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Background : Uncertainty exists about the efficacy and toxicity of bolus therapy with methylprednisolone or of the combination of methylprednisolone and cyclophosphamide in the treatment of lupus nephritis. Objective : To determine 1) whether intensive bolus therapy with methylprednisolone is an adequate substitute for bolus therapy with cyclophosphamide and 2) whether the combination of methylprednisolone and cyclophosphamide is superior to bolus therapy with methylprednisolone or cyclophosphamide alone. Design : Randomized, controlled trial with at least 5 years of follow-up. Setting : Government referral-based research hospital. Patients : 82 patients with lupus nephritis who had 10 or more erythrocytes per high-power field, cellular casts, proteinuria (>1 g of protein per day), and a renal biopsy specimen that showed proliferative nephritis. Interventions : Bolus therapy with methylprednisolone (1 g/m 2 body surface area), given monthly for at least 1 year ; bolus therapy with cyclophosphamide (0.5 to 1.0 g/m 2 body surface area), given monthly for 6 months and then quarterly ; or bolus therapy with both methylprednisolone and cyclophosphamide. Measurements : 1) Renal remission (defined as

Although the cause of systemic lupus erythematosus remains unknown, pathogenic mechanisms are becoming clearer. Both genetic and environmental factors have been implicated in the induction and in the perpetuation of lupus. Implicated environmental triggers include ultraviolet light, chemicals (hydrazines, hair dyes, drugs), some foods, and possibly infectious agents. Lupus is mediated by the immune system. Patients have excess numbers of antibody-forming cells, including those that produce antibodies reactive with self-antigens. Patients also have an increased number of activated T cells, some of which help B cells to produce autoantibodies. A loss of tolerance is a critical immune abnormality in lupus; many of the activated helper T cells may result from a failure in normal tolerance mechanisms. A hematopoietic stem-cell defect could give rise to both B- and T-cell abnormalities. Such a stem-cell abnormality might lead to both a loss of self-tolerance and polyclonal B-cell activation. Antigen-driven, T-cell-dependent expansion of B-cell clones would then give rise to pathogenic autoantibodies, including anti-DNA. We believe that lupus is a syndrome: Patients differ regarding specific inciting factors and immune defects. Some patients have genetically conditioned abnormalities, similar to those found in mice with lupus; others have a combination of genetic and acquired defects. We hope that insights into pathogenesis lead to improved and more individualized therapy.

With extended follow-up, pulse cyclophosphamide continued to show superior efficacy over pulse methylprednisolone alone for treatment of lupus nephritis. The combination of pulse cyclophosphamide a...

Although the cause of systemic lupus erythematosus remains unknown, pathogenic mechanisms are becoming clearer. Both genetic and environmental factors have been implicated in the induction and in the perpetuation of lupus. Implicated environmental triggers include ultraviolet light, chemicals (hydrazines, hair dyes, drugs), some foods, and possibly infectious agents. Lupus is mediated by the immune system. Patients have excess numbers of antibody-forming cells, including those that produce antibodies reactive with self-antigens. Patients also have an increased number of activated T cells, some of which help B cells to produce autoantibodies. A loss of tolerance is a critical immune abnormality in lupus; many of the activated helper T cells may result from a failure in normal tolerance mechanisms. A hematopoietic stem-cell defect could give rise to both B- and T-cell abnormalities. Such a stem-cell abnormality might lead to both a loss of self-tolerance and polyclonal B-cell activation. Antigen-driven, T-cell-dependent expansion of B-cell clones would then give rise to pathogenic autoantibodies, including anti-DNA. We believe that lupus is a syndrome: Patients differ regarding specific inciting factors and immune defects. Some patients have genetically conditioned abnormalities, similar to those found in mice with lupus; others have a combination of genetic and acquired defects. We hope that insights into pathogenesis lead to improved and more individualized therapy.

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.

