The long term outcomes of children born to mothers with Systemic Lupus Erythematous (SLE)

Introduction: Immunosuppressive agents are commonly used in Systemic Lupus Erythematous (SLE) during pregnancy, to ensure optimum outcome for both mother and child. However there is little literature regarding long term outcomes (LTO) of these children. Aims: This pilot study aims to test the hypothesis that the mother’s medications taken during pregnancy and/or antibodies are associated with an increased risk of adverse outcomes in children born to mothers with lupus. Methods: Women regularly attending specialist UK lupus clinics were identified and consented to take part in this study if they had children up to the age of 17 years born after the diagnosis of SLE. A standard questionnaire developed for this multi-centre study was used to collect the data. Results: In total data were collected for 285 children born to 199 mothers. Neonatal rash, complete heart block or congenital anomalies were each reported in 2% of children, and developmental problems in 17/284(6%). Hospital management was required for infection in 25% (69/274) of children, the only significant risk factors identified were birth weight and maternal aspirin use which are likely to be surrogate markers for more severe maternal disease. Conclusion: This study demonstrated reassuring LTO of children born to mothers with SLE

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

British Society for Rheumatology guideline on prescribing drugs in pregnancy and breastfeeding: immunomodulatory anti-rheumatic drugs and corticosteroids

BackgroundThe rationale behind this update of the 2016 BSR guidelines on prescribing anti-rheumatic drugs in pregnancy and breastfeeding (1, 2) was described in detail in the guideline scope (3). In brief, despite the existence of additional evidence-based guidelines on prescribing/managing rheumatic disease in pregnancy (4-7), the information contained within them requires continual review to include emerging information on the safety of new and existing drugs in pregnancy. Chronic disease adversely affects pregnancy. Data from Mothers and Babies: Reducing Risk through Audits and Confidential Enquiries across the UK (MBRRACE-UK), reports regularly from a national programme of work conducting surveillance and investigating the causes of maternal deaths, stillbirths and infant deaths (8). Data from 2017-19, found that 8.8 women per 100,000 died during pregnancy or up to six weeks after childbirth or the end of pregnancy, and most women who died had multiple health problems or other vulnerabilities (8). In all decisions regarding medication choices and changes, it is important to consider the potential for deterioration in the mother's wellbeing through side effects or reduced disease control (and its adverse impact on the baby). As such, the potential benefit to the fetus from any drug changes in the mother must be balanced against the possible risks to the fetus from loss of disease control in the mother (9).Need for guidelineThere has been an appreciable increase in the number of published pregnancy exposures to biologic disease modifying anti-rheumatic drugs (bDMARDs), and two of these drugs are now licenced for use in pregnancy. In addition, therapeutic advances in management of various inflammatory rheumatic diseases (IRDs) have led to an expansion of bDMARDs and biosimilars with different modes of action, as well as a new class of targeted synthetic DMARDs (tsDMARDs).The continuing expansion of existing and novel DMARDs means that uncertainty remains around use of many of these drugs in pregnancy. This uncertainty may still lead to withdrawal of treatment from pregnant women unnecessarily (10). Discontinuation of treatment in preparation for or during early pregnancy can increase the risk of disease activity and flares during pregnancy, and are reported following discontinuation of biologics in patients with IRDs (11). The compatibility of various immunosuppressive and disease-modifying medications relevant to rheumatic disease will be covered in this update. This