Emily E. Lewis

Population-Based Incidence and Prevalence of Systemic Lupus Erythematosus: The Michigan Lupus Epidemiology and Surveillance Program

OBJECTIVE To estimate the incidence and prevalence of systemic lupus erythematosus (SLE) in a sociodemographically diverse southeastern Michigan source population of 2.4 million people. METHODS SLE cases fulfilling the American College of Rheumatology classification criteria (primary case definition) or meeting rheumatologist-judged SLE criteria (secondary definition) and residing in Wayne or Washtenaw Counties during 2002-2004 were included. Case finding was performed from 6 source types, including hospitals and private specialists. Age-standardized rates were computed, and capture-recapture was performed to estimate underascertainment of cases. RESULTS The overall age-adjusted incidence and prevalence (ACR definition) per 100,000 persons were 5.5 (95% confidence interval [95% CI] 5.0-6.1) and 72.8 (95% CI 70.8-74.8). Among females, the incidence was 9.3 per 100,000 persons and the prevalence was 128.7 per 100,000 persons. Only 7 cases were estimated to have been missed by capture-recapture, adjustment for which did not materially affect the rates. SLE prevalence was 2.3-fold higher in black persons than in white persons, and 10-fold higher in females than in males. Among incident cases, the mean ± SD age at diagnosis was 39.3 ± 16.6 years. Black SLE patients had a higher proportion of renal disease and end-stage renal disease (ESRD) (40.5% and 15.3%, respectively) as compared to white SLE patients (18.8% and 4.5%, respectively). Black patients with renal disease were diagnosed as having SLE at younger age than white patients with renal disease (mean ± SD 34.4 ± 14.9 years versus 41.9 ± 21.3 years; P = 0.05). CONCLUSION SLE prevalence was higher than has been described in most other population-based studies and reached 1 in 537 among black female persons. There were substantial racial disparities in the burden of SLE, with black patients experiencing earlier age at diagnosis, >2-fold increases in SLE incidence and prevalence, and increased proportions of renal disease and progression to ESRD as compared to white patients.

The Apoptotic Ligands TRAIL, TWEAK, and Fas Ligand Mediate Monocyte Death Induced by Autologous Lupus T Cells

Individuals with systemic lupus erythematosus show evidence of a significant increase in monocyte apoptosis. This process is mediated, at least in part, by an autoreactive T cell subset that kills autologous monocytes in the absence of nominal Ag. We have investigated the apoptotic pathways involved in this T cell-mediated process. Expression of the apoptotic ligands TRAIL, TNF-like weak inducer of apoptosis (TWEAK), and Fas ligand on lupus T cells was determined, and the role of these molecules in the monocyte apoptotic response was examined. We report that these apoptotic ligands mediate the autologous monocyte death induced by lupus T cells and that this cytotoxicity is associated with increased expression of these molecules on activated T cells, rather than with an increased susceptibility of lupus monocytes to apoptosis induced by these ligands. These results define novel mechanisms that contribute to increased monocyte apoptosis characterizing patients with lupus. We propose that this mechanism could provide a source of potentially antigenic material for the autoimmune response and interfere with normal clearing mechanisms.

Population-Based Incidence and Prevalence of Systemic Lupus Erythematosus

OBJECTIVE To estimate the incidence and prevalence of systemic lupus erythematosus (SLE) in a sociodemographically diverse southeastern Michigan source population of 2.4 million people. METHODS SLE cases fulfilling the American College of Rheumatology classification criteria (primary case definition) or meeting rheumatologist-judged SLE criteria (secondary definition) and residing in Wayne or Washtenaw Counties during 2002-2004 were included. Case finding was performed from 6 source types, including hospitals and private specialists. Age-standardized rates were computed, and capture-recapture was performed to estimate underascertainment of cases. RESULTS The overall age-adjusted incidence and prevalence (ACR definition) per 100,000 persons were 5.5 (95% confidence interval [95% CI] 5.0-6.1) and 72.8 (95% CI 70.8-74.8). Among females, the incidence was 9.3 per 100,000 persons and the prevalence was 128.7 per 100,000 persons. Only 7 cases were estimated to have been missed by capture-recapture, adjustment for which did not materially affect the rates. SLE prevalence was 2.3-fold higher in black persons than in white persons, and 10-fold higher in females than in males. Among incident cases, the mean ± SD age at diagnosis was 39.3 ± 16.6 years. Black SLE patients had a higher proportion of renal disease and end-stage renal disease (ESRD) (40.5% and 15.3%, respectively) as compared to white SLE patients (18.8% and 4.5%, respectively). Black patients with renal disease were diagnosed as having SLE at younger age than white patients with renal disease (mean ± SD 34.4 ± 14.9 years versus 41.9 ± 21.3 years; P = 0.05). CONCLUSION SLE prevalence was higher than has been described in most other population-based studies and reached 1 in 537 among black female persons. There were substantial racial disparities in the burden of SLE, with black patients experiencing earlier age at diagnosis, >2-fold increases in SLE incidence and prevalence, and increased proportions of renal disease and progression to ESRD as compared to white patients.

