Ashit Syngle

Advanced glycation end-products inhibition improves endothelial dysfunction in rheumatoid arthritis

Aim:  Chronic inflammation in rheumatoid arthritis is associated with vascular endothelial dysfunction. The objective was to study the efficacy and safety of advanced glycation end products (AGEs) inhibitor (benfotiamine 50 mg + pyridoxamine 50 mg + methylcobalamin 500 μg, Vonder® (ACME Lifescience, Baddi, Himachal Pradesh, India)) on endothelial function in rheumatoid arthritis (RA).

Disease-modifying anti-rheumatic drugs improve autonomic neuropathy in arthritis: DIANA study

Autonomic neuropathy (AN) is a risk predictor for sudden cardiac death in rheumatoid arthritis (RA) and ankylosing spondylitis (AS). However, the impact of most commonly employed disease-modifying anti-rheumatic drug (DMARD) therapy on autonomic neuropathy in rheumatic diseases is not known. Hence, we investigated the efficacy of DMARDs on autonomic neuropathy in RA and AS. We performed autonomic function assessment in 60 patients in this open-label, 12-week pilot study including 42 patients with RA, 18 with AS, and 30 aged-matched healthy subjects. The methodology included assessment of cardiovascular autonomic reflex tests according to Ewing. Parasympathetic dysfunction was established by performing three tests: heart rate response to deep breathing, standing, and Valsalva tests. Sympathetic dysfunction was examined by applying two tests: blood pressure response to standing and handgrip tests. Sudomotor function was assessed by Sudoscan. Cardiovascular reflex tests were impaired significantly among the patients as compared to healthy subjects (p < 0.05). Autonomic neuropathy was more pronounced in biologic-naive RA and AS patients. After treatment with combination synthetic DMARDs, parasympathetic, and sudomotor dysfunction significantly (p < 0.05) improved in RA and AS. Biologic DMARDs significantly improved parasympathetic, sympathetic and peripheral sympathetic autonomic neuropathy (p < 0.05) in biologic-naive RA and AS patients. In conclusion, synthetic DMARDs improved parasympathetic and sudomotor dysfunction in both DMARD-naive RA and AS patients. However, biologic DMARDs improved parasympathetic, sympathetic and sudomotor dysfunction to a greater extent than synthetic DMARDs in both RA and AS patients.

Efficacy and tolerability of advanced glycation end-products inhibitor in osteoarthritis: a randomized, double-blind, placebo-controlled study.

Objectives:Advanced glycation end-products (AGEs) play an important role in pathogenesis of osteoarthritis (OA). The objective of this study was to evaluate the efficacy and tolerability of AGEs inhibitor (benfotiamine [50 mg]+pyridoxamine [50 mg]+methylcobalamin [500 µg]; Vonder [Cosme Farma Laboratories Limited, Goa, India]) in OA patients. Methods:A 24-week, double-blind, randomized placebo-controlled study in primary OA patients (n=30 [F/M=26/4; mean age, 57.26±2.16 y]) meeting the classification criteria of American College of Rheumatology, was conducted. Inflammatory disease activity scores on the Western Ontario and McMaster University (WOMAC) Osteoarthritis Index, Lequesne Index, and Pain scores were analyzed. Biomarkers: serum nitrite, AGEs, thiobarbituric acid reactive substances, C-reactive protein, erythrocyte sedimentation rate, were also measured. Time taken to walk 20 m was also recorded. Patients were randomized to either AGEs inhibitor or placebo tablets as thrice-daily regimen. Results:At 24 weeks, net decrease in pain score, −6.64±2.71 versus −8.20±1.28, P=0.003; total WOMAC score, −5.88±0.84 versus −8.26±1.24, P=0.013; Lequesne Index score, −0.60±0.06 versus −0.84±0.09, P=0.05; time taken for 20-m walk test, −5.0±1.39 versus −5.0±0.92 s, P=1.00, were observed in the placebo versus drug group, respectively. Net change in serum nitrite, −0.15±0.01 versus −0.79±0.12 µmol/L, P<0.001; AGEs, −0.12±0.02 versus −0.99±0.09, arbitrary florescence units, P=0.001; thiobarbituric acid reactive substances, −0.69±0.12 versus −1.80±0.12 nmol/L, P<0.01; C-reactive protein, −0.12±0.35 versus −2.45±0.60 mg/L, P<0.01, were observed in the placebo versus drug group, respectively. Discussion:This study shows the efficacy of an AGE inhibitor on decreasing pain and inflammation, and increasing daily activity and mobility in OA patients.

