A man with diabetes and a swollen leg.
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Adult↗
Biomedical subjects
F M Wigley
Publications and source records attributed to F M Wigley.
Production of type 2 cytokines by CD8+ lung cells is associated with greater decline in pulmonary function in patients with systemic sclerosis.
OBJECTIVE: This study addresses the hypothesis that a profibrotic pattern of cytokines is produced in the lungs of patients with systemic sclerosis (SSc) and causes fibrosis. METHODS: Using a reverse transcriptase-polymerase chain reaction technique, interleukin-4 (IL-4), IL-5, and interferon-gamma (IFNgamma) messenger RNA (mRNA) were measured in unseparated CD8+ and CD4+ bronchoalveolar lavage (BAL) cells from SSc patients and healthy controls. To confirm the results, CD8+ T cells were cloned from BAL fluids, and the pattern of cytokine mRNA made by these cells was determined. Serial pulmonary function tests were done. RESULTS: BAL cells from healthy controls made IFNgamma mRNA, with no or little IL-4 or IL-5 mRNA. In contrast, BAL cells from the majority of SSc patients made IL-4 and/or IL-5 mRNA, with or without approximately equal amounts of IFNgamma mRNA. This pattern of cytokines was made by CD8+ T cells, which were increased in the lungs of these SSc patients. Patients whose BAL cells made this type 2 pattern of cytokine mRNA had a significant decline in forced vital capacity over time after the BAL, whereas patients whose BAL cells made IFNgamma mRNA alone did not. Both wild-type and an alternative splice variant of IL-4 mRNA were increased in BAL cells from SSc patients. Both forms of IL-4 stimulated alpha2(I) collagen mRNA in human dermal and lung fibroblasts. CONCLUSION: The type 2 pattern of cytokine mRNA produced by BAL cells from SSc patients differs from unopposed IFNgamma production found in healthy BAL cells. This production of type 2 cytokine mRNA by CD8+ T cells is associated with a significant decline in lung function over time, which suggests a pathologic role for these T cells in interstitial fibrosis in SSc.
Adolescent↗
Body mass index in young men and the risk of subsequent knee and hip osteoarthritis.
PURPOSE: Obesity in middle age is associated with an increased risk of osteoarthritis of the knees in later life. We sought to determine whether body mass index in young men was a risk factor for the subsequent development of osteoarthritis of the knee and hip. SUBJECTS AND METHODS: Body mass index was assessed in 1,180 male medical students at age 23 +/- 2 (mean +/- SD) years and at several times during follow-up. The incidence of knee and hip osteoarthritis was ascertained by self-report and corroborated with information on symptoms and radiographic findings. RESULTS: During a median follow-up of 36 years, 62 participants developed knee osteoarthritis and 27 developed hip osteoarthritis. The incidence of knee, but not hip, osteoarthritis was strongly associated with body mass index assessed at ages 20 to 29 years and 30 to 39 years (both P <0.001). For body mass index assessed at ages 20 to 29 years, the incidence of knee osteoarthritis at age 65 years was 12.8% among the heaviest subjects (range 24.7 to 37.6 kg/m2), threefold greater than the incidence of 4.0% in the leanest (15.6 to 22.8 kg/m2) category of body mass index (P = 0.0001). Thus, for a man who was 180 cm (5'11") tall, each 8 kg (18 lb) greater weight at ages 20 to 29 years was associated with an increased risk of subsequent knee osteoarthritis (relative risk = 1.7, 95% confidence interval 1.3 to 2.1), after adjustment for year of birth, physical activity, and knee injury. Body mass index at ages 20 to 29 years was more predictive of future osteoarthritis than at ages 30 to 39 or 40 to 49 years. CONCLUSION: Greater body mass index in young men ages 20 to 29 years is associated with an increased risk of subsequent knee, but not hip, osteoarthritis, suggesting that cumulative exposure to greater weight during young adult life is an important cause of osteoarthritis.
Adult↗
Behavioral and pharmacologic interventions: the Raynaud's Treatment Study.