Accelerated Macrophage Apoptosis Induces Autoantibody Formation and Organ Damage in Systemic Lupus Erythematosus

Increased monocyte/macrophage (Mφ) apoptosis occurs in patients with systemic lupus erythematosus (SLE) and is mediated, at least in part, by an autoreactive CD4+ T cell subset. Furthermore, autoreactive murine CD4+ T cells that kill syngeneic Mφ in vitro induce a lupus-like disease in vivo. However, it is unclear whether increased Mφ apoptosis in SLE per se is sufficient to accelerate/promote autoimmunity. We have investigated whether increased Mφ apoptosis in vivo, induced by the administration of clodronate liposomes, can exacerbate the autoimmune phenotype in NZB × SWR (SNF1) lupus-prone mice, and induce autoantibody production in haplotype-matched BALB/c × DBA1 (DBF1) non-lupus-prone mice. Lupus-prone mice SNF1 mice that were treated with clodronate liposomes, but not mice treated with vehicle, developed significant increases in autoantibodies to dsDNA, nucleosomes, and the idiotypically related family of nephritic Abs IdLNF1, when compared with untreated SNF1 mice. Furthermore, clodronate treatment hastened the onset of proteinuria and worsened SNF1 lupus nephritis. When compared with vehicle-treated controls, clodronate-treated non-lupus-prone DBF1 mice developed significantly higher levels of anti-nucleosome and IdLNF1 Abs but did not develop lupus nephritis. We propose that Mφ apoptosis contributes to the pathogenesis of autoantibody formation and organ damage through both an increase in the apoptotic load and impairment in the clearance of apoptotic material. This study suggests that mechanisms that induce scavenger cell apoptosis, such as death induced by autoreactive cytotoxic T cells observed in SLE, could play a pathogenic role and contribute to the severity of the disease.

Type I Interferons Are Associated with Subclinical Markers of Cardiovascular Disease in a Cohort of Systemic Lupus Erythematosus Patients

Background Systemic lupus erythematosus (SLE) patients have a striking increase in cardiovascular (CV) comorbidity not fully explained by the Framingham risk score. Recent evidence from in vitro studies suggests that type I interferons (IFN) could promote premature CV disease (CVD) in SLE. We assessed the association of type I IFN signatures with functional and anatomical evidence of vascular damage, and with biomarkers of CV risk in a cohort of lupus patients without overt CVD. Methodology/Principal Findings Serum type I IFN activity (induction of five IFN-inducible genes; IFIGs) from 95 SLE patient and 38 controls was quantified by real-time PCR. Flow mediated dilatation (FMD) of the brachial artery and carotid intima media thickness (CIMT) were quantified by ultrasound, and coronary calcification by computed tomography. Serum vascular biomarkers were measured by ELISA. We evaluated the effect of type I IFNs on FMD, CIMT and coronary calcification by first applying principal components analysis to combine data from five IFIGs into summary components that could be simultaneously modeled. Three components were derived explaining 97.1% of the total IFIG variation. Multivariable linear regression was utilized to investigate the association between the three components and other covariates, with the outcomes of FMD and CIMT; zero-inflated Poisson regression was used for modeling of coronary calcification. After controlling for traditional CV risk factors, enhanced serum IFN activity was significantly associated with decreased endothelial function in SLE patients and controls (p<0.05 for component 3), increased CIMT among SLE patients (p<0.01 for components 1 and 2), and severity of coronary calcification among SLE patients (p<0.001 for component 3). Conclusions Type I IFNs are independently associated with atherosclerosis development in lupus patients without history of overt CVD and after controlling for Framingham risk factors. This study further supports the hypothesis that type I IFNs promote premature vascular damage in SLE.

The peroxisome-proliferator activated receptor-γ agonist pioglitazone modulates aberrant T cell responses in systemic lupus erythematosus.

PPAR-γ agonists can suppress autoimmune responses and renal inflammation in murine lupus but the mechanisms implicated in this process remain unclear. We tested the effect of the PPAR-γ agonist pioglitazone in human lupus and control PBMCs with regard to gene regulation and various functional assays. By Affymetrix microarray analysis, several T cell-related pathways were significantly highlighted in pathway analysis in lupus PBMCs. Transcriptional network analysis showed IFN-γ as an important regulatory node, with pioglitazone treatment inducing transcriptional repression of various genes implicated in T cell responses. Confirmation of these suppressive effects was observed specifically in purified CD4+ T cells. Pioglitazone downregulated lupus CD4+ T cell effector proliferation and activation, while it significantly increased proliferation and function of lupus T regulatory cells. We conclude that PPAR-γ agonists selectively modulate CD4+ T cell function in SLE supporting the concept that pioglitazone and related,-agents should be explored as potential therapies in this disease.

Systemic lupus erythematosus complicated by diffuse alveolar haemorrhage: risk factors, therapy and survival.

