Defining remission in childhood-onset lupus: PReS-endorsed consensus definitions by an international task force.

OBJECTIVE: To derive childhood-onset SLE (cSLE) specific remission definitions for future treat-to-target (T2T) trials, observational studies, and clinical practice. METHODS: The cSLE International T2T Task Force conducted Delphi surveys exploring paediatric perspectives on adult-onset SLE remission targets. A modified nominal group technique was used to discuss, refine, and agree on the cSLE remission target criteria. RESULTS: The Task Force proposed two definitions of remission: 'cSLE clinical remission on steroids (cCR)' and 'cSLE clinical remission off steroids (cCR-0)'. The common criteria are: (1) Clinical-SLEDAI-2 K = 0; (2) PGA score < 0.5 (0-3 scale); (4) stable antimalarials, immunosuppressive, and biologic therapy (changes due to side-effects, adherence, weight, or when building up to target dose allowed). Criterion (3) in cCR is the prednisolone dose ≤0.1 mg/kg/day (maximum 5 mg/day), whereas in cCR-0 it is zero. CONCLUSIONS: cSLE definitions of remission have been proposed, maintaining sufficient alignment with the adult-SLE definition to facilitate life-course research.

Increasing trends in a low 5-min Apgar score among (near) term singletons: a Dutch nationwide cohort study.

OBJECTIVE: To investigate trends in low Apgar scores in (near) term singletons using the Dutch Perinatal Registry. METHODS: In a cohort of 1,583,188 singletons liveborn ≥35 weeks of gestation in the period 2010-2019, we studied trends in low 5-min Apgar scores (<7 and <4) using Cochrane Armitage trend tests. RESULTS: The proportion of infants with low Apgar scores <7 and <4 increased significantly between 2010-2019 (1.04-1.42% (p < 0.001), 0.17-0.19% (p = 0.009), respectively). Neonatal mortality remained unchanged. Induction of labour, epidural analgesia and planned caesarean section showed an increasing trend. Instrumental vaginal delivery and emergency caesarean section were performed less frequently over time, but these intervention subgroups showed the highest relative increase in infants with low Apgar scores. CONCLUSIONS: In the Netherlands, the risk of a low 5-min Apgar score increased over the last decade. The highest relative increase was observed in subgroups of instrumental vaginal delivery and emergency caesarean section.

Risk indicators for obstetrical anal sphincter injury in vaginal birth after caesarean section compared to first vaginal delivery.

OBJECTIVES: Comparison of the rate of obstetric anal sphincter injury (OASI) between women having their first vaginal birth after caesarean section (CS) and true nulliparous women with a vaginal delivery. Assessment of risk indicators for OASI in women with vaginal birth after one CS (VBAC). STUDY DESIGN: 28 535 women with their first VBAC and a cohort of 275 439 nulliparous women with a vaginal delivery of a liveborn infant in a cephalic position from the Dutch perinatal registry were analyzed. We compared the OASI rate with univariate and multivariate analysis. In women with VBAC possible risk indicators for OASI were assessed using univariate and multivariate logistic regression analysis. RESULTS: The rate of OASI was 5.2% in women with vaginal birth after CS and 4.0% in women with a first vaginal delivery. The adjusted OR (aOR) for vaginal birth after an elective CS was higher (aOR 1.34, 95% CI 1.23-1.47) compared to vaginal birth after an emergency CS (aOR 1.16, 95% CI 1.08-1.25). In women with vaginal birth after emergency CS, the aOR for the indication non-progressive labor was 1.18 (95% CI 1.08-1.29), whereas CS for suspected fetal distress was not significantly associated with obstetric anal sphincter injury in VBAC. In the 28 535 women with a VBAC, mediolateral episiotomy (MLE), birth weight < 3000 g and maternal age < 25 years were associated with a significantly lower rate of OASI. A gestational age of 42 weeks, birth weight ≥ 3500 g, operative vaginal delivery and duration of the 2nd stage of labour of ≥ 60 min were associated with a significantly higher rate of OASI. CONCLUSIONS: Women with a VBAC have a higher rate of OASI in comparison with women with a first vaginal delivery, with the exception of women with a vaginal birth after an emergency CS for suspected fetal distress. Factors associated with a significantly lower rate for OASI were MLE, maternal age < 25 and birth weight < 3000 g. A gestational age of 42 weeks, birth weight between 3500 and 4000 g and ≥ 4000 g, operative vaginal delivery and duration of the 2nd stage of delivery longer dan 60 min were associated with a significantly higher rate of OASI.

