The prevalence and determinants of anti-DFS70 autoantibodies in an international inception cohort of systemic lupus erythematosus patients.

Autoantibodies to dense fine speckles 70 (DFS70) are purported to rule out the diagnosis of SLE when they occur in the absence of other SLE-related autoantibodies. This study is the first to report the prevalence of anti-DFS70 in an early, multinational inception SLE cohort and examine demographic, clinical, and autoantibody associations. Patients were enrolled in the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort within 15 months of diagnosis. The association between anti-DFS70 and multiple parameters in 1137 patients was assessed using univariate and multivariate logistic regression. The frequency of anti-DFS70 was 7.1% (95% CI: 5.7-8.8%), while only 1.1% (95% CI: 0.6-1.9%) were monospecific for anti-DFS70. In multivariate analysis, patients with musculoskeletal activity (Odds Ratio (OR) 1.24 [95% CI: 1.10, 1.41]) or with anti-ß2 glycoprotein 1 (OR 2.17 [95% CI: 1.22, 3.87]) were more likely and patients with anti-dsDNA (OR 0.53 [95% CI: 0.31, 0.92]) or anti-SSB/La (OR 0.25 [95% CI: 0.08, 0.81]) were less likely to have anti-DFS70. In this study, the prevalence of anti-DFS70 was higher than the range previously published for adult SLE (7.1 versus 0-2.8%) and was associated with musculoskeletal activity and anti-ß2 glycoprotein 1 autoantibodies. However, 'monospecific' anti-DFS70 autoantibodies were rare (1.1%) and therefore may be helpful to discriminate between ANA-positive healthy individuals and SLE.

The impact of tabalumab on the kidney in systemic lupus erythematosus: results from two phase 3 randomized, clinical trials.

INTRODUCTION: Tabalumab is a monoclonal antibody that neutralizes membrane and soluble B-cell activating factor. Two 52-week, randomized, double-blind, placebo controlled phase 3 trials evaluated the safety and efficacy of tabalumab in systemic lupus erythematosus. METHODS: Patients with moderate to severe active systemic lupus erythematosus (without severe active lupus nephritis) were randomly assigned 1:1:1 to receive tabalumab (120 mg subcutaneously every 2 or 4 weeks) or placebo for 52 weeks. Serum creatinine concentration, estimated glomerular filtration rate, urine protein/creatinine ratio, renal flares and renal adverse events were determined monthly. Data were analyzed for the intent-to-treat population and for intent-to-treat patients with baseline urine protein/creatinine ratio >20 mg/mmol (intent-to-treat plus urine protein/creatinine ratio). RESULTS: The trials enrolled 2262 patients. At baseline, demographics, systemic lupus erythematosus disease activity, serum creatinine concentration, estimated glomerular filtration rate and urine protein/creatinine ratio were similar among the treatment arms (with the exception of disease duration). In the intent-to-treat and intent-to-treat plus urine protein/creatinine ratio populations, there were no differences between the arms in the baseline-to-endpoint change in serum creatinine concentration, glomerular filtration rate, urine protein/creatinine ratio, or renal flare rates. Tabalumab resulted in a significant B-cell reduction and decreased immunoglobulin G levels at both doses. CONCLUSIONS: Compared to placebo, tabalumab did not significantly affect the serum creatinine concentration, glomerular filtration rate, urine protein/creatinine ratio, or renal flare rates over 1 year in intent-to-treat or intent-to-treat plus urine protein/creatinine ratio patients. There were no significant renal safety signals.ClinicalTrials.gov identifiers: NCT01205438 and NCT01196091 Lupus (2016) 25, 1597-1601.

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.

Effect of belimumab treatment on renal outcomes: results from the phase 3 belimumab clinical trials in patients with SLE.

A pooled post-hoc analysis of the phase 3, randomized, placebo-controlled BLISS trials (1684 patients with active systemic lupus erythematosus (SLE)) was performed to evaluate the effect of belimumab on renal parameters in patients with renal involvement at baseline, and to explore whether belimumab offered additional renal benefit to patients receiving mycophenolate mofetil at baseline. In addition to belimumab or placebo, all patients received standard SLE therapy. Patients with severe active lupus nephritis were excluded from the trials. Over 52 weeks, rates of renal flare, renal remission, renal organ disease improvement (assessed by Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index and British Isles Lupus Assessment Group), proteinuria reduction, grade 3/4 proteinuria, and serologic activity favored belimumab, although the between-group differences in most renal outcomes were not significant. Among the 267 patients with renal involvement at baseline, those receiving mycophenolate mofetil or with serologic activity at baseline had greater renal organ disease improvement with belimumab than with placebo. Limitations of this analysis included the small patient numbers and the post-hoc nature of this pooled analysis. The results suggest that belimumab may offer renal benefit in patients with SLE. Further study is warranted in patients with severe active lupus nephritis.

