Long-term effects of combination treatment with fludarabine and low-dose pulse cyclophosphamide in patients with lupus nephritis.

OBJECTIVES: To determine the safety and efficacy of a short course of fludarabine combined with cyclophoshamide in lupus nephritis. METHODS: A phase I/II open label pilot study. Thirteen patients with active proliferative lupus nephritis received monthly oral boluses of low-dose cyclophoshamide (0.5 gm/m(2) on day 1) and subcutaneous fludarabine (30 mg/m(2) on days 1-3) for 3-6 cycles. Concomitant prednisone was aggressively tapered from 0.5 mg/kg/day to a low-dose, alternate-day schedule. Patients were followed for at least 24 months after therapy. The primary outcome was the number of patients achieving renal remission defined as stable creatinine, proteinuria <1 gm/day and inactive urine sediment for at least 6 months. RESULTS: The study was terminated early because of bone marrow toxicity. Eleven patients who received at least three cycles were evaluated for efficacy. Ten patients improved markedly with seven patients achieving complete remission and three patients achieving partial remission. There were three serious haematological adverse events during the treatment with one death due to transfusion-associated graft vs host disease. Profound and prolonged CD4 (mean CD4: 98/microl at 7 months and 251/microl at 12 months) and CD20 lymphocytopenia was noted in most patients. Three patients developed Herpes zoster infections. CONCLUSIONS: A short course of low-dose fludarabine and cyclophoshamide can induce long-lasting remissions in patients with proliferative lupus nephritis, but severe myelosuppression limits its widespread use.

Membranous lupus nephritis.

Membranous lupus nephritis (MLN) represents about 20% of clinically significant renal disease in lupus. Few studies have addressed directly the pathogenesis of MLN. Our assumptions about the underlying mechanisms are based on the combination of extrapolations from idiopathic membranous nephritis (mainly from animal models) and proliferative lupus nephritis. Natural history studies of MLN suggest a relatively low rate of progression to end-stage renal disease but a high rate of significant comorbidities. Historical changes in the criteria for pathologic diagnosis and classification of membranous lupus nephropathy have precluded definitive descriptions of the natural history, prognosis and treatment of this disorder. Patients with membranous lupus nephropathy should be treated early with angiotensin antagonists to minimize proteinuria, as well as lifestyle changes and appropriate drugs to reduce attendant cardiovascular risk factors. In patients with protracted nephrotic syndrome, consideration should be given to immunosuppressive therapies, including corticosteroids, cyclosporine, mycophenolate and cyclophosphamide. Prospective controlled trials are clearly needed in order to establish solid clinical practice guidelines for use of these drugs and other experimental therapies currently under study in membranous lupus nephropathy.

Renal flares are common in patients with severe proliferative lupus nephritis treated with pulse immunosuppressive therapy: long-term followup of a cohort of 145 patients participating in randomized controlled studies.

OBJECTIVE: Immunosuppressive agents have become the standard of therapy for proliferative lupus nephritis, but some patients may relapse after discontinuing treatment. We reviewed the cases of renal flares in a cohort of patients who participated in 2 randomized controlled clinical trials at the National Institutes of Health and explored the prevalence, outcome, and predictive factors of renal flares. METHODS: Data were obtained on 145 patients treated with pulse cyclophosphamide, pulse methylprednisolone, or the combination of both. Patients had not received immunosuppressive therapy for at least 6 months and had experienced complete or partial response according to defined criteria. Renal flares were classified as either proteinuric or nephritic based on changes in urinary protein and sediment. Most patients who experienced a flare received additional immunosuppressive therapy. RESULTS: Seventy-three patients had a complete response, and 19 had partial response/stabilization. Forty-one of these patients (45%) experienced renal flares (nephritic in 33, proteinuric in 8) after a mean followup of 117 months; 31 of them received additional immunosuppressive therapy. The median time to renal flare was 36 months in the complete responders and 18 months in the partial responders. Eleven of the 41 patients (27%) progressed to end-stage renal disease (ESRD); 9 had nephritic flares (all severe except for 1) and 2 had proteinuric flares (1 in each responder group). Compared with patients who had a complete response, those with a partial response were more likely to experience a flare, to have a severe nephritic flare, or to progress to ESRD. Low C4 at the time of response and African American ethnicity were significant independent risk factors for renal flare, by multivariate Cox proportional hazards analysis. CONCLUSION: Nephritic flares are common in patients with proliferative lupus nephritis, even in those with a complete response to therapy, but they do not necessarily result in loss of renal function if treated with additional immunosuppressive agents. Renal flares are an important feature of the natural history of lupus nephritis and provide an opportunity for additional preventive strategies, as well as measures of efficacy in future therapeutic trials.

