Circulating microparticles and plasma levels of soluble E- and P-selectins in patients with systemic sclerosis.

OBJECTIVES: Microparticles (MPs) may be involved in the pathogenesis of systemic sclerosis (SSc), which includes vasculopathy, endothelial cell activation, and coagulation activation. Circulating MPs from SSc patients were characterized and their relationship with soluble markers of vascular activation investigated. METHOD: This study included 121 SSc patients [79 with limited (lcSSc) and 42 with diffuse cutaneous SSc (dcSSc)] and 49 sex- and age-matched healthy controls (HCs). The MPs were characterized by flow cytometry for annexin V (AnxV)-binding capacity and their expression of surface markers of platelets (PMPs), leucocytes (LMPs), or endothelial cells (EMPs). Plasma levels of soluble (s) E- and P-selectins were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: The total concentrations of MPs and of PMPs, LMPs, and EMPs were 22-42% lower in SSc patients than in HCs (p < 0.001). However, within the cell-derived MP pool, a 47% higher fraction of AnxV non-binding MPs (F-AnxV(-) MPs) was found in the SSc patients compared to the HCs (p < 0.05). The plasma levels of sE- and sP-selectins were increased by 47-64% in the SSc patients compared to HCs (p < 0.001). Multiple regression analysis showed that the raised plasma levels of sE- and sP-selectin were associated with F-AnxV(-) EMPs in dcSSc patients (p = 0.008 and p = 0.001, respectively) but not in lcSSc patients (p = 0.33 and p = 0.82, respectively). CONCLUSIONS: While the total number of MPs was decreased, the number of F-AnxV(-) MPs increased in SSc patients. The F-AnxV(-) EMPs were associated with plasma levels of markers of vascular activation in patients with dcSSc.

Clinical prediction of 5-year survival in systemic sclerosis: validation of a simple prognostic model in EUSTAR centres.

OBJECTIVE: Systemic sclerosis (SSc) is associated with a significant reduction in life expectancy. A simple prognostic model to predict 5-year survival in SSc was developed in 1999 in 280 patients, but it has not been validated in other patients. The predictions of a prognostic model are usually less accurate in other patients, especially from other centres or countries. A study was undertaken to validate the prognostic model to predict 5-year survival in SSc in other centres throughout Europe. METHODS: A European multicentre cohort of patients with SSc diagnosed before 2002 was established. Patients with SSc according to the preliminary American College of Rheumatology classification criteria were eligible for the study when they were followed for at least 5 years or shorter if they died. The primary outcome was 5-year survival after diagnosis of SSc. The predefined prognostic model uses the following baseline variables: age, gender, presence of urine protein, erythrocyte sedimentation rate (ESR) and carbon monoxide diffusing capacity (DLCO). RESULTS: Data were available for 1049 patients, 119 (11%) of whom died within 5 years after diagnosis. Of the patients, 85% were female, the mean (SD) age at diagnosis was 50 (14) years and 30% were classified as having diffuse cutaneous SSc. The prognostic model with age (OR 1.03), male gender (OR 1.93), urine protein (OR 2.29), elevated ESR (1.89) and low DLCO (OR 1.94) had an area under the receiver operating characteristic curve of 0.78. Death occurred in 12 (2.2%) of 509 patients with no risk factors, 45 (13%) of 349 patients with one risk factor, 55 (33%) of 168 patients with two risk factors and 7 (30%) of 23 patients with three risk factors. CONCLUSION: A simple prognostic model using three disease factors to predict 5-year survival at diagnosis in SSc showed reasonable performance upon validation in a European multicentre study.

Skin signs in Ehlers-Danlos syndrome: clinical tests and para-clinical methods.

