Increased urinary F2-isoprostanes in systemic sclerosis, but not in primary Raynaud's phenomenon: effect of cold exposure.
OBJECTIVE: F2-isoprostanes are free radical-dependent arachidonic acid metabolites that are used as clinical markers of lipid peroxidation in systemic sclerosis (SSc) and other microvascular diseases. The objectives of this study were to determine whether the basal urinary levels of F2-isoprostane in SSc patients differ from those in patients with primary Raynaud's phenomenon (RP) and to investigate whether F2-isoprostane formation correlates with the cutaneous microvascular perfusion decrease following cold exposure in SSc patients, patients with primary RP, and healthy controls. METHODS: Eleven women with RP secondary to SSc, 11 women with primary RP, and 11 healthy women were exposed to decreasing room temperature, from 25 degrees C to 15 degrees C, for 40 minutes. Urine samples were obtained before and after the test for gas chromatography/electronic impact mass spectrometry quantification of 15-F(2t)-isoprostane (15-F(2t)-IsoP; also called isoprostaglandin F(2alpha) type III). Cutaneous blood flow was monitored using a laser Doppler perfusion imager. RESULTS: The mean +/- SEM urinary 15-F(2t)-IsoP levels at baseline in SSc patients (178 +/- 32 pmoles/mmole of creatinine) were 1.9 times higher than those in healthy controls (95 +/- 11 pmoles/mmole of creatinine) and 1.7 times higher than those in patients with primary RP (107 +/- 19 pmoles/mmole of creatinine) (P < 0.05 for controls and patients with primary RP versus SSc patients). No significant correlation was found between basal urinary 15-F(2t)-IsoP levels and the temperature or cutaneous blood flow decrease in response to the whole-body cooling. Furthermore, the 15-F(2t)-IsoP response to the cooling test was not correlated with the cutaneous blood flow decrease. CONCLUSION: Lipid peroxidation is increased in SSc patients, but not in patients with primary RP. Cold exposure leads to a significant but small increase in 15-F(2t)-IsoP levels that is independent of the cutaneous blood flow decrease. F2-isoprostane quantification may be an interesting pharmacologic tool for monitoring responses to antioxidant treatment in SSc patients. (+info)
Autonomic nervous activity during hand immersion in cold water in patients with vibration-induced white finger.
Autonomic nervous function in response to cold was investigated in 21 patients with vibration-induced white finger (VWF) and 17 healthy controls of similar age, using power spectral analysis of heart rate variability. In a supine position, electrocardiogram and skin temperature of both index fingers were measured during immersion of right hand in cold water at 10 degrees C for 10 minutes. Autonomic nervous activity was evaluated from the power of the low-frequency component (LF: 0.02-0.15 Hz), the high-frequency component (HF: 0.15-0.40 Hz) and the ratio of the LF to the HF power (LF/HF ratio). The LF/HF ratio, an index of sympathetic nervous activity, significantly increased during the immersion in the VWF patients, but did not significantly increase in the controls. The LF/HF ratio was then significantly greater in the patients than in the controls during the first 1-2 minutes of the immersion. The HF power related to parasympathetic nervous activity did not change significantly in either group. Finger skin temperature of the immersed right hand was significantly lower in the VWF patients than in the controls during the last five minutes of the immersion and in the recovery period. The present results indicate that sympathetic nervous response to cold is significantly enhanced in VWF patients. The exaggerated sympathetic response to cold in these patients is considered to contribute to the enhanced vasoconstriction of their extremities. (+info)
Effect of ceramic-impregnated "thermoflow" gloves on patients with Raynaud's syndrome: randomized, placebo-controlled study.
OBJECTIVE: To determine the efficacy of ceramic impregnated gloves in the treatment of Raynaud's syndrome. DESIGN: Double-blind, placebo-controlled study. SETTING: Teaching hospital outpatient clinic. PARTICIPANTS: Ninety-three patients meeting the "Pal" criteria for Raynaud's syndrome. INTERVENTIONS: Treatment period of three months with use of ceramic-impregnated gloves. MAIN OUTCOME MEASURES: Primary end points: Pain visual analogue scale ratings and diary; Disabilities of the Arm, Shoulder, Hand questionnaire; Jamar grip strength; Purdue board test of hand dexterity. Secondary end points: Infrared skin temperature measurements; seven-point Likert scale rating of treatment. RESULTS: In 60 participants with complete data, improvements were noted in the visual analogue scale rating (p=0.001), DASH score (p=0.001), Jamar grip strength (p=0.002), infrared skin fingertip temperature (p=0.003), Purdue hand dexterity test (p=0.0001) and the Likert scale (p=0.001) with ceramic gloves over the placebo cotton gloves. CONCLUSION: The ceramic-impregnated "thermoflow" gloves have a clinically important effect in Raynaud's syndrome. (+info)
Raynaud's phenomenon, vibration induced white finger, and difficulties in hearing.