The Raynaud's Treatment Study (RTS) exemplified clinical trials with treatments that differ qualitatively both in their modes and in their methods of delivery. The RTS compared finger-temperature biofeedback to slow-release nifedipine, a calcium channel blocker, in patients with primary Raynaud's disease. Factors influencing the study design were the nature of the interventions and control measures of the protocol, the possibility of perceived differences by the patients between the treatments once the final protocol was developed, and concern on the part of the investigators over the fact that the primary endpoint was self-reported. This paper presents the final statistical model: a double parallel design with both a placebo group and a nonspecific behavioral control group.
Biofeedback, Psychology↗
Symptoms of Raynaud's phenomenon in an inner-city African-American community: prevalence and self-reported cardiovascular comorbidity.
The objective of this study was to determine the prevalence of symptoms and the morbidity associated with Raynaud's phenomenon (RP) among African Americans. A total of 2196 randomly selected residents of an inner-city community, in Baltimore, completed a health-assessment survey. Symptoms of RP consisted of cold sensitivity plus cold-induced white or blue digital color change. One third (n = 703) reported cold sensitivity and 14% (n = 308) reported digital color change; 84 residents with symptoms of RP were identified, yielding an overall prevalence rate of 3.8% (95% confidence interval [CI] 3.0-4.6). RP was associated with poor or fair health status (odds ratio [OR] = 1.82, CI 1.18-2.81), heart disease (OR = 2.32, CI 1.39-3.87), and stroke (OR = 2.20, CI 1.17-4.15), after adjustment for age, gender, and physician-diagnosed arthritis. The prevalence of symptoms of RP in this African-American community is comparable to published reports from other populations. These community-based data suggest that identification of RP among African Americans should raise consideration of possible comorbidity, particularly cardiovascular disease.
Adult↗
Raynaud's phenomenon in older adults: diagnostic considerations and management.
Raynaud's phenomenon (RP) is characterised by sensitivity to cold temperatures associated with either biphasic or uniphasic change in colour of the digits. Since few studies are available which include older adults, the prevalence of RP in the older adult population is estimated from surveys or studies of the general population. The causes of RP in older adults may differ significantly from those in young adults and, therefore, so would the evaluation of RP. Because of comorbitis that accompany advancing age, the management of RP in older adult patients must take into consideration toxicity and adverse reactions that may develop, especially in the frail individual. Although nonpharmacological therapy is preferable, slow-release calcium antagonists provide a relatively well tolerated and effective treatment for moderate to severe RP in older adult patients. Aggressive treatment including hospitalisation is appropriate for older adult patients during periods of critical digital ischaemia associated with RP.
Age Factors↗
Oral iloprost treatment in patients with Raynaud's phenomenon secondary to systemic sclerosis: a multicenter, placebo-controlled, double-blind study.
OBJECTIVE: To evaluate the efficacy and tolerability of an oral preparation of iloprost, a prostacyclin analog, in patients with Raynaud's phenomenon (RP) secondary to systemic sclerosis (scleroderma). METHODS: A multicenter, randomized, parallel-group, placebo-controlled double-blind study was performed at university and community-based medical centers. Patients were randomly assigned to receive either 50 microg of iloprost orally twice daily or an identical gelatin-coated capsule containing placebo for 6 weeks. Outcome measures included average total daily duration of RP attacks, average number of RP attacks, and RP condition scored via a standardized daily diary. RESULTS: Three hundred eight patients with scleroderma (272 women, 36 men, mean age 49 years [range 18-80]) were enrolled. One hundred fifty seven were assigned to receive iloprost and 151 to receive placebo. One hundred forty-three patients in the iloprost group (91.1%) and 144 in the placebo group (95.4%) completed the 6-week treatment phase. Fifteen of these treated patients (8 iloprost, 7 placebo) failed to complete all of the followup visits. The mean reduction in the average duration of attacks from baseline to week 5-6 was 24.32 minutes in the iloprost group and 34.34 minutes in the placebo group (P = 0.569). Likewise, the mean reduction from baseline to week 5-6 in the daily frequency of attacks was 1.02 in the iloprost group and 0.83 in the placebo group (P = 0.459). The Raynaud's condition score, a patient-completed assessment of the severity of RP attacks, was reduced by 1.32 in the iloprost group and 1.00 in the placebo group (P = 0.323). The lack of significant difference between treatment groups did not change when a variety of factors, including use of other vasodilators, duration of disease, classification of scleroderma (limited versus diffuse), or number of baseline digital ulcers were taken into account. Premature withdrawal from the study due to adverse events occurred in 10 patients (6.4%) in the iloprost group and 3 (2.0%) in the placebo group (P = 0.058). CONCLUSION: Oral iloprost at a dosage of 50 microg twice daily is no better than placebo for management of RP secondary to scleroderma, either during 6 weeks of treatment or during 6 weeks of posttreatment followup.
