Urine and Plasma Complement Ba Levels During Disease Flares in Patients With Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis.

Introduction: Although the alternative complement pathway has been implicated in the pathogenesis of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV), the specific nature of its involvement is unclear. This study measured levels of urine and plasma complement fragment Ba at multiple time points in a group of patients with AAV. Methods: The complement fragment Ba was measured by enzyme-linked immunosorbent assay in serial urine and plasma samples from 21 patients with AAV who developed a renal flare, 19 who developed a nonrenal flare, and 20 in long-term remission. Urine Ba levels were corrected for urine creatinine concentration. Changes in Ba levels were modeled using mixed linear-effect models. A logistic regression model was fit to predict a renal flare using Ba levels at the time of flare versus the nonrenal flare and long-term remission groups. Results: Data from 60 patients with AAV were used for this analysis; 53% were male, 93% were White, and 74% had antiproteinase3-ANCA. Urine Ba levels increased at renal flare (P < 0.001) but remained stable during a nonrenal flare or long-term remission. Plasma Ba levels were stable over time in all groups. Urine Ba levels predicted a renal flare with an area under the curve of 0.76 (P < 0.001), with a cutoff of 12.53 ng/mg urine creatinine yielding a sensitivity of 76.2% and a specificity of 68.4%. Conclusion: Urine Ba levels, but not plasma Ba levels, are increased at the time of a renal flare in AAV, suggesting intrarenal complement activation and highlighting the potential use of this biomarker for surveillance of active renal vasculitis.

Four Systemic Lupus Erythematosus Subgroups, Defined by Autoantibodies Status, Differ Regarding HLA-DRB1 Genotype Associations and Immunological and Clinical Manifestations.

OBJECTIVE: The heterogeneity of systemic lupus erythematosus (SLE) constitutes clinical and therapeutical challenges. We therefore studied whether unrecognized disease subgroups can be identified by using autoantibody profiling together with HLA-DRB1 alleles and immunological and clinical data. METHODS: An unsupervised cluster analysis was performed based on detection of 13 SLE-associated autoantibodies (double-stranded DNA, nucleosomes, ribosomal P, ribonucleoprotein [RNP] 68, RNPA, Smith [Sm], Sm/RNP, Sjögren's syndrome antigen A [SSA]/Ro52, SSA/Ro60, Sjögren's syndrome antigen B [SSB]/La, cardiolipin [CL]-Immunoglobulin G [IgG], CL-Immunoglobulin M [IgM], and ß2 glycoprotein I [ß2 GPI]-IgG) in 911 patients with SLE from two cohorts. We evaluated whether each SLE subgroup is associated with HLA-DRB1 alleles, clinical manifestations (n = 743), and cytokine levels in circulation (n = 446). RESULTS: Our analysis identified four subgroups among the patients with SLE. Subgroup 1 (29.3%) was dominated by anti-SSA/Ro60/Ro52/SSB autoantibodies and was strongly associated with HLA-DRB1*03 (odds ratio [OR] = 4.73; 95% confidence interval [CI] = 4.52-4.94). Discoid lesions were more common for this disease subgroup (OR = 1.71, 95% CI = 1.18-2.47). Subgroup 2 (28.7%) was dominated by anti-nucleosome/SmRNP/DNA/RNPA autoantibodies and associated with HLA-DRB1*15 (OR = 1.62, 95% CI = 1.41-1.84). Nephritis was most common in this subgroup (OR = 1.61, 95% CI = 1.14-2.26). Subgroup 3 (23.8%) was characterized by anti-ß2 GPI-IgG/anti-CL-IgG/IgM autoantibodies and a higher frequency of HLA-DRB1*04 compared with the other patients with SLE. Vascular events were more common in Subgroup 3 (OR = 1.74, 95% CI = 1.2-2.5). Subgroup 4 (18.2%) was negative for the investigated autoantibodies, and this subgroup was not associated with HLA-DRB1. Additionally, the levels of eight cytokines significantly differed among the disease subgroups. CONCLUSION: Our findings suggest that four fairly distinct subgroups can be identified on the basis of the autoantibody profile in SLE. These four SLE subgroups differ regarding associations with HLA-DRB1 alleles and immunological and clinical features, suggesting dissimilar disease pathways.

