Intertwin Membrane Perforation and Umbilical Cord Entanglement after Laser Surgery for Twin-Twin Transfusion Syndrome: Prevalence, Risk Factors, and Outcome.

INTRODUCTION: Perforation of the intertwin membrane can occur as a complication of fetoscopic laser surgery for twin-twin transfusion syndrome (TTTS). Data on the occurrence and the risk of subsequent cord entanglement are limited. The objective of this study was to assess the prevalence, risk factors and outcome of intertwin membrane perforation, and cord entanglement after laser surgery for TTTS. METHODS: In this multicenter retrospective study, we included all TTTS pregnancies treated with laser surgery in two fetal therapy centers, Shanghai (China) and Leiden (the Netherlands) between 2002 and 2020. We evaluated the occurrence of intertwin membrane perforation and cord entanglement after laser, based on routine fortnightly ultrasound examination and investigated the risk factors and the association with adverse short- and long-term outcomes. RESULTS: Perforation of the intertwin membrane occurred in 118 (16%) of the 761 TTTS pregnancies treated with laser surgery and was followed by cord entanglement in 21% (25/118). Perforation of the intertwin membrane was associated with higher laser power settings, 45.8 Watt versus 42.2 Watt (p = 0.029) and a second fetal surgery procedure 17% versus 6% (p < 0.001). The group with intertwin membrane perforation had a higher rate of caesarean section (77% vs. 31%, p < 0.001) and a lower gestational age at birth (30.7 vs. 33.3 weeks of gestation, p < 0.001) compared to the group with an intact intertwin membrane. Severe cerebral injury occurred more often in the group with intertwin membrane perforation, 9% (17/185) versus 5% (42/930), respectively (p = 0.019). Neurodevelopmental outcome at 2 years of age was similar between the groups with and without perforation of the intertwin membrane and between the subgroups with and without cord entanglement. CONCLUSION: Perforation of the intertwin membrane after laser occurred in 16% of TTTS cases treated with laser and led to cord entanglement in at least 1 in 5 cases. Intertwin membrane perforation was associated with a lower gestational age at birth and a higher rate of severe cerebral injury in surviving neonates.

Traditional and Disease-Specific Risk Factors for Cardiovascular Events in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Multinational Retrospective Study.

OBJECTIVE: To investigate the occurrence of cardiovascular events (CVEs) in a large cohort of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) across the European Union, China, Turkey, Russia, the United Kingdom, and the USA. METHODS: Patients with a definite diagnosis of AAV who were followed for ≥ 3 months and had sufficient documentation were included. Data on myocardial infarction (MI) and stroke were collected retrospectively from tertiary vasculitis centers. Univariate and multivariate Cox regression models were used to estimate hazard ratios (HRs) and 95% CIs. RESULTS: Over a median follow-up of 62.0 months (IQR 22.6-100.0), CVEs (mostly MIs) occurred in 245 (10.7%) of 2286 patients with AAV, with a higher frequency in China and the UK. On multivariate regression analysis, older age (55-64.9 yrs, HR 2.93, 95% CI 1.99-4.31), smoking (HR 1.98, 95% CI 1.48-2.64), Chinese origin (HR 4.24, 95% CI 3.07-5.85), and pulmonary (HR 1.50, 95% CI 1.09-2.06) and kidney (HR 3.02, 95% CI 2.08-4.37) involvement were independent variables associated with a higher occurrence of CVEs. CONCLUSION: We showed that geographic region and both traditional and disease-specific (kidney involvement in particular) factors were independently associated with CVEs. Proper assessment and management of modifiable cardiovascular (CV) risk factors are essential for prevention of CV morbidity in patients with AAV.

Association of venous thromboembolic events with skin, pulmonary and kidney involvement in ANCA-associated vasculitis: a multinational study.

