Breast cancer in systemic lupus erythematosus.

OBJECTIVE: Evidence points to a decreased breast cancer risk in systemic lupus erythematosus (SLE). We analyzed data from a large multisite SLE cohort, linked to cancer registries. METHODS: Information on age, SLE duration, cancer date, and histology was available. We analyzed information on histological type and performed multivariate logistic regression analyses of histological types according to age, SLE duration, and calendar year. RESULTS: We studied 180 breast cancers in the SLE cohort. Of the 155 cases with histology information, 11 were referred to simply as 'carcinoma not otherwise specified'. In the remaining 144 breast cancers, the most common histological type was ductal carcinoma (n = 95; 66%) followed by lobular adenocarcinoma (n = 11; 8%), 15 cancers were of mixed histology, and the remaining ones were special types. In our regression analyses, the independent risk factors for lobular versus ductal carcinoma was age [odds ratio (OR) 1.07, 95% confidence interval (CI) 1.01-1.14] and for the 'special' subtypes it was age (OR 1.06, 95% CI 1.01-1.10) and SLE duration (OR 1.05, 95% CI 1.00-1.11). CONCLUSIONS: Generally, up to 80% of breast cancers are ductal carcinomas. Though our results are not definitive, in the breast cancers that occur in SLE, there may be a slight decrease in the ductal histological type. In our analyses, age and SLE duration were independent predictors of histological status.

A targeted association study in systemic lupus erythematosus identifies multiple susceptibility alleles.

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease. Multiple genetic and environmental factors contribute to the pathogenesis of this disease. Recent genome-wide association studies have added substantially to the number of genes associated with SLE. To replicate some of these susceptibility loci, single-nucleotide polymorphisms reported to be associated to SLE were evaluated in a cohort of 245 well-phenotyped Canadian SLE trios. Our results replicate previously reported associations to alleles of interferon regulatory factor 5 (IRF5), major histocompatibility complex (MHC), tumor necrosis factor (ligand) superfamily member 4 (TNFSF4), Kell blood group complex subunit-related family member 6 (XKR6), B-cell scaffold protein with ankyrin repeats 1 (BANK1), protein tyrosine phosphatase non-receptor type 22 (PTPN22), ubiquitin-conjugating enzyme E2L 3 (UBE2L3) and islet cell autoantigen 1 (ICA1). We also identify putative associations to cytotoxic T-lymphocyte-associated protein 4 (CTLA4), a gene associated with several autoimmune disorders, and ERBB3, a locus on 12q13 that was previously reported to be associated with type 1 diabetes. This study confirms the existence of multiple genetic risk factors for SLE, and supports the notion that some risk factors for SLE are shared with other inflammatory disorders.

Effects of N-acetylcysteine and dithiothreitol on glutathione and protein thiol replenishment during acetaminophen-induced toxicity in isolated mouse hepatocytes.

Isolated mouse hepatocytes were incubated with 1.0 mM acetaminophen (AA) for 1.5 h to initiate glutathione (GSH) and protein thiol (PSH) depletion and cell injury. Cells were subsequently washed to remove non-covalently bound AA and resuspended in medium containing N-acetylcysteine (NAC, 2.0 mM) or dithiothreitol (DTT, 1.5 mM). The effects of these agents on the replenishment of GSH and total PSH content were related to the development of cytotoxicity. When cells exposed to AA were resuspended in medium containing NAC or DTT, both agents replenished GSH and total PSH content to levels observed in untreated cells but only DTT was able to attenuate cytotoxicity. Addition of the GSH synthesis inhibitor, buthionine sulfoximine (BSO, 1.0 mM, 1.5 h), to cells in incubation medium containing AA, enhanced GSH and total PSH depletion and potentiated cytotoxicity. Resuspension of these cells in medium containing NAC did not alter the potentiating effects of BSO; GSH and PSH levels were not replenished and no cytoprotective effects were observed. However, when cells exposed to AA and BSO were resuspended in medium containing DTT, PSH content was replenished but GSH levels were not restored. In addition, DTT was able to delay the development of cytotoxicity. It appears that DTT, unlike NAC, has a GSH-independent mechanism of PSH replenishment. These observations suggest that while replenishment of GSH and total PSH content does not result in cytoprotection, the regeneration of critical PSH by DTT may play an important role in the maintenance of proper cell structure and/or function.

