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Quantification of polyreactive immunoglobulin G facilitates the diagnosis of autoimmune hepatitis.
Taubert, R, Engel, B, Diestelhorst, J, Hupa-Breier, KL, Behrendt, P, Baerlecken, NT, Sühs, KW, Janik, MK, Zachou, K, Sebode, M, et al
Hepatology (Baltimore, Md.). 2022;(1):13-27
Abstract
BACKGROUND AND AIMS Detection of autoantibodies is a mainstay of diagnosing autoimmune hepatitis (AIH). However, conventional autoantibodies for the workup of AIH lack either sensitivity or specificity, leading to substantial diagnostic uncertainty. We aimed to identify more accurate serological markers of AIH with a protein macroarray. APPROACH AND RESULTS During the search for more-precise autoantibodies to distinguish AIH from non-AIH liver diseases (non-AIH-LD), IgG antibodies with binding capacities to many human and foreign proteins were identified with a protein macroarray and confirmed with solid-phase ELISAs in AIH patients. Subsequently, polyreactive IgG (pIgG) was exemplarily quantified by reactivity against human huntingtin-interacting protein 1-related protein in bovine serum albumin blocked ELISA (HIP1R/BSA). The diagnostic fidelity of HIP1R/BSA binding pIgG to diagnose AIH was assessed in a retrospective training, a retrospective multicenter validation, and a prospective validation cohort in cryoconserved samples from 1,568 adults from 10 centers from eight countries. Reactivity against HIP1R/BSA had a 25% and 14% higher specificity to diagnose AIH than conventional antinuclear and antismooth muscle antibodies, a significantly higher sensitivity than liver kidney microsomal antibodies and antisoluble liver antigen/liver pancreas antigen, and a 12%-20% higher accuracy than conventional autoantibodies. Importantly, HIP1R/BSA reactivity was present in up to 88% of patients with seronegative AIH and in up to 71% of AIH patients with normal IgG levels. Under therapy, pIgG returns to background levels of non-AIH-LD. CONCLUSIONS pIgG could be used as a promising marker to improve the diagnostic workup of liver diseases with a higher specificity for AIH compared to conventional autoantibodies and a utility in autoantibody-negative AIH. Likewise, pIgG could be a major source of assay interference in untreated AIH.
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Quantity of IgG response to SARS-CoV-2 spike glycoprotein predicts pulmonary recovery from COVID-19.
Nairz, M, Sahanic, S, Pizzini, A, Böhm, A, Tymoszuk, P, Mitterstiller, AM, von Raffay, L, Grubwieser, P, Bellmann-Weiler, R, Koppelstätter, S, et al
Scientific reports. 2022;(1):3677
Abstract
The CovILD study is a prospective, multicenter, observational cohort study to systematically follow up patients after coronavirus disease-2019 (COVID-19). We extensively evaluated 145 COVID-19 patients at 3 follow-up visits scheduled for 60, 100, and 180 days after initial confirmed diagnosis based on typical symptoms and a positive reverse transcription-polymerase chain reaction (RT-PCR) for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). We employed comprehensive pulmonary function and laboratory tests, including serum concentrations of IgG against the viral spike (S) glycoprotein, and compared the results to clinical data and chest computed tomography (CT). We found that at the 60 day follow-up, 131 of 145 (90.3%) participants displayed S-specific serum IgG levels above the cut-off threshold. Notably, the highly elevated IgG levels against S glycoprotein positively correlated with biomarkers of immune activation and negatively correlated with pulmonary function and the extent of pulmonary CT abnormalities. Based on the association between serum S glycoprotein-specific IgG and clinical outcome, we generated an S-specific IgG-based recovery score that, when applied in the early convalescent phase, accurately predicted delayed pulmonary recovery after COVID-19. Therefore, we propose that S-specific IgG levels serve as a useful immunological surrogate marker for identifying at-risk individuals with persistent pulmonary injury who may require intensive follow-up care after COVID-19.
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Pharmacokinetics of Asfotase Alfa in Adult Patients With Pediatric-Onset Hypophosphatasia.