Angioimmunoblastic lymphadenopathy with dysproteinemia is a disorder characterized by a sudden onset of constitutional symptoms and lymphadenopathy. Patients often have hypergammaglobulinemia, autoantibodies, rashes, thrombocytopenia, or hemolytic anemia. Diagnosis requires a lymph node biopsy that shows architectural effacement, absence of germinal centers, arborization of postcapillary venules, and a polymorphous infiltrate that includes immunoblasts. Early in the disease, activated T cells in blood and lymph nodes stimulate B cells to proliferate and produce antibody. However, late in the disease, immune suppression may result from increased suppressor function. Clonal rearrangements, which are seen in all patients with regard to either the T-cell receptor beta-chain gene or immunoglobulin genes, have been followed by malignant transformation and frank lymphoma in some patients. Thus, this disorder stands partway between benign lymphoid proliferation and clonal lymphoid transformation. The prognosis of this disorder is poor; 75% of patients die within 2 years or develop a lymphoid malignancy. The rest usually go into a sustained remission. Current treatment with corticosteroid and immunosuppressive agents is unsatisfactory, especially because of late immunosuppression and predisposition to infections.

Nephritis has long been considered one of the most ominous components of systemic lupus erythematosus. Accumulations of immune complexes and lymphoid cells in several locations within the kidney are the best-described elements of lupus nephritis. The extreme diversity of the renal changes indicates that many variables are likely to be involved. Inbred strains of lupus-prone mice have provided homogeneous subjects for study of pathogenesis and response to treatment. Comparable grouping of lupus nephritis in humans according to unique or dominant pathogenetic mechanisms is imprecise and limited by insufficient knowledge of the primary stimulus for the disease. Treatment is also imperfect and, at times, hazardous. Certain regimens incorporating cytotoxic drugs provide a significant therapeutic advantage over corticosteroids alone in the management of this disease.

Rheumatoid arthritis is a chronic inflammatory synovitis that primarily involves peripheral diarthrodial joints. Immunohistologic analysis of diseased synovium has shown a spectrum of abnormalities that resemble various stages of a cell-mediated, or delayed-type, immune reaction. The infiltrating mononuclear cells produce various factors that modulate adjacent tissues and appear to produce the characteristic destructive features of the disorder. Our understanding of the mechanisms of action of various therapeutic modes also indicates that the disease is primarily mediated by activated mononuclear cells. All effective therapies have been shown to affect either mononuclear cell function or the rates of production or elimination of these cells. The disorder likely represents the pathologic expression of a genetically controlled host immune response to an undefined causative stimulus. The stimulus could be an infectious agent(s), a product(s) derived from an infectious agent(s), a constituent(s) of synovial or connective tissue, or a combination of these.

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.

Systemic lupus erythematosus is a multisystem, antibody-mediated, autoimmune disorder that occurs spontaneously in humans and mice. Genetic factors appear to play an important predisposing role in the disorder: The presence of certain genes may produce a generalized immune abnormality, whereas others may lead to specific autoantibodies. Environmental triggers increase autoantibody production and augment the expression of illness. Bacterial and viral illnesses can provide stimulation by activating macrophages and T cells that, in turn, stimulate B cells. In the absence of normal control mechanisms, the stimulatory process is not suppressed, and excessive stem cell proliferation results in abnormal B-cell proliferation. A trigger for the disease is the signaling of the proliferating B cells to differentiate into antibody-forming cells. Most autoantibody-producing B cells can be eliminated from mice with lupus erythematosus by virtue of the presence of the gene, xid. In addition, administration of an analog of arachidonic acid is an effective treatment for murine lupus erythematosus.

The basis for using cytotoxic drugs in inflammatory diseases of uncertain cause is their immunosuppressive properties. These drugs interrupt nucleic acid and protein synthesis, thereby inh...

Eight patients with features of both Sjogren's syndrome and systemic lupus erythematosus are presented. Clinical and laboratory findings in these patients form a spectrum of disease. Outst...

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.