Human Complement C4B Allotypes and Deficiencies in Selected Cases With Autoimmune Diseases.

Human complement C4 is one of the most diverse but heritable effectors for humoral immunity. To help understand the roles of C4 in the defense and pathogenesis of autoimmune and inflammatory diseases, we determined the bases of polymorphisms including the frequent genetic deficiency of C4A and/or C4B isotypes. We demonstrated the diversities of C4A and C4B proteins and their gene copy number variations (CNVs) in healthy subjects and patients with autoimmune disease, such as type 1 diabetes, systemic lupus erythematosus (SLE) and encephalitis. We identified subjects with (a) the fastest migrating C4B allotype, B7, or (b) a deficiency of C4B protein caused by genetic mutation in addition to gene copy-number variation. Those variants and mutants were characterized, sequenced and specific techniques for detection developed. Novel findings were made in four case series. First, the amino acid sequence determinant for C4B7 was likely the R729Q variation at the anaphylatoxin-like region. Second, in healthy White subject MS630, a C-nucleotide deletion at codon-755 led to frameshift mutations in his single C4B gene, which was a private mutation. Third, in European family E94 with multiplex lupus-related mortality and low serum C4 levels, the culprit was a recurrent haplotype with HLA-A30, B18 and DR7 that segregated with two defective C4B genes and identical mutations at the donor splice site of intron-28. Fourth, in East-Asian subject E133P with anti-NMDA receptor encephalitis, the C4B gene had a mutation that changed tryptophan-660 to a stop-codon (W660x), which was present in a haplotype with HLA-DRB1*04:06 and B*15:27. The W660x mutation is recurrent among East-Asians with a frequency of 1.5% but not detectable among patients with SLE. A meticulous annotation of C4 sequences revealed clusters of variations proximal to sites for protein processing, activation and inactivation, and binding of interacting molecules.

The Influence of an Elastase-Sensitive Complement C5 Variant on Lupus Nephritis and Its Flare.

INTRODUCTION: A C5 polymorphism (rs17611, 2404G>A) exists where the G allele associates with enhanced C5a-like production by neutrophil elastase. This cohort study investigated the influence of this polymorphism as a risk factor for lupus nephritis (LN), and on C5a and membrane attack complex (MAC) levels in LN during flare. METHODS: A cohort of lupus patients (n = 155) was genotyped for the 2404G>A polymorphism. A longitudinal LN subset (n = 66) was tested for plasma and urine levels of C5a and MAC 4 and/or 2 months before and at nonrenal or LN flare. RESULTS: The 2404G allele and 2404-GG genotype were associated with LN in black, but not white, lupus patients. In the longitudinal cohort, neither urine nor plasma C5a levels changed at nonrenal flare regardless of 2404G>A genotype or race. Urine (but not plasma) C5a levels increased at LN flare independent of race, more so in 2404-GG patients where 8 of 30 LN flares exhibited very high C5a levels. Higher proteinuria and serum creatinine levels also occurred in these eight flares. Urine (but not plasma) MAC levels also increased at LN flare in 2404-GG patients and correlated with urine C5a levels. CONCLUSIONS: The C5 2404-G allele/GG genotype is a potential risk factor for LN uniquely in black lupus patients. The GG genotype is associated with sharp increases in urine C5a and MAC levels in a subset of LN flares that correspond to higher LN disease indices. The lack of corresponding changes in plasma suggests these increases reflect intrarenal complement activation.

Expanding the Role of Complement Therapies: The Case for Lupus Nephritis.

The complement system is an innate immune surveillance network that provides defense against microorganisms and clearance of immune complexes and cellular debris and bridges innate and adaptive immunity. In the context of autoimmune disease, activation and dysregulation of complement can lead to uncontrolled inflammation and organ damage, especially to the kidney. Systemic lupus erythematosus (SLE) is characterized by loss of tolerance, autoantibody production, and immune complex deposition in tissues including the kidney, with inflammatory consequences. Effective clearance of immune complexes and cellular waste by early complement components protects against the development of lupus nephritis, while uncontrolled activation of complement, especially the alternative pathway, promotes kidney damage in SLE. Therefore, complement plays a dual role in the pathogenesis of lupus nephritis. Improved understanding of the contribution of the various complement pathways to the development of kidney disease in SLE has created an opportunity to target the complement system with novel therapies to improve outcomes in lupus nephritis. In this review, we explore the interactions between complement and the kidney in SLE and their implications for the treatment of lupus nephritis.