updated information will provide advice for healthcare professionals and patients, to ensure more confident prescribing in these scenarios, and will highlight any medications that should be stopped and/or avoided in the reproductive age group unless highly effective contraception is used, in line with guidance issued by the Medicines and Healthcare Products Regulatory Agency (MHRA) and the Faculty of Sexual and Reproductive Healthcare (12, 13). Objectives of guidelineTo update the previous BSR guidelines on prescribing in pregnancy in rheumatic disease of the following drug categories: antimalarials; corticosteroids; conventional synthetic (cs)DMARDs and immunosuppressive therapies; bDMARDs; and tsDMARDs. The full list of medications is shown in appendix 1. This revised guideline was produced by systematically reviewing all evidence published since the previous guideline, to answer specific questions in relation to each drug, as follows: Should it be stopped pre-conception? Is it compatible with pregnancy? Is it compatible with breastmilk exposure? Where possible, recommendations are made regarding compatibility with paternal exposure.Target audienceThe primary audience consists of health professionals in the UK directly involved in managing patients with rheumatic disease who are (or are planning to become) pregnant and/or breastfeeding, men with rheumatic disease who are planning to conceive, and patients with rheumatic disease who have unintentionally conceived whilst taking these medications. This audience includes rheumatologists, rheumatology nurses/allied health professionals, rheumatology speciality trainees and pharmacists, as well as the patients themselves. The guideline will also be useful to obstetricians, obstetric physicians, midwives, renal physicians, dermatologists, gastroenterologists, respiratory physicians and general practitioners who prescribe these medications in pregnancy. This guideline uses the terms “woman”, “maternal” or “mother” throughout. These should be taken to include people who do not identify as women but are pregnant or have given birth (14). Where the term “breastfeeding” is used in this guideline it also refers to infant breastmilk exposure via other methods (e.g. expressed breastmilk, administered via a bottle). The areas the guideline does not coverThis guideline does not cover the management of infertility or the indications for these drugs in specific rheumatic diseases in pregnancy. Other drug categories (pain management; non-steroidal anti-inflammatory drugs (NSAIDs) and low dose aspirin; anticoagulants; bisphosphonates; anti-hypertensives; and pulmonary vasodilators) are considered in the BSR guideline on prescribing drugs in pregnancy and breastfeeding: comorbidity medications used in rheumatology practice (reference to be inserted once published). All recommendations in this guideline were formulated by the working group on the basis of published evidence at the time of the systematic literature search, and do not necessarily refer to licencing information or Summary of Product Characteristics for individual medications.Stakeholder involvementThis guideline was commissioned by the BSR Standards, Guidelines and Audit Working Group. A Guideline Working group (GWG) was created, consisting of a chair (IG), alongside representatives from relevant stakeholders shown in appendix 2. In accordance with BSR policy, all members of the GWG made declarations of interest, available on the BSR website.Involvement and affiliations of stakeholder groups involved in guideline developmentThe GWG consisted of rheumatologists from a range of clinical backgrounds, various allied health professionals, other specialists in women’s health, lay members and representatives from the United Kingdom Tetralogy Information Service (UKTIS). All members of the working group contributed to the process for agreeing key questions, guideline content, recommendations and strength of agreement. <br/

British Society for Rheumatology guideline on prescribing drugs in pregnancy and breastfeeding:comorbidity medications used in rheumatology practice