Administration, Oral↗
Management of systemic sclerosis: the art and science.
There have been substantial strides in the therapy of systemic sclerosis (SSc) in recent years, particularly in the management of individual organ manifestations. Effective treatments are available for SSc renal crisis and many of the gastrointestinal manifestations of the disease. Raynaud's phenomenon, a nearly universal problem in SSc, also may be effectively managed. Treatment of the pulmonary complications, pulmonary hypertension and interstitial lung disease, remains difficult. Patients with early, diffuse SSc are the best candidates for experimental therapies intended to modify the overall disease process. Most disease-modifying agents have been directed at the fibrotic and inflammatory processes characteristic of SSc and have achieved little success. Future therapies may target mediators of vascular dysfunction in SSc. The success of future therapeutic trials will depend on collaborative efforts between treatment centers.
Clinical Trials as Topic↗
African-American race and antibodies to topoisomerase I are associated with increased severity of scleroderma lung disease.
STUDY OBJECTIVES: To determine whether African-American race is independently associated with lung disease in scleroderma. DESIGN: Retrospective review. SETTING: University medical center in Baltimore. PATIENTS: One hundred one patients with diffuse cutaneous scleroderma with available serum samples. MEASUREMENTS: Patients underwent lung function testing as part of their routine clinical care. Percent predicted values adjusted for race were calculated for FVC, single-breath carbon monoxide diffusing capacity (Dco), and FEV1. Serum samples were assayed for the presence of antibodies to topoisomerase I and RNA polymerase II. RESULTS: Scleroderma patients of African-American race had lower percent predicted values than white patients for FVC (p<0.002), Dco (p<0.0001), and FEV1 (p<0.0001). Antibodies to topoisomerase I but not antibodies to RNA polymerase II were also associated with lung function. African-American scleroderma patients were distinct from white patients in having younger age of onset and higher prevalence of antibodies to topoisomerase I. In multivariate analyses accounting for sex, age, smoking history, years of scleroderma symptoms, and RNA polymerase II antibody status, African-American race and topoisomerase I antibody status independently predicted lower lung function. CONCLUSION: African-American race and antibodies to topoisomerase I are independent risk factors for scleroderma lung disease.
Autoantibodies↗
Safety and pharmacokinetics of recombinant human relaxin in systemic sclerosis.
OBJECTIVE: To investigate the safety and pharmacokinetics of a 28 day continuous subcutaneous infusion of recombinant human relaxin in patients with systemic sclerosis with diffuse scleroderma. METHODS: Thirty patients with stable diffuse scleroderma of moderate severity received recombinant human relaxin at 6, 12, 50, 100, and 200 microg/kg/day or placebo in a double blind, sequential panel, dose escalation study. RESULTS: All patients completed 28 days of study treatment. Steady state concentrations of serum relaxin were achieved by the 3rd day of infusion and were dose proportionate. Patients receiving 200 microg/kg/day achieved levels about 50-fold those of normal pregnancy. Pharmacokinetics of relaxin were nonlinear with hyperbolic increases of both t1/2 and volume of distribution and parallel decrease of elimination rate coefficient. An elimination transport system was suggested with saturation at serum relaxin concentration of 45 ng/ml. Adverse events included local infusion site rash and pain, minor bleeding episodes, and decreased hemoglobin concentration (mean reduction 1.1 g/dl). Standard measures of scleroderma were unchanged, although global assessment favored relaxin over placebo. CONCLUSION: Recombinant human relaxin in the doses used was safe and well tolerated. Longer term controlled trials are warranted to define the potential efficacy of relaxin in patients with diffuse scleroderma.
Adult↗
Depressive symptoms associated with scleroderma.
