Cancer Risk in a Large Inception Systemic Lupus Erythematosus Cohort: Effects of Demographic Characteristics, Smoking, and Medications.

OBJECTIVE: To assess cancer risk factors in incident systemic lupus erythematosus (SLE). METHODS: Clinical variables and cancer outcomes were assessed annually among incident SLE patients. Multivariate hazard regression models (overall risk and most common cancers) included demographic characteristics and time-dependent medications (corticosteroids, antimalarial drugs, immunosuppressants), smoking, and the adjusted mean Systemic Lupus Erythematosus Disease Activity Index 2000 score. RESULTS: Among 1,668 patients (average 9 years follow-up), 65 cancers occurred: 15 breast, 10 nonmelanoma skin, 7 lung, 6 hematologic, 6 prostate, 5 melanoma, 3 cervical, 3 renal, 2 each gastric, head and neck, and thyroid, and 1 each rectal, sarcoma, thymoma, and uterine cancers. Half of the cancers (including all lung cancers) occurred in past/current smokers, versus one-third of patients without cancer. Multivariate analyses indicated that overall cancer risk was related primarily to male sex and older age at SLE diagnosis. In addition, smoking was associated with lung cancer. For breast cancer risk, age was positively associated and antimalarial drugs were negatively associated. Antimalarial drugs and higher disease activity were also negatively associated with nonmelanoma skin cancer risk, whereas age and cyclophosphamide were positively associated. Disease activity was associated positively with hematologic and negatively with nonmelanoma skin cancer risk. CONCLUSION: Smoking is a key modifiable risk factor, especially for lung cancer, in SLE. Immunosuppressive medications were not clearly associated with higher risk except for cyclophosphamide and nonmelanoma skin cancer. Antimalarials were negatively associated with breast cancer and nonmelanoma skin cancer risk. SLE activity was associated positively with hematologic cancer and negatively with nonmelanoma skin cancer. Since the absolute number of cancers was small, additional follow-up will help consolidate these findings.

A randomized, controlled double-blind study comparing the efficacy and safety of dose-ranging voclosporin with placebo in achieving remission in patients with active lupus nephritis.

Calcineurin inhibitors added to standard-of-care induction therapy for lupus nephritis (LN) may increase complete renal remission (CRR) rates. The AURA-LV study tested the novel calcineurin inhibitor voclosporin for efficacy and safety in active LN. AURA-LV was a Phase 2, multicenter, randomized, double-blind, placebo-controlled trial of two doses of voclosporin (23.7 mg or 39.5 mg, each twice daily) versus placebo in combination with mycophenolate mofetil (2 g/d) and rapidly tapered low-dose oral corticosteroids for induction of remission in LN. The primary endpoint was CRR at 24 weeks; the secondary endpoint was CRR at 48 weeks. Two hundred sixty-five subjects from 79 centers in 20 countries were recruited and randomized to treatment for 48 weeks. CRR at week 24 was achieved by 29 (32.6%) subjects in the low-dose voclosporin group, 24 (27.3%) subjects in the high-dose voclosporin group, and 17 (19.3%) subjects in the placebo group (OR=2.03 for low-dose voclosporin versus placebo). The significantly greater CRR rate in the low-dose voclosporin group persisted at 48 weeks, and CRRs were also significantly more common in the high-dose voclosporin group compared to placebo at 48 weeks. There were more serious adverse events in both voclosporin groups, and more deaths in the low-dose group compared to placebo and high-dose voclosporin groups (11.2%, 1.1%, and 2.3%, respectively). These results suggest that the addition of low-dose voclosporin to mycophenolate mofetil and corticosteroids for induction therapy of active LN results in a superior renal response compared to mycophenolate mofetil and corticosteroids alone, but higher rates of adverse events including death were observed.