OBJECTIVE: The criteria for Ehlers-Danlos syndrome (EDS) and the hypermobility syndrome (HMS) should be reliable. Examination for general joint hypermobility has high reliability but there is only sparse information on the reliability of skin tests, and no information on the level of normal skin extensibility. The present study aimed to assess skin signs by means of clinical and para-clinical methods. METHODS: A total of 31 EDS patients and 28 healthy controls were examined blinded and in random order. Inter-examiner analysis of clinical tests for skin extensibility, consistency, scarring, and bruising was performed, followed by analyses of extensibility with the suction cup (SC), consistency with a soft tissue stiffness meter (STSM), and thickness with ultrasonography (US). Semi-quantitative assessment of skin extensibility in healthy controls was incorporated in the tests. RESULTS: The clinical analyses demonstrated kappa values of: 0.72 for extensibility, 0.23 for consistency, 0.53 for scarring, and 0.63 for bruising. Skin extensibility measurements in healthy controls (n = 28) were 2.79 and 2.93 cm (mean + 2 SD), respectively, by the two examiners. There were significant differences between patients with classical-type EDS and controls with respect to skin extensibility by SC (4.91 vs. 12.52 kPa/mm) and skin consistency by STSM (0.59 vs. 0.76 N). We found no difference in skin thickness. CONCLUSION: The reproducibility of the clinical skin tests was substantial to good, apart from the consistency measurements. We suggest that skin consistency is withdrawn as a diagnostic criterion. The upper level for normal skin extensibility should be 3 cm. SC and STSM are promising para-clinical methods, but their diagnostic sensitivity and specificity need to be determined.

A randomized controlled trial of R-salbutamol for topical treatment of discoid lupus erythematosus.

BACKGROUND: In a recent open pilot trial, R-salbutamol sulphate, a well-known molecule with anti-inflammatory effects, was tested successfully on patients with therapy-resistant discoid lupus erythematosus (DLE). OBJECTIVES: To compare the efficacy and safety of R-salbutamol cream 0.5% vs. placebo on DLE lesions in a multicentre, double-blinded, randomized, placebo-controlled phase II trial. METHODS: Thirty-seven patients with at least one newly developed DLE lesion were randomized - 19 to the R-salbutamol cream 0.5% and 18 to placebo - and treated twice daily for 8 weeks. Efficacy was evaluated through scores of erythema, scaling/hypertrophy and induration as well as pain and itching; general improvement scored by the investigator and global improvement scored by patients' assessment were also evaluated. RESULTS: The mean area under the curve of improvement for scaling/hypertrophy, pain, itching and global patient assessment was significantly better for the actively treated patients as compared with placebo (scaling/hypertrophy, P = 0.0262; pain, P = 0.0238; itching, P = 0.0135; global patient assessment, P = 0.045). Moreover, the percentage of patients without induration was significantly higher in the active group compared with the placebo group (P = 0.013), and a statistically significantly greater decrease in the size of the lesional area was also seen in the overall analysis of the R-salbutamol-treated patients (P = 0.0197). No serious adverse events were reported. CONCLUSIONS: Application of R-salbutamol cream 0.5% was safe and well tolerated. Statistically significant effects were seen on scaling/hypertrophy, induration, pain and itching as well as patient global assessment, suggesting that R-salbutamol could be a promising new topical therapy alternative for DLE.

Skin extensibility and consistency in patients with Ehlers-Danlos syndrome and benign joint hypermobility syndrome.

OBJECTIVES: The reproducibility of clinical tests for skin extensibility and consistency, essential for differentiating between types of Ehlers-Danlos syndrome (EDS) and benign joint hypermobility syndrome (BJHS), is unknown. Paraclinical methods may provide objective differential diagnostic methods. METHODS: Six EDS, 11 BJHS, and 19 controls completed the trial. We analysed the overall inter-examiner agreement on clinical tests for skin extensibility and consistency, in addition to analyses on suction cup (SC) and soft tissue stiffness meter (STSM) methods. RESULTS: Overall agreement on tests for skin extensibility and consistency varied between 0.44 and 0.72. Extensibility evaluated by SC showed an insignificant difference between EDS patients and controls (p = 0.056). Consistency evaluated by STSM showed significant differences (p = 0.001). CONCLUSIONS: Overall inter-examiner agreement on clinical tests for skin extensibility and consistency was below 0.80, which was required a priori to conduct a reproducibility study. Further refinement of tests and a training phase are necessary. The SC and STSM results are encouraging but must be reproduced in a larger study population.