Rheumatoid arthritis is a chronic inflammatory synovitis that primarily involves peripheral diarthrodial joints. Immunohistologic analysis of diseased synovium has shown a spectrum of abnormalities that resemble various stages of a cell-mediated, or delayed-type, immune reaction. The infiltrating mononuclear cells produce various factors that modulate adjacent tissues and appear to produce the characteristic destructive features of the disorder. Our understanding of the mechanisms of action of various therapeutic modes also indicates that the disease is primarily mediated by activated mononuclear cells. All effective therapies have been shown to affect either mononuclear cell function or the rates of production or elimination of these cells. The disorder likely represents the pathologic expression of a genetically controlled host immune response to an undefined causative stimulus. The stimulus could be an infectious agent(s), a product(s) derived from an infectious agent(s), a constituent(s) of synovial or connective tissue, or a combination of these.

Systemic lupus erythematosus, a disease of unknown cause and protean manifestations, continues to excite substantial investigational interest. These papers bring together recent advances i...

Systemic lupus erythematosus is a multisystem, antibody-mediated, autoimmune disorder that occurs spontaneously in humans and mice. Genetic factors appear to play an important predisposing...

Excerpt To the editor: Angioimmunoblastic lymphadenopathy is a rare clinicopathologic entity that is characterized by lymphadenopathy, systemic autoimmune features, and a high potential for lymphoi...

Cyclophosphamide is a potent anti-inflammatory and immunosuppressive cytostatic and cytotoxic drug used for such diverse medical problems as neoplasia, tissue transplantation, and inflamma...

Angioimmunoblastic lymphadenopathy with dysproteinemia is a disorder characterized by a sudden onset of constitutional symptoms and lymphadenopathy. Patients often have hypergammaglobuline...

Anemia occurs in more than one half of patients with systemic lupus erythematosus and is usually attributed to "chronic disease." Approximately 10% of patients with a positive Coombs' test manifest clinically significant hemolysis. Leukopenia affects both granulocytic and lymphocytic lines and may be caused by autoantibodies. Nevertheless, enhancement of B lymphocyte function occurs in active disease, perhaps due to a loss of regulatory T cells. Most patients have increased production and increased peripheral destruction of thrombocytes, with a normal circulation platelet count. Thrombocytopenia is usually caused by increased destruction. Qualitative abnormalities of platelet aggregation also occur. Circulation anticoagulants are not rare; however, spontaneous bleeding is uncommon. The anticoagulants, immunoglobulins directed against clotting factors, assume importance for invasive procedures. Most clinically significant hematopoietic abnormalities can be suppressed by corticosteroids; however, splenectomy, or immunosuppressive agents, or both, may be indicated for patients who respond inadequately to corticosteroids.

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.

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.

Nephritis has long been considered one of the most ominous components of systemic lupus erythematosus. Accumulations of immune complexes and lymphoid cells in several locations within the kidney are the best-described elements of lupus nephritis. The extreme diversity of the renal changes indicates that many variables are likely to be involved. Inbred strains of lupus-prone mice have provided homogeneous subjects for study of pathogenesis and response to treatment. Comparable grouping of lupus nephritis in humans according to unique or dominant pathogenetic mechanisms is imprecise and limited by insufficient knowledge of the primary stimulus for the disease. Treatment is also imperfect and, at times, hazardous. Certain regimens incorporating cytotoxic drugs provide a significant therapeutic advantage over corticosteroids alone in the management of this disease.

Excerpt To the editor: Burman (1) has managed to add another paper to his bibliography and reduce the percentage of multiauthored papers. However, he seems naive about the difficulty of deciding wh...

Excerpt To the editor: I have followed with interest the increasing journal articles, book chapters, and books on the use of cyclophosphamide in the treatment of patients with nonmalignant diseases...

Thirteen women with lupus nephritis were hospitalized for a 10-week double-blind therapeutic trial comparing oral cyclophosphamide with placebo. Concurrent corticosteroid therapy, up to 30...

Excerpt The contribution of Baldwin and co-workers, published elsewhere in this issue of the ANNALS, emphasizes again the importance of the renal histological findings in guiding the therapy of the...

This paper presents the first systematic study relating myxedema to coronary artery disease. It reviews the autopsy records of 38 white women with myxedema and a pathological diagnosis of ...