Lupus

In addition to genetic and environmental factors, viruses have been suspected as causes and/or contributors to human autoimmune diseases, although direct evidence for the association is generally lacking. Parvovirus B19, the cause of Fifth disease in childhood, and possible trigger in the spectrum of autoimmune diseases in adults, has emerged as one of the central viral candidates within the last few years. In this article we propose a possible model for parvovirus B19 association with systemic lupus erythematosus (SLE). The basis for our model is the secretion of hydrolyzing anti-ssDNA autoantibodies in 30—70% of cases with SLE, which in turn can either hydrolyze viral B19 ssDNA in blood and other fluids, or intranuclear, replicated viral ssDNA after re-activation and translocation of the virus into the nucleus of the host permissive cells. Both mechanisms contribute to perpetuation and maintenance of a ‘vicious cycle’ with concomitant flares in SLE, and involve inevitable TLR9 sensitization and genetic switch for anti-ssDNA autoantibody production from activated B cells in individuals prone to triggering. This model strongly suggests a major potential impact upon early prevention (vaccination) and targeted therapy of this subclass within the SLE spectrum of diseases. Incorporated in this new concept is an innovative idea for developing the tool for more precise (individualized) diagnosis, prevention, and therapy.

The objective of this study was to assess isolated pyuria in an unselected systemic lupus erythematosus sample, and to determine factors potentially associated with this manifestation. We studied patients followed in our lupus clinic, defining isolated pyuria as more than 10 white blood cells per high power field in the absence of hematuria, proteinuria, casts, or bacteriuria. We assessed the effects of various demographic and clinical factors on the occurrence of isolated pyuria, using univariate logistic regression analyses. We also performed multivariate models which included sex, age, race/ethnicity, systemic lupus erythematosus duration, non-renal systemic lupus erythematosus disease activity, systemic lupus erythematosus damage, number of non-renal and renal American College of Rheumatology criteria ever present, pre-existing hypertension, and current drug exposures. Of 264 subjects, 66 were excluded (43 had bacteriuria or a contaminated urine culture and 23 had no concomitant urine culture); 27 of the remaining 198 (13.6%) had isolated pyuria. Sixteen of 27 patients with sterile pyuria had previous American College of Rheumatology criteria for renal involvement (hematuria, casts, and/or proteinuria) compared to 62/171 patients without sterile pyuria (unadjusted odds ratio = 2.55; 95% confidence interval = 1.11—5.85). Our univariate analyses also suggested a trend towards higher non-renal disease activity in patients with isolated pyuria. Independent associations were not evident in adjusted analyses. Isolated pyuria was observed in a significant number of our systemic lupus erythematosus sample. Although the differential diagnosis for isolated pyuria is broad, this manifestation may be correlated with lupus activity even in the absence of hematuria or proteinuria. Lupus (2010) 19, 793—796.

Neuropsychiatric manifestations of systemic lupus erythematosus are common and disabling yet their pathogenesis is poorly understood. We investigated the role of cerebrovascular endothelial dysfunction in systemic lupus erythematosus and its neuropsychiatric manifestations. Subjects with systemic lupus erythematosus were recruited prospectively along with matched healthy control subjects. The presence of neuropsychiatric systemic lupus erythematosus syndromes was ascertained according to standard definitions. Cerebrovascular reactivity, an indicator of endothelial function, was measured using transcranial Doppler ultrasound. Sixty-one subjects (58 female, 3 male) with systemic lupus erythematosus and 70 control subjects were assessed. Sixty patients (98%) reported at least one neuropsychiatric manifestation, the most prevalent being headache and cognitive dysfunction. There was no significant difference in cerebrovascular reactivity between cases and controls (3.06 vs 3.06, p=0.99). Subjects with systemic lupus erythematosus and a history of stroke and/or transient ischaemic attack had significantly higher cerebrovascular reactivity than those without (3.99 vs 2.79, p = 0.007). No association was found between the presence of other neuropsychiatric syndromes or systemic lupus erythematosus-related variables and altered cerebrovascular reactivity. In conclusion, cerebrovascular endothelial dysfunction is not present in the majority of subjects with systemic lupus erythematosus. However, the role of endothelial dysfunction in the pathogenesis of stroke and transient ischaemic attack in systemic lupus erythematosus merits further investigation. Lupus (2010) 19, 797—802.

