Association study of genes related to bone formation and resorption and the extent of radiographic change in ankylosing spondylitis.

OBJECTIVE: To identify genetic associations with severity of radiographic damage in ankylosing spondylitis (AS). METHOD: We studied 1537 AS cases of European descent; all fulfilled the modified New York Criteria. Radiographic severity was assessed from digitised lateral radiographs of the cervical and lumbar spine using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). A two-phase genotyping design was used. In phase 1, 498 single nucleotide polymorphisms (SNPs) were genotyped in 688 cases; these were selected to capture >90% of the common haplotypic variation in the exons, exon-intron boundaries, and 5 kb flanking DNA in the 5' and 3' UTR of 74 genes involved in anabolic or catabolic bone pathways. In phase 2, 15 SNPs exhibiting p<0.05 were genotyped in a further cohort of 830 AS cases; results were analysed both separately and in combination with the discovery phase data. Association was tested by contingency tables after separating the samples into 'mild' and 'severe' groups, defined as the bottom and top 40% by mSASSS, adjusted for gender and disease duration. RESULTS: Experiment-wise association was observed with the SNP rs8092336 (combined OR 0.32, p=1.2×10(-5)), which lies within RANK (receptor activator of NFκB), a gene involved in osteoclastogenesis, and in the interaction between T cells and dendritic cells. Association was also found with the SNP rs1236913 in PTGS1 (prostaglandin-endoperoxide synthase 1, cyclooxygenase 1), giving an OR of 0.53 (p=2.6×10(-3)). There was no observed association between radiographic severity and HLA-B*27. CONCLUSIONS: These findings support roles for bone resorption and prostaglandins pathways in the osteoproliferative changes in AS.

Adherence to oral bisphosphonates and the risk of subtrochanteric and femoral shaft fractures among female medicare beneficiaries.

UNLABELLED: Previous studies have shown an association between duration of bisphosphonate use and atypical femur fractures. This cohort study showed an increasingly higher risk of subtrochanteric and femoral shaft fractures among those who were more adherent to oral bisphosphonates. INTRODUCTION: Long-term use of oral bisphosphonates has been implicated in an increased risk of atypical femur fractures located in subtrochanteric and femoral shaft regions. Another measure of drug exposure, medication adherence, however, has not been investigated. METHODS: Among all Medicare fee-for-service female beneficiaries from 2006-2010, we followed 522,287 new bisphosphonate users from their index prescription until being censored or having a primary diagnosis of closed subtrochanteric/femoral shaft or intertrochanteric/femoral neck fractures. Data about radiographs of fracture site and features were not available. Adherence was classified according to the medication possession ratio (MPR) as the following: MPR < 1/3 as less compliant, MPR ≥ 1/3- < 2/3 as compliant, and MPR ≥ 2/3 as highly compliant. Alternative cutoff points at 50 and 80% were also used. Survival analysis was used to determine the cumulative incidence and hazard of subtrochanteric/femoral shaft or intertrochanteric/femoral neck fractures. RESULTS: There was a graded increase in incidence of subtrochanteric/femoral shaft fractures as the level of adherence increased (Gray's test, P < 0.001). The adjusted hazard ratio (HR) for the highly compliant vs. the less compliant was 1.23 (95% Confidence Interval [CI] 1.06-1.43) overall, became significant after 2 years of follow-up (HR = 1.51, 95% CI 1.06-2.15) and reached the highest risk in the fifth year (HR = 4.06, 95% CI 1.47-11.19). However, age-adjusted incidence rates of intertrochanteric/femoral neck fractures were significantly lower among highly compliant beneficiaries, compared to less compliant users (HR = 0.69, 95% CI 0.66-0.73). Similar results were obtained when the cutoff points for being compliant and highly compliant were set at 50 and 80 %, respectively. CONCLUSIONS: Subtrochanteric/femoral shaft fractures, unlike intertrochanteric/femoral neck fractures, are positively associated with higher adherence to long-term (≥3 years) oral bisphosphonates in the elderly female Medicare population.

Tetrathiomolybdate-associated copper depletion decreases circulating endothelial progenitor cells in women with breast cancer at high risk of relapse.

