Breast cancer in systemic lupus.

Objective There is a decreased breast cancer risk in systemic lupus erythematosus (SLE) versus the general population. We assessed a large sample of SLE patients, evaluating demographic and clinical characteristics and breast cancer risk. Methods We performed case-cohort analyses within a multi-center international SLE sample. We calculated the breast cancer hazard ratio (HR) in female SLE patients, relative to demographics, reproductive history, family history of breast cancer, and time-dependent measures of anti-dsDNA positivity, cumulative disease activity, and drugs, adjusted for SLE duration. Results There were 86 SLE breast cancers and 4498 female SLE cancer-free controls. Patients were followed on average for 7.6 years. Versus controls, SLE breast cancer cases tended to be white and older. Breast cancer cases were similar to controls regarding anti-dsDNA positivity, disease activity, and most drug exposures over time. In univariate and multivariate models, the principal factor associated with breast cancers was older age at cohort entry. Conclusions There was little evidence that breast cancer risk in this SLE sample was strongly driven by any of the clinical factors that we studied. Further search for factors that determine the lower risk of breast cancer in SLE may be warranted.

Cardiovascular events prior to or early after diagnosis of systemic lupus erythematosus in the systemic lupus international collaborating clinics cohort.

OBJECTIVE: To describe the frequency of myocardial infarction (MI) prior to the diagnosis of systemic lupus erythematosus (SLE) and within the first 2 years of follow-up. METHODS: The systemic lupus international collaborating clinics (SLICC) atherosclerosis inception cohort enters patients within 15 months of SLE diagnosis. MIs were reported and attributed on a specialised vascular event form. MIs were confirmed by one or more of the following: abnormal ECG, typical or atypical symptoms with ECG abnormalities and elevated enzymes (≥2 times upper limit of normal), or abnormal stress test, echocardiogram, nuclear scan or angiogram. Descriptive statistics were used. RESULTS: 31 of 1848 patients who entered the cohort had an MI. Of those, 23 patients had an MI prior to SLE diagnosis or within the first 2 years of disease. Of the 23 patients studied, 60.9% were female, 78.3% were Caucasian, 8.7% black, 8.7% Hispanic and 4.3% other. The mean age at SLE diagnosis was 52.5±15.0 years. Of the 23 MIs that occurred, 16 MIs occurred at a mean of 6.1±7.0 years prior to diagnosis and 7 occurred within the first 2 years of follow-up. Risk factors associated with early MI in univariate analysis are male sex, Caucasian, older age at diagnosis, hypertension, hypercholesterolaemia, family history of MI and smoking. In multivariate analysis only age (OR=1.06 95% CI 1.03 to 1.09), hypertension (OR=5.01, 95% CI 1.38 to 18.23), hypercholesterolaemia (OR=4.43, 95% CI 1.51 to 12.99) and smoking (OR=7.50, 95% CI 2.38 to 23.57) remained significant risk factors. CONCLUSIONS: In some patients with lupus, MI may develop even before the diagnosis of SLE or shortly thereafter, suggesting that there may be a link between autoimmune inflammation and atherosclerosis.

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.

Sustained remission of lupus nephritis.

The aim of this study was to describe the clinical course of patients with lupus nephritis (LN) who attain a sustained remission (SR) and identify predictors of SR. A retrospective study of patients with biopsy-proven LN were followed for up to 10 years. SR was defined as normal renal function, urine protein <0.5g/day, and an inactive urine sediment without significant immunosuppressive maintenance therapy for no less than three years. Control patients had LN but did not fulfill the criteria for SR. Data was collected at diagnosis of LN (T0), at onset of remission (T1), and at final follow-up (T2). A total of 35 patients were identified, 16 with a SR of LN and 19 controls, with a mean +/- SD follow-up of 126.4 +/- 8.5 months. Remission of LN was achieved following 37.7 +/- 6.8 months of therapy. At diagnosis (T0) the WHO classification of nephritis, activity and chronicity scores of renal biopsies were comparable in the two groups. At final follow-up (T2), the mean estimated creatinine clearance for the SR group was significantly higher than in controls (P = 0.009) and disease activity (SLEDAI scores) was lower (P = 0.002). Cumulative damage (SDI scores) in the SR group did not increase after patients entered remission (P = 0.250), whereas the mean SDI score in the control group increased significantly (P = 0.014) even when renal variables were excluded (P = 0.016). Multivariate analysis revealed that female gender (P = 0.023), older age (P = 0.034), higher nonrenal SLEDAI scores (P = 0.016) at the time of diagnosis of LN and absence of azathioprine (P = 0.010) were predictive of SR. It was concluded that remission of LN occurs in a substantial proportion of systemic lupus erythematosus (SLE) patients and may be sustained without maintenance immunosuppressive therapy. It is associated with a significantly slower accrual of both renal and non-renal damage over the ensuing seven years.

