vasoactive-intestinal-peptide and Scleroderma--Systemic

Impaired gastric slow waves, frequent gastrointestinal (GI) symptoms and altered GI peptides have been reported in Scleroderma (SSc) patients. The aim of this study was to investigate the associations among these three important components in GI dysmotility. Seventeen fasted SSc patients underwent four channel surface electrogastrography, measuring % of normal gastric slow waves or dysrhythmia. Patients completed a questionnaire designed by us to assess demographics, upper and lower GI symptoms (symptom presence, frequency and impact on quality of life, QOL), by YES/NO, Likert Scales and Visual Analogue Scales 1-100 mm (called GI Dysmotility Questionnaire, GIDQ) and health-related QOL by SF-36. Fasting plasma vasoactive intestinal peptide (VIP) and motilin levels were measured by peptide immunoassays. There were significant correlations between percentages of gastric dysrhythmias (bradygastria or arrhythmia) and a number of major GI symptoms such as nausea, abdominal bloating and pain. The plasma level of VIP was correlated positively with % dysrhythmia but negatively with % normal slow waves. Motilin was positively correlated with slow wave coupling (coordination). No major differences were noted in the measured peptides or gastric slow waves between limited SSc and diffuse SSc. Correlations were noted between SF-36 domain scores and our GIDQ scores. In SSc patients, gastric dysrhythmias are correlated with certain GI symptoms. Correlations are also noted between plasma VIP/Motilin levels and gastric slow waves. Thus in SSc, gastric dysrhythmias may be predictive of development of certain dyspeptic symptoms. Plasma VIP may be involved in the development of dysrhythmias.

Topics: Adult; Disease Progression; Electromyography; Electrophysiology; Female; Gastrointestinal Diseases; Humans; Male; Middle Aged; Motilin; Nausea; Peptides; Scleroderma, Systemic; Skin; Stomach; Surveys and Questionnaires; Vasoactive Intestinal Peptide

Autoantibodies capable of binding the immunoregulatory neuropeptide vasoactive intestinal peptide (VIP) were detected in the sera of a mouse strain prone to autoimmune disease due to the lpr mutation (MRL/lpr). The autoantibodies were not present in control wildtype MRL/lpr mice, but they were readily detected in humans without autoimmune disease. The binding was due to low affinity VIP recognition. Increased VIP binding activity was evident in patients with systemic lupus erythematosus but not systemic sclerosis, Sjögren's syndrome (SS), rheumatoid arthritis or autoimmune thyroiditis. Recombinant VIP binding Fv clones (fragment variable; the variable domains of the light and heavy chains antibody subunits joined with a peptide linker) were isolated from a phage display library prepared from lupus patients. One Fv clone displaying VIP-selective binding and several clones displaying cross-reactivity with unrelated peptides were identified. Replacement mutations in the VIP-selective clone were preferentially localized in the regions known to make contacts with the antigen, i.e. the complementarity determining regions, suggesting that the selective binding activity is due to immunological maturation of the antibodies. Frequent occurrences of autoantibody responses to VIP indicate that immunological tolerance to this neuropeptide can be readily broken. The depletion of VIP by specific antibodies in autoimmune disease may interfere with VIP regulation of T cells and inflammatory cells and result in further amplification of autoreactive immunological responses.

Topics: Animals; Autoantibodies; Autoimmunity; Enzyme-Linked Immunosorbent Assay; Humans; Immunoglobulin Fragments; Lupus Erythematosus, Systemic; Mice; Radioimmunoassay; Scleroderma, Systemic; Vasoactive Intestinal Peptide