An assessment of disease flare in patients with systemic lupus erythematosus: a comparison of BILAG 2004 and the flare version of SELENA.

AIMS: To compare the British Isles Lupus Assessment Group (BILAG) 2004, the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) flare index (SFI) and physician's global assessment (PGA) in assessing flares of disease activity in patients with systemic lupus erythematosus (SLE). METHODS: Sixteen patients with active SLE were assessed by a panel of 16 rheumatologists. The order in which the patients were seen was randomised using a 4×4 Latin square design. Each patient's flare status was determined at each assessment using the BILAG 2004 activity index; the SFI and a PGA. A group of five specialists designated each patient into severe, moderate, mild or no flare categories. RESULTS: The rate of complete agreement (95% CI) of the four individual examining physicians for any flare versus no flare was 81% (55% to 94%), 75% (49% to 90%) and 75% (49% to 90%) for the BILAG 2004 index, SELENA flare instrument and PGA, respectively. The overall agreement between flare defined by BILAG 2004 and the SFI was 81% and when type of flare was considered was 52%. Intraclass correlation coefficients (95% CI), as a measure of internal reliability, were 0.54 (0.32 to 0.78) for BILAG 2004 flare compared with 0.21 (0.08 to 0.48) for SELENA flare and 0.18 (0.06 to 0.45) for PGA. Severe flare was associated with good agreement between the indices but mild/moderate flare was much less consistent. CONCLUSIONS: The assessment of flare in patients with SLE is challenging. No flare and severe flare are identifiable but further work is needed to optimise the accurate 'capture' of mild and moderate flares.

Genetic imprinting of autoantibody repertoires in systemic lupus erythematosus patients.

Systemic lupus erythematosus (SLE) is an autoimmune disease distinguished by great heterogeneity in clinical manifestations and autoantibody expression. While only a handful of autoantibody specificities have proved useful for clinical diagnosis, to characterize complex lupus-associated autoantibody profiles more fully we have applied proteome microarray technology. Our multiplex microarrays included control ligands and 65-autoantigens, which represent diverse nuclear and cytoplasmic antigens recognized by disease-associated and natural autoantibodies. From longitudinal surveys of unrelated SLE patients, we found that autoantibody profile patterns can be patient-specific and highly stable overtime. From profiles of 38 SLE patients that included 14 sets of SLE twins, autoantibodies to the phospholipid neo-determinants, malondialdehyde (MDA) and phosphorylcholine (PC), which are exposed on apoptotic but not healthy cells, were among the most prevalent and highly expressed. We also found that immunoglobulin M (IgM) reactivity to MDA and PC ligands had significant direct correlations with DNA-containing antigens, while such a general relationship was not found with a panel of RNA-related antigens, or for IgG-autoantibodies. Significantly, hierarchical analysis revealed co-distribution/clustering of the IgM autoantibody repertoire patterns for six of 14 twin sets, and such patterns were even more common (10 of 14) for IgG autoantibody profiles. Our findings highlight the potentially distinct roles of IgM and IgG autoantibodies, as we postulate that the direct correlations for IgM autoantibodies to DNA antigens with apoptosis-related determinants may be due to co-expression arising from common pro-homeostatic protective roles. In contrast, the sharing of IgG autoantibody fingerprints by monozygotic twins suggests that lupus IgG autoantibodies can arise in predisposed individuals in genetically determined patterns.

Current treatment of lupus nephritis.

This review on the management of lupus nephritis is based on the results of randomized clinical trials, and discusses the principles of treatment and the current options for induction and maintenance therapy. The respective place of mycophenolate mofetil and intravenous cyclophosphamide are balanced, taking into account efficacy, safety and patients' perspective. The authors anticipate that, in a few years, when long-term data on lupus nephritis patients induced with mycophenolate mofetil becomes available, it is probably that intravenous cyclophosphamide, which has been for so long the 'standard of care', will be prescribed only in specialized conditions such as documented necrotizing vasculitis.