Mandatory pharmacosurveillance--a Canadian model for access to therapy and research.

Regulatory authorities in Canada have expressed a vital need for pharmacoepidemiological data on long-term effectiveness, safety, and cost-benefit of new therapies, particularly in comparison to currently available therapies, in routine clinical practice to allow informed decision making in listing new therapies on formulary. We describe the evolution of a new model of pharmacosurveillance involving a partnership between academic and community rheumatologists, government, and industry whereby access to therapy is conditional on participation in an industry-funded pharmacosurveillance study that assesses long-term effectiveness, safety, and cost-benefit. Though funded by industry, the program is administered by government and designed and operated at arms length from industry. The clinic data sheets are available at www. altarheum.com. The program also provides a sustainable model for promoting observational research on therapeutics in general.

Autoantibodies in lupus nephritis patients requiring renal transplantation.

The goal of this nested case-control study was to compare autoantibody profiles in systemic lupus erythematosus (SLE) patients with lupus nephritis (LN), lupus nephritis patients requiring renal transplantation (LNTP) and a SLE control group without nephritis (CON). Sera were assayed for a variety of autoantibodies by addressable laser bead immunoassay (ALBIA) and enzyme-linked immunoassay (ELISA) and to dsDNA by Crithidia luciliae assay. The frequency of nucleosome autoantibodies was significantly greater in the LNTP group (79%) compared to the LN (18%) and CON (9%) groups (P < 0.0005). The frequency of other autoantibodies, including anti-dsDNA, did not differ significantly between groups. Among patients with LN, the odds of progressing to renal transplantation was 16-fold higher (OR 16.5 [95% CI 2.5, 125.7], P = 0.0005) in patients testing positive for anti-nucleosome antibodies compared to those who tested negative. Furthermore, the level of anti-nucleosome antibodies was significantly ( P < 0.00005) higher in the LNTP group (3.69 +/- 2.79) than the LN (0.51 +/- 0.51) and CON (0.34 +/- 0.44) groups. Review of 48 renal biopsies from 29 patients indicated that there was no difference in renal histological classification among patients with anti-nucleosome antibodies compared to those who tested negative. Our observations suggest that nucleosome autoantibodies are a biomarker for more severe SLE renal disease requiring transplantation.

Mortality related to cerebrovascular disease in systemic lupus erythematosus.

The objective of this study was to examine mortality rates related to cerebrovascular disease in systemic lupus erythematosus (SLE) compared to the general population. Our sample was a multisite Canadian SLE cohort (10 centres, n = 2688 patients). Deaths due to cerebrovascular disease were ascertained by vital statistics registry linkage using ICD diagnostic codes. Standardized mortality ratio (SMR, ratio of deaths observed to expected) estimates were calculated. The total SMR for death due to cerebrovascular disease was 2.0 (95% confidence interval [CI] 1.0, 3.7). When considering specific types of events, the category with the greatest increased risk was that of ill-defined cerebrovascular events (SMR 44.9 95% CI 9.3, 131.3) and other cerebrovascular disease (SMR 8.4, 95% CI 2.3, 21.6). Deaths due to cerebral infarctions appeared to be less common than hemorrhages and other types of cerebrovascular events. Our data suggest an increase in mortality related to cerebrovascular disease in SLE patients compared to the general population. The large increase in ill-defined cerebrovascular events may represent cases of cerebral vasculitis or other rare forms of nervous system disease; alternately, it may reflect diagnostic uncertainty regarding the etiology of some clinical presentations in SLE patients. The suggestion that more deaths are attributed to cerebral hemorrhage, as opposed to infarction, indicates that inherent or iatrogenic factors (eg, thrombocytopenia or anticoagulation) may be important. In view of the paucity of large-scale studies of mortality attributed to neuropsychiatric outcomes in SLE, our findings highlight the need for additional research in large SLE cohorts.

Damage in systemic lupus erythematosus and its association with corticosteroids.