Predictors of autonomic neuropathy in rheumatoid arthritis

OBJECTIVE Autonomic dysfunction occurs in rheumatoid arthritis (RA). However, the association between the autonomic dysfunction and inflammation has not been investigated in RA. We investigated the relationship between inflammation and ANS function in RA. METHODS In this cross-sectional study, 25 RA patients and 25 age and sex-matched healthy controls were recruited. Autonomic function assessed by five cardiovascular reflex tests according to Ewing. Parasympathetic dysfunction established by applying three tests: heart rate response to deep breath (HRD) and standing (HRS) and Valsalva tests. Sympathetic dysfunction examined by applying two tests: BP response to standing and handgrip test. Peripheral sympathetic autonomic function assessed by Sudoscan through measurement of electrochemical skin conductance of hands and feet. Sudoscan investigates the sweat gland activity and used as a surrogate to study the damage of sympathetic sudomotor nerves in neuropathy. It is an indirect assessment tool of sudomotor function. Disease-specific and inflammatory measures (DAS 28, ESR, CRP, TNF-α, IL-6 and IL-1) were determined. RESULTS RA patients had significantly impaired HRD, HRS, BP response to hand grip and sudomotor function as compared to healthy controls. Pro-inflammatory cytokines were significantly higher in RA as compared to healthy controls (p<0.05). DAS 28 significantly correlated with HRD in RA. ESR significantly correlated with HRD and HRS. TNF-α significantly correlated with HRD, HRS, BP response to standing and sudomotor function. Significant correlation was found between IL-6 and HRS. Seropositive patients had more pronounced CAN and sudomotor dysfunction. CONCLUSION Autonomic dysfunction in RA is related to disease activity, seropositivity and pro-inflammatory cytokines.

Endothelial progenitor cell biology in ankylosing spondylitis

Endothelial progenitor cells (EPCs) are unique populations which have reparative potential in overcoming endothelial damage and reducing cardiovascular risk. Patients with ankylosing spondylitis (AS) have increased risk of cardiovascular morbidity and mortality. The aim of this study was to investigate the endothelial progenitor cell population in AS patients and its potential relationships with disease variables.

Endothelial Progenitor Cells as a Marker of Endothelial Dysfunction and Atherosclerosis in Ankylosing Spondylitis: A Cross-Sectional Study

Abstract Endothelial progenitor cells (EPCs) have reparative potential in overcoming the endothelial dysfunction and reducing cardiovascular risk. EPC depletion has been demonstrated in the setting of established atherosclerotic diseases. We evaluated whether reduced EPCs population are associated with endothelial dysfunction, subclinical atherosclerosis, and inflammatory markers in ankylosing spondylitis (AS) patients without any known traditional cardiovascular risk factor. We performed a cross‐sectional study of 30 consecutive AS patients and 25 age‐ and sex‐matched healthy controls. Patients with traditional cardiovascular risk factors were excluded. Circulating EPCs (CD34+/CD133+) were quantified by flow cytometry. The assessment of endothelial function by brachial artery flow‐mediated dilatation (FMD) and ultrasound assessment of carotid intima‐media thickness (CIMT) was measured in both the groups. EPCs cells were significantly (0.020 ± 0.001 vs. 0.040 ± 0.010%, p < 0.001) reduced in patients with AS compared with healthy controls. Endothelial function (7.35 ± 2.54 vs. 10.27 ± 1.73, p = 0.002), CIMT (0.63 ± 0.01 vs. 0.35 ± 0.02, p < 0.001), and inflammatory markers were also significantly (p < 0.01) altered as compared with controls. EPCs inversely correlated with tumor necrosis factor (TNF)‐&agr; and C‐reactive protein (CRP) and positively correlated with endothelial function. Present study results demonstrate depleted EPC population in AS patients compared with controls. Increased level of CRP and TNF‐&agr; appears to play a key role in EPC depletion and the latter contributes to endothelial dysfunction and atherosclerosis in AS. EPC population would, therefore, represent an attractive measure of endothelial dysfunction and accelerated atherosclerosis disease associated with AS.

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

Objective Cardiovascular (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. Methods We 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. Results FMD 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. Conclusions In 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.

Disease-modifying antirheumatic drugs improve cardiovascular autonomic neuropathy in psoriatic arthritis.

