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

Intrathecal Injection of Spironolactone Attenuates Radicular Pain by Inhibition of Spinal Microglia Activation in a Rat Model

Microglia might play an important role in nociceptive processing and hyperalgesia by neuroinflammatory process. Mineralocorticoid receptor (MR) expressed on microglia might play a central role in the modulation of microglia activity. However the roles of microglia and MR in radicular pain were not well understood. This study sought to investigate whether selective MR antagonist spironolactone develop antinociceptive effects on radicular pain by inhibition neuroinflammation induced by spinal microglia activation.Radicular pain was produced by chronic compression of the dorsal root ganglia with SURGIFLO™. The expression of microglia, interleukin beta (IL-1β), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), NR1 subunit of the NMDA receptor (t-NR1), and NR1 subunit phosphorylated at Ser896 (p-NR1) were also markedly up-regulated. Intrathecal injection of spironolactone significantly attenuated pain behaviors as well as the expression of microglia, IL-1β, TNF-α, t-NR1, and p-NR1, whereas the production of IL-6 wasn't affected.These results suggest that intrathecal delivery spironolactone has therapeutic effects on radicular pain in rats. Decreasing the activation of glial cells, the production of proinflammatory cytokines and down-regulating the expression and phosphorylation of NMDA receptors in the spinal dorsal horn and dorsal root ganglia are the main mechanisms contributing to its beneficial effects

POS0945 IMPROVEMENT OF ENDOTHELIAL DYSFUNCTION AND INFLAMMATION IN ANKYLOSING SPONDYLITIS: IMPROVE-AS STUDY

BackgroundCardiovascular (CV) disease is the leading cause of death in Ankylosing Spondylitis (AS)1. The chronic inflammatory-driven endothelial dysfunction and accelerated atherosclerosis contribute to the enhanced CV risk in AS. However, the therapeutic options to treat the enhanced CV risk are limited.ObjectivesTo investigate the impact of Olmesartan and Rosuvastatin on endothelial dysfunction and inflammation in AS.Methods60 consequtive AS patients were randomized to receive 24-weeks of treatment with Olmesartan (OLME) (10 mg/day, n=20), Rosuvastatin (Rvs) (10 mg/day, n=20), or placebo (PL) (n=20) as an adjunct to existing stable csDMARDs. Endothelial function was assesed by brachial artery flow-mediated dilatation (FMD) using AngioDefender. EPCs (CD34+/CD133+) were estimated by flow cytometry. Serum nitrite, TBARS, ICAM-1, VCAM-1 and lipids levels estimated at baseline and after treatment. Inflammatory measures included: ASDAS, BASDAI, BASFI, ESR and CRP, pro-inflammatory cytokines. Quality of life and CV 10-year risk (SCORE high risk charts) were estimated using standard tools.ResultsBaseline levels of FMD and EPC population were impaired indicating endothelial dysfunction. Basal concentrations of inflammatory markers, pro-inflammatory cytokines and markers of endothelial dysfunction were elevated among three groups. After 24-weeks of treatment, FMD improved significantly in the rosuvastatin and olmesartan group as compared to placebo from their baseline levels: {OLME vs. PL (p≤0.01), Rvs vs. PL (p&lt;0.01), Rvs vs. OLME (p=0.10) (Figure 1A). EPCs and nitrite (Figure 1B) levels improved significantly in both rosuvastatin and olmesartan groups. A significant reduction found in ICAM-1 after rosuvastatin treatment (p&lt;0.01) where as olmesartan significantly decreased VCAM-1 (p=0.04) levels. Both rosuvastatin and olmesartan resulted in significant reductions of ASDAS, BASDAI, BASFI, ESR, CRP, IL-6 (Figure 1C) and TNF-α (Figure 1D) as compared to placebo. A significant reduction found in TBARS concentration after olmesartan treatment (p&lt;0.01) as compared with rosuvastatin and placebo. There was a significant reduction in SCORE, HAQ-DI &amp; SF-36 (PH) after treatment with rosuvastatin and olmesartan.ConclusionOlmesartan and rosuvastatin improve endothelial dysfunction and vascular inflammation and QoL in AS patients. Olmesartan and Rosuvastatin lower the proinflammatory cytokines, especially TNF-α, that upregulate eNOS and downregulates the production of adhesion molecules, CRP and nitric oxide which, in turn, improves endothelial dysfunction. Both drugs also decrease nitrite concentration and improve the EPC population in AS patients. The augmentation of EPCs by olmesartan and rosuvastatin represents a fascinating new approach for the management of AS. However, Rosuvastatin in addition also favorably impacted ICAM-1 and lipid abnormalities. In contrast, olmesartan has beneficial effect on blood pressure. Thus, both rosuvastatin and olmesartan have anti-inflammatory, immunomodulatory, vasculoprotective and cardioprotective effects in AS mediated through anti-proinflammatory cytokine action. These findings suggests that both drugs could mediate modest but clinically apparent anti-inflammatory effects with modification of CV risk in the context of high-grade autoimmune inflammation of AS and may provide a novel strategy to prevent cardiovascular events in these patients.References[1]Azevedo VF, Pecoits-Filho R. Atherosclerosis and endothelial dysfunction in patients with ankylosing spondylitis. Rheumatol Int 2010;30(11):1411–1416Disclosure of InterestsNone declared</jats:sec

