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Aims: This study aimed to determine if macrophages can attach and directly affect the oxide layers of 316L stainless steel, titanium alloy (Ti6Al4V), and cobalt-chromium-molybdenum alloy (CoCrMo) by releasing components of these alloys., Methods: Murine peritoneal macrophages were cultured and placed on stainless steel, CoCrMo, and Ti6Al4V discs into a 96-well plate. Cells were activated with interferon gamma and lipopolysaccharide. Macrophages on stainless steel discs produced significantly more nitric oxide (NO) compared to their control counterparts after eight to ten days and remained elevated for the duration of the experiment., Results: On stainless steel, both nonactivated and activated cell groups were shown to have a significant increase in metal ion release for Cr, Fe, and Ni (p < 0.001, p = 0.002, and p = 0.020 respectively) compared with medium only and showed macrophage-sized corrosive pits on the stainless steel surface. On titanium alloy discs there was a significant increase in aluminum (p < 0.001) among all groups compared with medium only., Conclusion: These results indicated that macrophages were able to attach to and affect the oxide surface of stainless steel and titanium alloy discs. Cite this article: Bone Joint J 2020;102-B(7 Supple B):116-121.

Development of speech and language is rapid in early years, yet if developmental problems in speech and language are not addressed they are likely to continue and impact negatively on a child's overall development and their life trajectory. Children who have experienced abuse and or neglect are particularly vulnerable. The aim of this study was to develop a tool to assist in identifying a child's need for assessment by a speech pathologist so that there could be early identification of problems. A culturally sensitive tool was developed to be completed by the child's carer included questions on language, speech and hearing, voice, fluency, understanding sentences, vocabulary and expression. Sixty-five children aged between 4 and 8 years, who had experienced abuse and/or neglect participated in the study. Fourteen percent were Aboriginal. A speech pathologist undertook an assessment for each child and the results were compared with the information on the Small Talk tool. The Tool was found to be high in sensitivity but low in specificity, requiring further refinement. However, it has the potential to assist non speech pathologists to identify a child's need for speech and language assessment with the findings identifying the Tool as promising practice., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background and Purpose: Several trials have compared vertebral augmentation with nonsurgical treatment for vertebral compression fractures. This trial compares the efficacy and safety of balloon kyphoplasty and vertebroplasty., Materials and Methods: Patients with osteoporosis with 1-3 acute fractures (T5-L5) were randomized and treated with kyphoplasty (n = 191) or vertebroplasty (n = 190) and were not blinded to the treatment assignment. Twelve- and 24-month subsequent radiographic fracture incidence was the primary end point. Due to low enrollment and early withdrawals, the study was terminated with 404/1234 (32.7%) patients enrolled., Results: The average age of patients was 75.6 years (77.4% female). Mean procedure duration was longer for kyphoplasty (40.0 versus 31.8 minutes, P < .001). At 12 months, 7.8% fewer patients with kyphoplasty (50/140 versus 57/131) had subsequent radiographic fracture, and there were 8.6% fewer at 24 months (54/110 versus 64/111). The results were not statistically significant (P > .21). When we used time to event for new clinical fractures, kyphoplasty approached statistical significance in longer fracture-free survival (Wilcoxon, P = .0596). Similar pain and function improvements were observed. CT demonstrated lower cement extravasation for kyphoplasty (157/214 versus 164/201 levels treated, P = .047). For kyphoplasty versus vertebroplasty, common adverse events within 30 postoperative days were procedural pain (12/191, 9/190), back pain (14/191, 28/190), and new vertebral fractures (9/191, 17/190); similar 2-year occurrence of device-related cement embolism (1/191, 1/190), procedural pain (3/191, 3/190), back pain (2/191, 3/190), and new vertebral fracture (2/191, 2/190) was observed., Conclusions: Kyphoplasty and vertebroplasty had similar long-term improvement in pain and disability with similar safety profiles and few device-related complications. Procedure duration was shorter with vertebroplasty. Kyphoplasty had fewer cement leakages and a trend toward longer fracture-free survival., (© 2014 by American Journal of Neuroradiology.)

NGC 4449 is a nearby Magellanic irregular starburst galaxy with a B-band absolute magnitude of -18 and a prominent, massive, intermediate-age nucleus at a distance from Earth of 3.8 megaparsecs (ref. 3). It is wreathed in an extraordinary neutral hydrogen (H I) complex, which includes rings, shells and a counter-rotating core, spanning ∼90 kiloparsecs (kpc; refs 1, 4). NGC 4449 is relatively isolated, although an interaction with its nearest known companion--the galaxy DDO 125, some 40 kpc to the south--has been proposed as being responsible for the complexity of its H I structure. Here we report the presence of a dwarf galaxy companion to NGC 4449, namely NGC 4449B. This companion has a V-band absolute magnitude of -13.4 and a half-light radius of 2.7 kpc, with a full extent of around 8 kpc. It is in a transient stage of tidal disruption, similar to that of the Sagittarius dwarf near the Milky Way. NGC 4449B exhibits a striking S-shaped morphology that has been predicted for disrupting galaxies but has hitherto been seen only in a dissolving globular cluster. We also detect an additional arc or disk ripple embedded in a two-component stellar halo, including a component extending twice as far as previously known, to about 20 kpc from the galaxy's centre.

Epithelial injury contributes to pathogenesis in idiopathic pulmonary fibrosis (IPF) but its role in the interstitial lung disease (ILD) of systemic sclerosis (SSc) is uncertain. We quantified the prognostic significance of inhaled technetium-99m ((99m)Tc)-labelled diethylene triamine pentacetate (DTPA) pulmonary clearance, a marker of the extent of epithelial injury, in both diseases. Baseline (99m)Tc-DTPA pulmonary clearance was evaluated retrospectively in patients with SSc-ILD (n = 168) and IPF (n = 97) against mortality and disease progression. In SSc-ILD, the rapidity of total clearance (hazard ratio (HR) 1.02, 95% CI 1.01-1.03; p = 0.001) and the presence of abnormally rapid clearance (HR 2.10; 95% CI 1.25-3.53; p = 0.005) predicted a shorter time to forced vital capcity (FVC) decline, independent of disease severity. These associations were robust in both mild and severe disease. By contrast, in IPF, delayed clearance of the slow component, an expected consequence of honeycomb change, was an independent predictor of a shorter time to FVC decline (HR 1.01, 95% CI 1.00-1.02; p<0.01). Epithelial injury should be incorporated in pathogenetic models in SSc-ILD. By contrast, outcome is not linked to the overall extent of epithelial injury in IPF, apart from abnormalities ascribable to honeycombing, suggesting that core pathogenetic events may be more spatially focal in that disease.