Background: Cardiovascular autonomic neuropathy (CAN) is a significant risk predictor for sudden cardiac death in autoimmune rheumatic diseases. As yet, there is no therapeutic treatment of CAN in psoriatic arthritis (PsA). Even now, the impact of the most commonly employed disease-modifying antirheumatic drug (DMARD) therapy on CAN in PsA is not known. Hence, we investigated the impact of DMARDs on CAN in PsA. Methods: In this prospective, cross-sectional study, 20 patients of PsA and 20 age- and sex-matched healthy controls were recruited. CAN was diagnosed by applying the five cardiovascular reflex tests according to Ewing. Parasympathetic dysfunction was established by performing three tests: heart-rate response to deep breathing, standing, and Valsalva tests. Sympathetic dysfunction was examined by applying two tests: blood pressure response to standing, and handgrip tests. Disease severity was assessed by the 28-joint-count disease activity score (DAS-28) and the disease activity score in psoriatic arthritis (DAPSA). Results: Cardiovascular reflex tests were impaired significantly among the PsA patients compared with well-matched healthy subjects (p < 0.05). Parasympathetic dysfunction was more prominent than sympathetic dysfunction. After 12 weeks treatment, parasympathetic dysfunction (heart rate response to deep breath and standing) significantly (p < 0.05) improved in patients with PsA, while there was no significant improvement in sympathetic function. Conclusion: These study results suggests parasympathetic autonomic dysfunction is more prominent than sympathetic dysfunction in PsA. Synthetic DMARDs improved parasympathetic dysfunction in PsA.

THU0236 Brachial Artery Vasodilator Function and Adhesion Molecules in Rheumatoid Arthritis

Background Cardiovascular (CV) event rates are increased in Rheumatoid Arthritis (RA). Traditional cardiovascular risk factors do not adequately account for the extent of cardiovascular disease in RA1. The relation among biomarkers of endothelial dysfunction, inflammation and vascular function remain uncertain. Hence, we investigated the relationship between biomarkers of endothelial dysfunction, inflammation and vascular function in RA patients. Objectives To investigate the relationship between biomarkers of endothelial dysfunction, inflammation and vascular function in RA patients. Methods 30 adult RA patients (4 male, 26 female) and 30 age and sex matched healthy controls (6 male, 24 female) were enrolled in the study. Assessment of FMD done by Angiodefender™ (Everest Genomic, United States). Soluble adhesion molecules (sICAM-1 and sVCAM-1) and pro-inflammatory cytokines (TNF-α, IL-6 and IL-1) was measured using standard ELISA kits. As surrogates for disease activity, DAS28, C-reactive protein and ESR levels were determined. Results Compared with healthy controls, RA patients had significantly (p<0.05) increased basal concentrations of soluble intracellular adhesion molecules (sICAM-1), soluble vascular cell adhesion molecule (sVCAM-1), tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1 (IL-1). A significant negative correlation was found between VCAM-1 and FMD (P<0.05) and positive correlation was found between VCAM-1 and TNF-α (P<0.05). while sICAM-1 was positively correlated with IL-1 (P<0.05). A significant positive correlation was found between VCAM-1 and inflammatory measures like DAS28 and CRP in RA patients. Conclusions In RA, endothelial activation correlates with FMD, through inappropriate secretion of cytokines. Our, study findings support the possibility that systemic inflammation may represent a mechanistic link between adhesion molecules and vascular dysfunction. This suggests that the expression of cell adhesion molecules is up regulated by pro-inflammatory cytokines and association with endothelial dysfunction may have a central role in the mechanism of immune-mediated inflammation and atherosclerosis. This is the first study which shows a relationship between adhesion molecule and vascular function assessed by brachial artery flow mediated vasodilatation. This study opens the possibility of employing therapeutic agents to protect the vessels from the effects of adhesion molecules. References Wolfe F, Freundlich B, Straus WL. Increase in cardiovascular and cerebrovascular disease prevalence in rheumatoid arthritis. J Rheumatol 2003;30:36-40. Acknowledgements This study was supported by Research Grant from Universal Grant Commission, New Delhi [F. No.41-725/2012 (SR)]. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.5330

SAT0224 Amelioration of inflammatory disease activity and vascular inflammation with hmg-coa reductase inhibition and angiotensin receptor blockade in rheumatoid arthritis

