-
1.
ECG Changes Through Immunosuppressive Therapy Indicate Cardiac Abnormality in Anti-MDA5 Antibody-Positive Clinically Amyopathic Dermatomyositis.
Matsuo, T, Sasai, T, Nakashima, R, Kuwabara, Y, Kato, ET, Murakami, I, Onizawa, H, Akizuki, S, Murakami, K, Hashimoto, M, et al
Frontiers in immunology. 2021;:765140
Abstract
Anti-melanoma differentiation-associated gene 5 (MDA5) antibody, a dermatomyositis (DM)-specific antibody, is strongly associated with interstitial lung disease (ILD). Patients with idiopathic inflammatory myopathy (IIM) who are anti-MDA5 antibody positive [anti-MDA5 (+)] often experience chest symptoms during the active disease phase. These symptoms are primarily explained by respiratory failure; nevertheless, cardiac involvement can also be symptomatic. Thus, the aim of this study was to investigate cardiac involvement in anti-MDA5 (+) DM. A total of 63 patients with IIM who underwent electrocardiography (ECG) and ultrasound cardiography (UCG) during the active disease phase from 2016 to 2021 [anti-MDA5 (+) group, n = 21; anti-MDA5-negative (-) group, n = 42] were enrolled in the study, and their clinical charts were retrospectively reviewed. The ECG and UCG findings were compared between the anti-MDA5 (+) and anti-MDA5 (-) groups. All anti-MDA5 (+) patients had DM with ILD. The anti-MDA5 (+) group showed more frequent skin ulcerations and lower levels of leukocytes, muscle enzymes, and electrolytes (Na, K, Cl, and Ca) than the anti-MDA5 (-) group. According to the ECG findings obtained during the active disease phase, the T wave amplitudes were significantly lower for the anti-MDA5 (+) group than for the anti-MDA5 (-) group (I, II, and V4-6 lead; p < 0.01; aVF and V3, p < 0.05). However, the lower amplitudes were restored during the remission phase. Except for the E wave, A wave and Sep e', the UCG results showed no significant differences between the groups. Four patients with anti-MDA5 (+) DM had many leads with lower T wave and cardiac abnormalities (heart failure, diastolic dysfunction, myocarditis) on and after admission. Though anti-MDA5 (+) patients clinically improved after immunosuppressive therapy, some of their ECG findings did not fully recover in remission phase. In conclusion, anti-MDA5 (+) DM appears to show cardiac involvement (electrical activity and function) during the active phase. Further studies are necessary to clarify the actual cardiac condition and mechanism of these findings in patients with anti-MDA5 (+) DM.
-
2.
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).
-
3.
Glycation and Oxidative Stress Increase Autoantibodies in the Elderly.
Khan, MWA, Al Otaibi, A, Sherwani, S, Khan, WA, Alshammari, EM, Al-Zahrani, SA, Saleem, M, Khan, SN, Alouffi, S
Molecules (Basel, Switzerland). 2020;(16)
Abstract
Aging causes gradual changes in free radicals, antioxidants, and immune-imbalance in the elderly. This study aims to understand links among aging, gluco-oxidative stress, and autoantibodies in asymptomatic individuals. In vitro glycation of human serum albumin (Gly-HSA) induces appreciable biochemical changes. Significant inhibition of advanced glycation end products (AGEs) formation was achieved using garlic extract (53.75%) and epigallocatechin-3-gallate from green tea (72.5%). Increased amounts of serum carbonyl content (2.42 ± 0.5) and pentosidine (0.0321 ± 0.0029) were detected in IV-S (S represent smokers) vs. IV group individuals. Direct binding ELISA results exhibited significantly high autoantibodies against Gly-HSA in group IV-S (0.55 ± 0.054; p < 0.001) and III-S (0.40 ± 0.044; p < 0.01) individuals as compared to the age matched subjects who were non-smokers (group IV and III). Moreover, high average percent inhibition (51.3 ± 4.1%) was obtained against Gly-HSA in IV-S group individuals. Apparent association constant was found to be high for serum immunoglobulin-G (IgG) from group IV-S (1.18 × 10-6 M) vs. serum IgG from IV group (3.32 × 10-7 M). Aging induced gluco-oxidative stress and AGEs formation may generate neo-epitopes on blood-proteins, contributing to production of autoantibodies in the elderly, especially smokers. Use of anti-glycation natural products may reduce age-related pathophysiological changes.
