Evaluation of the European Society of Cardiology Risk Assessment Score in Incident Systemic Sclerosis-Associated Pulmonary Arterial Hypertension.

OBJECTIVE: Patients with pulmonary arterial hypertension (PAH) may be stratified as low, intermediate, or high risk of 1-year mortality. In 2022, the European Society of Cardiology (ESC) updated and simplified its risk stratification tool, based on three variables: World Health Organization functional class, serum N-terminal pro-brain type natriuretic peptide and six-minute walk distance, applied at follow-up visits, intended to guide therapy over time. METHODS: We applied the 2022 ESC risk assessment tool at baseline and follow-up (within 2 years) to a multinational incident cohort of systemic sclerosis-associated PAH (SSc-PAH). Kaplan-Meier curves, Cox hazards regression, and accelerated failure time models were used to evaluate survival by risk score. RESULTS: At baseline (n = 260), the majority of SSc-PAH (72.2%) were graded as intermediate risk of death according to the 2022 tool. At follow-up, according to 2022 tool, half (55.5%) of the cohort were classified as low or intermediate-low risk. The 2022 risk model at follow-up was able to differentiate survival between risk strata. All three individual parameters (World Health Organization functional class, N-terminal pro-brain type natriuretic peptide, six-minute walk distance) were significantly associated with mortality at baseline and/or follow-up. CONCLUSION: The 2022 ESC risk assessment strategy applied at baseline and follow-up predicts survival in SSc-PAH. Treatment decisions for SSc-PAH should include risk assessments, aiming to achieve low-risk status according to the 2022 ESC guidelines.

Clinical utility of nailfold capillaroscopy.

Nailfold capillaroscopy (NFC) is a simple noninvasive microscopic technique used to identify characteristic morphological abnormalities in the nailfold capillaries. The presence of this microvasculopathy appears to be of fundamental importance in the pathological processes that underlie the scleroderma spectrum disorders (including dermatomyositis and antisynthetase myositis). This review discusses the different methodologies and techniques in performing NFC and stresses the diagnostic utility achieved with simple 'bedside' techniques utilising the ophthalmoscope, dermatoscope or smart phone. Recent advances in reporting abnormal microvascular patterns and vascular metrics (e.g. capillary density and dropout) are discussed. The aetiopathogenesis of the microvasculopathy is currently unknown but its close association with Raynaud Phenomena and specific autoantibodies together with recent observations from sequential NFC allows speculations on its possible mechanism. Finally, future developments in the use of NFC as a possible biomarker in the management of the scleroderma spectrum disorders are discussed, with a recommendation that NFC becomes more widely available, particularly in rheumatological, immunological and dermatological practice. NFC provides a clinically accessible window on the pathologic process fundamental to scleroderma-related disease.

Right ventricular myocardial deoxygenation in patients with pulmonary artery hypertension.

BACKGROUND: In pulmonary arterial hypertension (PAH), progressive right ventricular (RV) dysfunction is believed to be largely secondary to RV ischaemia. A recent pilot study has demonstrated the feasibility of Oxygen-sensitive (OS) cardiovascular magnetic resonance (CMR) to detect in-vivo RV myocardial oxygenation. The aims of the present study therefore, were to assess the prevalence of RV myocardial ischaemia and relationship with RV myocardial interstitial changes in PAH patients with non-obstructive coronaries, and corelate with functional and haemodynamic parameters. METHODS: We prospectively recruited 42 patients with right heart catheter (RHC) proven PAH and 11 healthy age matched controls. The CMR examination involved standard functional imaging, OS-CMR imaging and native T1 mapping. An ΔOS-CMR signal intensity (SI) index (stress/rest signal intensity) was acquired at RV anterior, RV free-wall and RV inferior segments. T1 maps were acquired using Shortened Modified Look-Locker Inversion recovery (ShMOLLI) at the inferior RV segment. RESULTS: The inferior RV ΔOS-CMR SI index was significantly lower in PAH patients compared with healthy controls (9.5 (- 7.4-42.8) vs 12.5 (9-24.6)%, p = 0.02). The inferior RV ΔOS-CMR SI had a significant correlation to RV inferior wall thickness (r = - 0.7, p < 0.001) and RHC mean pulmonary artery pressure (mPAP) (r = - 0.4, p = 0.02). Compared to healthy controls, patients with PAH had higher native T1 in the inferior RV wall: 1303 (1107-1612) vs 1232 (1159-1288)ms, p = 0.049. In addition, there was a significant difference in the inferior RV T1 values between the idiopathic PAH and systemic sclerosis associated PAH patients: 1242 (1107-1612) vs 1386 (1219-1552)ms, p = 0.007. CONCLUSION: Blunted OS-CMR SI suggests the presence of in-vivo microvascular RV dysfunction in PAH patients. The native T1 in the inferior RV segments is significantly increased in the PAH patients, particularly among the systemic sclerosis associated PAH group.

