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1.
Effect of levothyroxine on pregnancy outcomes in women with thyroid autoimmunity: a systematic review with meta-analysis of randomized controlled trials.
Wang, X, Zhang, Y, Tan, H, Bai, Y, Zhou, L, Fang, F, Faramand, A, Chong, W, Hai, Y
Fertility and sterility. 2020;(6):1306-1314
Abstract
OBJECTIVE To investigate whether levothyroxine is associated with improved live birth and other benefits in women with thyroid autoimmunity. DESIGN Systematic review and meta-analysis. SETTING Not applicable. PATIENT(S): Women positive for thyroid peroxidase antibody. INTERVENTION(S): MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched without any language restrictions. Pooled effect sizes were calculated using random-effects models. MAIN OUTCOME MEASURE(S): The primary outcome was the incidence of live birth, miscarriage, preterm birth, clinical pregnancy, ectopic pregnancy, neonatal admission, and birth weight. The summary measures were reported as relative risk (RR) with 95% confidence interval. RESULT(S): Levothyroxine supplementation was not associated with an increased rate of live birth or a decreased risk of miscarriage. Results were similar in subgroup analyses of live birth by age, baseline thyrotropin, baseline thyroid peroxidase antibody, body mass index, and use of assisted conception. For live birth, the effect estimate lay within the futility boundary for RR of 20% and 15%, but at a 10% RR, the effect estimate lay between the futility boundary and the inferior boundary. CONCLUSION(S): High- to moderate-quality evidence demonstrated that the use of levothyroxine was not associated with improvements in clinical pregnancy outcomes among women positive for thyroid peroxidase antibody. REGISTRATION NUMBER PROSPERO CRD42019132976.
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No association between anti-thyroidperoxidase antibodies and bipolar disorder: a study in the Dutch Bipolar Cohort and a meta-analysis.
Snijders, GJLJ, de Witte, LD, van den Berk, D, van der Laan, C, Regeer, E, Begemann, MJH, Berdenis van Berlekom, A, Litjens, M, Boks, MP, Ophoff, RA, et al
Psychoneuroendocrinology. 2020;:104518
Abstract
BACKGROUND Thyroid autoimmunity has been associated with bipolar disorder (BD). However, results from previous studies on the seroprevalence of anti-thyroid peroxidase antibodies (TPO-abs) in BD are inconsistent. OBJECTIVES The aim of the present study is to investigate whether the seroprevalence and titer levels of TPO-abs are related to BD. METHOD TPO-abs were measured in plasma samples of 760 patients with bipolar disorder, 261 first-degree relatives and 363 controls by enzyme-linked immunosorbent assay (ELISA). To address methodological limitations of previous studies, we assessed clinical characteristics with several (self-reported) questionnaires to investigate whether TPO-abs positivity is related to particular clinical subgroups of BD patients. We performed an additional meta-analysis of seroprevalences of TPO-abs in BD patients including data from present and previous studies. RESULTS Seroprevalence or titer levels of TPO-abs did not significantly differ between patients with BD, their first-degree relatives, and controls. In BD patients, the prevalence of TPO-abs was unrelated to specific clinical factors, including lithium use. Our meta-analysis of twelve studies showed an overall odds ratio of 1.3 (CI 95 %: 0.7-2.3; p = 0.30), reaffirming the absence of an association of BD with TPO-abs. CONCLUSIONS In the largest study of TPO-abs in BD to date, our findings indicate that TPO-abs are not associated with (the risk for) bipolar disorder.
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Comprehensive meta-analysis reveals an association of the HLA-DRB1*1602 allele with autoimmune diseases mediated predominantly by autoantibodies.