BACKGROUND: Bone marrow-derived endothelial progenitor cells (EPCs) are critical for metastatic progression. This study explores the effect of tetrathiomolybdate (TM), an anti-angiogenic copper chelator, on EPCs in patients at high risk for breast cancer recurrence. PATIENTS AND METHODS: This phase 2 study enrolled breast cancer patients with stage 3 and stage 4 without evidence of disease (NED), and stage 2 if triple-negative. TM 100 mg orally was administered to maintain ceruloplasmin <17 mg/dl for 2 years or until relapse. The primary end point was change in EPCs. RESULTS: Forty patients (28 stage 2/3, 12 stage 4 NED) were enrolled. Seventy-five percent patients achieved the copper depletion target by 1 month. Ninety-one percent of triple-negative patients copper-depleted compared with 41% luminal subtypes. In copper-depleted patients only, there was a significant reduction in EPCs/ml by 27 (P = 0.04). Six patients relapsed while on study, of which only one patient had EPCs maintained below baseline. The 10-month relapse-free survival was 85.0% (95% CI 74.6%-96.8%). Only grade 3/4 toxicity was hematologic: neutropenia (3.1% of cycles), febrile neutropenia (0.2%), and anemia (0.2%). CONCLUSIONS: TM is safe and appears to maintain EPCs below baseline in copper-depleted patients. TM may promote tumor dormancy and ultimately prevent relapse.

European League Against Rheumatism recommendations for monitoring patients with systemic lupus erythematosus in clinical practice and in observational studies.

OBJECTIVES: To develop recommendations for monitoring patients with systemic lupus erythematosus (SLE) in clinical practice and observational studies and to develop a standardised core set of variables to monitor SLE. METHODS: We followed the European League Against Rheumatism (EULAR) standardised procedures for guideline development. The following techniques were applied: nominal groups, Delphi surveys for prioritisation, small group discussion, systematic literature review and two Delphi rounds to obtain agreement. The panel included rheumatologists, internists, dermatologists, a nephrologist and an expert related to national research agencies. The level of evidence and grading of recommendations were determined according to the Levels of Evidence and Grades of Recommendations of the Oxford Centre for Evidence-Based Medicine. RESULTS: A total of 10 recommendations have been developed, covering the following aspects: patient assessment, cardiovascular risk factors, other risk factors (osteoporosis, cancer), infection risk (screening, vaccination, monitoring), frequency of assessments, laboratory tests, mucocutaneous involvement, kidney monitoring, neuropsychological manifestations and ophthalmology assessment. A 'core set' of minimal variables for the assessment and monitoring of patients with SLE in clinical practice was developed that included some of the recommendations. In addition to the recommendations, indications for specific organ assessments that were viewed as part of good clinical practice were discussed and included in the flow chart. CONCLUSIONS: A set of recommendations for monitoring patients with SLE in routine clinical practice has been developed. The use of a standardised core set to monitor patients with SLE should facilitate clinical practice, as well as the quality control of care for patients with SLE, and the collection and comparison of data in observational studies.

Nephritis and the risk of acute myocardial infarction in patients with systemic lupus erythematosus.

BACKGROUNDS: Patients with systemic lupus erythematosus (SLE) have an increased risk of acute myocardial infarction (AMI). We examined if nephritis or other clinical manifestations of SLE identified patients at increased risk. METHODS: In this population-based case-control study, we identified patients with SLE hospitalized with an AMI in California in 1996-2000. We compared the frequency of six manifestations of SLE (nephritis, pleuritis, hemolytic anemia, thrombocytopenia, psychosis/major depression, seizures) and of venous thrombosis/pulmonary embolism, in this group (n=535) to the frequency of these manifestations in two control groups: patients with SLE hospitalised for pulmonary disease (n=529), and patients with SLE hospitalised for gastrointestinal bleeding (n=349). RESULTS: Nephritis was present in 23.7% of patients with AMI, 11.0% of patients with pulmonary disease and 25.2% of patients with gastrointestinal bleeding. In adjusted analyses, nephritis was more common in the AMI group (odds ratio (OR) 2.85, 95% confidence interval (CI) 1.97-4.14; p<.0001) than in the pulmonary disease control group. Among women, nephritis was more common in the AMI group (OR 2.83; 95% CI 1.33-6.01; p=0.007) than in the gastrointestinal bleeding control group. Psychosis/major depression was less common among patients with AMI. CONCLUSIONS: Among patients with SLE, nephritis was associated with 2.8-fold increased risk of AMI.