When Distress Becomes Somatic: Dementia Family Caregivers' Distress and Genetic Vulnerability to Pain and Sleep Problems.

BACKGROUND AND OBJECTIVES: Stress can trigger physical pain and disturb sleep. Whether dementia family caregivers experience heightened pain is unknown. Cycles of unwanted thoughts about caregiving stressors and avoidance of these thoughts-that is, caregiving-related distress-may exacerbate both pain and sleep disturbances, and genetic susceptibility to stress may further modulate these associations. RESEARCH DESIGN AND METHODS: Dementia caregivers (72 spouses, 58 adult children, ages 34-89) rated the extent to which they experienced unintended thoughts about caregiving and tried to suppress such thoughts. They also reported their pain levels, sleep problems, and depressive symptoms. Peripheral blood leukocytes were genotyped for 5-HTTLPR (serotonin-transporter-linked polymorphic region) and 5-HT1A receptor polymorphism rs6295 on the 5HTR1A locus. RESULTS: Short-allele carriers for 5-HTTLPR experienced more pain and sleep problems in association with greater caregiving-related distress than those with other genotypes. For rs6295, C carriers also showed the strongest links between distress and sleep problems. Those who experienced more avoidance and intrusive thoughts about caregiving had more severe depressive symptoms, consistent with past work. DISCUSSION AND IMPLICATIONS: Caregivers' genetic profiles helped to explain whether caregiving-related distress predicted worse pain and sleep problems. These data reveal new somatic risks of caregiver distress and provide targets for intervention. According to plasticity theories, caregivers genetically predisposed to greater stress reactivity may also respond particularly well to interventions, and many brief treatments may effectively address caregivers' intrusions and avoidance.

Cq1 Exon Polymorphisms in Caucasian and African American Systemic Lupus Erythematosus patients.

BACKGROUND: C1q protein is composed of three protein chains (A, B and C) that are the products of separate genes. Genetic deficiencies in C1Q genes are important factors influencing the risk of systemic lupus erythematosus (SLE). Therefore, this study aimed to investigate the possible association of single nucleotide polymorphisms (SNPs) in the coding region of the C1Q genes with SLE. METHODS: To search for potential SNPs in the encoding regions of C1q A, B and C chains, Cq1 exons were initially amplified and directly sequenced from leukocyte DNA from a subset of Caucasian and African American SLE patients and healthy controls. The sequences were analyzed by the Phrap and Phred software analysis system and the SNPs were identified by visual inspection. To test if any of these SNPs were linked to susceptibility to SLE, they were measured in 210 SLE patients ((59 African Americans and 151 Caucasians) and 129 matched healthy controls (55 African Americans and 74 Caucasians) by restriction fragment length polymorphism analysis. RESULTS: The sequencing phase of the study identified three synonymous SNPs: Nucleotide 276G>A in C1QA, 66C>A in C1QB and 129G>A in C1QC. Statistically, no differences were found in genotype or allele frequencies between patients and controls for the 276G>A or 66C>A SNP. However, in Caucasians, the frequencies of the 129G>A genotypes were significantly different between SLE patients and controls (P = 0.005), specifically with the GG genotype being over represented in the controls (P = 0.004). CONCLUSION: The results show that the homozygous 129GG genotype is associated with protection against SLE onset. This protection is race dependent, being observed in Caucasians but not African Americans. The mechanism of this association is currently unclear.

Biomarkers of lupus nephritis histology and flare: deciphering the relevant amidst the noise.

