New insight into the pathogenesis and treatment of autoimmune congenital heart block

Background. Congenital atrioventricular block (CHB) is the most frequent manifestation of neonatal lupus which is attributed to anti-Ro/SSA and/or anti-La/SSB-mediated inflammation and subsequent fibrosis of the atrioventricular node. Despite the observation of a direct role for maternal antibodies in inducing CHB both in vitro and in vivo studies, the mechanisms involved remain unclear. Currently no therapy is found to be effective in the treatment of 2nd and 3rd degree CHB induced by maternal antibodies; also because the rarity of the disease does not allow for controlled clinical trials. Objectives. To explore the role of anti-Ro52 antibodies in the pathogenesis of CHB by identifying of the epitope specificity of anti-p200 antibodies. To study in an animal model the effect on heart conduction system of the different doses of injected human IgG antibodies from a CHB patient. To evaluate the clinical efficacy and safety of a combined therapy protocol utilizing plasmapheresis, intravenous immunoglobulin (IVIG) and betamethasone and the effect of this treatment on anti-Ro52, anti-p200 and anti-La antibody levels. Materials and Methods. Laboratory methods: ELISA assay, circular dichroism spectroscopy and antibody purification. Procedure: antibody transfer by intra-peritoneally injection of purified IgG. Instrumental methods: fetal ecocardiography and electrocardiogram recordings. Treatment strategy: Six consecutive women diagnosed CHB underwent a combination therapy protocol composed of weekly plasmapheresis, fortnightly 1 g/Kg IVIG and daily Betamethasone (4 mg/day) throughout pregnancy. IVIG (1 g/Kg) treatment in the neonates was begun at birth and administered every fifteen days until passive maternal antibodies became undetectable. Statistical analysis: Wilcoxon, Mann-Whitney U, two way ANOVA and Spearman’s tests; p<0.05 was considered as significant. Results and Conclusion. Part I: The epitope specificity of anti-p200 antibodies was the position 233. We suggest that this antibody specificity might be a tool to identify high risk pregnancies for CHB. The results might contribute to identify antibody specificity closely associated with development of CHB and to provide the possibility to explore the role of this antibody in the pathogenesis of CHB. Part II: We developed an animal model for CHB by a simple technique of passive transfer of human IgG from a patient with a child with CHB. High levels (4 mg) of anti-SSA/Ro and anti-SSB/La antibodies induce bradycardia, atrioventricular time prolongation and a decreased cardiac performance. Whereas, low levels (2 mg) of these antibodies determine a decrease in cardiac performance. Part III: The obtained results from these case series are: a) the efficacy in treating 2nd degree CHB, and b) the safety of plasmapheresis and IVIG therapies. The low number of treated cases, the relatively short follow-up (mean 22.7 months ± 10.4 SD, range 12-42 months) and the high cost of the procedure can all be considered limits. Part IV: Plasmapheresis reduces the levels of anti-Ro52, anti-p200 and anti-La antibodies. However, a decrease of antibody amounts in patients with the highest anti-Ro52 antibody levels has not been demonstrate

Effect of an oral preparation containing hyaluronic acid, chondroitin sulfate, hydrolyzed collagen type II and hydrolyzed keratin on synovial fluid features and clinical indices in knee osteoarthritis. A pilot study.

The aim of this study was to evaluate the effect of an oral preparation containing a naturally occurring matrix of hydrolyzed collagen type II, chondroitin sulfate (CS), and hyaluronic acid (HA), and bioactive oligopeptides of natural hydrolyzed keratin (K) in patients affected by knee OA through the evaluation of synovial fluid (SF) and clinical changes before and after treatment. Thirty patients with knee OA and swollen joint were included in the study and submitted to arthrocentesis. Patients were randomized in two groups: 1) the treatment group (N.15) took a dietary supplement containing 120 mg HA, 240 mg CS and 300 mg K once a day for 4 weeks; 2) the control group (N.15) was only submitted to arthrocentesis. Patient symptoms were evaluated at the beginning and at the end of the study by the WOMAC self-assessment questionnaire, the Lequesne algofunctional index, and the VAS forms. SF changes were evaluated by measuring local inflammatory indices, cytokines IL-1β, IL-8, IL-6, IL-10 and GM-CSF. The group of patients treated with the oral supplement showed an improvement in the clinical indices WOMAC (p<0.01), Lequesne (p=0.014) and VAS pain (p<0.01). On the contrary, no significant changes were found in the control group. The SF collected from the treated group showed a reduction of IL-8 (p=0.015), IL-6 and IL-10 levels, while no changes in cytokines were observed in the control group. This pilot study suggests that an oral administration of a preparation containing a combination of HA, CS and K can improve some clinical parameters and affect cytokine concentrations in SF in patients with knee OA

