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Objective: To estimate the prevalence and investigate the clinical features and the outcome of clinically significant renal involvement in a large cohort of patients with primary Sjögren's syndrome (SS)., Methods: Among 715 patients who met the American-European Consensus Group criteria for primary SS, those with clinically significant renal involvement were identified and their clinical and immunologic features were recorded. The prognosis in patients with primary SS with renal involvement was assessed by the clinical appearance of any of the following major outcomes: death, hemodialysis, chronic renal failure (CRF), and lymphoma. Kaplan-Meier analysis was applied to compare death rates between patients without and those with renal involvement., Results: Thirty-five patients with primary SS (4.9%) had clinically significant renal involvement, representing a total followup time after renal diagnosis of 252.2 person-years. Thirteen patients (37.1%) had interstitial nephritis alone, 17 patients (48.6%) had glomerulonephritis (GN) alone, and 5 patients (14.3%) had both entities. Nine patients died (25.7%), 11 developed CRF (including 4 requiring chronic hemodialysis) (31.4%), and 9 developed lymphoma (25.7%). The overall 5-year survival rate was 85%. Kaplan-Meier analysis showed statistically significant reduced survival for patients with primary SS with renal involvement compared to those without renal involvement (P < 0.0001 by log rank test), with GN patients displaying increased mortality. Eight of 9 reported deaths (89%) and 8 of 9 lymphomas (89%) were observed among patients with GN., Conclusion: The long-term prognosis varies for patients with primary SS who have clinically significant renal involvement. Patients with interstitial nephritis display a favorable prognosis, while patients with GN are at high risk of developing lymphoma and have poor survival., (Copyright © 2013 by the American College of Rheumatology.)

Objective: To assess graft and patient survival as well as causes for graft loss and patient death after renal transplantation in patients with systemic lupus erythematosus (SLE)., Methods: Eighty-seven renal transplantations were performed in 77 patients with SLE from 1972 to 2005. Each recipient with SLE was matched (for date of transplant, age, donor source [living versus deceased], and sex) with 2 renal graft recipients who had non-SLE glomerulonephritis, and the SLE and non-SLE groups were compared with regard to graft survival and patient survival., Results: The mean ± SD age of SLE patients at the time of transplantation was 37.4 ± 12.8 years, and the majority of SLE patients were female (80.5%). SLE patients were well matched to control transplant patients for date of transplant, age, and donor source (living versus deceased donor). The death-censored graft survival rate for SLE patients receiving transplants corresponded closely to that for the control groups; the 1-, 5-, and 10-year graft survival rates were 88%, 81%, and 71%, respectively, for SLE patients, and 91%, 83%, and 74%, respectively, for patients with non-SLE glomerulonephritis (P = 0.31). Patient survival differed significantly; the rates of survival for recipients with SLE were 94%, 83%, and 71% at 1, 5, and 10 years, respectively. The corresponding rates of patient survival in the non-SLE glomerulonephritis cohort were 96%, 92%, and 85% (P = 0.018). Cardiovascular events were the most prominent cause of death in SLE patients (66.7%, versus 39.5% in the control group; P = 0.03)., Conclusion: Transplant patients with SLE have a graft survival rate that matches that of recipients with non-SLE glomerulonephritis. SLE patients who receive transplants have a lower survival rate than control patients. The excessive mortality in SLE is attributed to a greater number of cardiovascular deaths., (Copyright © 2011 by the American College of Rheumatology.)

Objective: Interferon regulatory factor 5 (IRF-5) is a transcription factor that mediates intracellular signals activated by engagement of Toll-like receptors (TLRs). IRF5 polymorphisms are associated with an increased or decreased risk of systemic lupus erythematosus (SLE) in various human populations, but the precise role of IRF5 in SLE development is not fully understood. This study was undertaken to examine the role of IRF5 in the development of murine lupus., Methods: We crossed gene-targeted IRF5-deficient (IRF5(-/-) ) mice with MRL/MpJ-lpr/lpr (MRL/lpr) mice and examined the progeny for survival, glomerulonephritis, autoantibody levels, immune system cell populations, and dendritic cell function., Results: IRF5(-/-) MRL/lpr mice survived longer than control IRF5(+/+) MRL/lpr mice and displayed only very mild glomerulonephritis. Autoantibodies to SLE-related nuclear antigens were lower in IRF5(-/-) MRL/lpr mouse serum, and numbers of activated CD4+ T cells were reduced in the spleen. Splenic DCs from IRF5(-/-) MRL/lpr mice produced lower levels of inflammatory cytokines when treated in vitro with TLR-7 or TLR-9 ligands or immune complexes. Interferon-α production in response to CpG was also decreased., Conclusion: Our results show that IRF5 is a crucial driver of lupus development in mice, and indicate that IRF5 may be an attractive new target for therapeutic intervention to control disease in SLE patients., (Copyright © 2011 by the American College of Rheumatology.)

