Inderjeet Verma

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.

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

SAT0133 Sudomotor dysfunction in rheumatoid arthritis patients in the absence of traditional cardiovascular risk

Background Rheumatoid arthritis (RA) is an autoimmune chronic inflammatory disease associated with cardiovascular autonomic neuropathy. Cardiovascular autonomic neuropathy is a significant risk predictor for sudden cardiac death in rheumatoid arthritis.1 Sudomotor dysfunction reflects small fibre neuropathy, cardiovascular autonomic neuropathy and peripheral sympathetic autonomic neuropathy.2 However, sudomotor dysfunction and its relationship with inflammatory measures remain unexplored in RA patients in the absence of traditional cardiovascular (CV) risk factors. Objectives The aim of present study was to assess the sudomotor function and its association with disease specific measures: ESR, CRP and DAS-28 in RA patients with no apparent conventional cardiovascular risk factor. Methods In this cross-sectional study, 60 RA patients fulfilling 2010 Rheumatoid Arthritis Classification Criteria3 and 40 age and sex-matched healthy controls were recruited. Sudomotor function was assessed using Sudoscan (Impeto Medical, Paris, France) through measurement of electrochemical skin conductance of hands and feet.2 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. Inflammatory measures such as ESR and CRP and DAS-28 (disease activity score in 28 joints) were determined. Results Rheumatoid arthritis patients had significantly impaired sudomotor function (56.90±12.95 vs. 76.15±8.45 μs, p<0.00, Figure 1A), elevated ESR (31.30±12.34 vs. 16.72±4.46, p<0.001) and CRP (10.55±3.81 vs. 3.81±1.03, p=0.002) as compared to healthy controls, respectively. The mean disease duration of RA patients was 9.15±5.76 and they had high disease activity (mean DAS-28, 4.60±1.72). Sudomotor function was found to be inversely correlated with ESR (r =0.42, p=0.001, Figure 1B), CRP (r =0.60, p<0.001, Figure 1C) and DAS-28 (r =0.38, p=0.003, Figure 1D). Conclusions Cardiovascular autonomic neuropathy occurs in RA in the absence of traditional CV risk factors. Sudomotor dysfunction is significantly associated with increased level of ESR, CRP and disease activity suggesting that increased inflammation may cause sudomotor dysfunction. References Milovanovic B et al. Srp Arh Celok Lek 138:26–32. Mayaudon H et al. Diabetes Metab. 2010;36:450–54. Aletaha D et al. Arthritis Rheum. 2010;62:2569–81. Acknowledgements None. Disclosure of Interest None declared

