Neuropsychiatric lupus.

Neuropsychiatric abnormalities in patients with systemic lupus have been recognized for more than a century. Although the prognosis of lupus has improved, involvement of the nervous system continues to be a major feature, with some abnormality recognized in 50 to 66 per cent of lupus patients. Diagnosis and therapy of neurologic disease remain the most difficult clinical challenges in the management of SLE.

Lupus nephritis. Classification, prognosis, immunopathogenesis, and treatment.

There is great variation in the characteristics of renal histology, in its clinical expression and clinical course, and, most likely, in the pathogenic mechanisms of glomerular damage. As the ability to more precisely characterize these lesions improves and as we better understand the multiple pathogenic mechanisms and modulating factors at play in the disease, treatment advances and improved renal survival should follow.

Rheumatic disease and AIDS. An interesting but mysterious relationship.

Symptoms of rheumatic disease may be an indicator of HIV infection. In this article, Dr Golbus describes the spectrum of rheumatic syndromes in HIV-infected patients and how they differ from their idiopathic counterparts. His article brings a new perspective to the increasingly complex clinical picture of HIV infection and shows that very common complaints may be manifestations of HIV.

Treatment of rheumatoid arthritis. New thoughts on the classic pyramid approach.

Treatment of rheumatoid arthritis can be quite challenging. Toxicity profiles of the various anti-inflammatory agents are often unacceptable, mainly because of gastrointestinal intolerance or bleeding. In addition, epidemiologic data suggest that rheumatoid arthritis is a disease with substantial morbidity and increased mortality. Consequently, newer trends in therapy involve earlier use of remittive agents as well as use of low-dose steroids. These modifications of the classic pyramid approach and the investigation of other methods may significantly influence the future of rheumatoid arthritis therapy and improve quality of life in those with the disease.

Giant cell arteritis and peripheral neuropathy: a report of 2 cases and review of the literature.

Giant cell arteritis (GCA) is a systemic vasculitis primarily affecting large and medium sized vessels. While the disease may present with blindness or other signs of extracranial vasculitis, symptoms referable to the peripheral nervous system are uncommon. We describe 2 patients with biopsy proven GCA who simultaneously developed peripheral neurologic lesions. The first developed a mononeuritis multiplex superimposed on a diffuse, primarily sensory and distal polyneuropathy; the second, a symmetric, primarily motor and distal polyneuropathy. We review the published experience of GCA with peripheral nerve involvement and discuss a possible pathophysiologic basis for its occurrence.

Quantitative changes in T cell DNA methylation occur during differentiation and ageing.

DNA methylation is one of the mechanisms involved in the regulation of developmentally relevant genes. Previous experiments demonstrated that T cells treated with DNA methylation inhibitors reacquire some of the phenotypic and functional characteristics of thymocytes, suggesting that DNA methylation may be involved in regulating some of the changes in gene expression during thymic maturation. To further examine whether changes in DNA methylation occur during T cell differentiation, total DNA deoxymethylcytosine content was compared in human thymocyte subsets and mature T cells. A significant increase in deoxymethylcytosine was found at the end of T cell differentiation which then decreased with age. These results suggest that increased DNA methylation may serve to silence genes following T cell differentiation. The results also raise the possibility that age-related decreases in T cell DNA methylation may contribute to changes in T cell function occurring in the elderly.

Diminished response to an inhibitory signal in lymphocytes from patients with systemic lupus erythematosus.

Systemic lupus erythematosus is an autoimmune disease characterized by B-cell hyperactivity, resulting in polyclonal hypergammaglobulinaemia. One mechanism potentially resulting in excessive immunoglobulin synthesis is a diminished response to inhibitory signals. To test this hypothesis, anti-IgG antisera was used to inhibit pokeweed mitogen activation of cultured lymphocytes from lupus patients and controls. Inhibition of IgG secretion by B cells from lupus patients required more than 75 times as much anti-IgG as normal controls (P less than 0.005), indicating that lupus lymphocytes are hyporesponsive to this inhibitory signal. Similar studies with DR3+ controls demonstrated that diminished responsiveness to anti-IgG inhibition may in part be associated with the HLA-DR3 allele. Defects in this inhibitory mechanism may play a role in the B-cell hyperactivity observed in lupus.

Scleromyxedema with systemic involvement mimics rheumatic diseases.

Scleromyxedema is an infiltrative skin disease produced by hyaluronic acid deposition in the dermis. A benign monoclonal gammopathy is usually present. We report 2 patients with scleromyxedema and systemic illnesses. Both patients had muscle weakness, dysphagia, and weight loss in addition to the skin changes. One also had sclerodactyly, telangiectasias, and Raynaud's phenomenon. Scleromyxedema with systemic involvement may mimic rheumatic diseases.

An eosinophilia-myalgia syndrome associated with an L-tryptophan containing product.

