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Objectives The aim of this study was to explore outcomes in a cohort of dcSSc patients fulfilling eligibility criteria for stem cell transplantation (SCT) studies but receiving standard immunosuppression. Methods From a large single-centre dcSSc cohort (n = 636), patients were identified using the published SCT trials’ inclusion criteria. Patients meeting the trials’ exclusion criteria were excluded. Results Of the 227 eligible patients, 214 met the inclusion criteria for ASTIS (Autologous Stem Cell Transplantation International Scleroderma), 82 for SCOT (Scleroderma: Cyclophosphamide Or Transplantation) and 185 for the UPSIDE (UPfront autologous haematopoietic Stem cell transplantation vs Immunosuppressive medication in early DiffusE cutaneous systemic sclerosis) trial, and 66 were excluded based on age >65 years, low diffusing capacity of the lungs for carbon monoxide (DLco), pulmonary hypertension or creatinine clearance Conclusion SCT inclusion criteria identify patients with poor outcome despite current best practice treatment. Patients meeting the inclusion criteria for SCT but who would have been excluded from the trials because of age, pulmonary hypertension, poor kidney function or DLco

Objectives To analyse the effectiveness of tofacitinib for the treatment of refractory skin thickening in dcSSc. Methods Data from 10 patients with dcSSc treated with tofacitinib (5 mg twice daily) were analysed. A total of 12 dcSSc patients treated with intensive conventional immunosuppressants were selected as the historical comparator group. A clinically relevant response was defined as a decrease in the modified Rodnan skin score (mRSS) of >5 points and ≥25% from baseline. Clinical indicators were compared between the two groups to evaluate the effect of tofacitinib. Results The mRSS significantly improved the first month after tofacitinib treatment, with a mean change in the mRSS of −3.7 (95% CI −5.52, −1.88; P = 0.001) and greater than the comparators at 6 months [−10.0 (95% CI −14.74, −5.26) vs −4.1 (95% CI −7.49, −0.73), P = 0.026]. Tofacitinib-treated patients had a significantly shorter response time than the comparators (P = 0.015 by log-rank test), with overall response rates of 20% (2/10) vs 0% (0/12) and 60% (6/10) vs 16.7% (2/12) at 1 and 3 months, respectively. Conclusion Our results indicate that tofacitinib may be as effective as or even better than intensive conventional immunosuppressants, with a quicker and higher response rate in refractory dcSSc patients with progressive skin thickness.

Objectives To examine the treatment decision-making process of patients with dcSSc in the context of haematopoietic stem cell transplantation (HSCT). Methods A qualitative semi-structured interview study was done in patients before or after HSCT, or patients who chose another treatment than HSCT. Thematic analysis was used. Shared decision-making (SDM) was assessed with the 9-item Shared Decision Making Questionnaire (SDM-Q-9). Results Twenty-five patients [16 male/nine female, median age 47 (range 27–68) years] were interviewed: five pre-HSCT, 16 post-HSCT and four following other treatment. Whereas the SDM-Q-9 showed the decision-making process was perceived as shared [median score 81/100 (range 49–100)], we learned from the interviews that the decision was predominantly made by the rheumatologist, and patients were often steered towards a treatment option. Strong guidance of the rheumatologist was appreciated because of a lack of accessible, reliable and SSc-specific information, due to the approach of the decision-making process of the rheumatologist, the large consequence of the decision and the trust in their doctor. Expectations of outcomes and risks also differed between patients. Furthermore, more than half of patients felt they had no choice but to go for HSCT, due to rapid deterioration of health and the perception of HSCT as ‘the holy grail’. Conclusion This is the first study that provides insight into the decision-making process in dcSSc. This process is negatively impacted by a lack of disease-specific education about treatment options. Additionally, we recommend exploring patients’ preferences and understanding of the illness to optimally guide decision-making and to provide tailor-made information.

