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Antiphospholipid syndrome: advances in diagnosis, pathogenesis, and management
AbstractAntiphospholipid syndrome (APS) is a thrombo-inflammatory disease propelled by circulating autoantibodies that recognize cell surface phospholipids and phospholipid binding proteins. The result is an increased risk of thrombotic events, pregnancy morbidity, and various other autoimmune and inflammatory complications. Although antiphospholipid syndrome was first recognized in patients with lupus, the stand alone presentation of antiphospholipid syndrome is at least equally common. Overall, the diagnosis appears to affect at least one in 2000 people. Studies of antiphospholipid syndrome pathogenesis have long focused on logical candidates such as coagulation factors, endothelial cells, and platelets. Recent work has shed light on additional potential therapeutic targets within the innate immune system, including the complement system and neutrophil extracellular traps. Vitamin K antagonists remain the mainstay of treatment for most patients with thrombotic antiphospholipid syndrome and, based on current data, appear superior to the more targeted direct oral anticoagulants. The potential role of immunomodulatory treatments in antiphospholipid syndrome management is receiving increased attention. As for many systemic autoimmune diseases, the most important future direction is to more precisely identify mechanistic drivers of disease heterogeneity in pursuit of unlocking personalized and proactive treatments for patients.
Journal Article
Placenta Accreta Spectrum
Placenta accreta spectrum (abnormal adherence of the placental trophoblast to the uterine myometrium) is increasingly common. Previous cesarean delivery is a risk factor. Management generally involves planned preterm cesarean hysterectomy with the placenta left in situ.
Journal Article
Whole-genome sequencing analysis in families with recurrent pregnancy loss: A pilot study
One to two percent of couples suffer recurrent pregnancy loss and over 50% of the cases are unexplained. Whole genome sequencing (WGS) analysis has the potential to identify previously unrecognized causes of pregnancy loss, but few studies have been performed, and none have included DNA from families including parents, losses, and live births. We conducted a pilot WGS study in three families with unexplained recurrent pregnancy loss, including parents, healthy live births, and losses, which included an embryonic loss (<10 weeks’ gestation), fetal deaths (10–20 weeks’ gestation) and stillbirths (≥ 20 weeks’ gestation). We used the Illumina platform for WGS and state-of-the-art protocols to identify single nucleotide variants (SNVs) following various modes of inheritance. We identified 87 SNVs involving 75 genes in embryonic loss (n = 1), 370 SNVs involving 228 genes in fetal death (n = 3), and 122 SNVs involving 122 genes in stillbirth (n = 2). Of these, 22 de novo , 6 inherited autosomal dominant and an X-linked recessive SNVs were pathogenic (probability of being loss-of-function intolerant >0.9), impacting known genes (e.g., DICER1 , FBN2 , FLT4 , HERC1 , and TAOK1 ) involved in embryonic/fetal development and congenital abnormalities. Further, we identified inherited missense compound heterozygous SNVs impacting genes (e.g., VWA5B2 ) in two fetal death samples. The variants were not identified as compound heterozygous SNVs in live births and population controls, providing evidence for haplosufficient genes relevant to pregnancy loss. In this pilot study, we provide evidence for de novo and inherited SNVs relevant to pregnancy loss. Our findings provide justification for conducting WGS using larger numbers of families and warrant validation by targeted sequencing to ascertain causal variants. Elucidating genes causing pregnancy loss may facilitate the development of risk stratification strategies and novel therapeutics.
Journal Article
Recurrent Miscarriage
This article reviews current evaluation and management strategies for recurrent miscarriage and highlights both the lack of good evidence to support several interventions used in practice and the relatively high rate of subsequent live birth without intervention.
Foreword
This
Journal
feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the authors' clinical recommendations.
Stage
A 32-year-old woman presents for evaluation after three consecutive miscarriages. Before these miscarriages, she had one successful pregnancy. The patient reports no medical problems or previous surgeries. In her first miscarriage, uterine bleeding and cramping started in the 7th week of gestation, and an ultrasonographic evaluation showed an empty gestational sac of 6 weeks' size. In her next pregnancy, she presented with a miscarriage in the 8th week. The third miscarriage was identified by ultrasonographic testing as a dead embryo measuring 7.5 weeks' size. How should her case be evaluated and managed?
The Clinical Problem
Miscarriage is the spontaneous . . .