PReS-endorsed international childhood lupus T2T task force definition of childhood lupus low disease activity state (cLLDAS).

OBJECTIVE: To achieve a consensus-based definition of Low Disease Activity (LDA) for use in cSLE trials. METHODS: The International cSLE T2T Task Force, comprising of paediatric rheumatologists/nephrologists, and adult rheumatologists undertook a series of Delphi surveys/consensus meetings to discuss, refine, and vote upon cSLE LDA criteria. RESULTS: The Task Force agreed that LDA should be based upon the adult-SLE Lupus Low Disease Activity State definition (LLDAS), with modifications to make it applicable to cSLE (cLLDAS). They agreed upon five cLLDAS criteria: (1) SLE Disease Activity Index (SLEDAI)-2 K ≤4, with no activity in major organ systems; (2) no new features of lupus disease activity compared with the last assessment; (3) Physician Global Assessment score of ≤1 (0-3 scale); (4) prednisolone dose of ≤0.15 mg/kg/day, 7.5 mg/day/maximum; while on (5) stable antimalarials, immunosuppressives, and biologics. CONCLUSIONS: A cSLE-appropriate definition of cLLDAS has been generated, maintaining alignment with the adult-SLE definition to promote life-course research.

Birth-weight centile at term and school performance at 12 years of age: linked cohort study.

OBJECTIVE: Birth weight, fetal growth and placental function influence cognitive development. The gradient of these associations is understudied, especially among those with a birth weight considered appropriate-for-gestational age. The aim of this study was to evaluate the associations between birth-weight centile and intellectual development in term/near-term infants across the entire birth-weight spectrum, in order to provide a basis for better understanding of the long-term implications of fetal growth restriction and reduced placental function. METHODS: This was a population-based cohort study of 266 440 liveborn singletons from uncomplicated pregnancies, delivered between 36 and 42 weeks of gestation. Perinatal data were obtained from the Dutch Perinatal Registry over the period 2003-2008 and educational data for children aged approximately 12 years were obtained from Statistics Netherlands over the period 2016-2019. Regression analyses were conducted to assess the association of birth-weight centile with school performance. The primary outcomes were mean school performance score, on a scale of 501-550, and proportion of children who reached higher secondary school level. RESULTS: Mean school performance score increased gradually with increasing birth-weight centile, from 533.6 in the 1st -5th birth-weight-centile group to 536.8 in the 81st -85th birth-weight-centile group. Likewise, the proportion of children at higher secondary school level increased with birth-weight centile, from 43% to 57%. Compared with the 81st -85th birth-weight-centile group, mean school performance score and proportion of children at higher secondary school level were significantly lower in all birth-weight-centile groups below the 80th centile, after adjusting for confounding factors. CONCLUSIONS: Birth-weight centile is associated positively with school performance at 12 years of age across the entire birth-weight spectrum, well beyond the conventional and arbitrary cut-offs for suspected fetal growth restriction. This underlines the importance of developing better tools to diagnose fetal growth restriction and reduced placental function, and to identify those at risk for associated short- and long-term consequences. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Distinct tumor-infiltrating lymphocyte landscapes are associated with clinical outcomes in localized non-small-cell lung cancer.