Chen, Y, Li, S, Huang, R, Zhang, Z, Petersen, F, Zheng, J, Yu, X
Autoimmunity reviews. 2020;(6):102532
Abstract
The human leukocytes antigen (HLA)-DRB1*16:02 allele has been suggested to be associated with many autoimmune diseases. However, a validation of the results of the different studies by a comprehensive analysis of the corresponding meta data is lacking. In this study, we performed a meta-analysis of the association between HLA-DRB1*16:02 allele with various autoimmune disorders. Our analysis shows that HLA-DRB1*16:02 allele was associated with systemic lupus erythematosus, anti-N-Methyl-d-Aspartate receptor (NMDAR) encephalitis, Graves' disease, myasthenia gravis, neuromyelitis optica and antibody-associated systemic vasculitis with microscopic polyangiitis (AASV-MPA). However, no such association was found for multiple sclerosis, autoimmune hepatitis type 1, rheumatoid arthritis, type 1 diabetes and Vogt-Koyanagi-Harada syndrome. Re-analysis of the studies after their categorization into autoantibody-dependent and T cell-dependent autoimmune diseases revealed that the HLA-DRB1*16:02 allele was strongly associated with disorder predominantly mediated by autoantibodies (OR = 1.93; 95% CI = 1.63-2.28, P = 1.95 × 10-14) but not with those predominantly mediated by T cells (OR = 1.08; 95% CI = 0.87-1.34, P = .474). In addition, amino acid sequence alignment of common HLA-DRB1 subtypes demonstrated that HLA-DRB1*16:02 carries a unique motif of amino acid residues at position 67-74 which encodes the third hypervariable region. Taken together, the distinct pattern of disease association and the unique amino acid sequence of the third hypervariable region of the HLA-DRB1 provide some hints on how HLA-DRB1*16:02 is involved in the pathogenesis of autoimmune diseases.
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The association of anti-PLA2R with clinical manifestations and outcomes in idiopathic membranous nephropathy: a meta-analysis.
Rao, SJ, Shen, Q, Wang, HM, Tang, S, Wang, XY
International urology and nephrology. 2020;(11):2123-2133
Abstract
PURPOSE The meta-analysis aims to investigate the relationship between anti-phospholipase A2 receptor autoantibody (anti-PLA2R) and clinical characteristics and adverse outcomes of idiopathic membranous nephropathy (IMN). METHODS Related studies published before February 2020 were systematically retrieved from foreign and domestic databases, RevMan5.3 software was used for meta-analysis and subgroup analysis, and STATA 15.0 statistical software was used for its heterogeneity and testing publication bias. RESULTS Twenty studies were included, involving 2224 patients with IMN. Our results showed that a significant correlation existed between the expression of serum anti-PLA2R and age (MD = 2.91, 95% CI = 2.15-3.67, P < 0.00001), total serum cholesterol (MD = 35.52, 95% CI = 9.52-61.52, P = 0.007), urine protein by creatinine ratio (UPCR) (MD = 2.15, 95% CI = 1.86-2.44, P<0.00001), serum albumin (MD = -0.40, 95% CI = -0.56 to -0.23, P < 0.00001), eGFR (MD = -10.44, 95% CI = -12.19 to -8.68, P < 0.00001), unremission rate (RR = 1.76, 95% CI = 1.37-2.27, P < 0.0001). In addition, the high titer in seropositive group was closely correlated with serum albumin (MD = -0.40, 95% CI = -0.74 to -0.05, P = 0.03), eGFR (MD = -12.40, 95% CI = -16.29 to -8.52, P < 0.00001) and unremission rate (RR = 2.52, 95% CI = 1.79-3.55, P < 0.00001). No significant correlation was found between glomerular anti-PLA2R and clinical manifestations except for serum cholesterol (MD = 0.81, 95% CI = 0.21-1.41, P = 0.008). However, in terms of prognosis, glomerular anti-PLA2R showed a significant relevance to recurrence rate (RR = 2.25, 95% CI = 1.07-4.72, P = 0.03). CONCLUSION Compared with glomerular anti-PLA2R, serum anti-PLA2R may better reflect the activities of IMN disease, while the glomerular anti-PLA2R might be connected with the recurrence of the disease.
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The Relationship between High Iodine Consumption and Levels of Autoimmune Thyroiditis-Related Biomarkers in a Chinese Population: a Meta-Analysis.