We tested the hypothesis that intramuscular immunization with a multisubunit chlamydial vaccine candidate will induce long lasting immune responses in mice. Accordingly, groups of female C57BL/6 mice were immunized intramuscularly with Vibrio cholerae ghosts (VCG) expressing the Poring B and polymorphic membrane protein-D proteins of Chlamydia trachomatis or a control antigen. Humoral and cell-mediated immune responses were evaluated following immunization and after live chlamydial infection. Immunization induced an anamnestic response characterized by chlamydial-specific IgG2a and IgA antibodies in sera and vaginal lavage as well as specific genital and splenic T cell responses. The results also revealed that the local mucosal and systemic cellular and humoral immune effectors induced in mice following immunization with the vaccine candidate are long lasting. Vaccinated mice cleared intravaginal challenge with 10(5) chlamydial inclusion forming units within 12 days compared to control mice, which shed up to 2 × 10(3) IFUs at this time point. Moreover, rechallenge of mice 98 days after resolution of the primary infection resulted in the recall and retention of a relatively high frequency of chlamydial-specific Th1 cells and IgG2a in the genital mucosa. These results provide the first evidence that a VCG-based multisubunit chlamydial vaccine is capable of effectively stimulating anamnestic systemic and mucosal immune responses in mice. The data support further vaccine evaluation and testing for induction of long-term protective immunity., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Objective: Endothelin is implicated as a participatory pathway in systemic sclerosis (SSc). We tested this hypothesis in a 12-month trial of bosentan, a nonselective endothelin receptor antagonist, as a therapy for SSc-related interstitial lung disease (ILD)., Method: Patients with SSc and significant ILD were recruited to this prospective, double-blind, randomized, placebo-controlled, parallel group study. The inclusion criteria were designed to select a cohort enriched for patients with active and progressive disease. Exclusion factors included significant pulmonary hypertension. Patients with a diffusing capacity for carbon monoxide of <80% predicted and a 6-minute walk distance of 150-500 meters or a 6-minute walk distance of > or = 500 meters with a decrease in oxygen saturation received bosentan or placebo. The primary efficacy end point was a change in the 6-minute walk distance from baseline up to month 12. Secondary end points included time to death or worsening results of pulmonary function tests (PFTs). The safety and tolerability of bosentan were also assessed., Results: Among the 163 patients, 77 were randomized to receive bosentan, and 86 were randomized to receive placebo. No significant difference between treatment groups was observed for change in the 6-minute walk distance up to month 12. No deaths occurred in this study group. Forced vital capacity and diffusing capacity for carbon monoxide remained stable in the majority of patients in both groups. Significant worsening of PFT results occurred in 25.6% of patients receiving placebo and 22.5% of those receiving bosentan (P not significant)., Conclusion: No improvement in exercise capacity was observed in the bosentan-treated group compared with the placebo group, and no significant treatment effect was observed for the other end points. Although many outcome variables were stable, bosentan did not reduce the frequency of clinically important worsening. These data do not support the use of endothelin receptor antagonists as therapy for ILD secondary to SSc.

Background: Systemic sclerosis (SSc) has high mortality and morbidity. Current management focuses on early detection and treatment of organ-based manifestations., Aim: To determine whether the ascertainment of major organ complications of SSc has changed over time and if this is associated with better survival., Design: Retrospective cohort analysis., Methods: A total of 520 SSc patients, 234 with disease onset between 1990 and 1993 (historical cohort) and 286 with disease onset between 2000 and 2003 (contemporary cohort), were included. Survival and frequency of internal organ complications were compared between the two cohorts., Results: Five-year survival among diffuse cutaneous SSc (dcSSc) patients has improved from 69% in the 1990-93 cohort to 84% in the 2000-03 cohort (P = 0.018), whereas 5-year survival among the limited cutaneous SSc (lcSSc) patients has remained unchanged-93 and 91%, respectively. Sixteen per cent of the lcSSc subjects and 38% of the dcSSc subjects from the contemporary cohort were diagnosed for the clinically significant pulmonary fibrosis compared with 3 and 7%, respectively, of the historical cohort (P < 0.001). Similarly, the diagnosis of pulmonary arterial hypertension was more frequent in the patients from the contemporary cohort (8 and 7% for lcSSc and dcSSc, respectively) compared with [ < 1% (P = 0.002) and 1% (P = 0.148), respectively] the historical cohort. There was no significant difference between the two cohorts in terms of scleroderma renal crisis and cardiac involvement., Conclusion: Survival has substantially improved for the diffuse cutaneous subset of SSc with better and more complete ascertainment of lung complications as a result of systematic annual screening.

The integrated approach to the study of female genital tract infection (GTI) with Chlamydia trachomatis is a conceptual framework through which a consistent and comprehensive evidence-based understanding of C. trachomatis GTI could evolve. One application of this approach has been to identify candidate genes that may play a role in the course and severity of C. trachomatis GTI in women, using human clinical and genetic data together with results obtained in the female mouse model to guide the selection process This model has been proven robust enough: i) to identify stable phenotypic differences in the course and outcome of GTI among commonly used immunocompetent inbred mouse stains that are used in the construction of gene knockout (KO) and transgenic mice; as well as ii) to serve as a platform in which to assess the influence of genetic differences among human genital tract isolates of C. trachomatis as well as between this biovar and the mouse biovar, Chlamydia muridarum. This review presents a summary of published and unpublished results from 25 years of studies in immunodeficient and gene-deficient KO mice that both inform our present understanding of the immunogenetics of C. trachomatis GTI and serve to guide candidate gene selection., (Copyright 2009 Prous Science, S.A.U. or its licensors. All rights reserved.)

Aim: The safety and potential efficacy of a chimaeric anti-tumour necrosis factor alpha monoclonal antibody (infliximab) were examined in diffuse cutaneous systemic sclerosis (dcSSc)., Methods: A 26-week open-label pilot study in which 16 cases of dcSSc received five infusions of infliximab (5 mg/kg). Clinical assessment included skin sclerosis score, scleroderma health assessment questionnaire, self-reported functional score and physician global visual analogue scale. Collagen turnover, skin biopsy analysis and full safety evaluation were performed., Results: There was no significant change in skin score at 26 weeks but a trend for lower modified Rodnan skin score at 22 weeks (OR 17, 95% CI 6 to 46) compared with peak value (OR 29, 95% CI 11 to 44; p = 0.10). Serum aminoterminal propeptide of type III collagen level was significantly lower at week 26 compared with baseline (p = 0.03). Secretion of type I collagen by dermal fibroblasts was reduced at 26 weeks compared with baseline (p = 0.02). There were no deaths during the study and no suspected unexpected serious adverse reactions. 21 serious adverse events (AE) occurred in seven subjects, mostly attributable to dcSSc. 127 distinct AE occurred in 16 subjects. Of these, 19 AE (15%) were probably or definitely related to infliximab treatment. Eight (50%) patients prematurely discontinued infliximab. Anti-infliximab antibodies developed during the study in five subjects and were significantly associated with suspected infusion reactions (p = 0.025)., Conclusion: In dcSSc infliximab did not show clear benefit at 26 weeks but was associated with clinical stabilisation and a fall in two laboratory markers of collagen synthesis. The frequency of suspected infusion reactions may warrant additional immunosuppression in any future studies in systemic sclerosis.

Objectives: Oesophageal scintigraphy is an effective, non-invasive screening test to detect oesophageal dysmotility and reflux. Our objective was to assess the long term effect of lansoprazole therapy on gastroesophageal dysmotility in systemic sclerosis (SSc)., Methods: 24 SSc patients were randomised to receive either lansoprazole 30 mg or placebo for 12 months. Gastroesophageal motility was assessed by scintigraphy at baseline, after 6 months and after 12 months. Symptoms were evaluated by self-reported gastrointestinal questionnaire., Results: Of 21 patients starting treatment, 17 (81%) completed the first 6 months and 13 (62%) completed the study. 3 patients from each group were withdrawn due to adverse events. As expected, lansoprazole appeared to decrease frequency of gastroesophageal symptoms in the first 6 months of treatment, but long term benefit was not evident. Scintigraphy showed worsening oesophageal dysmotility in SSc patients irrespective of lansoprazole treatment. In addition, early signs of dysmotility were found in asymptomatic patients. We found no correlation of scintigraphy findings with symptoms of gastroesophageal dysmotility., Conclusion: Although lansoprazole 30 mg daily appears to suppress SSc-related gastroesophageal symptoms in the short term, benefit was not sustained at 12 months, and there was no evidence that progression of gastroesophageal motility was prevented. Scintigraphy findings did not correlate with symptoms of dysphagia.