ObjectivesSkin improvement in diffuse cutaneous SSc (dcSSc), measured with modified Rodnan skin score (mRSS), is frequently used as a primary outcome in clinical trials, but it is uncertain whether mRSS changes reflect changes in other organ systems. This aim of this study was to explore if skin changes in early dcSSc over 1 and 2 years are associated with changes in severity of other organ involvement.MethodsCanadian Scleroderma Research Group database patients with dcSSc, disease duration of ≤5 years, no evidence of initial end-stage organ damage and/or significant comorbidity who had 1 year (n = 154) and 2 years (n = 128) of follow-up data were included. mRSS changes of 25% and/or ≥5 points were considered significant. Organ involvement was assessed by Medsger Disease Severity Score and Canadian Scleroderma Research Group definitions using bivariate, chi-square, ANOVA, adjusted regression and longitudinal mixed effect model analyses.ResultsImprovement in mRSS was found in 41% of patients at 1 year and in 50% at 2 years. Improved patients showed less forced vital capacity decline (P = 0.012) and less frequent new cardiac involvement (P = 0.02) over 1 year, as well as better lung (by both Disease Severity Score, P = 0.006, and Δforced vital capacity%, P = 0.026), peripheral vascular (P = 0.006) and joint/tendon (P = 0.002) involvement over 2 years. mRSS worsening was consistently linked to less favourable lung outcomes at both 1- and 2-year follow-up visits, and more severe gastrointestinal disease at 2 years.ConclusionChanges in lung function in early dcSSc closely parallel skin changes. mRSS improvement reflects better prognosis for visceral disease and may be a reliable outcome measure in clinical trials.

OBJECTIVES: To screen for significant arrhythmias with an implantable loop recorder (ILR) in patients with SSc and no known cardiovascular disease, and identify associated disease phenotype, blood and cardiovascular magnetic resonance (CMR) biomarkers.METHODS: Twenty patients with SSc with no history of primary SSc heart disease, traditional cardiovascular disease, diabetes or maximum one traditional cardiovascular risk factor underwent clinical assessment, contrast-enhanced CMR and ILR insertion.RESULTS: ILR data were available for 19 patients: 63% female, mean (s.d.) age of 53 (12) years, 32% diffuse SSc. Eight patients had significant arrhythmias over 3 years: one complete heart block, two non-sustained ventricular tachycardia [all three dcSSc, two anti-topoisomerase antibodies (Scl70) positive, three interstitial lung disease and two previous digital ulceration] and five atrial arrhythmias of which four were with limited SSc. These required interventions with one permanent pacemaker implantation, four anti-arrhythmic pharmacotherapy, one anticoagulation.Patients with significant arrhythmia had higher baseline high-sensitivity troponin I and N-terminal pro-brain natriuretic peptide [mean difference (95% CI) 117 (-11, 245) and 92 (-30, 215) ng/l, respectively], and CMR-extracellular volume [mean (s.d.) 32 (2) vs 29 (4)%]. Late gadolinium enhancement was observed in five patients, only one with significant arrhythmia.CONCLUSION: This first ILR study identified potentially life-threatening arrhythmias in asymptomatic SSc patients attributable to a primary SSc heart disease. Disease phenotype, CMR-extracellular volume (indicating diffuse fibrosis) and cardiac biomarkers may identify at-risk patients that would benefit from ILR screening. Future studies can inform a risk model and provide insights into SSc-associated arrhythmia pathogenesis.

OBJECTIVES: Patient acceptable symptom state (PASS) as an absolute state of well-being has shown promise as an outcome measure in many rheumatologic conditions. We aimed to assess whether PASS may be effective in active diffuse cutaneous SSc differentiating active from placebo. METHODS: Data from the phase 2 Safety and Efficacy of Subcutaneous Tocilizumab in Adults with Systemic Sclerosis (faSScinate) trial were used, which compared tocilizumab (TCZ) vs placebo over 48 weeks followed by an open-label TCZ period to 96 weeks. Three different types of PASS questions were evaluated at weeks 8, 24, 48 and 96, including if a current state would be acceptable over time as a yes vs no response and Likert scales about how acceptable a current state is if remaining over time. Additional outcomes assessed included modified Rodnan skin score, HAQ disability index (HAQ-DI), physician and patient global assessments on a visual analogue scale, CRP and ESR. RESULTS: The placebo group consisted of 44 patients and the TCZ group had 43 patients. At baseline, 33% achieved a PASS for all three PASS questions, with the proportion increasing to 69, 71 and 78%, respectively, at 96 weeks. Changes in PASS scores showed a moderately negative correlation with HAQ-DI and patient and physician global assessments visual analogue scales, which indicates expected improvements as PASS improved. The PASS question, 'Considering all of the ways your scleroderma has affected you, how acceptable would you rate your level of symptoms?' showed significant correlations with patient-reported outcomes and differentiating placebo vs TCZ at 48 weeks (P = 0.023). Conclusion: PASS may be used as a patient-centred outcome in SSc, especially as a 7-point Likert scale. Further validation is required to determine the utility as an outcome measure in trials and clinical practice.

