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.

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.

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.

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 ( < 0.05). FMD was significantly impaired in RA patients than controls ( < 0.05). DAS28 was significantly higher in RA patients ( < 0.05). Levels of ESR, CRP, TNF-α, IL-1, and IL-6 were significantly higher in RA patients than controls ( < 0.05). Significant positive correlation was observed between nitrite and CRP ( = 0.46, < 0.05), TNF-α ( = 0.53, < 0.05), and inverse correlation with FMD ( =0.62, < 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 (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%, < 0.001) reduced in patients with AS compared with healthy controls. Endothelial function (7.35 ± 2.54 vs. 10.27 ± 1.73, = 0.002), CIMT (0.63 ± 0.01 vs. 0.35 ± 0.02, < 0.001), and inflammatory markers were also significantly ( < 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.