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

Management of MDA-5 antibody-positive dermatomyositis with interstitial lung disease—an Auckland case series

Abstract Objective The aim was to present our experience of managing six cases of anti-melanoma differentiation-associated gene 5 (anti-MDA-5) DM with associated interstitial lung disease (ILD), presenting between June 2017 and October 2020. Methods The electronic notes were reviewed for six patients being followed up by the Rheumatology service at Auckland District Health Board. Three patients were initially diagnosed and treated in neighbouring Counties Manukau District Health Board and later transferred to Auckland District Health Board. All had different initial treating clinicians at a time before any predefined treatment algorithm. Emphasis was placed on initial diagnosis and treatment, subsequent disease activity and changes in management. Local management was compared retrospectively with existing evidence relating to the treatment of anti-MDA-5 DM with ILD. Ethical approval was not obtained, according to the New Zealand Health and Disability Ethics Committee exemption for audits and related activities. Results Six patients with a variety of clinical presentations were identified appropriately as having anti-MDA-5 DM with ILD. They were commenced on different immunosuppressive regimens, with treatment adjusted according to response and on-going disease activity. Four have achieved clinical and biochemical remission, a fifth has improving active disease, and the sixth is in the early stages of their illness. Conclusion Anti-MDA-5 DM is commonly associated with ILD. This can be rapidly progressive, with a poor prognosis in spite of treatment, particularly among Asian patients. Disease activity can seemingly be monitored with serum ferritin. The most effective management of this condition remains poorly researched; however, increasing retrospective evidence favours early aggressive multi-agent immunosuppression and a low threshold for escalation of therapy. </jats:sec

Current management of male‐to‐female gender identity disorder in the UK

Gender identity disorder (GID), or transsexualism as it is more commonly known, is a highly complex clinical entity. Although the exact aetiology of GID is unknown, several environmental, genetic and anatomical theories have been described. The diagnosis of GID can be a difficult process but is established currently using standards of care as defined by the Harry Benjamin International Gender Dysphoria Association. Patients go through extensive psychiatric assessment, including the Real Life Experience, which entails living in the desired gender role 24 h a day for a minimum period of 12 months. The majority of GID patients will eventually go on to have gender realignment surgery, which includes feminising genitoplasty. The clinical features, diagnostic approach and management of male‐to‐female GID in the UK are reviewed, including the behavioural, psychological and surgical aspects

Rheumatoid Arthritis is Associated with IgG Antibodies to Human Endogenous Retrovirus Gag Matrix: A Potential Pathogenic Mechanism of Disease?

Human endogenous retrovirus (HERV)-K10 has been implicated in the etiology and pathogenesis of rheumatoid arthritis (RA). A secondary immune response to this virus might suggest an antigen-driven response in patients. The Gag region of HERV-K10 could provide a key epitope important for immunological reactivity. We investigated the presence of IgG antibodies to this region and assessed its significance in RA

Characterisation and outcomes of different subsets of low disease activity states in patients with systemic lupus erythematosus

Objectives The lupus low disease activity state (LLDAS) allows for certain clinical and/or serological activity of SLE, provided overall disease activity does not exceed predefined cut-offs. This study aimed to evaluate the outcomes of patients who achieved LLDAS with clinical activity, serological activity only or neither clinical nor serological activity.Methods Patients with SLE enrolled in a prospective multinational cohort from March 2013 to December 2020 who were in LLDAS at least once were included. Visits that fulfilled both LLDAS and Definition of Remission in SLE (DORIS) criteria were excluded.Results 2099 patients were included, with median follow-up of 3.5 (IQR 1.3–5.8) years. At 6150 visits, patients were in LLDAS but not DORIS criteria; of these 1280 (20.8%) had some clinical activity, 3102 (50.4%) visits had serological activity only and 1768 (28.8%) visits had neither clinical nor serological activity. Multivariable regression analysis showed that compared with non-LLDAS, all three subsets of LLDAS had a protective association with flares in the ensuing 6 months and damage accrual in the ensuing 36 months. LLDAS with no clinical or serological activity had a significantly stronger protective association with severe flares in the ensuing 6 months compared with LLDAS with clinical activity (HR 0.47, 95% CI (0.27 to 0.82), p=0.007).Conclusions LLDAS without any clinical activity accounted for almost 80% of LLDAS visits. This study confirms that all subsets of LLDAS are associated with reduced flare and damage accrual. However, LLDAS without any clinical or serological activity has the strongest protective association with severe flares

Frequency and Determinants of Flare and Persistently Active Disease in a Large Multinational Prospective Lupus Cohort

Objective In contrast to relapsing‐remitting patterns, persistently active disease (PAD) is a disease activity pattern in patients with systemic lupus erythematosus (SLE) that is inadequately studied. We sought to identify the frequency and determinants of flare and PAD in SLE. Methods Flare was defined using the Safety of Estrogens in Lupus Erythematosus National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index (SELENA–SLEDAI flare index), and PAD was defined as an SLEDAI‐2K score of ≥4, excluding serology only, on two or more consecutive visits with a maximum six‐month interval. Multivariable logistic regression was used to develop predictive models for flare and PAD, which were tested in an independent validation subset. Results Among 3,811 patients over 2.8 (interquartile range 1.0–5.3) years of follow‐up, 2,142 (56.2%) experienced flare and 1,786 (46.9%) had PAD, with 368 (9.7%) experiencing PAD but not flare. The most common flare features were nephritis and arthritis, whereas PAD was most commonly characterized by renal or mucocutaneous activity. After adjusting for prednisone dose and use of antimalarials and immunosuppressants, low gross domestic product in country of residence, smoking, arthritis, nephritis, and low complement levels were predictive for flare, whereas being in a low disease activity state for ≥50% of follow‐up time (LLDAS50) was a protective factor. Renal activity and higher time‐adjusted mean SLEDAI‐2K were predictive of PAD, whereas LLDAS50 was protective. The models developed gave 72.1% and 83.8% correct classification of flare and PAD, respectively, in the validation cohort. Conclusion Both flare and PAD are common disease activity patterns in SLE; both predict organ damage accrual but differ in disease features and predictive factors. Because 9.7% of patients experience PAD but not flare, flare measures alone do not adequately capture all patients in whom disease control is suboptimal