The objective of this study was to determine the frequency of Metabolic Syndrome (MetS) in patients with SLE and to analyze the association of MetS with traditional risk factors for CHD and lupus characteristics. In this cross-sectional study the frequency of MetS was determined according to the National Cholesterol Education Program Adult Treatment Panel III in patients with SLE. The association of MetS with the traditional risk factors for CHD not included in the syndrome definition, and with lupus characteristics was examined. The mean age (sd) of the 162 females patients was 38.8(11.2) years. The frequency of MetS was 32.1%. Abdominal obesity and hypertension were the two most common components of the syndrome (86.5% each) followed by low levels of HDL-cholesterol (84.6%), hypertriglyceridemia (69.2%) and hyperglycemia (15.4%). MetS was significantly associated with older age, family history of CHD, obesity, postmenopausal status, LDL-c ≥100mg/dl, and higher Framingham risk score. Lupus characteristics associated with MetS were history of nephrotic proteinuria during follow-up and current cyclophosphamide use, higher modified SLEDAI-2k, higher damage index score (SLICC/ACR), and older age at lupus diagnosis. In the logistic regression analysis, obesity, LDL-c ≥100mg/dl, older age at lupus diagnosis, higher damage index and nephrotic proteinuria were independently associated with MetS. We conclude that MetS diagnosis was frequent in patients with lupus. The syndrome was associated not only with traditional risk factors for CHD, confirming the clustering of those risk factors, but also with lupus characteristics. Some of those factors, especially LDL-c ≥100mg/dl and age at lupus diagnosis, have been associated with atherosclerosis in lupus patients. Lupus (2010) 19, 803—809.

Low vitamin D levels have been found in patients with autoimmune diseases, including type I diabetes, rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus. The main source of vitamin D is exposure to sunlight, but the same solar radiation is known to exacerbate lupus erythematosus. We investigated the prevalence of vitamin D insufficiency in patients with cutaneous lupus erythematosus (CLE). We designed a cross-sectional study including 55 patients with CLE to measure their serum 25-hydroxyvitamin D (25(OH)D) by chemiluminescence immunoassay and compare it with a control group consisting of 37 healthy sex and age-matched subjects recruited from the patients’ relatives as well as healthcare workers. Correlations with clinical and demographic variables were determined. Approximately 95% of patients with CLE had less than 30 ng/ml of serum 25(OH)D, which is accepted as the lower limit for vitamin D adequacy. Mean serum vitamin D values were significantly lower than controls (p = 0.038) and were associated with higher levels of parathyroid hormone (p = 0.050). A history of CLE was a strong predictor of insufficiency of vitamin D (odds ratio 4.2; 95% confidence interval 1.0—17.4). The results suggest a role of CLE in the metabolism of the vitamin and provide guidance for future studies looking at a potential role for vitamin D in the prevention and treatment of CLE. Lupus (2010) 19, 810—814.

To investigate the role of HLA-DQ2 in the pathogenesis of associated immune disorders, we generated transgenic mice that expressed HLA-DQ2 in the absence of endogenous murine class II molecules (AE⁰DQ2). These AE⁰DQ2 mice with a mixed genetic background spontaneously developed skin lesions on their ears, whereas control AE⁰DQ6 genotype control mice (also with a mixed genetic background) did not. The skin lesions were characterized by deep subepidermal blistering with hydropic degeneration and lymphoid infiltration in the subepidermal area as determined by histopathology. Immunofluorescence analysis revealed thick band-like granular deposition of IgG, IgM, and a thin band of IgA deposition along the basement membrane. AE⁰DQ2 mice also developed significant and progressive hematuria and proteinuria as compared with the AE⁰DQ6 mice (p < 0.05). Histopathology showed immune complex deposits in the glomeruli of AE⁰DQ2 mice. Immunofluorescence analysis showed progressive mesangial and capillary wall deposition of IgA, IgM, IgG and C1q in the kidney. With electron microscopy, the deposits showed a ‘fingerprint’ substructure; and tubuloreticular structures were identified within endothelial cells. Conversely, these changes were not observed in AE⁰DQ6 mice. Serum anti-double stranded (ds)DNA IgM and IgG levels were also significantly elevated among AE⁰DQ2 mice compared with AE⁰DQ6 mice (p < 0.001). In conclusion, AE⁰DQ2 mice spontaneously develop an autoimmune lupus-like syndrome and are useful model for this disease. It remains to be determined whether genetic admixture played a role in the development of this systemic lupus erythematosus-like syndrome in HLA-DQ2 transgenic mice. Lupus (2010) 19, 815—829.