-
4.
Open ADAMTS13, induced by antibodies, is a biomarker for subclinical immune-mediated thrombotic thrombocytopenic purpura.
Roose, E, Schelpe, AS, Tellier, E, Sinkovits, G, Joly, BS, Dekimpe, C, Kaplanski, G, Le Besnerais, M, Mancini, I, Falter, T, et al
Blood. 2020;(3):353-361
-
-
Free full text
-
Abstract
Recently, we showed that ADAMTS13 circulates in an open conformation during the acute phase of immune-mediated thrombotic thrombocytopenic purpura (iTTP). Although the cause of this conformational change remains elusive, ADAMTS13 is primarily closed in iTTP patients in remission with ADAMTS13 activity >50% and undetectable anti-ADAMTS13 autoantibodies, as well as after rituximab treatment, suggesting a role for anti-ADAMTS13 autoantibodies. Therefore, immunoglobulin G from 18 acute iTTP patients was purified and added to closed ADAMTS13 in healthy donor plasma. This resulted in open ADAMTS13 in 14 of 18 (78%) samples, proving that anti-ADAMTS13 autoantibodies can induce an open ADAMTS13 conformation. To further elucidate the conformation of ADAMTS13 in iTTP patients, we studied a novel iTTP patient cohort (n = 197) that also included plasma samples from iTTP patients in remission in whom ADAMTS13 activity was <50%. The open ADAMTS13 conformation was found during acute iTTP, as well as in patients in remission with ADAMTS13 activity <50% and in half of the patients with ADAMTS13 activity >50%, although free anti-ADAMTS13 autoantibodies were not always detected. Thus, open ADAMTS13 is a hallmark of acute iTTP, as well as a novel biomarker that can be used to detect subclinical iTTP in patients in remission. Finally, a long-term follow-up study in 1 iTTP patient showed that the open conformation precedes a substantial drop in ADAMTS13 activity. In conclusion, we have shown that anti-ADAMTS13 autoantibodies from iTTP patients induce an open ADAMTS13 conformation. Most importantly, an open ADAMTS13 conformation is a biomarker for subclinical iTTP and could become an important tool in TTP management.
-
5.
Efficacy of Rituximab in Refractory Inflammatory Myopathies Associated with Anti- Synthetase Auto-Antibodies: An Open-Label, Phase II Trial.
Allenbach, Y, Guiguet, M, Rigolet, A, Marie, I, Hachulla, E, Drouot, L, Jouen, F, Jacquot, S, Mariampillai, K, Musset, L, et al
PloS one. 2015;(11):e0133702
Abstract
OBJECTIVE Anti-synthetase syndrome (anti-SS) is frequently associated with myositis and interstitial lung disease (ILD). We evaluated prospectively, in a multicenter, open-label, phase II study, the efficacy of rituximab on muscle and lung outcomes. METHODS Patients were enrolled if they were refractory to conventional treatments (prednisone and at least 2 immunosuppressants). They received 1 g of rituximab at D0, D15, and M6. The primary endpoint was muscular improvement based on manual muscular testing (MMT10, Kendall score in 10 muscles) at M12. Secondary endpoints were normalization of creatine kinase (CK) level, ILD improvement based on forced vital capacity and/or diffuse capacity for carbon monoxide, and number and/or doses of associated immunosuppressants. RESULTS Twelve patients were enrolled, and 10 completed the study. Only 2 patients presented an improvement of at least 4 points on at least two muscle groups (primary end-point). Overall, seven patients had an increase of at least 4 points on MMT10. CK level decreased from 399 IU/L (range, 48-11,718) to 74.5 IU/L (range, 40-47,857). Corticosteroid doses decreased from 52.5 mg/d (range, 10-70) to 9 mg/d (range, 7-65) and six patients had a decrease in the burden of their associated immunosuppressants. At baseline, all 10 patients presented with ILD. At M12, improvement of ILD was observed in 5 out of the 10 patients, stabilization in 4, and worsening in 1. CONCLUSIONS This pilot study of rituximab treatment in patients with refractory anti-SS provided data on evolution of muscular and pulmonary parameters. Rituximab should now be evaluated in a larger, controlled study for this homogenous group of patients. TRIAL REGISTRATION Clinicaltrials.gov NCT00774462.