Exogenous peptide and protein expression levels using retroviral vectors in human cells.

Pseudotyped retroviral vectors combine the advantages of broad host range, high expression, stable chromosomal integration, and ease of preparation. These vectors greatly facilitate delivery into mammalian cells of sequences encoding individual peptide inhibitors-including those with therapeutic utility-and inhibitor libraries. However, retroviral vectors vary in behavior, particularly with respect to expression levels in different cell lines. Expression level is especially important in transdominant experiments because the concentration of an inhibitor (for example, an expressed peptide) is one of the key determinants in the degree of complex formation between the inhibitor and its target. Thus, inhibitor concentration should have an impact on the expressivity and/or penetrance of an induced phenotype. Here, we compare several retroviral vectors and human cell lines for relative expression levels using a green fluorescent protein reporter. We show for a subset of these lines that cellular protein concentrations produced by single-copy vectors range up to about 2 microM. We also examine other variables that contribute to expression level, such as the nature of the expressed protein's carboxy terminus. Finally, we test the effect of increased concentration on phenotype with a nine-amino-acid peptide derived from the human papilloma virus protein E7 which overcomes E7-mediated cell growth.

Combination therapy with pulse cyclophosphamide plus pulse methylprednisolone improves long-term renal outcome without adding toxicity in patients with lupus nephritis.

BACKGROUND: Controlled trials in lupus nephritis have demonstrated that cyclophosphamide therapy is superior to corticosteroid therapy alone. The long-term effectiveness and side-effect profiles of pulse immunosuppressive regimens warrant further study. OBJECTIVE: To define the long-term risk and benefit of monthly treatment with boluses of methylprednisolone, cyclophosphamide, or both. DESIGN: Extended follow-up (median, 11 years) of a randomized, controlled trial. SETTING: U.S. government research hospital. PATIENTS: 82 patients with proliferative lupus nephritis. MEASUREMENTS: Rates of treatment failure (defined as need for supplemental immunosuppressive therapy or doubling of serum creatinine concentration, or death) and adverse events. RESULTS: In an intention-to-treat survival analysis, the likelihood of treatment failure was significantly lower in the cyclophosphamide (P = 0.04) and combination therapy (P = 0.002) groups than in the methylprednisolone group. Combination therapy and cyclophosphamide therapy alone did not differ statistically in terms of effectiveness or adverse events. Of patients who completed the protocol (n = 65), the proportion of patients who had doubling of serum creatinine concentration was significantly lower in the combination group than in the cyclophosphamide group (relative risk, 0.095 [95% CI, 0.01 to 0.842]). CONCLUSION: 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 and methylprednisolone appears to provide additional benefit over pulse cyclophosphamide alone and does not confer additional risk for adverse events.

Enzyme replacement therapy in Fabry disease: a randomized controlled trial.

CONTEXT: Fabry disease is a metabolic disorder without a specific treatment, caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (alpha-gal A). Most patients experience debilitating neuropathic pain and premature mortality because of renal failure, cardiovascular disease, or cerebrovascular disease. OBJECTIVE: To evaluate the safety and efficacy of intravenous alpha-gal A for Fabry disease. DESIGN AND SETTING: Double-blind placebo-controlled trial conducted from December 1998 to August 1999 at the Clinical Research Center of the National Institutes of Health. PATIENTS: Twenty-six hemizygous male patients, aged 18 years or older, with Fabry disease that was confirmed by alpha-gal A assay. INTERVENTION: A dosage of 0.2 mg/kg of alpha-gal A, administered intravenously every other week (12 doses total). MAIN OUTCOME MEASURE: Effect of therapy on neuropathic pain while without neuropathic pain medications measured by question 3 of the Brief Pain Inventory (BPI). RESULTS: Mean (SE) BPI neuropathic pain severity score declined from 6.2 (0.46) to 4.3 (0.73) in patients treated with alpha-gal A vs no significant change in the placebo group (P =.02). Pain-related quality of life declined from 3.2 (0.55) to 2.1 (0.56) for patients receiving alpha-gal A vs 4.8 (0.59) to 4.2 (0.74) for placebo (P =.05). In the kidney, glomeruli with mesangial widening decreased by a mean of 12.5% for patients receiving alpha-gal vs a 16.5% increase for placebo (P =.01). Mean inulin clearance decreased by 6.2 mL/min for patients receiving alpha-gal A vs 19.5 mL/min for placebo (P =.19). Mean creatinine clearance increased by 2.1 mL/min (0.4 mL/s) for patients receiving alpha-gal A vs a decrease of 16.1 mL/min (0.3 mL/s) for placebo (P =.02). In patients treated with alpha-gal A, there was an approximately 50% reduction in plasma glycosphingolipid levels, a significant improvement in cardiac conduction, and a significant increase in body weight. CONCLUSION: Intravenous infusions of alpha-gal A are safe and have widespread therapeutic efficacy in Fabry disease.

