Severity Of Raynaud Research Articles

P146 A phase II, randomised, double-blind, placebo-controlled trial exploring pharmacokinetics, safety and efficacy of intravenous factor XIII treatment in adults with systemic sclerosis

Abstract Background/Aims Systemic sclerosis (SSc) is a multi-system autoimmune disease with significant morbidity and mortality, and an unmet therapeutic need. The pathogenesis of SSc involves dysfunctional immune signalling, fibroblast behaviour and vascular development. Factor XIII (FXIII) is an enzyme involved in coagulation, and in wound healing where it promotes angiogenesis via inhibition of thrombospondin-1 (TSP-1). Therapeutic administration of FXIII in SSc is proposed to increase angiogenesis via suppression of TSP-1, which is known to be dysregulated in SSc. Previous preclinical and clinical studies suggest that therapeutic administration of factor XIII could improve vascular function in SSc. Methods Two interlinked clinical trials were conducted at a single centre. First, a single-dose open-label study was performed to assess the safety and pharmacokinetics of FXIII treatment in SSc. Eight adult patients with limited or diffuse SSc received a single dose of intravenous purified human FXIII, followed by a 6-week monitoring period. Second, a phase II, double-blind, randomised, placebo-controlled study was performed to investigate the safety and efficacy of factor XIII treatment in SSc. 18 adult patients with limited or diffuse SSc were randomised 2:1 to receive study intervention (intravenous purified human FXIII) or placebo (intravenous 0.9% sodium chloride solution). Safety endpoints were assessment of the safety and tolerability of FXIII treatment via review of adverse events, physical examination and monitoring of physiological function. Efficacy was explored as change in skin severity by modified Rodnan skin score (mRSS) at week 24 compared to baseline, and change in severity of Raynaud’s phenomenon, assessed by review of the Raynaud’s Condition Score (RCS) at week 24, compared to baseline. The study is registered with ClinicalTrials.gov (number NCT02551042). Results The main objective of the clinical trial was met by demonstrating that FXIII is safe and well tolerated in SSc. Pharmacokinetic analysis showed a predictable rise and fall in FXIII level following therapeutic administration, with the mean time taken for the FXIII level to return to within 10 IU/dL of the endogenous level being 16.6 days (SD 8.7). Adverse event and safety monitoring did not reveal any concerning pattern. Study intervention-related adverse events were self-resolving and tolerable. There was no statistically significant change in mRSS or RCS during the trial, but there was a trend towards improvement in RCS in the FXIII group (mean change in RCS of -1.2 (95% CI -2.26 to -0.14) in the FXIII group versus -0.83 (95% CI -3.44 to 1.77) in the placebo group). Conclusion Our results suggest that therapeutic strategies to modulate links between coagulation and tissue repair using FXIII are safe and feasible. Further studies with different patient populations and FXIII doses could investigate the role of FXIII in SSc further. Disclosure A. Leslie: Other; A.L. is an employee of GSK. S. Vigneswaran: None. K. Khan: None. V. Ong: None. C.P. Denton: Consultancies; C. D. has received consulting fees from Roche, Janssen, GlaxoSmithKline, Sanofi, Galapagos, Boehringer Ingelheim, and CSL Behring, and Acceleron. Grants/research support; C. D. has received research funding from CSL Behring, Horizon, Abbvie, and GlaxoSmithKline.

ПРОГНОЗИРОВАНИЕ ПРОГРЕССИРОВАНИЯ ИНТЕРСТИЦИАЛЬНОГО ЗАБОЛЕВАНИЯ ЛЁГКИХ У ПАЦИЕНТОВ С СИСТЕМНОЙ СКЛЕРОДЕРМИЕЙ: АНАЛИЗ ДАННЫХ КОГОРТНОГО ИССЛЕДОВАНИЯ