BACKGROUND: Despite the importance of tumor-infiltrating T lymphocytes (TILs) in cancer biology, the relationship between TIL phenotypes and their prognostic relevance for localized non-small-cell lung cancer (NSCLC) has not been well established. PATIENTS AND METHODS: Fresh tumor and normal adjacent tissue was prospectively collected from 150 patients with localized NSCLC. Tissue was comprehensively characterized by high-dimensional flow cytometry of TILs integrated with immunogenomic data from multiplex immunofluorescence, T-cell receptor sequencing, exome sequencing, RNA sequencing, targeted proteomics, and clinicopathologic features. RESULTS: While neither the magnitude of TIL infiltration nor specific TIL subsets were significantly prognostic alone, the integration of high-dimensional flow cytometry data identified two major immunotypes (IM1 and IM2) that were predictive of recurrence-free survival independent of clinical characteristics. IM2 was associated with poor prognosis and characterized by the presence of proliferating TILs expressing cluster of differentiation 103, programmed cell death protein 1, T-cell immunoglobulin and mucin-domain containing protein 3, and inducible T-cell costimulator. Conversely, IM1 was associated with good prognosis and differentiated by an abundance of CD8+ T cells expressing cytolytic enzymes, CD4+ T cells lacking the expression of inhibitory receptors, and increased levels of B-cell infiltrates and tertiary lymphoid structures. While increased B-cell infiltration was associated with good prognosis, the best prognosis was observed in patients with tumors exhibiting high levels of both B cells and T cells. These findings were validated in patient tumors from The Cancer Genome Atlas. CONCLUSIONS: Our study suggests that although the number of infiltrating T cells is not associated with patient survival, the nature of the infiltrating T cells, resolved in distinct TIL immunotypes, is prognostically relevant in NSCLC and may inform therapeutic approaches to clinical care.

Effect of parental and ART treatment characteristics on perinatal outcomes.

STUDY QUESTION: Do parental characteristics and treatment with ART affect perinatal outcomes in singleton pregnancies? SUMMARY ANSWER: Both parental and ART treatment characteristics affect perinatal outcomes in singleton pregnancies. WHAT IS KNOWN ALREADY: Previous studies have shown that singleton pregnancies resulting from ART are at risk of preterm birth. ART children are lighter at birth after correction for duration of gestation and at increased risk of congenital abnormalities compared to naturally conceived children. This association is confounded by parental characteristics that are also known to affect perinatal outcomes. It is unclear to which extent parental and ART treatment characteristics independently affect perinatal outcomes. STUDY DESIGN, SIZE, DURATION: All IVF clinics in the Netherlands (n = 13) were requested to provide data on all ART treatment cycles (IVF, ICSI and frozen-thawed embryo transfers (FET)), performed between 1 January 2000, and 1 January 2011, which resulted in a pregnancy. Using probabilistic data-linkage, these data (n = 36 683) were linked to the Dutch Perinatal Registry (Perined), which includes all children born in the Netherlands in the same time period (n = 2 548 977). PARTICIPANTS/MATERIALS, SETTING, METHODS: Analyses were limited to singleton pregnancies that resulted from IVF, ICSI or FET cycles. Multivariable models for linear and logistic regression were fitted including parental characteristics as well as ART treatment characteristics. Analyses were performed separately for fresh cycles and for fresh and FET cycles combined. We assessed the impact on the following perinatal outcomes: birth weight, preterm birth below 37 or 32 weeks of gestation, congenital malformations and perinatal mortality. MAIN RESULTS AND THE ROLE OF CHANCE: The perinatal outcomes of 31 184 out of the 36 683 ART treatment cycles leading to a pregnancy were retrieved through linkage with the Perined (85% linkage). Of those, 23 671 concerned singleton pregnancies resulting from IVF, ICSI or FET. Birth weight was independently associated with both parental and ART treatment characteristics. Characteristics associated with lower birth weight included maternal hypertensive disease, non-Dutch maternal ethnicity, nulliparity, increasing duration of subfertility, hCG for luteal phase support (compared to progesterone), shorter embryo culture duration, increasing number of oocytes retrieved and fresh embryo transfer. The parental characteristic with the greatest effect size on birth weight was maternal diabetes (adjusted difference 283 g, 95% CI 228-338). FET was the ART treatment characteristic with the greatest effect size on birth weight (adjusted difference 100 g, 95% CI 84-117) compared to fresh embryo transfer. Preterm birth was more common among mothers of South-Asian ethnicity. Preterm birth was less common among multiparous women and women with 'male factor' as treatment indication (compared to 'tubal factor'). LIMITATIONS, REASONS FOR CAUTION: Due to the retrospective nature of our study, we cannot prove causality. Further limitations of our study were the inability to adjust for mothers giving birth more than once in our dataset, missing values for several variables and limited information on parental lifestyle and general health. WIDER IMPLICATIONS OF THE FINDINGS: Multiple parental and ART treatment characteristics affect perinatal outcomes, with birth weight being influenced by the widest range of factors. This highlights the importance of assessing both parental and ART treatment characteristics in studies that focus on the health of ART-offspring, with the purpose of modifying these factors where possible. Our results further support the hypothesis that the embryo is sensitive to its early environment. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by Foreest Medical School, Alkmaar, the Netherlands (grants: FIO 1307 and FIO 1505). B.W.M. reports grants from NHMRC and consultancy for ObsEva, Merck KGaA, iGenomics and Guerbet. F.B. reports research support grants from Merck Serono and personal fees from Merck Serono. A.C. reports travel support from Ferring BV. and Theramex BV. and personal fees from UpToDate (Hyperthecosis), all outside the remit of the current work. The remaining authors report no conflict of interests. TRIAL REGISTRATION NUMBER: N/A.

