Intensive and app-delivered occupational therapy to improve upper extremity function in early diffuse cutaneous systemic sclerosis: a pilot two-arm trial.

OBJECTIVE: SSc reduces upper extremity function and performance of everyday activities; however, there are few evidence-based rehabilitation interventions. This study examined short and longer-term effects of two occupational therapy interventions on hand disability. METHODS: Participants with diffuse cutaneous SSc were randomized to one of two 18-week interventions: Intensive group, receiving eight weekly in-person occupational therapy sessions with App-delivered home exercises, or App Alone group. The primary outcome was QuickDASH hand disability; secondary outcomes were physical function (PROMIS scale), and total active hand motion. Linear mixed models were used to examine treatment effects. RESULTS: Most participants were female (72%); the mean age was 52 years (13.4) (n = 32). There were no significant between-group effects on QuickDASH (P = 1.0; mean change -6.4 on 0-100 scale in both groups at 18 weeks). Left lateral pinch, an exploratory outcome, improved in App Alone compared with Intensive from baseline to 18 weeks. Within groups, the Intensive group had the largest improvements after 8 weeks (-8.5 on QuickDASH; P = 0.03), but then lost gains from 8 to 18 weeks while the App Alone group had modest improvements from baseline to 8 weeks, but then continued to improve. Of completers, 50% had clinically meaningful improvement on QuickDASH in the Intensive group and 64% had improvement in App Alone. CONCLUSION: Both interventions showed beneficial effects on hand disability. Participants in the App Alone group improved equally to the Intensive group at 18 weeks. Our findings provide support for further study into telehealth rehabilitation approaches. TRIAL REGISTRATION: NCT03482219.

Skin improvement is a surrogate for favourable changes in other organ systems in early diffuse cutaneous systemic sclerosis.

OBJECTIVES: Skin 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. METHODS: Canadian 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. RESULTS: Improvement 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. CONCLUSION: Changes 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.

State-of-the-art technologies provide new insights linking skin and blood vessel abnormalities in SSc-related disorders.

OBJECTIVE: A key unanswered question in systemic sclerosis (SSc) is how microvascular abnormality and fibrosis inter-relate. Our aim was to use state-of-the-art non-invasive imaging methods to gain new insights into pathophysiology, comparing patients with different subtypes of SSc, including early dcSSc, not only to healthy controls but also to patients with causes of Raynaud's phenomenon not progressing to fibrosis. METHODS: Laser Doppler imaging, nailfold capillaroscopy, spectroscopy, and ultrasound measured (respectively) perfusion, microvascular structure, oxygenation/oxidative stress, and skin thickening in the hands of 265 subjects: 31 patients with primary Raynaud's phenomenon (PRP), 35 with undifferentiated connective tissue disease (UCTD), 93 with limited cutaneous SSc (lcSSc), 46 with diffuse cutaneous SSc (dcSSc, including 27 'early') and 60 healthy controls. RESULTS: Mean perfusion was reduced in SSc groups compared to controls (lcSSc 172 perfusion units [standard deviation 157], late-dcSSc 90 [145], early-dcSSc 68 [137] vs. controls 211 [146]; p = 0.0002) as was finger-oxygenation (lcSSc 12.1 [13.6] arbitrary units [AU], late-dcSSc 12.2 [8.4], early-dcSSc 11.1 [11.3] vs controls 14.9 [10.5]; p = 0.0049). Oxidative stress was increased at the hand-dorsum in SSc groups (p = 0.0007). Perfusion positively correlated with oxygenation (r = 0.23, p < 0.001), and capillary density negatively with skin thickness (r = -0.26, p < 0.001). CONCLUSION: Our findings lend support to the hypothesis that in SSc, particularly early dcSSc, (but not in PRP or UCTD), reduced perfusion (together with structural microvascular abnormality) associates with reduced oxygenation, with oxidative stress and with skin thickening/fibrosis, most likely driving a vicious cycle which ultimately results in irreversible tissue injury. Findings in skin may mirror alterations in internal organs.

