Biomedical subjects
Publications and source records attributed to E M Ginzler.
Aortitis is an uncommon complication of systemic lupus erythematosus (SLE). Most cases of lupus-associated aortitis have been described in conjunction with aortic aneurysms or aortic dissection and have been documented either at autopsy or during surgery to repair a dissection. We describe an unusual case of aortitis associated with an aortic thrombus in a young man with SLE.
There is an increasing body of literature suggesting the efficacy and tolerability of mycophenolate mofetil (MMF) for the treatment of lupus nephritis. The rationale for its use is based upon its successful profile as an immunosuppressive agent for prevention of allograft rejection, as well as studies in murine models of lupus which have reported improved renal function and animal survival compared to placebo. This report reviews the data regarding MMF therapy in murine lupus models, and describes the initial anecdotal experience with MMF in human lupus, especially in patients with glomerulonephritis who were unresponsive to corticosteroids and cyclophosphamide, or who had unacceptable toxicity on this standard of care regimen. The results of several nonblinded, controlled clinical trials are also described, in which MMF was compared to intravenous or oral cyclophosphamide in patients with lupus nephritis. MMF was found to be well tolerated, with most studies showing fewer infections than that associated with cyclophosphamide. Efficacy of MMF was at least equivalent to cyclophosphamide, and therefore appears to provide an alternative as a standard of care for induction and maintenance treatment of lupus nephritis.
The American College of Rheumatology renal criteria require re-evaluation to incorporate recent advances in the classification of glomerulonephritidies. Renal biopsy is now common and safely performed by experienced nephrologists in community as well as academic settings. The optimal criterion is renal histopathology findings of an immune complex mediated glomerulonephritis as interpreted by an experienced pathologist employing accepted criteria. Renal biopsies should be analysed by routine histopathology, immunofluorescent and electron microscopy. Rating of activity and chronicity should be noted. Secondary criteria for patients unable to undergo renal biopsy includes a combination of findings. These include proteinuria, hypocomplementemia, elevated anti-dsDNA antibodies and an active urine sediment. Proteinuria is a nonspecific finding and, most importantly, can be associated with a number of comorbidities including diabetes, hypertension and atherosclerotic disease. Persistent proteinuria > 0.5 g per day or a spot protein to creatine ratio of > 0.5 should be accompanied by an additional feature supporting active lupus such as positive serologies (hypocomplementemia and/or elevated anti-dsDNA antibodies) and/or active urinary sediment. Similarly, active urinary sediment should be accompanied by the additional criterion of proteinuria to meet renal criteria. Decline in renal function is not a reliable criterion given the numerous medications, comorbidities and other clinical circumstances which may result in this feature.
Significant advances in the treatment of lupus nephritis have been made in the last 50 years, beginning with the use of high doses of corticosteroids. The addition of intravenous cyclophosphamide (IVC) to steroids, a regimen introduced by the National Institutes of Health, has become the standard of care therapy for severe active nephritis. However, not all patients respond to IVC, and among those who do, manifestations of toxicity (nausea, vomiting, alopecia, sterility, increased risk of infection, and increased risk of malignancy) are frequent. Despite successful induction and maintenance therapy with IVC, there is a relapse rate of more than 50% after 10 years. In recent years, new immunosuppressive agents have been studied as potential alternatives to IVC. The most promising of these appears to be mycofenolate mofetil, which is being evaluated in clinical trials. Biologic agents designed to interfere with the immunologic process leading to B- and T-lymphocyte activation are also being tested as alternative therapies in lupus nephritis.
Awareness of the impact of cardiovascular disease on the late morbidity and mortality in patients with Systemic Lupus Erythematosus (SLE) is increasing. Clinical events secondary to accelerated atherosclerosis have been documented in lupus cohorts across the globe. We review the history and epidemiology of cardiovascular disease in patients with SLE.
Corticosteroid therapy has had a major impact on improvement in disease activity and long-term survival in patients with systemic lupus erythematosus (SLE). Unfortunately, the therapeutic advantages are accompanied by many manifestations of toxicity, some of which are short term and potentially reversible, while others cause chronic irreversible damage. Many of these features of toxicity have similar presentations to manifestations of SLE disease activity, and must be distinguished in the individual patient. The features of corticosteroid toxicity are reviewed in this chapter, and means of prevention and/or treatment are discussed.