To determine the circulating levels of nerve growth factor (NGF), neuropeptide Y (NPY), and vasoactive intestinal peptide (VIP) in systemic sclerosis (SSc), and to correlate these levels with clinical and laboratory features.. Forty four patients with SSc were evaluated for circulating NGF (immunoenzymatic assay), NPY and VIP (radioimmunoassay), anticentromere and antitopoisomerase I autoantibodies, lung disease (pulmonary function tests with carbon monoxide transfer factor (TLCO), ventilation scintiscan with 99mTc DTPA radioaerosol, high resolution computed tomography (HRCT), pulmonary pressure (echo colour Doppler)), heart disease (standard and 24 ECG, echocardiography), cutaneous involvement (skin score), joint involvement (evidence of tender or swollen joints, or both), peripheral nervous system (PNS) involvement (electromyography), rheumatoid factor, angiotensin converting enzyme (fluorimetric method), von Willebrand factor (ELISA), and erythrocyte sedimentation rate (ESR) (Westergren).. Circulating NGF levels in SSc were significantly increased compared with controls (p<0.00001) and significantly higher in the diffuse than in the limited subset of patients (p<0.01). Patients with articular disease had significantly higher levels of NGF. A significant indirect correlation between NGF levels and TLCO was detected (p<0.01), but no correlation was found between NGF and HRCT, DTPA, skin score, PNS involvement and angiotensin converting enzyme and von Willebrand factor levels, antitopoisomerase or anticentromere antibodies, and ESR. NGF levels increased progressively as the disease worsened. Similarly, VIP circulating levels were significantly increased in patients with SSc (p<0.001), whereas the increase of NPY levels did not reach statistical significance. However, both neuropeptides, following the same trend as NGF, increased as the disease worsened (skin score and lung disease).. The increase of NGF and VIP in patients with SSc, the former in the diffuse subset of the disease, and in patients with prominent articular disease, may suggest a link between neurotransmitters and the disease pathogenesis. Neuropeptide circulating levels seem to increase only in patients with the most severe disease.

Topics: Biomarkers; Case-Control Studies; Data Interpretation, Statistical; Female; Humans; Lung; Male; Middle Aged; Nerve Growth Factor; Neuropeptide Y; Neuropeptides; Scleroderma, Systemic; Skin; Statistics, Nonparametric; Vasoactive Intestinal Peptide

Recent studies suggest that esophageal dysmotility occurring in systemic sclerosis might be caused by neurotransmitter levels decrease. The aim of the present study is to value VIP plasma levels, and to relate them with the pressure of the inferior esophageal sphincter (IES) and the capillaroscopy score in a group of patients affected by Systemic Sclerosis (SSc).. Eleven subjects affected by SSc (eight male and three female, age from 30 to 72 years old) have been studied through esophageal manometry, capillaroscopy and VIP plasma levels evaluation. Fifteen healthy volunteers, as control group, have been enlisted.. Our results show a decrease of VIP plasma levels in patients with SSc compared with control group. The difference between two groups has statistical significance (p < 0.01). Capillaroscopy has shown remarkable microcirculatory impairment and the esophageal manometry proved a decreased IES pressure. The scores of capillaroscopy, VIP plasma levels and pressures of IES have been compared and it has been observed that there is a relationship between VIP plasma level and pressure of IES.. VIP plasma levels decrease enhances the role of the autonomic disorder in SSc and may contribute to produce the alteration of vascular tone as well as the gastroenteric musculature dysfunction.

Topics: Adult; Aged; Esophageal Motility Disorders; Esophagus; Female; Humans; Male; Microcirculation; Middle Aged; Scleroderma, Systemic; Vasoactive Intestinal Peptide

Systemic sclerosis is characterized by vascular dysfunction. Itch is sometimes present in early stages of the disease. This prompted us to study the innervation of the skin by immunocytochemistry. Antibodies to neuropeptide Y and vasoactive intestinal peptide were used for autonomic nerves. Sensory innervation was studied using antibodies to substance P and calcitonin gene-related peptide. Protein gene product 9.5 was used as a general neuronal marker. Skin biopsies from affected (lower arm) and non-affected (upper back) sites on 10 patients with systemic sclerosis and from corresponding sites on 10 sex- and age-matched healthy controls were studied. Regional variations were found in the occurrence of peptidergic nerve fibers. In the patients the density of nerve fibers (measured semiquantitatively) stained by the panneuronal marker was lower in affected than in unaffected skin (p < 0.05). There were no significant differences in peptidergic innervation between patients and controls. However, there was a tendency to higher density of neuropeptide Y-positive nerve fibers in the forearm skin in 6 to 10 patients, as compared to only 1 of 10 healthy controls.