Wan, S, Jin, B, Ren, B, Qu, M, Wu, H, Liu, L, Boah, M, Shen, H
Biological trace element research. 2020;(2):410-418
Abstract
To comprehensively evaluate the relationship between high iodine concentration and biomarker abnormalities related to autoimmune thyroiditis in a Chinese population. Medline, PubMed, and Embase electronic databases were searched for articles published domestically and internationally on the relationship between high iodine concentrations and thyroid hormone antibodies and thyroid-stimulating hormone in China before March 2019. Articles published in Chinese were searched in the China Biology Medicine (CBM) disc, Wanfang Database, and China National Knowledge Infrastructure (CNKI). A total of 16 cross-sectional articles were included in this study, including 9061 participants. A meta-analysis was conducted in Stata 14.0. The binary categorical and continuous variables used odds ratios (ORs) and standardized mean differences (SMDs) with the corresponding 95% confidence intervals (CIs) as the effect statistics, respectively. The results showed that high iodine concentrations had a minimal association with the abnormal rates of thyroid peroxidase antibody (TPOAb) (OR = 1.274, 95% CI (0.957, 1.695), P > 0.05) and thyroglobulin antibody (TGAb) (OR = 1.217, 95% CI (0.911, 1.626), P > 0.05) in the entire population. The thyroid-stimulating hormone (TSH) level in the high iodine group was greater than that in the adaptive iodine group (SMD = 0.202, 95% CI (0.096, 0.309), P < 0.05). The results of the subgroup analysis showed that the abnormal TPOAb rate in pregnant women (OR = 1.519, 95% CI (1.007, 2.291), P < 0.05) and children (OR = 3.365, 95% CI (1.966, 5.672), P < 0.05) in the high iodine group was greater than that in the adaptive iodine group, and the abnormal TGAb rate of children in the high iodine group was greater than that in the adaptive iodine group. The TSH levels of lactating women (SMD = 0.24, 95% CI (0.053, 0.427), P < 0.05), pregnant women (SMD = 0.301, 95% CI (0.176, 0.426), P < 0.05), and children (SMD = 0.25, 95% CI(0.096, 0.309), P < 0.05) in the high iodine group were higher than those in the adaptive iodine group. Egger's and Begg's tests showed no significant (P > 0.1) publication bias. High iodine can increase the risk of abnormal levels of TPOAb, TGAb, and TSH related to autoimmune thyroiditis in pregnant women, lactating women, and children in China.
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The effect of vitamin D supplementation on thyroid autoantibody levels in the treatment of autoimmune thyroiditis: a systematic review and a meta-analysis.
Wang, S, Wu, Y, Zuo, Z, Zhao, Y, Wang, K
Endocrine. 2018;(3):499-505
Abstract
PURPOSE Although observational studies suggested that vitamin D plays a role in autoimmune thyroiditis (AIT), intervention trials yielded inconsistent findings. We therefore conducted a systematic review and a meta-analysis to evaluate the effects of Vitamin D on decreasing autoantibodies in patients with AIT. METHOD We identified all studies that assessed the changes of TPO-Ab and Tg-Ab in patients with AIT under the treatment of vitamin D from PubMed, Embase, The Cochrane Library, Chinese National Knowledge Infrastructure, Wanfang, and VIP Database. RESULTS Six randomized controlled trials (RCTs) were included in this systematic review representing a total of 344 patients with AIT. The results showed that Vitamin D supplementation significantly dropped TPO-Ab titers [three studies, random effects standardized mean difference (SMD): -1.11, 95% CI -1.52 to -0.70, P < 0.01] at six months, but not at no more than 3 months [random effects SMD: -0.12, 95% CI: -0.69 to 0.44, P = 0.67]. As compared with control group, participants who received vitamin D supplementation demonstrated significantly lower Tg-Ab [random effects SMD: -0.55, 95% CI: -1.05 to -0.04, P = 0.033]. In addition, no serious adverse effect was reported. CONCLUSIONS The current evidence suggests that vitamin D supplementation could decrease serum TPO-Ab and Tg-Ab titers of patients with AIT in the short-term (about six months). More high quality studies are needed to further confirm the effects, especially the long-term effects of Vitamin D supplementation on thyroid autoantibodies levels in the treatment of AIT.
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7.
Dose Dependency and a Functional Cutoff for TPO-Antibody Positivity During Pregnancy.
