History of pre-eclampsia does not appear to be a risk factor for vascular phenotype in women with systemic sclerosis.

BACKGROUND: Vascular phenotype is associated with a poor prognosis in systemic sclerosis (SSc). The identification of its risk factors could facilitate its early detection. OBJECTIVES: To explore risk factors for a vascular phenotype of SSc, among them a history of pre-eclampsia. METHODS: This observational multicentre case-control study enrolled adult women fulfilling European Alliance of Associations for Rheumatology 2013 diagnosis criteria for SSc and having a pregnancy history≥6 months before SSc diagnosis in 14 French hospital-based recruiting centres from July 2020 to July 2022. Cases had specific vascular complications of SSc defined as history of digital ischaemic ulcers, pulmonary arterial hypertension, specific cardiac involvement or renal crisis. Women with SSc were included during their annual follow-up visit and filled in a self-administered questionnaire about pregnancy. A case report form was completed by their physician, reporting data on medical history, physical examination, clinical investigations and current medication. The main outcome was the presence/absence of a personal history of pre-eclampsia before SSc diagnosis, according to the validated pre-eclampsia questionnaire. RESULTS: 378 women were included: 129 cases with a vascular phenotype and 249 matched controls. A history of pre-eclampsia was reported in 5 (3.9%) cases and 12 (4.8%) controls and was not associated with a vascular phenotype (OR=0.96, 95% CI 0.28 to 3.34, p=0.9). Besides, Rodnan skin score and disease duration≥5 years were risk factors for vascular phenotype. CONCLUSIONS: In women with SSc and a pregnancy history≥6 months before SSc, a history of pre-eclampsia is not associated with a vascular phenotype.

Characterisation of a high-risk profile for maternal thrombotic and severe haemorrhagic complications in pregnant women with antiphospholipid syndrome in France (GR2): a multicentre, prospective, observational study.

BACKGROUND: Prospective data about the risks of thrombotic and severe haemorrhagic complications during pregnancy and post partum are unavailable for women with antiphospholipid syndrome. We aimed to assess thrombotic and haemorrhagic events in a prospective cohort of pregnant women with antiphospholipid syndrome. METHODS: This multicentre, prospective, observational study was done at 76 centres in France. To be eligible for this study, women had to have diagnosis of antiphospholipid syndrome; have conceived before April 17, 2020; have an ongoing pregnancy that had reached 12 weeks of gestation; and be included in the study before 18 weeks of gestation. Exclusion criteria were active systemic lupus erythematosus nephropathy, or a multifetal pregnancy. Severe haemorrhage was defined as the need for red blood cell transfusion or maternal intensive care unit admission because of bleeding or invasive procedures, defined as interventional radiology or surgery, to control bleeding. The GR2 study is registered with ClinicalTrials.gov, NCT02450396. FINDINGS: Between May 26, 2014, and April 17, 2020, 168 pregnancies in 27 centres met the inclusion criteria for the study. 89 (53%) of 168 women had a history of thrombosis. The median term at inclusion was 8 weeks gestation. 16 (10%) of 168 women (95%CI 5-15) had a thrombotic (six [4%] women; 95% CI 1-8) or severe haemorrhagic event (12 [7%] women; 95% CI 4-12). There were no deaths during the study. The main risk factors for thrombotic events were lupus anticoagulant positivity at inclusion (six [100%] of six women with thrombosis vs 78 [51%] of 152 of those with no thrombosis; p=0·030) and placental insufficiency (four [67%] of six women vs 28 [17%] of 162 women; p=0·013). The main risk factors for severe haemorrhagic events were pre-existing maternal hypertension (four [33%] of 12 women vs 11 [7%] of 156 women; p=0·014), lupus anticoagulant positivity at inclusion (12 [100%] of 12 women vs 72 [49%] of 146 women; p<0·0001) and during antiphospholipid history (12 [100%] of 12 women vs 104 [67%] of 156 women; p=0·019), triple antiphospholipid antibody positivity (eight [67%] of 12 women vs 36 [24%] of 147 women; p=0·0040), placental insufficiency (five [42%] of 12 women vs 27 [17%] of 156 women; p=0·038), and preterm delivery at 34 weeks or earlier (five [45%] of 11 women vs 12 [8%] of 145 women; p=0·0030). INTERPRETATION: Despite treatment adhering to international recommendations, a proportion of women with antiphospholipid syndrome developed a thrombotic or severe haemorrhagic complication related to pregnancy, most frequently in the post-partum period. Lupus anticoagulant and placental insufficiency were risk factors for these life-threatening complications. These complications are difficult to prevent, but knowledge of the antenatal characteristics associated with them should increase awareness and help physicians manage these high-risk pregnancies. FUNDING: Lupus France, association des Sclérodermiques de France, association Gougerot Sjögren, Association Francophone contre la Polychondrite chronique atrophiante, AFM-Telethon, the French Society of Internal Medicine and Rheumatology, Cochin Hospital, the French Health Ministry, FOREUM, the Association Prix Veronique Roualet, and UCB.