Comparison and evaluation of lupus nephritis response criteria in lupus activity indices and clinical trials.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with diverse manifestations. Although the approval of new therapies includes only one agent in 50 years, a number of promising new drugs are in development. Lupus nephritis is a dreaded complication of SLE as it is associated with significant morbidity and mortality. Advancing the treatment of lupus nephritis requires well-designed clinical trials and this can be challenging in SLE. The major obstacles involve identifying the correct population of patients to enroll and ensuring that a clinically appropriate and patient-centered endpoint is being measured. In this review, we will first discuss the clinical utility of endpoints chosen to represent lupus nephritis in global disease activity scales. Second, we will review completed and active trials focused on lupus nephritis and discuss the endpoints chosen. There are many important lessons to be learned from existing assessment tools and clinical trials. Reviewing these points will help ensure that future efforts will yield meaningful disease activity measures and well-designed clinical trials to advance our understanding of lupus management.

Lymphoma risk in systemic lupus: effects of disease activity versus treatment.

OBJECTIVE: To examine disease activity versus treatment as lymphoma risk factors in systemic lupus erythematosus (SLE). METHODS: We performed case-cohort analyses within a multisite SLE cohort. Cancers were ascertained by regional registry linkages. Adjusted HRs for lymphoma were generated in regression models, for time-dependent exposures to immunomodulators (cyclophosphamide, azathioprine, methotrexate, mycophenolate, antimalarial drugs, glucocorticoids) demographics, calendar year, Sjogren's syndrome, SLE duration and disease activity. We used adjusted mean SLE Disease Activity Index scores (SLEDAI-2K) over time, and drugs were treated both categorically (ever/never) and as estimated cumulative doses. RESULTS: We studied 75 patients with lymphoma (72 non-Hodgkin, three Hodgkin) and 4961 cancer-free controls. Most lymphomas were of B-cell origin. As is seen in the general population, lymphoma risk in SLE was higher in male than female patients and increased with age. Lymphomas occurred a mean of 12.4 years (median 10.9) after SLE diagnosis. Unadjusted and adjusted analyses failed to show a clear association of disease activity with lymphoma risk. There was a suggestion of greater exposure to cyclophosphamide and to higher cumulative steroids in lymphoma cases than the cancer-free controls. CONCLUSIONS: In this large SLE sample, there was a suggestion of higher lymphoma risk with exposure to cyclophosphamide and high cumulative steroids. Disease activity itself was not clearly associated with lymphoma risk. Further work will focus on genetic profiles that might interact with medication exposure to influence lymphoma risk in SLE.

Non-lymphoma hematological malignancies in systemic lupus erythematosus.

OBJECTIVE: To describe non-lymphoma hematological malignancies in systemic lupus erythematosus (SLE). METHODS: A large SLE cohort was linked to cancer registries. We examined the types of non-lymphoma hematological cancers. RESULTS: In 16,409 patients, 115 hematological cancers [including myelodysplastic syndrome (MDS)] occurred. Among these, 33 were non-lymphoma. Of the 33 non-lymphoma cases, 13 were of lymphoid lineage: multiple myeloma (n = 5), plasmacytoma (n = 3), B cell chronic lymphocytic leukemia (B-CLL; n = 3), precursor cell lymphoblastic leukemia (n = 1) and unspecified lymphoid leukemia (n = 1). The remaining 20 cases were of myeloid lineage: MDS (n = 7), acute myeloid leukemia (AML; n = 7), chronic myeloid leukemia (CML; n = 2) and 4 unspecified leukemias. Most of these malignancies occurred in female Caucasians, except for plasma cell neoplasms (4/5 multiple myeloma and 1/3 plasmacytoma cases occurred in blacks). CONCLUSIONS: In this large SLE cohort, the most common non-lymphoma hematological malignancies were myeloid types (MDS and AML). This is in contrast to the general population, where lymphoid types are 1.7 times more common than myeloid non-lymphoma hematological malignancies. Most (80%) multiple myeloma cases occurred in blacks; this requires further investigation.

Cancer risk in systemic lupus: an updated international multi-centre cohort study.

