Interferon-induced 2'-5' adenylate synthetase in vivo and interferon production in vitro by lymphocytes from systemic lupus erythematosus patients with and without circulating interferon.

The interferon (IFN)-induced enzyme 2-5A synthetase was elevated in mononuclear cells from both serum IFN-positive and -negative systemic lupus erythematosus (SLE) patients. This suggests that a much higher percentage of patients than previously thought produce endogenous IFN. These results may partly explain findings that mononuclear cells from SLE patients are deficient in IFN production in vitro in response to certain IFN inducers. Although normal lymphocytes can produce an acid-labile alpha IFN after stimulation with C. parvum in vitro, the reason for endogenous production of this unusual alpha IFN by SLE patients remains unknown.

Autoantibodies to nucleosomal proteins: antibodies to HMG-17 in autoimmune diseases.

The relative amounts of autoantibodies against defined nucleosomal proteins present in serums from patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and mixed connective tissue disease (MCTD) have been examined by an enzyme-linked immunoassay. Autoantibodies to nucleosomal proteins were detected in 45 percent of the patients with SLE, 18 percent of the MCTD patients, and none of the RA patients. The results suggest that, in SLE, antibodies are formed against a subset of nucleosomes which contain protein HMG-17.

Systemic lupus erythematosus: presence in human serum of an unusual acid-labile leukocyte interferon.

A previously undescribed species of human leukocyte, or alpha, interferon is present in the serum of many patients with systemic lupus erythematosus. It was shown to be alpha-interferon by neutralization with specific antiserums, affinity column chromatography, and antiviral activity on bovine cells. However, 23 of 30 interferon samples tested were inactivated by incubation at pH 2, a characteristic of human "immune," or gamma, interferon. Multiple samples of interferon from the same patient had similar biological properties, but samples from different patients were not all identical, suggesting that several variants of this species of human alpha-interferon may exist.

Raynaud's phenomenon. The French tricolor.

Recent epidemiologic surveys indicate that episodic vasospasm of arterioles (Raynaud's phenomenon) is a common finding in the general population. In a small minority of these individuals, an underlying, often reversible cause or systemic disease associated with vasospasm can be identified. The range of these so-called secondary forms of vasospasm is broad and includes systemic rheumatic syndromes, vibration-induced vascular injury, drug-induced vasospasm, and infectious disorders. Several different physiologic mechanisms may be responsible for vasospasm; hyperactivity of the sympathetic nervous system and abnormal adrenergic receptor function appear to be most important.

End-stage renal disease and systemic lupus erythematosus.

OBJECTIVE: To provide an overview of the course of systemic lupus erythematosus (SLE) following the onset of end-stage lupus nephropathy, regarding clinical and serological manifestations, survival on dialysis, and renal transplant outcomes. METHODS: A review of the pertinent literature, identified by a comprehensive Grateful Med search, was performed. RESULTS: There is a tendency for decreased clinical and serological lupus activity following the onset of end-stage renal disease. The pathophysiology of this quiescence remains unclear. Survival of lupus patients on dialysis is no different from that of non-SLE dialysis patients, and is better than that of several other rheumatic diseases. Following renal transplantation, there is no difference in patient or graft survival in lupus versus nonlupus patients. Like their nonlupus counterparts, SLE transplant patients do better with living relative grafts and/or regimens containing cyclosporin A. Transplantation is not recommended within 3 months of the initiation of dialysis to allow possible recovery from the acute renal failure. Transplantation during an acute exacerbation of SLE is controversial, and may increase the risk of poor outcomes. Recurrence of lupus in transplanted allografts, often with the same histopathology as in the native kidney, occurs at a rate (2.7% to 3.8%) comparable to that for all allograft transplant failures (2% to 4%). CONCLUSIONS: End-stage lupus nephropathy patients require less medication owing to decreased disease activity. They are good candidates for dialysis and renal transplantation, with survival and recurrence rates no different from those of other patients with end-stage renal disease.

Fever in systemic lupus erythematosus.

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.

Avascular necrosis in systemic lupus erythematosus. Silent symmetric osteonecroses.

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.

Prognostic factors in lupus nephritis. Contribution of renal histologic data.

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.

A solid phase enzyme immunoassay (ELISA) for the detection and quantitation of anticardiolipin antibody.