OBJECTIVE: To evaluate the association between corticosteroid use and organ damage in patients with systemic lupus erythematosus (SLE). METHODS: The occurrence and date of organ damage, as measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, were determined for 539 patients enrolled in the Hopkins Lupus Cohort Study. The risk of damage associated with the cumulative prednisone dose, high-dose prednisone (> or =60 mg/day for > or =2 months), and pulse methylprednisolone (1,000 mg intravenously for 1-3 days) was estimated using Cox proportional hazards regression analyses, controlling for age, race, and sex. Risk estimates for the cumulative prednisone dose were based on a reference dose of 36.5 gm (e.g., 10 mg of prednisone daily for 10 years [or equivalent]). RESULTS: The cumulative prednisone dose was significantly associated with the development of osteoporotic fractures (relative risk [RR] 2.5, 95% confidence interval [95% CI] 1.7, 3.7), symptomatic coronary artery disease (RR 1.7, 95% CI 1.1, 2.5), and cataracts (RR 1.9, 95% CI 1.4, 2.5). Each intravenous pulse was associated with a small increase in the risk of osteoporotic fractures (RR 1.3, 95% CI 1.0, 1.8); however, this result failed to reach statistical significance (P = 0.07). Each 2-month exposure to high-dose prednisone was associated with a 1.2-fold increase in the risk of both avascular necrosis (95% CI 1.1, 1.4) and stroke (95% CI 1.0, 1.5). CONCLUSION: SLE patients receiving long-term prednisone therapy were at significant risk of morbidity due to permanent organ damage. Additional research is required to determine the relative contributions of SLE disease activity and corticosteroids to the pathogenesis of specific types of organ damage. Furthermore, new steroid-sparing therapies are needed in order to treat disease activity and minimize cumulative and high-dose prednisone exposure.

The nuclear pore complex protein Tpr is a common autoantigen in sera that demonstrate nuclear envelope staining by indirect immunofluorescence.

We studied the autoantigen targets of 75 human sera that had antibodies to the nuclear envelope (NE) as identified by indirect immunofluorescence (IIF) on HEp-2 cells. Several different IIF staining patterns could be identified when antibodies to different components of the nuclear membrane (NM) and nuclear pore complexes (NuPC) were identified: a smooth membrane pattern characteristic of antibodies to nuclear lamins, a punctate pattern typical of antibodies to the nuclear pore complex and more complex patterns that included antibodies to nuclear and cytoplasmic organelles. Western immunoblotting of isolated nuclear and NE proteins and immunoprecipitation of radiolabelled recombinant proteins prepared by using the full-length cDNAs of the Translocated promoter region (Tpr), gp210 and p62 were used to identify specific autoantibody targets. Fifty-two of the 75 (70%) sera bound to Tpr, 25 (33%) bound to lamins A, B or C, 15 (20%) reacted with gp210 and none reacted with p62. Sixteen (21%) did not react with any of the NE components tested in our assays. The clinical features of 37 patients with anti-NE showed that there were 34 females and three males with an age range of 16-88 years (mean 59 years). The most frequent clinical diagnosis (9/37 = 24%) was autoimmune liver disease (ALD; two with primary biliary cirrhosis), followed by seven (19%) with systemic lupus erythematosus (SLE), four (11%) with a motor and/or sensory neuropathy, three (8%) with anti-phospholipid syndrome (APS), two with systemic sclerosis (SSc), two with Sjögren's syndrome (SjS), and others with a variety of diagnoses. This report indicates that Tpr, a component of the NuPC, is a common target of human autoantibodies that react with the NE.

Patterns of disease activity in systemic lupus erythematosus.