OBJECTIVE: To investigate the occurrence of venous thromboembolic events (VTE) in a large cohort of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) across the European Union, Turkey, Russia, UK and North America. METHODS: Patients with a definite diagnosis of AAV who were followed for at least 3 months and had sufficient documentation were included. Data on VTE, including either deep vein thrombosis or pulmonary embolism, were collected retrospectively from tertiary vasculitis centres. Univariate and multivariate regression models were used to estimate odds ratios (ORs) and 95% CIs. RESULTS: Over a median follow-up of 63 (interquartile range: 29, 101) months, VTE occurred in 278 (9.7%) of 2869 AAV patients with a similar frequency across different countries (from 6.3% to 13.7%), and AAV subtype [granulomatosis with polyangiitis: 9.8% (95% CI: 8.3, 11.6%); microscopic polyangiitis: 9.6% (95% CI: 7.9, 11.4%); and eosinophilic granulomatosis with polyangiitis: 9.8% (95% CI: 7.0, 13.3%)]. Most VTE (65.6%) were reported in the first-year post-diagnosis. Multiple factor logistic regression analysis adjusted for sex and age showed that skin (OR 1.71, 95% CI: 1.01, 2.92), pulmonary (OR 1.78, 95% CI: 1.04, 3.14) and kidney [eGFR 15-60 ml/min/1.73 m2, OR 2.86 (95% CI: 1.27, 6.47); eGFR <15 ml/min/1.73 m2, OR 6.71 (95% CI: 2.94, 15.33)] involvement were independent variables associated with a higher occurrence of VTE. CONCLUSION: Two-thirds of VTE occurred during the initial phase of active disease. We confirmed previous findings from smaller studies that a decrease in kidney function, skin involvement and pulmonary disease are independently associated with VTE.

Developments in the Histopathological Classification of ANCA-Associated Glomerulonephritis.

BACKGROUND AND OBJECTIVES: The histopathologic classification for ANCA-associated GN distinguishes four classes on the basis of patterns of injury. In the original validation study, these classes were ordered by severity of kidney function loss as follows: focal, crescentic, mixed, and sclerotic. Subsequent validation studies disagreed on outcomes in the crescentic and mixed classes. This study, driven by the original investigators, provides several analyses in order to determine the current position of the histopathologic classification of ANCA-associated GN. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A validation study was performed with newly collected data from 145 patients from ten centers worldwide, including an analysis of interobserver agreement on the histopathologic evaluation of the kidney biopsies. This study also included a meta-analysis on previous validation studies and a validation of the recently proposed ANCA kidney risk score. RESULTS: The validation study showed that kidney failure at 10-year follow-up was significantly different between the histopathologic classes (P<0.001). Kidney failure at 10-year follow-up was 14% in the crescentic class versus 20% in the mixed class (P=0.98). In the meta-analysis, no significant difference in kidney failure was also observed when crescentic class was compared with mixed class (relative risk, 1.15; 95% confidence interval, 0.94 to 1.41). When we applied the ANCA kidney risk score to our cohort, kidney survival at 3 years was 100%, 96%, and 77% in the low-, medium-, and high-risk groups, respectively (P<0.001). These survival percentages are higher compared with the percentages in the original study. CONCLUSIONS: The crescentic and mixed classes seem to have a similar prognosis, also after adjusting for differences in patient populations, treatment, and interobserver agreement. However, at this stage, we are not inclined to merge the crescentic and mixed classes because the reported confidence intervals do not exclude important differences in prognosis and because an important histopathologic distinction would be lost.

Genetic Variants in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Bayesian Approach and Systematic Review.