BackgroundThe rationale behind this update on the 2016 BSR guidelines on prescribing anti-rheumatic drugs in pregnancy and breastfeeding [1, 2] was described in detail in the guideline scope [3]. In brief, despite the existence of additional evidence-based guidelines on prescribing/managing rheumatic disease in pregnancy [4-7] the information contained within them requires continual review to include emerging information on the safety of new and existing drugs in pregnancy.Chronic disease adversely affects pregnancy. Data from Mothers and Babies: Reducing Risk through Audits and Confidential Enquiries across the UK (MBRRACE-UK), reports regularly from a national programme of work conducting surveillance and investigating the causes of maternal deaths, stillbirths and infant deaths [8]. Data from 2017-19, found that 8.8 women per 100,000 died during pregnancy or up to six weeks after childbirth or the end of pregnancy, and most women who died had multiple health problems or other vulnerabilities[8]. In all decisions regarding medication choices and changes, it is also important to consider the potential for deterioration in the mother's wellbeing through side effects or reduced disease control (and its adverse impact on the baby). Therefore, the exposure of the fetus to different drugs when switches are made must be balanced against possible fetal gains, and understanding the potential impact of reduced control of the medical disorder on a pregnancy is vital [9].Need for guidelinePatients with inflammatory rheumatic disease (IRD) should be counselled to achieve and then maintain remission or low disease activity before/during pregnancy to reduce the risk of adverse pregnancy outcomes [10]. This goal is primarily achieved through adjustment of therapy to ensure disease control with disease modifying anti-rheumatic drugs (DMARDs) and/or immunosuppressive drugs that are compatible with pregnancy. These medications are reviewed in the BSR &amp; BHPR guideline on prescribing drugs in pregnancy and breastfeeding: immunomodulatory anti-rheumatic drugs and corticosteroids [11]. Many patients with IRD however, have an additional burden of pain and comorbid illness [12] that require treatment with other medications. The compatibility of various comorbidity medications relevant to rheumatic disease will be covered in this update. This updated information will provide advice for healthcare professionals and patients to ensure more confident prescribing in these scenarios and will highlight any medications that should be stopped and/or avoided in the reproductive age group unless highly effective contraception is used, in line with guidance issued by the Medicines and Healthcare Products Regulatory Agency (MHRA) and Faculty of Sexual and Reproductive Healthcare [13, 14]. Objectives of guidelineTo update the previous BSR guidelines on prescribing in pregnancy in rheumatic disease for the following drug categories: pain management; Non-steroidal anti-inflammatory drugs (NSAIDs) and low dose aspirin; anticoagulants; colchicine; dapsone; bisphosphonates; anti-hypertensives; and pulmonary vasodilators. This revised guideline was produced by consensus review of current evidence to answer specific questions in relation to each drug as follows. Should it be stopped pre-conception? Is it compatible with pregnancy? Is it compatible with breastmilk exposure? Where possible recommendations are made regarding compatibility with paternal exposure.Target audienceThe primary audience consists of health professionals in the UK directly involved in managing patients with rheumatic disease who are (or are planning to become) pregnant and/or breastfeeding, men planning to conceive, and patients who have unintentionally conceived whilst taking these medications. This audience includes rheumatologists, rheumatology nurses/allied health professionals, rheumatology speciality trainees and pharmacists, as well as the patients themselves. The guideline will also be useful to obstetricians, obstetric physicians, renal physicians, dermatologists and general practitioners who may prescribe these medications to patients in pregnancy. This guideline uses the terms “woman”, “maternal” or “mother” throughout. These should be taken to include people who do not identify as women but are pregnant or have given birth [15]. Where the term “breastfeeding” is used in this guideline it also refers to infant breastmilk exposure via other methods (e.g. expressed breastmilk, administered via a bottle).The areas the guideline does not coverThis guideline does not cover the management of infertility or acute pain relief during labour, hence morphine was excluded. Other drug categories: antimalarials; corticosteroids; disease modifying anti-rheumatic and immunosuppressive therapies; and biologic drugs are considered in another guideline (REF for part I). All recommendations in this guideline were formulated by the working group on the basis of published evidence at the time of the systematic literature search, and do not necessarily refer to licensing information or Summary of Product Characteristics for individual medications.Stakeholder InvolvementThis guideline was commissioned by the BSR Standards, Guidelines and Audit Working Group. A Guideline Working group (GWG) was created, consisting of a chair (IG), alongside representatives from relevant stakeholders (Table 1). In accordance with BSR policy, all members of the GWG made declarations of interest, available on the BSR website.Involvement and affiliations of stakeholder groups involved in guideline developmentThe GWG consisted of rheumatologists from a range of clinical backgrounds, various allied health professionals, other specialists in women’s health, lay members and representatives from the United Kingdom Tetralogy Information Service (UKTIS). All members of the working group contributed to the process for agreeing key questions, guideline content, recommendations and strength of agreement. <br/