OBJECTIVE: To examine the prevalence and correlates of depressive symptoms among patients with systemic sclerosis (SSc; scleroderma). METHOD: Fifty-four outpatients with scleroderma were administered the Beck Depression Inventory, the Neuroticism-Extraversion-Openness Personality Inventory, the Health Assessment Questionnaire, and the Psychosocial Adjustment to Illness Scale. In addition, patients underwent a comprehensive clinical assessment, and pulmonary function tests were obtained. RESULTS: Nearly half of the patients had mild depressive symptoms, and an additional 17% had symptoms in the moderate-to-severe range. Younger patients, those with digital ulceration, and those with more self-rate functional impairment had more depressive symptoms, but there were few other relationships between depressive symptoms and either demographic or physician-rated medical variables. In contrast, there were highly significant relationships between depression and aspects of personality, psychosocial adjustment to illness, and social support. CONCLUSION: Depressive symptoms in patients with SSc are more strongly related to personality, self-rated disability, and adequacy of emotional support than to objective medical indices of illness severity. Depression in scleroderma is a debilitating comorbid condition that should be recognized and treated in its own right.
Age Factors↗
Lack of association between augmentation mammoplasty and systemic sclerosis (scleroderma).
OBJECTIVE: To examine the possible association between augmentation mammoplasty and systemic sclerosis (SSc; scleroderma). METHODS: Eight hundred thirty-seven women with a clinical diagnosis of SSc, recruited as a volunteer sample from 3 university-based, tertiary care scleroderma clinical research centers, and 2,507 race-matched local control women, recruited by the technique of random-digit-dialing and frequency-matched on age, completed a questionnaire providing data on history of augmentation mammoplasty, including possible complications of the procedure. The odds ratio (OR) and 95 percent confidence interval (95% CI) for the association of augmentation mammoplasty with SSc were estimated by multivariate logistic regression analysis with adjustment for age, race and center, and by conditional logistic regression analysis with adjustment for age. RESULTS: Eleven (1.31%) of the 837 cases reported a history of augmentation mammoplasty prior to diagnosis of SSc, compared with 31 (1.24%) of the 2,507 controls. The adjusted OR from the unmatched analysis was 1.07 (95% CI 0.53-2.13), while that from the matched analysis was 1.11 (95% CI 0.55-2.24). CONCLUSION: These results fail to demonstrate a significant association between augmentation mammoplasty and SSc, and are consistent with those reported from other epidemiologic studies.
Adult↗
Raynaud's phenomenon.
Raynaud's phenomenon is a common clinical problem occurring in 3% to 5% of the general population. The first symptom of scleroderma is often Raynaud's phenomenon, which is associated with a diffuse small vessel vasculopathy and ischemia and reperfusion injury to skin and other organs targeted in this disease. Current studies support the concept that Raynaud's phenomenon is secondary to a local defect in the regulation of regional blood flow. New evidence demonstrates that there is a profound sensitivity to alpha 2-adrenoceptors mediated vasoconstriction in scleroderma vessels. Traditional treatment of Raynaud's phenomenon is cold avoidance and the use of vasodilators. Oral prostaglandins have shown promise as therapeutic agents.
Clinical Trials as Topic↗
Raynaud's phenomenon and other features of scleroderma, including pulmonary hypertension.
Longitudinal studies of large cohorts of patients with Raynaud's Phenomenon have addressed the predictors of developing a secondary disease. New insights have been reported into the pathogenesis of Raynaud's phenomenon and the consequences of ischemia. Studies have suggested that more than one defect may cause Raynaud's phenomenon, including increased alpha-2 sympathetic receptor activity on vessels, endothelial dysfunction, deficiency of calcitonin gene related peptide protein--containing nerves or some central thermoregulatory defect. The vasoconstricting and profibrotic cytokine endothelin-1 was found to be elevated in scleroderma but did not correlate with disease subset or with evidence of pulmonary hypertension. Oxidant stress is thought to be increased in scleroderma, causing tissue damage and provoking fibrosis. Treatment with infusion of prostacyclin for primary pulmonary hypertension was approved, paving the way for studies of secondary forms of pulmonary hypertension. Oral prostanoids are being tested for the treatment of Raynaud's phenomenon.
Animals↗
Frequency of augmentation mammoplasty in patients with systemic sclerosis: data from the Johns Hopkins-University of Maryland Scleroderma Center.