Impact and associates of digital pitting in patients with systemic sclerosis: a pilot study.

Objective: Despite being a cardinal clinical sign of systemic sclerosis (SSc), digital pitting has been little studied. Our objective was to test, in a pilot study, the hypothesis that pitting is painful and associated with digital vascular disease severity.Method: Fifty patients with SSc were recruited: 25 with and 25 without digital pitting. Fingertip pain was assessed on a 0-10 scale. Thermography of both hands assessed surface temperature, allowing calculation of the distal-dorsal difference (temperature gradient) for each finger. Nailfold capillaroscopy was performed in each finger using a dermatoscope, and graded on a 0-3 scale (0 = normal; 3 = grossly abnormal).Results: In the 25 patients with digital pitting, 65 fingers in total were affected (mainly the index and middle fingers). Pain scores were higher in 'pitting' patients [median 4 (interquartile range 3-8) vs 0 (0-2), p < 0.001], and pitting patients reported that pitting impacted on activities of everyday living. Temperature gradients along the fingers did not differ significantly between patients with and without pitting (p = 0.248). Pitting patients were more likely to have 'grossly abnormal' capillaries than those without pitting, and less likely to have 'no/mild' nailfold capillary changes.Conclusions: Digital pitting is painful and impacts on hand function. Capillaroscopy findings provide further support for an association between pitting and severity of digital vascular change. Larger, more comprehensive studies are required to examine the pathophysiology of pitting and to pave the way to therapeutic intervention, ideally including preventive strategies.

Colonic Manifestations and Complications Are Relatively Under-Reported in Systemic Sclerosis: A Systematic Review.

OBJECTIVES: Although systemic sclerosis (SSc) is known to affect the gastrointestinal (GI) tract, most of the literature focuses on esophageal, small intestinal, or anorectal manifestations. There have been no reviews focused on large bowel SSc complications in over 30 years. The aim of this study is to perform a systematic review of colonic manifestations and complications of SSc. METHODS: An experienced librarian conducted a search of databases, including English and Spanish articles. The search used keywords including "systemic sclerosis," "scleroderma," and "colon." A systematic review was performed using Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines. Case reports/series were screened for validity by adapting from criteria published elsewhere. RESULTS: Of 1,890 articles, 74 met selection criteria. Fifty-nine of the 77 articles were case reports/series. The most common article topics on colonic SSc complications were constipation/dysmotility (15), colonic volvulus (8), inflammatory bowel disease (7), microscopic colitis (6), megacolon (6), and telangiectasia (6). Colonic manifestations constituted 24% of articles on GI complications of SSc. There were a total of 85 cases (84% women, with a median age of onset of colon complication of 52 years). Limited cutaneous SSc phenotype (65.6%) was more common than diffuse (26.2%). Patients frequently had poor outcomes with high mortality related to colonic complications (27%). Recent studies explore contemporary topics such as the microbiome in SSc and prucalopride for chronic constipation in SSc. DISCUSSION: Colonic complications comprise a large proportion of the published reports on GI symptoms afflicting patients with SSc and require raised diagnostic suspicion and deliberate action to avoid potentially serious complications including death.

Distal radius and tibia bone microarchitecture impairment in female patients with diffuse systemic sclerosis.