Treatment of lupus nephritis.

Patients with lupus nephritis pose a therapeutic challenge and stimulate investigation of innovative treatment strategies. Although patient survival and renal function outcomes have improved over the last 4 decades, contemporary immunosuppressive regimens are not consistently effective and often require extended courses associated with insidious toxicities. Several strategies are under investigation to induce remissions more rapidly and to reduce the risk of long courses of cytotoxic drug therapy. The combination of pulse methylprednisolone and pulse cyclophosphamide may be more effective than pulse cyclophosphamide alone for patients with relatively severe proliferative lupus nephritis. Ongoing clinical studies evaluate the risk/benefit of other intensive induction regimens (eg, combination fludarabine with relatively low-dose pulse cyclophosphamide). A particularly vigorous strategy employs immunoablative cyclophosphamide with or without stem cell rescue. Several studies of sequential immunosuppressive therapy are in progress. It is anticipated that long-term toxicities can be lessened by substituting various maintenance agents (eg, azathioprine or mycophenolate mofetil) after initial cyclophosphamide therapy has induced a renal response. Additional information is needed to determine the role of this strategy. Furthermore, a number of standard and experimental immunosuppressive regimens (that do not include cyclophosphamide) are under investigation as well. Innovative approaches (eg, costimulatory blockade) offer the hope of more effective treatments without the risks of contemporary regimens.

Progress in the treatment of proliferative lupus nephritis.

Lupus nephritis is often well developed at the time of diagnosis. High-dose corticosteroids are universally accepted as the initial approach to the control of severe inflammation in the kidney. Long-term disease control and the minimization of iatrogenic risk usually require adjunctive therapies that target the more fundamental immunoregulatory disturbances of lymphoid cells. Of the available cytotoxic drugs, cyclophosphamide is currently among the most effective, although it cannot be considered ideal in terms of efficacy or toxicity. New prospects for the treatment of proliferative lupus nephritis include novel immunosuppressive agents (e.g. mycophenolate, cyclosporine, fludarabine), combination chemotherapy (e.g. cyclophosphamide plus fludarabine), and sequential chemotherapy (e.g. cyclophosphamide-azathioprine), immunological reconstitution using intensive cytoreductive chemotherapy (with or without stem cell rescue), co-stimulatory molecule inhibition (e.g. humanized anti-CD154 monoclonal antibody, CTLA4-Ig). Gene therapy remains an attractive prospect, but its feasibility clearly depends on the further definition of lupus-promoting genes and the availability of methods to establish stable expression of disease-corrective genes in the appropriate lymphoid cells.

New prospects for treatment of lupus nephritis.

Systemic lupus erythematosus (SLE) is envisioned to arise from hyperactivate helper T-cells that cause polyclonal B-cell secretion of pathogenic autoantibodies and formation of immune complexes which deposit in sites such as the kidney. The most widely used immunosuppressive drugs, notably corticosteroids and cyclophosphamide, are often criticized as being nonspecific. In fact, these agents may be effective in SLE and lupus nephritis because broad, rather than highly selective, effects are required to control the aberrant immune system. Nonetheless, these agents are not uniformly effective and are associated with substantial toxicities. The lack of universal efficacy raises the specter that lupus is a heterogeneous disorder with different etiopathogenesis in different subsets of patients (as in lupus-prone mice). Therapeutic prospects for the upcoming millennium include new forms and combinations of chemotherapeutic agents (mycophenolate and adenosine analogues), attempts to achieve immunological reconstitution using near-ablative chemotherapy (with or without bone marrow or stem cell rescue), monoclonal antibodies, and other inhibitors of T-cell costimulatory pathways (e.g., anti-CD154 and/or CTLA4-Ig). The prospect for gene therapy has already been realized in some animal models of SLE. In human SLE, the feasibility of gene therapy will depend on further definition of lupus-promoting genes and availability of methods to establish stable expression of potentially corrective genes.