A syndrome of eosinophilia and myalgias associated with the usage of L-tryptophan containing products has been recently described by the Centers for Disease Control. We report a case of this new clinical entity, highlighted by severe myositis, and compare this illness with similar reported syndromes.

Immunologic effects of plasmapheresis synchronized with pulse cyclophosphamide in systemic lupus erythematosus.

Extensive immunologic evaluation was made of a patient with severe systemic lupus erythematosus (SLE) undergoing 6 cycles of plasmapheresis combined with pulsed cyclophosphamide therapy. Clinical remission ensued accompanied by normalization of levels of circulating autoantibodies, immune complexes, complement proteins, interleukin 2 (IL-2) and IL-2 receptor. High spontaneous peripheral blood lymphocyte proliferation fluctuated widely with plasmapheresis, but was consistently reduced after cyclophosphamide. Circulating B cells fell by 85% and remained low at one year, despite recovery of the serum IgG level. Circulating T cells declined by 48%, chiefly in the immunologically naive CD4+CD45R+ T cell subset. This was associated with the emergence of a CD8+DR+CDw29+ T cell subset signifying immunologically mature, activated cytotoxic/suppressive T cells, which might have served to control the autoreactive B and T cell populations. Pulsed cyclophosphamide synchronized with plasmapheresis profoundly affected the immune system of our patient. The association of these immunological changes with clinical recovery warrants further investigation of this new therapeutic approach in SLE.

Increased immunoglobulin response to gamma-interferon by lymphocytes from patients with systemic lupus erythematosus.

The factors responsible for abnormal B-cell activation in systemic lupus erythematosus (SLE) are incompletely understood. This study tested the hypothesis that the abnormal B-cell activation observed in human SLE may be due to an augmented response to a helper signal. We demonstrated that non-T cells from 10 of 19 SLE patients increased IgG production in response to interferon-gamma (IFN-gamma) by a mean factor of 20.9 +/- 3.9 over resting levels, while controls stimulated a mean factor of 3.0 +/- 0.5 (P less than 0.005). We found no relationship of IFN-gamma responsiveness to disease activity. Serotyping for HLA A, B, C, and D loci suggested that the hyperresponsiveness may be genetically linked to HLA-Cw7. We conclude that IFN-gamma may contribute to the development and perpetuation of SLE in a subset of patients with SLE.

N-acetylprocainamide is a less potent inducer of T cell autoreactivity than procainamide.

We have reported that an inhibitor of DNA methylation, 5-azacytidine, makes cloned, antigen-specific CD4+ T cells autoreactive, and that procainamide and hydralazine mimic this effect. Those results suggested that procainamide and hydralazine may induce autoimmunity by inhibiting DNA methylation and causing T cell autoreactivity. We report now that N-acetylprocainamide, a procainamide derivative that does not induce lupus, is also a DNA methylation inhibitor, but it is 100 times less potent than procainamide in inducing T cell autoreactivity.

Clinical and immunologic effects of monthly administration of intravenous cyclophosphamide in severe systemic lupus erythematosus.

Severe systemic lupus erythematosus affecting the kidney or central nervous system may lead to organ failure or death despite treatment with high doses of corticosteroids. To evaluate the clinical and immunologic effects of intravenous cyclophosphamide in this setting, we treated nine patients with monthly intravenous infusions of cyclophosphamide for six months. A comparison of characteristics at entry and follow-up revealed improvements (by paired t-test) in creatinine clearance (66 vs. 96 ml per minute, P less than 0.001); 24-hour urinary protein level (4.11 vs. 0.90 g, P less than 0.05), Farr anti-DNA titer (43 vs. 8.5 percent, P less than 0.01); complement components C3 (894 vs. 1150 mg per liter, P less than 0.05), C4 (154 vs. 222 mg per liter, P less than 0.05), and total complement activity (CH50) (88.7 vs. 113.4 IU, P less than 0.05); and Westergren erythrocyte sedimentation rate (60.2 vs. 34.4 mm per hour, P less than 0.0005). Other manifestations of lupus improved markedly in most cases, despite a reduction in the mean daily dose of prednisone, from 45 mg at entry to 17 mg at follow-up (P less than 0.01). The numbers of lymphocytes positive for T3, T4, T8, and B1 declined progressively during treatment. At follow-up, persistent decreases were observed in the T-lymphocyte subsets, whereas the absolute number of B lymphocytes had returned to levels near base line. T-cell proliferative responses at follow-up were not significantly different from entry values, except that the response to mitogenic anti-T11 (CD2) antibodies was decreased (P less than 0.01). Our data indicate that monthly intravenous administration of cyclophosphamide was associated with a substantial amelioration of severe systemic lupus, in conjunction with discrete changes in T-lymphocyte markers and T-cell function. This was a preliminary, uncontrolled study, but the results warrant further investigation of this form of treatment.

B cell activation in patients with active procainamide induced lupus.