Pan, WJ, Pradhan, R, Pelto, R, Seefried, L
Journal of clinical pharmacology. 2021;(10):1334-1343
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Abstract
Hypophosphatasia is a rare metabolic disease resulting from variant(s) in the gene-encoding tissue-nonspecific isozyme of alkaline phosphatase. In this 13-week, phase 2a, multicenter, randomized, open-label, dose-response study (ClinicalTrials.gov: NCT02797821), the pharmacokinetics of asfotase alfa, an enzyme replacement therapy approved for the treatment of hypophosphatasia, was assessed in adult patients with pediatric-onset hypophosphatasia. In total, 27 adults were randomly assigned 1:1:1 to a single subcutaneous dose of asfotase alfa (0.5, 2.0, or 3.0 mg/kg) during week 1. From week 3 to week 9, patients received 0.5, 2.0, or 3.0 mg/kg subcutaneously 3 times per week (equivalent to 1.5, 6.0, or 9.0 mg/kg/wk, respectively). Noncompartmental analysis revealed exposure (maximum concentration in the dosing interval and area under the concentration-time curve from time 0 to infinity) to asfotase alfa increased between single- and multiple-dose administration and with increasing doses; however, extensive interindividual variability was observed in the concentration-time profiles within each dose cohort. Median terminal elimination half-life was ≈5 days following multiple-dose administration, with steady state achieved by approximately day 29. Dose-normalized exposure data indicated that asfotase alfa activity was approximately dose-proportional within the studied dose range. Additionally, dose-normalized exposure was comparable across body mass index categories of <25, ≥25 to <30, and ≥30 kg/m2 , indicating that asfotase alfa dosing bioavailability was consistent in these patients, including those who were obese. These data, together with previously published pharmacodynamic results in this study population, support the use of asfotase alfa at the recommended dose of 6 mg/kg/wk in adults with pediatric-onset hypophosphatasia.
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The IgG2 Isotype of Anti-Transcription Intermediary Factor 1γ Autoantibodies Is a Biomarker of Cancer and Mortality in Adult Dermatomyositis.
Aussy, A, Fréret, M, Gallay, L, Bessis, D, Vincent, T, Jullien, D, Drouot, L, Jouen, F, Joly, P, Marie, I, et al
Arthritis & rheumatology (Hoboken, N.J.). 2019;(8):1360-1370
Abstract
OBJECTIVE Anti-transcription intermediary factor 1γ (anti-TIF1γ) antibodies are the main predictors of cancer in dermatomyositis (DM). Yet, a substantial proportion of anti-TIF1γ-positive DM patients do not develop cancer. This study was undertaken to identify biomarkers to better evaluate the risk of cancer and mortality in DM. METHODS This multicenter study was conducted in adult anti-TIF1γ-positive DM patients from August 2013 to August 2017. Anti-TIF1γ autoantibody levels and IgG subclasses were identified using a newly developed quantitative immunoassay. Age, sex, DM signs and activity, malignancy, and creatine kinase (CK) level were recorded. Risk factors were determined by univariate and multivariate analysis according to a Cox proportional hazards regression model. RESULTS Among the 51 adult patients enrolled (mean ± SD age 61 ± 17 years; ratio of men to women 0.65), 40 (78%) had cancer and 21 (41%) died, with a mean ± SD survival time of 10 ± 6 months. Detection of anti-TIF1γ IgG2 was significantly associated with mortality (P = 0.0011) and occurrence of cancer during follow-up (P < 0.0001), with a 100% positive predictive value for cancer when the mean fluorescence intensity of anti-TIF1γ IgG2 was >385. None of the patients developed cancer after 24 months of follow-up. Univariate survival analyses showed that mortality was also associated with age >60 years (P = 0.0003), active DM (P = 0.0042), cancer (P = 0.0031), male sex (P = 0.011), and CK level >1,084 units/liter (P = 0.005). Multivariate analysis revealed that age >60 years (P = 0.015) and the presence of anti-TIF1γ IgG2 (P = 0.048) were independently associated with mortality. CONCLUSION Our findings indicate that anti-TIF1γ IgG2 is a potential new biomarker of cancer that should be helpful in identifying the risk of mortality in anti-TIF1γ-positive DM patients.
