Efficacy and tolerability of DPP4 inhibitor, teneligliptin, on autonomic and peripheral neuropathy in type 2 diabetes: an open label, pilot study.

BACKGROUND: Diabetic neuropathy increases risk of cardiovascular disease, peripheral artery disease, foot amputation and overall mortality. Not only hyperglycaemia induced nerve damage is harder to repair using currently approved medications, but also, the use of these agents is often limited by the extent of pain relief provided and side effects. METHODOLOGY: In this prospective, open-label, pilot study, 20 type-2 diabetes mellitus patients (male/female=13/7, mean age- 56.1±8.04 years), meeting inclusion/exclusion criteria, were treated with dipeptidyl peptidase-4 (DPP-4) inhibitor, Teneligliptin, 20mg once a day for three months. Efficacy parameters: Sudomotor function (Sudoscan score); parasympathetic dysfunction assessed using Ewing's criteria i.e. heart rate response to -standing (HRS), -valsalva (HRV) and -deep breath (HRD); sympathetic dysfunction assessed as blood pressure response to -standing (BPS) and -handgrip (BPH); ankle brachial index (ABI), vibration perception threshold (VPT), C-reactive protein, glycemic profile and health related quality of life (HRQoL); and, tolerability parameters: complete blood count, liver function tests, serum creatinine, thyroid stimulating hormone, QT- interval and serum vitamin B12 levels, were measured. RESULTS: There was no statistical difference in BMI, SBP, DBP, HRD, BPH and all safety parameters. After 12 weeks treatment, there was improvement in HRS (p<0.01) and HRV (p<0.01), but not in HRD (p=0.12). BPS was significantly lowered (p <0.01), but not the BPH (p =0.06). Sudoscan score was increased, while VPT was significantly decreased (both p<0.01). CONCLUSION: Teneligliptin not only improves the glycemic status but also improves sudomotor function, peripheral and autonomic neuropathy, and reduces vascular inflammation in type 2 diabetes.

Association of sudomotor function with peripheral artery disease in type 2 diabetes.

Peripheral artery disease (PAD) is the major risk factor for cardiovascular disease and lower extremity amputation in patients with diabetes. Autonomic neuropathy is a risk factor for cardiovascular-related morbidity and mortality. Sudomotor dysfunction is well established in type 2 diabetes mellitus (T2DM) and reflects small fibre neuropathy, cardiovascular autonomic neuropathy and peripheral sympathetic autonomic neuropathy. However, the relationship between sudomotor dysfunction and PAD remains unexplored. Therefore, the aim of present study was to explore the association of sudomotor function with ankle-brachial index (ABI) and C-reactive protein (CRP) in T2DM. In this cross-sectional study, we recruited 36 consecutive type 2 diabetes patients and 20 age- and sex-matched healthy controls. Sudomotor function was assessed using Sudoscan (Sudoscan-Impeto Medical Device, EZS 01750010193, Paris, France), which detects sweat gland function through measurement of electrochemical skin conductance of both hands and feet. Measurement of ankle-brachial ABI was carried out with sphygmomanometer and Doppler device (Hadeco Bidop ES-100V3). Glycated haemoglobin (HbA1c), fasting plasma glucose, and inflammatory marker CRP were also measured. Type 2 diabetic patients had significantly impaired sudomotor function (48.14 ± 8.28 vs. 76.48 ± 6.72 µs), lower ABI (0.89 ± 0.25 vs. 1.15 ± 0.11) and elevated CRP (5.32 ± 2.41 vs. 2.45 ± 1.11 mg/l) as compared to healthy controls, respectively (p < 0.01). Sudoscan scores were found to be inversely correlated with CRP and HbA1c, and directly correlated with ABI (p < 0.05) in the patients. Sudomotor dysfunction is associated with significant peripheral artery disease, vascular inflammation and impaired glycaemic status.