THU0193 Spironolactone as a Novel Dmard in Ankylosing Spondylitis: SPIR-as Study

Background Synthetic disease-modifying antirheumatic drugs (DMARDs) though effective have limitations often requiring use of expensive parenteral biologic DMARDs in ankylosing spondylitis. Hence there is a need for safe, efficacious economical therapies for management of disease and its co-morbidities. Anticytokine therapy with Biologic DMARDs is efficacious but has limitations. Given the anti-inflammatory and immunomodulatory potential of spironolactone (SPIR)1,2, we investigated the anti-inflammatory potential of SPIR in AS in randomized, placebo-controlled open label study. Objectives To investigate the anti-inflammatory effects of spironolactone in AS Methods Fifty ankylosing spondylitis patients fulfilling the 1984 Modified New York Criteria were randomized to receive 24 weeks of treatment with spironolactone (n=25, 2 mg/kg/day) or placebo (n=25) as an adjunct to existing stable antirheumatic drugs. Therapy results were evaluated by assessment of inflammatory measures BASDAI, ASDAS, BASFI, ESR and CRP and pro-inflammatory cytokines (TNF-α, IL-6 and IL-1) at baseline and after 24 weeks treatment. Assessment of endothelial function by brachial artery flow-mediated dilatation (FMD) and ultrasound assessment of carotid intima-media thickness (CIMT), ankle brachial index (ABI) and nitrite level was made. Circulating EPCs (CD34+ CD133+) were quantified by flow cytometry. Quality of life (QoL) was assessed using HAQ-DI Results The SPIR and placebo groups were well matched at baseline. Of the 50 randomized patients, 45 completed the study, 23 in the SPIR group and 22 in the placebo group. Two patients were excluded in the SPIR group (one due to protocol violation and other lost to follow-up) and three in the placebo group were lost to follow-up. After 24 weeks: inflammatory measures BASDAI, ASDAS, BASFI, ESR and CRP (All p<0.001) were significantly reduced after treatment with spironolactone but did not show significant change with placebo (p>0.05). Proinflammatory cytokines, TNF-α and IL-6, significantly reduced after treatment (Both p<0.001) in SPIR arm. After 24 weeks treatment, surrogates of vascular function including FMD, CIMT and nitrite level significantly improved p<0.001, p<0.001 and p=0.01 respectively in SPIR arm compared with placebo. EPCs significantly increased 0.027±0.009 to 0.033±0.005, p<0.001 after treatment with SPIR compared with Placebo 0.025±0.006 to 0.027±0.010, p=0.27. The effect of SPIR on IL-1 and ABI is less clear (p=0.063 and 0.065 respectively), though it showed a trend towards significance. QoL improved significantly in SPIR group as compared to placebo. A significant correlation was observed between clinical response, reflected by changes in BASDAI and the degree of increase in EPCs Conclusions First study to show that spironolactone significantly improves inflammatory disease activity, EPC biology and endothelial dysfunction in AS possibly through its anti-inflammatory effect via inhibition of proinflammatory cytokines. This anti-inflammatory and immunomodulatory effect of spironolactone may help to reduce disease activity as well as associated cardiovascular risk in AS. References Bendtzen K et al. Clin Exp Immunol. 2003;134:151–158. Syngle A et al. Arthritis Rheum. 2014;66 (11). S639. Acknowledgements We are very grateful to University Grant Commission, New Delhi (Govt. of India) for providing the research fellowship [No. F.10-15/2007 (SA-I)]. Disclosure of Interest None declared

AB0796 Disease Modifying Anti Rheumatic Drugs Improve Cardiovascular Autonomic Neuropathy in Psoriatic Arthritis

Background Cardiovascular autonomic neuropathy (CAN) is the commonest risk predictor for sudden cardiac death in autoimmune rheumatic diseases.1-2 As yet, there is no therapeutic treatment of cardiovascular autonomic neuropathy in psoriatic arthritis (PsA). Even, the impact of most commonly employed disease modifying antirheumatic drugs (DMARDs) therapy on cardiovascular autonomic neuropathy in PsA is not known. Objectives To investigate the efficacy of DMARDs on cardiovascular autonomic neuropathy in PsA. Methods In this perspective open label study, twenty DMARD naive PsA patients who fulfilling the CASPAR (Classification Criteria for Psoriatic Arthritis) criteria and 20 age and sex matched healthy controls were recruited. Cardiovascular autonomic neuropathy was diagnosed by applying the five cardiovascular reflex tests according to Ewing. Disease activity was assessed by 28-joint-count disease activity score (DAS28) and disease activity score in psoriatic arthritis (DAPSA). ESR was measured by Westergreen method and CRP level was determined using standard commercial kits. Autonomic measures were double blinded to the physician and patients for the study duration. Therefore, the patients were treated without influence of the autonomic function data. All clinical investigations were performed at baseline and after weeks 12. 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 (HR response to deep breath and standing) significantly (p<0.05) improved in patients with PsA, while there was no significant improvement in sympathetic function. 55% (11/20) DMARD naive patients had severe autonomic neuropathy score. After treatment, 72.7% (8/11) improvement was seen in severe autonomic neuropathy in DMARD naive PsA patients. Patients with normal cardiovascular autonomic function had no change in their cardiovascular autonomic function after 12 weeks treatment with synthetic DMARDs. Conclusions These study results suggest parasympathetic autonomic dysfunction is more prominent than sympathetic dysfunction in PsA. Synthetic DMARDs improved parasympathetic dysfunction in PsA. References Milovanovic B et al. Srp Arh Celok Lek. 2010; 138:26-32. Syngle et al. Clin Rheumatol. 2013;32:59-64. Acknowledgements We are very grateful to University Grant Commission, New Delhi (Govt. of India) for providing the research fellowship [No. F.10-15/2007 (SA-I)]. Disclosure of Interest None declared