Challenges comparing functional limitations in rheumatoid arthritis and ankylosing spondylitis.

Whether physical functioning in patients with rheumatoid arthritis (RA) differs from that in patients with ankylosing spondylitis (AS) is presently uncertain. Such a comparison poses challenges, not only because the two diseases differ in the domains of functioning affected, but also because of the different instruments used to measure functional limitations. Limiting our analysis to studies using similar self-report questionnaires, we examined published observational studies of unselected cohorts of patients with RA and patients with AS to compare and contrast the severity of functional limitations. Available studies from a few direct comparisons, and mostly indirect comparisons, suggested that patients with RA are generally more severely limited in physical functioning throughout the disease course than patients with AS. Since most studies did not adjust adequately for potentially important confounders, such as age, gender, comorbidity, and disease duration, reported differences in functional disability between patients with RA and patients with AS must be interpreted cautiously.

Localization and possible function of P2Y(4) receptors in the rodent retina.

Extracellular ATP acts as a neurotransmitter in the retina, via the activation of ionotropic P2X receptors and metabotropic P2Y receptors. The expression of various P2X and P2Y receptor subtypes has been demonstrated in the retina, but the localization of P2Y receptors and their role in retinal signaling remains ill defined. In this study, we were interested in determining the localization of the P2Y(4) receptor subtype in the rat retina, and using the electroretinogram (ERG) to assess whether activation of these receptors modulated visual transmission. Using light and electron microscopy, we demonstrated that P2Y(4) receptors were expressed pre-synaptically in rod bipolar cells and in processes postsynaptic to cone bipolar cells. Furthermore, we show that the expression of P2Y(4) receptors on rod bipolar cell axon terminals is reduced following dark adaptation, suggesting receptor expression may be dependent on retinal activity. Finally, using the electroretinogram, we show that intravitreal injection of uridine triphosphate, a P2Y receptor agonist, decreases the amplitude of the rod PII, supporting a role for P2Y receptors in altering inner retinal function. Taken together, these results suggest a role for P2Y(4) receptors in the modulation of inner retinal signaling.

Treatment-related improvement in physical function varies with duration of rheumatoid arthritis: a pooled analysis of clinical trial results.

BACKGROUND: Physical function in rheumatoid arthritis (RA) has reversible and irreversible components, and is typically assessed by the Health Assessment Questionnaire Disability Index (HAQ). Since irreversible components are expected to increase with longer duration of RA and reduce the ability for improvement in physical function, we analysed responsiveness of HAQ scores in patient populations with differing RA durations in randomised controlled trials (RCTs). METHODS: Data from all RCTs published between 1980 and 2005 that reported changes from baseline in HAQ at 6 and/or 12 months were analysed. Treatments were grouped as "biologics", or "traditional" disease modifying antirheumatic drugs (DMARDs), and "placebo". We computed effect sizes of HAQ in each trial, and contrasted the association between these effects and duration of RA among treatment groups using regression models. RESULTS: We identified 42 RCTs with complete data for the statistical models. The models indicate that discrimination of functional improvement between active drug groups and placebo is reduced in patients with a longer duration of RA (p = 0.02 for the change in discrimination over time). The placebo-adjusted HAQ responses decreased on average by 0.37 per year of RA duration. CONCLUSION: Responsiveness in HAQ scores is inversely associated with mean disease duration in RA. This impacts assessment of physical function, a key outcome measure in RCTs and practice, and impacts the ability to discriminate active treatment from placebo.

Clinical, radiographic and functional differences between juvenile-onset and adult-onset ankylosing spondylitis: results from the PSOAS cohort.

AIMS: Previous data suggests that patients with juvenile-onset ankylosing spondylitis (JoAS) have more severe disease and worse functional outcomes than adult-onset AS (AoAS). The purpose of this study was to evaluate clinical, functional and radiographic differences between patients with JoAS and AoAS in a large cohort of patients with long-standing disease. METHODS: A total of 402 subjects who met the Modified New York Criteria for definitive AS and had had disease >or=20 years were enrolled in a multi-centre cross-sectional study (Prospective Study of Outcomes in Ankylosing Spondylitis; PSOAS). JoAS was defined as initial symptoms

Temporal correlation of antibody responses to different epitopes of the human La autoantigen.