Topics: Adult; Aged; Aged, 80 and over; Biopsy, Needle; Calcitonin Gene-Related Peptide; Case-Control Studies; Female; Humans; Immunohistochemistry; Male; Middle Aged; Nerve Fibers; Neuropeptide Y; Neuropeptides; Scleroderma, Systemic; Skin; Substance P; Vasoactive Intestinal Peptide

In 12 patients suffering from systemic sclerosis (SSc) the influence of autogenic training on the plasma level of the neuropeptides substance P and vasoactive intestinal peptide (VIP) was studied. Compared with healthy controls the SSc patients exhibited significantly elevated levels of substance P (mean +/- SD: 7.1 +/- 3.2 pmol/l vs 1.6 +/- 1.6 pmol/l). Apart from variations the VIP plasma concentration did not significantly differ from that in healthy controls (mean +/- SD 10.7 +/- 7.1 pmol/l versus 12.0 +/- 5.3 pmol/l). Autogenic training did not bring about any significant changes in the plasma levels of neuropeptides.

Topics: Adolescent; Adult; Aged; Arousal; Autogenic Training; Female; Fingers; Humans; Male; Middle Aged; Raynaud Disease; Reference Values; Regional Blood Flow; Scleroderma, Systemic; Substance P; Vasoactive Intestinal Peptide

Image analysis quantification was used to assess the results of immunocytochemistry for a neuronal marker and neuropeptides in digital skin biopsies from Raynaud's phenomenon (RP) and systemic sclerosis (SS) patients, to verify the possibility of a selective quantitative abnormality of immunoreactive nerves. The field area of specific immunostaining and nerve counts were evaluated on coded specimens, and the data compared by statistical analysis. Nerves immunoreactive for protein gene product 9.5 (PGP), a marker for neuronal elements, were decreased significantly in epidermal and subepidermal layers of digital skin in RP patients (P less than 0.0001). This change was paralleled by a decrease of calcitonin gene-related peptide (CGRP) immunoreactive nerves in the epidermis and around capillaries in the dermal papillae (P = 0.005). In the skin of RP patients, these changes were readily demonstrated by image analysis, although they were not always apparent on visual screening. In digital skin of SS patients, there was a generalized and very significant decrease of PGP, CGRP, and VIP immunoreactivities in all areas (P less than 0.0001). These results demonstrate that neuropeptide-containing nerves are involved in the digital pathology of RP and SS, and that image analysis quantification is an accurate and sensitive method for assessing morphological changes in pathological samples.

Topics: Adult; Aged; Aged, 80 and over; Calcitonin Gene-Related Peptide; Female; Humans; Image Processing, Computer-Assisted; Immunohistochemistry; Male; Middle Aged; Neuropeptides; Raynaud Disease; Scleroderma, Systemic; Skin; Ubiquitin Thiolesterase; Vasoactive Intestinal Peptide

Dysphagia has been successfully treated by low-frequency transcutaneous nerve stimulation (TNS) in two patients with achalasia and in six patients with systemic sclerosis. A 30- to 45-min stimulation session was followed by augmentation of peristalsis in the lower half of the esophagus and relaxation of the gastroesophageal sphincter, with relief of dysphagia. The sclerotic patients were also relieved of invaliding Raynaud's phenomenon. One 30-min daily stimulation session, and later one session every 2nd or 3rd day, was sufficient to prevent relapse. After months or years of TNS treatment the stimulation could in three patients be withdrawn with no recurrence. A stimulation session produced about 30% increase in plasma vasoactive intestinal polypeptides. Activation of this neuromodulator is considered to be the cause of the beneficial effects on dysphagia and Raynaud's phenomenon.

Topics: Electric Stimulation Therapy; Esophageal Achalasia; Esophagus; Female; Humans; Male; Middle Aged; Peristalsis; Radiography; Raynaud Disease; Scleroderma, Systemic; Skin Temperature; Transcutaneous Electric Nerve Stimulation; Vasoactive Intestinal Peptide