Minocycline improves peripheral and autonomic neuropathy in type 2 diabetes: MIND study.

Diabetic peripheral neuropathy and diabetic autonomic neuropathy are serious and common complications of diabetes associated with increased risk of mortality and cardiovascular disease. We sought to evaluate the safety and efficacy of minocycline in type 2 diabetic patients with diabetic peripheral and autonomic neuropathy. In a randomized placebo controlled study, 50 outpatients were randomly assigned to receive 100 mg minocycline or placebo. Outcome measures included the vibration perception threshold (VPT), Leeds assessment of neuropathic symptoms and signs (LANSS), Pain Disability Index (PDI), Visual Analog Scale (VAS), beck depression inventory (BDI), health assessment questionnaire (HAQ) and autonomic neuropathy, assessed by cardiovascular reflex tests according to Ewing and peripheral sympathetic autonomic function was assessed by FDA approved Sudoscan. At baseline there were no significant differences between demographic variables and the neuropathy variables in the minocycline and placebo groups. After treatment, VPT significantly improved in the minocycline group as compared to the placebo group. Mean posttreatment scores on the LANSS, PDI and HAQ were significantly lower in the minocycline group compared with the placebo group. However, BDI and VAS significantly (p = 0.01) improved in both minocycline and placebo groups (Table 2). After treatment with minocycline, heart rate (HR) response to standing significantly improved, while there was a borderline significance toward a reduction in HR response to deep breath. These finding indicate that 6-week oral treatment with minocycline is safe, well tolerated and significantly improves peripheral and autonomic neuropathy in type 2 diabetic patients.

Angiotensin-Receptor Blockade Improves Inflammation and Endothelial Dysfunction in Ankylosing Spondylitis: ARB-AS Study.

Cardiovascular (CV) disease is the leading cause of premature death in ankylosing spondylitis (AS). Atherosclerosis and AS share similar pathogenic mechanisms. The proven benefits of angiotensin-receptor blockers (ARBs) in atherosclerotic cardiovascular disease and their role in immune mediation provide strong rationale to investigate its impact with olmesartan on inflammation and endothelial dysfunction in AS. To investigate the effect of olmesartan on inflammation and endothelial dysfunction in AS. 40 AS patients were randomized to receive 24 weeks of treatment with olmesartan (10 mg/day, n = 20) and placebo ( n = 20) as an adjunct to existing stable antirheumatic drugs. Markers of endothelial function included the following: flow-mediated dilation (FMD) assessed by AngioDefender, endothelial progenitor cells (EPCs) estimated by flow cytometry, nitrite (nitric oxide surrogate), intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and inflammatory measures including Bath ankylosing spondylitis disease activity index (BASDAI), ankylosing spondylitis disease activity score (ASDAS) and bath ankylosing spondylitis functional index (BASFI); erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP); proinflammatory cytokines (interleukin-1 [IL-1], IL-6, tumor necrosis factor-α [TNF-α]) and marker of oxidative stress- thiobarbituric acid reactive substances (TBARS) estimated at baseline and after treatment. Health assessment questionnaire disability index (HAQDI), 36-item short form survey (SF-36), and systematic coronary risk evaluation (SCORE) were estimated using standard tools. FMD improved significantly in the olmesartan group (5.83 ± 0.31% to 7.68 ± 0.27%, p ≤ 0.05) as compared with placebo (5.89 ± 0.35% to 6.04 ± 0.32%, p = 0.33). EPC population, nitrite, VCAM-1, and TBARS levels improved significantly in olmesartan group as compared with placebo ( p ≤ 0.05). Olmesartan significantly decreased ASDAS, BASDAI, BASFI, ESR, CRP, IL-6, TNF-α, and SCORE as compared with placebo. HAQDI and SF-36 (PH) scores improved significantly in olmesartan group as compared with placebo. Olmesartan reduces inflammatory disease activity, improves quality of life (QOL), and decreases CV risk demonstrating the immunomodulatory, vasculoprotective, and cardioprotective potential of this drug in 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.