To investigate the temporal relationship of antibody responses to different La epitopes, sequential sera from nine patients with systemic lupus erythematosus and Sjogren's syndrome were tested by enzyme-linked immunosorbent assay for antibody binding to a series of recombinant fusion proteins containing different regions of the La molecule. The results of this analysis indicate that antibody responses to four different La fragments vary in parallel over time. This finding is supported by a statistical analysis indicating that the changes in antibody levels between the six pairs of responses were highly correlated (P less than 0.001). Furthermore, we show by immunoaffinity purification that antibodies to the three nonoverlapping La protein fragments do not cross-react with other fragments and, hence, represent independent populations. These results suggest that anti-La antibodies are coordinately produced to different epitopes on the La molecule, possibly reflecting an antigen-driven mechanism.

Impact of complications on outcomes following aortic and mitral valve replacements in the United States.

AIM: Heart valve replacement surgeries account for 20% of all cardiac procedures. In-hospital mortality rates are approximately 6% for aortic valve replacements and 10% for mitral valve replacements. The objectives of the study are to provide nationally representative estimates of complications following aortic and mitral valve replacements and to quantify the impact of different types of complications on in-hospital outcomes. METHODS: The Nationwide Inpatient Sample was analyzed for years 2000-2003. The effect of complications on in-hospital mortality, length of stay (LOS), and hospital charges were examined using bivariate and multivariable logistic and linear regression analyses. The confounding effects of age, sex, primary diagnosis, type of valve replacement, type of admission, comorbid conditions, and hospital characteristics were adjusted. RESULTS: A total of 43,909 patients underwent aortic valve replacement as the primary procedure during the study period and 16,516 patients underwent mitral valve replacement. Complications occurred in 35.2% of those undergoing aortic valve replacements and in 36.4% of those undergoing mitral valve replacements. Almost half of these are cardiac complications and a quarter involve hemorrhage/hematoma/seroma. Complications were significantly associated with in-hospital mortality, LOS, and hospital charges even after adjusting for patient and hospital characteristics. CONCLUSION: Complications are prevalent and exert a considerable influence on outcomes following aortic and mitral valve replacements. Quality initiatives should focus on minimizing complications and improving processes of care that would enable complications to be better resolved if they occur.

Changes in the incidence of end-stage renal disease due to lupus nephritis, 1982-1995.

BACKGROUND: The availability of more effective treatments for severe lupus nephritis may have influenced the rate at which end-stage renal disease (ESRD) develops in these patients. OBJECTIVE: To examine changes in the incidence of ESRD due to lupus nephritis from 1982 to 1995. METHODS: All patients with incident ESRD included in the US Renal Data System from 1982 to 1995 were studied. The US Renal Data System includes information on all patients who receive Medicare-reimbursed renal replacement therapy, who constitute approximately 94% of all patients with ESRD in the United States. The incidence of ESRD due to lupus nephritis in each year, standardized to the age-sex-ethnicity composition of the US general population in 1990, was computed in this serial cross-sectional study. RESULTS: The standardized incidence rate of ESRD due to lupus nephritis increased steadily from 1.16 cases per million person-years in 1982 to 3.08 cases per million person-years in 1995. The rate of increase was comparable to that of ESRD due to all other primary renal diseases. CONCLUSION: The incidence of ESRD due to lupus nephritis increased steadily over the 14-year study period, despite the introduction of efficacious new treatment regimens for lupus nephritis during this time.

Factors predictive of acute renal failure in rhabdomyolysis.

In a historical cohort study, acute renal failure developed in 16.5% of 157 patients with rhabdomyolysis over a two-year study period. Underlying clinical, laboratory, and causative factors associated with the development of acute renal failure were examined. Factors predictive of renal failure in this setting, determined by multiple logistic regression analysis, included the degree of serum creatine kinase, serum potassium, and serum phosphorus level elevation; the degree of depression of serum albumin level; and the presence of dehydration at presentation or sepsis as the underlying cause. The predictive model that was developed correctly classified 93% of subjects and was statistically validated.