Journal Article
Mutations in Complement Regulatory Proteins Predispose to Preeclampsia: A Genetic Analysis of the PROMISSE Cohort
Pregnancy in women with systemic lupus erythematosus (SLE) or antiphospholipid antibodies (APL Ab)--autoimmune conditions characterized by complement-mediated injury--is associated with increased risk of preeclampsia and miscarriage. Our previous studies in mice indicate that complement activation targeted to the placenta drives angiogenic imbalance and placental insufficiency.
We use PROMISSE, a prospective study of 250 pregnant patients with SLE and/or APL Ab, to test the hypothesis in humans that impaired capacity to limit complement activation predisposes to preeclampsia. We sequenced genes encoding three complement regulatory proteins--membrane cofactor protein (MCP), complement factor I (CFI), and complement factor H (CFH)--in 40 patients who had preeclampsia and found heterozygous mutations in seven (18%). Five of these patients had risk variants in MCP or CFI that were previously identified in atypical hemolytic uremic syndrome, a disease characterized by endothelial damage. One had a novel mutation in MCP that impairs regulation of C4b. These findings constitute, to our knowledge, the first genetic defects associated with preeclampsia in SLE and/or APL Ab. We confirmed the association of hypomorphic variants of MCP and CFI in a cohort of non-autoimmune preeclampsia patients in which five of 59 were heterozygous for mutations.
The presence of risk variants in complement regulatory proteins in patients with SLE and/or APL Ab who develop preeclampsia, as well as in preeclampsia patients lacking autoimmune disease, links complement activation to disease pathogenesis and suggests new targets for treatment of this important public health problem.
ClinicalTrials.gov NCT00198068.
Journal Article
2023 ACR/EULAR antiphospholipid syndrome classification criteria
ObjectiveTo develop new antiphospholipid syndrome (APS) classification criteria with high specificity for use in observational studies and trials, jointly supported by the American College of Rheumatology (ACR) and EULAR.MethodsThis international multidisciplinary initiative included four phases: (1) Phase I, criteria generation by surveys and literature review; (2) Phase II, criteria reduction by modified Delphi and nominal group technique exercises; (3) Phase III, criteria definition, further reduction with the guidance of real-world patient scenarios, and weighting via consensus-based multicriteria decision analysis, and threshold identification; and (4) Phase IV, validation using independent adjudicators’ consensus as the gold standard.ResultsThe 2023 ACR/EULAR APS classification criteria include an entry criterion of at least one positive antiphospholipid antibody (aPL) test within 3 years of identification of an aPL-associated clinical criterion, followed by additive weighted criteria (score range 1–7 points each) clustered into six clinical domains (macrovascular venous thromboembolism, macrovascular arterial thrombosis, microvascular, obstetric, cardiac valve, and hematologic) and two laboratory domains (lupus anticoagulant functional coagulation assays, and solid-phase enzyme-linked immunosorbent assays for IgG/IgM anticardiolipin and/or IgG/IgM anti–β2-glycoprotein I antibodies). Patients accumulating at least three points each from the clinical and laboratory domains are classified as having APS. In the validation cohort, the new APS criteria vs the 2006 revised Sapporo classification criteria had a specificity of 99% vs 86%, and a sensitivity of 84% vs 99%.ConclusionThese new ACR/EULAR APS classification criteria were developed using rigorous methodology with multidisciplinary international input. Hierarchically clustered, weighted, and risk-stratified criteria reflect the current thinking about APS, providing high specificity and a strong foundation for future APS research.
Journal Article
Low frequency of flares during pregnancy and post-partum in stable lupus patients
Background
Lupus patients are at risk for pregnancy loss, and it has been generally accepted that women with SLE should have low disease activity prior to conception. However, there are conflicting results regarding the effect of pregnancy on SLE flares. This study aims to identify predictors of flares during and after pregnancy in SLE patients with inactive or stable disease activity during the first trimester and to characterize and estimate the frequency of post-partum flares in these patients.
Methods
SLE patients in the multicenter, prospective PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus) study were evaluated for flares during and after pregnancy using the SELENA-SLEDAI Flare Index. Flares during pregnancy were assessed in all 384 patients and post-partum flares in 234 patients with study visits 2–6 months post-partum. Logistic regression models were fit to the data to identify independent risk factors for flare.