Cellular immune abnormalities have been described in asymptomatic patients receiving procainamide therapy, but not in patients with active procainamide induced lupus. We tested patients with active procainamide lupus for evidence of T or B cell activation similar to that observed in idiopathic lupus. Symptomatic patients had a significant increase in spontaneous IgG synthesis, but T cells bearing activation markers were not significantly different from age matched controls. Our results demonstrate that patients with active procainamide lupus have evidence for B cell activation, similar to idiopathic lupus.

Hydralazine and procainamide inhibit T cell DNA methylation and induce autoreactivity.

Inhibitors of DNA methylation, such as 5-azacytidine, induce gene expression. We have previously reported that cloned T cells treated with 5-azacytidine lose the requirement for Ag and can be activated by autologous HLA-D molecules alone, thus becoming auto-reactive. This phenomenon could potentially mediate an autoimmune disease in vivo. Inasmuch as several drugs are known to cause autoimmune disease, we asked whether they exert the same effects on T cells as 5-azacytidine. We report that hydralazine and procainamide, two drugs associated with a lupus-like autoimmune disease, also inhibit DNA methylation and induce self-reactivity in cloned T cell lines. These results suggest that drug-induced autoimmune disease may be due to activation of as yet unidentified genes through mechanisms involving DNA methylation.

Soluble factors produced by isolated first-trimester chorionic villi directly inhibit proliferation of T cells.

Supernatants from human trophoblast cultures have been reported to be both suppressive and stimulatory of mitogen-induced T-lymphocyte transformation. These discordant observations have been attributed to methodologic differences among laboratories, but may instead relate to inadvertant cellular contamination during long-term culture. Retrieval of chorionic villi for genetic analysis has provided an opportunity to evaluate the immunoregulatory activity of the isolated villus preparation, unencumbered by extended culture techniques. Primary cytotrophoblast cultures were established from karyotypically and clinically normal pregnancies and the supernatants were recovered. Allogenic mononuclear cells, stimulated by phytohemagglutinin, were uniformly inhibited by trophoblast supernatant (mean inhibition, 34.3%). This inhibition was verified in one-way, mixed lymphocyte cultures and suppression of T cells occurred in a dose-dependent fashion over a range of trophoblast supernatant concentrations. No evidence of suppressor T-cell induction by trophoblast supernatant was noted with the use of both phenotypic studies of lymphocytes incubated with trophoblast supernatant and a functional suppressor T-cell inducer assay. We believe that the immunoregulatory properties of trophoblast supernatants identified with the use of these methods more closely approximate the paracrine function of the in situ villus.

Eosinophilia-myalgia syndrome: myopathic electrodiagnostic characteristics.

Eosinophilia-myalgia syndrome (EMS) is a disorder characterized by generalized muscle pain and eosinophilia. The etiology of this syndrome appears to be related to the ingestion of L-tryptophan. Most studies to date describe an associated peripheral neuropathy or combined myopathy and peripheral neuropathy. This report presents 2 EMS patients with myopathy, confirmed by muscle biopsy in 1 case and electrophysiology in both cases. No clinical evidence of neuropathy was found. Both routine and single fiber electromyography failed to demonstrate abnormalities, suggesting neuropathy. Electrodiagnostic abnormalities paralleled the clinical course. After 10 months, both patients continued to have symptoms of muscle cramping and reduced endurance, with mild electromyographic abnormalities, perhaps reflecting changes in their motor unit.

Urine free light chains in SLE: clonal markers of B-cell activity and potential link to in vivo secreted Ig.

As a marker of in vivo B-cell activity, urine levels of free light chain (FLC) were measured twice weekly by radioimmunoassay (RIA) and correlated with disease activity over periods of 5-10 months in seven patients with systemic lupus erythematosus (SLE). In addition, RIA-measured urine albumin was used to track glomerular injury, and alpha1-microglobulin (alpha1-M) levels, 28- to 32-kDa protein, provided control measurements on excretion of low-molecular-weight proteins. As controls, urine FLC levels were obtained from healthy normals and in subjects with acute pharyngitis, sickle-cell anemia, and acute sepsis or pneumonia. The control results showed that with acute sepsis/pneumonia had marked increases in urine FLC, while pharyngitis and sickle-cell controls had normal FLC levels. In SLE, active patients receiving intravenous cyclophosphamide and high-dose steroids exhibited highly increased urine FLC that fluctuated widely during therapy and fell to normal range levels with disease remission. During active SLE, urine albumin often was increased, while alpha1-M levels remained in normal range. In contrast to the increased FLC of active disease, inactive patients on low-dose maintenance therapy had predominantly normal FLC levels throughout the collection period. These results support our hypothesis that longitudinal levels of urine FLC can be used to track disease-related B-cell activity in SLE. Furthermore, we suggest that the urine FLC of active SLE would share LC idiotype with the clonal associated in vivo secreted Ig, and thus permit the identification of these antibodies that are targeted to the culprit immunogen(s) responsible for the pathogenesis of SLE.