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

POS0205 AMELIORATION OF ENDOTHELIAL DYSFUNCTION WITH JAK INHIBITION IN RHEUMATOID ARTHRITIS: JAK CV-RISK REDUCTION STUDY

Background:Cardiovascular (CV) disease is the leading cause of premature mortality and sudden death in Rheumatoid Arthritis (RA). Conventional CV risk factors and disease specific risk factors are responsible for endothelial dysfunction (ED) in RA. ED is the barometer of CV health and key initial event in atherosclerosis. Tofacitinib, a JAK inhibitor, is in clinical use since 2012 and has had the most extensive development program in RA, but its impact on ED has not yet been explored in humans.Objectives:To investigate the impact of tofacitinib on endothelial dysfunction in RAMethods:40 RA patients fulfilling the 2010 Rheumatoid Arthritis classification criteria with active disease (DAS28&gt;3.2) were randomized to receive 24 weeks of treatment with Tofacitinib (5mg bd, n=20) and placebo (n=20) as an adjunct to existing stable antirheumatic drugs. Primary endpoints included endothelial dysfunction assessed by FMD using Angiodefender and lipids were estimated at baseline and after 12 weeks of treatment. The secondary end points included: DAS28, ESR, CRP, HAQ-DI and cardiovascular risk using SCORE chart assessed at week 0 and 12.Results:At baseline, endothelial function was impaired and levels of inflammatory measures were elevated in both groups. CV risk SCORE was high and HAQ-DI was impaired at baseline. After treatment, FMD improved significantly in the tofacitinib group from (8.16±1.38% to 10.98±2.33%, p≤0.05) as compared to placebo (7.12±0.25% to 8.04±0.30%, p=0.35) (Fig. 1A). DAS28 (Fig. 1B), ESR and CRP (Fig. 1C) levels improved significantly in tofacitinib group as compared to placebo (p≤0.05). Tofacitinib significantly decreased HAQ-DI and SCORE (Fig. 1D) values as compared to placebo. There was significant increase in HDL (p≤0.05) after treatment with tofacitinib as compared to placebo. After 12 weeks of treatment, FMD and HDL increased by 34.55% and 13.58% respectively where as DAS28, ESR and CRP decreased by 37.40%, 36.10% and 76.59% respectively in the tofacitinib group. Significant negative correlation was observed between FMD and DAS28 (r= -0.50, p≤0.05) and CRP (r= -52, p≤0.05) after treatment with tofacitinib where as no such correlation was found in placebo group.Figure 1.Impact of Tofacitinib on FMD, DAS 28, CRP &amp; SCOREConclusion:First study to show that tofacitinib, apart from its anti inflammatory activity, improves endothelial dysfunction and cardiovascular risk in RA. Thus, JAK inhibition with tofacitinib has vasculoprotective and cardioprotective effect mediated through anti-inflammatory and probably other mechanisms. This study would stimulate further research in exploring the vasculoprotective and cardioprotective potential of tofacitinib in RA.References:[1]Tofacitinib reversed endothelial dysfunction in rheumatoid arthritis: mechanistic insights from the rat adjuvant-induced arthritis model. http://dx.doi.org/10.1136/annrheumdis-2020-eular.2747Disclosure of Interests:None declared</jats:sec