Clinical prognostic factors in lupus nephritis. The importance of hypertension and smoking.

BACKGROUND: Many previous studies of the influence of sociodemographic and clinical factors on the development of renal failure in patients with lupus nephritis have been based on selected subgroups of patients and have yielded conflicting results. We sought to determine the prognostic importance of patient demographic characteristics (age, gender, race, and socioeconomic status), smoking status, and hypertension in the development of end-stage renal disease (ESRD) among patients with lupus nephritis. METHODS: This retrospective cohort study followed an inception cohort of 160 adults with lupus nephritis. The outcome measure was the development of ESRD, defined as the institution of maintenance dialysis or measurement of a creatinine clearance of 10 mL/min or less. Life-table analysis was used to determine differences between patient subgroups in the time to development of ESRD. RESULTS: End-stage renal disease developed in 41 (26%) of 160 patients followed up for a median of 6.4 years. Hypertension and smoking status at the onset of nephritis were strongly associated with differences in the time to development of ESRD. The median time to ESRD among patients with moderate to severe hypertension (diastolic blood pressure, greater than or equal to 105 mm Hg) was 7 months, among patients with mild hypertension (diastolic blood pressure, 90 to 104 mm Hg) it was 146 months, and among normotensive patients it was greater than 273 months. The median time to ESRD among smokers was 145 months and among nonsmokers it was greater than 273 months. These effects persisted in multivariable analyses adjusting for differences among patients in age, gender, socioeconomic status, renal histology, and immunosuppressive treatment. The independent effects of hypertension and smoking resulted in shorter times to renal failure among patients who were both hypertensive and smoking, compared with nonsmoking hypertensive patients. The development of ESRD did not differ among patient demographic subgroups. CONCLUSION: Patient demographic characteristics had no detectable impact on the rate of progression to ESRD in this cohort. Hypertension and smoking appear to be important, potentially modifiable, factors influencing the prognosis of patients with lupus nephritis.

Clinical manifestations of systemic lupus erythematosus. Identification of racial and socioeconomic influences.

The identification of differences in the clinical manifestations of systemic lupus erythematosus (SLE) due to racial and socioeconomic factors has been hampered in previous studies by limitations in the numbers of black patients examined. We sought to define racial differences in the cumulative clinical manifestations of SLE in a large, racially balanced cohort (184 black patients and 174 white patients). Differences in the cumulative disease manifestations of SLE between black and white patients were evaluated by multivariate regression techniques, controlling for socioeconomic status and the potential confounding factors of age, gender, duration of follow-up, and treatments. Race was found to be an important factor influencing the prevalence of 9 of 24 clinical features of SLE. As a group, blacks more commonly manifested anti-Sm and anti-RNP antibodies, discoid skin lesions, and proteinuria, and less commonly manifested photosensitivity, than whites. Among specific age, gender, and socioeconomic subgroups, blacks were more likely than whites to have had psychosis, serositis, and urinary cellular casts, and less likely to have had sicca syndrome. Racial differences in the prevalence of renal failure were due to socioeconomic effects. These results suggest that race is under-recognized as a factor influencing the clinical heterogeneity of SLE.

Exercise and changes in health status in patients with ankylosing spondylitis.

BACKGROUND: Although exercise is a commonly recommended treatment for ankylosing spondylitis (AS), little is known about the effectiveness of unsupervised recreational and back exercises. We examined the effects of recreational exercise and back exercises on patient-reported pain severity, stiffness severity, and functional disability in a prospective longitudinal study of 220 patients with AS. METHODS: Participants provided information on exercise habits and health status every 6 months using mailed questionnaires (median follow-up, 4.5 years). Pain severity and stiffness severity were measured using visual analog scales, and functional disability was measured using the Health Assessment Questionnaire (HAQ) Disability Index. RESULTS: Among all patients, there were no associations between either the number of exercise minutes per week or the number of days of back exercise per week and short-term (6-month) changes in pain, stiffness, or HAQ Disability Index. However, among those who had AS for 15 years or less, pain scores were 0.18 points lower (on a scale of 0-3; P =.04), and stiffness scores were 6.4 points lower (on a scale of 0-100; P =.005) during periods with more than 200 minutes per week of exercise compared with periods with 0 to 30 minutes of exercise per week. Among those who had AS for more than 15 years, pain scores were 0.11 points lower (on a scale of 0-3; P =. 03), and HAQ Disability Indexes were 0.08 points lower (on a scale of 0-3; P<.001) during periods with 5 to 7 days per week of back exercise compared with periods when back exercises were not performed. Less intense levels of exercise were not associated with improvements in health status. CONCLUSIONS: Unsupervised recreational exercise improves pain and stiffness, and back exercise improves pain and function in patients with AS, but these effects differ with the duration of AS. Health status is improved when patients perform recreational exercise at least 30 minutes per day and back exercises at least 5 days per week. Arch Intern Med. 2000;160:2969-2975