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ABSTRACT. Objective. The effect of low-dose aspirin (LDA) on pregnancy outcome in antiphospholipid (aPL)-positive women not fulfilling the criteria for antiphospholipid antibody syndrome (APS) was evaluated retrospectively. Methods. We evaluated 139 pregnancies of 114 aPL-positive women not fulfilling the Sydney classification criteria for definite APS (104 treated with LDA, 35 untreated). Inclusion criteria consisted of (1) any titer of aPL and no previous pregnancy or no pregnancy losses (defined as aPL carriers); (2) any titer of aPL and 1 or 2 pregnancy losses before the 10th gestational week. No women had previous thrombosis. The rate of pregnancy loss, gestational age at delivery, and birth weight percentile were compared in the treated and untreated patients. Associations between clinical and laboratory characteristics and pregnancy outcomes were investigated. Results. The rate of pregnancy loss was low in both treated and untreated groups (7.7% vs 2.9%, respectively). There were no statistically significant differences in the rate of pregnancy loss, gestational age at birth, or birth weight percentile in the treated and untreated groups. There were significant associations between gestational age at birth ≤ 34th week and positivity for lupus anticoagulant (p = 0.025) and anti-ß 2 -glycoprotein I IgG antibodies at titers &gt; 99th (p = 0.016). Conclusion. LDA treatment does not appear to improve pregnancy outcome in low-risk women not fulfilling the criteria for APS. Because antibody profile seems to influence pregnancy outcome, further studies of patients stratified according to their antibody profile are warranted. (First Releas

New insight into the pathogenesis and treatment of autoimmune congenital heart block