Whole exome sequencing, a hypothesis-free approach to investigate recurrent early miscarriage.

RESEARCH QUESTION: Are there genetic determinants shared by unrelated women with unexplained recurrent early miscarriage (REM)? DESIGN: Thirty REM cases and 30 controls were selected with extreme phenotype among women from Eastern Brittany (France), previously enrolled in an incident case-control study on thrombophilic mutations. Cases and controls were selected based on the number of early miscarriages or live births, respectively. Peripheral blood was collected for DNA extraction at initial visit. The burden of low-frequency variants in the coding part of the genes was compared using whole exome sequencing (WES). RESULTS: Cases had 3 to 17 early miscarriages (20 cases: ≥5 previous losses). Controls had 1 to 4 live births (20 controls: ≥3 previous live births) and no miscarriages. WES data were available for 29 cases and 30 controls. A total of 209,387 variants were found (mean variant per patient: 59,073.05) with no difference between groups (P = 0.68). The top five most significantly associated genes were ABCA4, NFAM1, TCN2, AL078585.1 and EPS15. Previous studies suggest the involvement of vitamin B12 deficiency in REM. TCN2 encodes for vitamin B12 transporter into cells. Therefore, holotranscobalamin (active vitamin B12) was measured for both cases and controls (81.2 ± 32.1 versus 92.9 ± 34.3 pmol/l, respectively, P = 0.186). Five cases but no controls were below 50 pmol/l (P = 0.052). CONCLUSIONS: This study highlights four new genes of interest in REM, some of which belong to known networks of genes involved in embryonic development (clathrin-mediated endocytosis and ciliary pathway). The study also confirms the involvement of TCN2 (vitamin B12 pathway) in the early first trimester of pregnancy.

Hydroxychloroquine may be beneficial in preeclampsia and recurrent miscarriage.

Recurrent miscarriage (RM) and vasculoplacental disorders, such as preeclampsia (PE), affect women of childbearing age worldwide. Vascular endothelial dysfunction and immunological impairment are associated with both RM and PE. To date, there is no effective or optimal therapeutic approach for these conditions. Notably, aspirin use is only partially effective in the prevention of PE. Hydroxychloroquine (HCQ) has demonstrated beneficial effects on disease flares, pregnancy outcomes and cardiovascular impairment in systemic erythaematosus lupus (SLE) through its immunomodulatory, vasculoprotective and antithrombotic properties. Here, in the context of the underlying physiological dysregulation associated with PE and RM, the beneficial properties and potential therapeutic efficacy of HCQ are reviewed in anticipation of the results of current and future trials. Two related trials addressing RM in the absence of maternal autoimmune disease are ongoing. Other trials addressing pregnancy outcomes in the presence of maternal autoimmune disease are forthcoming. In this review, we hypothesise that the immunological and endothelial effects of HCQ may be beneficial in the context of PE and RM, regardless of the maternal autoimmune status.

Blood anti-Müllerian hormone is a possible determinant of recurrent early miscarriage, yet not conclusive in predicting a further miscarriage.

RESEARCH QUESTION: Is blood anti-Müllerian hormone (AMH) concentration a strong determinant of unexplained recurrent early miscarriage (REM)? DESIGN: In the first part of the study, AMH concentrations measured using an Immunotech ELISA Kit were compared between 188 unselected (mostly fertile) women consecutively referred for three or more miscarriages in the first trimester of pregnancy and 376 age-matched parous women without pregnancy loss. Cases and controls were previously enrolled in an incident case-control study on thrombophilic mutations. Blood samples were collected >2 months after any recognized obstetric event or hormonal treatment. In the second part of the study, a prospective 2-year follow-up of cases was performed. RESULTS: When considering all women irrespective of age, AMH concentration did not significantly differ between cases and controls. However, in the subgroup ≥25 years old (176 cases versus 358 controls of ∼33.5 years), the cases had significantly lower AMH concentrations than the controls (median [interquartile range]: 2.8 [1.4-4.7] versus 3.25 [1.7-5.5], P = 0.046) and the proportion of cases with an AMH concentration <1 ng/ml was significantly higher (17.6% versus 10.6%; odds ratio 1.80; 95% confidence interval 1.07-3.00, P = 0.028). With regard to the subsequent pregnancy, AMH concentration was not correlated with either the conception delay or the miscarriage occurrence. However, increased age and number of previous miscarriages were significantly predictive of a subsequent miscarriage (P = 0.046 and 0.03, respectively). CONCLUSION: An altered ovarian reserve is a possible determinant of unexplained REM. However, AMH blood concentration predicts neither the delay nor the outcome of a subsequent pregnancy.