BACKGROUND: An association has previously been reported between finger blanching and hearing difficulties, but only in workers with exposure to noise and hand transmitted vibration (HTV). AIMS: To explore the association in a community sample, including cases who lacked occupational exposure to noise or HTV. METHOD: A questionnaire was mailed to 12 606 subjects aged 35-64 years, chosen at random from the age-sex registers of 34 British general practices. Inquiry was made about years of employment in noisy jobs, lifetime exposure to HTV, hearing difficulties and tinnitus, and lifetime history of cold induced finger blanching. Subjects were classed as having severe hearing difficulty if they used a hearing aid or found it difficult or impossible to hear conversation in a quiet room. Associations of finger blanching with hearing difficulties and tinnitus were analysed by logistic regression. RESULTS: Among 8193 respondents were 185 who reported severe hearing difficulty and 1151 who reported finger blanching. After adjustment for age and years of work in noisy jobs, hearing difficulty was about twice as common in men and women who reported finger blanching, including those who had never been importantly exposed to noise and in those never exposed to HTV. CONCLUSIONS: These data support an association between finger blanching and hearing loss, which is not explained by confounding occupational exposure to noise, and suggest that it may extend to causes of blanching other than vibration induced white finger. Further investigations are warranted to confirm the association and explore possible mechanisms, such as sympathetic vasoconstriction in the cochlea. (+info)
Prevention of vascular damage in scleroderma with angiotensin-converting enzyme (ACE) inhibition.
Great strides have been made in identifying and managing the organ-based complications of systemic sclerosis (SSc). There is no room for the nihilism towards treating this disease that used to be so prevalent. However, there is still relatively little hard evidence on which to base treatment decisions. Previous trials have been constrained by the low disease prevalence and the difficulty in recruiting sufficient patients especially with disease of recent onset. The results of past trials have often been confounded by the failure to recognize the marked heterogeneity of SSc and the inclusion of patient subsets with widely varying disease expression, course and outcome. It is recognized that progress will only be made in this area with coordinated multicentre studies. As a result, national and international networks of clinicians with expertise in the management of SSc have been formed. In the UK, the Systemic Sclerosis Study Group has established a national scleroderma register and, together with the Scleroderma Special Interest Group of the British Society for Rheumatology (BSR), a multicentre base for therapeutic studies. As a result of developments in our understanding of the pathogenesis of scleroderma and our ability to subset patients more effectively, a number of rather more rational approaches to treating the disease and its complications are being tested. In parallel with this, considerable progress is being made in developing universally agreed measures of disease activity and severity and in identifying surrogate laboratory markers of disease activity that are relevant to therapeutic studies. These multicentre trials need substantial funding and often do not attract support from the pharmaceutical industry. It was because of the difficulty in financing long-term, multicentre studies in uncommon conditions that the ARC/BSR Clinical Trials Programme was established. The QUINS trial, which is funded by this Programme, is described here as an example of one of several therapeutic protocols being developed by the UK Systemic Sclerosis Study Group that are currently being tested in multicentre trials. Contact details are provided in the appendix for clinicians who are interested in registering patients on the UK Scleroderma Register or participating in this or in the other therapeutic studies. (+info)
Measuring disease activity and functional status in patients with scleroderma and Raynaud's phenomenon.
OBJECTIVE: To document disease activity and functional status in patients with scleroderma (systemic sclerosis [SSc]) and Raynaud's phenomenon (RP) and to determine the sensitivity to change, reliability, ease of use, and validity of various outcome measures in these patients. METHODS: Patients with SSc and moderate-to-severe RP participating in a multicenter RP treatment trial completed daily diaries documenting the frequency and duration of RP attacks and recorded a daily Raynaud's Condition Score (RCS). Mean scores for the 2-week periods prior to baseline (week 0), end of trial (week 6), and posttrial followup (week 12) were calculated. At weeks 0, 6, and 12, physicians completed 3 global assessment scales and performed clinical assessments of digital ulcers and infarcts; patients completed the Health Assessment Questionnaire (HAQ), the Arthritis Impact Measurement Scales 2 (AIMS2) mood and tension subscales, 5 specific SSc/RP-related visual analog scales (VAS), and 3 other VAS global assessments. We used these measures to document baseline disease activity and to assess their construct validity, sensitivity to change, and reliability in trial data. RESULTS: Two hundred eighty-one patients (248 women, 33 men; mean age 50.4 years [range 18-82 years]) from 14 centers participated. Forty-eight percent had limited cutaneous SSc; 52% had diffuse