Efficacy of sacroiliac corticosteroid injections in patients with inflammatory spondyloarthropathy: results of a 6 month controlled study.

OBJECTIVE: To evaluate changes in articular symptoms, spinal mobility, and global function over 6 months after intraarticular injections of long acting corticosteroid into the sacroiliac (SI) joints of patients with inflammatory low back pain (ILBP). METHODS: Nineteen patients with symptoms of ILBP were studied. Thirteen (68%) had radiographic evidence of sacroiliitis. The remaining 6 patients (32%) had normal imaging studies and thus were considered to have mechanical low back pain. All patients received bilateral SI joint injections of triamcinolone hexacetonide (40 mg/joint) under computer tomographic guidance. Outcome variables included the duration of low back morning stiffness, back pain (by visual analog scale, McGill Pain Questionnaire), spinal mobility (chest expansion, Schober test, 10 cm segments test, finger-fibula distance), and self-report health status (SF-36). RESULTS: Both groups of patients showed a transient improvement in stiffness and pain, spinal mobility, and general health status that was most pronounced at 1-3 months after intraarticular therapy. This did not reach statistical significance (p > 0.05) and by 6 months, followup all outcome variables had reverted to pretherapy levels in both groups. CONCLUSION: These preliminary observations suggest that SI corticosteroid injections are ineffective in the management of patients with inflammatory spondyloarthropathy.

Beta 2-glycoprotein I and anticardiolipin antibody binding to resting and activated cultured human endothelial cells.

OBJECTIVE: To examine beta 2-glycoprotein I (beta 2-GPI) binding and its ability to augment IgG anticardiolipin (aCL) antibody binding to resting and cytokine activated endothelial cells in vitro. To evaluate the ability of IgG aCL antibody positive sera to induce endothelial cell activation in vitro. METHODS: IgG with aCL activity was isolated by affinity purification from 6 patients with systemic lupus erythematosus (SLE) and 3 patients with primary antiphospholipid antibody syndrome (APS). Human umbilical vein endothelial cells (HUVEC) were cultured in serum-free conditions and examined in a resting state or after activation with tumor necrosis factor alpha (TNF-alpha). HUVEC were exposed to beta 2-GPI alone, IgG alone or IgG plus beta 2-GPI. Finally, we examined the ability of sera from the same patients with SLE and primary APS to activate HUVEC in culture. RESULTS: Neither beta 2-GPI, IgG aCL, nor IgG aCL plus beta 2-GPI bound to resting or cytokine activated endothelial cells. In addition, sera from the same patients did not induce in vitro activation of endothelial cells as assessed by enhanced surface expression of intercellular adhesion molecule, vascular cell adhesion molecule, and E-selectin. CONCLUSION: Results suggest that beta 2-GPI deposition on either resting or activated endothelial cells and modulation of its proposed in vivo anticoagulant activity through subsequent aCL antibody binding does not account for the thrombotic manifestations of APS.

Cutaneous sarcoidosis and foreign bodies.

A histopathological diagnosis of sarcoidosis is, by convention, one of exclusion and is reached only when other potential causes of granulomatous disease, such as foreign bodies, are eliminated. We report herein three cases of systemic sarcoidosis with cutaneous manifestations of the disease, in which polarizable foreign particles were associated with the granulomata in the skin. We submit (a) that a granulomatous foreign body reaction and sarcoidosis are not mutually exclusive, (b) that particulate foreign matter may actually serve as a nidus for granuloma formation in sarcoidosis, and (c) that the occasional presence of extraneous material within the granulomata of sarcoidosis requires greater recognition by pathologists.

Antibodies to brain integral membrane proteins in systemic lupus erythematosus.

Wheat germ lectin affinity chromatography and temperature-induced phase separation with Triton X-114 were evaluated for the isolation of surface neuronal antigens from rat and human brain and from human neuroblastoma cell lines IMR-6 and SK-N-SH. Both techniques yielded surface proteins which were free of contamination by intracellular proteins but temperature-induced phase separation was technically less demanding and less expensive, required a shorter assay time and resulted in a superior quantity and quality of isolated proteins. Rat brain surface proteins were used for characterization of antineuronal antibody reactivity in sera from patients with systemic lupus erythematosus (SLE). Western blotting identified reactivity in 15 of 75 (20%) SLE sera compared to five of 95 (5%) normal controls (P 0.006). In rat brain the molecular weight of the individual proteins identified ranged from 59 kDa to 22 kDa. Six of these were also present in human brain and two were present in neuroblastoma cell lines. Absorption studies indicated that some of the antigenic proteins were either restricted to brain tissue or shared with other non-neuronal tissues. These techniques should facilitate the characterization of antineuronal antibody reactivities and lead to a clearer understanding of their role in the pathogenesis of autoimmune neurologic disease.