Radius and tibia bone microarchitecture, analyzed through a high-resolution peripheral quantitative computed tomography, were significantly impaired in female patients with diffuse systemic sclerosis compared with healthy controls. Acroosteolysis, quality of life-grip strength, hand disability, and disease duration were significantly associated with this bone deterioration. INTRODUCTION: The effect of diffuse systemic sclerosis (dSSc) on the bone is not completely understood. The objective of this study was to analyze the volumetric bone mineral density (vBMD), microarchitecture, and biomechanical parameters at the distal radius and tibia using high-resolution peripheral quantitative computed tomography (HR-pQCT, XtremeCT) in female patients with dSSc and identify clinical and laboratory variables associated with these parameters. METHODS: Thirty-eight women with dSSc and 76 healthy controls were submitted to HR-pQCT at the distal radius and tibia. Clinical and laboratory findings, bone mineral density(BMD), nailfold capillaroscopy (NC), total passive range of motion(ROM), and quality of life (health assessment questionnaire-HAQ) were associated with HR-pQCT (Scanco Medical AG, Brüttisellen, Switzerland) parameters. Multiple linear regression models adjusted for clinical and laboratory variables, ROM and HAQ, were performed. RESULTS: Density, microarchitecture, and biomechanical parameters at the distal radius and tibia were significantly impaired in dSSc patients compared with healthy controls (p < 0.001). Multiple linear regression models showed that lower trabecular density (Tb.vBMD) (radius R2 = 0.561, p = 0.002; and tibia R2 = 0.533, p = 0.005), and lower trabecular number (Tb.N) (tibia R2 = 0.533, p = 0.005) were significantly associated with acroosteolysis. Higher trabecular separation (Tb.Sp) was associated with disease duration and higher HAQ-grip strength (radius R2 = 0.489, p = 0.013), while cortical density (Ct.vBMD) was associated with ROM (radius R2 = 0.294, p = 0.002). CONCLUSION: Bone microarchitecture in patients with dSSc, analyzed through HR-pQCT, showed impairment of trabecular and cortical bone at distal radius and tibia. Variables associated with hand involvement (acroosteolysis, quality of life-grip strength, and ROM) and disease duration may be considered prognostic factors of this bone impairment.

Changes in disability and their relationship with skin thickening, in diffuse and limited cutaneous systemic sclerosis: a retrospective cohort study.

OBJECTIVE: The burden of disability associated with systemic sclerosis (SSc) is being increasingly recognized. Our aim was to test the hypothesis that changes in functional ability over time differ between patients with limited (lcSSc) and diffuse cutaneous (dcSSc) subtypes, and that in dcSSc (but not lcSSc) these changes correlate with skin thickening. METHOD: This was a retrospective analysis of data collected prospectively between 2005 and 2016 at a single centre. Data recorded at annual review visits included modified Rodnan skin score (mRSS) and Health Assessment Questionnaire Disability Index (HAQ-DI). Yearly rates of mRSS and HAQ-DI change were assessed by individual linear regressions, and those gradients were compared between disease groups (lcSSc/dcSSc) for each of early/late disease (less/greater than 5 years' duration). RESULTS: The study included 402 patients (110 dcSSc, 292 lcSSc), with mean length of follow-up of 5.5 years (sd 3.5). Mean baseline HAQ-DI was 1.4 in dcSSc and 1.2 in lcSSc. In dcSSc, increased mRSS was associated with worsening disability (ρ = 0.36, p = 0.004) during early but not late disease (ρ = 0.12, p = 0.331). In lcSSc, changes in mRSS were not associated with changes in disability for early (ρ = -0.15, p = 0.173) or late disease (ρ = 0.10, p = 0.137). CONCLUSION: These findings confirm high disability in patients with SSc. A relationship between HAQ-DI and mRSS (worsening mRSS associated with increasing disability) was found only in patients with early dcSSc, suggesting that in other patient subgroups other factors play the major role.

The evaluation of a home-based program for hands in patients with systemic sclerosis.

