While in vitro studies have demonstrated a suppressive action of vitamin D on Ig production and the IFN signature,18,24,25 an association between vitamin D status in patients with SLE and these disease features has not been previously reported. ANA was measured using sera at a 1:80 dilution in NHANES. Meier, D.P. Moser KL, Kelly JA, Lessard CJ, et al. Vacca A, Cormier C, Piras M, et al. Vitamin D deficiency could also contribute to an increased IFN signature in myeloid dendritic cells. Patients with vitamin D deficiency also had higher mean (SD) serum IFN activity than patients without vitamin D deficiency (3.5 (6.6) vs 0.3 (0.3); p=0.02). We thank Drs. 0000147351 00000 n
Hochberg MC. 
An official website of the United States government. In contrast, the 18 controls who were ANA-negative had significantly higher 25(OH)D levels than the patients with SLE (p<0.01, figure 1A). We were not able to evaluate use of specific medications due to small numbers, but several indicators of health status and comorbid conditions, including high blood pressure, high triglycerides, high cholesterol, and smoking status, that were investigated as potential confounders were not found to be associated with the exposure or outcome, and results were in fact strengthened in an analysis that excluded hypertensives. This study has several strengths. Patients with high B cell activation had lower mean (SD) 25(OH)D levels than patients with low B cell activation (17.2 (5.1) vs 24.2 (3.9) ng/ml; p=0.009). Finally, NHANES does not include the institutionalized elderly, who are particularly prone to vitamin D deficiency; therefore, our findings may underestimate the relationship between vitamin D deficiency and ANA prevalence at older ages (27). All statistical analyses were carried out with GraphPad Prism Version 5.01 (GraphPad Software, San Diego, California, USA; http://www.graphpad.com). 0000021987 00000 n
Section 1734 solely to indicate this fact. Potential confounders were selected on the basis of a priori hypotheses or if they were associated with the exposure and outcome. A recent study sought to examine the effects of oral vitamin D supplementation on disease activity in SLE; however, more than 70% of the patients in the study still had insufficient levels of vitamin D after 2 years of treatment.36 While this study did not report any improvements in SLE disease activity after oral administration of vitamin D, interpretation of the results is limited by the small percentage of patients with SLE who achieved adequate 25(OH)D levels. The number of lupus-associated autoantibody specificities and 25(OH)D values are the predictor variables. The .gov means its official. The site is secure. 
Hormonal, environmental, and infectious risk factors for developing systemic lupus erythematosus. Bethesda, MD 20894, Web Policies Lower 25-hydroxyvitamin D (25(OH)D) levels are associated with increased B cell activation in patients with systemic lupus erythematosus (SLE). Kamen D, Aranow C. Vitamin D in systemic lupus erythematosus. 0000007249 00000 n
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Cooper GS, Dooley MA, Treadwell EL, et al. Twenty-three per cent of vitamin D-deficient patients versus 20% of non-deficient patients were receiving treatment with azathioprine (p=1.000), 77% versus 60% were taking hydroxychloroquine (p=0.407), 23% versus 10% were receiving mycophenolate mofetil (p=0.637) and 23% versus 10% were being treated with methotrexate (p=0.637) (Fisher exact test). Tan EM, Cohen AS, Fries JF, et al. Hypovitaminosis D is associated with greater body mass index and disease activity in pediatric systemic lupus erythematosus. Parks. Vitamin D deficiency also influences B-cell homeostasis directly, resulting in hyperactive B cells and increased immunoglobulin production (6, 7). Crow MK, Kirou KA. IFN activity values reported represent the number of SD above the mean of healthy donors (n=141). In these models the outcome variable was IFN activity, with high levels defined as IFN activity >1 SD above the mean of healthy controls and low levels defined as IFN activity <1 SD below the mean. Zold E, Szodoray P, Gaal J, et al. 0000002777 00000 n
This finding is interesting because patients with autoimmune disease, especially those with SLE, possess many risk factors for vitamin D deficiency whereas healthy controls do not. 0000019267 00000 n
Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Nonetheless, we performed a sensitivity analysis, excluding hypertensives. 0000004104 00000 n