Objectives Pulmonary hypertension (PH) is an important cause of morbidity and mortality in patients with SSc. The submaximal heart and pulmonary evaluation (step test) is a non-invasive, submaximal stress test that could be used to identify SSc patients with PH. Our aims were to determine whether change in end tidal carbon dioxide ([Formula: see text]) from rest to end-exercise, and the minute ventilation to carbon dioxide production ratio ([Formula: see text]), both as measured by the step test, differ between SSc patients with and without PH. We also examined differences in validated self-report questionnaires and potential PH biomarkers between SSc patients with and without PH. Methods We performed a cross-sectional study of 27 patients with limited or dcSSc who underwent a right heart catheterization within 24 months prior to study entry. The study visit consisted of questionnaire completion; history; physical examination; step test performance; and phlebotomy. [Formula: see text], [Formula: see text], self-report data and biomarkers were compared between patients with and without PH. Results SSc patients with PH had a statistically significantly lower median (interquartile range) [Formula: see text] than SSc patients without PH [-2.1 (-5.1 to 0.7) vs 1.2 (-0.7 to 5.4) mmHg, P = 0.035], and a statistically significantly higher median (interquartile range) [Formula: see text] [53.4 (39-64.1) vs 36.4 (31.9-41.1), P = 0.035]. There were no statistically significant differences in self-report data or biomarkers between groups. Conclusion [Formula: see text] and [Formula: see text] as measured by the step test are statistically significantly different between SSc patients with and without PH. [Formula: see text] and [Formula: see text] may be useful screening tools for PH in the SSc population.

OBJECTIVE Data from a small study testing imatinib to treat SSc were used to determine if cytokine changes were related to differences in clinical parameters to model future early phase trials pairing cytokine changes and clinical parameters. METHODS Plasma and punch skin biopsy specimens collected at baseline and 6 months were analysed for levels of 26 fibrotic and inflammatory cytokines using multiplexed immunoassays and ELISA. Seven of nine patients on active treatment had paired data. Biopsies were biopulverized and standardized to protein levels in the tissue homogenate. Plasma was frozen at -80°C and analysed using multiplexed immunoassays or ELISAs standardized to CRP. Correlations between fold changes in cytokines and differences in clinical parameters (skin score, physician and patient global assessments and HAQ) were performed. P < 0.01 was considered significant. RESULTS After 6 months of imatinib treatment, plasma levels of soluble vascular cell adhesion molecule 1 decreased significantly (P < 0.001), while tissue levels of soluble intercellular adhesion molecule 1 increased (P < 0.01). Some significant correlations between fold changes in certain plasma fibrotic and inflammatory cytokines and changes in clinical parameters after 6 months of treatment were found: patient global scores and IL-13 (r = 0.964, P < 0.0001); ESR and IL-12p70 (r = -0.903, P < 0.01); in tissue samples, patient global score and soluble E-selectin (r = 0.913, P < 0.01); and physician global score with sCD40L (r = -0.883, P < 0.01). CONCLUSION Some serum and tissue cytokines may have a role in early phase clinical trials of SSc, correlating with changes in clinical parameters. Serum and tissue samples could be analysed in early phase trials to determine whether they support the clinical observations. TRIAL REGISTRATION http://clinicaltrials.gov/show/NCT01545427.