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Efficacy and Safety of Asfotase Alfa in Infants and Young Children With Hypophosphatasia: A Phase 2 Open-Label Study.
Hofmann, CE, Harmatz, P, Vockley, J, Högler, W, Nakayama, H, Bishop, N, Martos-Moreno, GÁ, Moseley, S, Fujita, KP, Liese, J, et al
The Journal of clinical endocrinology and metabolism. 2019;(7):2735-2747
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Abstract
CONTEXT Long-term data on enzyme replacement treatment of hypophosphatasia (HPP) are limited. OBJECTIVE To evaluate efficacy and safety of asfotase alfa in patients aged ≤5 years with HPP followed for up to 6 years. DESIGN Phase 2 open-label study (July 2010 to September 2016). SETTING Twenty-two sites; 12 countries. PARTICIPANTS Sixty-nine patients [median (range) age: 16.0 (0.02 to 72) months] with severe HPP and sign/symptom onset before age 6 months. INTERVENTION Asfotase alfa 2 mg/kg three times/week or 1 mg/kg six times/week subcutaneously. MAIN OUTCOME MEASURES Primary efficacy measure: Radiographic Global Impression of Change (RGI-C) score [-3 (severe worsening) to +3 (complete/near-complete healing)]. Additional outcome measures: respiratory status, growth, and safety. Post hoc analysis: characteristics of radiographic responders vs nonresponders at Year 1 (RGI-C: ≥+2 vs <+2). RESULTS During median (minimum, maximum) 2.3 (0.02, 5.8) years of treatment, RGI-C scores improved significantly at Month 6 [+2.0 (-1.7, +3.0)], Year 1 [+2.0 (-2.3, +3.0)], and Last Assessment [+2.3 (-2.7, +3.0); P < 0.0001 all]. Of 24 patients requiring respiratory support at Baseline, 11 (46%) no longer needed support. Height/weight z scores generally increased. Nine patients died (13%). All patients experienced at least one adverse event; pyrexia was most common. Compared with responders [n = 50 (72%)], nonresponders [n = 19 (28%)] had more severe disease at Baseline and a higher rate of neutralizing antibodies (NAbs) at Last Assessment. CONCLUSIONS Most infants/young children given asfotase alfa showed early radiographic and clinical improvement sustained up to 6 years; radiographic nonresponders had more severe disease and more frequent NAbs at Last Assessment.
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MOG-IgG in primary and secondary chronic progressive multiple sclerosis: a multicenter study of 200 patients and review of the literature.
Jarius, S, Ruprecht, K, Stellmann, JP, Huss, A, Ayzenberg, I, Willing, A, Trebst, C, Pawlitzki, M, Abdelhak, A, Grüter, T, et al
Journal of neuroinflammation. 2018;(1):88
Abstract
BACKGROUND Antibodies to human full-length myelin oligodendrocyte glycoprotein (MOG-IgG) as detected by new-generation cell-based assays have recently been described in patients presenting with acute demyelinating disease of the central nervous system, including patients previously diagnosed with multiple sclerosis (MS). However, only limited data are available on the relevance of MOG-IgG testing in patients with chronic progressive demyelinating disease. It is unclear if patients with primary progressive MS (PPMS) or secondary progressive MS (SPMS) should routinely be tested for MOG-IgG. OBJECTIVE To evaluate the frequency of MOG-IgG among patients classified as having PPMS or SPMS based on current diagnostic criteria. METHODS For this purpose, we retrospectively tested serum samples of 200 patients with PPMS or SPMS for MOG-IgG using cell-based assays. In addition, we performed a review of the entire English language literature on MOG-IgG published between 2011 and 2017. RESULTS None of 139 PPMS and 61 SPMS patients tested was positive for MOG-IgG. Based on a review of the literature, we identified 35 further MOG-IgG tests in patients with PPMS and 55 in patients with SPMS; the only reportedly positive sample was positive just at threshold level and was tested in a non-IgG-specific assay. In total, a single borderline positive result was observed among 290 tests. CONCLUSION Our data suggest that MOG-IgG is absent or extremely rare among patients with PPMS or SPMS. Routine screening of patients with typical PPMS/SPMS for MOG-IgG seems not to be justified.