Objective: To examine whether the platelet-derived growth factor (PDGF) receptor antagonist imatinib ameliorates glomerulonephritis in MRL/lpr mice, a condition that is similar to severe lupus nephritis in humans., Methods: Sixteen-week-old MRL/lpr female mice having an advanced stage of glomerulonephritis were divided into 3 groups according to treatment: 1) 50 mg/kg or 2) 10 mg/kg of imatinib (administered orally 4 times a week up to 24 weeks of age) or 3) vehicle solution (untreated group). The histopathologic condition of the kidneys and salivary glands of each mouse as well as the cumulative survival rates, extent of lymphadenopathy and splenomegaly, and serum chemistry and immunologic values were assessed., Results: In mice treated with 50 mg/kg imatinib, neither proliferation of glomerular cells nor crescent formation occurred. A drastic decrease in mesangial matrix was noted. Mice treated with 50 mg/kg imatinib had a prolonged life span compared with mice treated with 10 mg/kg imatinib and untreated mice. Expression of PDGF receptor and transforming growth factor beta messenger RNA in the kidneys was significantly reduced in the 50 mg/kg imatinib-treated mice compared with that in the 10 mg/kg imatinib-treated mice (P < 0.05) and the untreated mice (P < 0.01). Intriguingly, lymphadenopathy and salivary gland inflammation were also attenuated in imatinib-treated mice, in a dose-dependent manner. Serum levels of IgG and anti-double-stranded DNA antibodies were also reduced in the imatinib-treated mice., Conclusion: These findings indicate that imatinib has a pleiotropic therapeutic effect, namely, the inhibition of PDGF signaling and immunosuppression, on the glomerulonephritis of MRL/lpr mice, which suggests a potential application of this drug in the treatment of human lupus nephritis.

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.

NZB/NZW F1 hybrid mice develop a spontaneous autoimmune disease characterized by the appearance of antinuclear antibodies and premature death due to immune complex glomerulonephritis. To investigate the possible effects of cellular immune stimulation on this disorder, groups of female NZB/NZW mice, aged 2, 5, and 7 months, were treated either with the nonspecific immunostimulatory agent Mycobacterium bovis strain BCG or with saline. Mice treated with BCG at ages 5 and 7 months died sooner than age-matched controls, and death was associated with severe glomerulonephritis, suggesting that BCG may have accelerated autoimmunity in these mice. Since BCG is known to stimulate the production of type II (or gamma) interferon, a substance with potent immunoregulatory effects, a second study was carried out to assess the effects of type II interferon on NZB/NZW disease. A greater number of type II interferon-treated mice died by 9 months of age when compared to controls, and the increased death rate was associated with a more rapid development of antinuclear antibodies and histologically confirmed glomerulonephritis. These data, together with a recent report of increases in the level of serum type II interferon in patients with active systemic lupus erythematosus, suggest that type II interferon may play a role in the pathogenesis of autoimmune disease.

NZB/NZW F1 female mice received levamisole in an attempt to increase suppressor T cell function. Responses varied with dosage of drug and age of mice. When treatment with 25 microgram/gm doses (intermittent or daily) was begun at 12 weeks of age, nephritis was accelerated in spite of transient reduction of anti-DNA antibodies. When treatment was begun at 4 weeks, or when doses of 250 microgram/gm were given, no clinical effects were observed. In the mice with accelerated disease, delayed hypersensitivity and antibody responses to sheep erythrocytes increased; antibody responses to pneumococcal polysaccharide were unaffected. It is possible that some increased immune responses associated with levamisole are undesirable in murine lupus.

Treatment of female NZB/W F1 mice with Nafoxidine, an anti-estrogen, led to delayed manifestation of autoimmune features. Such treated mice had reduced anti-DNA antibodies, reduced proteinuria, and improved survival. These results support the hypothesis that sex hormones play an important role in the expression of autoimmunity and suggest that estrogens may accelerate autoimmunity in NZB/W F1 mice.

Young, syngeneic thymocytes and spleen cells were administered to F1 hybrids of New Zealand Black by New Zealand White (NZB/W) mice beginning at 3 weeks of age and were continuted at 2-week intervals for 8 to 9 months. The development of autoimmunity as assessed by measuring the incidence and level of anti-DNA antibody, the degree of renal involvement, and the survival of recipient mice was evaluated and compared to a control group of animals. No significant differences were noted in these parameters in mice receiving cell transfers as compared to the control group. Therefore, in contrast to other reports, these results suggest that the transfer of young thymus or spleen cells into aging NZB/W mice fails to influence immunoregulation and the subsequent development of autoimmunity.

NZB/W F1 female mice were treated from 20 weeks of age with ribavirin (a broad spectrum antiviral drug), cyclophosphamide, or saline. Treatment with ribavirin (250 mg/kg twice weekly) prolonged survival from 9.8 to 18.5 months, reduced anti-DNA antibodies, and prevented proteinuria. Ability of ribavirin to prolong survival was dose related when given on a twice weekly schedule. However, daily ribavirin (25 mg/kg/day) was as effective as higher intermittent doses. Optimal ribavirin therapy was equal to cyclophosphamide treatment with regard to prolongation of survival. Ribavirin treatment did not significantly alter the body weight, hematocrit, WBC count, serum immunoglobulins, or Coombs reactivity. No alterations in either cellular or humoral immune responses were noted in NZB/W F1 or BALB/c mice treated for prolonged periods with ribavirin. The impressive therapeutic response to a broad spectrum antiviral agent seen in mice already manifesting immune complex nephritis provides a new therapeutic approach to the treatment of autoimmunity.