A pilot study of low-dose fludarabine in membranous nephropathy refractory to therapy.

BACKGROUND: Lymphocytes are believed to play a role in the induction and perpetuation of membranous nephropathy. Fludarabine is a purine nucleoside analog with selective activity against both dividing and resting lymphocytes. We evaluated the tolerance, toxicity, pharmacokinetics, immunologic, and clinical effects of fludarabine in patients with membranous nephropathy in an single arm pilot study. PATIENTS AND METHODS: Eight patients with idiopathic (n = 7) or lupus (n = 1) membranous nephropathy who had failed high-dose prednisone (n = 8) and/or alkylating agents (n = 2), or cyclosporine (n = 1) were treated with 6-monthly cycles of fludarabine (cycles 1-2, 20 mg/m2/day x 2 days, cycles 3-6, 20 mg/m2/day x 3 days). Mean proteinuria was 9 g/day with a mean duration of disease of 25 months (range 12-48). Proteinuria, GFR and effective renal plasma flow were compared before and after completing the treatment. RESULTS: Seven patients completed the protocol. CD3, CD4, CD8 and B cell counts decreased by 53%, 46%, 61% and 84%, respectively, at the end of treatment and remained at lower than pretreatment levels 6 months after completing the trial. Despite lymphopenia, serum immunoglobulin levels remained unchanged. Both naive (CD45RA+) and memory CD4+ T cells (CD45RO+) were reduced (naive > memory). Proteinuria decreased by > or = 50% in 5 out of 7 patients (p = 0.11). Filtration fraction improved in all patients with decreased filtration fraction at baseline. The only side-effect observed was one episode of acute bacterial sinusitis that responded promptly to antibiotic therapy. CONCLUSION: We conclude that low-dose fludarabine treatment in patients with membranous nephropathy is well tolerated and results in significant lymphopenia involving B more than T cells. In this pilot study improvement in proteinuria and filtration rate were observed. Additional studies are required to determine the optimal dose and clinical efficacy of fludarabine.

Natural history and treatment of lupus nephritis.

Renal involvement occurs in the majority of patients with systemic lupus erythematosus. Contemporary therapeutic regimens for immunosuppression and for the treatment of hypertension, hyperlipidemia, infections, and seizures have likely contributed to improvements in the prognosis of these patients over the last four decades. Corticosteroids usually ameliorate the manifestations of lupus nephritis but achieve less complete and sustained remissions than do cytotoxic drugs. Among the cytotoxic drugs, pulse cyclophosphamide has one of the best profiles of efficacy and toxicity. Because each episode of exacerbation of lupus nephritis results in cumulative scarring, atrophy and fibrosis, we recommend continued maintenance treatment for 1 year beyond the point of complete remission of proliferative lupus nephritis. Studies are in progress to determine whether innovative treatment strategies will enhance efficacy and minimize toxicity associated with cytotoxic drug therapies. Lupus membranous nephropathy poses a lower risk of renal failure, but persistent nephrotic syndrome confers risks of cardiovascular events; this form of lupus nephritis is usually treated with less intensive regimens of corticosteroids, cytotoxic drugs, or cyclosporine. The prognosis and overall success of treatment for lupus nephritis seem to vary widely among geographically and racially diverse populations. The causes for the apparently worse prognosis and poorer responses to treatment of lupus nephritis in Black patients are currently unexplained and require further study. Until such data are available, caution is clearly warranted in extrapolating evidence, particularly about prognosis and effects of treatment, among different populations of patients with lupus nephritis.

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.

Clinical evaluation and monitoring of lupus kidney disease.

Lupus renal involvement encompasses a broad range of clinical and histologic presentations and poses numerous therapeutic challenges. Accurate clinical assessment and monitoring requires a comprehensive approach, with attention to the urinalysis, the urinary protein excretion rate, the test of kidney function, and alterations in serologic parameters.

Ongoing immunologic activity after short courses of pulse cyclophosphamide in the NZB/W murine model of systemic lupus erythematosus.

