Loss of opportunities in the diagnosis and treatment of primary obstetric antiphospholipid syndrome (POAPS): from theory to reality.

OBJECTIVES: (I) To identify and measure the clinical consequences of a delayed diagnosis in patients with primary obstetric antiphospholipid syndrome (POAPS), in terms of time and events associated to antiphospholipid syndrome (APS), and (II) to evaluate the impact of their treatment status on perinatal outcomes, before and after diagnosis. METHODS: This retrospective multicentre study included 99 POAPS women who were separated in two groups of timelines based on their diagnostic status: group 1: women who met the clinical criteria for POAPS; group 2: included the same patients from group 1 since they meet the laboratory criteria for APS. In group 1, we assessed the following variables: obstetric events, thrombotic events and time (years) to diagnosis of APS. We also compared perinatal outcomes between patients in group 1 vs. group 2. Women in group 2 were treated with standard of care for POAPS. Simple and multivariable logistic regression analyses were performed. RESULTS: Regarding the impact of the delay on diagnosis, a total of 87 APS-related events were recorded: 46 miscarriages, 32 foetal losses and 9 premature deliveries before the 34th week due to preeclampsia, and one thrombosis. The estimated rate of preventable events was 20.58 per year/100 patients. The mean diagnostic delay time was 4.27 years. When we compared both groups during pregnancy, we found that patients in group 1 (no treatment) had a higher association with pregnancy losses [OR = 6.71 (95% CI: 3.59-12.55), p < 0.0001]. CONCLUSION: Our findings emphasize the negative impact of POAPS underdiagnosis on patient health and the critical importance of a timely intervention to improve pregnancy outcomes. Key Points •Our study shows the relevance of underdiagnosis on primary obstetric antiphospholipid syndrome (POAPS). •These patients presented a high risk of APS-related events with each passing year. •Shorter diagnostic delay time was observed in the reference centres.

Clinical and therapeutic value of the adjusted Global Antiphospholipid Syndrome Score in primary obstetric antiphospholipid syndrome.

OBJECTIVES: (1) To assess the clinical utility of the adjusted global antiphospholipid syndrome score (aGAPSS) to predict new obstetric events during follow-up in primary obstetric antiphospholipid syndrome (POAPS) patients under standard-of-care treatment (SC) based on the use of low-dose aspirin (LDA) + heparin and (2) to study the risk of a first thrombotic event and to evaluate whether stratification according to this score could help to identify POAPS patients who would benefit from long-term thromboprophylaxis. METHODS: This is a retrospective, multicentre study. 169 women with POAPS were evaluated for the presence of a new obstetric event and/or a first thrombotic event during follow-up [time period: 2008-2020, median: 7 years (6-12 years)]. The outcomes of 107 pregnancies from these POAPS patients with SC were studied to evaluate relapses. Simple and multivariable logistic regression analyses were performed. RESULTS: Regarding obstetric morbidity, only triple positivity for antiphospholipid antibodies (aPLs) [OR = 8.462 (95% CI: 2.732-26.210); p < 0.0001] was found to be a strong risk factor independently associated with treatment failure. On the other hand, triple positivity for aPLs [OR=10.44 (95% CI: 2.161-50.469), p = 0.004] and an aGAPSS ≥7 [OR = 1.621 (95% CI: 1.198-2.193), p = 0.002] were independent risk factors associated with a first thrombotic event. LDA was marginally associated with a decrease in the risk of thrombosis only in patients with aGAPSS ≥ 7 (p = 0.048). CONCLUSION: aGAPSS appears to be useful in predicting the occurrence of a first thrombotic event in POAPS patients, and these stratification of patients could be helpful in selecting patients who would benefit from thromboprophylaxis with LDA.

A focus on the roles of histones in health and diseases.

Over time, the knowledge on the role of histones has significantly changed. Initially, histones were only known as DNA packaging proteins but later, it was discovered that they act extracellularly as powerful antimicrobial agents and also as potentially self-detrimental agents. Indeed, histones were found to be the most abundant proteins within neutrophil extracellular traps what ultimately highlighted their microbicidal function. In addition, extracellular histones proved to be involved in triggering exacerbated inflammatory and coagulation responses, depending on the cell type affected. Consequently, several investigations were conducted towards studying the potential of histones and their derivatives as either biomarkers or therapeutic target candidates in different diseases in which inflammation and thrombosis have a key pathophysiological role, such as sepsis, thrombosis and different types of cancer. The main objective of this review is to summarize and discuss the current state of the art with regard to both beneficial and harmful roles of histones and also their possible use as biomarkers and therapeutic targets.