Scleroderma renal crisis: observations from the South Australian Scleroderma Register.

BACKGROUND: Scleroderma renal crisis (SRC) is a rare but feared complication with high morbidity and mortality. Its aetiopathogenesis is unclear. AIM: To investigate epidemiological, serologic and clinical features of all patients with SRC listed on the population-based South Australian Scleroderma Register and to examine possible factors in aetiopathogenesis. METHOD: A case note review was performed on all SRC patients with relevant data extracted to determine incidence, clinical phenotype, presence of autoantibodies and survival. Possible precipitating and aetiopathogenic factors were also examined. Data from the South Australian Scleroderma Register and Australia Bureau of Statistics was sourced for comparative purposes. RESULTS: Over the 34-year period (1985-2018), 30 patients (21 females, 9 males) presented with SRC giving a South Australian mean annual incidence of 0.58/million/year (95% CI 0.39-0.89). Twenty-eight of these patients had diffuse cutaneous scleroderma and two with limited cutaneous scleroderma. The mean age at first symptom of scleroderma was 51.2 ± 15.9 (mean ± SD) years with SRC occurring 4.6 years later (median = 3.0 years, range 0.1-20 years). Possible precipitating factors for SRC included high dose steroids in five patients. Twelve patients were anti- RNA polymerase3 (RNAPol3) positive and two were anti-topoisomerase 1 (Topo1) positive. Renal outcome was poor with 13 patients requiring renal replacement therapy and two proceeding to renal transplantation. The mean age at death was 61.2 ± 11.6 years with SRC patient survival being significantly shorter than patients with diffuse scleroderma without renal involvement (P = 0.002). There was no significant difference in survival between the 1985-2002 and the 2003-2018 SRC cohorts (P = 0.2). Nailfold capillaroscopy performed in 10 patients revealed extensive microvascular damage with prominent capillary drop out. CONCLUSION: SRC is a rare occurrence with an incidence of 0.58/million/year in South Australia. This frequency has not changed over time. It continues to have a severe adverse outcome with frequent requirement for renal replacement therapy and poor survival. Nailfold capillaroscopy revealed evidence of extensive capillary damage. No improvement in survival was observed over the 34-year study period.

Left ventricular ischemia in pre-capillary pulmonary hypertension: a cardiovascular magnetic resonance study.

BACKGROUND: Prognosis in pulmonary arterial hypertension (PAH) is largely dependent on right ventricular (RV) function. However, recent studies have suggested the presence of left ventricular (LV) dysfunction in PAH patients. The potential role of LV ischemia, as a contributor to progressive LV dysfunction, has not been systematically studied in PAH. We aim to assess the presence and extent of LV myocardial ischemia in patients with known PH and without obstructive coronary artery disease (CAD), using oxygen-sensitive (OS) cardiovascular magnetic resonance (CMR) and stress/rest CMR T1 mapping. METHODS: We prospectively recruited 28 patients with right heart catheter-proven PH and no significant CAD, 8 patients with known CAD and 11 normal age-matched controls (NC). OS-CMR images were acquired using a T2* sequence and T1 maps were acquired using Shortened Modified Look-Locker Inversion recovery (ShMOLLI) at rest and adenosine-induced stress vasodilatation; ΔOS-CMR signal intensity (SI) index (stress/rest SI) and ΔT1 reactivity (stress-rest/rest T1 mapping) were calculated. RESULTS: Global LV ΔOS SI index was significantly lower in PH patients compared with controls (11.1%±6.7% vs. 20.5%±10.5%, P=0.016), as was ΔT1 reactivity (5.2%±4.5% vs. 8.0%±2.9%, P=0.047). The ischemic segments of CAD patients had comparable ΔOS SI (10.3%±6.4% vs. 11.1%±6.7%, P=0.773) to PH patients, but lower ΔT1 reactivity (1.1%±4.2% vs. 5.2%±4.5%, P=0.036). CONCLUSIONS: Decreased OS-CMR SI and T1 reactivity signify the presence of impaired myocardial oxygenation and vasodilatory response in PH patients. Given their unobstructed epicardial coronary arteries, this is likely secondary to coronary microvascular dysfunction (CMD).