Learn more 0000005586 00000 n Numerous studies have confirmed the association between raised IFN levels and increased disease activity in SLE.21 Strong evidence for the pathogenic role of IFN in SLE comes from clinical studies showing treatment with recombinant IFN for malignancies or hepatitis causes de novo SLE, with resolution after discontinuation of treatment.21 Induction of IFN from stimulation of TLRs by nucleic acid-containing immune complexes is thought to be one of the mechanisms by which patients with SLE have increased IFN activity.21 Supporting this hypothesis is evidence that activation of the IFN pathway is associated with the presence of autoantibodies directed against DNA and RNA binding proteins.22,23. Data were extracted from the medical records of the patients with SLE for ACR classification criteria, age of diagnosis and medication use. endstream endobj 427 0 obj <>>>/Metadata 424 0 R/Names 428 0 R/Outlines 412 0 R/Pages 423 0 R/Type/Catalog/ViewerPreferences<>>> endobj 428 0 obj <> endobj 429 0 obj <>/ExtGState<>/Font<>/ProcSet[/PDF/Text/ImageC]/XObject<>>>/Rotate 0/Tabs/W/Thumb 417 0 R/TrimBox[0.0 0.0 595.276 841.89]/Type/Page>> endobj 430 0 obj [431 0 R] endobj 431 0 obj <>/Border[0 0 0]/H/N/Rect[444.871 793.605 543.251 783.094]/Subtype/Link/Type/Annot>> endobj 432 0 obj <> endobj 433 0 obj <> endobj 434 0 obj <> endobj 435 0 obj <> endobj 436 0 obj <> endobj 437 0 obj [/ICCBased 461 0 R] endobj 438 0 obj <> endobj 439 0 obj <> endobj 440 0 obj [466 0 R] endobj 441 0 obj <>stream Vitamin D-deficient patients had a mean (SD) serum IFN activity of 3.5 (6.6) compared with 0.34 (0.33) in non-vitamin D-deficient patients. Bars indicate IQR. Welchs correction was used in instances of unequal variance. LCL, lower 95% confidence limit; UCL, upper 95% confidence limit. Data from NHANES 2003 to 2004 cycle were adjusted for assay drift (21). Kirou KA, Lee C, George S, et al. After permeabilisation, cells were incubated with anti-CD79a-PE (BD Biosciences) and anti-phospho-Erk (pERK1/2) (Cell Signaling Technology, Danvers, Massachusetts, USA). A study was undertaken to explore the impact of low vitamin D levels on autoantibody production in healthy individuals, as well as B cell hyperactivity and interferon (IFN) activity in patients with systemic lupus erythematosus (SLE). Federal government websites often end in .gov or .mil. Hua J, Kirou K, Lee C, et al. Vitamin D deficiency (25(OH)D <20 ng/ml) was significantly more frequent among patients with SLE (n=32, 69%) and antinuclear antibody (ANA)-positive controls (n=14, 71%) compared with ANA-negative controls (n=18, 22%) (OR 7.7, 95% CI 2.0 to 29.4, p=0.003 and OR 8.8, 95% CI 1.8 to 43.6, p=0.011, respectively). official website and that any information you provide is encrypted Experiments were performed in accordance with the Helsinki Declaration and approved by the Institutional Review Boards at the Oklahoma Medical Research Foundation and the University of Oklahoma Health Sciences Center. 0000003697 00000 n Together with genetic susceptibility and other environmental factors, vitamin D deficiency could contribute to increased B cell activation and autoantibody production. **p=0.002 (unpaired t test). Antinuclear antibody (ANA)-positive healthy individuals and patients with systemic lupus erythematosus (SLE) are more likely to be deficient in vitamin D. (A) Median (IQR) 25-hydroxyvitamin D levels were 17.3 (11.921.2) ng/ml in patients with SLE (n=32), 17.4 (14.525.8) ng/ml in ANA-positive controls (n=14) and 29.4 (19.036.3) ng/ml in ANA-negative controls (n=18). 0000146686 00000 n The costs of publication of this article were defrayed in part by the payment of page charges. Novel biomarkers in autoimmune diseases: prolactin, ferritin, vitamin D, and TPA levels in autoimmune diseases. 2016 AACR. Continuous variables were analysed using an unpaired t test. 0000136449 00000 n The mean age of the 14 ANA-positive controls was significantly higher than the ANA-negative controls (54.1 vs 42.8 years; p=0.029, unpaired t test). ): H.C.S.
0000010054 00000 n While vitamin D deficiency has been reported in many autoimmune diseases, this is the first observation in ANA-positive healthy individuals. Comorbid conditions or medications could contribute to the association between ANA and vitamin D. Ability to perform moderate/vigorous physical activity is only a crude indication of possibly comorbidity. Patients with SLE who had high IFN activity (>1 SD above the mean of healthy controls) had an increased number of lupus-associated autoantibody specificities compared with those who had low IFN activity (<1 SD above the mean of healthy controls) (2.6 vs 0.9; p=0.002, unpaired t test; figure 3B).