Background: Rheumatoid Arthritis (RA) has 50% increased risk of cardiovascular (CV) mortality1. Similarities between atherosclerosis and RA and proven benefit of Angiotensin receptor Blockers and HMG-CoA reductase inhibitors in atherosclerotic vascular disease provide strong rationale to investigate the impact of Rosuvastatin, HMG-CoA reductase inhibitor and Olmesartan, an angiotensin receptor blocker on inflammatory disease activity and vascular inflammation in RA. Objectives: To investigate the impact of Rosuvastatin and Olmesartan on inflammatory disease activity and vascular inflammation in RA Methods: 84 RA patients randomized to 3 groups to receive 24 weeks of treatment with Rosuvastatin (Rvs) (10 mg/day, n=28), Olmesartan (OLME) (10 mg/day, n=28) and placebo (PL) (n=28) as an adjunct to existing stable antirheumatic drugs. 2 patients from the OLME group were lost to follow up. FMD was assessed by AngioDefender. EPCs were estimated by flow cytometry. Measures of vascular inflammation: serum nitrite, TBARS, adhesion molecules (ICAM-1 and VCAM-1) and lipids were measured at baseline and after treatment. In&xFB02;ammatory measures included DAS28, SDAI, CRP and ESR, pro-inflammatory cytokines (TNF-α, IL-6 and IL-1). SCORE system estimated the 10 year risk of a first fatal atherosclerotic event. Quality of life was assessed with HAQ-DI and SF-36.Figure 1A Effect on Flow Mediated Dilation (FMD). Rvs vs. OLME vs. PL (Rvs vs. PL (p<0.01), OLME vs. PL (p≤0.01), Rvs vs. OLME (p=0.03) after 24 weeks. Figure 1B Effect on Disease Activity Score of 28 joints (DA S28). Rvs vs. OLME vs. PL (Rvs vs. PL (p<0.01), OLME vs. PL. (p≤0.01), Rvs vs. OLME (p=0.08) after 24 weeks. Figure 1C Effect on C-Reactive Protein (CRP).Rvs vs. OLME vs. PL (Rvs vs. PL (p<0.01), OLME vs. PL (p≤0.01), Rvs vs. OLME (p=0.05) after 24 weeks. Figure 1D Effect on Tumour Necro sis Factor-alpha (TNF-α). Rvs vs. OLME vs. PL (Rvs vs. PL (p<0.01), OLME vs. PL (p≤0.01), Rvs vs. OLME (p=0.86) after 24 weeks. Results: At baseline, FMD correlated inversely with DAS28 (r= -0.42, p<0.05) and TNF- α (r= -0.50, p<0.05) and positively correlated with EPCs (r= 0.44, p<0.05) in all three groups indicating high inflammatory disease activity and decreased EPCs population associated with endothelial dysfunction. FMD also correlated inversely with CRP in both Rvs (r= -0.46, p<0.05) and OLME (r= -0.40, p<0.05) groups. After treatment, FMD improved significantly in the Rvs vs. OLME vs. PL group from their baseline levels, respectively {Rvs vs. PL (p<0.01), OLME vs. PL (p≤0.01), Rvs vs. OLME (p=0.03)} (Fig.1A). The improvement in FMD after treatment with Rvs was significantly greater than OLME [Rvs vs. OLME (p=0.03)]. EPCs and nitrite levels were improved significantly in both Rvs and OLME groups. A significant reduction was found in ICAM-1 after Rvs treatment (p<0.01) where as OLME significantly decreased VCAM-1 and TBARs (p=0.04), (p=0.01) respectively. Both Rvs and OLME resulted in significant reductions of DAS28 (figure 1B), SDAI, ESR, CRP (figure 1C), IL-6 and TNF-α (figure 1D) vs. PL. There was a significant reduction in the SCORE, HAQ-DI and SF-36 score after treatment with Rvs and OLME. Conclusions: Rvs and OLME ameliorate inflammatory disease activity and vascular inflammation in RA. Both Rvs and OLME lowers the TNF-α & IL-6 which down regulates the production of CRP and NO and improved EPC population and FMD. However, Rvs also favourably impacted ICAM-1 and lipid abnormalities while OLME has beneficial effect on VCAM-1, TBARs and blood pressure. Thus, both Rvs and OLME ameliorate inflammatory disease activity, reduce cardiovascular risk in context of vascular inflammation, endothelial dysfunction and EPCs biology. Reference 1López-Mejías R, Castañeda C, González-Juanatey C, et al. Autoimmunity Reviews2016;15:1013–1030. Disclosure of Interest: None declared