AB0613 AUTONOMIC NEUROPATHY AND ITS PREDICTORS IN SYSTEMIC SCLEROSIS

Background:Systemic sclerosis (SSc), a chronic autoimmune disease, is associated with autonomic neuropathy1. Autonomic neuropathy, especially cardiovascular autonomic neuropathy (CAN) is significant risk predictor of sudden cardiac death. However, its relationship with disease specific measures remains unexplored in SSc.Objectives:To assess cardiovascular autonomic neuropathy and sudomotor function and its predictors in systemic sclerosis.Methods:In this cross-sectional study, 16 SSc patients meeting the 2013 European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) classification criteria and 15 age and sex-matched healthy controls were recruited. Cardiovascular autonomic function assessed by five cardiovascular reflex tests according to Ewing. Peripheral sympathetic autonomic function assessed by FDA approved Sudoscan (Impeto Medical, Paris) through measurement of electrochemical skin conductance. Disease-specific measures (Disease duration, Modified Rodnan Skin Score (mRSS), EUSTAR activity score), and inflammatory measures (ESR, CRP) were determined. Quality of life measured by Scleroderma Health Assessment Questionnaire (SHAQ).Results:Systemic sclerosis patients had significantly impaired parasympathetic [Heart rate response to deep breath (HRD) (Fig. 1A), Heart rate response to standing (HRS) (Fig. 1B) and Heart rate response to valsalva manoeuvre (Fig. 1C)] and symapathetic [BP response to hand grip (BPH) (Fig. 1D)] function as compared to healthy controls. Scleroderma patients had significantly impaired sudomotor function (p&lt;0.05) as compared to healthy controls. Levels of mRSS, EUSTAR score, ESR, CRP and SHAQ were significantly higher in SSc patients as compared to healthy controls (p≤0.05). Parasympathetic (HRD &amp; HRS) dysfunction inversely correlated with ESR, CRP and mRSS. Sudomotor function positively correlated with mRSS, disease duration and CRP.Conclusion:CAN and Sudomotor function are significantly impaired in SSc. Parasympathetic dysfunction is more pronounced than sympathetic dysfunction in SSc. CAN and Sudomotor dysfunction are associated with disease-duration, skin-score, ESR and CRP. These could serve as potential predictors of Cardiovascular Autonomic neuropathy and sudomotor dysfunction in SSc.References:[1]Dessein PH, Joffe BI, Metz RM, Millar DL, Lawson M, Stanwix AE. Autonomic dysfunction in systemic sclerosis: sympathetic overactivity and instability. The American journal of medicine. 1992;93(2):143-50.Acknowledgments:NoneDisclosure of Interests:None declared</jats:sec