Objective: To investigate the relationship of Chlamydia trachomatis (CT) outer membrane protein A (OmpA) type to the clearance of CT infection before treatment., Methods: CT OmpA genotyping, with amplification and sequencing of ompA, was utilised to study the natural history of CT infection (spontaneous resolution vs persistence) in 102 individuals with chlamydia-positive screening tests returning for treatment., Results: CT OmpA distribution was associated with spontaneous resolution of CT, most notably with CT OmpA genotype J/Ja detected more often from the initial screening CT test than other genotypes in those who then had spontaneous resolution of CT noted at the time of treatment. Five individuals with presumed persisting CT infection had discordant CT OmpA genotypes at the screening and treatment visits, suggesting possible new interval CT infection., Conclusions: Clearance of chlamydia by the host before treatment may be influenced by the CT OmpA genotype infecting the host. CT OmpA genotyping may be a valuable tool in understanding the natural history of chlamydial infections.

Objectives: Nitric oxide (*NO) is an important physiological signalling molecule and a potent vasodilator. We have previously demonstrated abnormal *NO metabolism in the plasma of patients with systemic sclerosis (SSc; scleroderma), a disease that features vascular dysfunction as well as collagen overproduction and fibrosis. The aim of the present study was to examine nitric oxide synthase (NOS) expression and activity and assess the potential role of antioxidants in the scleroderma-like syndrome of the tight-skin 1 (TSK-1/+) mouse, an experimental animal model for fibrosis., Methods: Skin, lung or plasma was taken from TSK-1/+ (n = 15) and wild-type (WT; n = 12) littermate mice. Type 1 collagen, endothelial NOS (eNOS), haemoxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) protein and gene expression were determined by western blot and reverse transcriptase-polymerase chain reaction. eNOS expression was further determined by immunohistochemistry. NOS activity was evaluated by conversion of [14C] L-arginine to [14C] L-citrulline. Levels of circulating plasma nitrite/nitrate (NO(x)) were also measured. Total antioxidant activity was evaluated by ABTS+ production (ABTS = 2,2'-azino-bis-[3-ethylbenz-thiazoline-6-sulphonic acid)., Results: In the skin, eNOS was present in the epidermal layer, hair follicles and also in the endothelial cells lining the blood vessels. Expression of both the eNOS protein and gene was significantly reduced in TSK-1/+ skin tissue, while type 1 collagen protein was elevated compared with WT. Furthermore, there was decreased NOS activity in TSK-1/+ skin tissue; however, there was no measurable difference in plasma NO(x). Correspondingly, the protective antioxidant enzyme HO-1 and the associated transcription factor Nrf2 showed reduced protein and gene expression levels in TSK-1/+ skin, while there was also less total antioxidant activity. In TSK-1/+ lung tissue, however, we observed no difference in collagen protein expression, *NO metabolism or HO-1 expression and total antioxidant activity compared with WT., Conclusions: The findings suggest that there is also abnormal *NO metabolism in the TSK-1/+ mouse model of fibrosis, particularly in the skin, while expression and activity of protective antioxidants are reduced. The TSK-1/+ mouse may also be useful for testing treatments that target vascular endothelial cell function in patients with SSc.

Objective: The chemokine CCL2 has been consistently found to be up-regulated in systemic sclerosis. To explore the potential value of serum CCL2 measurement in disease assessment, we have compared CCL2 levels with clinical phenotype and investigated effect of therapy on circulating CCL2., Methods: Serum samples from a well characterised cohort of 94 systemic sclerosis (SSc) patients, 16 patients with primary Raynaud phenomenon and 11 healthy controls were examined by ELISA. Our cohort of patients included 50 patients with limited cutaneous (lc)SSc (20 with lcSSc alone and 30 with pulmonary arterial hypertension-lcSSc), and 44 with diffuse cutaneous (dc)SSc, 30 of which had early-onset dcSSc., Results: Serum levels of CCL2 were increased in both major SSc subsets. In early stage dcSSc 18/30 (60%) cases demonstrated markedly elevated CCL2, and this was associated with anti-topoisomerase or anti-RNA polymerase I/III antibody reactivity, and with greater frequency of major organ-based complications. Elevation of CCL2 serum levels in the lcSSc subset was not associated with pulmonary arterial hypertension, although there was a trend for reduction following treatment with prostacyclin analogues or bosentan., Conclusion: These findings suggest that the CCL2/CCR2 axis is a potential therapeutic target in SSc, particularly in the early dcSSc subset. CCL2 measurement may be useful for risk stratification in early stage disease, but its value in disease monitoring is questionable.

Background: Vascular damage is a key pathological process in systemic sclerosis (SSc) and accounts for significant disease-related morbidity. To determine the clinical burden of severe digital vasculopathy (SDV), we have reviewed hospital-based treatment for this important complication of SSc in a large single centre cohort., Methods: Cases were identified from a cohort of 1168 patients with a diagnosis of SSc who were reviewed during an 18-month period. Patients with recorded episodes of SDV-related complications (digital ulceration, critical digital ischaemia or digital gangrene), requiring surgical amputation, digital sympathectomy or admissions for intravenous prostacyclin or calcitonin gene related peptide (CGRP) and/or intravenous antibiotic treatment were identified., Results: From this large SSc cohort, 17.4% had SDV-related complications. Contrary to expectation, their frequency was significantly higher among the patients with the diffuse cutaneous subset of SSc (27.5%) compared with 13% among the patients with limited cutaneous SSc (p<0.0001). 16.6% had at least one recorded episode of digital ulcers, and 12% required at least one hospitalisation during the 18 months for treatment with intravenous prostacyclin/CGRP. Overall, there were 242 admissions with a mean duration of 6 days., Conclusions: Digital vasculopathy is a serious complication of SSc contributing significant morbidity and often requiring hospital-based management.

Objective: To evaluate the efficacy and tolerability of prolonged administration of quinapril, a long-acting angiotensin-converting enzyme inhibitor, in the management of the peripheral vascular manifestations of limited cutaneous systemic sclerosis (lcSSc) and in the prevention of the progression of visceral organ involvement in the disease., Methods: This was a multicenter, randomized, double-blind, placebo-controlled study evaluating quinapril 80 mg/day, or the maximum tolerated dosage, in 210 patients with lcSSc or with Raynaud's phenomenon (RP) and the presence of SSc-specific antinuclear antibodies. Treatment was for 2-3 years. The primary outcome measure was the number of new ischemic ulcers appearing on the hands; secondary measures were the frequency and severity of RP attacks, skin score, treatments for ischemia, health status (measured by the Short Form 36 instrument), measures of kidney and lung function, and echocardiographic estimates of pulmonary artery pressure. An intent-to-treat analysis was used., Results: Quinapril did not affect the occurrence of digital ulcers or the frequency or severity of RP episodes. It did not alter the treatments that were prescribed for either infected ulcers or severe RP symptoms. There was no apparent effect on the estimated tricuspid gradient. Health status was not affected by quinapril, and one-half of the patients who believed they had benefited from the trial treatment were in the placebo arm. Quinapril was not tolerated by one-fifth of the patients, with dry cough being the most frequent side effect., Conclusion: Administration of quinapril for up to 3 years had no demonstrable effects on the occurrence of upper limb digital ulcers or on other vascular manifestations of lcSSc in this patient population.