Biomarker development in lupus nephritis (LN) has traditionally relied on comparing the characteristics of candidate markers to clinical findings in patients and controls from cross-sectional cohorts. In this work, two additional strategies for LN biomarker development that are gaining ground will be discussed. One approach compares analytes directly to kidney histology. The second strategy utilizes longitudinal measurements of biomarker levels at regular intervals as patients move from disease quiescence to disease flare. These approaches have begun to empower biomarkers as diagnostic and prognostic tools in LN and have revealed novel and sometimes unexpected roles for these biomarkers in the pathogenesis and prediction of LN disease activity.

The Urine Preservative Acetic Acid Degrades Urine Protein: Implications for Urine Biorepositories and the AASK Cohort Study.

Patients enrolled in the African American Study of Kidney Disease and Hypertension (AASK) Cohort Study who exhibited overt proteinuria have been reported to show high nonalbumin proteinuria (NAP), which is characteristic of a tubulopathy. To determine whether African American Study of Kidney Disease and Hypertension nephropathy (AASK-N) is a tubulopathy, we obtained urine samples of 37 patients with AASK-N, with 24-hour protein-to-creatinine ratios (milligrams per milligram) ranging from 0.2 to 1.0, from the National Institute of Diabetes and Digestive Kidney Diseases repository and tested for seven markers of tubular proteinuria. By protocol, each sample had been collected in acetic acid (0.5%; mean final concentration). Compared with samples from patients with lupus nephritis or healthy black controls, AASK-N samples had lower amounts of six markers. Four markers (albumin, ß-2-microglobulin, cystatin C, and osteopontin) were undetectable in most AASK-N samples. Examination by SDS-PAGE followed by protein staining revealed protein profiles indicative of severe protein degradation in 34 of 37 AASK-N urine samples. Treatment of lupus nephritis urine samples with 0.5% acetic acid produced the same protein degradation profile as that of AASK-N urine. We conclude that the increased NAP in AASK-N is an artifact of acetic acid-mediated degradation of albumin. The AASK-N repository urine samples have been compromised by the acetic acid preservative.

Relationship of Circulating Anti-C3b and Anti-C1q IgG to Lupus Nephritis and Its Flare.

BACKGROUND AND OBJECTIVES: Autoantibodies to complement C1q (anti-C1q) are associated with the diagnosis of lupus nephritis. In this study, we compare anti-C1q IgG with another complement autoantibody, anti-C3b IgG, as a biomarker of lupus nephritis and lupus nephritis flare. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Our investigation involved the Ohio SLE Study, a prospective observational cohort of patients with recurrently active lupus who were followed bimonthly. Serum anti-C1q and anti-C3b IgG levels were assessed cross-sectionally by ELISA in 40 normal controls and 114 patients in the Ohio SLE Study (41 nonrenal and 73 lupus nephritis) at study entry, and longitudinally in a subset of patients in the Ohio SLE Study with anti-C1q-positive lupus nephritis in samples collected every 2 months for 8 months leading up to lupus nephritis flare (n=16 patients). RESULTS: In the cross-sectional analysis, compared with anti-C1q IgG, anti-C3b IgG was less sensitive (36% versus 63%) but more specific (98% versus 71%) for lupus nephritis. Only anti-C3b IgG was associated with patients with lupus nephritis who experienced at least one lupus nephritis flare during the Ohio SLE Study period (P<0.01). In the longitudinal analysis, circulating levels of anti-C1q IgG increased at the time of lupus nephritis flare only in patients who were anti-C3b positive (P=0.02), with significant increases occurring from 6 (38% increase) and 4 months (41% increase) before flare. Anti-C3b IgG levels also trended up at lupus nephritis flare, although the change did not reach statistical significance (P=0.07). Neither autoantibody increased 2 months before flare. CONCLUSIONS: Although not as prevalent as anti-C1q IgG, anti-C3b IgG showed nearly complete specificity for lupus nephritis. The presence of anti-C3b IgG identified patients with lupus nephritis who were prone to flare and in whom serial measurements of markers associated with complement, such as anti-C1q IgG, may be useful to monitor lupus nephritis activity.

The Complement System in Lupus Nephritis.