Objective. Dyspnoea is a common, multifactorial source of functional impairment among patients with dcSSc. Our objective was to assess the reliability, construct validity and responsiveness to change of the Saint George’s Respiratory Questionnaire (SGRQ) in patients with early dcSSc participating in a multicentre prospective study. Methods. At enrolment and 1 year, patients completed the SGRQ (a multi-item instrument with four scales: symptoms, activity, impact and total), a visual analogue scale (VAS) for breathing and the HAQ Disability Index (HAQ-DI) and underwent 6 min walk distance and pulmonary function tests, physician and patient global health assessments and high-resolution CT (HRCT). We assessed internal consistency reliability using Cronbach’s α. For validity we examined the ability of the SGRQ to differentiate the presence vs absence of interstitial lung disease (ILD) on HRCT or restrictive lung disease and evaluated the 1 year responsiveness to change using pulmonary function tests and patient- and physician-reported anchors. Correlation coefficients of 0.24–0.36 were considered moderate and >0.37 was considered large. Results. A total of 177 patients were evaluated. Reliability was satisfactory for all SGRQ scales (0.70–0.93). All scales showed large correlations with the VAS for breathing and diffusing capacity of the lung for carbon monoxide in the overall cohort and in the subgroup with ILD. Three of the four scales in the overall cohort and the total scale in the ILD subgroup showed moderate to large correlation with the HAQ-DI and the predicted forced vital capacity (r = 0.33–0.44). Each scale discriminated between the presence and absence of ILD and restrictive lung disease (P ≤ 0.0001–0.03). At follow-up, all scales were responsive to change using different anchors. Conclusion. The SGRQ has acceptable reliability, construct validity and responsiveness to change for use in a dcSSc population and differentiates between patients with and without ILD.

Objective. To assess the tendon and joint involvement at wrists and ankles of patients suffering from diffuse SSc and to identify the morphological substrate of tendon friction rubs (TFRs).Methods. Fifteen consecutive patients suffering from diffuse SSc were included. All patients had two musculoskeletal US (MSUS) examinations of the wrists and ankles. MRI was performed at the most affected joints as detected by MSUS and in all sites in which TFRs were present.Results. No clinically overt arthritis or tenosynovitis was detected in the wrists and/or ankles prior to MSUS. Synovitis, tenosynovitis and tendon tear were identified in 8, 4 and 2 of 15 patients, respectively, by both MSUS and MRI. At entry, 5 patients had palpable TFRs (4 bilateral and 1 unilateral) and 10 patients did not. Tenosynovitis was more frequently found in ankles with TFRs (3/9) than in those without TFRs (3/21), although the difference was not statistically different (P = 0.3). Using MRI, deep connective tissue infiltrates surrounding tendons were present in all sites with TFRs but in only one patient without TFRs.Conclusion. Both MSUS and MRI are effective in detecting synovitis and tenosynovitis in diffuse SSc patients. Tenosynovitis, synovitis and thickened retinacula are not infrequently seen in these patients. Our data suggest that juxta-tendinous connective tissue infiltrates might be the morphological substrate of tendon friction rubs, which may thus be a misnomer for tissue friction rubs.

Objective. To determine the skin and fibroblast expression of ephrins (EphB4 and EphrinB2) and thrombospondins (TSPs: TSP1 and TSP2) in patients with SSc. Methods. All experiments were performed in skin sections and dermal fibroblasts issued from control and clinically involved/non-involved SSc skin biopsies. Dermal fibroblasts were stimulated with hypoxia or TGF-b, or treated with TGF-b-neutralizing antibodies. Ephrin and TSP mRNA levels were assessed in skin tissue and dermal fibroblasts by in situ hybridization and quantitative RTPCR, respectively, and protein levels were assessed by immunohistochemistry and western blots, respectively. Results. Enhanced ephrin and TSP mRNA and protein levels were observed in clinically involved SSc skin. EphrinB2, TSP1 and TSP2 mRNA and protein levels were also up-regulated in non-involved SSc skin. Similar mRNA and protein levels of ephrinB2 and EphB4 were detected in unstimulated and stimulated control and SSc dermal fibroblasts. TSP1 and TSP2 mRNA and protein levels were significantly increased in fibroblasts issued from involved and non-involved SSc skin. This up-regulation was not modified by hypoxic exposure, but was markedly reduced by the addition of TGF-b-neutralizing antibodies. Stimulation of healthy fibroblasts with TGF-b significantly increased TSP1 and TSP2 mRNA and protein levels. Conclusion. EphB4 and EphrinB2 are up-regulated in clinically involved skin of SSc patients, suggesting their participation in SSc-perturbed angiogenesis. TSP1 and TSP2 are up-regulated in both clinically involved and non-involved SSc skin and are constitutively overexpressed in a TGF-b-dependent and hypoxia-independent manner in SSc dermal fibroblasts, suggesting their potential early contribution in SSc pathogenesis.