Background: Scleroderma renal crisis (SRC) is an important complication of systemic sclerosis, causing acute renal failure, and usually hypertension., Aims: To review the clinical and pathological features of SRC, and correlate them with renal outcomes and mortality., Design: Retrospective case series., Methods: We identified 110 cases of SRC managed at a single centre between 1990 and 2005., Results: SRC occurred in 5% of scleroderma cases under follow-up. Cases were predominantly female (81%), with diffuse cutaneous disease (78%). RNA polymerase antibodies were found in 59% of cases tested. Almost all (108/110) received treatment with ACE inhibitors (ACEIs). Dialysis was not required in 36%, was required temporarily (for up to 3 years) in 23%, was required permanently in 41%. Patients not on dialysis showed improvement in estimated glomerular filtration rate after SRC (mean change +23 ml/min over 3 years). Poor renal outcome was associated with lower blood pressure at presentation, and with higher age in those requiring dialysis. Steroid use, microangiopathic haemolytic anaemia, and antibody profile were not related to renal outcome. In the 58 renal biopsies available for clinical correlation, acute changes of mucoid intimal thickening in arteries and fibrinoid necrosis in arterioles were associated with a poorer renal outcome. Mortality was high (59% survival at 5 years), and was higher in men., Discussion: Despite the efficacy of ACEIs in managing SRC, the poor long-term outcome warrants evaluation for additional treatments for this devastating complication of systemic sclerosis.

Objectives: This study compares the scleroderma Functional Score (FS) with the validated Disability Index of the Health Assessment Questionnaire (HAQ-DI) and other outcome measures. The aim is to determine if the FS is useful as an objective assessment tool for longitudinal evaluation of the functional impact of systemic sclerosis (SSc)., Methods: A cohort of 135 patients was studied (M:F, 15:120), with a mean age of 45.7 (S.D. = 13.2) at SSc disease onset. 69 (51%) had diffuse cutaneous scleroderma (dcSSc) and 66 (49%) had limited disease (lcSSc). The mean interval between the two assessments was 1.8 yrs (S.D. = 1.2). Functional impact was determined by evaluating archived self-reported questionnaires (FS, HAQ and scleroderma-VAS). Concurrent evaluation of the disease severity score was derived from clinical data stored in the hospital database and from medical case note reviews., Results: At baseline, the mean FS was 11.0 (S.D. = 9.0) and at reassessment 12.0 (S.D. = 9.2). The mean absolute change in FS between the two assessments was 4.1 (S.D. = 4.9). With time 49% (n = 66) showed a clinically significant change in their functional ability with regard to FS, of these 29% (n = 39) worsened and 20% (n = 27) improved. There was an excellent cross-sectional correlation between the FS and the HAQ-DI (rho = 0.90; P < 0.0001). Also, a strong correlation between longitudinal change in these two outcome measures (rho = 0.59, P < 0.0001) was observed., Conclusions: This is the first longitudinal study of the scleroderma FS. It demonstrates that the FS can capture bidirectional and clinically significant changes in SSc related disability over time. The concurrent validity of the FS is asserted through its strong correlation with the HAQ-DI. The FS is a disease-specific, inexpensive and practical instrument for assessing functional status in SSc. It is a promising self-administered assessment tool for use in evaluating new SSc treatments.

Objectives: We have assessed indications, duration and tolerability of treatment with mycophenolate mofetil (MMF) in patients with diffuse cutaneous systemic sclerosis (dcSSc), and compared clinical outcome with a control cohort treated with other immunosuppressive drugs., Methods: The clinical records of 109 patients treated with MMF and 63 control subjects receiving other immunosuppressive drugs were reviewed. Data covering a 5-yr period from commencement of treatment or until last assessment date were collected., Results: MMF and control groups were well-matched in terms of basic demographic and clinical parameters. Treatment with MMF was very well tolerated. Of all patients, 12% experienced adverse reactions with gastrointestinal (GI) tract disturbances and infections being most frequent. MMF was discontinued due to disease stabilization in 9%, side effects in 8% and no effect on the disease activity in 14% of the patients. There was a significantly lower frequency of clinically significant pulmonary fibrosis in the MMF-treated cohort (P = 0.037) and significantly better 5-yr survival from disease onset and from commencement of treatment (P = 0.027 and P = 0.012, respectively). There was no significant difference between the two groups in terms of modified Rodnan skin score and forced vital capacity (FVC) change., Conclusions: MMF is very well tolerated and appears to be at least as effective as the other current therapies for dcSSc. Our results provide support for further evaluation of MMF in a prospective trial.

Background: The 6-min walk test (6MWT) is increasingly used as an outcome measure in interstitial lung disease (ILD)., Aim: To evaluate the usefulness of the 6MWT in a cohort of patients with ILD secondary to systemic sclerosis (SSc) and to correlate with established physiological parameters., Methods: 163 patients with SSc-ILD were recruited for a multicentre, randomised, double-blind clinical trial. Available data at protocol screening included repeated 6MWTs, pulmonary function testing with diffusing capacity, Doppler echocardiography and high-resolution computed tomography of the thorax. Borg Dyspnoea Index was evaluated before and after 6MWT., Results: Mean (standard deviation (SD)) distance walked during walk test 1 was 396.6 (84.55) m compared with 399.5 (86.28) m at walk test 2. The within-subject, intertest correlation as determined by Pearson's correlation coefficient testing was 0.95 (p<0.001). However, only weak correlations of 6MWT with percentage forced vital capacity and the Borg Dyspnoea Index were observed, and no correlation was observed with percentage diffusing capacity., Conclusion: These data confirm the high reproducibility of the 6MWT in patients with SSc-ILD and therefore the validity of the test in this cohort. The lack of correlation of 6MWT with standard physiological parameters of ILD suggests a multifactorial basis for limited exercise capacity in patients with SSc and calls into question the utility of the 6MWT as a measure of outcome in future studies on SSc-ILD.

Objective: It has been suggested that macrovascular disease is more common in patients with scleroderma (SSc). We investigated the prevalence of coronary artery disease (CAD) in SSc using coronary angiography., Methods: Coronary angiography was performed in 172 patients with SSc and suspected CAD to examine the prevalence of significant CAD. The prevalence of CAD was estimated in the whole group and also according to age, gender and type of symptoms (typical angina, atypical angina and non-anginal pain or breathlessness). Standardized prevalence ratios (SPRs) were calculated in each symptomatic group in order to compare CAD rates amongst our observed population with those predicted using the Diamond and Forrester (D & F) probability analysis. This analysis provides an estimate of the probability of CAD based on gender, age and symptoms in subjects aged between 30-69 yrs., Results: The observed prevalence of CAD in the whole population was 22% (38/172); 17% (6/36) in males and 23% (32/136) in females. A total of 41 patients were excluded because they were outside the age range for D & F analysis. Compared with the reference population, the SPRs for CAD in the three SSc groups were: 47% (95% CI 21.7-89.9) in the typical angina group (22 patients), 50% (95% CI 13.6-128) in the atypical angina group (22 patients) and 93% (95% CI 49.4-158.8) in the non-anginal pain or breathlessness group (87 patients)., Conclusion: The prevalence of CAD in patients with SSc is similar and not greater to that expected in individuals without SSc.

Background: Ischaemia is known to induce angiogenesis, but the effects of critical leg ischaemia (CLI) on angiogenesis remain unclear. The aim of this study was to examine the physiological angiogenic response in CLI by investigating the extent of neovascularization, characterizing microvessel subtypes and determining the microvessel ultrastructure., Methods: Gastrocnemius muscles were biopsied from 12 patients with CLI and 12 without leg ischaemia. Microvessels were evaluated immunohistochemically using three endothelial markers (anti-CD31, anti-CD34 and PAL-E) and anti-alpha smooth muscle actin (SMA) as a mural cell marker to label arterioles. Ki67 was used to demonstrate active cell proliferation. Further microvessel ultrastructural characteristics were determined by transmission electron microscopy., Results: The CLI group had significantly higher microvessel density and microvessel : muscle fibre ratio for all endothelial subtypes examined (P < 0.001). PAL-E staining demonstrated the highest increase: 4.7 times higher in CLI muscle. There was no significant difference in alphaSMA-positive microvessel density (P = 0.118) or microvessel: muscle fibre ratio (P = 0.214). Ki67 staining showed no active cell proliferation. Transmission electron microscopy showed CLI microvessels had abnormal morphology, mainly a thick basement membrane., Conclusion: A physiological angiogenic response was found in CLI, but the microvessels had an abnormal ultrastructure. A lack of active cell proliferation suggests that the angiogenic response may have been exhausted.