OBJECTIVE: Short courses of intermittent pulse cyclophosphamide (CY) have mitigated ovarian toxicity but have also led to incomplete or unsustained remissions of active systemic lupus erythematosus (SLE) in many patients, prompting an evaluation of the immunologic effects of this regimen in the NZB/W female mouse (B/W) model of human SLE. METHODS: Phenotypic and functional characteristics of spleen lymphocytes from B/W mice treated with short courses of intraperitoneal (i.p.) CY were compared to those from untreated control B/W mice. RESULTS: After a single dose (250 mg/kg) of i.p. CY, spleen lymphocyte subpopulations fell abruptly but recovered within 4 weeks. Four monthly doses of i.p. CY (starting at 5 months of age) led to a sustained reduction in spleen lymphocyte subpopulations and a parallel decrease in the number of spleen cells spontaneously secreting immunoglobulin and anti-DNA antibody to about 30% of the number seen in untreated control B/W mice. Lipopolysaccharide induced secretion of total IgG and IgG anti-DNA by cultured spleen cells was not diminished one month after the 4 month course of i.p. CY. CONCLUSION: The 4 month course of i.p. CY produced a marked reduction in the number of activated B cells producing autoantibody, but did not achieve sustained immunomodulation judged by the unaltered proportion of spleen B cells spontaneously secreting immunoglobulin and anti-DNA, as well as the response to polyclonal activators of B cells. These results suggest a continued susceptibility to flares of SLE activity after brief courses of intensive immunosuppressive therapy.

Treatment of lupus nephritis.

Lupus nephritis is a prototype of immune complex-mediated glomerulonephritis. A broad range of clinical presentations and histological changes (proliferative, membranous, or both) are observed. Patients are at risk for progressive renal function deterioration as a result of the interaction of various active immunologic and chronic sclerosing mechanisms of kidney injury. Hypertension and hyperlipidemia contribute to morbidity and mortality. Monitoring serological parameters, urinary protein excretion rate and, especially, the urinary sediment facilitate the prompt recognition and treatment of this disorder. Kidney biopsy evaluation often clarifies the type, severity, and potential reversibility of the underlying renal lesions. Although contemporary immunosuppressive regimens for proliferative lupus nephritis have reduced the risk of end-stage renal failure, they are potentially toxic and not universally effective. Decisions regarding the intensity and duration of these treatments are difficult and are based on the severity of the disease, the initial response to therapy, and the risk for drug-induced toxicities. Studies are in progress to evaluate alternative regimens for proliferative lupus nephritis and membranous lupus nephropathy.

Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. A randomized, controlled trial.

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/m2 body surface area), given monthly for at least 1 year; bolus therapy with cyclophosphamide (0.5 to 1.0 g/m2 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 < 10 dysmorphic erythrocytes per high-power field, the absence of cellular casts, and excretion of < 1 g of protein per day without doubling of the serum creatinine level), 2) prevention of doubling of the serum creatinine level, and 3) prevention of renal failure requiring dialysis. RESULTS: Renal remission occurred in 17 of 20 patients in the combination therapy group (85%), 13 of 21 patients in the cyclophosphamide group (62%), and 7 of 24 patients in the methylprednisolone group (29%) (P < 0.001). Twenty-eight patients (43%) did not achieve renal remission. By life-table analysis, the likelihood of remission during the study period was greater in the combination therapy group than in the methylprednisolone group (P = 0.028). Combination therapy and cyclophosphamide therapy were not statistically different. Adverse events were amenorrhea (seen in 41% of the cyclophosphamide group, 43% of the combination therapy group, and 7.4% of the methylprednisolone group), cervical dysplasia (seen in 11% of the cyclophosphamide group. 7.1% of the combination therapy group, and 0% of the methylprednisolone group), avascular necrosis (seen in 11% of the cyclophosphamide group, 18% of the combination therapy group, and 22% of the methylprednisolone group), herpes zoster (seen in 15% of the cyclophosphamide group, 21% of the combination therapy group, and 3.7% of the methylprednisolone group) and at least one infection (seen in 26% of the cyclophosphamide group. 32% of the combination therapy group, and 7.4% of the methylprednisolone group). CONCLUSIONS: Monthly bolus therapy with methylprednisolone was less effective than monthly bolus therapy with cyclophosphamide. A trend toward greater efficacy with combination therapy was seen.

Outpatient monthly oral bolus cyclophosphamide therapy in systemic lupus erythematosus.