Interferon-γ is a potent Th1-type cytokine and a key molecule in the pathogenesis of autoimmune diseases including lupus nephritis. Retinoic acid-inducible gene-I is a putative RNA helicase that plays an important role in immune and inflammatory reactions. We previously demonstrated the increased expression of the retinoic acid-inducible gene-I protein in the kidney tissue of patients with lupus nephritis, and the presence of a significant amount of retinoic acid-inducible gene-I mRNA in the urinary sediment of patients with this inflammatory renal disease. In the present study, interferon-γ was found to induce the expression of retinoic acid-inducible gene-I in human mesangial cells in culture. Knockdown of retinoic acid-inducible gene-I inhibited the interferon-γ-induced upregulation of interferon regulatory factor 7, a transcriptional factor involved in immune and inflammatory reactions. These findings suggest that retinoic acid-inducible gene-I produced by mesangial cells may be involved in the pathogenesis of lupus nephritis.

Antiphospholipid syndrome (APS) is defined as a combination of antiphospholipid antibodies, arterial and/or venous thrombosis, and, in women, recurrent fetal loss. The mechanisms underlying this prothrombotic tendency are unclear. Here we determined plasma levels of the angiogenic growth factors vascular endothelial growth factor (VEGF), placental growth factor (PlGF) and stromal cell-derived factor-1 (SDF-1) in 34 patients with APS (median age 40 years) compared with 180 healthy controls and with 80 age-matched deep-venous thrombosis patients in whom the diagnosis of APS had been excluded. All of the patients met updated APS criteria and two-thirds of them were triply positive for antiphospholipid antibodies (lupus anticoagulant, anti-β2-glycoprotein I and anti-cardiolipin antibodies). Angiogenic cytokines were quantified at least 6 months after an acute thrombotic event. VEGF levels were similar in the patients and controls, but were significantly higher in the patients with arterial thrombosis than in the patients with venous thrombosis. Plasma levels of SDF-1 and PlGF were significantly elevated in the patients, regardless of the arterial/venous nature of the thrombosis. Together, these results suggest that APS is associated with an angiogenic process, but that the angiogenic signal differs between patients with arterial and venous thrombosis. Lupus (2010) 19, 837—843.

Our aims were to assess the frequency of false-positive IgM antibodies for cytomegalovirus in pregnant women with autoimmune diseases and in healthy women (controls) and to determine their relationship with pregnancy outcome. Data from 133 pregnancies in 118 patients with autoimmune diseases and from 222 pregnancies in 198 controls were assessed. When positive IgM for cytomegalovirus was detected, IgG avidity, cytomegalovirus isolation and polymerase chain reaction for CMV-DNA in maternal urine and amniotic fluid samples were performed in order to identify primary infection or false positivity. A statistically significantly higher rate of false-positive IgM was found in pregnancies with autoimmune diseases (16.5%) in comparison with controls (0.9%). A worse pregnancy outcome was observed among patients with autoimmune disease and false cytomegalovirus IgM in comparison with those without false positivity: earlier week of delivery (p = 0.017), lower neonatal birth weight (p = 0.0004) and neonatal birth weight percentile (p = 0.002), higher rate of intrauterine growth restriction (p = 0.02) and babies weighing less than 2000 g (p = 0.025) were encountered. The presence of false cytomegalovirus IgM in patients with autoimmune diseases could be used as a novel prognostic index of poor pregnancy outcome: it may reflect a non-specific activation of the immune system that could negatively affect pregnancy outcome. Lupus (2010) 19, 844—849.

Systemic lupus erythematosus (SLE) has been considered as stem cell disorder. The objective of this study was to examine the phenotype, growth and immunomodulatory effect of mesenchymal stem cells (MSCs) from SLE patients compared with those from age- and sex-matched healthy donors. MSCs were expanded from bone marrow aspirate and were examined for morphological appearance, quantified in different passages to determine growth rate and evaluated for ability of adipogenesis and osteogenesis. Telomerase activity was measured by telomerase repeat amplification protocol. The immunomodulatory effect of MSCs was evaluated by mixed lymphocyte reaction. MSCs from SLE patients were found to be bigger and flattened in appearance after passage 3 and demonstrated slower growth rate compared with fibroblast-like MSCs from normal controls. These cells were not able to reach confluence after passage 4. Telomerase activity was upregulated in five SLE patients mostly with active disease compared with two with negative expression with lesser activity. MSCs from SLE patients were, otherwise, comparable to normal controls in terms of their surface marker (CD73, CD90 and CD105) expression and extent of suppression on proliferation of allogeneic T lymphocytes. In conclusion, MSCs from SLE demonstrated early signs of senescence which may be a corollary of active lupus or a contributory factor to disease pathogenesis. Lupus (2010) 19, 850—859.