H-Ferritin-nanocaged olaparib: a promising choice for both BRCA-mutated and sporadic triple negative breast cancer.

Poly(ADP-ribose) polymerase (PARP) inhibitors represent a promising strategy toward the treatment of triple-negative breast cancer (TNBC), which is often associated to genomic instability and/or BRCA mutations. However, clinical outcome is controversial and no benefits have been demonstrated in wild type BRCA cancers, possibly due to poor drug bioavailability and low nuclear delivery. In the attempt to overcome these limitations, we have developed H-Ferritin nanoformulated olaparib (HOla) and assessed its anticancer efficacy on both BRCA-mutated and non-mutated TNBC cells. We exploited the natural tumor targeting of H-Ferritin, which is mediated by the transferrin receptor-1 (TfR1), and its physiological tropism toward cell nucleus. TNBC cell lines over-expressing TfR-1 were successfully recognized by H-Ferritin, displaying a fast internalization into the cells. HOla induced remarkable cytotoxic effect in cancer cells, exhibiting 1000-fold higher anticancer activity compared to free olaparib (Ola). Accordingly, HOla treatment enhanced PARP-1 cleavage, DNA double strand breaks and Ola delivery into the nuclear compartment. Our findings suggest that H-Ferritin nanoformulation strongly enhances cytotoxic efficacy of Ola as a stand-alone therapy in both BRCA-mutated and wild type TNBC cells, by promoting targeted nuclear delivery.

Prediction of Time to Delivery Week-by-Week in Women with a Triplet Pregnancy.

Objective Some clinicians advise prophylactic administration of antenatal steroids for fetal lung maturation in women with a triplet pregnancy. However, the effect of corticosteroids is limited to 10 to 14 days after administration. The aim of this study was to assess the natural course of triplet pregnancies to allow a better anticipation for administration of corticosteroids. Study Design We collected data on all triplet pregnancies in the Netherlands from 1999 to 2007 from the Netherlands Perinatal Registration. We calculated time to delivery, the risk of delivery in 2-week intervals at different gestational ages, and the time frame between hospital admission and delivery of the first child. Results Median gestational age at delivery of 494 women with a triplet pregnancy was 33+4 weeks (interquartile range of 31-35+1 weeks). Twenty-one women (4.3%) delivered between 22 and 24 weeks and 146 women (29.6%) delivered before 32 weeks. At a gestational age of 24 weeks, the chance to deliver within the next week was 0.6%. For 26, 28, 30, 31, and 32 weeks, these risks were 2.4, 2.5, 8.1, 7, and 16.7%, respectively. Conclusion Before 32 weeks of gestation, prophylactic administration of steroids is not indicated as the risk to deliver within 7 days is < 10%.

Plasma endocannabinoid behaviour in total knee and hip arthroplasty.