Korevaar, TIM, Pop, VJ, Chaker, L, Goddijn, M, de Rijke, YB, Bisschop, PH, Broeren, MA, Jaddoe, VWV, Medici, M, Visser, TJ, et al
The Journal of clinical endocrinology and metabolism. 2018;(2):778-789
Abstract
OBJECTIVE To investigate a dose dependency of thyroperoxidase antibody (TPOAb) concentrations in relation to thyroid function and premature delivery and define a population-based, pregnancy-specific, functional cutoff for TPOAb positivity. DESIGN Individual participant meta-analysis of three prospective birth cohorts: the Amsterdam Born Children and their Development study, and the Holistic Approach to Pregnancy. SETTING Population-based studies in the Netherlands (2002 to 2014). PARTICIPANTS A total of 11,212 pregnant women (<20 weeks' gestation). MAIN OUTCOME MEASURES Thyrotropin (TSH) and FT4 concentrations, premature delivery. RESULTS In all cohorts, there was a dose-dependent positive association of TPOAb concentrations with TSH concentrations, as well as a dose-dependent negative association with FT4 concentrations during early pregnancy (all P < 0.0001). There was a dose-dependent association of TPOAb concentrations with the risk of premature delivery, which was also modified by TSH concentrations. Women with TPOAb concentrations from the 92nd percentile upward had a higher TSH and a higher risk of a TSH >2.5 mU/L (range, 19.4% to 51.3%). Stratified analyses showed that women with TPOAb concentrations below manufacturer cutoffs already had a higher risk of premature delivery, especially when TSH concentrations were high or in the high-normal range. CONCLUSIONS This study demonstrated a dose-dependent relationship between TPOAbs and thyroid function as well as the risk of premature delivery. Furthermore, our results indicate that the currently used cutoffs for TPOAb positivity may be too high. Furthermore, the use of a population-based cutoff for TPOAbs may identify women with a clinically relevant extent of thyroid autoimmunity and a higher risk of premature delivery but that would not be considered TPOAb positive or eligible for treatment otherwise.
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Tests for Serum Transglutaminase and Endomysial Antibodies Do Not Detect Most Patients With Celiac Disease and Persistent Villous Atrophy on Gluten-free Diets: a Meta-analysis.
Silvester, JA, Kurada, S, Szwajcer, A, Kelly, CP, Leffler, DA, Duerksen, DR
Gastroenterology. 2017;(3):689-701.e1
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Abstract
BACKGROUND & AIMS Tests to measure serum endomysial antibodies (EMA) and antibodies to tissue transglutaminase (tTG) were developed to screen for celiac disease in patients consuming gluten. However, they are commonly used to monitor patients on a gluten-free diet (GFD). We conducted a meta-analysis to assess the sensitivity and specificity of tTG IgA and EMA IgA assays in identifying patients with celiac disease who have persistent villous atrophy despite a GFD. METHODS We searched PUBMED, EMBASE, BIOSIS, SCOPUS, clinicaltrials.gov, Science Citation Index, and Cochrane Library databases through November 2016. Inclusion criteria were studies of subjects with biopsy-confirmed celiac disease, follow-up biopsies, and measurement of serum antibodies on a GFD, biopsy performed on subjects regardless of symptoms, or antibody test results. Our analysis excluded subjects with refractory celiac disease, undergoing gluten challenge, or consuming a prescribed oats-containing GFD. Tests were considered to have positive or negative findings based on manufacturer cut-off values. Villous atrophy was defined as a Marsh 3 lesion or villous height:crypt depth ratio below 3.0. We constructed forest plots to determine the sensitivity and specificity of detection for individual studies. For the meta-analysis, a bivariate random effects model was used to jointly model sensitivity and specificity. RESULTS Our search identified 5408 unique citations. Following review of abstracts, 442 articles were reviewed in detail. Only 26 studies (6 of tTG assays, 15 of EMA assays, and 5 of tTG and EMA assays) met our inclusion criteria. The most common reason studies were excluded from our analysis was inability to cross-tabulate histologic and serologic findings. The serum assays identified patients with persistent villous atrophy with high levels of specificity: 0.83 for the tTG IgA assay (95% CI, 0.79-0.87) and 0.91 for the EMA IgA assay (95% CI, 0.87-0.94). However, they detected villous atrophy with low levels of sensitivity: 0.50 for the tTG IgA assay (95% CI, 0.41-0.60) and 0.45 for the EMA IgA assay (95% CI, 0.34-0.57). The tests had similar levels of performance in pediatric and adult patients. CONCLUSIONS In a meta-analysis of patients with biopsy-confirmed celiac disease undergoing follow-up biopsy on a GFD, we found that tests for serum tTG IgA and EMA IgA levels had low sensitivity (below 50%) in detection of persistent villous atrophy. We need more-accurate non-invasive markers of mucosal damage in children and adults with celiac disease who are following a GFD.