Risk factors for early severe preeclampsia in obstetric antiphospholipid syndrome with conventional treatment. The impact of hydroxychloroquine.

OBJECTIVE: The first aim was to retrospectively identify risk factors for the development of early severe preeclampsia (sPE) in patients with obstetric antiphospholipid syndrome (OAPS) who received conventional treatment (CT). The second aim was to evaluate the impact of hydroxychloroquine (HCQ) in preventing early sPE among a subgroup of patients considered at high risk. METHODS: A total of 102 women diagnosed with OAPS and treated with CT since the diagnosis of pregnancy were selected. At the end of pregnancy, we identified risk factors associated with early sPE. According to these risk factors, we collected a new cohort of 42 patients who presented high-risk factors for developing early sPE and split them into two groups according to the treatment received: group A, CT (30 patients); and group B, CT+HCQ (12 patients). We evaluated and compared pregnancy outcomes in both groups. RESULTS: According to the multivariate analysis, risk factors associated with early sPE and CT were triple positivity for antiphospholipid antibodies (aPL) (OR = 24.70, [4.27-142.92], p < 0.001) and a history of early sPE (OR = 7.11, [1.13-44.64], p = 0.036). A low-risk aPL profile was associated with a good response to CT in preventing early sPE (OR = 0.073, [0.014-0.382], p = 0.002). High-risk patients treated with CT+HCQ had a significantly lower early sPE rate than those treated with CT only (8.3% vs 40.0%; p = 0.03). CONCLUSION: Triple positivity for aPL and a history of early sPE are potential strong risk factors for the development of early sPE. HCQ might be an interesting therapeutic option for patients with high-risk factors for early sPE.

Inherited thrombophilia and pregnancy loss. Study of an Argentinian cohort. / Trombofilia hereditaria y pérdidas de embarazo. Estudio de una cohorte de Argentina.

BACKGROUND AND OBJECTIVES: Thrombophilia might increase the risk of suffering from obstetric complications by adversely affecting the normal placental vascular function. Our aim was to study the distributions of five thrombosis-associated genetic variants: factor V Leiden, prothrombin G20210A, -675 4G/5G PAI-1, 10034C/T gamma fibrinogen and 7872C/T factor XI and the frequencies of the deficiencies of protein C, S and antithrombin in Argentinian patients with recurrent pregnancy loss (RPL) and, therefore, to analyse their association with the risk and timing of RPL and the risk of suffering other vascular obstetric pathologies. PATIENTS AND METHODS: We performed a case-control study that included 247 patients with idiopathic RPL (cases), 107 fertile controls and 224 subjects from general population (reference group). Cases were stratified according to the gestational time of the losses (early RPL, n = 89; late losses, n = 158; foetal losses, n = 107) and according to the type of vascular obstetric pathologies. RESULTS: No differences were found in the distribution of the genetic variants among RPL group vs. control/reference group (p >.05). Similarly, no differences were observed in their distributions when analysing RPL patients stratified according to gestational times or vascular obstetric pathologies (p >.05), except for the factor V Leiden carriage in patients with foetal growth retardation vs. controls (11.8%, 4/34 vs. 1.9%, 2/107; p = .04) (OR = 7.11 [1.24-40.93], p = .03). CONCLUSIONS: Factor V Leiden might have a significant impact on certain obstetric pathologies such as foetal growth retardation. The genetic variants, 10034C/T gamma fibrinogen and 7872C/T factor XI, associated with thromboembolic disease, would not have an impact on PRE.

Maternal carriers of the ANXA5 M2 haplotype are exposed to a greater risk for placenta-mediated pregnancy complications.