Nitric Oxide: Link between Inflammation and Endothelial Dysfunction in Rheumatoid Arthritis.

Nitric oxide (NO) plays an important role in inflammatory joint disease and endothelial function. Endothelial dysfunction has been attributed to a reduction in NO bioactivity in rheumatoid arthritis (RA). However, the relationship of NO with inflammation and endothelial dysfunction in RA has not yet been investigated. To investigate the relationship of nitrite with inflammation and endothelial dysfunction in RA. Total 28 patients satisfying 2010 Rheumatoid Arthritis Classification Criteria were recruited for the study. Serum nitrite estimation was performed by Griess reaction. Flow-mediated dilation (FMD) assessed using AngioDefender. Inflammatory disease activity measures included disease activity score of 28 joints (DAS28), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Proinflammatory cytokines (TNF-α, IL-6, and IL-1) measured using standard ELISA kits. Twenty-five healthy controls matched for age and sex were included for comparison. The serum nitrite level in patients with RA was markedly elevated as compared with controls ( p < 0.05). FMD was significantly impaired in RA patients than controls ( p < 0.05). DAS28 was significantly higher in RA patients ( p < 0.05). Levels of ESR, CRP, TNF-α, IL-1, and IL-6 were significantly higher in RA patients than controls ( p < 0.05). Significant positive correlation was observed between nitrite and CRP ( r = 0.46, p < 0.05), TNF-α ( r = 0.53, p < 0.05), and inverse correlation with FMD ( r =0.62, p < 0.05). Inflammatory disease activity and endothelial dysfunction in RA are associated with increased concentration of proinflammatory cytokines and NO. Inflammatory triggered release of cytokines induced NO production that mediates endothelial dysfunction. These findings suggest a role for NO in inflammation-induced endothelial dysfunction in RA.

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

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)-α 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-α 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.

Cost-effective analysis of disease-modifying anti-rheumatic drugs in rheumatoid arthritis.

The main objective of the study was to perform the pharmacoeconomic analysis of synthetic disease-modifying anti-rheumatic drugs in rheumatoid arthritis patients. A prospective, observational study was conducted in 98 rheumatoid arthritis (RA) patients meeting 2010 Rheumatoid Arthritis Classification Criteria. Treatment-naive RA patients were initiated on synthetic disease-modifying anti-rheumatic drugs (DMARD/s) and followed up for 3 months. Average cost-effectiveness analysis was done by taking Health Assessment Questionnaire Disability Index (HAQ-DI) score as a measure of effectiveness. Out of the 98 RA patients, 15.30% were males and 84.69% females. 80.61% RA patients are seropositive. Majority of the study population patients (55%) were on combination of three synthetic DMARDs and almost a quarter (24.48%) were on combination of two synthetic DMARDs. The mean value of DAS 28 at baseline was 6.07 ± 1.33 and after 3 months treatment, the mean was 3.84 ± 1.11. The mean disability index measured by HAQ-DI was significantly reduced from 1.43 ± 0.71 to 0.81 ± 0.61, p < 0.001, after 3 months treatment. The direct medical cost of treatment of RA per month is 997.05 rupees. The average cost-effectiveness ratio of combination of synthetic DMARDs was 1533.92 rupees. Treatment of RA with synthetic DMARDs controls disease activity and improves disability with reasonable cost of treatment. The majority of the direct medical cost is attributable to cost of medicine and laboratory investigation. Use of quality generic drugs and an early diagnosis would minimize the economic burden on the patient.

Atherosclerosis in Psoriatic Arthritis: A Multiparametric Analysis Using Imaging Technique and Laboratory Markers of Inflammation and Vascular Function.