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Cardiometabolic biomarkers in chronic plaque psoriasis before and after etanercept treatment.
Puig, L, Strohal, R, Fuiman, J, Pedersen, R, Szumski, A, Koenig, AS, Robertson, D, Drexel, H
The Journal of dermatological treatment. 2014;(6):470-81
Abstract
OBJECTIVE To assess cardiometabolic biomarkers in patients with psoriasis before and after etanercept treatment. METHODS Patients with moderate-to-severe plaque psoriasis were randomized to etanercept 50 mg once or twice weekly, double-blinded. Cardiometabolic biomarkers were assessed at baseline and after 12 weeks of treatment (n = 273). RESULTS At baseline, 42% of patients had metabolic syndrome. Etanercept was not associated with any clinically relevant adverse effects on cardiometabolic biomarkers. In the once-weekly subgroup, significant mean percentage changes from baseline (p < 0.05) were observed for the quantitative insulin-sensitivity check index (QUICKI; -2.2%), apolipoprotein (Apo) A1 (3.2%), Apo B:Apo A1 ratio (-3.5%), leptin (8.6%) and high-sensitivity C-reactive protein (hsCRP) (-65.5%); and in the twice-weekly subgroup for plasma insulin (15.9%), QUICKI (-2.7%), high-density lipoprotein cholesterol (HDL-C; 2.9%), apolipoprotein (Apo) A1 (2.8%), Apo B:Apo A1 (-4.6%) and hsCRP (-74.4%). CONCLUSION Metabolic syndrome was common in these patients with moderate-to-severe psoriasis. Etanercept treatment may provide some potentially favorable modulation of insulin sensitivity, HDL-C, Apo A1 and Apo B:Apo A1 ratio.
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Plasma autoantibodies against apolipoprotein B-100 peptide 210 in subclinical atherosclerosis.
McLeod, O, Silveira, A, Fredrikson, GN, Gertow, K, Baldassarre, D, Veglia, F, Sennblad, B, Strawbridge, RJ, Larsson, M, Leander, K, et al
Atherosclerosis. 2014;(1):242-8
Abstract
OBJECTIVE Experimental studies have suggested that autoimmunity is involved in atherosclerosis and provided evidence that both protective and pro-atherogenic immune responses exist. This concept has received support from small clinical studies implicating autoantibodies directed against apolipoprotein B-100 (apoB-100) in human atherosclerosis. We examined circulating autoantibodies directed against native and malondialdehyde (MDA)-modified epitope p210 of apoB-100 (IgG-p210nat and IgM-p210MDA) in relation to early atherosclerosis in a large, European longitudinal cohort study of healthy high-risk individuals. APPROACH AND RESULTS IgG-p210nat and IgM-p210MDA were quantified in baseline plasma samples of 3430 participants in the IMPROVE study and related to composite and segment-specific measures of severity and rate of progression of carotid intima-media thickness (cIMT) determined at baseline and after 30 months. IgM-p210MDA autoantibody levels were independently related to several cIMT measures both in the common carotid artery and in the carotid bulb, including measures of cIMT progression, higher levels being associated with lower cIMT or slower cIMT progression. Consistent inverse relationships were also found between plasma levels of IgG-p210nat and baseline composite measures of cIMT. These associations disappeared when adjusting for established and emerging risk factors, and there were no associations with rate of cIMT progression besides in certain secondary stratified analyses. CONCLUSIONS The present study provides further evidence of involvement of autoantibodies against native and MDA-modified apoB-100 peptide 210 in cardiovascular disease in humans and demonstrates that these associations are present already at a subclinical stage of the disease.