STUDY DESIGN: This study used a quasi-experimental design where patients were evaluated before and after participation in the self-management program. INTRODUCTION: Hands are commonly affected in systemic sclerosis (SSc). Strategies to maintain or improve hand function are indicated upon diagnosis and throughout the course of the disease. PURPOSE OF THE STUDY: The purpose of this study was to develop and evaluate a home-based program for hands in patients with SSc. METHODS: A home-based self-management program that consisted of concise instructions about SSc and hand exercises was developed and evaluated in a group of patients with SSc during 8 weeks. Primary outcome measures were hand pain (Visual Analogue Scale) and hand function (Cochin Hand Function Scale). Secondary outcome measures were disability (Scleroderma Health Assessment Questionnaire), finger motion (delta finger-to-palm), grip strength, tip and key pinch strength, Raynaud phenomenon and digital ulcers impact, quality of life (Short Form Health Survey). For comparisons between different times analysis of variance for repeated measures was used. To calculate the effect size (ES), the Cohen's test was performed. To evaluate skin moisturizing and warming habits before and after intervention, the McNemar test was used. Statistical significance was set at P ≤ .05. RESULTS: Twenty-two SSc patients (19 women: 3 men; 16 limited scleroderma: 6 diffuse scleroderma) completed the program. Significant improvements were noted for hand pain (3.97 vs 2.21, ES: 0.69), Cochin Hand Function Scale (19.24 vs 12.48, ES: 0.48), Scleroderma Health Assessment Questionnaire (0.95 vs 0.48, ES: 1.01), delta finger-to-palm (92.86 vs 106.33, ES: 0.40), grip strength (14.43 vs 19, ES: 0.58), tip pinch strength (2.49 vs 4.18, ES: 1.15), key pinch strength (4.01 vs 5.22, ES: 0.76), Raynaud phenomenon impact (0.94 vs 0.47, ES: 0.75), Short Form Health Survey-role physical (47.38 vs 60.14, ES: 0.61), physical functioning (34.62 vs 61.9, ES: 0.18), social functioning (60.71 vs 75.6, ES: 0.64), bodily pain (50.55 vs 63.38, ES: 0.58), vitality (45.95 vs 62, ES: 2.22), mental health (56.62 vs 72.38, ES: 0.84) moisturizing, and cold avoidance habits. Patients considered the program easy to follow with no adverse effects related to exercises. DISCUSSION: We developed a home based hand care program to be offered to SSc patients. Improvements in hand function, strength, disability, motion, and overall quality of life were independent of age, income, education level, disease duration, and skin score. Our findings support those of other studies that reported the benefits of hand exercises in SSc. Some study limitations include the lack of a control group, the small number of subjects and the short-time follow up. CONCLUSIONS: This home-based program for patients with SSc improved hand pain, function, mobility, and strength at the end of 8 weeks. Patient adherence and sustained efficacy is still to be determined.

Patient acceptable symptom state in scleroderma: results from the tocilizumab compared with placebo trial in active diffuse cutaneous systemic sclerosis.

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.

Disability, fatigue, pain and their associates in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study.

Objectives: Our aim was to describe the burden of early dcSSc in terms of disability, fatigue and pain in the European Scleroderma Observational Study cohort, and to explore associated clinical features. Methods: Patients completed questionnaires at study entry, 12 and 24 months, including the HAQ disability index (HAQ-DI), the Cochin Hand Function Scale (CHFS), the Functional Assessment of Chronic Illness Therapy-fatigue and the Short Form 36 (SF36). Associates examined included the modified Rodnan skin score (mRSS), current digital ulcers and internal organ involvement. Correlations between 12-month changes were also examined. Results: The 326 patients recruited (median disease duration 11.9 months) displayed high levels of disability [mean (s.d.) HAQ-DI 1.1 (0.83)], with 'grip' and 'activity' being most affected. Of the 18 activities assessed in the CHFS, those involving fine finger movements were most affected. High HAQ-DI and CHFS scores were both associated with high mRSS (ρ = 0.34, P < 0.0001 and ρ = 0.35, P < 0.0001, respectively). HAQ-DI was higher in patients with digital ulcers (P = 0.004), pulmonary fibrosis (P = 0.005), cardiac (P = 0.005) and muscle involvement (P = 0.002). As anticipated, HAQ-DI, CHFS, the Functional Assessment of Chronic Illness Therapy and SF36 scores were all highly correlated, in particular the HAQ-DI with the CHFS (ρ = 0.84, P < 0.0001). Worsening HAQ-DI over 12 months was strongly associated with increasing mRSS (ρ = 0.40, P < 0.0001), decreasing hand function (ρ = 0.57, P < 0.0001) and increasing fatigue (ρ = -0.53, P < 0.0001). Conclusion: The European Scleroderma Observational Study highlights the burden of disability in early dcSSc, with high levels of disability and fatigue, associating with the degree of skin thickening (mRSS). Impaired hand function is a major contributor to overall disability.