PURPOSE: Annexin A5 (ANXA5) is a protein abundantly expressed in normal placenta where it contributes to the healthy outcome of a pregnancy. Lower ANXA5 levels have been observed in M2/ANXA5 haplotype carrying chorion. Consequently, this study aimed to assess the potential association of M2 maternal carrier status with the risk of recurrent pregnancy loss (RPL), the timing of miscarriages, and other obstetric complications, for the first time in a population from Latin America. METHODS: This study was designed as a prospective recruitment of RPL patients with post hoc analysis. The distribution of the M2/ANXA5 haplotype was compared between a group of 229 Argentine women with RPL and 100 parous controls, and was further analyzed in subgroups of patients stratified according to the timing of miscarriages and in relation to other obstetric complications. RESULTS: No significant differences were found in the distribution of M2 haplotype among either RPL patients or the subgroups with embryonic, early fetal, or late fetal losses compared to parous controls. Notwithstanding, maternal M2/ANXA5 was found to be independently associated with a higher risk of suffering intrauterine growth restriction (IUGR) and/or preeclampsia (PE). Simultaneously, the presence of inherited and/or acquired thrombophilia also proved to be an independent risk factor for these. CONCLUSIONS: The association found between the maternal carriage of the M2/ANXA5 haplotype and an elevated risk of IUGR and/or PE supports the hypothesis that carrier status of this haplotype and the consequently reduced placental ANXA5 expression might be responsible, at least partially, for the onset of these gestational vascular complications.

The -2518 A/G polymorphism in the monocyte chemoattractant protein 1 gene (MCP-1) is associated with an increased risk of rheumatoid arthritis in Argentine patients.

The aim of this study was to analyze the influence of nucleotide transition (G/A) in position -2518 of the MCP-1 gene related to the susceptibility of developing RA. Two hundred twenty-three consecutive RA patients according to 2010 ACR/EULAR criteria were included; 120 healthy subjects were used as controls. MCP-1 -2518 A/G polymorphism (AG + GG) was present in 162 (72.6 %) RA patients and in 63 (52.5 %) healthy subjects [OR 2.44 (IC95% 1.53-3.88, p = 0.0002)]; associations for heterozygotes and homozygotes were OR 1.92 (IC95% 1.19-3.15, p = 0.001) and OR 5.19 (IC95% 2.34-11.51, p = 0.001), respectively. In Argentine patients, MCP-1 gene polymorphism confers susceptibility for developing RA.

The -308 G/A polymorphism in the tumor necrosis factor-α gene is not associated with development and progression of rheumatoid arthritis in Argentinean patients.

AIM: A polymorphism in the tumor necrosis factor-alpha (TNF-α) promoter region has been associated with disease susceptibility and progression in rheumatoid arthritis (RA). The presence of an adenosine (TNF2 allele) instead of a guanine (TNF1 allele) at position -308 may be responsible for a general increase in the transcriptional activity of the TNF-α gene. Our aim was to evaluate the association of the TNF2 allele with the risk of disease development and/or progression of RA in an Argentine population cohort. METHODS: Two hundred and twenty-three consecutive patients with RA according to the 1987 criteria of the American College of Rheumatology were included in the study. Clinical variables, Disease Activity Score 28, Health Assessment Questionnaire and Rheumatoid Arthritis Quality of Life were recorded. The radiographic erosions were determined by the method of Sharp/van der Heijde. A group of 111 healthy subjects matched by sex and age was used as a control. All samples were genotyped for the -308 G/A TNF-α polymorphism. RESULTS: No significant differences were observed either in the frequency of the TNF2 allele or in the genotypic distributions of the -308 G/A TNF-α polymorphism (P > 0.05) between the control group and the RA patients. No association was found between the TNF2 allele and the variables related to the course and outcome of the disease (P > 0.05). CONCLUSION: In this cohort of Argentinean patients with RA, the TNF2 allele was neither associated with susceptibility to the disease nor was it associated with the variables related to the course and outcome of the disease.

4G/5G plasminogen activator inhibitor-1 and -308 A/G tumor necrosis factor-α promoter gene polymorphisms in Argentinean lupus patients: focus on lupus nephritis.