OBJECTIVE: To update estimates of cancer risk in SLE relative to the general population. METHODS: A multisite international SLE cohort was linked with regional tumor registries. Standardized incidence ratios (SIRs) were calculated as the ratio of observed to expected cancers. RESULTS: Across 30 centres, 16,409 patients were observed for 121,283 (average 7.4) person-years. In total, 644 cancers occurred. Some cancers, notably hematologic malignancies, were substantially increased (SIR 3.02, 95% confidence interval, CI, 2.48, 3.63), particularly non-Hodgkin's lymphoma, NHL (SIR 4.39, 95% CI 3.46, 5.49) and leukemia. In addition, increased risks of cancer of the vulva (SIR 3.78, 95% CI 1.52, 7.78), lung (SIR 1.30, 95% CI 1.04, 1.60), thyroid (SIR 1.76, 95% CI 1.13, 2.61) and possibly liver (SIR 1.87, 95% CI 0.97, 3.27) were suggested. However, a decreased risk was estimated for breast (SIR 0.73, 95% CI 0.61-0.88), endometrial (SIR 0.44, 95% CI 0.23-0.77), and possibly ovarian cancers (0.64, 95% CI 0.34-1.10). The variability of comparative rates across different cancers meant that only a small increased risk was estimated across all cancers (SIR 1.14, 95% CI 1.05, 1.23). CONCLUSION: These data estimate only a small increased risk in SLE (versus the general population) for cancer over-all. However, there is clearly an increased risk of NHL, and cancers of the vulva, lung, thyroid, and possibly liver. It remains unclear to what extent the association with NHL is mediated by innate versus exogenous factors. Similarly, the etiology of the decreased breast, endometrial, and possibly ovarian cancer risk is uncertain, though investigations are ongoing.

Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus.

OBJECTIVE: The Systemic Lupus International Collaborating Clinics (SLICC) group revised and validated the American College of Rheumatology (ACR) systemic lupus erythematosus (SLE) classification criteria in order to improve clinical relevance, meet stringent methodology requirements, and incorporate new knowledge regarding the immunology of SLE. METHODS: The classification criteria were derived from a set of 702 expert-rated patient scenarios. Recursive partitioning was used to derive an initial rule that was simplified and refined based on SLICC physician consensus. The SLICC group validated the classification criteria in a new validation sample of 690 new expert-rated patient scenarios. RESULTS: Seventeen criteria were identified. In the derivation set, the SLICC classification criteria resulted in fewer misclassifications compared with the current ACR classification criteria (49 versus 70; P = 0.0082) and had greater sensitivity (94% versus 86%; P < 0.0001) and equal specificity (92% versus 93%; P = 0.39). In the validation set, the SLICC classification criteria resulted in fewer misclassifications compared with the current ACR classification criteria (62 versus 74; P = 0.24) and had greater sensitivity (97% versus 83%; P < 0.0001) but lower specificity (84% versus 96%; P < 0.0001). CONCLUSION: The new SLICC classification criteria performed well in a large set of patient scenarios rated by experts. According to the SLICC rule for the classification of SLE, the patient must satisfy at least 4 criteria, including at least one clinical criterion and one immunologic criterion OR the patient must have biopsy-proven lupus nephritis in the presence of antinuclear antibodies or anti-double-stranded DNA antibodies.

Gonadal failure with cyclophosphamide therapy for lupus nephritis: advances in fertility preservation.

Intravenous cyclophosphamide remains an important therapy for patients with severe systemic lupus erythematosus--including lupus nephritis, which primarily affects women in their reproductive years. As prognosis improves, the chronic toxicity of this therapy assumes greater importance. This article reviews cyclophosphamide use, its effect on gonadal function, and protection of gonadal reserve during therapy. Egg, embryo, or gonadal tissue cryopreservation and alternative therapeutic strategies are considered.

Nonrenal disease activity following mycophenolate mofetil or intravenous cyclophosphamide as induction treatment for lupus nephritis: findings in a multicenter, prospective, randomized, open-label, parallel-group clinical trial.