Mortality risks associated with specific clinical manifestations of systemic lupus erythematosus.

BACKGROUND: Mortality in patients with systemic lupus erythematosus (SLE) is often related to disease in particular organ systems. We examined the risks of mortality associated with 8 clinical manifestations of SLE and determined whether these risks differed among patients with different sociodemographic characteristics. METHODS: Using life table analysis, we determined the associations of hemolytic anemia, leukopenia, thrombocytopenia, arthritis, serositis, nephritis, psychosis, and seizures with both all-cause mortality and SLE-related mortality in a cohort of 408 patients. RESULTS: Over a median duration of follow-up of 11 years, 144 patients died; 78 deaths (54%) were SLE related. In univariate analyses, the presence of hemolytic anemia, serositis, nephritis, psychosis, and seizures was associated with greater all-cause mortality, while the presence of arthritis was protective. In multivariate analyses that controlled for patient demographic characteristics, nephritis (relative risk, 2.34) and seizures (relative risk, 1.77) were associated with poorer overall survival. Nephritis and seizures, along with thrombocytopenia, were also associated with greater SLE-related mortality, while leukopenia was protective. The risk of death in association with these clinical manifestations did not differ among patient age, sex, race, or socioeconomic subgroups. CONCLUSIONS: The presence of nephritis and seizures each increased the risk of death in patients with SLE approximately 2-fold. Thrombocytopenia also increased the risk of SLE-related mortality, while leukopenia was protective.

Progression of functional disability in patients with rheumatoid arthritis. Associations with rheumatology subspecialty care.

BACKGROUND: To determine whether patients with rheumatoid arthritis and their physicians make appropriate decisions regarding referral to rheumatologists and the need for continuing rheumatology care, we examined the relationship between the progression of functional disability in these patients and their use of rheumatology subspecialty care over time. METHODS: A cohort of 282 patients with rheumatoid arthritis was followed prospectively for up to 10 years. Participants were categorized into three subgroups based on the pattern of care received from rheumatologists over the study period: patients who were never treated by a rheumatologist; patients treated by a rheumatologist only intermittently; and patients treated by a rheumatologist at least once during each 6-month study period. The outcome was the rate of progression of functional disability, measured using the Health Assessment Questionnaire Disability Index. RESULTS: Among the 52 patients who had not been referred to a rheumatologist, 30 (58%) had rates of progression of functional disability that were stable or improving over time (rate < 0.01 Disability Index units per year), while 22 (42%) had rates that were worsening (rate > or = 0.01 Disability Index units per year). Among patients treated by rheumatologists, the average rate of progression was substantially lower among the 69 patients who were treated regularly by a rheumatologist than among 161 patients treated by rheumatologists intermittently (0.008 Disability Index units per year vs 0.020 Disability Index units per year). This difference was associated with more intensive use of second-line antirheumatic medications, and more frequent joint surgeries, among patients treated by rheumatologists on a regular basis. CONCLUSIONS: Most patients with rheumatoid arthritis in this community cohort were treated by a rheumatologist, but 42% of those not referred had progressively increasing functional disability. Among patients treated by rheumatologists, those who had continuing care from rheumatologists experienced lower rates of progression of functional disability than those who had only intermittent care. These results suggest that use of rheumatology subspecialty care is associated with better health outcomes in rheumatoid arthritis.

Soluble interleukin-2 receptor levels in patients with dermatitis herpetiformis.