Objectives While diffuse alveolar haemorrhage (DAH) is recognised as a life-threatening complication of systemic lupus erythematosus (SLE), little is known about its risk factors and response to treatment. We describe 22 cases of DAH in a US lupus cohort of approximately 1000 patients, and compare them to 66 controls from the same outpatient cohort. Methods We captured variables pertaining to diagnoses of SLE and secondary antiphospholipid syndrome (APS), and analysed them by univariate testing. Those variables with p values <0.05 were then further considered in a multivariate model. Kaplan-Meier curves were constructed for each group, and survival was analysed by Log-rank test. Results Of the 22 patients with DAH, 59% were diagnosed with DAH within 5 years of lupus diagnosis. By univariate testing, several manifestations of SLE and APS were more common in patients with DAH, including history of thrombocytopenia, cardiac valve disease, low C3, leucopenia, neuropsychiatric features, haemolysis, arterial thrombosis, lupus anticoagulant, secondary APS and low C4. On multivariate analysis, history of thrombocytopenia and low C3 were maintained as independent risk factors. Importantly, only two patients had platelet counts <50 000/µL at the time of the DAH episode, arguing that DAH was not simply a haemorrhagic complication of thrombocytopenia. All patients were treated with increased immunosuppression, including various combinations of corticosteroids, plasmapheresis, cyclophosphamide, rituximab and mycophenolate mofetil. Notably, all patients in the cohort survived their initial episode of DAH. While the patients with DAH did well in the short-term, their long-term survival was significantly worse than controls. Several of the deaths were attributable to thrombotic complications after recovering from DAH. Conclusions To the best of our knowledge, this is the largest case–control study of lupus DAH to date. History of thrombocytopenia was strongly predictive of DAH (OR ∼40). A number of APS manifestations correlated with DAH by univariate analysis, and deserve further consideration in larger studies.

Effects of Prasterone (dehydroepiandrosterone) on markers of cardiovascular risk and bone turnover in premenopausal women with systemic lupus erythematosus: a pilot study

DHEA (dehydroepiandrosterone) is a weak androgen with proposed efficacy in the treatment of mild to moderate lupus, and possible beneficial effects on cardiovascular risk and bone mineral density. We hypothesized that treatment with 200 mg a day of Prasterone (DHEA) would improve pre-clinical measures of atherosclerosis: flow-mediated dilatation (FMD), nitroglycerin-mediated dilatation (NMD), and circulating apoptotic endothelial cells (CD 146AnnV +), as well markers of bone metabolism. Thirteen premenopausal female patients with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) ≤8 were enrolled in a double-blind placebo-controlled crossover trial for 22 weeks with a 6-week washout between treatment periods. Results reveal high-density lipoprotein (HDL) levels significantly decreased with Prasterone (48.5 versus 56.3 with placebo, p ≤ 0.001), and there was a trend towards impairment of endothelial function with Prasterone (brachial artery FMD 3.4% versus 4.4% with placebo, mean difference -1.07, NMD 19.5% versus 24.4% with placebo, mean difference -4.9, p = NS). There were no differences between groups in SLEDAI, CD146 AnnV+ cells, or receptor activator for nuclear factor kB ligand (RANKL)/osteoprotegerin, although RANKL was higher after treatment with Prasterone (mean difference -29.5 units; p = 0.097). This pilot study does not support the use of Prasterone in mild lupus for prevention of atherosclerosis or osteoporosis, and confirms other findings of potentially harmful effects on lipids.

The ratio of erythrocyte sedimentation rate to C-reactive protein is useful in distinguishing infection from flare in systemic lupus erythematosus patients presenting with fever:

Background Both C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) can be elevated in systemic lupus erythematosus (SLE) flare and infection, and are therefore of limited utility for distinguishing between the two conditions in febrile SLE patients. Methods A medical records review of hospitalizations (1997–2006) of SLE patients in the Michigan Lupus Cohort was performed. Eligible hospitalizations were those in which patients presented with a temperature of >100.3°F or with subjective fevers as a presenting complaint at admission. Detailed demographic, clinical, and laboratory data were collected. Multivariable logistic regression was used to examine the associations between ESR and CRP and the outcome of flare vs infection, adjusted for confounders. Results Among 557 SLE patients screened, there were 53 eligible hospitalizations (28 flares and 25 infections). Each unit increase in the ratio of ESR:CRP was associated with a 17% increase in the odds of fever being attributable to SLE flare compared to infection (OR 1.17, 95% CI 1.04, 1.31; p = 0.009), when adjusted for white blood cell count, SLE duration, sex, race, and age. ESR and CRP were not individually associated with flare vs infection when modeled with their ratio. Conclusions The ratio of ESR:CRP may provide diagnostic value beyond individual ESR and CRP levels in distinguishing flare vs infection in SLE patients presenting with fever.

Utility and Associated Risk of Pulmonary Embolism Computed Tomography Scans in the Michigan Lupus Cohort

Systemic lupus erythematosus patients are frequently evaluated for chest pain and may have multiple pulmonary embolism (PE) computed tomography (CT) scans. This study was undertaken to determine the incidence of pulmonary embolism in the University of Michigan Lupus Cohort patients who have undergone PE CT scans and to estimate the associated increased risk of breast and lung cancer from radiation exposure.