OBJECTIVE: To assess the effect of mycophenolate mofetil compared with intravenous pulses of cyclophosphamide on the nonrenal manifestations of lupus nephritis. METHODS: Patients with active lupus nephritis (renal biopsy class III, IV, or V) were recruited for the study (n = 370) and treated with mycophenolate mofetil (target dosage 3 gm/day) or intravenous cyclophosphamide (0.5-1.0 gm/m(2)/month), plus tapered prednisone, for 24 weeks. Nonrenal outcomes were determined using measures of whole body disease activity, including the British Isles Lupus Assessment Group (BILAG) disease activity index, the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and immunologic variables. RESULTS: Both treatments were effective on whole body disease activity in the systems examined, as indicated by changes in the classic BILAG index. With either treatment, remission was induced, notably in the mucocutaneous, musculoskeletal, cardiovascular/respiratory, and vasculitis systems, and flares were rare, as measured by the SELENA-SLEDAI. Levels of complement C3, C4, and CH50 and titers of anti-double-stranded DNA antibodies were normalized after treatment with either mycophenolate mofetil or intravenous cyclophosphamide. CONCLUSION: In addition to the efficacy of both treatments on the renal system, this analysis showed that remission could also be induced in other systems. There was no clear difference in efficacy between mycophenolate mofetil and intravenous cyclophosphamide in ameliorating either the renal or nonrenal manifestations. Mycophenolate mofetil is, therefore, a suitable alternative to cyclophosphamide for the treatment of renal and nonrenal disease manifestations in patients with biopsy-proven lupus nephritis.

Predictors of relapse and end stage kidney disease in proliferative lupus nephritis: focus on children, adolescents, and young adults.

BACKGROUND AND OBJECTIVES: The prevalence and significance of remission and relapse in children, adolescents, and young adults with lupus nephritis in the United States are poorly understood. Patterns and predictors of disease progression in a southeastern U.S. pediatric cohort with severe lupus nephritis are presented. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS: Individuals age 21 or less with kidney biopsy-proven lupus nephritis followed in the Glomerular Disease Collaborative Network were included. Cox regression models were used to evaluate predictors of relapse and end stage kidney disease (ESKD). RESULTS: Seventy-three subjects with a mean age of 15.6 +/- 3.4 yr were included. Five-year kidney survival was 77%. Complete and partial remission rates within 1 yr of induction therapy were 25 and 64%, respectively. Relapse and ESKD rates were similar between complete and partial responders. Relapse occurred in 35% of responders (complete or partial) in 45 +/- 32 mo. Disease relapse was a predictor of ESKD (HR = 10.12, P < 0.0001). Treatment resistance was documented in African Americans more often than non-African Americans (eight versus 0; P = 0.03). ESKD HR associated with treatment resistance was 6.25, P < 0.002. CONCLUSIONS: Remission whether complete or partial is associated with improved kidney survival in children with lupus nephritis. Nephritis relapse is a strong predictor of progression to ESKD. Treatment resistance portends a high risk of ESKD and disproportionately affects African American children with lupus nephritis.

Pharmacokinetics of mycophenolic acid in patients with lupus nephritis.