Background. Congenital atrioventricular block (CHB) is the most frequent manifestation of neonatal lupus which is attributed to anti-Ro/SSA and/or anti-La/SSB-mediated inflammation and subsequent fibrosis of the atrioventricular node. Despite the observation of a direct role for maternal antibodies in inducing CHB both in vitro and in vivo studies, the mechanisms involved remain unclear. Currently no therapy is found to be effective in the treatment of 2nd and 3rd degree CHB induced by maternal antibodies; also because the rarity of the disease does not allow for controlled clinical trials. Objectives. To explore the role of anti-Ro52 antibodies in the pathogenesis of CHB by identifying of the epitope specificity of anti-p200 antibodies. To study in an animal model the effect on heart conduction system of the different doses of injected human IgG antibodies from a CHB patient. To evaluate the clinical efficacy and safety of a combined therapy protocol utilizing plasmapheresis, intravenous immunoglobulin (IVIG) and betamethasone and the effect of this treatment on anti-Ro52, anti-p200 and anti-La antibody levels. Materials and Methods. Laboratory methods: ELISA assay, circular dichroism spectroscopy and antibody purification. Procedure: antibody transfer by intra-peritoneally injection of purified IgG. Instrumental methods: fetal ecocardiography and electrocardiogram recordings. Treatment strategy: Six consecutive women diagnosed CHB underwent a combination therapy protocol composed of weekly plasmapheresis, fortnightly 1 g/Kg IVIG and daily Betamethasone (4 mg/day) throughout pregnancy. IVIG (1 g/Kg) treatment in the neonates was begun at birth and administered every fifteen days until passive maternal antibodies became undetectable. Statistical analysis: Wilcoxon, Mann-Whitney U, two way ANOVA and Spearman’s tests; p<0.05 was considered as significant. Results and Conclusion. Part I: The epitope specificity of anti-p200 antibodies was the position 233. We suggest that this antibody specificity might be a tool to identify high risk pregnancies for CHB. The results might contribute to identify antibody specificity closely associated with development of CHB and to provide the possibility to explore the role of this antibody in the pathogenesis of CHB. Part II: We developed an animal model for CHB by a simple technique of passive transfer of human IgG from a patient with a child with CHB. High levels (4 mg) of anti-SSA/Ro and anti-SSB/La antibodies induce bradycardia, atrioventricular time prolongation and a decreased cardiac performance. Whereas, low levels (2 mg) of these antibodies determine a decrease in cardiac performance. Part III: The obtained results from these case series are: a) the efficacy in treating 2nd degree CHB, and b) the safety of plasmapheresis and IVIG therapies. The low number of treated cases, the relatively short follow-up (mean 22.7 months ± 10.4 SD, range 12-42 months) and the high cost of the procedure can all be considered limits. Part IV: Plasmapheresis reduces the levels of anti-Ro52, anti-p200 and anti-La antibodies. However, a decrease of antibody amounts in patients with the highest anti-Ro52 antibody levels has not been demonstratedPremesse. Il blocco atrioventricolare congenito (CHB) è la manifestazione più frequente del lupus neonatale. Esso è causato dal passaggio transplacentare degli anticorpi anti-Ro/SSA e/o anti-La/SSB con successiva infiammazione e fibrosi del nodo atrioventricolare. Nonostante la dimostrazione di un ruolo diretto degli anticorpi materni nell'indurre CHB sia in vitro che in vivo, i meccanismi coinvolti rimangono poco chiari. Inoltre finora nessuna terapia è risultata efficace nel trattamento del CHB sia di secondo che terzo grado, anche perché la rarità della malattia non consente studi clinici controllati. Obiettivi. Studiare il ruolo degli anticorpi anti-Ro52 nella patogenesi del CHB attraverso la definizione della specificità epitopica degli anticorpi anti-p200. Sviluppare un modello animale per studiare l'effetto sul sistema di conduzione cardiaco degli anticorpi IgG purificati da una paziente con CHB fetale. Infine valutare l'efficacia clinica e la sicurezza di un protocollo di terapia combinato comprendente l’impiego di plasmaferesi, immunoglobuline per via endovenosa (IVIG) e betametasone, nonchè l'effetto di questo trattamento su i livelli degli anticorpi anti-Ro52, anti-p200 e anti-La. Materiali e Metodi. Metodi di laboratorio: ELISA, spettroscopia con dicroismo circolare e purificazione di IgG umane. Procedura sperimentale: trasferimento per via intra-peritoneale degli anticorpi mediante l’iniezione di IgG purificate da una madre con CHB. Metodi strumentali: ecocardiografia fetale ed elettrocardiografia dopo la nascita. Strategia di trattamento: Sei donne diagnosticate con CHB sono state trattate durante la gravidanza con un protocollo di terapia di associazione composta da plasmaferesi settimanale, IVIG 1g/kg a cadenza quindicinale e Betametasone giornaliero (4 mg). Inoltre, IVIG (1 g/kg) sono state somministrate ai neonati ogni quindici giorni subito dopo la nascita fino alla negativizzazione degli anticorpi materni passivi. Analisi statistica: Wilcoxon, Mann-Whitney U, ANOVA e Spearman tests. Il valore di p<0,05 è stato considerato significativo. Risultati e Conclusioni. Parte I: La specificità epitopica dell’anticorpo anti-p200 è stata localizzata nella posizione 233. Tale epitopo potrebbe essere utile per identificare la specificità anticorpale strettamente associata allo sviluppo del CHB e costituire quindi uno strumento per individuare le gravidanze ad alto rischio per CHB. Inoltre potrebbe contribuire a chiarire il ruolo di questo anticorpo nella patogenesi del CHB. Parte II: Abbiamo sviluppato un modello animale del CHB con una semplice tecnica di trasferimento passivo di IgG umane purificate da un paziente con CHB fetale. Gli alti livelli (4 mg) degli anticorpi anti-Ro/SSA ed anti-La/SSB hanno indotto bradicardia, prolungamento dell’intervallo PR e una depressione delle funzione cardiaca nel animale. Invece, i bassi livelli (2 mg) hanno determinato solo una diminuzione della funzione cardiaca. In questo modo è stato dimostrato la patogenicità degli anticorpi anti-Ro/SSA ed anti-La/SSB sul sistema di conduzione cardiaco. Parte III: I risultati ottenuti da queste serie di casi sono i seguenti: a) l’efficacia nel trattamento del CHB di 2° grado, e b) la sicurezza della plasmaferesi e delle IVIG. Tuttavia il basso numero di casi trattati, e il follow-up relativamente breve (media 22,7 mesi ± 10,4 DS, range 12-42 mesi), come anche l'alto costo della procedura possono essere considerati limiti. Parte IV: La plasmaferesi riduce i livelli degli anticorpi anti-Ro52, anti-p200 e anti-La. Tuttavia, un decremento significativo anticorpale non è stato dimostrato nelle pazienti con livelli molto alti di anticorpi anti-Ro5