A number of genome-wide association studies (GWASs) and meta-analyses of genetic variants have been performed in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. We reinterpreted previous studies using false-positive report probability (FPRP) and Bayesian false discovery probability (BFDP). This study searched publications in PubMed and Excerpta Medica Database (EMBASE) up to February 2018. Identification of noteworthy associations were analyzed using FPRP and BFDP, and data (i.e., odds ratio (OR), 95% confidence interval (CI), p-value) related to significant associations were separately extracted. Using filtered gene variants, gene ontology (GO) enrichment analysis and protein⁻protein interaction (PPI) networks were performed. Overall, 241 articles were identified, and 7 were selected for analysis. Single nucleotide polymorphisms (SNPs) discovered by GWASs were shown to be noteworthy, whereas only 27% of significant results from meta-analyses of observational studies were noteworthy. Eighty-five percent of SNPs with borderline p-values (5.0 × 10-8 < p < 0.05) in GWASs were found to be noteworthy. No overlapping SNPs were found between PR3-ANCA and MPO-ANCA vasculitis. GO analysis revealed immune-related GO terms, including "antigen processing and presentation of peptide or polysaccharide antigen via major histocompatibility complex (MHC) class II", "interferon-gamma-mediated (IFN-γ) signaling pathway". By using FPRP and BFDP, network analysis of noteworthy genetic variants discovered genetic risk factors associated with the IFN-γ pathway as novel mechanisms potentially implicated in the complex pathogenesis of ANCA-associated vasculitis.

Incidence of Malignancy Prior to Antineutrophil Cytoplasmic Antibody-associated Vasculitis Compared to the General Population.

OBJECTIVE: Previous studies have reported an increased malignancy risk preceding antineutrophil cytoplasmic antibody-associated vasculitis (AAV), suggesting common pathogenic pathways in these 2 entities. However, the study results were conflicting and often limited to patients with granulomatosis with polyangiitis (GPA). Here, we study the malignancy risk prior to AAV diagnosis [either GPA or microscopic polyangiitis (MPA)] to elaborate on the putative association between malignancy and AAV. METHODS: A total of 203 patients were selected for the current study. Malignancies prior to AAV diagnosis were identified using a nationwide pathology database, and their occurrence was verified by reviewing the medical files of 145 patients (71.4%). The malignancy incidence was compared to the general population by calculation of standardized incidence ratios (SIR), matching for sex, age, and time period. SIR were calculated for 2 intervals: < 2 years and ≥ 2 years prior to AAV diagnosis. Separate analyses were performed for GPA and MPA. RESULTS: The overall risk for malignancy prior to AAV diagnosis was similar to that of the general population (SIR 0.96, 95% CI 0.55-1.57), as was true when risks were analyzed by malignancy type, including skin, bladder, kidney, lung, stomach, rectum, and uterus (SIR ranged from 1.64 to 4.14). We found no significant difference in malignancy risk between patients with GPA and MPA. CONCLUSION: Our findings do not support the hypothesis that preceding malignancies and AAV have a causal relationship or shared pathogenic pathways.

Effect of rituximab on malignancy risk in patients with ANCA-associated vasculitis.

OBJECTIVES: Patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treated with cyclophosphamide have an increased malignancy risk compared with the general population. We investigated whether treatment with rituximab instead of cyclophosphamide has decreased the malignancy risk in patients with AAV. METHODS: The study included patients with AAV treated at a tertiary vasculitis referral centre between 2000 and 2014. The malignancy incidence in these patients was compared with the incidence in the general population by calculating standardised incidence ratios (SIRs), adjusted for sex, age and calendar year. Malignancy incidence was compared between rituximab-treated and cyclophosphamide-treated patients. RESULTS: Of the 323 included patients, 33 developed a total of 45 malignancies during a mean follow-up of 5.6 years. This represented a 1.89-fold increased (95% CI 1.38 to 2.53) malignancy risk, and a non-significantly increased risk if non-melanoma skin cancer was excluded (SIR, 1.09; 95% CI 0.67 to 1.69). The risk of non-melanoma skin cancer was 4.58-fold increased (95% CI 2.96 to 6.76). Cyclophosphamide-treated patients had an increased malignancy risk compared with the general population (SIR, 3.10; 95% CI 2.06 to 4.48). In contrast, rituximab-treated patients had a malignancy risk similar to the general population (SIR, 0.67; 95% CI 0.08 to 2.43). The malignancy risk in cyclophosphamide-treated patients was 4.61-fold higher (95% CI 1.16 to 39.98) than in rituximab-treated patients. CONCLUSIONS: The malignancy risk in patients with AAV was lower in rituximab-treated patients than in cyclophosphamide-treated patients. Notably, rituximab treatment was not associated with an increased malignancy risk compared with the general population. Rituximab could therefore be a safe alternative to cyclophosphamide in the treatment of AAV.