We investigated the relationship between the 4G/5G plasminogen activator inhibitor (PAI-1) and -308 A/G tumor necrosis factor-α (TNF-α) polymorphisms and the clinical and biochemical features of systemic lupus erythematosus (SLE) in an Argentinean patient cohort. A total of 402 patients were studied, including 179 SLE patients and 223 healthy individuals. PCR-RLFP was used to determine the genotypes of the 4G/5G PAI-1 and -308 A/G TNF-α polymorphisms. SLE patients with lupus nephritis (LN) (n = 86) were compared with patients without LN (n = 93). Additionally, LN patients were divided into proliferative LN and non-proliferative LN groups according to the results of the renal biopsies. No significant differences were noted in the genotype distributions or allele frequencies of these TNF-α and PAI-1 polymorphisms between SLE patients and controls. There were higher numbers of criteria for SLE, more lupus flares and higher damage scores in LN patients, but there were similar frequencies of anti-phospholipid antibody (APA) positivity and anti-phospholipid syndrome. No significant difference was noted for any studied variable between the proliferative LN and non-proliferative LN groups except for the presence of APA. We found no significant differences in the TNF-α and PAI-1 genotype distributions or allele frequencies between groups. We found that the -308 A/G TNF-α and 4G/5G PAI-1 polymorphisms are not associated with susceptibility to SLE in an Argentinean population. We also did not find any association between the presence of any specific allele or genotype and the development of LN in SLE patients. Finally, no association was noted between either of the two polymorphisms and the severity of renal disease.

[Annexins and recurrent pregnancy loss]. / Anexinas y pérdidas recurrentes de embarazo.

Recurrent Pregnancy Loss (RPL) affects public health and directly compromises the quality of life of hundreds of women, with a detrimental effect on their physical and mental health. Approximately 50% of RPL are not associated to any of the currently known etiology and will be considered idiopathic. Recently, it has been demonstrated that the expression of annexin 5 (ANXA5), a protein found on the trophoblastic surface, plays a fundamental role in the development of pregnancy due to its immunomodulator and anticoagulant function at the placentary level. Some genetic haplotypes of ANXA5 are associated to alterations in the expression of this gene, such as haplotype M2 which is associated to a decrease in the expression of ANXA5. The presence of this haplotype is related to the following conditions occurring during pregnancy: RPL, foetal intrauterine growth restriction, low child weight at birth, preeclampsia and maternal pulmonary thromboembolism. This review describes the structure, function and genetic expression of ANXA5, as well as its possible implication in RPL.

Anexinas y pérdidas recurrentes de embarazo / Annexins and recurrent pregnancy loss

Las pérdidas de embarazo recurrentes (PER), afectan a la salud pública y comprometen en forma directa la calidad de vida de cientos de mujeres, con detrimento de su salud física y psíquica. Aproximadamente un 50% de las PER no se asocian a alguna de las etiologías conocidas, y por lo tanto se consideran idiopáticas. Recientemente se ha demostrado que la expresión de la anexina 5 (ANXA5), una proteína ubicada en la superficie trofoblástica, juega un papel fundamental en el mantenimiento del embarazo ya que cumple un rol como inmunomodulador y anticoagulante a nivel de la placenta. Algunos haplotipos genéticos de la ANXA5 se asocian a alteraciones en la expresión de este gen, como el haplotipo M2 que se vincula a una reducción en la expresión de la ANXA5. La presencia de dicho haplotipo se relaciona con los siguientes eventos del embarazo: PER, restricción del crecimiento fetal intrauterino, bajo peso al nacer, preclampsia y tromboembolismo pulmonar materno. Esta revisión describe la estructura, función y expresión genética de la ANXA5, así como también su posible implicancia en la PER.

Recurrent Pregnancy Loss (RPL) affects public health and directly compromises the quality of life of hundreds of women, with a detrimental effect on their physical and mental health. Approximately 50% of RPL are not associated to any of the currently known etiology and will be considered idiopathic. Recently, it has been demonstrated that the expression of annexin 5 (ANXA5), a protein found on the trophoblastic surface, plays a fundamental role in the development of pregnancy due to its immunomodulator and anticoagulant function at the placentary level. Some genetic haplotypes of ANXA5 are associated to alterations in the expression of this gene, such as haplotype M2 which is associated to a decrease in the expression of ANXA5. The presence of this haplotype is related to the following conditions occurring during pregnancy: RPL, foetal intrauterine growth restriction, low child weight at birth, preeclampsia and maternal pulmonary thromboembolism. This review describes the structure, function and genetic expression of ANXA5, as well as its possible implication in RPL.