Endocannabinoids are a class of lipid mediators involved in a wide range of physiological pathways including pain perception, and immunological defences. In particular, the involvement of endocannabinoids in bone metabolism and bone resorption has recently been studied. Moreover, one study on total knee arthroplasty describes the probable role of endocannabinoids in pain perception after surgery. The aim of the present study was to evaluate variations of endocannabinoid concentrations in patients undergoing total hip or total knee arthroplasty before and after surgery. Sera from 23 patients were collected at three different times: before surgery and at two different times during rehabilitation, and endocannabinoids were quantified by HPLC-MS/MS analysis. Mean values of endocannabinoids in presurgical serum samples were: 6.11±0.5 ng/ml for N-palmitoylethanolamide, 1.39±0.08ng/ml for N-stearoylethanolamide, 4.84±0.04 ng/ml for N-oleoylethanolamide, 0.44±0.03ng/ml for N-arachidonoylethanolamide, 0.84±0.05ng/ml for N-linoleoylethanolamide, 0.17±0.01ng/ml for N-α-linolenoylethanolamide. Statistical analysis showed a significant decrease of all the endocannabinoids after surgery, while there were no remarkable differences between total hip and total knee arthroplasties or between genders. Moreover, the results show no significant correlation between endocannabinoid concentrations and C-reactive protein and Erythrocyte sedimentation rate. The present study shows for the first time a specific and univocal behaviour of six endocannabinoids and N-acylethanolamides in orthopaedic surgery, suggesting the endocannabinoid system as a possible pharmacological target for presurgical therapeutics.

Evidence-based diagnosis and treatment of macrophage activation syndrome in systemic juvenile idiopathic arthritis.

BACKGROUND: Macrophage activation syndrome (MAS) is a severe and potentially lethal complication of several inflammatory diseases but seems particularly linked to systemic juvenile idiopathic arthritis (sJIA). Standardized diagnostic and treatment guidelines for MAS in sJIA are currently lacking. The aim of this systematic literature review was to evaluate currently available literature on diagnostic criteria for MAS in sJIA and provide an overview of possible biomarkers for diagnosis, disease activity and treatment response and recent advances in treatment. METHODS: A systematic literature search was performed in MEDLINE, EMBASE and Cochrane. 495 papers were identified. Potentially relevant papers were selected by 3 authors after which full text screening was performed. All selected papers were evaluated by at least two independent experts for validity and level of evidence according to EULAR guidelines. RESULTS: 27 papers were included: 7 on diagnosis, 9 on biomarkers and 11 on treatment. Systematic review of the literature confirmed that there are no validated diagnostic criteria for MAS in sJIA. The preliminary Ravelli criteria, with the addition of ferritin, performed well in a large retrospective case-control study. Recently, an international consortium lead by PRINTO proposed a new set of diagnostic criteria able to distinguish MAS from active sJIA and/or infection with superior performance. Other promising diagnostic biomarkers potentially distinguish MAS complicating sJIA from primary and virus-associated hemophagocytic lymphohistiocytosis. The highest level of evidence for treatment comes from case-series. High dose corticosteroids with or without cyclosporine A were frequently reported as first-line therapy. From the newer treatment modalities, promising responses have been reported with anakinra. CONCLUSION: MAS in sJIA seems to be diagnosed best by the recently proposed PRINTO criteria, although prospective validation is needed. Novel promising biomarkers for sJIA related MAS are in need of prospective validation as well, and are not widely available yet. Currently, treatment of MAS in sJIA relies more on experience than evidence based medicine. Taking into account the severity of MAS and the scarcity of evidence, early expert consultation is recommended as soon as MAS is suspected.

Intrapartum and neonatal mortality in primary midwife-led and secondary obstetrician-led care in the Amsterdam region of the Netherlands: A retrospective cohort study.

OBJECTIVE: To compare intrapartum- and neonatal mortality and intervention rates in term women starting labour in primary midwife-led versus secondary obstetrician-led care. DESIGN: Retrospective cohort study. SETTING: Amsterdam region of the Netherlands. PARTICIPANTS: Women with singleton pregnancies who gave birth beyond 37+0 weeks gestation in the years 2005 up to 2008 and lived in the catchment area of the neonatal intensive care units of both academic hospitals in Amsterdam. Women with a primary caesarean section or a pregnancy complicated by antepartum death or major congenital anomalies were excluded. For women in the midwife-led care group, a home or hospital birth could be planned. MEASUREMENTS: Analysis of linked data from the national perinatal register, and hospital- and midwifery record data. We assessed (unadjusted) relative risks with confidence intervals. Main outcome measures were incidences of intrapartum and neonatal (<28 days) mortality. Secondary outcomes included incidences of caesarean section and vaginal instrumental delivery. FINDINGS: 53,123 women started labour in primary care and 30,166 women in secondary care. Intrapartum and neonatal mortality rates were 37/53,123 (0.70‰) in the primary care group and 24/30,166 (0.80‰) in the secondary care group (relative risk 0.88; 95% CI 0.52-1.46). Women in the primary care group were less likely to deliver by secondary caesarean section (5% versus 16%; RR 0.31; 95% CI 0.30-0.32) or by instrumental delivery (10% versus 13%; RR 0.76; 95% CI 0.73-0.79). KEY CONCLUSIONS: We found a low absolute risk of intrapartum and neonatal mortality, with a comparable risk for women who started labour in primary versus secondary care. The intervention rate was significantly lower in women who started labour in primary care. IMPLICATIONS FOR PRACTICE: These findings suggest that it is possible to identify a group of women at low risk of complications that can start labour in primary care and have low rates of medical interventions whereas perinatal mortality is low.