Cardiovascular disease is one of the leading causes of death in psoriatic arthritis (PsA). Pathogenesis of accelerated atherosclerosis in PsA remains to be elucidated. Endothelial dysfunction (ED) often precedes manifesting atherosclerosis. This study aims to assess carotid intima-media thickness (CIMT), a marker of atherosclerosis in PsA, in context of markers of inflammation and vascular function. A cross-sectional study was performed in 18 PsA patients who were compared with 18 controls matched for age and sex. Flow-mediated dilatation (FMD) assessed by AngioDefender (Everist Health, Ann Arbor, MI), endothelial progenitor cells (EPCs) quantified by flow cytometry and CIMT measured ultrasonographically. Inflammatory measures included disease activity score of 28 joints count and disease activity index in psoriatic arthritis. We also assayed markers of inflammation, including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), proinflammatory cytokines (interleukin [IL]-1, IL-6, and tumor necrosis factor [TNF]-α), and endothelial dysfunction, including lipids, intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and EPCs. CIMT is significantly higher in PsA patients compared with controls (0.062 ± 0.18 vs. 0.045 ± 0.10 cm, p < 0.01) whereas FMD%, EPCs%, and high-density lipoproteins (HDL) cholesterol are significantly reduced in PsA compared with controls (p < 0.05). Compared with controls, PsA patients had significantly increased concentrations of ESR, CRP, TNF-α, IL-6, ICAM-1, and VCAM-1. In PsA, CIMT positively correlated with IL-6 and ICAM-1 and inversely correlated with FMD, HDL, and EPCs (p < 0.05). In PsA, FMD and CIMT were impaired, indicating endothelial dysfunction and accelerated atherosclerosis, respectively. PsA-related inflammatory mechanisms (TNF-α, IL-6) and markers of vascular function (CRP, ICAM-1, and EPCs) may all be involved in the development of vascular disease in PsA. Cytokine-triggered inflammation upregulates expression of adhesion molecules, depletes EPCs with endothelial dysfunction, and increased CIMT in PsA.

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.

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.

AIM: 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. METHODS: Endothelial progenitor cells were measured in peripheral blood samples from 20 AS and 20 healthy controls by flow cytometry on the basis of CD34 and CD133 expression. Disease activity was evaluated by using Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Functional ability was monitored by using Bath Ankylosing Spondylitis Functional Index (BASFI). RESULTS: EPCs were depleted in AS patients as compared to healthy controls (CD34(+) /CD133(+) : 0.027 ± 0.010% vs. 0.044 ± 0.011%, P < 0.001). EPC depletions were significantly associated with disease duration (r = -0.52, P = 0.01), BASDAI (r = -0.45, P = 0.04) and C-reactive protein (r = -0.5, P = 0.01). CONCLUSION: This is the first study to demonstrate endothelial progenitor cell depletion in AS patients. EPC depletions inversely correlate with disease duration, disease activity and inflammation, suggesting the pivotal role of inflammation in depletion of EPCs. EPC would possibly also serve as a therapeutic target for preventing cardiovascular disease in AS.

Interleukin-6 blockade improves autonomic dysfunction in rheumatoid arthritis.

Autonomic nervous system (ANS) involvement in rheumatoid arthritis (RA) is well recognised and contributes to arrhythmia and sudden death. However, there is no study documented the therapeutic efficacy on autonomic neuropathy (AN) in RA. This is the first reported observation of improvement in AN with interleukin-6 (IL-6) blockade with tocilizumab in RA. We report a case of 61-year old female with seropositive RA with severe disease activity, investigated for autonomic neuropathy. A battery of non invasive tests was used for accurate assessment of AN function based on assessment of peripheral sympathetic autonomic function and cardiovascular reflex tests. Tocilizumab 8 mg/kg intravenous infusion at weeks 0, 4 and 8 was added to her treatment regimen. Cardiovascular autonomic function tests at baseline showed marked abnormalities of parasympathetic cardiovascular reflexes. After the first dose of tocilizumab there was a rapid improvement with normalization of parasympathetic autonomic activity with subsequent doses. IL-6 blockade with tocilizumab seems to have the potential to improve the vagus nerve mediated parasympathetic neuropathy and hence has the potential to restore cholinergic anti-inflammatory pathway.