STUDY OBJECTIVES: To evaluate and describe the pharmacokinetics of mycophenolic acid and its metabolite, mycophenolic acid glucuronide (MPAG), in patients with lupus nephritis, and to determine the effects of clinical parameters (urinary protein excretion as measured by the urinary protein:creatinine ratio, serum albumin level, and creatinine clearance) and demographic variables (age, race, sex) on the pharmacokinetics of total and unbound mycophenolic acid and MPAG. DESIGN: Pharmacokinetic analysis. SETTING: University-affiliated general clinical research center. PATIENTS: Eighteen patients with biopsy-confirmed lupus nephritis who were receiving maintenance therapy with mycophenolic acid for at least 2 weeks. INTERVENTION: Plasma and urine samples were collected for 24 hours and were assayed by high-performance liquid chromatography with ultraviolet detection. MEASUREMENTS AND MAIN RESULTS: Time to maximum concentration was variable (0.5-8 hrs). Mean +/- SD fraction of unbound mycophenolic acid was 2.6 +/- 1.9%, and oral clearance (Cl/F) was about 2-fold higher (343 +/- 200 ml/min) than previously reported. Multiple regression analysis showed that Cl/F of mycophenolic acid was predicted by creatinine clearance and serum albumin level: ln Cl/F = 5.358 + 0.0092 (creatinine clearance) - 0.078 (ranked albumin), R(2)=51.1%, p=0.0195. Patients with urinary protein excretion of 1 g/day or higher had lower minimum (trough) concentrations and area under the concentration-time curve (AUC(0-12)) profiles and higher Cl/F values compared with patients with urinary protein excretion of less than 1 g/day. Patients with serum albumin levels less than 4 g/dl had higher mycophenolic acid unbound clearance and MPAG renal clearance from 0-12 hours versus those with serum albumin levels of 4 g/dl or greater. Recycling AUC (AUC(6-12)), as well as sex and age (both equally), predicted renal clearance of MPAG. CONCLUSION: Both creatinine clearance and serum albumin level were identified as primary contributors to mycophenolic acid exposure and should be considered when evaluating dosages. The results of future studies should clarify the interactions of other variables on drug exposure and treatment responses. Clinicians need to be mindful of clinical changes that occur throughout the course of lupus nephritis in order to maintain efficacy and reduce toxicity from mycophenolic acid therapy.

Therapy Insight: preserving fertility in cyclophosphamide-treated patients with rheumatic disease.

Cyclophosphamide remains a necessary treatment for severe rheumatic diseases, despite the continued search for alternative therapies with less gonadal toxicity. The risk of premature gonadal failure and sterility might lead young patients to delay treatment with cyclophosphamide. The patient's age at treatment and the cumulative dose received remain important risk factors for cyclophosphamide-induced gonadal failure in both males and females. Estrogen-containing oral contraceptives for females and testosterone for males are suggested to reduce the gonadal toxicity of cyclophosphamide, although few studies support these interventions. Owing to increased side effects, hormonal therapy is often avoided in patients with edema, hypertension, nephrotic syndrome or antiphospholipid antibodies. Agonists and antagonists of gonadotropin receptors are under study. Gonadotropin-receptor agonists might have beneficial effects in addition to suppression of sex-hormone production. The outcome of attempted cryopreservation of eggs, embryos or ovaries remains uncertain for women seeking to preserve their reproductive potential. Storing male gametes before chemotherapy is widely practiced and technically successful. As recovery of menses or production of testosterone does not predict individual fertility, identification of biomarkers of gonadal function and reserve, including serum levels of several hormones, ultrasonographic measurements of ovarian volume and antral follicle count, are necessary.

A novel subset of memory B cells is enriched in autoreactivity and correlates with adverse outcomes in SLE.

We previously reported that some systemic lupus erythematosus (SLE) patients have a population of circulating memory B cells with >2-fold higher levels of CD19. We show here that the presence of CD19(hi) B cells correlates with long-term adverse outcomes. These B cells do not appear anergic, as they exhibit high basal levels of phosphorylated Syk and ERK1/2, signal transduce in response to BCR crosslinking, and can become plasma cells (PCs) in vitro. Autoreactive anti-Smith (Sm) B cells are enriched in this population and the degree of enrichment correlates with the log of the serum anti-Sm titer, arguing that they undergo clonal expansion before PC differentiation. PC differentiation may occur at sites of inflammation, as CD19(hi) B cells have elevated CXCR3 levels and chemotax in response to its ligand CXCL9. Thus, CD19(hi) B cells are precursors to anti-self PCs, and identify an SLE patient subset likely to experience poor clinical outcomes.

Similar CD19 dysregulation in two autoantibody-associated autoimmune diseases suggests a shared mechanism of B-cell tolerance loss.