The objective was to determine the frequency of augmentation mammoplasty in female patients with systemic sclerosis (SSc). Female patients with a clinical diagnosis of SSc were identified from the registry of the Johns Hopkins-University of Maryland Scleroderma Center, Washington D.C. Chapter of the Scleroderma Foundation, and files of practicing rheumatologists in the Baltimore-Washington metropolitan area. A pretested questionnaire was mailed to all eligible cases. Of 339 cases, 210 (62%) returned completed questionnaires. Three cases reported augmentation mammoplasty with silicone gel-filled prosthesis: 2 (1%) prior to and 1 (0.5%) after physician-diagnosis of SSc. The frequency of augmentation mammoplasty prior to physician-diagnosis of SSc of 9.5 per 1000 does not appear to differ from the expected frequency of 3.3-8.2 per 1000 derived from national population samples. A well-designed case-control study with population-based controls and adequate statistical power is being conducted to examine this possible association.
Adolescent↗
Treatment of scleroderma.
Although no new agents were studied in the treatment of scleroderma this year, major steps were taken to improve our investigative approach to this disease. The American College of Rheumatology Committee on Design and Outcomes in Clinical Trials in Systemic Sclerosis (Scleroderma) published guidelines for clinical trials in scleroderma. These guidelines suggest that great care should be taken in the design of therapeutic trials in scleroderma so that the clinical impact of new treatments can be properly understood. Excellent reviews were published this year on how to manage scleroderma and its complications, particularly in the area of gastrointestinal involvement. The need to better understand the treatment of lung disease in scleroderma was emphasized in several reports. Provocative new insight into the pathogenesis of scleroderma has suggested several potential targets for novel approaches to treatment. The challenge for scleroderma clinical researchers in the future is to prioritize treatment options and organize large collaborative studies that are prospective, controlled, and well designed.
Adrenal Cortex Hormones↗
Prevalence of self-reported physician-diagnosed systemic lupus erythematosus in the USA.
The objective of this study was to estimate the prevalence of self-reported physician-diagnosed systemic lupus erythematosus (SLE) in the USA. During the conduct of an epidemiologic study of systemic sclerosis (scleroderma), 16 607 randomly selected telephone numbers in the continental USA were called to recruit controls. All potentially eligible women were asked 'Have you ever been told by a doctor that you have lupus or SLE'? Of 4034 women aged 18 and above who completed telephone screening, 15 stated they had a physician diagnosis of SLE, corresponding to a prevalence of 372 cases per 100 000 (95% confidence intervals: 208, 614). After review of available medical records in six cases, however, the prevalence of 'validated' SLE was revised to 124 cases per 100 000 (95% confidence intervals: 40, 289). In conclusion, these data suggest that the prevalence of SLE in the USA may be up to three to 10-fold greater than previously estimated. Based on 1990 census data, we would project that over 275 000 women aged 18 and above have SLE in the USA.
Adolescent↗
Posterior tibial tendon dysfunction in rheumatoid arthritis.
Although hindfoot pathology in rheumatoid arthritis is a significant cause of disability for patients, the etiology of the planovalgus deformity is controversial. The present study surveys 99 patients with clinically proven rheumatoid arthritis for the presence and severity of hindfoot pathology. Specific attention was directed at the function of the posterior tibial tendon, as disruption of this structure has been implicated by some investigators as a cause of hindfoot deformity in rheumatoid arthritis. Assessment of posterior tibial function was by manual testing using two different grading scales, as well as by examination for several signs associated with posterior tibial tendon dysfunction. Between 13% and 64% of the study population could be considered to have posterior tibial tendon dysfunction, depending upon the specific diagnostic criteria used. Using the presence of all three of the most stringent criteria for diagnosis, 11% of patients were believed to have posterior tibial tendon dysfunction. These criteria were loss of the longitudinal arch, inability to perform a heel-rise, and lack of a palpable posterior tibial tendon. This study demonstrates that planovalgus deformity in rheumatoid arthritis can be due to clinically evident dysfunction of the posterior tibial muscle-tendon unit. There is a complex interplay between hindfoot joint disruption due to the inflammatory process and deformity due to tendinous dysfunction. If there is primary subtalar joint instability secondary to the inflammatory process, the posterior tibial tendon is rendered dysfunctional due to deranged hindfoot mechanics, as with primary posterior tibial tendon rupture. Since treatment of either condition (i.e., primary hindfoot instability or primary posterior tibial tendon rupture) is similar, the distinction is not important clinically.(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