-
6.
Alloantibody and autoantibody monitoring predicts islet transplantation outcome in human type 1 diabetes.
Piemonti, L, Everly, MJ, Maffi, P, Scavini, M, Poli, F, Nano, R, Cardillo, M, Melzi, R, Mercalli, A, Sordi, V, et al
Diabetes. 2013;(5):1656-64
-
-
Free full text
-
Abstract
Long-term clinical outcome of islet transplantation is hampered by the rejection and recurrence of autoimmunity. Accurate monitoring may allow for early detection and treatment of these potentially compromising immune events. Islet transplant outcome was analyzed in 59 consecutive pancreatic islet recipients in whom baseline and de novo posttransplant autoantibodies (GAD antibody, insulinoma-associated protein 2 antigen, zinc transporter type 8 antigen) and donor-specific alloantibodies (DSA) were quantified. Thirty-nine recipients (66%) showed DSA or autoantibody increases (de novo expression or titer increase) after islet transplantation. Recipients who had a posttransplant antibody increase showed similar initial performance but significantly lower graft survival than patients without an increase (islet autoantibodies P < 0.001, DSA P < 0.001). Posttransplant DSA or autoantibody increases were associated with HLA-DR mismatches (P = 0.008), induction with antithymocyte globulin (P = 0.0001), and pretransplant panel reactive alloantibody >15% in either class I or class II (P = 0.024) as independent risk factors and with rapamycin as protective (P = 0.006) against antibody increases. DSA or autoantibody increases after islet transplantation are important prognostic markers, and their identification could potentially lead to improved islet cell transplant outcomes.
-
7.
The presence of GAD and IA-2 antibodies in youth with a type 2 diabetes phenotype: results from the TODAY study.
Klingensmith, GJ, Pyle, L, Arslanian, S, Copeland, KC, Cuttler, L, Kaufman, F, Laffel, L, Marcovina, S, Tollefsen, SE, Weinstock, RS, et al
Diabetes care. 2010;(9):1970-5
-
-
Free full text
-
Abstract
OBJECTIVE To determine the frequency of islet cell autoimmunity in youth clinically diagnosed with type 2 diabetes and describe associated clinical and laboratory findings. RESEARCH DESIGN AND METHODS Children (10-17 years) diagnosed with type 2 diabetes were screened for participation in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. Measurements included GAD-65 and insulinoma-associated protein 2 autoantibodies using the new National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health (NIDDK/NIH) standardized assays, a physical examination, and fasting lipid, C-peptide, and A1C determinations. RESULTS Of the 1,206 subjects screened and considered clinically to have type 2 diabetes, 118 (9.8%) were antibody positive; of these, 71 (5.9%) were positive for a single antibody, and 47 were positive (3.9%) for both antibodies. Diabetes autoantibody (DAA) positivity was significantly associated with race (P < 0.0001), with positive subjects more likely to be white (40.7 vs. 19%) (P < 0.0001) and male (51.7 vs. 35.7%) (P = 0.0007). BMI, BMI z score, C-peptide, A1C, triglycerides, HDL cholesterol, and blood pressure were significantly different by antibody status. The antibody-positive subjects were less likely to display characteristics clinically associated with type 2 diabetes and a metabolic syndrome phenotype, although the range for BMI z score, blood pressure, fasting C-peptide, and serum lipids overlapped between antibody-positive and antibody-negative subjects. CONCLUSIONS Obese youth with a clinical diagnosis of type 2 diabetes may have evidence of islet autoimmunity contributing to insulin deficiency. As a group, patients with DAA have clinical characteristics significantly different from those without DAA. However, without islet autoantibody analysis, these characteristics cannot reliably distinguish between obese young individuals with type 2 diabetes and those with autoimmune diabetes.
