Search

To determine whether exposure to canine lupus is a risk for human lupus, we studied 83 members of 23 households exposed to 19 dogs with high titer antinuclear antibodies and compared these contact households to 50 members of 18 control households matched for dog age, sex, and primary veterinarian. No differences were found between contacts and controls in titer of antinuclear, antiDNA, antiRNA, and antilymphocyte antibodies, frequency of positive rheumatoid factor, or elevated serum immunoglobulins. Further analysis of subgroups by age, sex, and intensity of dog exposure did not reveal any serologic differences between contacts and controls. No cases of lupus were identified in either group. Three contact households and no controls reported a family history (remote from the household) of lupus. This study did not detect any clinical or serologic effect of human household exposure to dogs with high titer antinuclear antibodies.

In this study, we show that sera from 2 of 13 patients with clinically active systemic lupus erythematosus (SLE) contained anti-interferon alpha (anti-IFN alpha) antibody. In contrast, anti-IFN alpha activity was not detected in sera from patients with clinically inactive SLE, rheumatoid arthritis (RA), Sjögren's syndrome, or in normal individuals. None of the sera exhibited anti-IFN gamma activity. These studies show that anti-IFN antibody, like IFN itself, is most frequently observed in patients with clinically active SLE. It is also possible that the presence of IFN-anti-IFN complexes may contribute, in part, to the pathogenesis of this disease.

The bladder complications of 54 patients treated with oral cyclophosphamide for systemic lupus erythematosus (43) or rheumatoid arthritis (11) were reviewed. During an observation period of 241 patient years, we saw seven cases of acute hemorrhagic cystitis and two cases of transitional cell carcinoma of the bladder. Bladder carcinoma was identified 28 and 60 months after withdrawal of the drug and resulted in the death of one patient. The late-occurring serious toxicities of cyclophosphamide should limit the use of the drug in the treatment of nonmalignant inflammatory rheumatic conditions.

Nine patients with active systemic lupus erythematosus entered a double-blind randomized trial to study the therapeutic effect of vigorous versus sham reinfusion plasmapheresis. Four of them received real plasmapheresis while five received sham reinfusion plasmapheresis. In the present communication we report the effects of these procedures on T lymphocytes in peripheral mononuclear cells, proliferative response to mitogens, allogeneic mixed lymphocyte reaction and cell-mediated lympholysis, as well as the effect of plasmapheresis on the spontaneous and pokeweed mitogen induced immunoglobulin secreting cells in peripheral blood. Several mononuclear cell functions were abnormal at the beginning of the study but no significant changes related to plasmaphersis occurred in any of the parameters studied.

In Caucasians with systemic lupus erythematosus (SLE), we have identified 3 risk markers in the HLA-D region -- HLA-DR2, HLA-DR3, and la-715 -- and have used these markers to probe 7 families in which more than 1 case of lupus had occurred. In 6 of the 7 families studied, persons with SLE were either homozygous for HLA-DR2, had 2 haplotypes carrying reactivity with la-715, or had at least 2 of the 3 risk markers HLA-DR2, HLA-DR3, and la-715. Several normal individuals in these kindreds also had these multiple risk markers but had no signs or symptoms of lupus. This limited study of lupus families suggests a role for coinheritance of HLA-D region genes as a factor in the development of SLE.

Forty-one patients with systemic lupus erythematosus and glomerulonephritis were studied in a randomized drug trial. Thirteen patients received prednisone only (Group 1), 16 received oral cyclophosphamide and oral azathioprine (1 mg/kg body weight . d of each initially) (Group 2), and 12 were given boluses of intravenous cyclophosphamide (0.5 to 1.0 g/m2 body surface area every 3 months) (Group 3). The mean observation period was 42 months (range 1 to 6.5 years). Renal function deteriorated in four of 12 patients in Group 1 and three of 27 patients in Groups 2 and 3 (p = 0.114). By life-table analysis, 86% of the entire group survived 5 years after entry to the study. Marked hypertension, fluctuating changes in serum creatinine, erratic changes in levels of antibody to DNA, reduced C3 levels, increasing proteinuria or sustained hematuria, and flares of extrarenal disease activity occurred more commonly in Group 1. Infectious complications were not commoner in Groups 2 and 3. We conclude that any marginal benefits produced by the programs tested cannot be shown in this class of patients without markedly increasing the sample size. Our current studies involve more vigorous treatment of patients with more acute disease and less treatment during prolonged periods of relatively good health.

The principal causes of death of 68 patients with lupus glomerulonephritis were reviewed. Renal failure (40%), vascular events (25%), and infections (16%) were the predominant causes. Diffuse proliferative glomerulonephritis was associated with an increased frequency of renal failure. A bimodal pattern of early deaths due to active lupus and sepsis and late deaths from vascular events was found superimposed on a constant rate of death from renal failure.