Introduction. Systemic sclerosis (scleroderma) is an autoimmune disease that often causes inflammatory fibrosing lesions of the pulmonary interstitial tissue, referred to as interstitial lung disease. It is associated with a significant reduction in survival and is the leading immediate cause of the systemic scleroderma patients’ death. Progression rate of interstitial lung disease varies greatly. Since the specific immunosuppressive and antifibrotic treatment is only justified in case of progressive lesions, predicting the interstitial lung disease progression is of great practical importance. Aim: To develop approaches to predicting the progression of interstitial lung disease in systemic scleroderma patients. Materials and Methods. Our analysis included the data of patients observed in the Registry of Myositis, Systemic Scleroderma and Mixed Diseases (REMISSiZ). Inclusion criteria: Age 18+ years, the proven case of systemic scleroderma, eligibility for ACR/EULAR (2013), and the repeated high-resolution computed tomography of lungs with an interval of at least 1 year. All patients underwent 6-minute walking tests. Results and Discussion. The study included 44 patients (43 women) aged 62.9 ± 11.5 years in average. The average follow-up duration was 530 ± 231 days. Radiological progression was associated with younger age, p=0.03, severity of Raynaud’s phenomenon, p=0.032, shorter disease duration, p=0.038, and shorter distance covered in the 6-minute walk test, p=0.05. The progression of functional impairment, determined by the dynamics of the distance covered in the 6-minute walk test, was associated with a decrease in blood oxygen saturation at rest (p=0.003), the severity of breath shortness according to the Borg scale (p=0.006), the initial distance of the 6-minute walk test (p <0.001), the presence of topoisomerase I antibodies (anti-Scl-70, p=0.034), and complaints of breath shortness (p=0.043) and dysphagia (p=0.034). As a result of reverse stepwise selection of variables, three independent significant predictors were selected from the above indicators: Dysphagia, anti-Scl-70, and the initial walking distance in the 6-minute walk test. Based on these indicators, a regression formula is presented for predicting the progression of functional impairment in systemic scleroderma patients. Conclusions. X-ray-detected progression of interstitial lung disease in systemic sclerosis patients is associated with younger age and Raynaud’s phenomenon severity. To predict the decline in the systemic sclerosis patients’ functionality, it is advisable to consider the presence of dysphagia and topoisomerase I antibodies (anti-Scl-70).

Prostaglandin E1 — salvage therapy in the treatment of difficult-to-heal ulcers in systemic sclerosis

Involvement of blood vessels in the form of Raynaud’s phenomenon and microcirculatory dysfunction as well as accompanying skin lesions of the fingers in patients with systemic sclerosis lead to easy skin damage and difficult-to-heal ulcers. Patient education regarding, among other things, the avoidance of injuries, exposure to cold or smoking and pharmacological treatment are becoming important. The choice of drugs listed in current recommendations depends on the clinical manifestation, i.e. the presence and severity of Raynaud’s phenomenon, the treatment or prevention of ulceration and the response to previous treatment. The paper presents a case of a 79-year-old woman with advanced necrotic lesions of the fingers in the course of systemic sclerosis diagnosed late in life. Due to the advancement of the lesions and the lack of improvement after first-line oral medications, the patient required intravenous prostaglandin. Six months of effective therapy and additional surgical treatment led to complete healing and inhibition of new ulcer formation. Intravenous prostaglandin is an effective alternative for the treatment of difficult-toheal ulcers in the course of systemic sclerosis while preventing the formation of new lesions.

The Relationship between Smoking, Raynaud's Phenomenon, Digital Ulcers, and Skin Thickness in the Waikato Systemic Sclerosis Cohort.

