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1.
Activating Antibodies to The Calcium-sensing Receptor in Immunotherapy-induced Hypoparathyroidism.
Lupi, I, Brancatella, A, Cetani, F, Latrofa, F, Kemp, EH, Marcocci, C
The Journal of clinical endocrinology and metabolism. 2020;(5)
Abstract
CONTEXT Immune checkpoint inhibitors (ICIs), such as programmed cell death protein-1 (PD-1), programmed cell death protein-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen-4 (CTLA-4) monoclonal antibodies, are approved for the treatment of some types of advanced cancer. Their main treatment-related side-effects are immune-related adverse events (irAEs), especially thyroid dysfunction and hypophysitis. Hypoparathyroidism, on the contrary, is an extremely rare irAE. OBJECTIVES The aim of the study was to investigate the etiology of autoimmune hypoparathyroidism in a lung cancer patient treated with pembrolizumab, an anti-PD-1. METHODS Calcium-sensing receptor (CaSR) autoantibodies, their functional activity, immunoglobulin (Ig) subclasses and epitopes involved in the pathogenesis of autoimmune hypoparathyroidism were tested. RESULTS The patient developed hypocalcemia after 15 cycles of pembrolizumab. Calcium levels normalized with oral calcium carbonate and calcitriol and no remission of hypocalcemia was demonstrated during a 9-month follow-up. The patient was found to be positive for CaSR-stimulating antibodies, of IgG1 and IgG3 subclasses, that were able to recognize functional epitopes on the receptor, thus causing hypocalcemia. CONCLUSION The finding confirms that ICI therapy can trigger, among other endocrinopathies, hypoparathyroidism, which can be caused by pathogenic autoantibodies.
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2.
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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3.
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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Relationship between anti-erythropoietin receptor autoantibodies and responsiveness to erythropoiesis-stimulating agents in patients on hemodialysis: a multi-center cross-sectional study.
Hara, A, Koshino, Y, Kurokawa, Y, Shinozaki, Y, Miyake, T, Kitajima, S, Toyama, T, Iwata, Y, Sakai, N, Shimizu, M, et al
Clinical and experimental nephrology. 2020;(1):88-95
Abstract
BACKGROUND A decreased response to erythropoiesis-stimulating agents (ESAs) leads to refractory anemia and worse prognosis in patients with chronic kidney disease. We examined the association between autoantibodies to the erythropoietin receptor (EPOR) and responsiveness to ESAs in patients on maintenance hemodialysis. METHODS A total of 108 Japanese patients on maintenance hemodialysis at three institutions were enrolled. Sera from these patients were screened for anti-EPOR antibodies using an enzyme-linked immunosorbent assay. An ESA resistance index (ERI) was calculated, and patients in the highest ERI quartile were defined as ESA hyporesponsive. RESULTS Anti-EPOR antibodies were detected in 11 patients (10%). Body mass index and hemoglobin, platelet, magnesium, and ferritin levels decreased with higher ERI levels. On the other hand, C-reactive protein (CRP) levels and the prevalence of anti-EPOR antibodies increased with higher ERI levels. In multivariate analysis, the presence of anti-EPOR antibodies together with CRP was a significant risk factor for ESA hyporesponsiveness. CONCLUSIONS Anti-EPOR antibodies were detected in patients on maintenance hemodialysis, and these autoantibodies were independent factors for hyporesponsiveness to ESAs in these patients.
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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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7.
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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Stop testing for autoantibodies to the VGKC-complex: only request LGI1 and CASPR2.
Michael, S, Waters, P, Irani, SR
Practical neurology. 2020;(5):377-384
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Abstract
Autoantibodies to leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein like-2 (CASPR2) are associated with clinically distinctive syndromes that are highly immunotherapy responsive, such as limbic encephalitis, faciobrachial dystonic seizures, Morvan's syndrome and neuromyotonia. These autoantibodies target surface-exposed domains of LGI1 or CASPR2, and appear to be directly pathogenic. In contrast, voltage-gated potassium channel (VGKC) antibodies that lack LGI1 or CASPR2 reactivities ('double-negative') are common in healthy controls and have no consistent associations with distinct syndromes. These antibodies target intracellular epitopes and lack pathogenic potential. Moreover, the clinically important LGI1 and CASPR2 antibodies comprise only ~15% of VGKC-positive results, meaning that most VGKC-antibody positive results mislead rather than help. Further, initial VGKC testing misses some cases that have LGI1 and CASPR2 antibodies. These collective observations confirm that laboratories should stop testing for VGKC antibodies and instead, test only for LGI1 and CASPR2 antibodies. This change in practice will lead to significant patient benefit.