Genetic variants in ANCA-associated vasculitis: a meta-analysis.

BACKGROUND: Genetic factors may influence the pathogenic pathways leading to antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We performed a meta-analysis to determine the genetic variants most likely associated with AAV and investigated whether diagnostic and serological subtypes within AAV have distinct genetic backgrounds. METHODS: Studies investigating the association between genetic variants and AAV in humans were searched in PubMed, EMBASE and Web of Science. All variants investigated in at least two studies were selected. Subsequently, all studies assessing these variants were included in this meta-analysis. Additionally, data on these variants from the largest genome-wide association studies in AAV were included to increase the validity of this meta-analysis. RESULTS: The literature search yielded 5180 articles. 62 articles investigating 140 genetic variants were included, 33 of which were associated with AAV in a meta-analysis. These genetic variants were in or near the following genes: CD226, CTLA-4, FCGR2A, HLA-B, HLA-DP, HLA-DQ, HLA-DR, HSD17B8, IRF5, PTPN22, RING1/RXRB, RXRB, STAT4, SERPINA1 and TLR9. Moreover, we identified genetic distinctions between granulomatosis with polyangiitis and microscopic polyangiitis and between proteinase 3 ANCA vasculitis and myeloperoxidase ANCA vasculitis. In 76% of the genetic variants, subdivision based on ANCA serotype resulted in higher ORs than subdivision based on clinical diagnosis. CONCLUSIONS: This meta-analysis identified 33 genetic variants associated with AAV, supporting a role for alpha-1-antitrypsin, the major histocompatibility complex system, and several distinct inflammatory processes in AAV pathogenesis. Our results indicate that subdivision of AAV based on ANCA serotype has a stronger genetic basis than subdivision based on clinical diagnosis.

The Dutch Transplantation in Vasculitis (DUTRAVAS) Study: Outcome of Renal Transplantation in Antineutrophil Cytoplasmic Antibody-associated Glomerulonephritis.

BACKGROUND: Data on the outcome of renal transplantation in antineutrophil cytoplasmic antibody-associated glomerulonephritis (AAGN) patients are still limited. In particular, how disease recurrence in the renal allograft defines graft outcome is largely unknown. Therefore, we conducted a multicenter observational clinical and histopathological study to establish recurrence rate of AAGN in the allograft and the impact of recurrence on allograft survival. METHODS: Using the nationwide Dutch Pathology Registry (PALGA), we retrospectively collected clinical and histopathological data of consecutive AAGN patients who had developed end-stage renal failure and received a kidney allograft in 1 of 6 Dutch university hospitals between 1984 and 2011. Transplant biopsies were scored using the Banff '09 classification. Renal disease recurrence was scored using the histopathological classification of AAGN. RESULTS: The posttransplantation recurrence rate of AAGN was 2.8% per patient year, accumulating to recurrence in a total of 11 of 110 AAGN patients within the first 5 years after transplantation. Four of these 11 patients lost their graft, with 1-year and 5-year graft survival rates of 94.5% and 82.8%, respectively. By multivariate analysis, AAGN recurrence was independently associated with subsequent graft loss. CONCLUSIONS: In this study in 110 Dutch patients, the recurrence rate of AAGN within 5 years after kidney transplantation appeared slightly higher than in previous reports. Moreover, recurrence of AAGN contributed independently to kidney allograft loss, emphasizing the importance of clinical vigilance, because early treatment might be critical to rescuing the allograft.

Incidence of Malignancies in Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Diagnosed Between 1991 and 2013.