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.

Rosuvastatin improves endothelial dysfunction in ankylosing spondylitis.

Enhanced cardiovascular risk in ankylosing spondylitis (AS) provides a strong rationale for early therapeutical intervention. In view of the proven benefit of statins in atherosclerotic vascular disease, we aimed to investigate the effect of rosuvastatin on endothelial dysfunction (ED) and inflammatory disease activity in AS. In a single-blind, placebo-controlled, parallel study, 32 AS patients were randomized to receive 24 weeks of treatment with rosuvastatin (10 mg/day, n = 17) and placebo (n = 15) as an adjunct to existing stable antirheumatic drugs. Flow-mediated dilatation (FMD) was assessed by AngioDefender™ (Everest Genomic Ann Arbor, USA). Inflammatory measures (BASDAI, BASFI, CRP and ESR) and pro-inflammatory cytokines (tumour necrosis factor-alpha [TNF-α], interleukin-6 [IL-6] and interleukin-1 [IL-1]) were measured at baseline and after treatment. Lipids and adhesion molecules (intracellular adhesion molecule [ICAM-1] and vascular cell adhesion molecule [VCAM-1]) were estimated at baseline and after treatment. At baseline, inflammatory measures, pro inflammatory cytokines and adhesion molecules were elevated among both groups. After treatment with rosuvastatin, FMD improved significantly (p < 0.01). Levels of inflammatory measures, TNF-α, IL-6 and ICAM-1 decreased significantly (p < 0.01) after treatment with rosuvastatin. Rosuvastatin exerted positive effect on lipid spectrum. No significant change in the placebo group. Significant negative correlation was observed between FMD and IL-6, ICAM-1, CRP after treatment with rosuvastatin. First study to show that rosuvastatin improves inflammatory disease activity and ED in AS. Rosuvastatin lowers the proinflammatory cytokines, especially IL-6 and TNF-α, which downregulates adhesion molecules and CRP production which in turns improves ED. Improvement in ED in AS occurs through both cholesterol-independent and cholesterol-dependent pathways. Rosuvastatin can mediate modest but clinically apparent anti-inflammatory effects with modification of vascular risk factors in the context of high-grade autoimmune inflammation of AS.

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.

Autonomic dysfunction in psoriatic arthritis.

Autonomic nervous system (ANS) involvement has been studied in systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, Sjogren's syndrome, and ankylosing spondylitis but still has not been studied in psoriatic arthritis (PsA). The aim of this study was to investigate the prevalence and the nature of autonomic neuropathy in patients with PsA. Sixteen patients of PsA and 15 age and sex matched control subjects were studied prospectively using a battery of noninvasive tests. Cardiovascular autonomic neuropathy (CAN) was diagnosed by applying four cardiovascular reflex tests, and peripheral sympathetic autonomic function was assessed by Sudoscan. Patients with PsA had significantly higher heart rate response to standing (p = 0.01), blood pressure response to standing (p = 0.02), and Sudoscan (p = 0.01) when compared with healthy controls. Fifty percent (n = 8) of the patients with PsA had at least two or more abnormal CAN parasympathetic dysfunction; of these, 18.75% (n = 3) of the patients had abnormal parasympathetic and sympathetic dysfunction, 68.7% (n = 11) and 25% (n = 4) of the patients had at least one abnormal parasympathetic and sympathetic parameters, respectively, and 37.5% (n = 6) of the patients had moderate sudomotor dysfunction. About 18.7% (n = 3) of our parasympathetic dysfunction patients had autonomic symptoms. None of healthy volunteers had abnormal ANS dysfunction. Heart rate response significantly correlated with erythrocyte sedimentation rate (p < 0.05) and C-reactive protein (p < 0.05) levels. In conclusion, cardiovascular autonomic and peripheral sympathetic neuropathy occurs in PsA. Parasympathetic function is more commonly found to be abnormal than sympathetic function. There is no correlation of peripheral sympathetic dysfunction with cardiovascular autonomic neuropathy.