Systemic sclerosis (SSc) is a heterogeneous complex autoimmune connective tissue disease with variable presentation as a consequence of multisystem involvement. One of the key features of SSc is Raynaud's phenomenon along with vascular endothelial dysfunction that leads to digital ulcers (DUs). Raynaud's tends to be triggered by decreasing thermal gradient exposure, while stress and smoking also play a role. DUs arising as a consequence of severe Raynaud's and vasculopathy are a major cause of morbidity and disability in SSc. We set out to determine the relationship between smoking, Raynaud's phenomenon, DUs, and skin thickness in our Waikato Systemic Sclerosis cohort. The Waikato Systemic Sclerosis (SSc) database was used to extract data. Variables collected included demographics, age of diagnosis, SSc subtypes, age at first non-Raynaud's phenomenon, medications used for treatment of Raynaud's phenomenon or ulcers, and maximal modified Rodnan skin score (mRSS). Raynaud's phenomenon and finger DUs (severity for each over the past week and since diagnosis) and a Scleroderma Health Assessment Questionnaire (SHAQ) visual analog 10 cm scale were collected. The lead rheumatologist completed a physician's assessment of Raynaud's and the disease severity questionnaire. Of the cohort of 143 patients, 100 patients were eligible to complete the questionnaires. Seventy-five patients returned completed questionnaires. Of these, the majority were female (88%), 52 (69.3%) had limited cutaneous systemic sclerosis (lcSSc), 17 (22.7%) had diffuse cutaneous systemic sclerosis (dcSSc), and 6 (8%) had an overlap syndrome. Thirty-six (48%) had a smoking history (in the time frame of collection of serial data). Mean ± standard deviation (SD) pack-years smoked were 17.11 ± 15.29 years. Thirty-five participants had a history of DUs, with a median of 4 DU (range 1-20). Of 17 patients with dcSSc, 12 (70.6%) had ulcers in comparison with 17 of 52 (32.7%) patients with lcSSc. There was a significant relationship between SSc subtype and the number with ulcers (X2 = 10.1, P = 0.007). There was also a significant relationship between physician severity of Raynaud's and presence of ulcers (t = 6.1, P < 0.001), which was not evident between patients' severity of Raynaud's and presence of ulcers (t = 1.9, P = 0.06). On the SHAQ score, smokers had significantly worse Raynaud's phenomenon over the prior week (t = 3.08, P = 0.03) and were more likely to note DUs over the preceding week, although the latter was not statistically significant (t = 1.95, P = 0.055). There was no association between smoking and skin thickness as measured by mRSS (r = 0.23, P = 0.19). Our study demonstrates that smokers have had worse Raynaud's phenomenon over the past week and they were also more likely to note DUs with a trend toward significance but not statistically significant most likely due to our small sample size. Our study also demonstrated that patients with dcSSc had more ulcers in comparison with lcSSc. This study justifies physicians strongly recommending smoking cessation in patients with SSc.

Impact of global warming on Raynaud’s phenomenon: a modelling study

Background: Raynaud’s phenomenon is induced by excessive vasoconstriction of the peripheral microcirculation in response to environmental factors, essentially cold, but also stress or emotions. The objective of the present study is to evaluate the impact of global warming on the worldwide prevalence and severity of Raynaud’s phenomenon over the 21 st century. Method: We first estimated the correlation between average temperature and prevalence and severity of Raynaud’s phenomenon. Then, we mapped the prevalence and the severity of Raynaud’s phenomenon worldwide at Christmas 1999 using historical data and, using climate projections from the Inter-Sectoral Impact Model Intercomparison Project, we predicted the prevalence and severity of Raynaud’s phenomenon at Christmas 2099 according to four greenhouse-gas emission scenarios. Results: The prevalence of Raynaud’s phenomenon in the general population is expected to decrease by 0.5% per degree Celsius increase. Furthermore, patients are expected to suffer from one less attack per week for each increase of 2.5 degrees Celsius. Conclusions: Our study shows that global warming may have a significant impact on the prevalence and the severity of Raynaud’s phenomenon over the 21 st century. However, as expected, this will greatly depend on the level of greenhouse-gas emissions.

Impact of global warming on Raynaud's phenomenon: a modelling study.

Background:Raynaud's phenomenon is induced by excessive vasoconstriction of the peripheral microcirculation in response to environmental factors, essentially cold, but also stress or emotions. The objective of the present study is to evaluate the impact of global warming on the worldwide prevalence and severity of Raynaud's phenomenon over the 21 st century. Method: We first estimated the correlation between average temperature and prevalence and severity of Raynaud's phenomenon. Then, we mapped the prevalence and the severity of Raynaud's phenomenon worldwide at Christmas 1999 using historical data and, using climate projections from the Inter-Sectoral Impact Model Intercomparison Project, we predicted the prevalence and severity of Raynaud's phenomenon at Christmas 2099 according to four greenhouse-gas emission scenarios. Results: The prevalence of Raynaud's phenomenon in the general population is expected to decrease by 0.5% per degree Celsius increase. Furthermore, patients are expected to suffer from one less attack per week for each increase of 2.5 degrees Celsius. Conclusions: Our study shows that global warming may have a significant impact on the prevalence and the severity of Raynaud's phenomenon over the 21 st century. However, as expected, this will greatly depend on the level of greenhouse-gas emissions.