Background: Endothelin-1 is considered to be a central pathogenic factor in connective tissue diseases (CTDs) such as systemic sclerosis (SSc), leading to vasoconstriction, fibrosis, hypertrophy and inflammation. A frequent complication of CTD is pulmonary arterial hypertension (PAH), which has a major effect on functioning and quality of life, and is associated with a particularly poor prognosis., Objective: To present a subgroup analysis that summarises experiences from the pivotal studies and their open-label extensions with the oral dual endothelin-1 receptor antagonist bosentan in patients with PAH and CTD, mostly SSc and lupus erythematosus., Methods: 66 patients with PAH secondary to CTD, in World Health Organization functional class III or IV, were randomised to two double-blind, placebo-controlled studies and followed up for 12 and 16 weeks, respectively. The primary end point was change in exercise capacity, assessed using the 6-min walk test. In both studies and their extensions, survival was assessed from start of treatment to death or data cut-off and analysed as Kaplan-Meier estimates., Results: 44 patients with PAH secondary to CTD who were treated with bosentan were stable in 6-min walk distance at the end of the study (+19.5 m, 95% confidence interval (CI) -3.2 to 42.2), whereas patients treated with placebo deteriorated (-2.6 m, 95% CI -54.0 to 48.7). 64 patients subsequently received bosentan in an open-label long-term extension study. Mean (standard deviation (SD)) exposure to bosentan was 1.6 (0.9) years, and duration of observation was 1.8 (0.8) years. 8 (16%) patients received epoprostenol as add-on treatment and 7 (14%) after discontinuation of bosentan. Survival in those receiving bosentan was 85.9% after 1 year and 73.4% after 2 years., Conclusion: Short-term bosentan treatment in a subgroup of patients with PAH secondary to CTD seems to have a favourable effect compared with placebo. The long-term follow-up of these patients suggests that first-line bosentan, with the subsequent addition of other PAH treatments if required, is safe for long-term treatment and may have a positive effect on outcome.

Objectives: To measure survival, haemodynamic function and functional class in patients with systemic sclerosis associated pulmonary arterial hypertension (SSc-PAH) in two treatment eras., Methods: Six year longitudinal study of 92 consecutive patients with SSc-PAH diagnosed by cardiac catheterisation. Data were collected both prospectively and retrospectively. Patients were given basic treatment (diuretics, digoxin, oxygen and warfarin). Where clinically indicated, a prostanoid was used as advanced treatment (historical control group). From 2002, the range of treatments available expanded to include bosentan, which was generally the preferred treatment (current treatment era group). Survival was measured from the date of diagnosis of pulmonary hypertension by cardiac catheterisation. Six minute walking distance and haemodynamic function were measured at the time of diagnosis and at least one month after treatment was started., Results: The historical control group comprised 47 patients, all of whom received basic treatment; 27 of these were also treated with prostanoids. The current treatment era group comprised 45 patients, all of whom received bosentan as preferred treatment. Kaplan-Meier survival in the historical control group was 68% at one year and 47% at two years. Survival in the current treatment era group was 81% and 71% (p = 0.016) at one and two years, respectively. Pulmonary vascular resistance increased in the historical control group (by 147 dyn.s.cm(-5)), whereas in the current treatment era group, it remained stable over an average of nine months (decrease of 16 dyn x s x cm(-5), p < 0.006)., Conclusion: Survival of selected patients with SSc-PAH has improved in the current treatment era. In contrast to patients treated historically with basic drugs and prostanoids, patients treated in the current treatment era had improved survival associated with a lack of deterioration in cardiac haemodynamic function.

Objective: To investigate the hypothesis that increased formation of reactive nitrogen species may contribute to the vascular pathology that develops in patients with connective tissue disease such as scleroderma., Patients and Methods: The level of protein-bound nitrotyrosine in plasma was measured by stable isotope dilution gas chromatography/negative ion chemical ionisation mass spectrometry in 11 patients with primary Raynaud's phenomenon, 37 with scleroderma, 13 with chronic renal impairment, and in 23 healthy controls., Results: Plasma protein-bound nitrotyrosine was markedly decreased in patients with primary Raynaud's phenomenon (mean (SEM) 0.60 (0.06) ng/mg dry protein) compared with patients with scleroderma (1.78 (0.21) ng/mg protein), chronic renal impairment (1.42 (0.17) ng/mg protein) or healthy controls (1.63+/-0.15 ng/mg protein, ANOVA p<0.001)., Conclusion: These data suggest that there is decreased nitration of plasma proteins, or increased degradation of nitrated proteins from the circulation of patients with primary but not secondary Raynaud's phenomenon.

Systemic sclerosis (SSc) is a connective tissue disease of unknown aetiology characterized by fibrosis of the skin and internal organs, vascular abnormalities and humoral autoimmunity. Strong T-cell-dependent autoantibody and HLA associations are found in SSc subsets. The co-stimulatory molecule, CD86, expressed by antigen-presenting cells, plays a crucial role in priming naïve lymphocytes. We hypothesized that SSc, or one of the disease subsets, could be associated with single-nucleotide polymorphisms of the CD86 gene. Using sequence specific primer-polymerase chain reaction (SSP-PCR) methodology, we assessed four CD86 polymorphisms in 221 patients with SSc and 227 healthy control subjects from the UK. Haplotypes were constructed by inference and confirmed using PHASE algorithm. We found a strong association between SSc and a specific haplotype (haplotype 5), which was more prevalent in patients than in controls (29% vs 15%, OR = 2.3, chi(2) = 12, P = 0.0005). This association could be attributed to the novel -3479 promoter polymorphism; a significant difference was observed in the distribution of the CD86 -3479 G allele in patients with SSc compared to controls (43.7% vs. 32.4%, OR = 1.7, chi(2) = 12.1, P = 0.0005). TRANSFAC analyses suggest that the CD86-3479T allele contains putative GATA and TBP sites, whereas G allele does not. We assessed the relative DNA protein-binding activity of the -3479 polymorphism in vitro using electromobility gel shift assays (EMSA), which showed that the -3479G allele has less binding affinity compared to the T allele for nuclear proteins. These findings highlight the importance of co-stimulatory pathways in SSc pathogenesis.

Objectives: Endothelial dysfunction is a primary event in systemic sclerosis; however, the aetiology of events and the role of nitric oxide (NO) is still unclear. The aim of the present study is to investigate whether there are abnormalities in NO metabolism in plasma from patients with primary Raynaud's phenomenon (RP) and in the pathogenesis of systemic sclerosis (SSc): limited SSc (lSSc) and diffuse (dSSc). We also wanted to investigate the effect of factors within patients' SSc serum on NO metabolism in human microvascular endothelial cells (HMECs)., Methods: Plasma (n=89) or serum (n=80) was assayed for total nitrate and nitrite (NOx), nitration of proteins and the NO inhibitor asymmetric dimethylarginine (ADMA). HMECs were treated with patients' SSc serum and assayed for indicators of NO metabolism., Results: Plasma NOx was elevated in patients with RP or lSSc (P<0.002), but not in patients with dSSc, compared with controls. Nitrated proteins in plasma, however, were found to be very high in dSSc patients (P<0.03), compared with RP, lSSc or controls. Patients with dSSc also showed increased levels of serum ADMA (P<0.05). The high level of nitrated proteins in dSSc was strongly associated with the severity and duration of dSSc disease. Skin biopsy sections from dSSc patients also showed enhanced nitrotyrosine staining compared with controls. In HMECs, pre-incubation with SSc serum impaired the activity of nitric oxide synthase (NOS) but not the expression of inducible or endothelial NOS. SSc serum also induced a reduction in intracellular cGMP synthesis, and NOx production in the cell culture medium, but was not associated with increased cell cytotoxicity., Conclusions: NO formation is increased in patients with primary RP or lSSc, but nitration of proteins and elevated ADMA is a particular feature of dSSc and may reflect abnormal NO regulation and/or contribute to endothelial dysfunction in SSc.