A solid-phase enzyme-linked immunoabsorbent assay (ELISA) is described for the detection and quantitation of anticardiolipin antibodies (ACAs) IgG and IgM in sera. In these assays, non-specific binding was controlled by using antigen-negative wells for all serum dilutions tested. Quadruplicate 100-microliters serum samples diluted 1:20 for ACA-IgG and 1:40 for ACA-IgM were incubated for two hours, after which alkaline phosphatase-conjugated antihuman IgG or IgM was added. A standard serum was used on each plate to provide reproducibility of the assay. Upper limits of normal for ACA-IgG and IgM were established by testing 161 sera from normal persons. Sixty-one selected patients with SLE were tested; and, from these results, categories of positivity were defined from negative to 4+. All screen-positive sera (greater than or equal to 1+) were assayed in a quantitative ELISA assay for ACAs, using multiple dilutions of the unknowns. These data were fit on a standard curve generated with dilutions of a reference serum on each plate using a computerized data reduction system based on the 2 Plus 2 model. The standard curves were compared with the international standards for IgG and IgM anticardiolipin. The ability to quantitate ACA concentrations allows better definition of positive sera, as well as the opportunity to accurately evaluate and follow this antibody in a variety of patient groups.

Is aggressive therapy effective for lupus?

Intravenous cyclophosphamide is an effective form of aggressive therapy for the management of a wide range of serious manifestations of systemic lupus erythematosus. Although it has been best studied in patients with progressive lupus nephritis, recent evidence indicates an important role for this therapy for other clinical lupus indications, particularly acute neurologic diseases. The available comparative data suggest that intravenous cyclophosphamide is far more effective than intensive corticosteroid therapies, including conventional high-dose oral therapy as well as bolus intravenous therapy. Differences in efficacy compared with oral regimens of cyclophosphamide or azathioprine are less clear, although clinical experience would seem to suggest that intravenous cyclophosphamide has a more rapid onset of action clinically than low-dose oral therapies. Finally, the toxicity profile of intravenous cyclophosphamide compares favorably with other aggressive approaches to drug management and does not pose an unacceptable risk. The future impact of several current investigational therapies remains to be defined.

Apheresis.

The removal of pathologic humors by various methods is an ancient medical remedy used in the management of diseases whose pathophysiology is poorly understood and whose effective treatment modalities are lacking. The contemporary means for such an approach involves apheresis, which is now possible due to advances in blood banking technologies. Apheresis has been used in most of the major rheumatic diseases, in particular systemic lupus erythematosus and rheumatoid arthritis. Although numerous case reports describe clinical benefits of apheresis in rheumatologic disorders, data from clinical trials are discouraging and suggest a limited role for apheresis in rheumatic disease management.

Update on cyclophosphamide for systemic lupus erythematosus.

Over the past decade cyclophosphamide has come to assume an increasingly prominent role in the management of severe, life-threatening manifestations of SLE. Intermittent, intravenous pulse cyclophosphamide has become the standard of treatment of diffuse proliferative lupus nephritis (WHO Class IV), and there is now substantial clinical literature to suggest an indication for intermittent cyclophosphamide therapy in most other forms of serious lupus affecting major organ systems, in particular lupus vasculitis and acute central nervous system manifestations. This update reviews the use of cyclophosphamide in the management of lupus nephritis, expands on its role in other manifestations of SLE, and discusses potential complications of the drug.

Studies of immunosuppressive drugs in the treatment of lupus nephritis.

Long-term, controlled trials to evaluate the efficacy and toxicities of immunosuppressive drug therapies compared to treatment with corticosteroids alone in the management of patients with lupus nephritis have been performed. The studies demonstrate that immunosuppressive drug regimens, particularly intravenous cyclophosphamide, reduce the likelihood of end-stage renal failure. However, toxicities such as herpes zoster and ovarian failure were found to be increased in patients with cyclophosphamide.

Successful treatment of generalized discoid skin lesions with azathioprine. Its use in a patient with systemic lupus erythematosus.

A 20-year-old patient had systemic lupus erythematosus and extensive generalized discoid disease that failed to respond to conventional treatment with topical steroids and high doses of hydroxychloroquine sulfate (Plaquenil). The skin lesions responded dramatically to 100 mg of azathioprine sodium daily, flared when the drug treatment was discontinued, and again responded on reinstatement of the same dosage of azathioprine. The case report suggests that extensive discoid skin lesions can be successfully treated with oral azathioprine.