The EULAR Outcome Measures Library: development and an example from a systematic review for systemic lupus erythematous instruments.

OBJECTIVES: Patient reported outcomes (PROs) are relevant in rheumatology. Variable accessibility and validity of commonly used PROs are obstacles to homogeneity in evidence synthesis. The objective of this project was to provide a comprehensive library of "validated PROs". METHODS: A launch meeting with rheumatologists, PROs methodological experts, and patients, was held to define the library's aims and scope, and basic requirements. To feed the library we performed systematic reviews on selected diseases and domains. Relevant information on PROs was collected using standardised data collection forms based on the COSMIN checklist. RESULTS: The EULAR Outcomes Measures Library (OML), whose aims are to provide and to advise on PROs on a user-friendly manner albeit based on scientific grounds, has been launched and made accessible to all. PROs currently included cover any domain and, are generic or specifically target to the following diseases: rheumatoid arthritis, osteoarthritis, spondyloarthritis, low back pain, systemic lupus erythematosus, gout, osteoporosis, juvenile idiopathic arthritis, and fibromyalgia. Up to 236 instruments (106 generic and 130 specific) have been identified, evaluated, and included. The systematic review for SLE, which yielded 10 specific instruments, is presented here as an example. The OML website includes, for each PRO, information on the construct being measured and the extent of validation, recommendations for use, and available versions; it also contains a glossary on common validation terms. CONCLUSIONS: The OML is an in progress library led by rheumatologists, related professionals and patients, that will help to better understand and apply PROs in rheumatic and musculoskeletal diseases.

Optimal timing of delivery in small for gestational age fetuses near term: a national cohort study.

OBJECTIVE: Our aim was to study the competing risks of antepartum versus intrapartum/neonatal death in small for gestational age (SGA) and non-SGA fetuses. STUDY DESIGN: We performed a national cohort study using all singletons delivered between 36 and 42(6/7) weeks without hypertension, preeclampsia, diabetes, congenital anomalies, or noncephalic presentation from the Netherlands Perinatal Registry (1999-2007). The resultant cohort was divided in three groups based on birth weight by gestational age (SGA < P5 group, 61,021 deliveries; SGA P5-10 group, 58,902 deliveries; non-SGA group 1,168,523 deliveries). We compared the mortality risk of delivery with expectant management. RESULTS: Delivery was associated with more mortality than expectant management for 1 week from 39 weeks onward in the non-SGA group (relative risk [RR], 1.26; 95% confidence interval [CI], 1.05-1.50). For the SGA < P5, expectant management for 1 more week was associated with more mortality from 38 weeks onward although this only reached statistical significance from 40 weeks onward (RR, 2.46; 95% CI, 1.80-3.36). CONCLUSION: At 36 and 37 weeks, delivery is associated with a higher risk of mortality in SGA < P5 fetuses than expectant management. Delivery of SGA < P5 fetuses at 38 and 39 weeks is associated with the best perinatal outcome whereas for non-SGA fetuses this is at 39 to 40 weeks.

Optimisation of disease assessments in juvenile idiopathic arthritis.