: We report here that dysregulation of CD19, a coreceptor that augments B-cell receptor (BCR) signaling, occurs at two B-cell differentiative stages in patients with systemic lupus erythematosus (SLE) and antineutrophil cytoplasmic autoantibody (ANCA) associated small vessel vasculitis (SVV). The naïve B cells of nearly all SLE and ANCA-SVV patients express approximately 20% less CD19 than healthy control (HC) B cells. In contrast, a subset of memory B cells of some SLE and ANCA-SVV Pts (25-35%) express two to fourfold more CD19 than HC B cells. These CD19(hi) memory B cells are activated and exhibit evidence of antigen selection. Proteome array analysis of 67 autoantigens indicates that CD19(hi) SLE Pts exhibit a distinct autoantibody profile characterized by high levels of antibodies to small nuclear ribonucleoproteins and low levels of antiglomerular autoantibodies. These findings have implications for autoreactive B-cell activation and suggest a shared mechanism of B-cell tolerance loss in these two diseases.

Association of Epstein-Barr virus with systemic lupus erythematosus: effect modification by race, age, and cytotoxic T lymphocyte-associated antigen 4 genotype.

OBJECTIVE: Epstein-Barr virus (EBV) is hypothesized to play a role in the development of systemic lupus erythematosus (SLE). Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is important in regulating T cell-mediated immunity, encompassing the first line of response to viral infections, and genetic variation in CTLA-4 has been associated with SLE. This study examined the seroprevalence of EBV in a population-based study of SLE patients from the southeastern United States, and potential interactions with CTLA-4 polymorphisms were assessed. METHODS: Cases comprised 230 subjects recently diagnosed as having SLE (144 African American and 86 white) from university and community-based clinics, and controls comprised 276 age-, sex-, and state-matched subjects (72 African American and 204 white) recruited from driver's license registries. Antibodies to EBV capsid antigen were determined by enzyme-linked immunosorbent assay, with results expressed as positive or negative using the international standardized ratio (ISR) (a ratio of the sample absorbance to a known standard). CTLA-4 genotypes were identified by polymerase chain reaction-based methods. RESULTS: In African Americans, EBV-IgA seroprevalence was strongly associated with SLE (odds ratio [OR] 5.6, 95% confidence interval [95% CI] 3.0-10.6). In whites, the modest association of SLE with EBV-IgA (OR 1.6) was modified by age, in that the strongest association was observed in those older than age 50 years (OR 4.1, 95% CI 1.6-10.4). The seroprevalence of EBV-IgM and that of EBV-IgG were not associated with SLE. Higher EBV-IgG absorbance ratios were observed in SLE patients, with a significant dose response across units of the ISR in African Americans (P < 0.0001). Allelic variation in the CTLA-4 gene promoter (-1661A/G) significantly modified the association between SLE and EBV-IgA (P = 0.03), with a stronger association among those with the -1661AA genotype. CONCLUSION: These findings suggest that repeated or reactivated EBV infection, which results in increased EBV-IgA seroprevalence and higher IgG antibody titers, may be associated with SLE, and that the CTLA-4 genotype influences immune responsiveness to EBV in SLE patients. The observed patterns of effect modification by race, age, and CTLA-4 genotype should be examined in other studies and may help frame new hypotheses regarding the role of EBV in SLE etiology.

Angiotensin-converting enzyme (insertion/deletion) and endothelial nitric oxide synthase polymorphisms in patients with systemic lupus erythematosus.