Prediction of organ involvement in systemic sclerosis by serum biomarkers and peripheral endothelial function.

OBJECTIVES: To identify prognostic factors among serum biomarkers and endothelial vasodilator function findings in patients with systemic sclerosis (SSc). METHODS: This is a clinical observational study. We assessed 60 consecutive SSc patients (44 limited cutaneous-type, 16 diffuse cutaneous-type). Circulating growth differentiation factor-15 (GDF-15), placenta growth factor (PlGF), endostatin, vascular endothelial growth factor (VEGF), and pentraxin 3 (PTX3) were measured by ELISA. Peripheral endothelial function was measured by forearm blood dilatation response to brachial artery occlusion using noninvasive plethysmography (EndoPAT2000), which is associated with nitric-oxide-dependent vasodilatation and yields a reactive hyperemia index (RHI). We evaluated whether abnormalities in these values were associated with type of SSc - namely, diffuse cutaneous SSc (dcSSc) or limited cutaneous SSc (lcSSc) - or organ involvement including interstitial lung disease (ILD), digital ulcer (DU) and estimated right ventricular systolic pressure (RVSP) by echocardiography >30 mmHg. RESULTS: SSc patients showed significantly elevated serum GDF-15, PlGF, endostatin and VEGF but not PTX3 compared with controls. GDF-15 and PlGF were high in dcSSc patients. EndoPAT-RHI was low, and incidence of RVSP >30 mmHg was high in dcSSc. Multivariate analysis revealed that elevated GDF-15 was highly predictive of dcSSc, ILD or RVSP >30 mmHg. PlGF for DU was also found. Conversely, a low EndoPAT-RHI value was predictive of the presence of dcSSc, ILD or DU. CONCLUSIONS: This is the first study to inclusively investigate the relationships among biomarkers, EndoPAT-RHI and organ involvement in patients with SSc. Our data suggest a complex pathological progression of SSc through fibrotic impairment and microvascular damage.

Interstitial lung disease in systemic sclerosis: data from the spanish scleroderma study group.

OBJECTIVES: To evaluate the clinical characteristics of patients with interstitial lung disease (ILD) in the setting of a large cohort of systemic sclerosis (SSc) patients, and to analyse the differences according to the SSc subtype (following the modification of classification criteria of the American College of Rheumatology for SSc proposed by LeRoy and Medsger), factors are associated with moderate-to-severe impairment of lung function, as well as mortality and causes of death. METHODS: A descriptive study was performed, using the available data from the Spanish Scleroderma Study Group. RESULTS: Twenty-one referral centers participated in the registry. By April 2014, 1374 patients with SSc had been enrolled, and 595 of whom (43%) had ILD: 316 (53%) with limited cutaneous SSc (lcSSc), 240 (40%) with diffuse cutaneous SSc (dcSSc), and 39 (7%) with SSc sine scleroderma (ssSSc). ILD in the lcSSc and the ssSSc subsets tended to develop later, and showed a less impaired forced vital capacity (FVC) and a ground glass pattern on high-resolution computed tomography (HRCT) less frequently, compared with the dcSSc subset. Factors related to an FVC < 70% of predicted in the multivariate analysis were: dcSSc, positivity to anti-topoisomerase I antibodies, a ground glass pattern on HCRT, an active nailfold capillaroscopy pattern, lower DLco, older age at symptoms onset, and longer time between symptoms onset and ILD diagnosis. Finally, SSc-associated mortality and ILD-related mortality were highest in dcSSc patients, whereas that related to pulmonary arterial hypertension was highest in those with lcSSc-associated ILD. CONCLUSIONS: Our study indicates that ILD constitutes a remarkable complication of SSc with significant morbidity and mortality, which should be borne in mind in all three subgroups (lcSSc, dcSSc, and ssSSc).