Objective. To evaluate the efficacy and safety of mycophenolate mofetil for the treatment of SSc. Methods. We recruited 15 patients with dcSSc to take part in an open-label study using mycophenolate mofetil to treat their disease over a 12-month period. The primary outcome measure was the modified Rodnan skin score (mRSS), whereas secondary outcomes included the Medsger severity score, pulmonary function studies, 2D echocardiograms and the Short Form Health Survey (SF)-36 questionnaire. Results. The mRSS significantly improved in those patients who tolerated the medication for >3 months (P < 0.0001), and there was a statistically significant improvement in the Medsger severity scores of the general (P ¼ 0.05), peripheral vascular involvement (P ¼ 0.05) and skin (P ¼ 0.0003) scores. The SF-36 scores improved (P ¼ 0.05) and the pulmonary function studies showed a trend towards improvement, though not of statistical significance. The mean pulmonary artery pressure by 2D echocardiography did not change. Conclusions. In this prospective open-label study of mycophenolate mofetil for the treatment of dcSSc, we observed significant improvements in skin scores, peripheral vascular involvement and patient-perceived health status. Pulmonary function studies did not worsen as expected, but instead showed a trend towards improvement. Controlled trials are needed to further investigate this trend for improved pulmonary function studies.

OBJECTIVES: The recently developed cold stimulus fingertip lacticemy test (CS-FTL) provides biochemical assessment of peripheral perfusion in patients with Raynaud's phenomenon (RP). We evaluated how the CS-FTL test can assess the acute effect of nifedipine in microvascular dynamics on primary RP and RP secondary to SSc. METHODS: A double-blinded controlled trial with crossover design was performed in 20 primary RP and 20 SSc patients. Patients received one single sublingual placebo or 10 mg nifedipine capsule, with crossover after a 15-day washout period. FTL was determined in resting conditions (pre-CS-FTL) and 10 min after CS (post-CS-FTL), before and 1 h after drug administration. Percent variation in post- vs pre-CS-FTL was expressed as deltaCS-FTL. RESULTS: Before intervention, CS induced FTL decrease in primary RP (deltaCS-FTL = -21.3 +/- 13.0%) and FTL increase in SSc patients (deltaCS-FTL = +24.5 +/- 21.2%). Placebo had no effect on pre-CS-FTL, post-CS-FTL and deltaCS-FTL in primary RP and SSc. Nifedipine induced a significant decrease in pre-CS-FTL (1.94 +/- 0.45 vs 1.57 +/- 0.41 mg/dl; P = 0.005) and post-CS-FTL (1.53 +/- 0.35 vs 1.32 +/- 0.37 mg/dl; P = 0.004) in primary RP and a significant decrease in post-CS-FTL (3.18 +/- 1.43 vs 2.56 +/- 1.30 mg/dl; P = 0.028) and deltaCS-FTL (+15.9 +/- 24.7% vs -12.9 +/- 16.6%; P = 0.001) in SSc. CONCLUSIONS: The CS-FTL test was able to demonstrate and quantify a dual effect of nifedipine on the biochemical dimension of peripheral perfusion in primary RP and in SSc patients in which there was a significant improvement in tissue perfusion in resting conditions and after exposure to a CS. The CS-FTL test will enrich the armamentarium for investigation and clinical evaluation of conditions associated with RP.

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.

Objective. To determine serum levels and clinical correlation of 8-isoprostane, which is produced in vivo through free radicalcatalysed peroxidation of arachidonic acid and reflects oxidative stress, in patients with systemic sclerosis (SSc). Methods. Serum 8-isoprostane levels from 32 patients with diffuse cutaneous SSc (dSSc) and 25 patients with limited cutaneous SSc (lSSc) were examined by enzyme-linked immunosorbent assay. Results. Serum 8-isoprostane levels were elevated in dSSc and lSSc patients by 75-fold compared with normal controls (n^32). Serum 8-isoprostane levels correlated negatively with pulmonary function, such as percentage vital capacity and diffusion capacity for carbon monoxide, and correlated positively with renal vascular damage determined by colour flow Doppler ultrasonography. Serum 8-isoprostane levels also correlated positively with serum levels of IgG and anti-agalactosyl IgG autoantibody. Conclusion. Increased 8-isoprostane levels correlated with the severity of pulmonary fibrosis, the extent of renal vascular damage and immunological abnormalities in SSc, suggesting that enhanced oxidative stress is related to the development of SSc.