The burden of air pollution and temperature on Raynaud's phenomenon secondary to systemic sclerosis.

to evaluate the effect of air pollution (ozone - O3 and particulate matter <=10 μm and <=2.5 μm - PM10 and PM2.5) on the severity of Raynaud's phenomenon (RP) secondary to systemic sclerosis (SSc). cross-sectional, observational, and single centre study. all consecutive SSc patients residing in Lombardy (Northern Italy) were enrolled. PM10, PM2.5, and O3 concentrations were calculated for each patient at municipality resolution in the week before the evaluation. Similar considerations were made for meteorological variables (temperature and humidity). patients were asked to assess RP severity during the week before the evaluation according to a visual analogue scale (VAS). Ordinal logistic regression models were fitted to evaluate the short-term effect of temperature and air pollution with respect to RP. A univariate linear regression model was created to consider the association between temperature and pollutants. in this study, 87 SSc patients were enrolled. Temperature was confirmed to strongly influence RP severity. PM10 and PM.5 were found to significantly worsen RP severity for the first four days before the evaluation, including the day of the visit, and as mean up to six days before the evaluation. O3 seemed to exert a protective effect on RP severity that was significant for the first four days before the evaluation, including the day of the visit, and as mean up to seven days before the evaluation. since the overwhelming effect of temperature on RP, final conclusions about the exact contribution of pollutants on RP severity cannot be drawn because of the strong inter-correlation between air pollution and temperature.

A patient-centered approach to the burden of symptoms in patients with scleroderma treated with Bosentan: A prospective single-center observational study.

Systemic sclerosis (SSc) is a rare and complex autoimmune disease associated with poor vital and functional outcomes. The functional hindrance in patients derives from various disease-specific manifestations, including Raynaud's phenomenon and digital ulcers (DUs). Bosentan is an endothelin receptor antagonist capable of preventing the appearance of new DUs in patients with scleroderma. The present study aimed to evaluate the effects of Bosentan on the severity of Raynaud's phenomenon, DU-related symptoms and functional impairment during the first year of treatment. A prospective study that included adult patients with SSc admitted to the Rheumatology Department between January 2016 and January 2017 that were candidates for Bosentan therapy, was performed. All patients were asked to evaluate the burden of symptoms secondary to Raynaud's and DUs using a visual analogue scale (VAS), whereas functional hindrance was assessed via Health Assessment Questionnaire Disability Index (HAQ-DI). The outcomes were assessed at baseline and every 3 months during 1 year of therapy. Among the 41 patients included initially, 2 participants discontinued the treatment after 1 month due to adverse events (elevation of liver enzymes). The study cohort exhibited a significant improvement in HAQ-DI, VAS-R and VAS-DU scores in response to Bosentan therapy over the 1-year follow-up period. Higher scores at baseline predicted a weaker treatment-related improvement, with the risk of a poor outcome being increased by 220% for VAS-R, 116% for VAS-DU, whereas no increase was observed for HAQ-DI. The post-treatment improvement in VAS-DU levels was associated with a better outcome for HAQ-DI (R=0.44; P=0.005). This association was not identified for VAS-R (R=0.24; P=0.137). Throughout the follow-up period, patients with dyspnea presented with significantly higher HAQ-DI scores compared with non-dyspneic patients. Bosentan therapy may indirectly influence functionality and quality of life in patients with scleroderma by reducing the burden of Raynaud's and DU-related symptoms. Nonetheless, patients with SSc with a decreased symptom burden at baseline exhibited improved outcomes.

Inhomogeneity of capillaroscopic findings in systemic sclerosis.

Despite the great interest in capillaroscopy in systemic sclerosis (SSc), research on the possible combinations of different microvascular phenomena at different fingers in SSc patients have not been performed until now. To assess the diversity of capillaroscopic findings in SSc. The study includes analysis of the capillaroscopic findings in 40 SSc patients who were divided into the following categories: "scleroderma", type pattern - "early", "active", "late" phase, normal and/or nonspecific findings. The data were analyzed using descriptive statistics and t test. In 77% of the patients, inhomogeneity of the capillaroscopic findings of the fingers was detected. The most frequent combinations of capillaroscopic patterns were "early+active" (n=7), "active+late" phase (n=7), "active" phase+normal and/or nonspecific findings (n=6), "early+active" phase+normal and/or nonspecific findings (n=4). Concomitant presence of normal and/or nonspecific findings and "late" phase was detected in only 3 cases. Inhomogeneity of the capillaroscopic findings in SSc is a frequent phenomenon. The results indicate that combinations of "scleroderma" type capillaroscopic findings from different phases could be observed as well as concomitant appearance of pathological and normal/or nonspecific findings of different digits. This phenomenon could be a result of the complex action of different factors eg, disease duration, severity of Raynaud's phenomenon, presence of digital ulcers, local action of different angiogenic and angiostatic factors, gradual transition from one phase to another due to the extensive capillary area, therapeutic interventions.