Results
During pregnancy, 20.8% of patients had mild/moderate flares and 6.25% had severe. Post-partum, 27.7% of patients had mild/moderate flares and 1.7% had severe. The mild flares rarely required treatment. Younger age, low C4 and higher PGA at baseline were independently associated with higher risk of having at least one mild/moderate or severe flare during pregnancy. Older patients were at decreased risk of flare, as well as those with quiescent disease at baseline. No variables evaluated at baseline or the visit most proximal to delivery was significantly associated with risk of flare post-partum. Medications were not associated with flare during or after pregnancy.
Conclusion
In patients with inactive or stable mild disease activity at the time of conception, lupus disease flares during and after pregnancy are typically mild and occur at similar rates. Flares during pregnancy are predicted by the patients’ age and clinical and serological activity at baseline.
Journal Article
Complement activation predicts adverse pregnancy outcome in patients with systemic lupus erythematosus and/or antiphospholipid antibodies
ObjectiveStudies in mouse models implicate complement activation as a causative factor in adverse pregnancy outcomes (APOs). We investigated whether activation of complement early in pregnancy predicts APOs in women with systemic lupus erythematosus (SLE) and/or antiphospholipid (aPL) antibodies.MethodsThe PROMISSE Study enrolled pregnant women with SLE and/or aPL antibodies (n=487) and pregnant healthy controls (n=204) at <12 weeks gestation and evaluated them monthly. APOs were: fetal/neonatal death, preterm delivery <36 weeks because of placental insufficiency or preeclampsia and/or growth restriction <5th percentile. Complement activation products were measured on serial blood samples obtained at each monthly visit.ResultsAPO occurred in 20.5% of SLE and/or aPL pregnancies. As early as 12–15 weeks, levels of Bb and sC5b-9 were significantly higher in patients with APOs and remained elevated through 31 weeks compared with those with normal outcomes. Moreover, Bb and sC5b-9 were significantly higher in patients with SLE and/or aPL without APOs compared with healthy controls. In logistic regression analyses, Bb and sC5b-9 at 12–15 weeks remained significantly associated with APO (ORadj=1.41 per SD increase; 95% CI 1.06 to 1.89; P=0.019 and ORadj=1.37 per SD increase; 95% CI 1.05 to 1.80; P=0.022, respectively) after controlling for demographic and clinical risk factors for APOs in PROMISSE. When analyses were restricted to patients with aPL (n=161), associations between Bb at 12–15 weeks and APOs became stronger (ORadj=2.01 per SD increase; 95% CI 1.16 to 3.49; P=0.013).ConclusionIn pregnant patients with SLE and/or aPL, increased Bb and sC5b-9 detectable early in pregnancy are strongly predictive of APOs and support activation of complement, particularly the alternative pathway, as a contributor to APOs.
Journal Article
Codeine and promethazine: Exploratory study on “lean” or “sizzurp” using national survey data and an online forum
The concoction known as \"lean\" containing codeine and promethazine, holds a prominent cultural presence and is often referenced in mass media platforms (e.g., music and social media). Surprisingly, there's a scarcity of national data characterizing the use of lean. Therefore, the current study investigated the use of lean using national survey data and online forum participant input, and focused on identifying concurrent substance use, exploring co-administration with other substances (e.g., alcohol, cannabis), and determining lean-related experiences.
We analyzed data from the National Survey on Drug Use and Health (NSDUH) spanning 2007-2019, identifying persons who used lean (weighted N = 42,275). Additionally, we conducted a Reddit-based study to gather insights about lean consumtion (N = 192).
The NSDUH data indicated that lean use was most prevalent among teenagers and young adults (ages 13-21), accounting for 66% of the sample. This trend was more pronounced in male respondents (75%) compared to females. Additionally, the use was predominantly observed among Black/African American (29%), Hispanic (28%), and White (33%) populations, with these groups also reporting higher levels of concurrent alcohol and cannabis use. Similarly, findings from Reddit showed that individuals who used lean were predominantly male (67%) and exhibited elevated concurrent rates of alcohol (83%) and cannabis (46%) use in the past 30 days. Moreover, approximately 66% of respondents met criteria for severe lean use disorder, and 37% acknowledged driving under its influence.
The NSDUH data found that mostly young adult males reported consuming lean in the past twelve months, though the racial/ethnic breakdown of persons who used lean was diverse. The Reddit data found that most individuals in the sample met the criteria for a substance use disorder pertaining to their lean consumption. These findings underscore the clinical significance and necessity for further controlled research on lean.
Journal Article