Factors affecting survival in juvenile systemic sclerosis.

OBJECTIVES: To determine whether demographic, clinical and immunological features may predict the outcome in juvenile SSc (JSSc). METHODS: Clinical and laboratory characteristics of patients with JSSc collected from paediatric rheumatology centres worldwide were analysed. First, univariate tests identified those features significantly related with fatal outcome, and then multivariate logistic regression analysis was applied to determine the predictors of mortality. RESULTS: One hundred and thirty-four patients from 40 centres were eligible for the analysis. Sixteen patients died and a rapidly fatal course was observed in most of them: 4/16 died within 1 yr after diagnosis and 10/16 within 5 yrs. At the moment of diagnosis, patients with poor outcome showed a significantly higher frequency of internal organ involvement, particularly cardiac, respiratory and gastrointestinal systems. No significant difference emerged for entity of skin, vascular and musculo-skeletal involvement, nor for auto-antibodies profile and laboratory tests. Multivariate analysis showed the following factors to be significant predictors of mortality: fibrosis on chest X-rays [odds ratio (OR) 11.2], raised creatinine levels (OR 22.7) and pericarditis (OR 41.3), while a short disease duration at diagnosis conferred protection (OR 0.3). CONCLUSIONS: All patients with JSSc and fatal outcome were affected by the diffuse form of the disease, and most of them showed a very rapid progression and early signs of internal organ involvement. This suggests that, in children, SSc may have two possible courses: a rapid development of internal organ failure leading to severe disability and eventually to death, or a slow course of the disease with lower mortality.

High serum levels of YKL-40 in patients with systemic sclerosis are associated with pulmonary involvement.

OBJECTIVES: YKL-40, a growth factor of connective tissue cells, is elevated in sera from patients with diseases characterized by inflammation, tissue remodelling, or fibrosis. The aim of the study was to determine serum YKL-40 levels in patients with systemic sclerosis (SSc) and to explore any possible clinical and prognostic associations. METHODS: YKL-40 was measured in sera from 88 patients with SSc (26 with diffuse and 62 with limited skin involvement) and in sera from 88 matched healthy controls. Immunohistochemical staining for YKL-40 antigen was performed in a biopsy from a patient with pulmonary SSc. RESULTS: Serum YKL-40 levels of the SSc patients were significantly higher than those of the controls (p<0.00001). Patients with pulmonary fibrosis by chest X-ray, obstructive ventilatory pattern, reduced diffusing capacity (DLco), and digital joint deformity due to skin retraction had significantly higher serum YKL-40 compared with patients without these findings. Patients with elevated serum YKL-40 had shorter survival times than patients with normal serum YKL-40 (p = 0.0005), although this was not independent of age and pulmonary function. YKL-40 protein expression was found in inflammatory cells in fibrosing pulmonary tissue from a patient with SSc. CONCLUSIONS: Serum YKL-40 is elevated in patients with SSc with pulmonary involvement.

Absence of high-affinity calreticulin autoantibodies in patients with systemic rheumatic diseases and coeliac disease.

Calreticulin has been reported to be an autoantigen in various autoimmune connective tissue diseases and in coeliac disease. Previous studies have used incubation buffers with low salt and low detergent concentrations (low stringency conditions) with serum albumin or other proteins as a blocking agent. Using these conditions we found a relatively high level of non-specific binding in many sera. Antibodies to proteins that are used as blocking reagents in ELISA (bovine serum albumin (BSA), ovalbumin, skimmed milk powder) are frequently present in sera, and these may cause false-positive results. Moreover, the low isoelectric point of calreticulin and its chaperone properties may give rise to false-positive results under low stringency conditions. We report that the use of a simple buffer without protein (50 mM Tris, pH 7.5, 1% Tween 20, 0.3 M NaCl) removes most of the problems with unwanted binding (high stringency conditions). Using the high stringency conditions, we screened sera from 107 patients with systemic lupus erythematosus, sera from patients with other systemic autoimmune diseases and from children with coeliac disease for the presence of high-affinity calreticulin autoantibodies by immunoblotting and ELISA. None of the sera contained high-affinity calreticulin antibodies. It is concluded that calreticulin is not a common autoantigen in patients with autoimmune connective tissue diseases or coeliac disease.