Hydroxychloroquine for prevention of recurrent miscarriage: study protocol for a multicentre randomised placebo-controlled trial BBQ study.

INTRODUCTION: Recurrent miscarriage (RM), defined by three or more consecutive losses during the first trimester of pregnancy, affects 1%-2% of fertile couples. Standard investigations fail to reveal any apparent cause in ~50% of couples. However, on the basis of animal models and clinical studies, several hypotheses have been put forward concerning underlying mechanisms of RM: altered ovarian reserve, progesterone defect, thrombotic and/or endothelial dysfunction and immunological disturbances. Nonetheless, no study has yet reached conclusive beneficial clinical evidence for a potential treatment in unexplained RM. Hydroxychloroquine (HCQ) is a molecule with extensive safety data during pregnancy. The pharmacological properties of HCQ (eg, antithrombotic, vascular protective, immunomodulatory, improved glucose tolerance, lipidlowering and anti-infectious) could be effective against some mechanisms of unexplained RM. Furthermore, eventhough clinical benefit of HCQ is suggested in prevention of thrombotic and late obstetric events in antiphospholipid (APL) syndrome, there are no data suggesting the benefit of HCQ in RM in the presence of APL antibodies. METHODS AND ANALYSIS: Taken all together and given the low cost of HCQ, the aim of this multicentre, randomised, placebo-controlled, double-blind study is to investigate whether HCQ would improve the live birth rate in women with RM, irrespective of maternal thrombophilic status: (1) no known thrombophilia, (2) inherited thrombophilia or (3) APL antibodies. The primary end point is a live and viable birth. After confirming eligibility and obtaining consent, 300 non-pregnant women will be randomised into two parallel groups for a daily oral treatment (HCQ 400 mg or placebo), initiated before conception and stopped at 10 weeks' gestation. If pregnancy does not occur after 1 year, the treatment will be stopped. ETHICS AND DISSEMINATION: Agreement from the French National Public Health and Drug Security Agency (160765A-22) and ethical approval from the Committee for the Protection of Persons of NORD-OUEST I (2016-001330-97) have been obtained. TRIAL REGISTRATION NUMBERS: NCT0316513; Pre-results.

Minisci-Photoredox-Mediated α-Heteroarylation of N-Protected Secondary Amines: Remarkable Selectivity of Azetidines.

The development of a general, mild, and functional-group-tolerant direct functionalization of N-heteroarenes by C-H functionalization with N-protected amines, including azetidines under Minisci-mediated photoredox conditions, is reported. A broad scope of substituted azetidines, including spirocyclic derivatives, and heterocycles were explored. This reaction enables the production of sp3-rich complex druglike structures in one step from unactivated feedstock amines and heterocycles.

Clinical Characteristics of Pruritus in Systemic Sclerosis Vary According to the Autoimmune Subtype.

Pruritus is a frequent symptom in systemic sclerosis (SSc), with a prevalence of 40-65%, but its pathophysiology is poorly understood. This study investigated the immunological component of pruritus. Fifty-six patients with SSc responded to a standardized questionnaire regarding both SSc disease and pruritus characteristics. Among patients with SSc, those with pruritus did not display a particular immunological profile (inflammatory, humoral, and/or cellular factors), but pruritus was, in most cases, concomitant with the development of SSc. Thus, pruritus characteristics were evaluated further, according to the detection of anti-centromere autoantibodies (ACA), into ACA+ (n = 17) and ACA- (n = 19). The ACA+ subgroup was characterized by a longer evolution of SSc and pruritus, pruritus present outside the sclerotic area, and a shorter daily duration of pruritus. In conclusion, the concomitant appearance of the 2 processes and the differences observed between ACA+ and ACA- subgroups support the presence of an immunological component in pruritus.