Optimisation of botulinum toxin type a treatment for the management of Raynaud\u2019s phenomenon using a dorsal approach: a prospective case series

IntroductionRaynaud’s phenomenon (RP) is a common condition and causes pain, paraesthesia, ulceration and gangrene. Botulinum toxin A (Btx-A) is effective when injected via a digital palmar approach, in the treatment of severe RP. However, hand weakness resulting from lumbrical malfunction is a recognized complication. This study aimed to determine the effect of Btx-A injected via a dorsal approach.MethodForty patients received 100 units of Btx-A, injected across both hands via a dorsal approach. Each patient had a baseline, 6- and 12-week hand assessment and thermographic image (FLIR E60bx) performed for the study.ResultsEighty-eight percent of patients reported an improvement in symptoms including reduction in pain, improved colour change with reduced swelling and edema at 6 weeks. Of these patients, 80% reported an improvement in cold intolerance with a reduction in the frequency and severity of Raynaud’s attacks. There was a significant improvement in both the DASH score (p = 0.001), Kapandji score (p = 0.001) and hand strength (p < 0.05). No patients reported weakness. Improvements in hand function and symptoms of RP were still evident at 12 weeks.ConclusionsBtx-A injected via a dorsal approach improves symptoms and reduces the number of RP. We have shown an effective non-surgical approach technique to treat RP.Key Points• Raynaud’s phenomenon is a common vasospastic disorder of the digital vessels, which can cause severe pain, restrictions to hand function and ulceration.• Dorsal botulinum toxin type A injections can improve the symptoms of secondary Raynaud’s phenomenon and hand function for approximately 3 months.

Geographic variation as a risk factor for digital ulcers in systemic sclerosis patients: a multicentre registry

Objective: To evaluate the influence of geographic variation on the risk of digital ulcer (DU) development in systemic sclerosis (SSc) patients.Methods: This cross-sectional, multicentre study evaluated patients with SSc from centres located in different geographic regions of Brazil (subtropical and tropical climate zones). Demographic and clinical data were collected.Results: The study included 141 patients with SSc (26 from the subtropical and 115 from the tropical zone). In total, 43 DUs were observed in 23 (16%) of the patients. By a simple logistic regression model, the presence of DUs was associated with a higher modified Rodnan skin score, previous necrosis or amputation of the extremities, flexion contracture of the fingers, active smoking, higher avascular score on capillaroscopy, higher severity of Raynaud’s phenomenon, a higher Health Assessment Questionnaire Disability Index (HAQ-DI) score, a higher visual analogue scale score for Raynaud’s phenomenon and overall disease, and the subtropical climate zone. Using multiple logistic regression, the presence of DUs was significantly associated with patients living in the subtropical climate zone [odds ratio (OR) = 5.4, p = 0.002], necrosis or amputation (OR = 5.2, p = 0.011), and a higher HAQ-DI score (OR = 2.6, p = 0.021).Conclusion: In this multicentre study in a continental country with different climates, patients with SSc living in a subtropical climate region had a 5.4 times higher risk of developing DUs than patients living in a warmer region (tropical climate), suggesting a more severe course of peripheral vasculopathy among patients living in geographic regions with relatively cold weather.

Atteinte macrovasculaire de la sclérodermie systémique : étude descriptive prospective de 20 patients en échodoppler