OBJECTIVE: To describe patterns of systemic lupus (SLE) disease activity over time. METHODS: Disease activity was measured in a prospective cohort of 204 consecutive SLE patients followed up quarterly for 2.0-7.5 years (911 person-years of followup). Physician's global assessment (PGA) and modified SLE Disease Activity Index (M-SLEDAI; omitting serology) scores were plotted against time for each patient. Definitions for disease activity patterns were developed by consensus using these plots, and the proportion of total follow-up time represented by each pattern was calculated. RESULTS: Three patterns of SLE activity were apparent: relapsing-remitting (RR), chronic active (CA), and long quiescent (LQ). The CA pattern was the most frequent for both the PGA and M-SLEDAI, representing 58% and 40% of total person-years, respectively. The least common pattern was LQ (PGA 16%, M-SLEDAI 25%), while the RR pattern was intermediate in frequency (PGA 26%, M-SLEDAI 35%). Average disease activity during RR periods tended to be mild, while that during CA periods was more likely to be moderately severe. The most common discrepancy between instruments was that the PGA depicted CA when the M-SLEDAI showed an RR pattern. The M-SLEDAI did not appear to capture mild degrees of activity. CONCLUSION: SLE activity was readily classified into 1 of 3 patterns: RR, CA, or LQ. The CA pattern was most common, suggesting that significant morbidity may arise from persistent disease activity. These findings may have important implications regarding the choice of outcome measures in SLE clinical trials, since comparison of flare rates may not account for chronic disease activity.

Decreases in anti-double-stranded DNA levels are associated with concurrent flares in patients with systemic lupus erythematosus.

OBJECTIVE: To determine the degree to which changes in anti-double-stranded DNA (anti-dsDNA), as determined by Crithidia and enzyme-linked immunosorbent assays (ELISAs), precede or coincide with changes in systemic lupus erythematosus (SLE) activity, as measured by 5 clinical indices, the physician's global assessment (PGA), modified SLE Disease Activity Index (M-SLEDAI), modified Lupus Activity Index (M-LAI), Systemic Lupus Activity Measure (SLAM), and the modified British Isles Lupus Assessment Group (M-BILAG). METHODS: Disease activity and anti-dsDNA were measured monthly in 53 SLE patients who were followed up for 1 year. Lupus flare was defined as an increase in PGA of > or = 1.0, M-SLEDAI > or = 3, M-LAI > or = 0.1, SLAM > or = 3, and M-BILAG > or = 4 within a 1-month period. Flare rates were calculated for groups, which were defined by "previous" (1 month prior to the flare) or "concurrent" (at the time of the flare) changes in anti-dsDNA. Logistic regression models were used to determine the significance of the association between recent changes in anti-dsDNA and flare, controlling for the prednisone dosage. RESULTS: Flares occurred at 12% of visits, based on the PGA measure of disease activity. Using the other indices, flare rates were 19% (M-SLEDAI), 25% (M-LAI), 13% (SLAM), and 12% (M-BILAG). A concurrent decrease in anti-dsDNA (ELISA) was associated with significantly higher flare rates based on PGA (18 of 84, 21%; P = 0.0014), M-SLEDAI (27 of 89, 30%; P = 0.0019), M-LAI (37 of 89, 42%; P = 0.0001), and M-BILAG (19 of 89, 21%; P = 0.0264) scores. Flare rates were also significantly higher after a previous increase in anti-dsDNA (ELISA) based on M-SLEDAI (26 of 93, 30%; P = 0.0022) and M-LAI (34 of 93, 37%; P = 0.0117) scores. Flare rates tended to be lowest when there was a concurrent increase in anti-dsDNA (ELISA). Analysis of specific organ systems showed that a concurrent decrease in anti-dsDNA (ELISA) was significantly associated with increases in renal disease activity. Similar results were obtained using the Crithidia assay. CONCLUSION: A previous increase in anti-dsDNA levels occurred before SLE flares, as measured by the M-SLEDAI and M-LAI only. However, during lupus flares, including the subset of renal flares, anti-dsDNA levels frequently decreased. We hypothesize that this decrease in anti-dsDNA represents deposition in tissue at the time of flare.

A decrease in complement is associated with increased renal and hematologic activity in patients with systemic lupus erythematosus.