OBJECTIVE: An open label study to determine the feasibility and acute toxicity of a 6 month course of outpatient intermittent bolus high dose oral cyclophosphamide in patients with active systemic lupus erythematosus (SLE). METHODS: Oral cyclophosphamide in a single dose of 0.5 to 1.0 g/m2 was given monthly for 6 consecutive months. Disease activity was monitored by quantitative assessments of urine sediment, 24h urine protein excretion, and the Systemic Lupus Activity Measure (SLAM). RESULTS: Twelve patients (11 with glomerulonephritis and one with thrombocytopenia) were studied. Improvements in SLAM scores, proteinuria, and urinary cellular casts were observed in the majority of the 9 patients with nephritis who completed the study. Adverse effects included mild nausea in most patients and intercurrent infections in 2 patients (herpes zoster, cellulitis, urinary tract infection). Three patients failed to complete the 6 month course of therapy because of treatment failure in the patient with thrombocytopenia, pregnancy, and severe vomiting, respectively. CONCLUSION: High dose pulse oral cyclophosphamide is an acceptable alternative for the aggressive outpatient management of selected patients with lupus nephritis.

Long-term outcome of hepatitis B virus-related glomerulonephritis after therapy with interferon alfa.

BACKGROUND & AIMS: Glomerulonephritis is an uncommon complication of chronic hepatitis B virus (HBV) infection in adults. A high percentage of patients seem to have short-term response to interferon therapy with improvement of proteinuria. The aim of this study was to assess the long-term response of patients with HBV-related glomerulonephritis to interferon alfa therapy. METHODS: All patients with chronic hepatitis B and glomerulonephritis who were treated with interferon alfa at the National Institutes of Health between 1985 and 1993 were assessed. RESULTS: Of the 15 patients treated, 8 (53%) had a long-term serological response with sustained loss of serum hepatitis B e antigen and HBV DNA. After 1-7 years of follow-up, all 8 responders have normal serum aminotransferase levels and 5 are hepatitis B surface antigen negative. Seven of the responders also showed a gradual but marked improvement in proteinuria. In contrast, the 7 nonresponders continued to have evidence of active renal disease and 1 required long-term dialysis therapy. All 8 responders had membranous glomerulonephritis, whereas 4 of 7 nonresponders had membranoproliferative glomerulonephritis. CONCLUSIONS: Interferon alfa therapy resulted in long-term remission in liver disease in 8 of 15 patients with chronic hepatitis B and glomerulonephritis. This response was accompanied by significant improvement in markers of renal disease in the majority of patients.

Systemic lupus erythematosus: emerging concepts. Part 2: Dermatologic and joint disease, the antiphospholipid antibody syndrome, pregnancy and hormonal therapy, morbidity and mortality, and pathogenesis.

PURPOSE: To review 1) advances in the pathogenesis, diagnosis, and management of dermatologic and joint disease and the antiphospholipid antibody syndrome in patients with systemic lupus erythematosus; 2) controversies related to pregnancy and hormonal therapy and to morbidity and mortality in these patients; and 3) current views on the pathogenesis of systemic lupus erythematosus. DATA SOURCES AND STUDY SELECTION: Review of the English-language medical literature with emphasis on articles published within the last 5 years. More than 400 articles were reviewed. DATA SYNTHESIS: Despite considerable overlap, cutaneous lesions specific to lupus erythematosus may be divided into subsets with distinct clinical, histologic, and immunofluorescent features. A recent short-term, prospective, uncontrolled trial found hydroxychloroquine and retinoids to be of similar efficacy in the treatment of cutaneous lupus erythematosus. Optimal treatment for patients with lupus and the anticardiolipin antibody syndrome remains to be defined; uncontrolled, retrospective, and treatment-withdrawal studies suggest that warfarin may be more protective than aspirin. Whether pregnancy induces lupus flares has not yet been established; existing data suggest both that it does and that it does not. Oral contraceptive use and postmenopausal estrogen replacement therapy appear not to cause clinical deterioration in patients with lupus. Recent studies have documented a substantial improvement in the survival of patients with systemic lupus erythematosus; they found 5-year survival rates of 90% or more and 10-year survival rates of more than 80%. Most data suggest that systemic lupus erythematosus results from the activation of self-reactive T cells and B cells by genetic or environmental factors. CONCLUSIONS: The optimal treatment for dermatologic disease and the antiphospholipid antibody syndrome in patients with systemic lupus erythematosus remains unknown. Although mortality has decreased substantially, the morbidity related to the disease itself and to complications of therapy is still considerable. More studies are needed to further elucidate the effects of pregnancy on this condition and the pathogenetic mechanisms responsible for the development of this disease.