Systemic lupus erythematosus, a disease capable of exhibiting virtually any clinical manifestation, is discussed in detail and the findings are compared to those in other, presumably systemic lupus erythematosus-related connective tissue diseases. More emphasis has been placed on the clinical features than on the numerous laboratory manifestations. The conference begins and ends with a brief consideration of current concepts of pathogenesis and suggests some future investigational directions.

From 1969 to 1975, 53 patients with lupus nephritis took part in randomized trials comparing prednisone, oral azathioprine plus low-dose prednisone, and oral cyclophosphamide plus low-dose prednisone. After a mean follow-up of 85 months, cyclophosphamide appears marginally superior to prednisone for maintaining renal function (p = 0.03) and preventing end-stage renal failure (p = 0.07). Chronic change shown by renal biopsy assessed by a chronicity index was found useful in predicting renal function outcomes and response to immunosuppressive therapy. Three of 21 patients with a low chronicity index and 9 of 10 patients with a high chronicity index doubled their serum creatinine (p less than 0.00003). The probability of renal functional deterioration was not different among the treatments studied. However, in 14 patients with an intermediate chronicity index, 1 of 11 patients treated with azathioprine or cyclophosphamide doubled the serum creatinine level whereas all 3 patients treated with prednisone have progressed to end-stage renal failure (p = 0.005). The study suggests that single-drug oral immunosuppressive treatment combined with prednisone is most beneficial in lupus patients with intermediate chronic change shown by renal biopsy.

Thirty-eight patients with diffuse glomerulonephritis of systemic lupus erythematosus were randomly assigned to add cyclophosphamide, azathioprine, or nothing to low-dose corticosteroid treatment and have been followed for a mean of 21/3 years thereafter. Of the 11 patients with unfavorable outcomes (8 deaths and 2 beginning hemodialyses), 2 occurred on cyclophosphamide, 4 on azathioprine, and 5 on prednisone only. Deaths due to infection occurred on the cytotoxics, while deaths ascribed to central nervous system lupus erythematosus occurred exclusively on prednisone only. Gradual deterioration of renal function was observed in all three groups, most frequently on prednisone only. Undesirable events, some due to drugs, were observed. At the time of reporting, the cytotoxic agents seemed to add marginally to the control of the disease; other treatment schedules should be evaluated.

Systemic lupus erythematosus, a disease of unknown cause and protean manifestations, continues to excite substantial investigational interest. These papers bring together recent advances in concepts of its immunopathogenesis, evidence for a major genetic role in the causation of the process, developing systems for the morphologic assessment of its often fatal nephritis, and data from ongoing trials of cytotoxic drugs in its management.

Forty patients with systemic lupus erythematosus randomly received inactivated bivalent (A/NJ and A/Victoria) influenza vaccine or saline in a double-blind study. During 20 weeks of follow-up, no deterioration in major organ function or increase in disease flares was observed in the immunized group as compared with the group that received saline. Preimmunization antibody titers to A/Victoria were lower in the 40 patients with lupus erythematosus than in age-matched control subjects. Response to immunization, as measured by serum antibody titers, was also lower in the patients with lupus erythematosus, indicating that immune responses must be evaluated on an individual patient basis. Nevertheless, influenza vaccination can be safely carried out in patients with systemic lupus erythematosus.

We evaluated renal function in 107 patients with active lupus nephritis who participated in long-term randomized therapeutic trials (median follow-up, seven years). For patients taking oral prednisone alone, the probability of renal failure began to increase substantially after five years of observation. Renal function was better preserved in patients who received various cytotoxic-drug therapies, but the difference was statistically significant only for intravenous cyclophosphamide plus low-dose prednisone as compared with high-dose prednisone alone (P = 0.027). The advantage of treatment with intravenous cyclophosphamide over oral prednisone alone was particularly apparent in the high-risk subgroup of patients who had chronic histologic changes on renal biopsy at study entry. Patients treated with intravenous cyclophosphamide have not experienced hemorrhagic cystitis, cancer, or a disproportionate number of major infections. We conclude that, as compared with high-dose oral prednisone alone, treatment of lupus glomerulonephritis with intravenous cyclophosphamide reduces the risk of end-stage renal failure with few serious complications.