Comparison of change in end tidal carbon dioxide after three minutes of step exercise between systemic sclerosis patients with and without pulmonary hypertension.

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.

Angiogenic and angiostatic factors in renal scleroderma-associated vasculopathy.

BACKGROUND: The angiogenesis in systemic sclerosis (SSc) is impaired. An imbalance of pro-angiogenic factors and angiogenesis inhibitors has been implicated in the progression of peripheral microvascular damage, defective vascular repair and fibrosis. Intrarenal resistance index are considered markers of renal vasculopathy. The aim of the study is to evaluate angiogenic and angiostatic factors (VEGF and endostatin) in SSc patients and to correlate with intrarenal hemodynamic parameters. METHODS: 91 SSc patients were enrolled in this study. Serum VEGF and endostatin levels were determined. All patients underwent a renal Doppler ultrasound RESULTS: A significant positive correlation was observed between endostatin and renal Doppler parameters (p<0.0001). A negative correlation was observed between serum levels of endostatin and eGFR (p<0.01). In SSc patients with high resistive index, serum levels of endostatin were significantly (p<0.01) higher than in SSc patients with normal resistive index. The serum levels of endostatin significantly increased with progression of nailfold videocapillaroscopy damage (p<0.01) and were significantly (p<0.05) higher in SSc patients with digital ulcers than in SSc patients without digital ulcers. CONCLUSION: This is the first study that assess in SSc patients intrarenal hemodynamic parameters and endostatin. In SSc patients, endostatin represents a marker of renal scleroderma-associated vasculopathy.

Causes of death, survival and risk factors of mortality in Thai patients with early systemic sclerosis: inception cohort study.

Inception cohort study regarding the causes of death and risk factors for mortality in patients with early systemic sclerosis (SSc), especially diffuse SSc (dcSSc) has not been well elucidated. Therefore, the aim of our study was to determine the causes of death, survival rates, and risk factors for mortality in Thai patients with early SSc of whom the majority belonged to the dcSSc subset. We used an inception cohort of early-SSc patients seen between January 2010 and August 2014. All patients were evaluated for clinical and laboratory data at the study entry and then every 6 months. A total of 115 patients (68 female, 91 dcSSc) were enrolled. The mean ± SD age at onset, duration of disease, and duration of follow-up were 52.5 ± 8.5 years, 12.3 ± 9.2 months, and 27.5 ± 16.4 months, respectively. During the follow-up, 11(9.6%) SSc patients died. The mortality rate was 4.17 per 100 person-years (95% CI 2.31, 7.53). The leading cause of SSc-related death was dilated cardiomyopathy (27.2%). Infection was the most common cause of non-SSc-related death (18.2%). Survival rates at 1, 2, 3, and 4 years after the study entry were 93, 91, 88, and 88%, respectively. In the multivariate Cox regression analysis, ESR ≥ 40 mm/h [HR 8.65 (95% CI 1.66,45.17)], hemoglobin < 10 mg/dL [HR 4.57 (95% CI 1.14,18.34)], and mRSS [HR 1.09 (95% CI 1.03,1.15)] were independent risk factors for mortality. Our data suggest that dilated cardiomyopathy was the most common SSc-related cause of death in Thai patients with early SSc, of whom majority was dcSSc subset. Elevated ESR, anemia, and increased mRSS predicted poor outcome.

Prediction of improvement in skin fibrosis in diffuse cutaneous systemic sclerosis: a EUSTAR analysis.