Influence of clinical features, serum antinuclear antibodies, and lung function on survival of patients with systemic sclerosis.

OBJECTIVE: To evaluate the independent contribution of several clinical and laboratory variables to the mortality of a cohort of Danish patients with systemic sclerosis (SSc). METHODS: A cohort of 174 patients with incident SSc was retrospectively identified using clinical charts and study records of all new patients with SSc. Disease onset was defined as the time of onset of cutaneous sclerosis. Vital status and causes of death were determined at the end of the observation period. Data on clinical status and pulmonary function were obtained. Antitopoisomerase I (anti-topo I), anticentromere, anti-U1-RNP, anti-U3-RNP, anti-Th-RNP, and anti-RNA polymerase (anti-RNAP) antibodies were determined by means of double immunodiffusion, immunofluorescence, hemagglutination technique, radioactively labelled antisense riboprobes, and ELISA, respectively. RESULTS: Patients were followed for a mean period of 13.3 yrs; 16 died of an SSc related condition and 50 of other causes. Pulmonary fibrosis, DLCO reduction < 40% of the expected, diffuse cutaneous involvement, SSc nephropathy, cardiac disease, and anti-topo I and anti-RNAP antibody were related to decreased survival due to SSc. Variables that entered a Cox regression model of SSc related mortality were right heart failure (RR 12.4, 95% CI 2.5-60), diffuse SSc (RR 7.8, 95% CI 1.8-35), SSc nephropathy (RR 6.1, 95% CI 1.8-21), and DLCO < 40% (RR 4.8, 95% CI 1.1-20). The relative risk of developing right heart failure and diffuse SSc given the presence of anti-RNAP antibody was 14 (p = 0.0001) and 1.9 (p = 0.01), respectively. The corresponding figures for anti-topo I antibody were 4.6 (p = 0.02) and 2.0 (p = 0.01). CONCLUSION: SSc related mortality was associated with right heart failure and diffuse SSc, both of which were also associated with the presence of anti-topo I and anti-RNAP antibody. The prognostic value of these autoantibodies may lie in the early course of the disease when specific morbidity has not yet evolved.

Predictors of PTSD symptom severity and social reactions in sexual assault victims.

Demographics, assault variables, and postassault responses were analyzed as correlates of PTSD symptom severity in a sample of 323 sexual assault victims. Regression analyses indicated that less education, greater perceived life threat, and receipt of more negative social reactions upon disclosing assault were each related to greater PTSD symptom severity. Ethnic minority victims reported more negative social reactions from others. Victims of more severe sexual victimization reported fewer positive, but more negative reactions from others. Greater extent of disclosure of the assault was related to more positive and fewer negative social reactions. Telling more persons about the assault was related to more negative and positive reactions. Implications of these results for developing contextual theoretical models of rape-related PTSD are discussed.

Viscoelastic properties and flexibility of the human muscle-tendon unit in benign joint hypermobility syndrome.