Objectives. Endothetial 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 (ISSc) and diffuse (dSSe). 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 ISSc (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, ISSc 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 ISSc, 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.

Systemic sclerosis, scleroderma (SSc) is a disabling condition that shortens life expectancy. Disease heterogeneity and difficulties separating SSc from SSc-like conditions make classification an important issue. Limited cutaneous and diffuse cutaneous SSc, with different severity and survival, have been recognized for several years as distinct subsets. Some authors have suggested an intermediate cutaneous form with intermediate survival. This issue remains unsettled, however. The technique of capillaroscopy is helpful as an adjunct diagnostic tool to separate idiopathic Raynaud's phenomenon from SSc. Digitized video-capillaroscopy is developing as a powerful new method to assess individual capillaries over time. Using the simpler techniques of video-capillaroscopy, different patterns have been described and named 'early', 'active', 'late' and 'slow'. The value of nailfold video-capillaroscopy to distinguish different subsets or provide prognostic information for use in daily practice remains to be assessed. The features of CREST (calcinosis, Raynaud's, oesophagus dysmotility, sclerodactyly, telangiectasias) are not confined to single subsets of SSc. There is no convincing evidence of any advantage for distinguishing the limited, intermediate and diffuse forms of SSc rather than only the limited and diffuse forms.

Objective. We investigated HLA class II alleles in women with systemic sclerosis (SSc), a rare disease that preferentially affects women. Methods. Specific alleles of DRB1, DQA1 and DQB1 were determined by DNA-based HLA typing for women with SSc (n ¼ 102) and healthy women (n ¼ 533). All study subjects were Caucasian. DRB1, DQA1 and DQB1 allele frequencies of women with SSc were compared with those of healthy women. Results. Among women with SSc, 29.4% (30/102) and among healthy women 10.7% (57/533) had DRB1*11. Allele frequencies were compared for women with SSc and healthy women (each woman has two alleles). The allele frequency of DRB1*11 was 15.7% (32/204 alleles) in SSc women and 5.8% (62/1066 alleles) in healthy women (P ¼ 0.000002). The increase of DRB1*11 was found both in diffuse (P ¼ 0.0001) and limited SSc (P ¼ 0.002) (allele frequencies 15.0 and 17.2%, respectively). Among women with diffuse SSc, there was a disproportionate increase of the DRB1*1104 allele (P ¼ 0.0004) with no increase of DRB1*1101 (P ¼ 1.00). In contrast, in limited SSc the strongest association was with DRB1*1101 (P ¼ 0.008), with a less significant increase of DRB1*1104 (P ¼ 0.04). Conclusions. An increase of DRB1*11 in SSc is consistent with other reports. Although present in both diffuse and limited SSc disease subsets, the increase was predominantly due to over-representation of DRB1*1104 in women with diffuse SSc. Women with limited SSc had a preponderance of DRB1*1101, the most common allele in healthy women. DRB1*1104 and DRB1*1101 differ by a single amino acid at position 86, where the former has valine and the latter glycine.

To study the stiffness of large arteries in relation to the extent of skin and lung fibrosis, aortic distensibility was examined in patients with diffuse and limited systemic sclerosis (SSc).Consecutive patients (55 with diffuse and 51 with limited SSc) without signs and symptoms of heart failure or a previous history of arterial hypertension underwent echocardiography and lung function tests. Aortic stiffness was determined non-invasively by aortic distensibility and aortic strain measurements in all patients and in 50 healthy subjects, matched for age and gender.Aortic distensibility in patients with either diffuse (2.03 +/- 0.26 x 10(-6) cm(2) dyn(-1)) or limited SSc (2.12 +/- 0.33) was similarly decreased compared with controls (2.49 +/- 0.36, P0.001). Moreover, aortic strain was significantly reduced in both patient groups compared with controls, confirming that aortic stiffness is increased in SSc independently of the extent of skin involvement. Left ventricular performance was similar between patients and controls, while left ventricular mass and tricuspid systolic gradient were significantly increased in both SSc groups, the latter being associated with aortic stiffness in multivariate analysis. No association with serum levels of C-reactive protein or lung function abnormalities indicative of pulmonary fibrosis were found.Stiffness of the aorta is increased in patients with established SSc regardless of the extent of the inflammatory fibrotic process in the skin and lungs, suggesting that additional pathogenetic mechanisms contribute to the compromise of large arteries.