Spironolactone improves endothelial dysfunction in ankylosing spondylitis.

Chronic inflammation in ankylosing spondylitis (AS) is associated with vascular endothelial dysfunction which leads to accelerated atherosclerosis. Accelerated atherosclerosis contributes to premature cardiovascular disease and increased cardiovascular mortality in AS. Spironolactone inhibits the production of proinflammatory cytokines and improves endothelial dysfunction in rheumatoid arthritis. This study aimed to determine the effect of spironolactone in antitumor necrosis factor (TNF)-naive AS patients. Twenty anti-TNF-naive AS patients (M/F = 15/5) with high disease activity (Bath ankylosing spondylitis disease activity index, BASDAI >4) despite treatment with stable doses of conventional disease-modifying antirheumatic drugs were investigated. Inflammatory disease activity (BASDAI and Bath ankylosing spondylitis functional index (BASFI) scores, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) levels), serum nitrite concentration, and endothelium-dependent and -independent vasodilatation of the brachial artery were measured at baseline and after 12 weeks of therapy with oral spironolactone 2 mg/kg/day. Ten healthy subjects matched for age and sex acted as the control. Flow-mediated dilation (FMD) in AS patients at baseline was significantly impaired compared with healthy control group (p < 0.001). After treatment, FMD improved from 11.3 ± 1.70 to 24.69 ± 2.34% (p < 0.001); nitrite concentration reduced from 7.9 ± 0.28 to 4.79 ± 0.19 µmol/L (p < 0.001); ESR from 33.8 ± 4.38 to 15.13 ± 1.30 mm in the first hour, (p < 0.001); and CRP level from 22.39 ± 3.80 to 6.3 ± 1.29 mg/dL, (p < 0.001). BASDAI and BASFI also reduced significantly (p < 0.001). The study suggests that in AS endothelial dysfunction is a part of the disease process. This is the first study to show that treatment with spironolactone improves both endothelial dysfunction and inflammatory disease activity in AS.

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). METHODS: Twenty-four patients with established active RA with high disease activity (Disease Activity Score of 28 joints [DAS28 score] > 5.1) despite treatment with stable doses of conventional disease-modifying antirheumatic drugs were investigated. Inflammatory disease activity (DAS28 and Health Assessment Questionnaire-Disability Index [HAQ-DI] scores, erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP]), markers of endothelial dysfunction, serum nitrite concentration and endothelium-dependent and -independent vasodilation of the brachial artery were measured before and after 12 weeks therapy with twice a day oral AGEs inhibitor. RESULTS: After treatment, flow-mediated vasodilation improved from 9.64 ± 0.65% to 15.82 ± 1.02% (P < 0.01), whereas there was no significant change in endothelium-independent vasodilation with nitroglycerin and baseline diameter; serum nitrite concentration significantly reduced from 5.6 ± 0.13 to 5.1 ± 0.14 µmol/L (P = 0.004), ESR from 63.00 ± 3.5 to 28.08 ± 1.5 mm in the first h (P < 0.01) and CRP levels from 16.7 ± 4.1 to 10.74 ± 2.9 mg/dL (P < 0.01). DAS28 and HAQ-DI scores were significantly reduced, from 5.9 ± 0.17 to 3.9 ± 0.17 (P < 0.01) and 4.6 ± 0.17 to 1.7 ± 0.22 (P < 0.01), respectively. CONCLUSIONS: Advanced glycation end products inhibitor improves endothelial dysfunction and inflammatory disease activity in RA. In RA, endothelial dysfunction is part of the disease process and is mediated by AGEs-induced inflammation.