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Hydroxychloroquine to Prevent Recurrent Congenital Heart Block in Fetuses of Anti-SSA/Ro-Positive Mothers.
Izmirly, P, Kim, M, Friedman, DM, Costedoat-Chalumeau, N, Clancy, R, Copel, JA, Phoon, CKL, Cuneo, BF, Cohen, RE, Robins, K, et al
Journal of the American College of Cardiology. 2020;(3):292-302
Abstract
BACKGROUND Experimental and clinical evidence support the role of macrophage Toll-like receptor signaling in maternal anti-SSA/Ro-mediated congenital heart block (CHB). OBJECTIVES Hydroxychloroquine (HCQ), an orally administered Toll-like receptor antagonist widely used in lupus including during pregnancy, was evaluated for efficacy in reducing the historical 18% recurrence rate of CHB. METHODS This multicenter, open-label, single-arm, 2-stage clinical trial was designed using Simon's optimal approach. Anti-SSA/Ro-positive mothers with a previous pregnancy complicated by CHB were recruited (n = 19 Stage 1; n = 35 Stage 2). Patients received 400 mg daily of HCQ prior to completion of gestational week 10, which was maintained through pregnancy. The primary outcome was 2° or 3° CHB any time during pregnancy, and secondary outcomes included isolated endocardial fibroelastosis, 1° CHB at birth and skin rash. RESULTS By intention-to-treat (ITT) analysis, 4 of 54 evaluable pregnancies resulted in a primary outcome (7.4%; 90% confidence interval: 3.4% to 15.9%). Because 9 mothers took potentially confounding medications (fluorinated glucocorticoids and/or intravenous immunoglobulin) after enrollment but prior to a primary outcome, to evaluate HCQ alone, 9 additional mothers were recruited and followed the identical protocol. In the per-protocol analysis restricted to pregnancies exposed to HCQ alone, 4 of 54 (7.4%) fetuses developed a primary outcome as in the ITT. Secondary outcomes included mild endocardial fibroelastosis (n = 1) and cutaneous neonatal lupus (n = 4). CONCLUSIONS These prospective data support that HCQ significantly reduces the recurrence of CHB below the historical rate by >50%, suggesting that this drug should be prescribed for secondary prevention of fetal cardiac disease in anti-SSA/Ro-exposed pregnancies. (Preventive Approach to Congenital Heart Block With Hydroxychloroquine [PATCH]; NCT01379573).
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Serum Levels of Autoantibodies Against Extracellular Antigens and Neutrophil Granule Proteins Increase in Patients with COPD Compared to Non-COPD Smokers.
Ma, A, Wen, L, Yin, J, Hu, Y, Yue, X, Li, J, Dong, X, Gupta, Y, Ludwig, RJ, Krauss-Etschmann, S, et al
International journal of chronic obstructive pulmonary disease. 2020;:189-200
Abstract
BACKGROUND Chronic obstructive pulmonary disease (COPD) is a highly prevalent disease leading to irreversible airflow limitation and is characterized by chronic pulmonary inflammation, obstructive bronchiolitis and emphysema. Etiologically, COPD is mediated by toxic gases and particles, eg, cigarette smoke, while the pathogenesis of the disease is largely unknown. Several lines of evidence indicate a link between COPD and autoimmunity but comprehensive studies are lacking. METHODS By using a protein microarray assaying more than 19,000 human proteins we determined in this study the autoantibody profiles of COPD and non-COPD smokers. The discovery cohort included 5 COPD patients under acute exacerbation (AECOPD) and 5 age- and gender-matched non-COPD smokers. One putative candidate autoantibody, anti-lactoferrin IgG, was further investigated by using immunoblotting with a large validation cohort containing 124 healthy controls, 92 patients with AECOPD and 52 patients with stable COPD. RESULTS We show that i) autoantigens targeted by autoantibodies with higher titers in COPD patients were enriched in extracellular regions, while those with lower titers in COPD patients were enriched in intracellular compartments. ii) levels of IgG autoantibodies against many neutrophil granule proteins were significantly higher in COPD patients than in non-COPD smokers. Furthermore, increased levels of anti-lactoferrin antibodies in COPD patients were confirmed in a cohort with a large number of samples. CONCLUSION The comprehensive autoantibody profiles from COPD patients established in this study demonstrated for the first time a shift in the cellular localization of antigens targeted by autoantibodies in COPD.