these obstacles has never been greater