OBJECTIVE: To determine the degree to which changes in C3 and C4 precede or coincide with changes in systemic lupus erythematosus (SLE) activity, as measured by 5 global activity indices, the physician's global assessment (PGA), modified SLE Disease Activity Index (M-SLEDAI), modified Lupus Activity Index (M-LAI), Systemic Lupus Activity Measure (SLAM), and the modified British Isles Lupus Assessment Group (M-BILAG), and to evaluate the association between changes in C3 and C4 levels and SLE activity in individual organ systems. METHODS: Fifty-three lupus patients were observed monthly for 1 year in a longitudinal study. Lupus disease activity and complement levels were measured at each visit. Lupus flare was defined as a 1.0 (or greater) increase in the PGA, a 3-point increase in the M-SLEDAI, a 0.1 increase in the M-LAI, a 3-point increase in the SLAM, or a 4-point increase in the M-BILAG within a 1-month period. Flare rates were calculated for subgroups defined by previous (1 month before) or concurrent changes in complement levels. Logistic regression models were used to determine the significance of the association between recent changes in complement levels and flare, controlling for prednisone dosage. Similar models were used to assess the association between changes in C3 or C4 levels and increased SLE activity in specific organ systems. RESULTS: Lupus flares occurred at 12% of visits based on the PGA, 19% based on the M-SLEDAI, 25% based on the M-LAI, 13% based on the SLAM, and 12% based on the M-BILAG. Recent changes in C3 and C4 levels were not associated with flares based on 3 of the 5 activity indices. Flares defined by the M-LAI were more frequent when there was a concurrent decrease in C3 (odds ratio [OR] 1.9, 95% confidence interval [95% CI] 1.1-3.1) or C4 (OR 2.1, 95% CI 1.3-3.6). Higher flare rates, as defined by the SLAM, were associated with previous increases in C3 (OR 1.6, 95% CI 1.0-2.6) and C4 (OR 2.2, 95% CI 1.2-3.9). When individual organ systems were analyzed, decreases in C3 and C4 were associated with a concurrent increase in renal disease activity (OR 2.2, 95% CI 1.4-3.5 and OR 1.9, 95% CI 1.1-3.4, respectively). Decreases in C3 were also associated with concurrent decreases in the hematocrit (OR 4.6, 95% CI 1.7-12.3), platelet (OR 2.5, 95% CI 1.5-4.1), and white blood cell (OR 2.2, 95% CI 1.3-3.6) counts. Previous increases in C3 levels were associated with a decrease in platelets (OR 1.7, 95% CI 1.1-2.7). A decrease in C4 was associated with a concurrent decrease in the hematocrit level (OR 3.2, 95% CI 1.3-7.5) and platelet count (OR 1.6, 95% CI 1.0-2.5). CONCLUSION: Decreases in complement levels were not consistently associated with SLE flares, as defined by global measures of disease activity. However, decreasing complement was associated with a concurrent increase in renal and hematologic SLE activity.

A clinical study of the relationship between silicone breast implants and connective tissue disease.

OBJECTIVE: This study was a blinded, concurrent assessment of a historical cohort derived from a provincial registry (1978 to 1986) of breast implant recipients (cosmetic, not reconstructive) and controls (other cosmetic surgery) to test the hypothesis that connective tissue disease (CTD) is increased in breast implant recipients. METHODS: Women who underwent breast implant or other cosmetic surgery during the interval from 1978 to 1986 were contacted confidentially by Alberta Health and asked to participate in the study. Those willing to participate completed an extensive questionnaire and supplied a blood sample, subsequent to which all surgical records were reviewed to confirm implant type(s) or cosmetic surgery(ies). All participants with any suggestion of rheumatic disease were assessed blindly by a rheumatologist for CTD. RESULTS: One thousand five hundred seventy-six breast implant recipients were recruited, including 1112 who had received silicone gel-filled implants (> 13,500 person yrs exposure). Seven hundred twenty-six controls were recruited. Prevalence rates adjusted for sex and age for rheumatoid arthritis, systemic lupus erythematosus, scleroderma, and Sjögren's syndrome (the principal targeted conditions) were consistent with published reports for Caucasian women. While breast implant recipients self-reported significantly greater rates of symptoms than controls, post-surgical diagnoses of the principal targeted conditions did not indicate an increased incidence of typical or atypical CTD. CONCLUSION: The results of the study do not support the hypothesis that silicone gel-filled implants induce or promote CTD.