The complement system is composed of a family of soluble and membrane-bound proteins that historically has been viewed as a key component of the innate immune system, with a primary role of providing a first-line defense against microorganisms. Although this role indeed is important, complement has many other physiological roles, including the following: (1) influencing appropriate immune responses, (2) disposing of waste in the circulation (immune complexes, cellular debris), and (3) contributing to damage of self-tissue through inflammatory pathways. These three roles are believed to be significant factors in the pathogenesis of systemic lupus erythematosus, particularly its renal manifestation (lupus nephritis), contributing both protective and damaging effects. In this review, we provide an overview of the human complement system and its functions, and discuss its intricate and seemingly contradictory roles in the pathogenesis of lupus nephritis.

End-stage renal disease in African Americans with lupus nephritis is associated with APOL1.

OBJECTIVE: Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE) that exhibits familial aggregation and may progress to end-stage renal disease (ESRD). LN is more prevalent among African Americans than among European Americans. This study was undertaken to investigate the hypothesis that the apolipoprotein L1 gene (APOL1) nephropathy risk alleles G1/G2, common in African Americans and rare in European Americans, contribute to the ethnic disparity in risk. METHODS: APOL1 G1 and G2 nephropathy alleles were genotyped in 855 African American SLE patients with LN-ESRD (cases) and 534 African American SLE patients without nephropathy (controls) and tested for association under a recessive genetic model, by logistic regression. RESULTS: Ninety percent of the SLE patients were female. The mean ± SD age at SLE diagnosis was significantly lower in LN-ESRD cases than in SLE non-nephropathy controls (27.3 ± 10.9 years versus 39.5 ± 12.2 years). The mean ± SD time from SLE diagnosis to development of LN-ESRD in cases was 7.3 ± 7.2 years. The G1/G2 risk alleles were strongly associated with SLE-ESRD, with 25% of cases and 12% of controls having 2 nephropathy alleles (odds ratio [OR] 2.57, recessive model P = 1.49 × 10(-9)), and after adjustment for age, sex, and ancestry admixture (OR 2.72, P = 6.23 × 10(-6)). The age-, sex-, and admixture-adjusted population attributable risk for ESRD among patients with G1/G2 polymorphisms was 0.26, compared to 0.003 among European American patients. The mean time from SLE diagnosis to ESRD development was ∼2 years earlier among individuals with APOL1 risk genotypes (P = 0.01). CONCLUSION: APOL1 G1/G2 alleles strongly impact the risk of LN-ESRD in African Americans, as well as the time to progression to ESRD. The high frequency of these alleles in African Americans with near absence in European Americans explains an important proportion of the increased risk of LN-ESRD in African Americans.

Novel estrogen target gene ZAS3 is overexpressed in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a prototypic, inflammatory autoimmune disease characterized by significant gender bias. Previous studies have established a role for hormones in SLE pathogenesis, including the sex hormone estrogen. Estrogen regulates gene expression by translocating estrogen receptors (ER) α and ß into the nucleus where they induce transcription by binding to estrogen response elements (EREs) of target genes. The ZAS3 locus encodes a signaling and transcriptional molecule involved in regulating inflammatory responses. We show that ZAS3 is significantly up-regulated in SLE patients at both the protein and mRNA levels in peripheral blood mononuclear cells (PBMCs). Furthermore, estrogen stimulates the expression of ZAS3 in vitro in several leukocyte and breast cancer cell lines of both human and murine origin. In vivo estrogen treatment mediates induction of tissue specific ZAS3 expression in several lymphoid organs in mice. Estrogen stimulation also significantly up-regulates ZAS3 expression in primary PBMCs, while treatment with testosterone has no effect. Mechanistically, estrogen induces differential ERα binding to putative EREs within the ZAS3 gene and ERα knockdown with siRNA prevents estrogen induced ZAS3 up-regulation. In contrast, siRNA targeting IFNα has no effect. These data demonstrate that ZAS3 expression is directly regulated by estrogen and that ZAS3 is overexpressed in lupus. Since ZAS3 has been shown to regulate inflammatory pathways, its up-regulation by estrogen could play a critical role in female-biased autoimmune disorders.

High-sensitivity C-reactive protein, disease activity, and cardiovascular risk factors in systemic lupus erythematosus.