Current therapy of lupus nephritis. Which is the best option?

Renal involvement in systemic lupus erythematosus (SLE) is an important cause of morbidity and mortality, reaching a prevalence of 39% during the course of the disease. Currently, the therapy for severe lupus nephritis is based on the use of high-dose corticosteroids and immunosuppressive drugs, being traditionally cyclophosphamide the most frequently used agent. Recent studies have demonstrated the efficacy of mycophenolate mofetil as induction therapy for lupus nephritis. Azathioprine, a safe drug during pregnancy, has not been demonstrated to be as effective as mycophenolate or cyclophosphamide as induction therapy, although it is an effective drug for maintenance of remission.

Current therapy of lupus nephritis. Which is the best option?

La afectación renal en el lupus eritematoso sistémico (LES) es una causa importante de morbilidad y mortalidad, llegando a afectar hasta al 39% de los pacientes diagnosticados de LES durante su evolución. Actualmente, el tratamiento de la nefritis lúpica grave se basa en el uso de dosis altas de corticosteroides y fármacos inmunosupresores, de entre los cuales, tradicionalmente, la ciclofosfamida ha sido el más utilizado. Estudios recientes han demostrado la eficacia del micofenolato de mofetilo como terapia de inducción para la nefritis lúpica. La azatioprina, de uso seguro durante la gestación, no ha demostrado ser tan eficaz como el micofenolato o la ciclofosfamida como terapia de inducción, aunque sí ha resultado ser efectiva para el mantenimiento de la remisión

Renal involvement in systemic lupus erythematosus (SLE) is an important cause of morbidity and mortality, reaching a prevalence of 39% during the course of the disease. Currently, the therapy for severe lupus nephritis is based on the use of high-dose corticosteroids and immunosuppressive drugs, being traditionally cyclophosphamide the most frequently used agent. Recent studies have demonstrated the efficacy of mycophenolate mofetil as induction therapy for lupus nephritis. Azathioprine, a safe drug during pregnancy, has not been demonstrated to be as effective as mycophenolate or cyclophosphamide as induction therapy, although it is an effective drug for maintenance of remission (AU)

Aortitis and aortic thrombus in systemic lupus erythematosus.

Aortitis is an uncommon complication of systemic lupus erythematosus (SLE). Most cases of lupus-associated aortitis have been described in conjunction with aortic aneurysms or aortic dissection and have been documented either at autopsy or during surgery to repair a dissection. We describe an unusual case of aortitis associated with an aortic thrombus in a young man with SLE.

Mycophenolate mofetil in lupus nephritis.

There is an increasing body of literature suggesting the efficacy and tolerability of mycophenolate mofetil (MMF) for the treatment of lupus nephritis. The rationale for its use is based upon its successful profile as an immunosuppressive agent for prevention of allograft rejection, as well as studies in murine models of lupus which have reported improved renal function and animal survival compared to placebo. This report reviews the data regarding MMF therapy in murine lupus models, and describes the initial anecdotal experience with MMF in human lupus, especially in patients with glomerulonephritis who were unresponsive to corticosteroids and cyclophosphamide, or who had unacceptable toxicity on this standard of care regimen. The results of several nonblinded, controlled clinical trials are also described, in which MMF was compared to intravenous or oral cyclophosphamide in patients with lupus nephritis. MMF was found to be well tolerated, with most studies showing fewer infections than that associated with cyclophosphamide. Efficacy of MMF was at least equivalent to cyclophosphamide, and therefore appears to provide an alternative as a standard of care for induction and maintenance treatment of lupus nephritis.

Review of ACR renal criteria in systemic lupus erythematosus.

The American College of Rheumatology renal criteria require re-evaluation to incorporate recent advances in the classification of glomerulonephritidies. Renal biopsy is now common and safely performed by experienced nephrologists in community as well as academic settings. The optimal criterion is renal histopathology findings of an immune complex mediated glomerulonephritis as interpreted by an experienced pathologist employing accepted criteria. Renal biopsies should be analysed by routine histopathology, immunofluorescent and electron microscopy. Rating of activity and chronicity should be noted. Secondary criteria for patients unable to undergo renal biopsy includes a combination of findings. These include proteinuria, hypocomplementemia, elevated anti-dsDNA antibodies and an active urine sediment. Proteinuria is a nonspecific finding and, most importantly, can be associated with a number of comorbidities including diabetes, hypertension and atherosclerotic disease. Persistent proteinuria > 0.5 g per day or a spot protein to creatine ratio of > 0.5 should be accompanied by an additional feature supporting active lupus such as positive serologies (hypocomplementemia and/or elevated anti-dsDNA antibodies) and/or active urinary sediment. Similarly, active urinary sediment should be accompanied by the additional criterion of proteinuria to meet renal criteria. Decline in renal function is not a reliable criterion given the numerous medications, comorbidities and other clinical circumstances which may result in this feature.