OBJECTIVE: Genetic polymorphisms in the angiotensin-converting enzyme (ACE) and endothelial nitric oxide synthase (eNOS) are linked with expression and/or progression of renal disease. We hypothesized that polymorphisms in the genes coding for ACE and eNOS may influence the development and/or progression of systemic lupus erythematosus (SLE) and lupus nephritis given their linkage with other renal diseases. METHODS: DNA from patients with SLE (n = 227) and their age and sex matched controls (n = 275) from the Carolina Lupus (CLU) Study cohort was assessed for ACE and eNOS polymorphisms. Seventy patients had biopsy-proven lupus nephritis. Two different eNOS polymorphisms (eNOS promoter T-786(R)C nucleotide substitution and eNOS 27 base pair tandem repeat in intron 4) and the ACE insertion/deletion (I/D) polymorphism in intron 16 were examined by restriction fragment length polymorphism-polymerase chain reaction. RESULTS: Allele frequency of the eNOS polymorphisms varied significantly between SLE patients and controls. There was no association of these polymorphisms with lupus within ethnic groups. We found no association of the polymorphism with the development of renal disease. No association was observed for the ACE I/D polymorphism with SLE or nephritis, or with ethnicity or sex. CONCLUSION: eNOS genetic polymorphisms differed significantly across ethnic groups. There was no significant increased risk of SLE and/or lupus nephritis associated with eNOS or ACE polymorphisms in either the African American or Caucasian groups compared to ethnically matched controls. These studies emphasize the need to control for ethnicity when investigating genetic polymorphisms and disease.

Genetic polymorphisms in tumor necrosis factor (TNF)-alpha and TNF-beta in a population-based study of systemic lupus erythematosus: associations and interaction with the interleukin-1alpha-889 C/T polymorphism.

Tumor necrosis factor (TNF) is involved in the pathogenesis of systemic lupus erythematosus (SLE), but the role of TNF polymorphisms in SLE susceptibility remains unclear. Previous studies in different populations report an inconsistent association of the TNF-alpha -308A allele with SLE, sometimes depending on the presence of HLA-DR3. We examined the association of polymorphisms in TNF-alpha (-308G/A, -238G/A) and TNFbeta (+252A/G) in a population-based study of SLE in the southeastern United States and considered TNF-SLE associations with respect to HLA-DR3 and DR2 and the interleukin (IL)-1alpha -889C/T polymorphism, previously linked to SLE in this population. Genotypes were analyzed for 230 recently diagnosed SLE patients who met American College of Rheumatology classification criteria and 276 age- and sex-matched controls, randomly selected from driver's license registries. Carriage of the TNF-alpha -308A allele was significantly associated with SLE in Caucasians (OR = 2.3; 95% CI 1.4, 3.9), but not African Americans. Analyses stratified by IL-1alpha -889 genotypes (C/C vs C/T or T/T) revealed independent associations of SLE with TNF-alpha -308A or HLA-DR2 and DR3. This reflected a significant interaction of TNF and IL-1 genotypes in Caucasians, and yielded a strong association (OR = 8.0, p < 0.00001) for the combined "HLA-DR3, TNF-alpha -308A, IL-1alpha -889C/C" genotype. These findings provide evidence of cytokine gene epistasis in SLE susceptibility.

Hormonal and reproductive risk factors for development of systemic lupus erythematosus: results of a population-based, case-control study.

OBJECTIVE: Estrogen and prolactin may accelerate the progression of murine systemic lupus erythematosus (SLE). In humans, 85% of lupus patients are women, which also suggests the importance of hormonal factors in disease pathogenesis. The purpose of this study was to examine hormonal and reproductive risk factors for lupus among women. METHODS: This population-based, case-control study included 240 female SLE patients diagnosed between January 1, 1995 and July 31, 1999 who fulfilled the American College of Rheumatology classification criteria. Female controls (n = 321) were identified through driver's license records. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) as measures of association, adjusting for age, state, race, and education. Analyses were limited to exposures before diagnosis. RESULTS: Breast-feeding was associated with a decreased risk of developing SLE (OR 0.6, 95% CI 0.4-0.9), with a statistically significant trend for number of babies breast-fed and total weeks of breast-feeding. There were no associations with number of pregnancies or live births. Natural menopause occurred earlier in women with subsequent development of SLE compared with controls (P < 0.001). There was little association between SLE and current use or duration of use of hormone replacement therapy or oral contraceptives, and no association with previous use of fertility drugs. CONCLUSION: We found little evidence that estrogen- or prolactin-related exposures are associated with an increased risk of lupus. The reduced risk observed among women who had breast-fed one or more babies should be examined in other studies. Early natural menopause, rather than decreasing risk of SLE because of reduced estrogen exposure, may be a marker of susceptibility to development of SLE.