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In Vitro Gluten Challenge Test for Celiac Disease Diagnosis.
Khalesi, M, Jafari, SA, Kiani, M, Picarelli, A, Borghini, R, Sadeghi, R, Eghtedar, A, Ayatollahi, H, Kianifar, HR
Journal of pediatric gastroenterology and nutrition. 2016;(2):276-83
Abstract
OBJECTIVES The in vitro gluten challenge test is an important diagnostic modality in celiac disease (CD), especially in patients who begin treatment with a gluten-free diet before adequate diagnostic workup or in cases with atypical CD. Available literature was reviewed regarding the accuracy of the in vitro gluten challenge test for CD diagnosis. METHODS MEDLINE, Scopus, and Google Scholar were searched, and studies that used serology and bowel biopsy as the criterion standard for diagnosis were included in our study. Data on authors, publication year, characteristics of the patient and control groups, patients' diet, duration of the gluten challenge test, histology findings, endomysial antibody (EMA) and anti-tissue transglutaminase (tTG) levels, CD markers, and intercellular cell adhesion molecule-1, and human leukocyte antigens before and after the gluten challenge test were extracted. RESULTS Overall, 15 studies were included in this meta-analysis. Pooled sensitivity %/specificity % was 84/99 for EMA after the challenge, 52/96 for EMA without the challenge, 95.5/98.3 for anti-tTG after the challenge, and 95.1/98.3 for anti-tTG without the challenge test. Sensitivity/specificity for immunological markers were 89/97 for the percentage of CD25⁺-lamina propria lymphocytes, 96/91 for the percentage of CD3⁺-lamina propria lymphocytes, and 96.1/85.7 for the percentage of intercellular cell adhesion molecule-1-lamina propria lymphocytes. The factors that increased the sensitivity of EMA were longer test duration, and the evaluation of patients on a gluten-containing diet or short-term gluten-free diet. CONCLUSIONS The in vitro gluten challenge test can be a useful part of the diagnostic workup of CD, rather than only a model to evaluate its mechanisms.
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Selenium Supplementation Significantly Reduces Thyroid Autoantibody Levels in Patients with Chronic Autoimmune Thyroiditis: A Systematic Review and Meta-Analysis.
Wichman, J, Winther, KH, Bonnema, SJ, Hegedüs, L
Thyroid : official journal of the American Thyroid Association. 2016;(12):1681-1692
Abstract
BACKGROUND Selenium supplementation may decrease circulating thyroid autoantibodies in patients with chronic autoimmune thyroiditis (AIT), but the available trials are heterogenous. This study expands and critically reappraises the knowledge on this topic. METHODS A literature search identified 3366 records. Controlled trials in adults (≥18 years of age) with AIT, comparing selenium with or without levothyroxine (LT4), versus placebo and/or LT4, were eligible. Assessed outcomes were serum thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) autoantibody levels, and immunomodulatory effects. After screening and full-text assessment, 16 controlled trials were included in the systematic review. Random-effects meta-analyses in weighted mean difference (WMD) were performed for 3, 6, and 12 months of supplementation in two different populations: one receiving LT4 therapy and one newly diagnosed and LT4-untreated. Heterogeneity was estimated using I2, and quality of evidence was assessed per outcome, using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidelines. RESULTS In LT4-treated populations, the selenium group had significantly lower TPOAb levels after three months (seven studies: WMD = -271 [confidence interval (CI) -366 to -175]; p < 0.0001; I2 = 45.4%), which was consistent at six months (three studies) and 12 months (one study). TgAb decreased at 12 months, but not at three or six months. In LT4-untreated populations, the selenium group showed a decrease in TPOAb levels after three months (three studies: WMD = -512 [CI -626 to -398]; p < 0.0001, I2 = 0.0%), but not after 6 or 12 months. TgAb decreased at 3 months, but not at 6 or 12 months. Quality of evidence was generally assessed as low. Study participants receiving selenium had a significantly higher risk than controls of reporting adverse effects (p = 0.036). CONCLUSIONS Selenium supplementation reduced serum TPOAb levels after 3, 6, and 12 months in an LT4-treated AIT population, and after three months in an untreated AIT population. Whether these effects correlate with clinically relevant measures remains to be demonstrated.