The effects of intensive plasma exchange on the serological and clinical manifestations of mildly active systemic lupus erythematosus were evaluated in a controlled, double-blind trial. Twenty patients were randomised to receive either six 4-litre plasma exchanges or a seemingly identical control procedure over a 2-week period. Plasma exchange produced significant reductions in serum levels of IgG, IgM, IgA, and circulating immune complexes measured by an 125I-Clq binding assay. These serological measures returned to baseline 4 weeks after plasma exchange without a rebound above baseline values. Antibodies to DNA were reduced immediately after plasma exchange; however, they often returned to pre-treatment levels before the next procedure. No changes in any of the serological measures were observed in the control group. In sixteen of the eighteen patients who completed the clinical trial activity had either remained stable or improved; the frequency and degree of clinical improvement was the same in both plasma exchange and control groups.

We retrospectively studied the evolution of histopathologic features in successive renal biopsies in patients with lupus nephritis, to evaluate the effects of various treatment regimens. Repeat renal biopsies had been performed in 62 patients after more than 18 months of observation (median interval, 44 months) in randomized therapeutic trials comparing prednisone with cytotoxic drugs. Renal histopathologic features were graded individually, and a composite score reflecting the number and severity of irreversible lesions was defined as a chronicity index. The chronicity index for patients treated with conventional high-dose prednisone increased linearly with the interval between biopsies, whereas the index in the group receiving cytotoxic-drug treatments did not increase over time. After statistical adjustment for important prognostic factors (age and initial chronicity index) identified by multiple linear regression, the difference in the slopes between the group receiving prednisone and the group receiving cytotoxic drugs was significant (P less than 0.0001). We conclude that cytotoxic-drug treatment reduces the likelihood of progressive renal scarring in lupus nephritis.

The frequency, causes, clinical and laboratory features, and outcome of febrile episodes in 160 hospitalized patients with systemic lupus erythematosus were reviewed. Eighty-three febrile episodes were identified in 63 patients and were ascribed to active lupus erythematosus alone (60 per cent), infections (23 per cent) and miscellaneous causes (17 per cent). Bacteremia was present in nine of the 19 infectious episodes and resulted in a fatal outcome in a third of the patients. Leukocytosis, neutrophilia, shaking chills and normal levels of anti-DNA antibodies were associated with infection in febrile patients with lupus erythematosus.

The activity of phospholipase inhibitory protein, lipomodulin, partially purified from rabbit neutrophils, was markedly decreased after treatment with sera from patients with rheumatic diseases such as systemic lupus erythematosus, rheumatoid arthritis, and dermatomyositis. The decrease of the protein's inhibitory activity on phospholipase A2 paralleled the amount of [35S]methionine-labeled lipomodulin precipitated by the sera. Absorption of patients' sera with anti-human IgM (mu chain) or protein A-agarose, but not with anti-human IgG (gamma chain), decreased their ability to decrease the activity of lipomodulin on phospholipase A2 or to precipitate the radioactive lipomodulin. The IgM fraction of patients' sera could precipitate [35S]methionine-labeled lipomodulin (40,000 daltons) which comigrated with highly purified lipomodulin on gel electrophoresis with sodium dodecyl sulfate. All of these observations suggest that the sera of many patients with rheumatic diseases contain autoantibody against lipomodulin. A monoclonal antibody against lipomodulin was also obtained. Stimulating human fibroblasts with bradykinin in the presence of monoclonal antilipomodulin antibody markedly enhanced arachidonic acid release due to the activation of phospholipase(s) in the intact cells, and this stimulatory effect was blocked by adding purified lipomodulin. These findings suggest that lipomodulin regulates the activity of phospholipase(s) on the cell surface and that autoantibodies against lipomodulin may play a role in certain symptoms of rheumatic diseases, especially by the formation of prostaglandins and other metabolites of arachidonic acid.

The immunogenicity and potential for disease modification of pneumococcal polysaccharide vaccine in systemic lupus erythematosus were evaluated in a controlled, double-blind study. Forty patients were randomly chosen to receive an intramuscular injection of either vaccine or placebo. Changes in mean antibody concentrations (nanograms antibody nitrogen per milliliter serum) to 12 type-specific pneumococcal capsular antigens from prevaccination to one month after vaccination were 177 to 1045 in the vaccine (P less than 0.001) and 164 to 153 in the placebo-treated patients. In the month after vaccination, neither vaccine nor placebo-treated patients had a significant change in lupus disease activity as assessed by a composite clinical, laboratory, and serologic index. We conclude that patients with systemic lupus erythematosus can be successfully immunized with pneumococcal vaccine without detectable alterations of the underlying disease.