Histocompatibility antigen combinations in rheumatoid arthritis.

The frequencies of HLA-A, -B, -C, DR and MT lymphocyte alloantigens in clinical and serologic subsets of rheumatoid arthritis (RA) were determined in 65 Caucasian patients with definite or classical disease and compared to frequencies observed in normal individuals. The elevation in frequency of several antigens controlled by different genes in the major histocompatibility complex (MHC) suggested that combinations of antigens may be associated with RA. Significant associations were found for HLA-A1-DR4 and A1-MT2 (p less than 0.001), Bw40-DR4 (p less than 0.002) and Cw3-DR4 (p less than 0.001). The results indicate that combinations of genes in the MHC are influential in predisposing to RA.

Angiotensin I converting enzyme gene polymorphisms in systemic lupus erythematosus: decreased prevalence of DD genotype in African American patients.

The presence of the D (deletion) allele at the angiotensin converting enzyme (ACE) gene has been associated with a) adverse vascular events contributing to early mortality and b) progressive deterioration of renal function in a variety of chronic glomerular diseases. We investigated the potential role of ACE polymorphisms in patients with systemic lupus erythematosus (SLE). Two hundred and sixteen (216) SLE patients (121 Caucasians; 78 African Americans; and 17 other) and 200 normal controls were studied; 134 patients had evidence of renal disease. ACE genotypes were determined by a polymerase chain reaction based assay. The frequency of genotype DD was increased in African American normal controls compared to Caucasians (55% vs. 37%, p = 0.017) and in African American normal controls vs. African American lupus patients (55% vs. 30%, p = 0.008). Trend analysis of the genotype distribution across the three African American groups (renal, non-renal, controls) revealed a trend of increased frequency of I and decreased frequency of D as likelihood of renal disease increases (p = 0.008). No association between any ACE genotype with parameters of renal disease and/or response to therapy was identified. African American patients with lupus have a lower frequency of DD genotype as compared to African American normal controls. Further studies will be necessary to address whether this is due to decreased survival of these patients, a protective effect of DD genotype from developing the disease or a chance sample effect.

Oral effects of steroid therapy in a patient with systemic lupus erythematosus: report of case.

Steroids are used extensively in modern medicine and dentistry for their anti-inflammatory and immunosuppressive properties. However, this class of drugs can lead to adverse effects on other organs. In this case, developmental and functional disturbances of the primary and permanent dentition are seen. The patient's dental development and pharmacological history suggest prednisone as the offending agent.

Is malignancy a major concern in rheumatoid arthritis patients?

There are several major issues related to malignancy that are of importance to the practicing clinician caring for patients with rheumatoid arthritis. Although it has been clearly established that rheumatoid arthritis is associated with an increased risk of hematologic malignancies including non-Hodgkin's lymphoma and multiple myeloma, the absolute risk of developing a hematologic malignancy is less than 1%. In rheumatoid arthritis patients with secondary Sjogren's syndrome, Felty's syndrome, or paraproteinemia, the risks for developing hematologic malignancy are likely to be even higher. These risks are balanced by reduced rates of gastrointestinal cancers. There are no conclusive data that link the FDA-approved second line therapeutic agents with the subsequent development of malignancy. However, the renal transplant experience suggests that immunosuppression alone increases the risk of subsequent malignancy. This should be a guiding principle when obtaining informed consent as well as in planning future therapeutic approaches to rheumatoid arthritis. Alkylating agents markedly increase the risk of leukemia and skin, bladder, and hematologic malignancies when used to treat rheumatoid arthritis.

Systemic lupus erythematosus: demographics, prognosis, and outcome.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder with an annual incidence of 50 to 70/million and a prevalence of 500/million population. The highest incidence is observed in women aged 20 to 40 years. The clinical manifestations of SLE are remarkably heterogeneous. Major organ system involvement may occur in the heart, lungs, kidneys, and central nervous system and is responsible for most of the mortality and morbidity caused by the disease. Complications of drug treatment, in particular corticosteroid side effects, contribute to longterm morbidity. The major causes of death are directly related to the disease and include acute vascular neurologic events, renal failure, cardiovascular or pulmonary involvement, infection, and coronary artery disease.