Nivolumab-induced synovitis is characterized by florid T cell infiltration and rapid resolution with synovial biopsy-guided therapy.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are associated with rheumatic and musculoskeletal immune-related adverse events (irAEs) in 5%-20% of patients. Currently, patients refractory to corticosteroids and conventional disease-modifying antirheumatic drugs (cDMARD) are treated with biological DMARDs (bDMARDs) targeting tumor necrosis factor α (TNFα) and interleukin-6, although without a clear biological rationale. Synovial tissue (ST) biopsy presents a valuable opportunity to investigate irAE pathogenesis and appropriately stratify bDMARD use in refractory irAE patients. CASE PRESENTATION: We provide the first report of comparative, parallel ST and synovial fluid (SF) analyses of severe, cDMARD-refractory, seronegative polyarthritis, classified as a grade 3 irAE occurring in response to nivolumab treatment for metastatic squamous cell lung cancer, in comparison with ST and SF from patients with untreated rheumatoid arthritis (RA). We investigated immunohistochemical labeling of ST cytokine expression as a biological rationale for selecting therapy. Flow cytometric analysis of lymphocytes from ST, SF and blood collected before and after synovial biopsy-guided therapy, in comparison with RA, were evaluated for insights into the immunopathogenesis of irAE. Immunolabeling of ST demonstrated an excess of TNFα cytokine expression. Subsequent treatment with infliximab resulted in resolution of inflammatory symptoms and a significant reduction in C reactive protein levels. Flow cytometric analysis of synovial infiltrates indicated absence of programmed cell death protein-1 (PD-1) receptor positivity despite cessation of nivolumab approximately 200 days prior to the analyzes. CONCLUSIONS: A deeper understanding of the immunopathogenetic basis of immune activation in irAEs is required in order to select therapy that is likely to be the most effective. This is the first report investigating parallel blood, ST and SF in ICI-induced severe rheumatic irAE. Use of a bDMARD directed by the dominant inflammatory cytokine achieved resolution of synovitis while maintaining cancer remission.

The use of a risk assessment and decision support tool (CRISP) compared with usual care in general practice to increase risk-stratified colorectal cancer screening: study protocol for a randomised controlled trial.

BACKGROUND: Australia and New Zealand have the highest incidence rates of colorectal cancer worldwide. In Australia there is significant unwarranted variation in colorectal cancer screening due to low uptake of the immunochemical faecal occult blood test, poor identification of individuals at increased risk of colorectal cancer, and over-referral of individuals at average risk for colonoscopy. Our pre-trial research has developed a novel Colorectal cancer RISk Prediction (CRISP) tool, which could be used to implement precision screening in primary care. This paper describes the protocol for a phase II multi-site individually randomised controlled trial of the CRISP tool in primary care. METHODS: This trial aims to test whether a standardised consultation using the CRISP tool in general practice (the CRISP intervention) increases risk-appropriate colorectal cancer screening compared to control participants who receive standardised information on cancer prevention. Patients between 50 and 74 years old, attending an appointment with their general practitioner for any reason, will be invited into the trial. A total of 732 participants will be randomised to intervention or control arms using a computer-generated allocation sequence stratified by general practice. The primary outcome (risk-appropriate screening at 12 months) will be measured using baseline data for colorectal cancer risk and objective health service data to measure screening behaviour. Secondary outcomes will include participant cancer risk perception, anxiety, cancer worry, screening intentions and health service utilisation measured at 1, 6 and 12 months post randomisation. DISCUSSION: This trial tests a systematic approach to implementing risk-stratified colorectal cancer screening in primary care, based on an individual's absolute risk, using a state-of-the-art risk assessment tool. Trial results will be reported in 2020. TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry, ACTRN12616001573448p . Registered on 14 November 2016.

'Why don't I need a colonoscopy?' A novel approach to communicating risks and benefits of colorectal cancer screening.