Clinical trials in lupus nephritis.

Significant advances in the treatment of lupus nephritis have been made in the last 50 years, beginning with the use of high doses of corticosteroids. The addition of intravenous cyclophosphamide (IVC) to steroids, a regimen introduced by the National Institutes of Health, has become the standard of care therapy for severe active nephritis. However, not all patients respond to IVC, and among those who do, manifestations of toxicity (nausea, vomiting, alopecia, sterility, increased risk of infection, and increased risk of malignancy) are frequent. Despite successful induction and maintenance therapy with IVC, there is a relapse rate of more than 50% after 10 years. In recent years, new immunosuppressive agents have been studied as potential alternatives to IVC. The most promising of these appears to be mycofenolate mofetil, which is being evaluated in clinical trials. Biologic agents designed to interfere with the immunologic process leading to B- and T-lymphocyte activation are also being tested as alternative therapies in lupus nephritis.

Epidemiology of cardiovascular disease in systemic lupus erythematosus.

Awareness of the impact of cardiovascular disease on the late morbidity and mortality in patients with Systemic Lupus Erythematosus (SLE) is increasing. Clinical events secondary to accelerated atherosclerosis have been documented in lupus cohorts across the globe. We review the history and epidemiology of cardiovascular disease in patients with SLE.

Prevention and treatment of adverse effects of corticosteroids in systemic lupus erythematosus.

Corticosteroid therapy has had a major impact on improvement in disease activity and long-term survival in patients with systemic lupus erythematosus (SLE). Unfortunately, the therapeutic advantages are accompanied by many manifestations of toxicity, some of which are short term and potentially reversible, while others cause chronic irreversible damage. Many of these features of toxicity have similar presentations to manifestations of SLE disease activity, and must be distinguished in the individual patient. The features of corticosteroid toxicity are reviewed in this chapter, and means of prevention and/or treatment are discussed.

Antibodies to C1q in systemic lupus erythematosus: characteristics and relation to Fc gamma RIIA alleles.

Autoantibodies to the collagen-like region of the first complement component (C1qAB) are found in patients with systemic lupus erythematosus (SLE), particularly those with renal disease. In a cohort of 46 SLE patients with diffuse proliferative glomerulonephritis, we found declining C1qAB titers in 77% of treatment responders and in only 38% of treatment non-responders (P < 0.03). To further characterize this autoantibody, we tested 240 SLE patients for the presence of C1qAB. Positive titers were found in 44% of patients with renal disease and 18% of patients without renal disease (chi2 P < 0.0003). Analysis of IgG subclass revealed IgG2 C1qAB alone in 34%, IgG1 C1qAB alone in 20%, and both IgG1 and IgG2 in 46% of patients. Fewer than 10% of patients had measurable titers of IgG3 or IgG4 C1qAB. The pathogenic role of these IgG2-skewed C1qAB may relate to impaired immune complex clearance by the mononuclear phagocyte system: IgG2 antibodies are efficiently recognized by only one IgG receptor, the H131 allele of Fc gamma RIIa (Fc gamma RIIa-H131). In contrast, Fc gamma RIIa-R131, which is characterized by minimal IgG2 binding, has recently been associated with lupus nephritis. In our C1qAB positive patients, the presence of Fc gamma RIIA-R131 was associated with an increased risk for renal disease. Autoantibodies to C1q may have pathogenic significance in SLE patients with genetic defects in the ability to clear IgG2 containing immune complexes.

Fc gamma RIIA alleles are heritable risk factors for lupus nephritis in African Americans.