OBJECTIVE: To examine the passive energy absorption of the hamstring muscle-tendon unit in 9 women with benign joint hypermobility syndrome (BJHS) and 9 age and sex matched controls. METHODS: Resistance to stretch was measured as knee flexion moment (N.m) with an isokinetic dynamometer during passive knee extension. The angle that induced a stretch sensation without pain was the maximal stretch angle. Force, angle, angular velocity (0.09 rad/s), and electromyograph were simultaneously and continuously recorded during the stretch. Hamstring cross sectional area was obtained with magnetic resonance imaging. RESULTS: Forearm skin extensibility was greater for BJHS (3.6+/-0.5 cm) than for controls (1.3+/-0.2 cm) (p < 0.01). Similarly, the Beighton score was greater for BJHS (6.6+/-0.8) than for controls (0.4+/-0.2) (p < 0.001). Maximal stretch angle was greater for BJHS (delta1.35+/-0.07 rad) compared to controls (delta0.98+/-0.05 rad) (p < 0.001), and the corresponding peak moment was also greater for BJHS (1.3+/-0.4 Nm/cm2) than for controls (0.6+/-0.1 Nm/cm2) (p < 0.01). For a given mutual angle the passive energy absorption was the same for both groups, but at the maximal stretch angle the total area-normalized energy was greater for BJHS (0.36+/-0.04 J/cm2) than for controls (0.18+/-0.28 J/cm2) (p < 0.001). CONCLUSION: The lack of difference in passive energy absorption for a given mutual stretch angle suggests that passive properties of the muscle-tendon unit of BJHS are similar to those of controls. However, the greater maximal stretch angle and corresponding peak moment in BJHS suggests a greater subjective tolerance to passive stretch. That is, increased flexibility in BJHS is not a function of altered passive properties of the muscle-tendon complex. It remains unknown if the enhanced tolerance to passive tension plays a role in the development of musculoskeletal ailment.

Social reactions to sexual assault victims from various support sources.

This study examined positive and negative social reactions received by 323 victims disclosing sexual assaults to informal and formal support providers. Analyses of both quantitative and qualitative data indicated that both positive and negative reactions are commonly received by victims disclosing their assaults to others, but that victims seeking help from formal support sources are more commonly faced with negative reactions of victim blame, stigmatizing responses, and controlling reactions from others. Qualitative analysis of written responses provided by respondents also revealed other less common but unhelpful reactions of assault disclosure such as rape myths, violations of the victim's confidential disclosures, and revictimization. Preliminary analyses of the effects of specific reactions on adjustment from different types of support providers suggested that reactions of friends are particularly important for recovery. Positive reactions from friends appear to be more helpful, whereas negative reactions appear to be harmful from both informal and formal support sources. Implications for research and treatment of sexual assault victims are discussed.

Determination of autoantibodies to annexin XI in systemic autoimmune diseases.

Annexin XI, a calcyclin-associated protein, has been shown to be identical to a 56,000 Da antigen recognized by antibodies found in sera from patients suffering from systemic autoimmune diseases. In this work hexahistidine-tagged recombinant annexin XI (His6- rAnn XI) was used as antigen in ELISA experiments for determination of autoantibodies to annexin XI in sera of patients with systemic rheumatic autoimmune diseases. Immunoblotting with HeLa cell extract and with His6-rAnn XI as antigen was used for confirmation of positive ELISA results. We found eleven anti-annexin XI positive sera (3.9%) out of 282 sera from patients with systemic rheumatic diseases. The highest number of annexin XI positive sera were found in primary antiphospholipid syndrome (3/17), and in subacute lupus erythematosus (1/6), while lower frequencies of positive sera were found in patients with systemic sclerosis (5/137), rheumatoid arthritis (1/21), and systemic lupus erythematosus (1/58). Sera from healthy donors and patients with chronic infections were negative, except for one Salmonella typhimurium antibody positive serum. Autoantibodies to annexin XI were found to relate to thrombosis, but not to other clinical or laboratory features. A relation between antibodies to annexins and thrombosis has so far only been known for annexin V.

Alcohol and adult sexual assault in a national sample of women.

PURPOSE: Alcohol use is commonly present in sexual assault incidents, but the nature of its role in these offenses remains unclear. Researchers have argued that the propensity to abuse alcohol generally and the use of alcohol prior to assault by offenders and victims may be associated with increased severity of sexual abuse and physical injury to sexual assault victims. In particular, there is speculation that offender drinking may facilitate offenders' use of greater physical aggression against victims in their attacks, resulting in more serious injuries to victims. METHODS: The role of alcohol in sexual assault incidents (n = 163) identified from a national sample of women was studied. RESULTS: In the present sample, offender pre-assault drinking and offender aggression used in the offense were each strong predictors of victim physical injury. Victim heavy episodic drinking did not predict victim injury controlling for other assault characteristics, victim and offender drinking prior to assault, and victim demographic characteristics. Drinking by offenders and victims was more common in assaults where victims were less well acquainted with their assailants prior to attack. Higher levels of offender aggression and victim injury were also associated with stranger attacks. IMPLICATIONS: Implications of the results for the study of alcohol and sexual assault are discussed.