Lymphocyte Disturbances in Primary Antiphospholipid Syndrome and Application to Venous Thromboembolism Follow-Up.

Among patients with venous thromboembolism (VTE), the persistent detection of antiphospholipid (aPL) antibodies (Ab) represents an independent high risk factor for recurrence. However, oral anticoagulation vitamin K antagonist therapy, frequently used in these patients, is problematic in assessing and/or confirming a diagnosis of primary aPL syndrome (pAPS), suggesting use of alternative strategies. For this reason, and by analogy with other autoimmune diseases, a flow cytometer approach testing peripheral T cell subsets (CD3, CD4, and CD8), B cell subsets (B1, transitional, naive, and memory), and NK cells can be proposed. As an example and to validate the concept, pAPS patients selected from the monocentric VTE case-control EDITH's cohort were selected during their follow-up. As suspected and in contrast to non-APS VTE patients, other autoimmune diseases, and controls, pAPS VTE patients displayed specific lymphocyte disturbances. Quantitative and qualitative modifications were related to total CD4+ T cell reduction, a lower CD4/CD8 ratio, and disturbance in B cell homeostasis with increased proportions of B1 cells, transitional B cells (CD24++CD38++), and naive B cells (IgD+CD27-), while memory B cells (IgD+CD27+ and IgD-CD27+) were reduced. Interestingly, the absolute number of CD4+ T cells positively correlated with IgG anti-cardiolipin Ab levels. Altogether, disturbances of T and B cell homeostasis characterized pAPS VTE patients during their follow-up. This suggests a means of profiling that could be used in addition to existing criteria to characterize them.

Enoxaparin for prevention of unexplained recurrent miscarriage: a multicenter randomized double-blind placebo-controlled trial.

It is common practice in many centers to offer antithrombotic medications to women with unexplained recurrent miscarriage, in the presence or absence of inherited thrombophilia. Although no benefit of aspirin vs placebo has been clearly demonstrated, a double-blind placebo-controlled trial on the effect of low-molecular-weight heparin is lacking. We enrolled 258 pregnant women with a history of unexplained recurrent miscarriage (≥2 consecutive miscarriages before 15 weeks' gestation) and a negative thrombophilia workup. They were randomly assigned to receive one daily subcutaneous injection of enoxaparin 40 mg or placebo until 35 weeks' gestation. We included 256 women (mean age 32 years, ≥3 miscarriages: 72%; mean gestational age 39 days of amenorrhea) in the intention-to-treat analysis; 66.6% of 138 who received enoxaparin had a live birth vs 72.9% of 118 who received placebo. The absolute difference was -6% (95% CI, -17.1 to 5.1), excluding a 10% increase in the rate of live-birth on enoxaparin (P = .34). In this first randomized, double-blind, placebo-controlled trial, enoxaparin (40 mg once daily) did not improve the chance of a live birth in nonthrombophilic women with unexplained recurrent miscarriage. This trial is registered at www.ClinicalTrials.gov as #NCT00740545 and the French National Health and Drug Safety Agency (EudraCT #2006-003350-18).

Structure-Based Design of Type II Inhibitors Applied to Maternal Embryonic Leucine Zipper Kinase.

A novel Type II kinase inhibitor chemotype has been identified for maternal embryonic leucine zipper kinase (MELK) using structure-based ligand design. The strategy involved structural characterization of an induced DFG-out pocket by protein-ligand X-ray crystallography and incorporation of a slender linkage capable of bypassing a large gate-keeper residue, thus enabling design of molecules accessing both hinge and induced pocket regions. Optimization of an initial hit led to the identification of a low-nanomolar, cell-penetrant Type II inhibitor suitable for use as a chemical probe for MELK.

Unexplained pregnancy loss: a marker of basal endothelial dysfunction?

OBJECTIVE: To compare the microparticle levels of women referred for unexplained pregnancy loss with those of parous controls. DESIGN: Incident case-control study. SETTING: University medical center. PATIENT(S): 124 women consecutively referred for unexplained pregnancy losses (two or more losses at or before 21 weeks of gestational age, or at least one later loss), and 273 parous women without pregnancy loss. INTERVENTION(S): Numeration of circulating microparticles by flow cytometry after differentiation of subpopulations according to the expression of membrane-specific antigens (CD51, CD144, or CD146 for endothelial, CD41 for platelet, CD45 and CD66b for leukocyte and neutrophil microparticles). MAIN OUTCOME MEASURE(S): Plasma levels of microparticles. RESULTS: A relative hypercoagulable state assessed by thrombin generation test had been previously reported in such cases, so we hypothesized that this could be explained by an excess of procoagulant microparticles. The study women displayed statistically significantly lower platelet and higher endothelial microparticle levels than the controls. The parameters of the thrombin generation test were only correlated with the level of endothelial microparticles, with a low coefficient of Speerman's correlation (r=0.15). CONCLUSION(S): The difference in microparticle levels between the patients and controls does not clearly explain the hypercoagulable state reported in the patients but could reflect chronic endothelium damage.