-
8.
A comparative crossover study of the effects of fluvastatin and pravastatin (FP-COS) on circulating autoantibodies to oxidized LDL in patients with hypercholesterolemia.
Zhang, B, Noda, K, Matsunaga, A, Kumagai, K, Saku, K
Journal of atherosclerosis and thrombosis. 2005;(1):41-7
Abstract
This study compared the effects of fluvastatin and pravastatin on the in vivo oxidation of LDL in a crossover design to evaluate whether or not it is justified to switch between the two statins with regard to serum levels of lipids, lipoproteins, and apolipoproteins (apo), and circulating autoantibodies to oxidized LDL (OxLDL-Ab). Patients with hypercholesterolemia (n = 46) were randomly assigned into groups who received fluvastatin (20 mg/d) or pravastatin (10 mg/d). After 3 months, they were crossed to receive the other statin for another 3 months. Circulating levels of OxLDL-Ab were measured by an OxLDL IgG ELISA test. Fluvastatin and pravastatin similarly decreased serum levels of total cholesterol (TC), LDL-C, and apo B, and increased HDL(2)-C levels. After crossover to the other statin, these lipid parameters were not further changed by either statin. Before crossover, circulating levels of OxLDL-Ab were decreased in patients with fluvastatin treatment, but not in those with pravastatin treatment. After switching from the other statin, both fluvastatin and pravastatin further decreased OxLDL-Ab levels. In conclusion, fluvastatin at 20 mg/d and pravastatin at 10 mg/d are similar with regard to their efficacy in decreasing TC, LDL-C, and apo B levels and increasing HDL(2)-C levels. Fluvastatin lowered circulating levels of OxLDL-Ab, and these effects continued after switching to pravastatin.
-
9.
Development of antibodies specific to polyanion-modified platelet factor 4 during treatment with fondaparinux.
Pouplard, C, Couvret, C, Regina, S, Gruel, Y
Journal of thrombosis and haemostasis : JTH. 2005;(12):2813-5
-
10.
Relationship of family history of type 2 diabetes, hypoglycemia, and autoantibodies to weight gain and lipids with intensive and conventional therapy in the Diabetes Control and Complications Trial.
Purnell, JQ, Dev, RK, Steffes, MW, Cleary, PA, Palmer, JP, Hirsch, IB, Hokanson, JE, Brunzell, JD
Diabetes. 2003;(10):2623-9
-
-
Free full text
-
Abstract
Intensive therapy for type 1 diabetes results in greater weight gain than conventional therapy. Many factors may predispose to this greater weight gain, including improved glycemic control, genetic susceptibility to obesity, and hypoglycemia. To study this, relationships among family history of type 2 diabetes, frequency of severe hypoglycemia, beta-cell autoantibodies, and weight gain were examined in 1,168 subjects aged > or =18 years at baseline randomized to intensive and conventional therapy groups in the Diabetes Control and Complications Trial. With intensive therapy, subjects with a family history of type 2 diabetes had greater central weight gain and dyslipidemia characterized by higher triglyceride levels and greater cholesterol in VLDLs and intermediate-density lipoproteins compared with subjects with no family history. Neither the frequency of severe hypoglycemia nor positivity to GAD65 and insulinoma-associated protein 2 antibodies was associated with increased weight gain with either intensive or conventional therapy. These data support the hypothesis that increased weight gain with intensive therapy might be explained, in part, by genetic traits.