cutaneous SSc. Fifty-nine patients (21%) had digital ulcers at baseline. Patients had 3.89 +/- 2.33 (mean +/- SD) daily RP attacks (range 0.8-14.6), with a duration of 82.1 +/- 91.6 minutes/attack. RCS for RP activity (possible range 0-10) was 4.30 +/- 1.92. HAQ scores (0-3 scale) indicated substantial disability at baseline (total disability 0.86, pain 1.19), especially among the subscales pertaining to hand function (grip, eating, dressing). AIMS2 mood and tension scores were fairly high, as were many of the VAS scores. Patients with digital ulcers had worse RCS, pain, HAQ disability (overall, grip, eating, and dressing), physician's global assessment, and tension, but no significant difference in the frequency of RP, duration of RP, patient's global assessment, or mood, compared with patients without digital ulcers. VAS scores for digital ulcers as rated by the patients were not consistent with the physician's ratings. Factor analysis of the 18 measures showed strong associations among variables in 4 distinct domains: disease activity, RP measures, digital ulcer measures, and mood/tension. Reliability of the RCS, HAQ pain and disability scales, and AIMS2 mood and tension subscales was high. The RP measures demonstrated good sensitivity to change (effect sizes 0.33-0.76). CONCLUSION: Our findings demonstrate that the significant activity, disability, pain, and psychological impact of RP and digital ulcers in SSc can be measured by a small set of valid and reliable outcome measures. These outcome measures provide information beyond the quantitative metrics of RP attacks. We propose a core set of measures for use in clinical trials of RP in SSc patients that includes the RCS, patient and physician VAS ratings of RP activity, a digital ulcer/infarct measure, measures of disability and pain (HAQ), and measures of psychological function (AIMS2). (+info)
Association of novel polymorphisms with the expression of SPARC in normal fibroblasts and with susceptibility to scleroderma.
OBJECTIVE: Fibroblasts from patients with systemic sclerosis (SSc) have an activated phenotype characterized by increased synthesis of extracellular matrix (ECM) components. SPARC (secreted protein, acidic and rich in cysteine) regulates the deposition or assembly of ECM components. The aim of this study was to investigate the role of SPARC in SSc susceptibility by functional and genetic association studies. METHODS: Complementary DNA (cDNA) microarrays were used to obtain gene expression data on cultured dermal fibroblasts from SSc patients. SPARC protein levels were assessed by Western blotting. Five polymorphic microsatellite markers within 5 cM of the SPARC gene (chromosome 5q31-32) were genotyped in Choctaw Indians, a population previously shown to have a high prevalence of SSc. Discovery of single-nucleotide polymorphisms (SNPs) was accomplished by sequencing the SPARC cDNA. These SNPs were then genotyped in a multi-ethnic cohort of SSc patients to determine potential associations with disease susceptibility in a broader population of SSc patients, as well as with various clinical and immunologic features of SSc. The functional relevance of these SNPs with regard to transcript stability of SPARC was also assessed. RESULTS: Microarrays demonstrated increased expression of SPARC, along with other ECM genes, in SSc patients compared with normal controls. SSc fibroblasts also had increased SPARC protein levels. Three of 5 microsatellite markers near SPARC showed significant associations with SSc in the Choctaw SSc patients. Sequencing of SPARC cDNA revealed 3 novel SNPs in the 3'-untranslated region at +998 (C-->G), +1551 (C-->G), and +1922 (T-->G). Homozygosity for the C allele at SNP +998 was significantly increased in SSc patients across ethnic lines. SPARC SNPs +1551 and +1922 demonstrated correlations with Raynaud's phenomenon and pulmonary fibrosis, respectively. Functional studies of SPARC SNP +998 in normal fibroblast cultures suggested a correlation between the SNP +998 C allele polymorphism and an increased messenger RNA half-life. CONCLUSION: This study is the first to show that polymorphisms of the SPARC gene are associated with susceptibility to, and clinical manifestations of, SSc and that they may also be functionally important in influencing SPARC expression in skin fibroblasts. (+info)
Thoracoscopic sympathectomy for palmar hyperhidrosis and Raynaud's phenomenon of the upper limb and excessive facial blushing: a five year experience.
Primary hyperhidrosis of the palms, face, and axillae has a strong negative impact on social and professional life. A retrospective analysis of 40 laparoscopic transaxillary thoracic sympathectomies performed in a district general hospital over a five year period was undertaken in order to determine the effectiveness of this procedure. A postal questionnaire was sent to all patients to assess the benefit from the operation; postoperative pain and time off work were collated. Immediate failure was noted in three patients, of whom two later underwent successful reoperation. Recurrence was noted in three patients (8%). Though immediate complications were minimal, the major long term postoperative morbidity was compensatory hyperhidrosis on the back, chest, and thigh (77%) along with gustatory sweating over the face (22%). Thoracoscopic sympathectomy is a safe, effective, and minimally invasive surgical treatment for hyperhidrosis, Raynaud's phenomenon of the upper limb, and excessive facial blushing; however, the chance of long term compensatory hyperhidrosis is high. (+info)