OBJECTIVE: To investigate the incidence of malignancies during longitudinal followup of patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV), and to examine the effect of immunosuppressive therapy on malignancy risk in these patients. METHODS: The study population consisted of patients with histopathologically confirmed AAV, diagnosed between 1991 and 2013 at a large university hospital. The mean duration of followup was 10 years. Malignancy incidence was assessed using the Dutch National Pathology Database. Incidence rates from the Netherlands Cancer Registry were used to compare malignancy incidence in the AAV cohort to that in the general Dutch population. RESULTS: Thirty-six of 138 patients with AAV developed a total of 85 malignancies during a mean followup of 9.7 years. The sex-, age-, and calendar year-adjusted malignancy risk was 2.21-fold higher (95% confidence interval [95% CI] 1.64-2.92) than that in the general population. Non-melanoma skin cancers occurred most frequently (standardized incidence ratio 4.23 [95% CI 2.76-6.19]). The incidence rates of other malignancies were not significantly increased. Malignancy risk was associated with the duration of cyclophosphamide (CYC) therapy and, interestingly, was not increased in patients who had received CYC for <1 year. CONCLUSION: Patients with AAV have a higher risk of malignancy than the general population, but this risk is accounted for solely by non-melanoma skin cancers. Over the years, the risk of other malignancies-specifically bladder and hematologic malignancies-has decreased in patients with AAV. This finding reflects ongoing efforts to reduce CYC exposure by developing new treatment regimens.

Renal function and ear, nose, throat involvement in anti-neutrophil cytoplasmic antibody-associated vasculitis: prospective data from the European Vasculitis Society clinical trials.

OBJECTIVE: We investigated whether ENT involvement is associated with renal biopsy findings and renal function in patients with ANCA-associated vasculitis (AAV). METHODS: Newly diagnosed AAV patients derived from three international, multicentre trials were included. To investigate an association between ENT involvement and estimated glomerular filtration rate (eGFR) at diagnosis and 5-year follow-up, we performed multivariable regression analyses including clinical and histopathological parameters. To investigate whether our findings are specific to ENT involvement, we performed comparable analyses between eGFR and other early disease manifestations (arthralgia/arthritis, cutaneous and lung involvement). RESULTS: One hundred and eighty-five of the 414 patients had ENT involvement. The mean presenting eGFR of patients with and without ENT involvement was 39.16 and 23.88 ml/min/1.73 m(2), respectively (P < 0.001). Mean eGFR increased by 6.76 ml/min/1.73 m(2) with each added ENT symptom (P = 0.007). Patients with ENT involvement had less interstitial fibrosis and tubular atrophy and a prognostically more favourable histopathological class on renal biopsy examination. Multivariable regression analyses correcting for clinical and histopathological parameters showed that ENT involvement is associated with both baseline and 5-year follow-up eGFR. There were no associations between baseline and 5-year follow-up eGFR and arthralgia/arthritis, cutaneous or lung involvement, suggesting that our findings are specific to ENT involvement. CONCLUSION: The presence of ENT involvement in AAV patients is associated with prognostically favourable renal biopsy findings and better renal function. These results indicate that there may be different phenotypes of AAV defined by ENT involvement.

Histopathological classification of antineutrophil cytoplasmic antibody-associated glomerulonephritis: an update.

PURPOSE OF REVIEW: This review discusses the findings of studies validating the histopathological classification of antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis, which was devised in 2010 by an international working group of pathologists and nephrologists in collaboration with the European Vasculitis Society. RECENT FINDINGS: So far, eight studies have validated the histopathological classification of ANCA-associated glomerulonephritis. The studies came from Japan, China, Australia, the United States, the Netherlands, and Turkey. These validation studies confirmed that the histopathological classification of ANCA-associated glomerulonephritis is of predictive value for renal outcome. This was especially the case for patients with either a focal or sclerotic-class renal biopsy, whereas the crescentic and mixed classes showed different results in the validation studies. These differences could be due to differences in patient populations or therapy, inter-rater reliability and lack of inclusion of tubulointerstitial lesions in the classification. Therapy is known to influence renal outcome, but due to the retrospective design of the to-date performed validation studies, this parameter could not be fully accounted for in these validation studies. Inter-rater reliability among three histopathologists was investigated in one study and was moderate. SUMMARY: The histopathological classification of ANCA-associated glomerulonephritis predicts renal outcome during follow-up, especially in patients with a focal or sclerotic-class renal biopsy. A large international validation study is currently being performed. VIDEO ABSTRACT: http://links.lww.com/CONH/A6.