Obstetric Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is characterized by thrombotic events and obstetric complications in the presence of persistently positive antiphospholipid antibodies. Obstetric manifestations include, recurrent miscarriages, fetal death at or beyond the 10th week of gestation, and premature birth due to pre-eclampsia/placental insufficiency. Even now, both clinical features and laboratory parameters are controversial. Both can be used to stratify women with APS in terms of risk of adverse pregnancy outcome, and thus adjust treatment. APS pregnancies should be classified into low, medium and high-risk classes based on clinical and laboratory features. Depending on the risk class, the most appropriate therapy must be then selected. Heparin plus LDA is considered the standard of care for patients with a confirmed diagnosis of obstetric APS and generally results in over 70–80% successful pregnancies. The 20–30% pregnancies in which treatment fails are defined as “high-risk” or “refractory” pregnancies. Numerous treatments have been used in addition to standard of care, to treat these patients, but no well-designed trial has yet been conducted. New insights into the etiopathogenetic mechanisms of obstetric APS have led to the testing of new therapeutic approaches, that may soon change the way we manage this condition

Are biological drugs safe in pregnancy?

The introduction of biological therapies has significantly improved the outcome of inflammatory rheumatic diseases. As most of these diseases affect women and men in childbearing age, some concerns have been voiced as to the safety of these drugs in relation to reproduction and pregnancy. Data from many hundreds of pregnancies in patients affected by inflammatory bowel disease and inflammatory arthritis have suggested that exposure to anti-TNF therapies at conception and/or during pregnancy is not associated with adverse pregnancy outcomes or any increase in congenital abnormalities. However, the exposure to anti-TNFα agents, particularly to monoclonal antibodies, in late pregnancy is associated with high drug levels in the newborn and their long-term effects on children remain unknown. Therefore, limiting the use of anti-TNFα to the first 30 weeks of pregnancy is recommended to reduce fetal exposure. Live-virus vaccines should be given only when levels of anti-TNFα drugs are undetectable in the serum of infants. Studies suggest that many of these drugs do enter breast milk in small amounts, but the extent to which the infant absorbs them is less clear. Limited reports have not suggested adverse pregnancy outcomes in women whose partners were exposed to anti-TNF therapies at the time of conception. Pregnancy data for rituximab, abatacept, anakinra, tocilizumab and belimumab are limited and their use in pregnancy cannot currently be recommended

Treatment of Refractory/High-Risk Pregnancies With Antiphospholipid Syndrome: A Systematic Review of the Literature

none4Different treatment protocols have been employed to manage heparin/low-dose aspirin refractory or high-risk pregnancies in antiphospholipid antibody syndrome (APS) pregnancies. A systematic review of the literature on additional treatments used in refractory and/or high-risk APS pregnancies was conducted. Records from February 2006 to October 2021 were retrieved from PubMed, Web of Science, Cochrane, and the www.clinicaltrials.gov platform. Twenty-one studies met our eligibility criteria. Live birth rate is this study's primary endpoint, while pregnancy complications and adverse events are secondary endpoints. A total of 434 pregnancies, 162 (37.3%) refractory and 272 (62.7%) high-risk/refractory pregnancies, were included. Both IVIG &lt;2 gr/kg/monthly/HCQ/LDS and PEX/IA ± LDS led to 100% viable infants in refractory APS. Furthermore, HCQ 200-400&nbsp;mg showed a higher live birth rate than HCQ + LDS (88.6% vs. 82.7%). Following treatment protocol with HCQ 200-400&nbsp;mg and IVIG &lt;2 gr/kg/monthly/HCQ/LDS, pregnancy complications rates of 16.7 and 83.3% were registered, respectively. Pravastatin 20&nbsp;mg, IA weekly + IVIG 2 gr/monthly, and PEX weekly + IVIg 2 gr/kg/monthly showed higher live birth rates in high-risk APS pregnancies of 100, 100 and 92%, respectively, whereas the lower severe pregnancy complications were reported in pregnancies treated with PEX weekly + IVIg 2 gr/kg/monthly (11.1%). One (0.6%) case of dermatitis during treatment with HCQ was observed. The results of this study showed that HCQ 200-400&nbsp;mg and PEX weekly + IVIG 2&nbsp;gr/kg/monthly achieved a higher live birth rate in refractory APS and high-risk/refractory APS, respectively. The results presented provide clinicians with up-to-date knowledge in the management of APS pregnancies according to risk stratification.Hoxha, Ariela; Tormene, Daniela; Campello, Elena; Simioni, PaoloHoxha, Ariela; Tormene, Daniela; Campello, Elena; Simioni, Paol