Cognitive impairment and autoantibodies in systemic lupus erythematosus.

Nervous system involvement in systemic lupus erythematosus (SLE) includes a wide array of manifestations some of which have been associated with specific autoantibodies. These include reactivity to surface neuronal and lymphocyte antigens, ribosomal P and cardiolipin. The aim of the present study was to examine the association between cognitive abnormalities and these autoantibodies in an unselected female population of SLE patients. Using a battery of standardized neuropsychological tests, cognitive impairment was identified in 15/70 (21%) SLE patients compared to 1/25 (4%) patients with rheumatoid arthritis and 1/23 (4%) healthy subjects (P = 0.04). Circulating antineuronal antibodies were measured by indirect immunofluorescence using human neuroblastoma cell lines IMR-6 and SK-N-SH. Lymphocytotoxic antibodies were measured by microcytotoxicity. Antibodies to ribosomal P and cardiolipin were measured by ELISA. Antineuronal antibodies were detected in 34%, lymphocytotoxic antibodies in 47%, anti-P antibodies in 17% and anticardiolipin antibodies in 24% of patients. In the cognitively impaired and unimpaired SLE patients there was no significant difference in the prevalence of antineuronal antibodies (33 vs 35%), lymphocytotoxic antibodies (40 vs 50%), anti-P antibodies (20 vs 17%) or anticardiolipin antibodies (7 vs 29%). The titre and isotype of autoantibodies were also similar in both groups. These results suggest that autoantibodies which have previously been associated with nervous system manifestations of SLE are not likely to be directly involved in the pathogenesis of cognitive dysfunction.

Phenotypic characteristics of dissociated mononuclear cells from rheumatoid synovial membrane.

The phenotypic characteristics of enzymatically dissociated synovial membrane mononuclear cells from 8 patients (14 samples) with rheumatoid arthritis (RA) were assessed by fluorescence activated flow cytometry and compared to peripheral blood (PB) mononuclear cells from 18 patients with RA and 14 normal controls. There was no significant difference between the percentage of CD4+ and CD8+ lymphocytes in synovial membrane compared to RA and normal PB. Double labelling experiments revealed similar percentages of CD4+ CDw29+ (helper-inducer) and CD4+ CD45R+ (suppressor-inducer) cells in RA and normal PB. In contrast, SM CD4+ CDw29+ cells were present in significantly higher proportions than in RA and normal PB (p less than 0.001). Conversely, synovial membrane CD4+ CD45R+ cells were present in significantly lower proportions than in RA and normal PB (p less than 0.001). A similar pattern of CDw29 and CD45R antigen expression was noted on CD8+ lymphocytes reflecting increased killer-effector (p less than 0.001) and decreased suppressor-effector (p less than 0.001) cells, respectively. Other experiments revealed a significant increase in the percentage of synovial membrane CD20+ cells (B lymphocytes) and HLA-DR+ cells compared to RA PB (p less than 0.02 and p less than 0.001) and normal PB (p less than 0.01 and p less than 0.005), and similar proportions of CD14+ cells (monocytes/macrophages). Our results suggest that RA synovial membrane contains populations of T and B lymphocytes that differ quantitatively and qualitatively from those in PB. These may account for some of the abnormalities in intraarticular humoral and cellular immune responses in patients with RA.

Liver lymphoma in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) has been associated with an increased incidence of lymphoma. We describe the occurrence of hepatic lymphoma, which was likely primary in origin, in a patient with SLE and discuss the etiologic and diagnostic implications.

Lymphoid irradiation in intractable rheumatoid arthritis. Long-term followup of patients treated with 750 rads or 2,000 rads.

Twenty patients with intractable rheumatoid arthritis were randomized to receive 750 or 2,000 rads of lymphoid irradiation (LI) in a double-blind comparative study, and were followed for a maximum of 48 months (mean 40 months) after treatment. During followup, sustained immunomodulation (including lymphopenia, particularly of the T helper cell subset; reduced ratio of helper cells to suppressor cells; and impaired in vitro lymphocyte proliferation in response to phytohemagglutinin and pokeweed mitogen) was observed. Significant improvements in early morning stiffness, Ritchie articular index, pain score, grip strength, and 15-meter walk time were observed in both treatment groups, but these were not sustained through the followup period. Progressive joint damage was observed radiologically in both groups during followup. Thus, LI induced sustained immunosuppression, but resulted in only short-lived clinical improvement and was associated with progressive joint erosion in these patients.