A variety of clinical measures are available for assessment of disease status of children with juvenile idiopathic arthritis (JIA) in clinical trials, clinical care and long-term outcome surveys. The American College of Rheumatology (ACR) Pediatric 30 remains the preferred primary outcome measure for registrative trials, although in most therapeutic studies performed in the 2000s patients were also evaluated for more stringent levels of improvement, that is, applying the ACR Pediatric 50, 70, 90, and 100 response criteria. Because the recent therapeutic advances have made inactive disease an achievable goal in most patients, it has been suggested that endpoints for future clinical trials incorporate the evaluation of disease activity state, namely the assessment of inactive disease and low disease activity. The introduction of the Juvenile Arthritis Disease Activity Score (JADAS) and the establishment of its cut-offs for various disease activity states may foster the implementation of the treat-to-target strategy in both clinical trials and routine practice. In recent years, there has been an increased focus on the inclusion of patient and child perspectives in health outcome measures through the use of parent/child-reported outcomes. Integration of these measures in the clinical evaluation is considered important as they reflect the parent's and child's perception of the disease course and effectiveness of therapeutic interventions. Future studies will show whether the newer imaging modalities, namely magnetic resonance imaging and ultrasound, can replace conventional radiography for the assessment of structural joint damage and its progression.

Optimal timing of near-term delivery in different ethnicities: a national cohort study.

OBJECTIVE: To study possible ethnic disparities in perinatal mortality and morbidity independent of the occurrence of pregnancy complications. In addition, to study the probabilities of adverse neonatal outcome for delivery, compared with 1 week of expectant management for each week of gestational age in the range of 36-42 weeks of gestation. DESIGN: National cohort study. SETTING: The Netherlands. POPULATION: All women who were recorded as being of white European (982,318), Mediterranean (94,130), or African-Caribbean (25,253) descent with singleton cephalic births delivered between 36(+0) and 42(+6) weeks of gestation. Women with hypertension, pre-eclampsia, or diabetes, or with fetuses that were small for gestational age (below the tenth percentile) or with congenital abnormalities, were excluded. Data were obtained from the Netherlands Perinatal Registry (1999-2007). METHODS: Numbers of antepartum and intrapartum/neonatal death, and neonatal morbidity, were expressed using the fetus/neonate-at-risk approach. For each week of gestation, we compared the probability of adverse neonatal outcome (intrapartum/neonatal death in that week) for delivery with the probability of adverse neonatal outcome for expectant management (antepartum death in that week plus intrapartum/neonatal death and morbidity in the subsequent week). RESULTS: Women of Mediterranean and African-Caribbean descent who were near term were at increased risk of antepartum and intrapartum/neonatal death, and neonatal morbidity, compared with white European women. Expectant management from 40 weeks of gestation onwards was associated with an increased probability of adverse neonatal outcome in white European women and in women of Mediterranean descent, compared with delivery (risk ratio, RR 1.45, 95% confidence interval, 95% CI 1.25-1.68, versus RR 1.69, 95% CI 1.11-2.60, and with number needed to deliver to prevent one adverse neonatal outcome being 563 and 364, respectively). This was not observed for women of African-Caribbean descent. CONCLUSIONS: Ethnic disparities in perinatal outcomes were observed, with higher risks for women of Mediterranean descent. Expectant management in white European and Mediterranean women after 39 weeks of gestation is associated with an increased risk of adverse neonatal outcome.

Performance of the new SLICC classification criteria in childhood systemic lupus erythematosus: a multicentre study.

OBJECTIVES: The Systemic Lupus International Collaborating Clinics (SLICC) group has recently proposed a new set of criteria for the classification of systemic lupus erythematosus (SLE). We aimed to compare the sensitivity and specificity of the new SLICC criteria with those of the American College of Rheumatology (ACR) criteria in our childhood-onset SLE patients. METHODS: Three main paediatric lupus centres from Europe participated in this study. Of these centres, one was predominantly a paediatric nephrology centre (Great Ormond Street Hospital, London, UK), one was predominantly a paediatric rheumatology centre (Istituto Giannina Gaslini, Genoa, Italy), and one was a combined centre taking care of both group of patients (Hacettepe University, Ankara, Turkey). The features present at disease onset in patients with childhood-onset SLE, younger than 18 years of age, seen between January 2000 and December 2012 were retrospectively reviewed. For the evaluation of specificity, patients admitted to each centre between May and December 2012 for conditions other than SLE, in whom ANA was deemed necessary within the diagnostic work-up were included as controls. PASW 18.0 for Windows was used for statistical analyses. RESULTS: Both sets of classification criteria were analysed in 154 childhood SLE patients with a mean age at disease onset of 12.7 years and in 123 controls with a mean age of 8.9 years. The sensitivity and specificity of the ACR criteria were 76.6% and 93.4%, respectively, whereas those of the SLICC criteria were 98.7% and 85.3%, respectively. Four patients out of 5 with haemolytic uraemic syndrome (HUS) and 4 patients out of 8 with juvenile dermatomyositis (JDM) met four of the SLICC criteria, whereas 22 lupus nephritis patients failed to meet four of the ACR criteria. CONCLUSIONS: In our paediatric series, the SLICC criteria showed better sensitivity (p<0.001) and led to fewer misclassifications, but were less specific (p<0.001) than the ACR criteria.