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Impact of the metabolic syndrome on long-term outcomes in simultaneous kidney-pancreas transplantation.
Rogers, J, Stratta, RJ, Lo, A, Alloway, RR
Transplantation proceedings. 2005;(8):3549-51
Abstract
The metabolic syndrome (MS) has been implicated as an important nonimmunologic risk factor for chronic renal transplant dysfunction. The aim of this study was to determine the impact of the MS on outcomes in simultaneous kidney-pancreas transplantation (SKPT). Data were available on 241 patients enrolled in a prospective, multicenter randomized study of daclizumab compared with no antibody induction in SKPT. Presence of MS before and after SKPT was defined using NCEP-ATP III (National Cholesterol Education Program Adult Treatment Panel III) criteria. Body mass index (BMI) was used as a surrogate for waist circumference. MS was present in 59% of patients pretransplantation but only in 19% of patients 1 year after SKPT (P < .0001). Demographic and transplant characteristics were well matched for those with MS (MS+) and without MS (MS-) at 1 year. Presence of MS at 1 year was associated with the following changes at 3 years: increased serum creatinine level (1.65 mg/dL MS- vs 2.05 mg/dL MS+; P = .13); decreased modification of diet in renal disease calculated glomerular filtration rate (GFR; 58 mL/min MS- vs 48 mL/min MS+; P = .02); increased HgbA1C level (5.6% MS- vs 6.6% MS+; P < .001); and lower pancreas graft (PG) survival rate (88% MS- vs 71% MS+; P = .01). Linear regression analysis identified MS+ and the subgroup of MS+ without functioning PG at 1 year as independent risk factors for renal dysfunction, whereas MS+ with functioning PG at 1 year was not a risk factor for renal dysfunction. Presence of MS at 1 year is associated with long-term renal dysfunction after SKPT. Efforts to decrease early PG failure may help mitigate against MS-associated renal dysfunction.
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Antibody-mediated suppression of Vbeta5.2/5.3(+) T cells in multiple sclerosis: results from an MRI-monitored phase II clinical trial.
Killestein, J, Olsson, T, Wallström, E, Svenningsson, A, Khademi, M, Blumhardt, LD, Fagius, J, Hillert, J, Landtblom, AM, Edenius, C, et al
Annals of neurology. 2002;(4):467-74
Abstract
The objective of this study was to evaluate the safety and efficacy of the humanized antibody ATM-027 in a baseline versus treatment magnetic resonance imaging-monitored study. Expansion of Vbeta5.2/5.3(+) T cells has been demonstrated in the peripheral blood, cerebrospinal fluid, and brain lesions of MS patients. In a phase I study, ATM-027 depleted these cells in peripheral blood and, in parallel, T-cell MBP reactivity and IFN-gamma expression were reduced. We studied 59 patients with relapsing-remitting MS (47 on ATM-027 and 12 on placebo) stratified for HLA-DR2 status. Monthly intravenous injections were given for 6 months. Individual dose titration was employed to obtain depletion of the target T-cell level and downregulation of antigen receptor density as monitored by flow cytometry. Five monthly magnetic resonance imaging scans were performed before treatment to establish baseline activity, six during treatment, and three during follow-up. Additional immunological assessments were performed to elucidate the mechanism of action of ATM-027. The treatment was safe and well tolerated, inducing consistent suppression of the target cell population. During run-in, active lesions were found in 78.7% (37/47) of patients treated with ATM-027. During treatment, the median number of lesions was reduced by 33% (p = 0.13) independent of DR2 status. The corresponding volume of enhancement was 221 mm(3) at baseline, with a reduction of 10% during treatment. Decreased numbers of cells expressing interferon-gamma messenger RNA, and decreased T-cell reactivity to several myelin antigens were found in ATM-027 treated patients. In conclusion, consistent suppression of Vbeta 5.2/5.3(+) T cells was achieved. However, the effect size on magnetic resonance imaging was considerably less than the targeted 60%.