INTERLEUKIN-17INHIBITION WITH SECUKINUMAB IMPROVES SUDOMOTOR DYSFUNCTION IN PSORIATIC ARTHRITIS

Psoriatic arthritis (PsA) is a relapsing inflammatory disease, most commonly a seronegative oligoarthritis found in patients with psoriasis, characterized by the absence of rheumatoid factor in serum, with differentiating features of distal joint involvement and in extreme cases of arthritis mutilans (which is a destructive form of PsA). Cardiovascular autonomic and peripheral sympathetic neuropathy occurs in PsA. However, there is no specific treatment recommendation for autonomic neuropathy (AN) in psoriatic diseases. Secukinumab, a recently approved therapeutic advancement for psoriasis and psoriatic arthritis, is an immunoglobulin G (IgG) 1k fully monoclonal antibody that selectively inhibits the effector function of interleukin (IL)-17A. Its effect on sudomotor dysfunction in PsA has not yet been reported. This is the first reported observation of improvement in peripheral sympathetic autonomic neuropathy with secukinumab in PsA. We report a case of a 52-year-old male with PsA on methotrexate 15 mg/week with severe disease activity treated with the addition of subcutaneous secukinumab 150 mg once a week for 5 w followed by once a month dose. We found significant improvement in sudomotor dysfunction after 4 and 8 w of treatment

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

Predictors of endothelial dysfunction and atherosclerosis in rheumatoid arthritis in Indian population

AbstractObjectiveCardiovascular (CV) disease is leading cause of mortality in rheumatoid arthritis (RA). Dysfunction of the vascular endothelium is a hallmark of most conditions that are associated with atherosclerosis and is therefore an early feature in atherogenesis. Biomarkers for rapid evolution of CV complications would be highly desirable for risk stratification. Finally, predictive biomarkers for cardiovascular risk would allow tailoring therapy to the individual. We assessed endothelial function and atherosclerosis utilizing carotid intima-media thickness (CIMT) in RA in context of clinical and laboratory markers in Indian RA population.MethodsWe performed a prospective study of 35 consecutive RA patients and 25 age- and sex matched healthy controls. Patients with traditional CV risk factors were excluded. Flow mediated dilatation (FMD) as measures of endothelial function and CIMT as measures of atherosclerosis were assessed. Disease-specific measures, inflammatory measures, serum cytokines, serum nitrite, lipids and endothelial progenitor cells (EPCs) were estimated.ResultsFMD was significantly lower in RA (6.53%±1.81%) compared to controls (10.77%±0.53%; p<0.001). CIMT (mm) was significantly increased in RA (0.62±0.17) vs. controls (0.043±0.07; p=0.003). In RA patients, FMD% inversely correlated with CIMT, CRP, DAS-28, TNF-α, serum nitrite and positively correlated with EPC. CIMT correlated with age, DAS-28, IL-6, HDL, LDL, and inversely correlated with EPC.ConclusionsIn the present study, FMD and CIMT were impaired in RA, indicating endothelial dysfunction and accelerated atherosclerosis respectively. CRP, TNF-α, serum nitrite, DAS-28 and depleted EPC population predicted endothelial dysfunction. Age, IL-6, HDL, LDL and depleted EPC population predicted accelerated atherosclerosis

Predictors of Atherosclerosis in Ankylosing Spondylitis

OBJECTIVE: Accelerated atherosclerosis associated with an enhanced inflammatory state, which characterizes ankylosing spondylitis (AS), is the leading cause of increased cardiovascular risk. The objective of this study was to assess carotid intima-media thickness (CIMT) as a surrogate for subclinical atherosclerosis in AS patients and its possible correlation with disease-related clinical parameters. METHODS: We performed a prospective study of 30 consecutive patients meeting modified New York criteria for AS compared to 25 controls matched for age and sex. Patients with traditional CV risk factors were excluded. Disease-specific measures and inflammatory measures (ESR, CRP, TNF-α, IL-6 and IL-1) were determined. CIMT was measured in the right common carotid artery using high-resolution B-mode ultrasound. RESULTS: AS patients exhibited increased CIMT compared to matched healthy controls (0.62 ± 0.12 vs. 0.53 ± 0.09 mm). CIMT was positively correlated with age, disease duration, disease activity (BASDAI and ASDAS) and the inflammatory measures ESR (r = 0.45, P = 0.11) and TNF-α (r = 0.62, P < 0.001). CIMT did not correlate with the BMI, BASFI, IL-6, IL-1 or cholesterol levels. CONCLUSIONS: This study shows increased CIMT in AS patients without traditional cardiovascular risk factors compared to healthy controls. An increase in age, disease duration, disease activity (BASDAI and ASDAS), biomarkers of inflammation (ESR and CRP) and TNF-α may predict the occurrence of accelerated atherosclerosis in AS

Therapeutic effects of spironolactone on a collagen-induced arthritis model of rheumatoid arthritis

AbstractBackgroundRheumatoid arthritis (RA) is an autoimmune disease characterized by increased inflammation of synovial joint. The collagen-induced arthritis (CIA) is a widely used animal model for RA. Spironolactone possesses potent anti-inflammatory and immune modifying properties that might make it an excellent medical intervention for rheumatic diseases.Aim of the workThe present study was conducted to evaluate the therapeutic effect of spironolactone (SPIR) in collagen-induced arthritis model in mice.Materials and methodsDBA/1mice were divided into eight groups and CIA mice treated with SPIR (20, 40 and 80mg/kg/day), methotrexate (MTX) and vehicle was administered beginning on day 21 (arthritis onset) until day 42. The effects of treatment in the mice were assessed by clinical, oxidative markers, inflammatory cytokines; tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) as well as histological changes in ankle joints.ResultsMice immunized with collagen II with complete and incomplete Freund’s adjuvant developed inflammatory arthritis. Spironolactone (40 and 80mg/kg/day) was effective in bringing significant changes on all the parameters (paw swelling, arthritis score, oxidative markers) studied. Oral administration of SPIR significantly reduced the level of TNF-α and IL-6. The protective effect of SPIR against RA was also evident from the ankle joint histopathology and its effect was found comparable to that of MTX.ConclusionAmelioration of paw swelling, antioxidant properties, inflammatory mediators TNF-α and IL-6 and histopathological changes indicates that SPIR can be considered with MTX among the treatment armamentarium of arthritis. Spironolactone may be considered for use as a novel therapeutic treatment against human arthritis