A novel neuronal antigen identified by sera from patients with systemic lupus erythematosus.

Using human neuroblastoma cell lines (IMR-6, NMB-7, SK-N-Mc, SK-N-SH) as sources, we characterized surface neuronal antigens as an initial step in determining the pathogenic role and clinical significance of neuronal antibodies in systemic lupus erythematosus (SLE) patients. SLE sera were screened for the presence of surface neuronal antibodies using a mixed hemadsorption assay. Thirty SLE sera were further tested by Western blotting and immunoprecipitation of lysed IMR-6 cells. Western blotting revealed binding to predominantly intracellular antigens, none of which was restricted to neuroblastoma cells. In contrast, immunoprecipitation experiments demonstrated binding to a 97K antigen, which appeared to be of surface origin, by 3 SLE sera. This was not present on non-neuronal cells and was not precipitated by sera from healthy or disease controls. This 97K antigen was also precipitated from the neuroblastoma cell line NMB-7, but was not present on SK-N-Mc or SK-N-SH cells. Precipitation was depleted by preabsorption with viable IMR-6 and NMB-7 cells, but not with non-neuronal cells. Thus, some SLE sera recognize a 97K neuronal antigen on select neuroblastoma cells.

Lymphoid irradiation in intractable rheumatoid arthritis. A double-blind, randomized study comparing 750-rad treatment with 2,000-rad treatment.

Twenty patients with intractable rheumatoid arthritis were treated with 750-rad or 2,000-rad lymphoid irradiation in a randomized double-blind comparative study. Over a 12-month followup period, there was a significant improvement in 4 of 7 and 6 of 7 standard parameters of disease activity following treatment with 750 rads and 2,000 rads, respectively. Transient, short-term toxicity was less frequent with the lower dose. In both groups, there was a sustained peripheral blood lymphopenia, a selective depletion of T helper (Leu-3a+) lymphocytes, and reduced in vitro mitogen responses. These changes did not occur, however, in synovial fluid. These results suggest that 750-rad lymphoid irradiation is as effective as, but less toxic than, that with 2,000 rads in the management of patients with intractable rheumatoid arthritis.

Lymphoid irradiation in intractable rheumatoid arthritis: effects on the production of immunoglobulins and rheumatoid factors.

Changes in the production of immunoglobulins and rheumatoid factors (RF's) were studied in 20 patients with intractable rheumatoid arthritis (RA) following total doses of 750 rad or 2,000 rad lymphoid irradiation. Over a 12 month follow up period there was no consistent change in absolute serum or synovial fluid levels, or in synovial membrane production of either total IgG, IgA or IgM, or the corresponding RF fractions. The invitro production of immunoglobulins and IgM RF by peripheral blood mononuclear cells was also unaltered, except for one patient who had a dramatic rise in IgM RF production. Over the same period there was a significant overall reduction in disease activity following both doses of radiotherapy. It is concluded that the clinical response which occurs following lymphoid irradiation is not due to a reduction in RF production. Furthermore, the production of RF's appears to be unaffected by the changes in T cell immunity which occur following lymphoid irradiation.

Hypovitaminosis D and response to supplementation in older patients with cystic fibrosis.

This study reports serum 25-hydroxy vitamin D (25-(OH)D) levels, bone mineral content and bone maturation in 20 adolescent and adult patients with cystic fibrosis, and their response to the internationally recommended dose of supplementary vitamin D (800 iu/day; 20 micrograms/day). Serum 25-(OH)D values were below normal in 75 per cent of patients and serum alkaline phosphatase values, corrected for age, were increased in 60 per cent. Bone mineral content, measured by photon beam absorptiometry, was below the normal range in 45 per cent of patients and bone age retarded in 45 per cent. Following supplementation with vitamin D 40 per cent of patients failed to achieve normal serum 25-(OH)D levels. We concluded that hypovitaminosis D occurs frequently in older patients with cystic fibrosis and is accompanied by osteopenia and retarded bone maturation.

Massive osteolysis in the hand and response to radiotherapy.

We report a case of severe bony and articular destruction in the hand of a 62-year-old woman, secondary to localized vascular proliferation. A short course of radiotherapy (total dose 3000 rad) resulted in rapid relief of symptoms and prevention of further osseous destruction over a 6-year followup period.