Backgrounds and Aims: To evaluate the prognosis of primary biliary cirrhosis (PBC) together with systemic sclerosis (SSc), as this is unknown., Methods and Results: A PBC database of 580 patients identified 43 with PBC and SSc: two patients with PBC alone were matched to each PBC-SSc patient for serum bilirubin concentration at the initial visit. Forty (93%) patients had limited cutaneous SSc. At diagnosis of PBC, median values were: 49.7 years, bilirubin 17 micromol/l, and albumin 40.5 g/l. Liver diagnosis occurred a median 4.9 years after SSc in 24 (56%) patients. In matched patients, median values at diagnosis were: 53.2 years, bilirubin 12 micromol/l, and albumin 41 g/l. Median follow up was similar: 3.16 years (PBC-SSc) and 4.8 years (PBC alone). The risk of transplantation or death from diagnosis, adjusting for sex, age, log bilirubin, and alkaline phosphatase was significantly lower in PBC-SSc (hazard ratio 0.116, p=0.01) due to less transplantation (hazard ratio 0.068, p=0.006). The rate of bilirubin increase was less in PBC-SSc (p=0.04). Overall survival was similar (hazard ratio 1.11, p=0.948); there were nine deaths (21%) in PBC-SSc (six SSc related and two liver related) and nine (11%) in PBC alone (six liver related)., Conclusions: Liver disease has a slower progression in PBC-SSc compared with matched patients with PBC alone.

Objectives: To determine the relationship between clinical features and circulating levels of active transforming growth factor (TGF) beta1 in the major subsets of systemic sclerosis (SSc)., Methods: In a cross-sectional study cases of diffuse cutaneous SSc (dose) (n = 27) or limited cutaneous SSc (dose) (n = 20) were compared with healthy controls (n = 22). Active and total TGFbeta1 was measured in serum and plasma by a high-sensitivity enzyme-linked immunosorbent assay., Results: There were no significant differences between levels of total serum TGFbeta1. However, cases of dcSSc had lower levels of active TGFbeta1 than cases of lcSSc or controls. In addition, more cases of dcSSc (18/27; 66%, P < 0.025) had no detectable active TGFbeta1 than controls (7/22, 32%) or lcSSc (7/20, 35%). In dcSSc, serum active TGFbeta1 levels correlated negatively with skin score and positively with disease duration., Conclusions: Contrary to expectation, levels of active TGFbeta1 are reduced in dcSSc and this correlates with two variables known to associate with disease activity, shorter duration and more extensive skin sclerosis. This suggests that active TGFbeta1 may be sequestered in active involved SSc skin and that serum levels are reduced despite strong evidence implicating TGFbeta isoforms in the pathogenesis of fibrosis. Our findings may have implications for systemic TGFbeta-trapping therapies in this disease.

Background: Over-expression of connective tissue growth factor (CTGF) is a hallmark of fibrotic disease, including scleroderma. CTGF acts with the pro-fibrotic cytokine TGFbeta to promote sustained fibrotic responses in vivo. Elevated production of CTGF might be responsible for maintenance of the fibrotic phenotype in scleroderma. Assays of CTGF or of its fragments are potential non-invasive measures of the fibrotic response in scleroderma., Aim: To determine the utility of whole, N-terminal, and C-terminal CTGF as surrogate markers for fibrosis in scleroderma., Design: Cross-sectional controlled study., Methods: Plasma was collected prospectively from 47 scleroderma patients (26 diffuse scleroderma, 21 limited scleroderma) and 18 healthy controls. At the same time, dermal interstitial fluid was derived by a suction blister technique from the lesional skin of scleroderma patients, and from the forearm skin of healthy controls. Whole, N-terminal, and C-terminal CTGF were assayed by ELISA, using monoclonal antibodies specific for N- and C-terminal epitopes., Results: N-terminal cleavage products of CTGF were present at elevated levels in the plasma and dermal interstitial fluid of scleroderma patients, compared to healthy controls. N-terminal CTGF levels in plasma and dermal interstitial fluid correlated with severity of skin disease and (negatively) with disease duration. Whole and C-terminal CTGF levels were low in blister fluid and plasma levels were not elevated in disease., Discussion: These results support a role for CTGF in scleroderma-associated fibrosis and the utility of N-terminal CTGF as a marker of fibrosis.

Objective: SPARC (secreted protein, acidic and rich in cysteine) is a matricellular protein that modulates cell-cell and cell-extracellular matrix interactions. SPARC expression is restricted mainly to sites of tissue remodelling and wound repair, and is prominent in fibrotic disorders. Single-nucleotide polymorphisms (SNPs) in the SPARC gene are reportedly linked to scleroderma in four ethnic groups: Choctaw Indians, Caucasians, African Americans and Mexican Americans. We set out to reproduce and to positionally clone these disease associations in a set of UK Caucasian scleroderma patients and ethnically matched controls., Methods: One hundred and twenty-one scleroderma subjects and 200 controls were genotyped by polymerase chain reaction with sequence-specific primers differing only in the 3' nucleotide corresponding to each allele of the biallelic SNPs. Scleroderma patients were analysed against controls and on the basis of their fibrosing alveolitis status as judged by high-resolution computed tomography evaluation and the extent of cutaneous involvement., Results: Eight biallelic SNPs were genotyped: three from the last untranslated exon, which had been described previously, and an additional five novel SNPs: two in the promoter region, one in exon three and two in the 3' untranslated region. Six major haplotypes were constructed across all eight SNP positions. No significant differences in genotype, allele or haplotype frequency were observed between scleroderma and controls or within scleroderma subgroups., Conclusions: SNPs in the SPARC gene are not associated with susceptibility to scleroderma. This research adds to the genetic knowledge of the SPARC gene by identifying five novel SNPs spanning the whole gene and inserting these within the context of clearly defined haplotypes.

Objective: To investigate the contribution of cold induced pulmonary vasospasm by peripheral and central cold stimulus in exacerbating pulmonary arterial hypertension (PAH) in patients with systemic sclerosis undergoing cardiac catheterisation., Methods: In a prospective pilot study, 21 patients with systemic sclerosis and catheter proven PAH had mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR), and cardiac output (CO) measured before and after peripheral (hand immersion into cold water at 10-15 degrees C for two minutes if tolerated) and central (direct cold water at 4 degrees C injected into the right atrium) cold pressor challenge. Markers of endothelial activation, platelet function, and nitric oxide degradation were measured in blood sampled from the pulmonary artery., Results: 19 of the patients (mean (SD) age, 56 (4) years; baseline mPAP, 34 (8) mm Hg; PVR, 420 (87) dyne.s.cm(-5); CO, 6.4 (1.8) l/min) tolerated cold hand immersion for the maximum two minute duration. All 21 tolerated central cold pressor challenge (three to five injections of 10 ml saline boluses at 4 degrees C). There was no significant change in haemodynamics after cold challenge by either route of provocation. Levels of endothelin-1, von Willebrand factor, fibrinogen, and 3-nitrotyrosine were raised compared with control values in patients with systemic sclerosis but without PAH, but did not change significantly after peripheral cold challenge., Conclusions: Pulmonary vasospasm in response to peripheral and centrally administered cold pressor challenge is unlikely to contribute to persistence of pulmonary arterial hypertension in patients with systemic sclerosis.