Systemic sclerosis is characterized by cutaneous sclerosis, vascular disease and immunological dysfunction. The prevalence of macrovascular disease remains controversial. This was a descriptive prospective single-center study conducted in the vascular medicine department of the University Hospital of Bordeaux from July 1 to September 1, 2015. All inpatients followed for systemic scleroderma were included. Each patient had a Doppler ultrasound of the supra-aortic, upper and lower limb, and digital arteries as well as the aorta. The main objective of the study was to describe the presence and location of arterial lesions in patients with systemic sclerosis. Of the twenty patients included, there were 13women and 7men; mean age was 58±16years. Patients exhibited wall thickening (n=16, 80%), calcified plaques (n=10, 50%), hemodynamically significant stenoses (n=3, 15%) and arterial occlusions (n=12, 60%). Ankle brachial pressure index (ABPI) was 0.98±0.16on the right and 0.99±0.21on the left. Two patients had ABPI<0.8. The mean brachial systolic blood pressure was 113±14mmHg. Arterial mapping (860arterial sites) found wall thickening (n=93arteries, 10%), calcified plaques (n=47, 5%), hemodynamically significant stenoses (n=7) and occlusions (n=22). Arterial occlusions were located in the ulnar arteries (n=2), the digital arteries (n=18), the posterior tibial artery (n=1) and the dorsalis pedis artery (n=1). The data of our study correlate with macrovascular disease described in the literature. This finding raises two questions: how does this concept integrate with the severity of Raynaud's phenomenon and the risk of digital ulcers and changes in patients' capillaroscopic landscape during follow-up? What is the cause of these vascular anomalies, some of which are very different from what is observed in atherosclerosis?

SAT0317 Baseline MRA Predicts the Treatment Response to Vasodilator Udenafil in Patients with Secondary Raynaud's Phenomenon

BackgroundHigh-resolution MR angiography (HR-MRA) demonstrates blood flow in the digital arteries, which correlates with the severity of Raynaud's phenomenon (RP)ObjectivesThis study investigates whether baseline HR-MRA of the hand can predict...

SAT0300 Microcirculation and Macrovascular Disease in Systemic Sclerosis – A Nailfold Capillary Study

BackgroundEmerging evidence demonstrate that patients with systemic sclerosis (SSc) suffer from both micro- and macrovascular disease. Structural changes in nailfold capillaries, a marker of microvascular involvement, has been associated with...

OP0091 A Retrospective Look at the Recurrence of Digital Ulcers in Patients with Scleroderma after Discontinuation of Oral Treprostinil

BackgroundIschemic digital ulcers (DU) are a frequent complication in systemic sclerosis, estimated to occur in over 40% of patients. Treprostinil diethanolamine, a newer prostacyclin analog that has been developed for...

THU0342 Neuropathic pain in patients with systemic sclerosis

BackgroundSystemic sclerosis (SSc) is a connective tissue disease characterized by fibrosis of the skin and internal organs, pronounced alterations in the microvasculature and frequent cellular and humoral immunity abnormalities (1)....

Prospective, open-label, uncontrolled pilot study to study safety and efficacy of sildenafil in systemic sclerosis–related pulmonary artery hypertension and cutaneous vascular complications

Pulmonary artery hypertension (PAH) remains the leading cause of morbidity and mortality in systemic sclerosis, while Raynaud's phenomenon and digital ulcers significantly add to the morbidity in systemic sclerosis (SSc). This study was undertaken to evaluate the role of sildenafil in PAH, Raynaud's phenomenon, and digital ulcers in systemic sclerosis patients. A prospective, open-label, uncontrolled pilot study was done at a tertiary care centre in India to study the safety and efficacy of oral sildenafil in PAH, Raynaud's phenomenon, digital infarcts, and ulcers in SSc. Seventeen patients fulfilling ACR classification criteria for scleroderma and having PAH were recruited. Six-minute walk test, WHO class of dyspnoea, severity of Raynaud's phenomenon, and 2D ECHO were performed in all the study subjects at baseline and at 3 months post-treatment. All patients were treated with oral sildenafil 25 mg three times a day for a period of 3 months. The pre- and post-treatment values of mean pulmonary artery pressure (PAP), 6-min walk test, WHO class of dyspnoea, and severity of Raynaud's phenomenon were compared to look for any significant change. Sixteen patients who completed 3-month follow-up had shown statistically significant improvement in 6-min walk test, WHO class of dyspnoea, severity of Raynaud's phenomenon, and mPAP. Also, there was no occurrence of new digital infarcts or ulcers, and existing ulcers showed signs of healing. Sildenafil is highly efficacious cheaper and safe alternative to other available therapies for SSc-associated PAH, Raynaud's phenomenon, and digital infarcts/ulcers.