OBJECTIVE: To study the level of high-sensitivity C-reactive protein (hsCRP) and its relationship with disease activity, damage, and cardiovascular risk factors in patients with systemic lupus erythematosus (SLE). METHODS: Consecutive patients who fulfilled ≥4 American College of Rheumatology criteria for SLE who did not have a concurrent infection were recruited. Blood was assayed for hsCRP level, and disease activity, organ damage of SLE, and cardiovascular risk factors were assessed. Linear regression analyses were performed for the relationship between hsCRP levels, SLE activity, damage, and cardiovascular risk factors. RESULTS: In total, 289 patients were studied (94% women, mean ± SD age 39.0 ± 13.1 years, and mean ± SD SLE duration 7.8 ± 6.7 years). The mean ± SD Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score was 4.9 ± 5.6 and clinically active SLE was present in 122 patients (42%). The mean ± SD hsCRP level was 4.87 ± 12.7 mg/liter, and 28 patients with active SLE (23%) had an undetectable hsCRP level (<0.3 mg/liter). The linear regression analyses revealed a significant correlation between hsCRP level and musculoskeletal disease (ß = 0.21), hematologic disease (ß = 0.19), active serositis (ß = 0.46), and clinical SLEDAI score (ß = 0.24) after adjusting for age, sex, body mass index, serum creatinine, and the use of various medications (P < 0.005 for all). hsCRP levels correlated significantly with anti-double-stranded DNA titer (ß = 0.33, P < 0.001) but did not correlate with complement C3 (ß = -0.07, P = 0.26). An hsCRP level >3 mg/liter was significantly associated with male sex, long-term smoking, diabetes mellitus, a higher atherogenic index, and a history of arterial thrombosis. hsCRP levels correlated significantly with pulmonary and endocrine damage scores. CONCLUSION: hsCRP was detectable in 77% of SLE patients with clinically active disease and correlated with SLEDAI scores, particularly in serositis and in the musculoskeletal and hematologic systems. Elevated hsCRP levels in SLE were associated with certain cardiovascular risk factors and a history of arterial thromboembolism.

FcγRIIb on liver sinusoidal endothelium clears small immune complexes.

It has long been known that the ITIM-bearing IgG Fc receptor (FcγRIIb, RIIb) is expressed on liver sinusoidal endothelial cells (LSEC) and that the liver is the major site of small immune complex (SIC) clearance. Thus, we proposed that RIIb of LSEC eliminates blood-borne SIC, thereby controlling immune complex-mediated autoimmune disease. Testing this hypothesis, we found most RIIb of the mouse, fully three-quarters, to be expressed in liver. Moreover, most (90%) liver RIIb was expressed in LSEC, the remainder in Kupffer cells. An absent FcRγ in LSEC implied that RIIb is the sole FcγR expressed. Testing the capacity of liver RIIb to clear blood-borne SIC, we infused mice intravenously with radio-iodinated SIC made of OVA and rabbit IgG anti-OVA. Tracking decay of SIC from the blood, we found the RIIb knockout strain to be severely deficient in eliminating SIC compared with the wild-type strain, terminal half-lives being 6 and 1.5 h, respectively. RIIb on LSEC, a major scavenger, keeps SIC blood concentrations low and minimizes pathologic deposition of inflammatory immune complex.

Characterization of glomerular diseases using proteomic analysis of laser capture microdissected glomeruli.

The application of molecular techniques to characterize clinical kidney biopsies has the potential to provide insights into glomerular diseases that cannot be revealed by traditional renal pathology. The present work is a proof-of-concept approach to test whether proteomic analysis of glomeruli isolated from clinical biopsies by laser capture microdissection can provide unique information regarding differentially expressed proteins relevant to disease pathogenesis. The proteomes of glomeruli isolated by laser capture microdissection from biopsies of normal kidneys (living-related donor kidneys) were compared with those from patients with diabetic nephropathy, lupus nephritis, and fibronectin glomerulopathy. Glomerular proteins were extracted, trypsin digested, and subjected to liquid chromatography-tandem mass spectrometry for identification and quantitation. Relative to normal glomeruli, all disease-associated glomeruli showed an increased presence of complement components, a marked decline in podocyte-associated proteins, and a decrease in proteins associated with cellular metabolism. Additionally, fibronectin glomerulopathy glomeruli differed from all the other glomeruli because of a significant accumulation of fibronectin and fibulin. This study demonstrates that our method acquires reproducible and quantitative proteomic information from laser capture microdissection isolates that can be used to characterize the molecular features of glomerular diseases.