AB0577 ENDOTHELIAL DYSFUNCTION AND ATHEROSCLEROSIS IN SYSTEMIC SCLEROSIS: A MULTIPARAMETRIC ANALYSIS USING IMAGING TECHNIQUE AND LABORATORY MARKERS OF INFLAMMATION AND VASCULAR FUNCTION: SCLERODERMA CV RISK STUDY

Background:Systemic sclerosis (SSc) patients have an increased risk for atherosclerotic cardiovascular disease (CVD), possibly mediated by inflammatory and fibrotic mechanisms1. However, pathogenesis of accelerated atherosclerosis in SSc remains to be elucidated. Endothelial dysfunction is the key initial event in atherosclerosis. Predictors for rapid evolution of cardiovascular complications would be highly desirable for CV risk stratification. This study aims to assess endothelial function and atherosclerosis in SSc, in context of markers of inflammation and vascular function in SSc patients.Objectives:To assess endothelial function and atherosclerosis in SSc in context of markers of inflammation and vascular function in SSc patients.Methods:A cross-sectional study was performed in 20 SSc patients meeting the 2013 European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) classification criteria and 18 healthy controls matched for age and sex. Flow-mediated dilatation (FMD) assessed by AngioDefender and CIMT measured ultrasonographically. Disease-specific measures included: Disease duration, Modified Rodnan Skin Score (mRSS), EUSTAR activity score in SSc. We also assayed markers of inflammation, including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), proinflammatory cytokines (interleukin IL-1, IL-6, and IL-17), and endothelial dysfunction including lipids, serum nitrite and TBARS (marker of oxidative stress). Quality of life measured by Scleroderma Health Assessment Questionnaire (SHAQ).Results:FMD is significantly lower in SSc patients compared with controls (6.13±0.35% vs. 9.12±0.25%, p≤0.05). CIMT is significantly higher in SSc patients compared with controls (0.071±0.04cm vs. 0.035±0.02cm p≤0.05). Compared with controls, SSc patients had significantly (p≤0.05) elevated mRSS, EUSTAR score, ESR, CRP, IL-1, IL-6, IL-17, nitrite, TBARS and SHAQ whereas HDL levels are significantly reduced in SSc compared with controls (p≤0.05). In SSc, FMD inversely correlated with EUSTAR score, mRSS, IL-6 (Fig. 1A), serum nitrite (Fig. 1B), TBARS (Fig. 1C) and CIMT (Fig. 1D). CIMT positively correlated with age (Fig. 2A), disease duration, CRP (Fig. 2B) and IL-17 (Fig. 2C) and inversely correlated with HDL (Fig. 2D) (p&lt; 0.05).Conclusion:In the present study, FMD and CIMT are impaired in SSc, indicating endothelial dysfunction and accelerated atherosclerosis, respectively. EUSTAR score, mRSS, IL-6, serum nitrite, CIMT and TBARS predicted endothelial dysfunction. Age, disease duration, CRP, IL-17, HDL and impaired FMD predicted accelerated atherosclerosis. SSc-related inflammatory mechanisms (IL-6, IL-17) and markers of vascular function (CRP, serum nitrite and TBARS) may all be involved in the development of vascular disease in SSc. Cytokine-triggered inflammation mediated by nitrite and TBARS is associated with endothelial dysfunction and accelerated atherosclerosis in SSc. These markers would possibly serve as predictors of endothelial dysfunction and atherosclerosis and more importantly therapeutic targets to prevent premature atherosclerosis and cardiovascular disease in SSc.References:[1]Pagkopoulou E, Poutakidou M, Garyfallos A, Kitas G, Dimitroulas T. Cardiovascular risk in systemic sclerosis: Micro- and Macro-vascular involvement. Indian Journal of Rheumatology 2017;12:S211-7.Acknowledgments:NoneDisclosure of Interests:None declared</jats:sec