Occupational exposure to crystalline silica and risk of systemic lupus erythematosus: a population-based, case-control study in the southeastern United States.

OBJECTIVE: Crystalline silica may act as an immune adjuvant to increase inflammation and antibody production, and findings of occupational cohort studies suggest that silica exposure may be a risk factor for systemic lupus erythematosus (SLE). We undertook this population-based study to examine the association between occupational silica exposure and SLE in the southeastern US. METHODS: SLE patients (n = 265; diagnosed between January 1, 1995 and July 31, 1999) were recruited from 4 university rheumatology practices and 30 community-based rheumatologists in 60 contiguous counties. Controls (n = 355), frequency-matched to patients by age, sex, and state of residence, were randomly selected from driver's license registries. The mean age of the patients at diagnosis was 39 years; 91% were women and 60% were African American. Detailed occupational and farming histories were collected by in-person interviews. Silica exposure was determined through blinded assessment of job histories by 3 industrial hygienists, and potential medium- or high-level exposures were confirmed through followup telephone interviews. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated by logistic regression. RESULTS: More patients (19%) than controls (8%) had a history of medium- or high-level silica exposure from farming or trades. We observed an association between silica and SLE (medium exposure OR 2.1 [95% CI 1.1-4.0], high exposure OR 4.6 [95% CI 1.4-15.4]) that was seen in separate analyses by sex, race, and at different levels of education. CONCLUSION: These results suggest that crystalline silica exposure may promote the development of SLE in some individuals. Additional research is recommended in other populations, using study designs that minimize potential selection bias and maximize the quality of exposure assessment.

Effects of an osteoporosis prevention program incorporating tailored educational materials.

PURPOSE: To evaluate the effects of two interventions on calcium intake and exercise and assess whether intervention effects varied as a function of participants' stage of change. DESIGN: The study used a 2 by 2 factorial research design. Baseline, 3-, 6-, and 12-month follow-up data were collected. SETTING: Twelve counties in western North Carolina. SUBJECTS: Of 714 women recruited, 547 (76.6%) completed all data collection procedures. INTERVENTION: One intervention, conducted at the individual level, compared the effects of tailored vs. nontailored educational materials. The tailored educational intervention was delivered via two packets of written materials and one telephone counseling session. The written materials and counseling session were tailored according to participants' current calcium intake and exercise level, perceived adequacy of these behaviors, stage of change, behavioral goals, and perceived barriers to change. A community-based intervention was also evaluated. This intervention, implemented in 6 of the 12 counties, included establishing an Osteoporosis Resource Center, conducting a workshop on osteoporosis prevention, and offering free bone density screening. MEASURES: Outcome measures were calcium intake and exercise level. Stage of change was assessed as a moderating variable. RESULTS: Irrespective of intervention group, among women not consuming adequate calcium at baseline, intake increased an average of about 500 mg/d over the course of the study. Changes involving exercise were more modest. Repeated measures regression analyses were used to evaluate intervention effects. The effect of the tailored educational intervention varied, in appropriate ways, among women in different stages of change at baseline (F2,527 = 6.37, p < .002). Among women in the Engaged stage, the tailored intervention was associated with a greater increase in calcium intake. In contrast, among women who were obtaining adequate calcium at baseline (i.e., Action stage), the tailored intervention appeared to forestall inappropriate increases in calcium intake. The community-based intervention had no consistent effects on calcium intake, either alone, or in combination with the tailored intervention. Finally, neither intervention had an effect on exercise, either alone or in combination. CONCLUSIONS: Limited support for the superiority of tailored vs. nontailored educational interventions was found. The differential effects observed could be due to the telephone counseling received by women in the Tailored Education Group, however.