Autoantibodies to the collagen-like region of the first complement component (C1qAB) are found in patients with systemic lupus erythematosus (SLE), particularly those with renal disease. In a cohort of 46 SLE patients with diffuse proliferative glomerulonephritis, we found declining C1qAB titers in 77% of treatment responders and in only 38% of treatment non-responders (P < 0.03). To further characterize this autoantibody, we tested 240 SLE patients for the presence of C1qAB. Positive titers were found in 44% of patients with renal disease and 18% of patients without renal disease (chi2 P < 0.0003). Analysis of IgG subclass revealed IgG2 C1qAB alone in 34%, IgG1 C1qAB alone in 20%, and both IgG1 and IgG2 in 46% of patients. Fewer than 10% of patients had measurable titers of IgG3 or IgG4 C1qAB. The pathogenic role of these IgG2-skewed C1qAB may relate to impaired immune complex clearance by the mononuclear phagocyte system: IgG2 antibodies are efficiently recognized by only one IgG receptor, the H131 allele of Fc gamma RIIa (Fc gamma RIIa-H131). In contrast, Fc gamma RIIa-R131, which is characterized by minimal IgG2 binding, has recently been associated with lupus nephritis. In our C1qAB positive patients, the presence of Fc gamma RIIA-R131 was associated with an increased risk for renal disease. Autoantibodies to C1q may have pathogenic significance in SLE patients with genetic defects in the ability to clear IgG2 containing immune complexes.
Allelic variants of Fc gamma R confer distinct phagocytic capacities providing a mechanism for heritable susceptibility to immune complex disease. Human Fc gamma RIIa has two codominantly expressed alleles, R131 and H131, which differ substantially in their ability to ligate human IgG2. The Fc gamma RIIa-H131 is the only human Fc gamma R which recognizes IgG2 efficiently and optimal IgG2 handling occurs only in the homozygous state. Therefore, since immune complex clearance is essential in SLE, we hypothesized that Fc gamma RIIA genes are important disease susceptibility factors for SLE, particularly lupus nephritis. In a two-stage cross-sectional study, we compared the distribution of Fc gamma RIIA alleles in African Americans with SLE to that in African American non-SLE controls. A pilot study of 43 SLE patients and 39 controls demonstrated a skewed distribution of Fc gamma RIIA alleles, with only 9% of SLE patients homozygous for Fc gamma RIIa-H131 compared with 36% of controls (odds ratio, 0.18; 95% CI, 0.05-0.69, P = 0.009). This was confirmed with a multicenter study of 214 SLE patients and 100 non-SLE controls. The altered distribution of Fc gamma RIIA alleles was most striking in lupus nephritis. Trend analysis of the genotype distribution showed a highly significant decrease in Fc gamma RIIA-H131 as the likelihood for lupus nephritis increased (P = 0.0004) consistent with a protective effect of the Fc gamma RIIA-H131 gene. The skewing in the distribution of Fc gamma RIIA alleles identifies this gene as a risk factor with pathophysiologic importance for the SLE diathesis in African Americans.
As patients with systemic lupus erythematosus (SLE) survive their episodes of disease activity, increasing morbidity is shown to be related to chronic cardiovascular complications. The objective of this study was to assess the cardiac parasympathetic autonomic functional status, as reflected by heart rate variability, in SLE patients with and without corticosteroid treatment. A cross-sectional study of SLE patients attending the Arthritis Clinic was done, using age and gender-matched controls. Thirty-four female patients, age 39 +/- 11, were entered, 20 of whom were receiving steroids at the time of study. Time and frequency domain heart rate variability indices were significantly reduced in the SLE groups with and without corticosteroid therapy, as compared to controls. The indices were not, however, significantly different in the two SLE groups.
OBJECTIVE: To assess the effect of hypertension on the development of renal functional deterioration, end stage renal disease and death in patients with systemic lupus erythematosus (SLE). METHODS: Person-years analysis using regression techniques to adjust for other baseline risk factors for adverse renal and patient survival outcomes. RESULTS: Six hundred eighty-five patients with SLE were followed for a total of 4,137 person-years. The risk of renal deterioration (doubling of serum creatinine) and endstage renal disease (ESRD) both increased with increasing baseline mean arterial pressure (MAP) (both p > 0.05). Even after adjustment for age, sex, baseline serum creatinine, C3, erythrocyte sedimentation rate, hematocrit, anti-DNA antibodies, and proteinuria, those in the highest quartile of MAP had 2.3 times the odds of renal deterioration at 12 months and 4.6 times the odds of ESRD compared to those in the lowest quartile of MAP (both p < 0.01 comparing highest to lowest quartile of MAP). Also, hypertension increased the risk of mortality, especially between one and 2 years after blood pressure determination. The effect of hypertension was also independent of corticosteroid dose. CONCLUSION: In patients with SLE, hypertension is a potent independent risk factor for adverse renal outcomes, and it also increases the risk of death.
OBJECTIVE: The purpose of this study was to test the hypothesis that patients with systemic lupus erythematosus (SLE) who have, as part of their disease, persistent rheumatoid-like arthritis are less likely to be hypertensive than are other patients with SLE. METHODS: A retrospective chart analysis of 662 patients with SLE seen in a university clinic was performed. RESULTS: Data analysis revealed that hypertension and persistent arthritis were inversely correlated, particularly in those patients without nephritis and particularly in black patients. CONCLUSION: We conclude that rheumatoid-like arthritis in patients with SLE is protective against hypertension, and speculate that this protection is conferred by a higher frequency of the DR4 allele.