Risk of maternal and neonatal complications in subsequent pregnancy after planned caesarean section in a first birth, compared with emergency caesarean section: a nationwide comparative cohort study.

OBJECTIVE: To compare the difference in risks of neonatal and maternal complications, including uterine rupture, in a second birth following a planned caesarean section versus emergency caesarean section in the first birth. DESIGN: Prospective cohort study. SETTING: Population-based cohort in the Netherlands. POPULATION: Linked data set of outcomes for term caesarean section in a first birth followed by a consecutive delivery. METHODS: We conducted a prospective cohort analysis using data from the Dutch Perinatal Registry. We included primiparous women who gave birth to term singleton infants through planned or emergency caesarean from January 2000 through December 2007, and who had a second singleton delivery during the same period (n = 41,109). Odds ratios and adjusted odds ratios were calculated. MAIN OUTCOME MEASURES: Maternal and neonatal complications, specifically uterine rupture, in second births associated with planned and emergency caesareans in the first birth. RESULTS: Women with a history of a planned caesarean section in the first birth (n = 11,445) had a 0.24% risk for uterine rupture, compared with a 0.16% risk for women with a history of emergency caesarean section (n = 29,664; aOR 1.4, 95% CI 0.8-2.4). In multivariate logistic regression, women with planned caesareans in a first birth had a significantly increased risk of stillbirth (aOR 1.5, 95% CI 1.0-2.2) and postpartum haemorrhage (aOR 1.1, 95% CI 1.0-1.2) in second births, compared with women with emergency caesareans in the first birth. CONCLUSIONS: We found a moderately increased risk of postpartum haemorrhage and a small to moderately increased risk of uterine rupture and stillbirth as a long-term effect of prior planned caesarean delivery on second births.

MRI versus conventional measures of disease activity and structural damage in evaluating treatment efficacy in juvenile idiopathic arthritis.

OBJECTIVE: To compare the American College of Rheumatology paediatric (ACRp) response criteria and conventional radiography with MRI findings in a cohort of patients with juvenile idiopathic arthritis. METHODS: Forty consecutive patients (30 girls, 10 boys; median age 10.8 years) with arthritis of the wrist starting treatment with disease-modifying antirheumatic drugs or biological agents were recruited. At 1-year follow-up the treatment response was assessed by ACRp criteria and radiographic progression using the adapted Sharp/van der Heijde method. Wrist MRIs were evaluated using both the paediatric-MRI and the OMERACT rheumatoid arthritis MRI scores. Sensitivity to change of clinical and imaging variables was assessed by standardised response mean (SRM) and relative efficiency (RE) was used to compare SRMs. RESULTS: ACRp90 responders showed a significantly higher decrease in MRI synovitis score (median change -4) than non-responders (median change 0), ACRp30-50 responders (median change 0) and ACRp70 responders (median change -1) (p=0.0006, Kruskal-Wallis test). Non-responders showed significantly higher radiographic progression than ACRp90 responders (pB=0.016). The MRI synovitis score showed a greater responsiveness to change (SRM 1.69) compared with the majority of ACR core set of variables. MRI erosion scores were less responsive than conventional radiography in detecting destructive changes (RE <1). MRI follow-up revealed no signs of inflammation in four out of 24 wrists with clinically inactive disease. CONCLUSION: Only ACRp90 responders showed a significant decrease in synovitis and the halting of structural damage, suggesting that levels of response higher than ACRp30 are more appropriate for assessing drug efficacy. The excellent responsiveness of MRI and its ability to detect subclinical synovitis make it a promising outcome measure.