The predictive value of laboratory results and renal histologic data was examined in 102 patients upon entry into prospective, randomized, therapeutic trials of lupus nephritis. Three clinical features at the time of entry into the study were individually associated with increased rates of renal failure: age less than 24 years, male gender, and an elevated serum creatinine level. Subjects with diffuse proliferative or membranoproliferative glomerulonephritis were at a modest but significantly increased risk for the development of end-stage renal disease compared with patients with other classes of lupus nephritis. Semiquantitative scores of histologic features (specified by activity and chronicity indexes) identified subgroups of patients with comparatively high renal failure rates. To address the controversial issue of whether renal histologic data significantly improve the outcome predictions in patients with lupus nephritis, multivariate survival models were generated, permitting simultaneous consideration of multiple prognostic factors. Outcome predictions based on the strongest clinical predictors (age, sex, and serum creatinine level) were significantly enhanced by the addition of activity and chronicity indexes. Only age and chronicity index contributed significantly to the five-variable model and together constituted a two-variable model, the predictions of which were similar to observed outcomes. In the context of the highly significant prognostic indicators (age and chronicity index), immunosuppressive agents appeared to provide a slight therapeutic advantage over oral corticosteroids alone.

The female predominance among patients with systemic lupus erythematosus and the protective effects of androgens in the murine lupus model prompted us to assess the androgenic status of 12 men with the disease. Save for minor abnormalities explained by treatment or renal insufficiency, normal serum testosterone, luteinizing hormone, and follicle stimulating hormone levels were found. Hypogonadism or androgen deficiency was not evident.

We examined B-lymphocyte alloantigens in 41 patients with systemic lupus erythematosus and 184 controls, using a panel of 47 pregnancy serums, and compared reaction frequencies of individual serums. One serum, la-715, reacted with B lymphocytes from 75.6 per cent of patients and 14.1 per cent of controls (Pc less than 0.005, relative risk 18.8). Twenty-eight of the patients were also typed with a panel of HLA-D-related serums from the Seventh International Histocompatibility Workshop, HLA-DRw types assigned, and compared to 490 Workshop controls. Both HLA-DRw2 (57.1 per cent vs. 26.4 per cent, Pc less than 0.004) and HLA-DRw3 (46.4 per cent vs. 22.2 per cent, Pc less than 0.03) were increased in systemic lupus erythematosus. This study demonstrates that select B-lymphocyte alloantigens, which are controlled by genes in the major histocompatibility complex, are present in increased frequency in systemic lupus erythematosus.

Twenty-six patients with active systemic lupus erythematosus partially controlled by prednisone 30 mg daily or less were randomly selected to receive levamisole 150 mg weekly or placebo. Many patients showed increased disease activity over the 6-month trial period, and most required increased steroid dosage. Those on levamisole did no better than those on placebo.

Sera of patients with systemic lupus erythematosus (SLE) showed significantly higher complement fixation reactivities with 8 of 10 virus antigen preparations compared to sera of normal subjects, including virus workers, confirming earlier observations. However, one-third of SLE sera were also reactive with cellular antigens, prepared in a manner identical to viral antigens, but from cells not infected with virus. By contrast, only one of 49 normal sera showed reactivity with one of nine cellular antigens, at a minimal titer. Apparently heightened reactivities of SLE sera with virus antigens could be explained in many instances on the basis of reactions with cellular antigens. Serum reactivities with nonviral tissue antigens in SLE must be considered in interpretation of immunologic studies related to viruses and SLE.

The symptomatic joint disease secondary to avascular necrosis of bone (ANB) in 31 of 375 (8 per cent) patients with systemic lupus erythematosus (SLE) was characterized by polyarticular (90 per cent) and symmetric (83 per cent) involvement. Progressive deterioration requiring orthopedic intervention occurred in 11 (35 per cent) patients. No distinguishing clinical or treatment differences were found comparing patients with symptomatic ANB and selected cortico-steroid-treated, asymptomatic, control subjects with SLE. Complete roentgenographic surveys revealed symmetric, polyarticular abnormalities of subchondral and cortical bone consistent with ANB in eight of 31 (26 per cent) of the control subjects. A positive correlation was found between roentgenographic ANB and disease treatment with high doses of corticosteroids. The study suggests that ANB may be present in excess of 30 per cent of the patients with SLE and is most often subclinical, asymptomatic and nonprogressive.

In the context of prospective trials of immunosuppressive drugs in systemic lupus erythematosus (SLE) nephritis, 83 patients were studied with regard to development of herpes zoster. Herpes zoster was found to occur with high frequency (21%) in patients with SLE nephritis treated with immunosuppressive agents. The course of herpes zoster was benign: no deaths occurred and only 2 of the 18 patients developed generalized disease, which resolved without sequelae. Specific antiviral therapy was not necessary and there appears to be no need to decrease immunosuppressive medications. Zoster occurred when the SLE was relatively inactive and did not exacerbate the SLE. No statistical difference in the incidence of zoster was found among the patient groups treated with different immunosuppressive regimens.