Studies of renal involvement in systemic lupus erythematosus continue to dominate the clinical literature. Reports of the prognostic significance of both clinical and histologic parameters at the time of renal biopsy are discussed. The potential impact of anticardiolipin antibodies on the development of renal insufficiency is described. The outcome of renal transplantation in patients with systemic lupus erythematosus is assessed in a study concerned with both allograft survival and recurrence of active nephritis in the transplanted kidney. The incidence and prognosis of various features of neuropsychiatric systemic lupus erythematosus are discussed, while the search for an accurate indicator of lupus involvement of the central nervous system continues. Magnetic resonance imaging and single-photon-emission computed tomography are considered. Abnormalities of pulmonary gas exchange are featured in several reports. Features of the antiphospholipid antibody syndrome are presented, stressing predisposition to thrombosis. The definition and characteristics of systemic lupus erythematosus disease flares is discussed, in relation to several recently developed disease activity indexes. The attempt to distinguish systemic lupus erythematosus activity from infection and preeclampsia is also considered. Finally, the association of systemic lupus erythematosus with the development of cancer is discussed.
Although nephritis remains a very important clinical disease manifestation of systemic lupus erythematosus (SLE), the focus has shifted from issues of mortality to morbidity. An improved method for measuring renal function is presented, and the value of renal biopsy, specifically the chronicity index, is confirmed as a predictor of end-stage renal disease. Several studies detailing the generally favorable course in SLE patients with renal failure who have eventually required chronic dialysis or renal transplantation are discussed. A high frequency of cardiovascular manifestations, often subclinical, is documented, including abnormalities of ventricular and valvular function. The clinical course and response to treatment of SLE patients with diffuse interstitial lung disease and pulmonary hypertension are outlined. Cases of the unusual gastrointestinal presentation of protein-losing enteropathy in SLE have been described by several authors. The clinical correlates and significance of persistent rheumatoid-like arthritis and radiologic erosive and cystic bony lesions in SLE are discussed. Serologic markers of specific SLE disease manifestations and general predictors of disease activity are evaluated. Complications related to infection, malignancy, and pregnancy are described.
Previous publications suggest that in patients with systemic lupus erythematosus (SLE), rheumatoid factor (RF) may be "protective" against nephritis. In our study of 662 patients with SLE, we found that persistent, rheumatoid-like arthritis showed a much stronger inverse correlation with nephritis than RF. Of 186 such patients, 59 developed clinically evident nephritis (32%) compared to 263 of the other 476 patients (55%) (p less than 10(-7). RF showed only a weak inverse relationship to nephritis (p = 0.064). We conclude that the presence of persistent rheumatoid-like arthritis in patients with SLE identifies a clinical subset of patients who are less likely to develop nephritis than those with no arthralgia, no objective arthritis or only episodic arthritis. We hypothesize that such patients represent a genetically determined subset among patients with SLE and that perhaps they are more likely to bear the HLA-DR4 allele.
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We have attempted to assess the factors associated with prognosis in SLE, and to document the temporal changes in outcome, related not only to improvements in survival but to the emergence of an increased prevalence or morbidity, related to disease manifestations, complications of treatment, and co-morbid conditions.
A retrospective study of factors influencing survival in 1,103 patients with systemic lupus erythematosus (SLE) was carried out at 9 university centers diverse in geographic, socioeconomic, and racial characteristics. The mortality and disease characteristics of the patients at study entry varied widely among centers. The survival rates from the time patients with a diagnosis of SLE were first evaluated at the participating center was 90% at 1 year, 77% at 5 years, and 71% at 10 years. Patients with a serum creatinine greater than 3 mg/dl at study entry had the lowest survival rates: 48%, 29%, and 12% at 1, 5, and 10 years, respectively. Survival rate also correlated independently with the entry hematocrit, degree of proteinuria, number of preliminary American Rheumatism Association criteria for SLE satisfied, and source of funding of medical care. When data were corrected for socioeconomic status, race/ethnic origin did not significantly influence survival. Survival rates varied widely at different participating institutions, generally due to differences in disease severity. Place of treatment was independently associated with survival only in the second year after study entry. Disease duration before study entry did not account for the differences in disease severity.
Causes of death were examined for 1,103 systemic lupus erythematosus patients who were followed from 1965 to 1978 at 9 centers that participated in the Lupus Survival Study Group. A total of 222 patients (20%) died. Lupus-related organ system involvement (mainly active nephritis) and infection were the most frequent primary causes of death. Causes of death were similar throughout the followup period. Hemodialysis had little impact on the length of survival for patients with nephritis. Active central nervous system disease and myocardial infarction were infrequent causes of death. There were no deaths from malignancy.