Acute coronary syndrome with a totally occluded culprit artery: relation of the ST injury vector with ST-elevation and non-ST elevation ECGs.

BACKGROUND: In acute coronary syndrome (ACS), ST-segment elevation (STE), often associated with a completely occluded culprit artery, is an important ECG criterion for primary percutaneous coronary intervention (PCI). However, several studies showed that in ACS a completely occluded culprit artery can also occur with a non-ST-elevation (NSTE) ECG. In order to elucidate reasons for this discrepancy we examined ST injury vector orientation and magnitude in ACS patients with and without STE, all admitted for primary PCI and having a completely occluded culprit artery. METHODS: We studied the ECGs of 300 ACS patients (214/86 STE/NSTE; 228/72 single/multivessel disease) who had a completely occluded culprit artery during angiography prior to primary PCI. The J+60 injury vector orientation and magnitude were computed from Frank XYZ leads derived from the 10-s standard 12-lead ECG. RESULTS: Demographic and anthropomorphic characteristics of the STE and NSTE patients did not differ. STE patients had a higher rate of right coronary artery occlusions, and a lower rate of left circumflex occlusions than NSTE patients (43 vs. 31%, and 13 vs. 22%, respectively; P<0.05). Injury vector elevation and magnitude were larger in STE than in NSTE patients (32° ± 37° vs. 6° ± 39°, and 304 ± 145 µV vs. 134 ± 72 µV, respectively; P<0.0001). CONCLUSION: STE criteria favor certain injury vector directions and larger injury vector magnitudes. Obviously, several ACS patients with complete culprit artery occlusions requiring primary PCI do not fulfill these criteria. Our study suggests that STE-NSTE-based ACS stratification needs further enhancement.

Role of the vectorcardiogram-derived spatial QRS-T angle in diagnosing left ventricular hypertrophy.

INTRODUCTION: Current criteria for electrocardiographic (ECG) diagnosis of left ventricular hypertrophy (LVH) have a low diagnostic accuracy. Addition of demographic, anthropomorphic, and additional ECG variables may improve accuracy. As hypertrophy affects action potential morphology and intraventricular conduction, QRS prolongation and T-wave morphology may occur and become manifest in the vectorcardiographic variables spatial QRS-T angle (SA) and spatial ventricular gradient. In this study, we attempted to improve the diagnostic accuracy for LVH by using a combination of demographic, anthropomorphic, ECG, and vectorcardiographic variables. METHODS: The study group (n = 196) was divided in 4 subgroups with, on one hand, echocardiographically diagnosed LVH or a normal echocardiogram and, on the other hand, with any of the conventional ECG signs for LVH or with normal ECGs. Each subgroup was randomly split into halves, yielding 2 equally-sized (n = 98) data sets A and B. Age, sex, height, weight, body mass index, body surface area (BSA), frontal QRS axis, QRS duration, QT duration, maximal QRS vector magnitude, SA, and ventricular gradient magnitude and orientation were univariate studied by receiver operating characteristic analysis and were used to build a stepwise linear discriminant model using P < .05 as entry and P > .10 as removal criterion. The discriminant model was built in set A (model A) and tested on set B. Stability checks were done by building a discriminant model on set B and testing on set A and by cross-validation analysis in the complete study group. RESULTS: The discriminant model equation was D = 5.130 × BSA - 0.014 × SA - 8.74, wherein D greater than or equal to 0 predicts a normal echocardiogram and D less than 0 predicts LVH. The diagnostic accuracy (79%) was better than the diagnostic accuracy of conventional ECG criteria for LVH (57%). CONCLUSION: The combination of BSA and SA yields a diagnostic accuracy of LVH that is superior to that of the conventional ECG criteria.