OBJECTIVES: Improvement of skin fibrosis is part of the natural course of diffuse cutaneous systemic sclerosis (dcSSc). Recognising those patients most likely to improve could help tailoring clinical management and cohort enrichment for clinical trials. In this study, we aimed to identify predictors for improvement of skin fibrosis in patients with dcSSc. METHODS: We performed a longitudinal analysis of the European Scleroderma Trials And Research (EUSTAR) registry including patients with dcSSc, fulfilling American College of Rheumatology criteria, baseline modified Rodnan skin score (mRSS) ≥7 and follow-up mRSS at 12±2 months. The primary outcome was skin improvement (decrease in mRSS of >5 points and ≥25%) at 1 year follow-up. A respective increase in mRSS was considered progression. Candidate predictors for skin improvement were selected by expert opinion and logistic regression with bootstrap validation was applied. RESULTS: From the 919 patients included, 218 (24%) improved and 95 (10%) progressed. Eleven candidate predictors for skin improvement were analysed. The final model identified high baseline mRSS and absence of tendon friction rubs as independent predictors of skin improvement. The baseline mRSS was the strongest predictor of skin improvement, independent of disease duration. An upper threshold between 18 and 25 performed best in enriching for progressors over regressors. CONCLUSIONS: Patients with advanced skin fibrosis at baseline and absence of tendon friction rubs are more likely to regress in the next year than patients with milder skin fibrosis. These evidence-based data can be implemented in clinical trial design to minimise the inclusion of patients who would regress under standard of care.

Correlations between skin blood perfusion values and nailfold capillaroscopy scores in systemic sclerosis patients.

OBJECTIVES: To correlate blood perfusion (BP) values assessed by laser speckle contrast analysis (LASCA) in selected skin areas of hands and face with nailfold capillary damage scores in systemic sclerosis (SSc) patients. METHODS: Seventy SSc patients (mean SSc duration 6 ± 5 years) and 70 volunteer healthy subjects were enrolled after informed consent. LASCA was performed at different areas of the face (forehead, tip of nose, zygomas and perioral region) and at dorsal and volar regions of hands. Microvascular damage was assessed and scored by nailfold videocapillaroscopy (NVC) and the microangiopathy evolution score (MES) was calculated. RESULTS: SSc patients showed a significantly lower BP than healthy subjects at fingertips, periungual areas and palm of hands (p<0.0001), but not at the level of face and dorsum of hands. A gradual decrease of BP at fingertips, periungual and palm areas, was found in SSc patients with progressive severity of NVC patterns of microangiopathy ("early", "active", or "late") (p<0.01). A negative correlation was observed between MES and BP values, as well as between loss of capillaries and BP, at the same areas (p<0.001 and p<0.01, respectively). Patients with diffuse cutaneous SSc (dcSSc) showed lower BP than those with limited cutaneous SSc (p<0.04). CONCLUSIONS: LASCA detects a significant reduction of BP only in those areas usually affected by Raynaud's phenomenon (fingertips, periungual and palm areas), especially in dcSSc patients, and BP values significantly correlate with the nailfold capillaroscopy scores of microangiopathy.

Disease progression in systemic sclerosis-overlap syndrome is significantly different from limited and diffuse cutaneous systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc)-overlap syndromes are a very heterogeneous and remarkable subgroup of SSc-patients, who present at least two connective tissue diseases (CTD) at the same time, usually with a specific autoantibody status. OBJECTIVES: To determine whether patients, classified as overlap syndromes, show a disease course different from patients with limited SSc (lcSSc) or diffuse cutaneous SSc (dcSSc). METHODS: The data of 3240 prospectively included patients, registered in the database of the German Network for Systemic Scleroderma and followed between 2003 and 2013, were analysed. RESULTS: Among 3240 registered patients, 10% were diagnosed as SSc-overlap syndrome. Of these, 82.5% were female. SSc-overlap patients had a mean age of 48±1.2 years and carried significantly more often 'other antibodies' (68.0%; p<0.0001), including anti-U1RNP, -PmScl, -Ro, -La, as well as anti-Jo-1 and -Ku antibodies. These patients developed musculoskeletal involvement earlier and more frequently (62.5%) than patients diagnosed as lcSSc (32.2%) or dcSSc (43.3%) (p<0.0001). The onset of lung fibrosis and heart involvement in SSc-overlap patients was significantly earlier than in patients with lcSSc and occurred later than in patients with dcSSc. Oesophagus, kidney and PH progression was similar to lcSSc patients, whereas dcSSc patients had a significantly earlier onset. CONCLUSIONS: These data support the concept that SSc-overlap syndromes should be regarded as a separate SSc subset, distinct from lcSSc and dcSSc, due to a different progression of the disease, different proportional distribution of specific autoantibodies, and of different organ involvement.