Objectives: To identify the immunodominant T cell epitopes of the topoisomerase I protein in patients with systemic sclerosis (SSc) and control subjects, using computational analysis software (TEPITOPE) and T cell proliferation assays., Methods: Six oligopeptides, predicted by TEPITOPE software as potential topoisomerase protein epitopes, were used to perform T cell proliferation assays in 21 patients with SSc and 15 healthy controls., Results: A positive response to at least one of the peptides was seen in 10/21 patients and 7/15 healthy controls. Among responders, the proliferative response was limited to a single peptide in 6/7 healthy controls, whereas 5/10 patients responded to more than one peptide. In responding patients a significant correlation was found between disease duration and number of peptides inducing a response (p = 0.007)., Conclusions: Several T cell epitopes of the topoisomerase I protein have been identified and evidence has been found to suggest epitope spreading in patients with SSc.

Rationale: The aim of the study was to evaluate the validity of collagen type I metabolites as markers of disease activity in scleroderma (SSc), through a systematic review of the literature and by validating the results by measuring collagen type I metabolites in well characterized patients with scleroderma spectrum disorders and in Raynaud's phenomenon., Methods: A systematic review was performed of studies of collagen type I metabolites in scleroderma spectrum disorders published from 1980 to 2003. The collected results from the literature were compared with our own measurements of collagen type I metabolites (PINP and ICTP) in a small number of well characterized patients within the scleroderma spectrum and in patients with primary and "autoimmune" Raynaud's phenomenon. Peptide concentrations from all sources, including the present study, were compared. Reported correlations between peptide concentrations and clinical variables were also analysed., Results: Of 19 papers identified by an extensive Medline search, 12 were eligible for systematic analysis. There was a considerable heterogeneity in the results with a wide range of metabolite concentrations. Values from disease groups and healthy controls overlapped. These findings were confirmed by our study where, similarly, there was a large range of values in all groups, but particularly in the diffuse SSc subset. When the correlation between peptide levels and clinical variables was assessed, large discordance between the studies was observed., Conclusions: We have not found sufficient evidence to support the use of serum markers of collagen turnover in the assessment of scleroderma activity and severity, in view of their low specificity and the heterogeneity of the results of various studies. Lack of standardized routine evaluation of SSc patients in clinical studies might have accounted for the variability of the findings. However, due to the small sizes of most published studies, demonstration of no effect should come from large-scale randomised trials. Longitudinal serial analysis of these molecules in individual patients may play a future role in the evaluation of the response to fibroblast-targeting therapeutic strategies in scleroderma patients.

Objective: A prospective study to evaluate echocardiography and gas transfer (DLCO) by comparison with cardiac catheterization in discriminating between patients with and without systemic sclerosis-associated pulmonary arterial hypertension (SScPAH)., Method: A total of 137 (52 with and 85 without pulmonary fibrosis) had echocardiography and lung function tests within 3 months of their definitive invasive study., Results: At cardiac catheterization 99 of these patients were found to have PAH, while PAH was excluded in 38. Echocardiographically estimated tricuspid gradient (TG) showed a moderate positive correlation (r(2) = 0.44, P<0.005) with both mean pulmonary pressure and invasively determined tricuspid gradient. DLCO showed a weak correlation (r(2 )= 0.09, P = 0.006), when compared with mean pulmonary arterial pressure. In total, 97% of patients with an echocardiographically determined TG of > 45 mmHg were found to have pulmonary hypertension at catheterization. However, no threshold could be defined with either screening test that safely excluded PAH., Conclusions: The positive predictive accuracy of currently used non-invasive tests are adequate for the diagnosis of advanced PAH provided sufficiently high thresholds (TG > 45 mmHg or DLCO < 55% predicted) are used. These tests cannot be relied upon to exclude pulmonary hypertension where pre-test probability is high.

Objective: Large-vessel arterial disease is increasingly recognized as a major cause of morbidity in autoimmune rheumatic disorders. Recent evidence suggests that scleroderma (systemic sclerosis, SSc) may be linked to altered fibrillin-1 metabolism associated with a defect in chromosome 15q. If this is the case, we may expect to see changes in the arterial wall mechanics of large vessels not clinically involved in the disease process. We undertook a study to determine whether the biomechanical properties and intima-media thickness (IMT) of the elastic carotid artery and the muscular femoral artery are altered in subjects with limited (lcSSc) and diffuse (dcSSc) cutaneous SSc., Methods: Measurements of carotid and femoral wall mechanics were made in 33 patients with lcSSc, 19 patients with dcSSc and 21 control subjects, using a duplex scanner coupled to a Wall Track system. Their age, gender, body mass index, heart rate, systolic and diastolic blood pressures, presumed cardiovascular load, and plasma creatinine, fasting cholesterol, triglyceride and glucose concentrations were also measured., Results: There was a progressive and significant reduction (P < 0.001) in the elastic properties of the carotid artery from the control group (compliance, 16.24 +/- 4.39 %mmHg(-1) x 10(-2)) to the lcSSc group (10.89 +/- 2.43 %mmHg(-1) x 10(-2)) to the dcSSc group (7.65 +/- 2.08 %mmHg(-1) x 10(-2)), even after adjustment for the systemic physiological and biochemical variables studied, which are known to influence the mechanics of arterial walls. There was no apparent difference between the groups in the mean elastic indices of the femoral artery and the IMT of the carotid and femoral arteries., Conclusion: The elastic properties of the carotid artery are significantly altered in SSc, and the two major subsets of SSc may be distinguished by their carotid artery biomechanics. This suggests that connective tissue abnormality occurs at sites not previously assessed.

Objectives: A single centre pilot study to investigate the role of the plasma N-terminal pro-brain natriuretic peptide (N-T proBNP) assay to risk stratify patients with suspected pulmonary arterial hypertension (PAH) from a background SSc population., Methods: Out of 49 SSc patients, 23 had and 26 did not have PAH. Right ventricular haemodynamic variables, six-minute walk test and plasma N-T proBNP levels were recorded from patients catheterised for suspected PAH (23 with PAH and 11/26 without PAH)., Results: Mean value of N-T proBNP for SSc patients with PAH was 3365 (standard error 1095) pg/ml compared to 347 (174) pg/ml for patients without PAH. There was a statistically significant correlation (P < 0.05) between N-T proBNP values and (i) mean pulmonary artery pressure (r = 0.53), (ii) right ventricular end diastolic pressure (r = 0.59) and (iii) pulmonary vascular resistance (r = 0.49). Receiver operator characteristic curve analysis showed that a cut-off value of 395.34 pg/ml had a sensitivity of 0.69 and specificity of 1.0., Conclusions: N-T proBNP estimation in systemic sclerosis-related pulmonary hypertension is a potentially useful diagnostic tool with a high specificity and negative predictive value. This test has the potential to have an important role in risk stratification and monitoring of therapy in the future.

Objective: To determine the prevalence of systemic sclerosis associated pulmonary arterial hypertension (SScPAH), evaluate outcome, and identify predictors of mortality in a large patient cohort., Methods: A prospective four year follow up study of 794 patients (722 from our own unit and 72 referrals). All patients screened for PAH using a combination of echocardiography, lung function testing, and clinical assessment. Patients with suspected raised pulmonary artery systolic pressures of >35 mm Hg, carbon monoxide transfer factor (TLCO) <50% predicted, or a precipitous fall in TLCO >20% over a one year period with no pulmonary fibrosis, and patients with SSc with breathlessness with no pulmonary fibrosis found were investigated with right heart catheterisation. All patients with SScPAH were treated in accordance with current best practice., Results: The prevalence of PAH was 12% (89/722) by right heart catheter. The survival was 81%, 63%, and 56% at 1, 2, and 3 years from the diagnosis (in 89 patients from our own cohort and 59/72 referrals). Haemodynamic indices of right ventricular failure--raised mRAP (hazard ratio 21), raised mPAP (hazard ratio 20), and low CI (hazard ratio 11) predicted an adverse outcome There was no significant difference in survival between patients with SScPAH with (n=40) and without (n=108) pulmonary fibrosis (p=0.3)., Conclusions: The prevalence of SScPAH in this cohort was similar to that of other catheter based studies and lower than that of previous echo based studies. The 148 patients with SScPAH actively treated had comparable outcomes to those of the cohorts with primary pulmonary hypertension. A high mRAP was the strongest haemodynamic predictor of mortality. To improve prognosis, future treatments need to be implemented at an earlier disease stage to prevent right ventricular decompensation.