Sex, ethnicity, and slow acetylator profile are the major causes of hepatotoxicity induced by antituberculosis drugs.

BACKGROUND AND AIM: Treatment with antituberculosis (TB) drugs produces liver damage in a large proportion of patients. Isoniazid, an antibacterial drug, is primarily responsible for this hepatotoxicity. Several polymorphisms of the N-acetyltransferase 2 (NAT-2) and cytochrome P450 2E1 enzymes, which are involved in the metabolism of isoniazid, may be directly associated with the development of hepatotoxicity. This study was designed to analyze the association between the NAT-2 and CYP2E1 polymorphisms with the development of anti-TB drug-induced hepatotoxicity (ATDH). METHODS: One hundred and seventy-five TB patients who had been treated with anti-TB drugs were studied. The allelic and genotypic frequency distributions of the NAT-2 and CYP2E1 enzymes were studied using polymerase chain reaction-restriction fragment length polymorphisms methodology. A binary logistic regression analysis was used to compare the results between TB patients with and without the development of hepatotoxicity. RESULTS: Having a slow acetylator status (odds ratio [OR] = 2.615; confidence interval [CI] = 1.264-5.411; P = 0.01), being female (OR = 2.734; CI = 1.325-5.639, P = 0.006), and having Bolivian ethnicity (OR = 2.711; CI = 1.307-6.625, P = 0.007) were found to be independent predictor variables for ATDH. CONCLUSIONS: This study showed that a patient's NAT-2 acetylator status, gender, and ethnic origin may be regarded as important risk factors for developing hepatotoxicity. Contrary to expectations, the CYP2E1 c1/c2 polymorphism did not show a significant association with hepatotoxicity in this study. Given the increases in TB cases and ATDH incidence levels, as well as the associated hospitalization costs, it may also be helpful to know patients' acetylator status prior to or at the beginning of the TB treatment regimen.

The distribution of allelic and genotypic frequencies of N-Acetyltransferase-2 variants in an Argentine population.

INTRODUCTION: Arylamine N-acetyltransferase-2 (NAT-2) is a key human enzyme in drug detoxification and elimination. Mutations in NAT-2 affect the activity of anti-tuberculosis drugs and result in three different phenotypes: rapid (RA), intermediate (IA) and slow acetylators (SA). METHODOLOGY: The allelic, genotypic and phenotypic frequencies of NAT-2 were studied in 185 patients from Buenos Aires by restriction fragment length polymorphism. RESULTS: The following allele frequencies were obtained: *4 = 29.9%, *5 = 37.0, *6 = 25.6%, *7 = 8% and *14 = 1.3%. With regard to the phenotype, we observed that 53.6% of the population was SA, 35.7% was IA and 10.7% was RA. CONCLUSION: A high prevalence of SA might have an impact on anti-TB drug-induced hepatotoxicity.

The -2518 A/G polymorphism in the monocyte chemoattractant protein 1 gene is associated with the risk of developing systemic lupus erythematosus in Argentinean patients: a multicenter study.

Systemic lupus erythematosus (SLE) is a systemic, autoimmune disorder. Monocyte chemoattractant protein 1 (MCP-1), a chemokine involved in the recruitment and migration of monocytes/macrophages, has been shown to be increased in the plasma of SLE patients. The aim of our study was to evaluate the possible association of the polymorphism -2518 of the MCP-1 gene with the risk of developing SLE, manifesting lupus nephritis (LN) and with other clinical features of SLE in an Argentinean population. A group of 171 SLE patients and 120 control subjects were examined. Genotypic and allelic frequencies of the MCP-1 -2518 A/G polymorphism showed significant differences between the SLE and the control groups (p=0.001 and p=0.01, respectively). However, the polymorphism showed no association with LN or with the other clinical variables studied. Our results suggest that the presence of the MCP-1 -2518 A/G polymorphism might be a risk factor for developing SLE in genetically predisposed individuals, but it does not seem to have a role in the evolution of the disease in the Argentinean population.