This study sought to examine the long-term outcomes of transtrochanteric anterior rotational osteotomy (ARO) as treatment for osteonecrosis of the femoral head (ONFH) in patients with systemic lupus erythematosus (SLE). Twenty-one patients (33 hips), aged 20—40 years, underwent ARO between 1980 and 1988. We examined 16 patients (25 hips), a 76% follow-up rate. A Kaplan—Meier curve was used for survivorship analysis. Patients with surviving hips were evaluated by the modified Oxford hip score and Short Form 36 (SF-36). Twelve hips in eight patients had survived at the final follow-up. The average length of hip survival was 24.6 years (range: 20.1—27.2 years). Three patients (six hips) had died of unrelated causes without any subsequent operation. Based on Kaplan—Meier analysis with the endpoint defined as the need for a subsequent operation, the hip survival rate at 25 years was 73.7% (95% confidence interval, ±19.8%). Based on classification by the modified Oxford hip score, five hips were classified as excellent, two hips were good, and the remaining five hips were fair. The average SF-36 summary score for the physical and mental components was 38.7 and 47.2 points, respectively. The physical component summary scores for three patients exceeded the normal level of the Japanese population. Lupus (2010) 19, 860—865.

Our objective was to analyse the clinical characteristics of systemic lupus erythematosus (SLE) patients with gastrointestinal manifestations. Medical charts of 177 hospitalized SLE patients were systematically reviewed, including demographic data, clinical features, laboratory findings, and treatments, as well as outcomes. Thirty-nine cases (22.0%) had SLE-related gastrointestinal manifestations, and in 12 cases (30.8%), gastrointestinal manifestations occurred as the initial symptoms. Twenty-five cases (64.1%) had abdominal pain, 22 cases (56.4%) had nausea and vomiting, 12 cases (30.8%) had diarrhea, and gastrointestinal hemorrhage occurred in three cases (7.7%). Protein losing enteropathy and intestinal pseudo-obstruction were the most common identifiable gastrointestinal complications, though other reasons such as superior mesenteric venous thrombosis, pancreatitis, peritonitis, and liver impairment could also occur in SLE. The incidences of Raynaud’s phenomenon and pyeloureterectasis were significantly higher in patients with gastrointestinal complications than those without (p < 0.05). Multivariable analysis indicated Raynaud’s phenomenon, decreased C3, CH50, and anti-neutrophil cytoplasmic antibody positivity were independent predictors of gastrointestinal involvements (p < 0.05). Gastrointestinal complications are common, diverse, and could be the initial and major manifestations of lupus. SLE patients who had Raynaud’s phenomenon, hypocomplementemia and positive anti-neutrophil cytoplasmic antibody were at increasing risk of developing gastrointestinal complication.

Previously, cases of systemic lupus erythematosus (SLE) and Klinefelter syndrome (KS) in men have been reported in Western populations. We report the case of a 30-year-old man from southern India with known infertility who was diagnosed to have SLE and KS by fluorescence in-situ hybridization, as routine karyotype cultures failed. The diagnosis has implications in management and highlights the need for strong clinical suspicion and laboratory confirmation of KS by molecular methods when suspected in all men with SLE. Quicker, long-term remission and genetic counseling of such individuals can help in better management and coping with this chronic, potentially fatal disease. Lupus (2010) 19, 870—871.

We describe a case of systemic lupus erythematosus complicated by strongyloidiasis. The parasitic infection appeared with diarrhoea, weight loss and peripheral eosinophilia in association with recurrence of polyarthritis, probably due to a flare of systemic lupus erythematosus. The literature about the coexistence of systemic lupus erythematosus and strongyloidiasis has been reviewed.

Two cases of Afro-Caribbean women with an association of sickle cell disease (SCD) and systemic lupus erythematosus (SLE) are presented. We discuss the clues to the diagnosis of this combination with a review of the literature. Owing to a substantial overlap between the clinical manifestations of the two disorders, the diagnosis of SLE in patients with SCD may be difficult to establish and is often delayed.

Pancreatitis as an initial manifestation of systemic lupus erythematosus is rare. Two cases are reported of young female patients who presented with fever, abdominal pain, vomiting and elevated levels of pancreatic enzymes. They were diagnosed with acute severe pancreatitis associated with systemic lupus erythematosus. There are a few reports in the literature about this association, but the pathogenesis and treatment are still controversial.