Tumour necrosis factor (TNF) is a pro-inflammatory cytokine with a role in the pathogenesis of a number of conditions including rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis and Crohn's disease. Etanercept (Enbrel; Immunex Corp., Seattle, WA, USA) is a recombinant soluble fusion protein of TNF-alpha type II receptor and IgG which acts by blocking the action of TNF-alpha. It is licensed for use in rheumatoid arthritis and juvenile chronic arthritis. A number of studies report the development of antinuclear and anti-double-stranded DNA antibodies in patients treated with TNF antagonists for rheumatoid arthritis. There are few reports of the development of clinical features of discoid, subacute or systemic lupus erythematosus. We present one of the first reported cases of etenercept-induced systemic lupus erythematosus and review the literature of lupus and TNF antagonists.

Objective: To further assess the construct validity of the three European Scleroderma Study Group (EScSG) preliminary activity indices for systemic sclerosis (SSc): for SSc as a whole, for diffuse SSc (dcSSc), and for limited SSc (lcSSc)., Methods: 30/290 SSc clinical charts collected for the EScSG study used to develop activity criteria for SSc were selected and sent to four clinical experts in SSc. The experts ranked the charts from 1 to 30 (1=lowest activity, 30=highest activity). The relationships among the ranks given by each investigator and each of the three scores, and between any two of the ranks were investigated., Results: A consistently significant correlation (r(s)=0.530-0.712) was found between the ranks given by each of the four investigators and the index for the entire patient group. A similar level of agreement was detected between each couple of the four experts (r(s)=0.428-0.720). Moreover, the ranks given in patients with an index >3 were significantly higher than those given for patients with an index < or =3. This cut off point had previously been shown to best discriminate patients with active disease., Conclusions: Of the originally developed activity indexes, the whole series index has been externally validated. The index comprises the first preliminary, but necessary, groundwork to improve the concept of disease activity in SSc, which is still ill defined. It can be used as a preliminary activity index in clinical investigational studies.

Objectives: In scleroderma, outcome measures such as skin score provide only limited information about the functional impact of the disease. The requirement for validated and convenient instruments that reliably reflect disease morbidity is now recognized. This study compares the Disability Index of the Health Assessment Questionnaire (HAQ-DI) with two more recently developed scleroderma-specific tools: scleroderma-visual analogue scales (scleroderma-VAS) and the UK scleroderma Functional Score (UKFS). In addition, the use of clinical and laboratory measures as predictors of disease severity have been examined., Methods: One hundred and fifteen consecutive patients were studied. Subjects completed the 20-item HAQ-DI, the scleroderma-VAS and a questionnaire related to hand and muscle function (UKFS). Clinical details, measurement of maximal hand-spread, fist-closure and investigations for internal organ involvement were recorded., Results: Over 68% of patients with diffuse disease had moderate to severe disease on the UKFS, compared with 44% with limited disease. The mean UKFS in diffuse disease was 14.7 (s.d. 9.1) and 10.6 (s.d. 8.5) in the limited subset (P=0.02). The mean HAQ-DI in diffuse disease was 1.23 (s.d. 0.77) and 0.79 (s.d. 0.75) in the limited subset (P=0.005). The HAQ-DI showed significant correlation with UKFS (r=0.9; P < 0.001). Several clinical and laboratory measures were associated with higher HAQ-DI and UKFS., Conclusions: This is the first comparative study of the UKFS and the HAQ-DI. These data show a strong correlation between assessment methods. Higher scores correlated with clinical and laboratory indicators of severe disease. Used together, these inexpensive tools assess general and organ-specific symptoms, as well as functional limitation.

Introduction: primary Raynaud's disease may be difficult to differentiate clinically from the secondary form with an underlying connective tissue, haematological, neurovascular or drug-induced disorder. We undertook a study to determine the elastic carotid and muscular femoral arterial biomechanical properties and intima-media thickness (IMT) in subjects with primary and secondary Raynaud's disease, to assess whether these parameters could differentiate the two conditions., Methods: twenty patients with primary Raynaud's disease and 53 subjects with secondary Raynaud's associated with scleroderma (systemic sclerosis, SSc) had measurements of their carotid and femoral wall mechanics with a duplex scanner coupled to a Wall Track system. Their age, gender, body mass index, heart rate, systolic and diastolic blood pressures, presumed cardiovascular load, plasma creatinine, fasting cholesterol, triglyceride and glucose concentrations were also measured., Results: the carotid elastic properties [mean (SD): elastic modulus: 560 (180) vs 1204 (558) mmHg,p <0.001 and stiffness index: 5.69 (1.35) vs 11.92 (6.4), p<0.001 for primary and secondary Raynaud's respectively] were significantly impaired in patients with secondary Raynaud's disease even after adjustment for potentially influencing physiological and biochemical variables. There were no statistical differences in the femoral elastic properties or the carotid and femoral IMTs between the two groups., Conclusion: Duplex determination of the carotid elasticity or stiffness is different in primary Raynaud's phenomenon compared with secondary Raynaud's associated with SSc. This may be a useful non-invasive tool, in addition to autoantibody markers and nail-fold capillaroscopy, to differentiate between the two forms of Raynaud's phenomenon.

Endothelial cell injury is implicated in the development of radiation induced tissue damage and may also be involved in the pathophysiology of secondary Raynaud's phenomenon. Two patients are presented in whom the typical symptoms and signs of Raynaud's phenomenon developed as a late complication of radical radiotherapy. One had Raynaud's of the tongue and one of the lip. Both patients had a prior history of primary Raynaud's phenomenon and in each case the symptoms were repeatedly precipitated by sudden cold exposure. The possible pathogenesis of radiation induced Raynaud's phenomenon in the head and neck region is discussed.

Objectives: To estimate the incidence of severe lung disease in patients with scleroderma and identify the combination(s) of features present at first assessment which would be useful to predict future risk of severe lung disease., Methods: Data were analysed on 561 patients with disease onset occurring on or after 1 January 1982 and disease duration of less than five years before the first assessment. Detailed clinical and laboratory assessments were undertaken at the initial visit. End stage lung disease was defined as pulmonary hypertension requiring continuous ambulatory iloprost, or pulmonary fibrosis requiring continuous oxygen, or death from a scleroderma related lung disease. Patient status was determined at 31 December 1997. The best subset of predictors was identified by Cox regression analysis., Results: In all, 24 patients reached end stage lung disease. The cumulative incidences were 4%, 6%, and 12% at five, seven, and 14 years respectively. As expected, the lung function tests at baseline, including being in the lowest third of either diffusing lung capacity (hazard ratio (HR) = 18.2, 95% confidence interval (CI) 3.5 to 93.8) or of forced vital capacity (HR=4.1, 95% CI 1.1 to 15.2), were highly significant predictors of end stage lung disease. Interestingly, apart from the presence of proteinuria, none of the other baseline variables, including the extent of skin disease and serological markers, were predictive of severe lung disease., Conclusion: End stage lung disease was infrequent in this large cohort, but the cumulative incidence increased importantly with time. The risk can be predicted from baseline assessment of pulmonary function. In particular, those with normal pulmonary function at baseline are at very low risk.