Objective To determine serum levels of soluble cytotoxic T-lymphocyte associated molecule-4 (sCTLA-4) and clinical association in patients with systemic sclerosis (SSc). Methods Serum sCTLA-4 levels from 32 patients with diffuse cutaneous SSc (dSSc) and 27 patients with limited cutaneous SSc (lSSc) were examined by enzyme-linked immunosorbent assay (ELISA). For a longitudinal study, 211 sera from 30 SSc patients were analysed (follow-up 2.1-7.0 yr). Results Serum sCTLA-4 levels were elevated in dSSc patients compared with normal controls (n = 41), lSSc patients and patients with active systemic lupus erythematosus (SLE) (n = 23). By contrast, sCTLA-4 levels in patients with lSSc or SLE were normal. SSc patients with elevated sCTLA-4 levels had a shorter disease duration and more frequent presence of digital pitting scars, contracture of phalanges, diffuse pigmentation, pulmonary fibrosis and decreased percentage vital capacity (%VC) than those with normal sCTLA-4 levels. sCTLA-4 levels correlated positively with the extent of skin fibrosis, serum IgG levels and anti-topoisomerase I antibody levels. In a longitudinal study, sCTLA-4 levels decreased on a parallel with improvement of skin sclerosis in five dSSc patients. Skin sclerosis did not improve in two of six dSSc patients with high sCTLA-4 levels throughout the follow-up, while the remaining four patients showed improvement of skin sclerosis. Conclusion These results suggest that sCTLA-4 correlates with disease severity and activity of SSc and that sCTLA-4 plays a role in immunological abnormalities of SSc, since sCTLA-4 may augment humoral immune responses as well as T-cell responses by interfering with B7-CTLA-4 interactions that induce negative signals in T and B cells.

Objective To assess the prevalence of systemic sclerosis (SSc) in a French multi-ethnic population and to examine ethnic differences. Methods This survey was conducted in Seine-Saint-Denis County, a suburb of Paris, home to 1,094,412 adults (>/=15 yr), among whom 26% are of non-European background with mainly northern and sub-Saharan African, Asian and Caribbean ancestries. The study period comprised the entire calendar year 2001. Patients were ascertained through four sources: public and private hospitals, general practitioners and community specialists, the French SSc patient support group, and the National Public Health Insurance System database. Only cases meeting either the 1980 ACR and/or LeRoy and Medsger's classification criteria were included and assigned to three clinical subsets: limited (normal skin) (l), limited cutaneous (lc) or diffuse cutaneous (dc) SSc. Capture-recapture (CR) analyses using log-linear modelling were performed to correct for incomplete case finding. Results We retained a total of 119 patients with SSc, including 15 extrapolated from inaccessible files. CR analysis estimated that 54.2 additional cases were missed by all the sources. The overall SSc prevalence (per million adults) was 158.3 (95% confidence interval, 129-187); those of lSSc, lcSSc and dcSSc were, respectively, 32.3 (16-48), 83.1 (66-101) and 42.9 (25-60); and respective values for Europeans and non-Europeans were 140.2 (112-170) and 210.8 (128-293). Conclusion Regarding the heterogeneity of previously published estimates, this population-based survey using CR analysis might contribute to obtaining a better appraisal of SSc prevalence. Despite overlapping confidence intervals, the higher prevalence observed for non-Europeans could support potential influences of ethnic origin on the pathogenesis of SSc.