Vitamin D levels in Chinese patients with systemic lupus erythematosus: relationship with disease activity, vascular risk factors and atherosclerosis.

OBJECTIVES: To study the relationship of 25(OH)D(3) level with disease activity, vascular risk factors and atherosclerosis in SLE. METHODS: Consecutive patients who fulfilled four or more ACR criteria for SLE were recruited for assay of 25(OH)D(3) level. Disease activity was assessed by the SLEDAI and physicians' global assessment (PGA). Patients with vascular risk factors were screened for atherosclerosis at the coronary or carotid arteries. Correlation between 25(OH)D(3) levels and SLEDAI scores was studied by linear regression. The link between vascular risk factors, atherosclerosis and vitamin D deficiency was also examined. RESULTS: A total of 290 SLE patients were studied [94% women; mean (s.d.) age 38.9 (13.1) years; disease duration 7.7 (6.7) years; 78% patients had clinical or serological lupus activity]. Two hundred and seventy-seven (96%) patients had vitamin D insufficiency [25(OH)D(3) < 30 ng/ml] and 77 (27%) patients had vitamin D deficiency (<15 ng/ml). Levels of 25(OH)D(3) correlated inversely with PGA (ß -0.20; P = 0.003), total SLEDAI scores (ß -0.19; P = 0.003) and subscores due to active renal, musculoskeletal and haematological disease. Subjects with vitamin D deficiency had significantly higher total/high-density lipoprotein (HDL) cholesterol ratio [3.96 (2.94) vs 3.07 (0.80); P = 0.02] and prevalence of aPLs (57 vs 39%; P = 0.007). Of 132 patients, 58 (44%) with vascular risk factors screened were positive for subclinical atherosclerosis. No association could be demonstrated between 25(OH)D(3) level and atherosclerosis, which was mainly associated with increasing age, menopause, obesity and hyper-triglyceridaemia. CONCLUSIONS: In this large cross-sectional study of SLE patients, 25(OH)D(3) level correlates inversely with disease activity. Vitamin D deficiency is associated with dyslipidaemia. In patients with vascular risk factors, subclinical atherosclerosis is not associated with hypovitaminosis D.

An approach to validating criteria for proteinuric flare in systemic lupus erythematosus glomerulonephritis.

OBJECTIVE: Published criteria on the degree of proteinuria increase that defines a proteinuric flare in systemic lupus erythematosus (SLE) with glomerulonephritis (GN) vary widely, likely because they are not evidence based, but are largely based on expert opinion. Ideally, the threshold for proteinuric flare should be set sufficiently high that spontaneous variation in proteinuria does not likely explain the increase, but not so high that the patient needlessly experiences prolonged severe proteinuria before a flare is declared and therapy is increased. The present study was undertaken to develop an evidence-based approach to setting the threshold for proteinuric flare, based on quantifying the spontaneous variation in the urine protein:creatinine ratio in SLE GN patients who are not experiencing SLE flare. METHODS: SLE GN patients (n = 71) in the Ohio SLE Study were tested at prespecified bimonthly intervals within windows of ±1 week. The median duration of followup was >44 months, and the rate of visit compliance was >90%. To assess spontaneous variation in the protein:creatinine ratio under no-flare conditions, we excluded protein:creatinine ratios measured within 4 months before or after renal flare. RESULTS: Our findings showed that in the group of SLE GN patients with a mean no-flare protein:creatinine ratio of ≤0.5, the published flare thresholds are set well above the 99% confidence interval of the no-flare protein:creatinine ratio. The opposite was seen in the group with a mean no-flare protein:creatinine ratio of ≥1.0. CONCLUSION: Current thresholds for defining proteinuric flare appear to be set either too high or too low. A randomized trial would be needed to test whether resetting the thresholds would result in faster remission, reduction in therapy, and decrease in the frequency of chronic kidney disease.