Baseline vWF factor predicts the development of elevated pulmonary artery pressure in systemic sclerosis

Objectives. This study aims to examine the utility of von Willebrand factor (vWF) as a biomarker in lcSSc, in particular the ability of vWF to predict the future development of disease manifestations in this disease.Methods. vWFAg concentrations were measured in the serum of patients with lcSSc at baseline and at 3 years, during the QUINs trial [Prevention of Vascular Damage in Scleroderma with Angiotensin-Converting Enzyme (ACE) Inhibition]. %DLCO, %KCO, %FVC, pulmonary artery pressure (PAP) estimation by echocardiography, Raynaud’s attack frequency, Raynaud’s severity, digital ulcer frequency, urinary protein excretion, estimated glomerular filtration rate (eGFR), modified Rodnan skin score and Medsger disease activity score were also measured at baseline and 3 years.Results. Baseline serum vWF concentrations were related to concurrent Medsger disease activity score, %DLCO, %FVC, urinary protein excretion, eGFR and PAP >30 mmHg. In logistic regression models, baseline serum vWF concentrations were able to predict the future development of elevated PAP by echocardiography (PAP >40 mmHg, P = 0.001).Conclusions. Pulmonary artery hypertension is a life-threatening complication of lcSSc. vWF is a marker of endothelial cell activation. Raised serum concentrations of vWF in lcSSc increase the risk of developing subsequent elevation in PAP. Therefore screening patients with lcSSc for vWF may identify a group at risk of developing PAH. These patients could potentially be targeted with agents that stabilize the endothelium, e.g. statins.

Modeling smoking in systemic sclerosis: A comparison of different statistical approaches

To determine the effect of different methods of modeling smoking on vascular outcomes in rheumatic diseases. Data from the Canadian Scleroderma Research Group Registry were used. Patients self-reported their smoking history. Vascular outcomes were severity of Raynaud's phenomenon, presence of finger ulcers, and severity of finger ulcers. Several models were developed to capture the experience of smoking: 1) ever compared to never smoking; 2) current and past smoking compared to never smoking; 3) never, past, and current smoking compared using polynomial contrasts; 4) smoking intensity, duration, and time since cessation assessed separately; and 5) smoking modeled using the Comprehensive Smoking Index (CSI), which integrates intensity, duration, and time since cessation into a single covariate. This study included 606 patients, of which 16% were current, 42% were past, and 42% were never smokers. Current and past smokers smoked a mean±SD of 25±17 and 17±18 pack-years, respectively. Smoking duration was shorter in past compared to current smokers (18.3 versus 31.7 years). Past smokers reported having stopped smoking approximately mean±SD 16±12 years prior, although this ranged from 1 to 50 years. Smoking had no effect on vascular outcomes in the simplest model comparing ever to never smokers. Models that isolated past smokers revealed the presence of a healthy smoker bias in that group. The model using the CSI demonstrated a strong negative effect of smoking on vascular outcomes. Proper modeling of the effect of smoking is essential in studies of vascular outcomes of rheumatic diseases.

Discordance between Patient and Physician Assessments of Disease Severity in Systemic Sclerosis

To describe the magnitude and correlates of discordance between patient and physician assessments of disease severity in patients with systemic sclerosis (SSc). Subjects were patients enrolled in the Canadian Scleroderma Research Group Registry. The outcomes of interest were patient and physician global assessments of disease severity (scales ranging from 0-10). Predictors of disease severity represented the spectrum of disease in SSc (skin involvement, severity of Raynaud's phenomenon, shortness of breath, gastrointestinal symptoms and pain, number of fingertip ulcers, tender and swollen joints, creatinine, and fatigue). The results of the analysis were validated in an independent sample of patients with SSc from the United States. Patients perceived greater disease severity than physicians (mean difference 0.78 ± 2.65). The agreement between patient and physician assessments of disease severity was, at best, modest (intraclass correlation 0.3774; weighted κ 0.3771). Although both patients and physicians were influenced by skin scores, breathlessness, and pain, the relative importance of these predictors differed. Patients were also influenced by other subjective symptoms, while physicians were also influenced by disease duration and creatinine. The predictors explained 56% of the deviance in the patient global assessments and 29% in the physician assessments. These findings were confirmed in the US dataset. Patients and physicians rate SSc disease severity differently in magnitude and are influenced by different factors. Patient-assessed and physician-assessed measures of severity should be considered as complementary and used together in future studies of SSc.