Prognostic value of renal biopsy and clinical variables in patients with lupus nephritis and normal serum creatinine.

OBJECTIVE: To evaluate factors with possible influence on the renal outcome in patients with lupus nephritis but without chronic renal insufficiency (CRI). METHODS: Renal biopsies from 94 patients were re-assessed with regard to WHO class, activity, chronicity and tubulointerstitial indices without knowledge of clinical features. The outcome parameters were CRI defined as irreversibly increased serum creatinine and renal end stage disease. RESULTS: The risk ratios (RR) of developing CRI were 2.6 for active urinary sediment, 3.1 for hyaline thrombi and 7.3 for glomerular leukocyte exudation. The RR of renal end stage disease was 5.0 when the duration of renal disease exceeded one year at the time of biopsy and 4.3 when biopsy disclosed a class IV lesion. Glomerular sclerosis was also associated to renal end stage disease. CONCLUSION: Early renal biopsy and the abovementioned signs of active renal disease carry prognostic information that may have significant therapeutic implications.

Twisted collagen fibrils in acrocyanosis.

Essential acrocyanosis (EA) present as a dusky discoloration of the hands as the sole symptom without any other abnormal results from laboratory investigation. Previously, the authors have found twisted collagen fibrils (TCF) in the normal skin of an EA patient. This study was intended to evaluate the significance of TCF in EA. Thirteen patients showing dusky discoloration were randomly selected and studied for TCF in normal skin by routine electron microscopy. TCF were found in 10 of 13 patients; 3 patients with only the discoloration (EA), 3 with the mild symptoms which were supposed to be Ehlers-Danlos syndrome (EDS), 1 with definite symptoms of EDS, 1 with Raynaud's disease and 2 with hyperglobulinemia. TCF were the ultrastructural sign for inherited malformation of collagen fibrils. EA was probably elucidated as a vascular disorder in TCF-carrying people. EA could be included in the disease category of EDS but it seems unreasonable to force EA patients into one of the subtypes of EDS. For pathogenesis, the inherited dysfunction in the hypertrophic pericytes of the subpapillary vascular plexus was presumed.

A comparison of gang and individual rape incidents.

This study examined differences between gang and individual offender rape incidents reported to the Chicago police. Analyses showed that victims and offenders in gang rape incidents were younger, more likely to be unemployed, but not different in marital status or race than victims and offenders in individual rapes (e.g., single offender, single victim crimes). Gang rapes were characterized by more alcohol and drug involvement, fewer weapons, more night attacks, less victim resistance, and more severe sexual assault outcomes compared with individual rapes. Regression analyses revealed distinct correlates of physical injury outcomes for gang and individual rape incidents. Implications for treatment and prevention of these types of assaults are discussed.

[Scleroderma--systemic sclerosis. Serology, lung function and survival]. / Sklerodermi--systemisk sklerose. Serologi, lungefunktion og overlevelse.

Patients with systemic sclerosis (SSc) were studied with regard to the presence of antinuclear antibodies (ANA) and their clinical correlates (n = 230), pulmonary function (n = 176), and mortality and causes of death (n = 344). ANA were found in 85%. Anti-centromere antibodies were found in 34%, anti-Scl-70 antibodies in 13% and anti-U1-RNP antibodies in 6.5%. These serological groups were associated with limited SSc, diffuse SSc, and myositis/arthritis, respectively. The most prevalent finding at first lung function test was isolated reduction of diffusion capacity (47%). Further deterioration of diffusion capacity was related to the presence of anti-centromere antibodies and increased sedimentation rate. The standardized mortality rate (SMR) was 2.9, higher in young patients (SMR = 13) and patients with diffuse SSc (SMR = 4.5).