Objective. Scoring poorly on the health assessment questionnaire (HAQ) has recently been shown to be a strong predictor of morbidity and mortality in rheumatoid arthritis (RA), while a good HAQ score is predictive of a better outcome. In patients presenting with early diffuse scleroderma prognosis is variable. Our goal was to determine possible baseline predictors of future good outcomes. Methods. We used the raw data from two randomized controlled trials (RCTs) in early diffuse scleroderma: methotrexate (Pope et al.) and D-penicillamine (Clements et al.). Subjects in the methotrexate trial were divided into the following groups: (1) those with at least 20% improvement in the primary outcome measurements [patient global assessment, physician global assessment, UCLA skin tethering score, modified Rodnan skin score (MRSS), DLCO as % predicted and HAQ disability] at 1 yr vs (2) the others. Baseline factors (including age, gender, skin scores, physician and patient global assessments, HAQ disability and pain scores, DLCO and physical parameters) were analysed to find baseline variables strongly correlated with later improvement. These variables were explored in the D-penicillamine trial to determine if (in a separate trial) they were still predictive of improved outcome at 1 and 2 yr. Adjusted models were used to find baseline predictors of good outcome. The median HAQ-DI was 1.3 (methotrexate) and 1.0 (D-penicillamine). Results. A baseline HAQ disability score of less than the median was predictive of at least a 20% improvement at I and 2 yr with odds ratios of 1.77 to 5.05, in four of the five outcome measurements (in both groups); with strongly significant P values for 3 of 5 outcomes (UCLA skin score, MRSS, patient global skin score; P < 0.02) from the methotrexate study group. These three outcomes were strongly correlated with improvement (r between 0.25 and 0.35). Although data from the D-penicillamine trial were less convincing, in both trials the less than median HAQ-DI and HAQ pain scores showed a stronger association with improved outcome, more so than age, gender, skin score and baseline global assessment. Conclusion. A low baseline HAQ (defined as less than the median HAQ score) is predictive of improved outcome in diffuse scleroderma at 1 and 2 yr.

Objectives. Fibrosis, a feature of systemic sclerosis (SSc), is more severe in the diffuse compared with the limited disease variant. Interleukin 10 (IL-10) is an antiinflammatory cytokine which reduces type 1 collagen mRNA levels in human fibroblasts. The 5 0 flanking region of the IL-10 gene is highly polymorphic, with three single base pair substitutions at position –1082(G/A), –819(C/T) and –592(C/A), which results in differential IL-10 production. The GCC/GCC genotype is associated with high IL-10 production while the ATA/ATA genotype with low production. We postulated that there would be a difference in IL-10 polymorphisms in patients with limited (lSSc) and diffuse (dSSc) disease. Methods. Patients with limited (lSSc, n ¼ 89) or diffuse (dSSc, n ¼ 51) disease plus controls (n ¼ 94) were recruited. DNA was isolated from peripheral blood and polymorphisms analysed using amplification refractory mutation system (ARMS) polymerase chain reaction (PCR). Results. dSSc patients were less likely to carry the genotype indicative of high IL-10 production when compared with controls (controls vs dSSc; 29 vs 4%, � 2 ¼ 15.7, 5 df, P ¼ 0.005) and lSSc patients (lSSc vs dSSc; 21 vs 4%, � 2 ¼ 17.5, 5 df, P ¼ 0.002). There was no difference between control and lSSc patients. While there was no difference between controls and lSSc haplotypes, the GCC haplotype distribution did differ significantly between controls and dSSc patients (controls vs dSSc; 54 vs 36%, � 2 ¼ 11.2, 2 df, P ¼ 0.001). A significant difference was also observed between lSSc and dSSc haplotype distribution (lSSc vs dSSc; 48 vs 36%, � 2 ¼ 13.5, 2 df, P < 0.001). Conclusion. We demonstrate that IL-10 genotypes associated with high IL-10 production are under-represented in dSSc. This may have implications in the disease pathology. Systemic sclerosis or scleroderma (SSc) describes several distinct disorders of which the diffuse (dSSc) and limited (lSSc) variants are the best characterized. The clinical features and outcome of the two differ, although rarely there may be an overlap. In both there are microvascular changes, excess deposition of extracellular matrix (ECM) and immunological abnormalities of which characteristic autoantibody production is best described. A fundamental difference between lSSc and dSSc is the extent of ECM deposition. Excess ECM is more a