Increased thrombin generation measured in the presence of thrombomodulin in women with early pregnancy loss.

Compared with 537 parous controls with no history of pregnancy loss, a lower thrombomodulin-related inhibition of the endogenous thrombin potential was measured in 264 cases with previous unexplained pregnancy loss, especially when losses occurred between 9 and 12 weeks of gestation. Adjusting age, protein S, factor VIII, factor V Leiden, and prothrombin G20210A did not change the results.

Impact of atazanavir-based HAART regimen on the carotid intima-media thickness of HIV-infected persons: a comparative prospective cohort.

OBJECTIVE: With the advent of highly active antiretroviral therapy regimens, it is crucial to consider their long-term benefits to risk ratios among HIV-infected persons. The impact of protease inhibitors on the cardiovascular risk is controversial. DESIGN: This observational cohort was designed to investigate the cardiovascular impact of boosted atazanavir (ATV/r), a protease inhibitor that does not provide major dyslipidemia or insulin resistance. SETTING: This study was carried out at the University Hospital of Brest (France). PATIENTS: Among the 229 HIV-infected persons of the cohort, 33 cases treated by ATV/r-containing regimen since less than 6 months were compared to 99 age-matched and sex-matched ATV/r naive controls. INTERVENTION: None. MAIN OUTCOME MEASURE: The main outcome measure was carotid intima-media thickness (cIMT) at the baseline, 6, 12, and 18 months. RESULTS: Although the cIMT was not different at inclusion (0.633 ± 0.05 vs. 0.666 ± 0.09, P = 0.07), the cIMT course significantly decreased (P = 0.018) in cases at 18 months. The differences remained significant even after adjustment on the variables that differed between cases and controls (P < 0.1) at inclusion (high-density lipoprotein cholesterol, cardiovascular family history) and the cumulated and current exposure to the nucleosidic reverse transcriptase inhibitor, nonnucleosidic reverse transcriptase inhibitor, and protease inhibitor class. CONCLUSION: Despite similar HIV and cardiovascular characteristics at baseline, cIMT decreased after 6 months of follow-up among the patients exposed to ATV/r, even after adjustment for the exposure to the three antiretroviral classes. Considering the shortcomings of this study, especially the absence of randomization and the heterogeneity of the control group, the benefit of ATV/r treatment in patients with high cardiovascular should be confirmed by randomized trials.

Statin use does not affect the outcome of acute infection: a prospective cohort study.

UNLABELLED: Statins are used to prevent atherosclerosis because of their hypolipemic effects. In vitro testing and murine models suggest that statins may affect outcome in sepsis. Our meta-analysis of epidemiological studies in humans confirms that previous statin use appears to have a protective effect on infection rates and outcomes. The studies considered, however, were very different and heterogeneity was high, especially for mortality criteria. OBJECTIVE: To compare outcome for current statin users and nonusers hospitalized with fever, under pragmatic circumstances. DESIGN: Prospective cohort study. SETTING: University Hospital of Brest (France). PARTICIPANTS: Febrile (>38 degrees C) patients older than 40 years, admitted to the hospital on an emergency basis in 2005. Patients' outcome was compared according to their exposure to statins (current user or nonuser). MAIN OUTCOME MEASURES: Mortality, length of hospitalization, admission to ICU and to convalescent homes RESULTS: Of 40 343 patients referred for admission by the emergency department in 2005, 964 patients older than 40 years had a fever higher than 38 degrees C and were included in the study. Statin-user status, however, was available for only 921. The ICU admission rate (relative risk: 4.69; 95% CI: 2.42-9.08) was significantly higher (p=0.009) among statin users (n=139) than nonusers (n=782). The groups had similar lengths of hospitalization and similar rates of mortality and of convalescent home admissions. CONCLUSION: Our study does not confirm that statin use affects infection outcome and suggests that previous findings may be associated instead with more cautious care or nonspecific cardiovascular prevention rather than with a specific infection-related effect. Thus, these data support the continuation of statin therapy during physiological aggression, including infection.