Allelic variants of Fc gamma R confer distinct phagocytic capacities providing a mechanism for heritable susceptibility to immune complex disease. Human Fc gamma RIIa has two codominantly expressed alleles, R131 and H131, which differ substantially in their ability to ligate human IgG2. The Fc gamma RIIa-H131 is the only human Fc gamma R which recognizes IgG2 efficiently and optimal IgG2 handling occurs only in the homozygous state. Therefore, since immune complex clearance is essential in SLE, we hypothesized that Fc gamma RIIA genes are important disease susceptibility factors for SLE, particularly lupus nephritis. In a two-stage cross-sectional study, we compared the distribution of Fc gamma RIIA alleles in African Americans with SLE to that in African American non-SLE controls. A pilot study of 43 SLE patients and 39 controls demonstrated a skewed distribution of Fc gamma RIIA alleles, with only 9% of SLE patients homozygous for Fc gamma RIIa-H131 compared with 36% of controls (odds ratio, 0.18; 95% CI, 0.05-0.69, P = 0.009). This was confirmed with a multicenter study of 214 SLE patients and 100 non-SLE controls. The altered distribution of Fc gamma RIIA alleles was most striking in lupus nephritis. Trend analysis of the genotype distribution showed a highly significant decrease in Fc gamma RIIA-H131 as the likelihood for lupus nephritis increased (P = 0.0004) consistent with a protective effect of the Fc gamma RIIA-H131 gene. The skewing in the distribution of Fc gamma RIIA alleles identifies this gene as a risk factor with pathophysiologic importance for the SLE diathesis in African Americans.

Heart rate variability in patients with systemic lupus erythematosus.

As patients with systemic lupus erythematosus (SLE) survive their episodes of disease activity, increasing morbidity is shown to be related to chronic cardiovascular complications. The objective of this study was to assess the cardiac parasympathetic autonomic functional status, as reflected by heart rate variability, in SLE patients with and without corticosteroid treatment. A cross-sectional study of SLE patients attending the Arthritis Clinic was done, using age and gender-matched controls. Thirty-four female patients, age 39 +/- 11, were entered, 20 of whom were receiving steroids at the time of study. Time and frequency domain heart rate variability indices were significantly reduced in the SLE groups with and without corticosteroid therapy, as compared to controls. The indices were not, however, significantly different in the two SLE groups.

Hypertension increases the risk of renal deterioration in systemic lupus erythematosus.

OBJECTIVE: To assess the effect of hypertension on the development of renal functional deterioration, end stage renal disease and death in patients with systemic lupus erythematosus (SLE). METHODS: Person-years analysis using regression techniques to adjust for other baseline risk factors for adverse renal and patient survival outcomes. RESULTS: Six hundred eighty-five patients with SLE were followed for a total of 4,137 person-years. The risk of renal deterioration (doubling of serum creatinine) and endstage renal disease (ESRD) both increased with increasing baseline mean arterial pressure (MAP) (both p > 0.05). Even after adjustment for age, sex, baseline serum creatinine, C3, erythrocyte sedimentation rate, hematocrit, anti-DNA antibodies, and proteinuria, those in the highest quartile of MAP had 2.3 times the odds of renal deterioration at 12 months and 4.6 times the odds of ESRD compared to those in the lowest quartile of MAP (both p < 0.01 comparing highest to lowest quartile of MAP). Also, hypertension increased the risk of mortality, especially between one and 2 years after blood pressure determination. The effect of hypertension was also independent of corticosteroid dose. CONCLUSION: In patients with SLE, hypertension is a potent independent risk factor for adverse renal outcomes, and it also increases the risk of death.

Clinical manifestations of systemic lupus erythematosus, measures of disease activity, and long-term complications.

Studies of renal involvement in systemic lupus erythematosus continue to dominate the clinical literature. Reports of the prognostic significance of both clinical and histologic parameters at the time of renal biopsy are discussed. The potential impact of anticardiolipin antibodies on the development of renal insufficiency is described. The outcome of renal transplantation in patients with systemic lupus erythematosus is assessed in a study concerned with both allograft survival and recurrence of active nephritis in the transplanted kidney. The incidence and prognosis of various features of neuropsychiatric systemic lupus erythematosus are discussed, while the search for an accurate indicator of lupus involvement of the central nervous system continues. Magnetic resonance imaging and single-photon-emission computed tomography are considered. Abnormalities of pulmonary gas exchange are featured in several reports. Features of the antiphospholipid antibody syndrome are presented, stressing predisposition to thrombosis. The definition and characteristics of systemic lupus erythematosus disease flares is discussed, in relation to several recently developed disease activity indexes. The attempt to distinguish systemic lupus erythematosus activity from infection and preeclampsia is also considered. Finally, the association of systemic lupus erythematosus with the development of cancer is discussed.