Pilot study to determine whether transient receptor potential melastatin type 8 (TRPM8) antibodies are detected in scleroderma.

OBJECTIVES: A key mediator in cold-sensation is the protein transient receptor potential melastatin 8 (TRPM8), which is expressed on sensory nerves and cutaneous blood vessels. These receptors are activated by cold temperatures and play a key role in body thermoregulation. Cold sensitivity and Raynaud's phenomenon are frequent clinical features in scleroderma, and are thought to be secondary to a local defect in cutaneous thermoregulation. We investigated whether autoantibodies targeting TRPM8 were present in the sera of patients with scleroderma as evidence for a possible mechanism for an acquired immune mediated defect in thermoregulation. METHODS: Sera from 50 well-characterised scleroderma patients with Raynaud's phenomenon were studied. TRPM8 autoantibodies were assayed as follows: 1. immunoprecipitation with 35S-methionine-labelled TRPM8 generated by in vitro transcription and translation, 2. immunoblotting lysates made from cells transiently transfected with TRPM8 cDNA, 3. Immunoprecipitation of TRPM8 transfected lysates with detection by blotting and 4. flow cytometry. RESULTS: Fifty scleroderma patients with Raynaud's phenomenon (41 female, 39 Caucasian, 23 with limited scleroderma, and 20 with history of cancer) were studied. Four different methods to assay for TRPM8 antibodies were set up, optimised and validated using commercial antibodies. All 50 scleroderma patients' sera were assayed using each of the above methods, and all were negative for TRPM8 autoantibodies. CONCLUSIONS: Antibodies against TRPM8 are not found in scleroderma patient sera, suggesting that the abnormal cold sensitivity and associated abnormal vascular reactivity in scleroderma patients is not the result of an immune process targeting TRPM8.

Bosentan blocks the antiangiogenic effects of sera from systemic sclerosis patients: an in vitro study.

OBJECTIVES: In systemic sclerosis (SSc), clinical evidence has shown that Bosentan may foster the regeneration of the peripheral microcirculatory network. The aim of this study was to verify in vitro the influence of Bosentan on the angiogenic performance of dermal microvascular endothelial cells (MVECs) and its possible capacity to counteract the antiangiogenic effects of SSc sera. METHODS: Healthy dermal MVECs were challenged with Bosentan at different concentrations (0.1 µM, 1 µM, 10 µM) or with sera from patients with diffuse cutaneous SSc (n=8) and healthy subjects (n=8), alone or in combination with Bosentan (10 µM). Cell viability and chemoinvasion were determined by WST-1 and Boyden chamber assays, respectively. Angiogenesis was evaluated by capillary morphogenesis on Matrigel. RESULTS: Challenge of dermal MVECs with SSc sera induced a significant reduction in angiogenesis (p<0.005 vs. basal condition; p<0.001 vs. healthy sera). The addition of Bosentan could significantly restore angiogenesis in the presence of SSc sera (p<0.01 vs. SSc sera alone). Healthy sera promoted cell viability which was, instead, significantly reduced with SSc sera (p<0.005 vs. healthy sera). The addition of Bosentan to MVECs challenged with SSc sera significantly increased cell viability (p<0.005 vs. SSc sera alone), reaching levels similar to MVECs treated with healthy sera. Co-incubation of MVECs with Bosentan and SSc sera significantly increased chemoinvasion (p<0.005 vs. SSc sera alone) which was inhibited by SSc sera (<0.001 vs. healthy sera). CONCLUSIONS: Bosentan effectively counteracts the antiangiogenic effects of SSc sera on dermal MVECs and fosters the restoration of a proangiogenic environment.