Serum samples were tested for IgG autoantibodies to human cellular antigens using standard immunofluorescence methods described previously (14). Meier, D.P. Frozen serum samples (20C) collected at mobile examination centers were shipped to the National Center for Environmental Health (Atlanta, GA) for testing. This provides epidemiological evidence to suggest that vitamin D deficiency in autoimmunity is not solely a consequence of lifestyle changes associated with the disease. PMC legacy view This observation suggests that vitamin D deficiency could be playing a role in the B cell hyperactivity seen in patients with SLE, thus contributing to an increased production of autoantibodies. Anti-double stranded DNA (dsDNA) antibodies were detected using a Crithidia luciliae indirect immunofluorescent assay (INOVA Diagnostics) according to the manufacturers instructions. B, Weighted prevalence (95% CI) of ANA by race/ethnic-specific vitamin D levels in the U.S. population ages 50+, NHANES 20012004 (N = 1,012); low,
As the first analysis conducted in a large, U.S. representative sample, this adds to a suggestive literature on vitamin D deficiency and ANA based on clinical studies of lupus patients and one small sample of clinical controls (7, 15). H\00Q(T/ X/;_\BO#8lm=7|kb{K"uS[]D8z5ynaMxjPshNF{}ov5e{-lqP|3Y:L|C/l. (A) Increased B cell activation (as measured by phospho-ERK (pERK1/2)) was correlated with decreased 25(OH)D levels in patients with SLE (r=0.40, p=0.03). 0000068201 00000 n Activation of the interferon-alpha pathway identifies a subgroup of systemic lupus erythematosus patients with distinct serologic features and active disease. Among individuals in the U.S. population ages 50 and older, vitamin D deficiency was associated with higher prevalence of ANA. Kamen DL, Tangpricha V. Vitamin D and molecular actions on the immune system: modulation of innate and autoimmunity. Vitamin D deficiency was associated with an increased presence of autoantibodies in healthy controls. 0000135920 00000 n Adorini L, Penna G. Control of autoimmune diseases by the vitamin D endocrine system. The impact of vitamin D on dendritic cell function in patients with systemic lupus erythematosus. The reporter cells (Wistar Institute, Susan Hayflick cells, ATCC No. 0 We examined the prevalence of vitamin D deficiency in antinuclear antibody (ANA)-positive healthy individuals in comparison with ANA-negative healthy individuals and patients with SLE. 0000185445 00000 n 0000146938 00000 n 22). FOIA Kamen DL, Cooper GS, Bouali H, et al. 19, 20). 8600 Rockville Pike startxref Of those, 118 participants with missing covariate information were excluded, resulting in a final sample of 1,012. We also showed evidence of a relationship between vitamin D levels in patients with SLE and the magnitude of B lymphocyte activation in PBMCs, as determined by pERK1/2 levels. This suggests that, although the number of autoantibody specificities and 25(OH)D levels are correlated (r2=0.138, p=0.037), both are good independent predictors of IFN activity.
Additional adjustment for BMI and physical activity had little impact on observed associations (severe deficiency POR: 2.64; 95% CI, 1.086.45; deficiency POR: 1.83; 95% CI, 1.013.30 and insufficiency POR: 2.01; 95% CI, 1.093.7; Ptrend = 0.05). No correlation was seen between B cell activity and 25(OH)D levels in controls (pERK1/2: r=0.05, p=0.79). 0000000016 00000 n (B) Patients with SLE with 25(OH)D levels <20 ng/ml had higher B cell activation (as measured by pERK1/2) than patients with 25(OH)D levels >20 ng/ml; *p=0.045 (unpaired t test with Welchs correction of log-transformed data). 1X$2x^@\6BA*`(faRf0!!h-5X3_f~8q*BeL ;|020gWZ\0(`6V=]OkOipj`A1qFw2hz4!q-+i~1`bbdg`dpOe"C/PIF.I^fj4A3`!0 500oh`B3JP6 #T 1,25-Dihydroxyvitamin D3 selectively modulates tolerogenic properties in myeloid but not plasmacytoid dendritic cells. Prevalence varied by sex (20.7% of females and 13.9% of males were ANA positive) and by race/ethnicity (15.9% of non-Hispanic white, 26.7% of non-Hispanic black and 21.9% of other were ANA positive), but only the sex difference was statistically significant (P = 0.02; Table 1). Search for other works by this author on: National Institute of Environmental Health Sciences. Serum concentrations of 25-OH vitamin D in patients with systemic lupus erythematosus (SLE) are inversely related to disease activity: is it time to routinely supplement patients with SLE with vitamin D? 1Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA, 2Departments of Medicine and Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA, 3Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, Illinois, USA, 4Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA, 5Division of Rheumatology, Cincinnati Children's Hospital Medical Center and US Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA. 44 +!"\A}BZX+kcX{kbV=ZX+kcX{nTSQ"LE }Fg }Fg }Fg }Fg }Fg }Fg)EFTgSx*O3xTg{219`!2/gEH3"}F_}>/gEHQk"k"_>}qDo)|~?iwm}ne:-ig;7e )0\2 0000013397 00000 n The estimated weighted prevalence of ANA positivity (score 3 or 4) was 17.5% in the U.S. population aged 50 and older.
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