To determine the role of T-cell activation in dermatitis herpetiformis (DH), soluble IL-2R levels were measured by enzyme-linked immunosorbent assay (ELISA) in the sera of 30 patients with DH. Levels of this shed receptor are considered to be a measure of in vivo T-lymphocyte activation, and are elevated in the sera of many patients with inflammatory and immune-mediated diseases. Fifteen of the thirty (50%) patients with DH had elevated levels of soluble IL-2R compared to one of 31 (3%) healthy HLA-B8 or HLA-DR3 control subjects (p less than 0.00001) and one of 10 (10%) healthy non-HLA-B8/-DR3 subjects (p less than 0.0018). In addition, the mean soluble IL-2R level in the patients with DH (744 +/- 381 U/ml) was also significantly higher than that seen in 31 healthy HLA B8 or HLA DR3 individuals (388 +/- 160 U/ml, p = 0.0001) and 10 healthy non-HLA-B8/DR3 individuals (397 +/- 201 U/ml, p = 0.002). Only two of the 30 patients with DH had active skin lesions at the time of serum sampling, one of whom had elevated levels of IL-2R. Measurement of soluble IL-2R levels in sequential serum samples, available in four patients with DH at times of active and inactive skin disease, demonstrated a temporal association between soluble IL-2R level elevations and active skin disease in two patients and no association in two patients. In one patient a marked elevation in soluble IL-2R levels occurred with the onset of gastrointestinal symptoms, which decreased by 14% with institution of a gluten-free diet. In order to determine if soluble IL-2R levels are related to the mucosal immune response, the IL-2R levels were compared to the level of IgA antibodies directed against the dietary antigen beta-lactoglobulin. Ten of eleven (91%) patients with circulating IgA anti-beta lactoglobulin antibodies were also found to have elevated levels of IL-2R. In contrast, in the patients with no detectable IgA anti-beta lactoglobulin antibodies, only four of 16 (25%) had elevated levels of IL-2R (p = 0.001). Because IL-2R levels are not related to activity of the skin disease in patients with DH but are associated with the presence of IgA antibodies against the dietary antigen beta-lactoglobulin, these results suggest that some of the T-cell activation commonly present in DH reflects an ongoing immune response in the gastrointestinal tract.

Cardiovascular and cerebrovascular morbidity and mortality among women with end-stage renal disease attributable to lupus nephritis.

Cardiovascular and cerebrovascular diseases are common causes of morbidity and mortality in women with systemic lupus erythematosus (SLE) and are also common in patients with end-stage renal disease (ESRD). To determine whether women with ESRD caused by lupus nephritis are at greater risk for morbidity from these conditions than women with other causes of ESRD, data from the US Renal Data System were used to compare incidence rates of hospitalizations for acute myocardial infarction and cerebrovascular accident between women with ESRD caused by lupus nephritis and women with ESRD from other causes. The age- and race-adjusted incidences of hospitalizations for acute myocardial infarction during dialysis were 16.4 hospitalizations/1,000 patient-years among women with ESRD caused by lupus nephritis and 17.3 hospitalizations/1,000 patient-years among women in the comparison group (adjusted hazard ratio, 0.80; 95% confidence interval [CI], 0.58 to 1.08; P = 0.14). Adjusted incidence rates for acute myocardial infarction after renal transplantation also did not differ between these groups. Adjusted incidence rates for hospitalizations for cerebrovascular accident during dialysis were 18.5 hospitalizations/1,000 patient-years among women with ESRD caused by lupus nephritis and 19.2 hospitalizations/1,000 patient-years among women in the comparison group (adjusted hazard ratio, 0.87; 95% CI, 0.66 to 1.14; P = 0.30); incidence rates after transplantation also did not differ between groups. Risks for death from cardiovascular or cerebrovascular diseases also were not increased among women with ESRD caused by lupus nephritis. Sepsis was the most common cause of death in this group. Morbidity and mortality from acute myocardial infarction and cerebrovascular accident were substantially greater among women with ESRD caused by diabetes mellitus. Although morbidity and mortality from cardiovascular and cerebrovascular diseases are common among women with SLE, risks for these outcomes are not greater among women with ESRD caused by lupus nephritis than among other women without diabetes with ESRD.