BACKGROUND AND OBJECTIVES: There is significant growth in demand for colonoscopies, with over 700,000 performed in Australia in 2012-13. For every one million Australians aged 50 years and older, 80,000 people at average risk of colorectal cancer are being over-screened with colonoscopy, and 29,000 people at increased risk are not having the colonoscopy they need. METHOD: Using monitoring data from the Australian National Bowel Cancer Screening Program and published data on colonoscopic screening, we have developed expected frequency trees (EFTs) to demonstrate projected outcomes of different colorectal cancer screening options for participants at different levels of colorectal cancer risk in Australia. RESULTS: The EFTs highlight the overall balance in favour of faecal occult blood screening for those at average risk in terms of fewer deaths and complications. DISCUSSION: This novel method of risk communication can be used to promote appropriate patient choice of colorectal cancer screening modality and potentially reduce the number of referrals for colonoscopy in patients who are not at increased risk of colorectal cancer.

The CRISP-Q study: Communicating the risks and benefits of colorectal cancer screening

Background and objectives: Many Australians at average risk of colorectal cancer (CRC) are undergoing unnecessary colonoscopic screening, while many at increased risk are getting inadequate screening. The aim of this study was to test different ways of communicating the risks and benefits of CRC screening, as part of the development of a CRC risk prediction (CRISP) tool. Method: General practice patients were shown five different risk presentations for hypothetical 'average' and 'increased' risk cases and were asked to choose the screening method they would undergo. Associations were explored between risk presentation type and 'risk-appropriate screening' choice. Results: All risk formats were associated with improved risk-appropriate screening by participants (n = 204); however, there was a statistical trend favouring absolute risk with a government recommendation and an 'expected frequency tree'. The icon array was most weakly associated with appropriate screening. Discussion: This research will inform approaches to communicating risk in CRISP and may be of wider relevance to supporting informed decisions about cancer screening.

A Treat-to-Target Strategy Preserves Work Capacity in a Rheumatoid Arthritis Inception Cohort Treated With Combination Conventional DMARD Therapy.

OBJECTIVES: Quantification of work disability in patients with early rheumatoid arthritis (RA) receiving conventional DMARDs according to a treat-to-target strategy. METHODS: This is a retrospective cohort analysis of RA patients who received combination conventional DMARDs, escalated to achieve DAS28(ESR) remission and completed an annual work and arthritis questionnaire. Random effect mixed modeling was used to assess associations between average hours worked per week (HWPW), and baseline prognostic factors. HWPW were compared with matched population averages. Cox proportional hazards modeling was employed to evaluate associations between permanent loss of employment and treatment response, disease and demographic factors. RESULTS: Work data from 135 patients working at baseline and 137 working at any point followed for up to 14 years (range 1-14) were available for analysis. The mean age was 45 years, 70% were female, and 70% and 68% were seropositive for rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP), respectively. Men worked more hours than women; there was a highly significant association between working hours lost and increasing age (0.28 hours, P = 0.04) and female gender (11.92 hours, P < 0.001). HWPW were maintained over the study time comparable to the general population (loss of 0.78 vs. 0.24 HWPW). EULAR good responders at 6 months were more likely to be working at 10 years compared to those with moderate/no response. Permanent loss of employment and baseline age were strongly associated for anti-CCP positive participants (P = 0.04). CONCLUSIONS: Treat-to-target combination conventional DMARD therapy maintains work capacity, particularly in good responders, comparable to the general population. Improving treatment response in moderate/no responders early in disease may increase work retention.

The CRISP colorectal cancer risk prediction tool: an exploratory study using simulated consultations in Australian primary care.

BACKGROUND: In Australia, screening for colorectal cancer (CRC) with colonoscopy is meant to be reserved for people at increased risk, however, currently there is a mismatch between individuals' risk of CRC and the type of CRC screening they receive. This paper describes the development and optimisation of a Colorectal cancer RISk Prediction tool ('CRISP') for use in primary care. The aim of the CRISP tool is to increase risk-appropriate CRC screening. METHODS: CRISP development was informed by previous experience with developing risk tools for use in primary care and a systematic review of the evidence. A CRISP prototype was used in simulated consultations by general practitioners (GPs) with actors as patients. GPs were interviewed to explore their experience of using CRISP, and practice nurses (PNs) and practice managers (PMs) were interviewed after a demonstration of CRISP. Transcribed interviews and video footage of the 'consultations' were qualitatively analyzed. Themes arising from the data were mapped onto Normalization Process Theory (NPT). RESULTS: Fourteen GPs, nine PNs and six PMs were recruited from 12 clinics. Results were described using the four constructs of NPT: 1) Coherence: Clinicians understood the rationale behind CRISP, particularly since they were familiar with using risk tools for other conditions; 2) Cognitive participation: GPs welcomed the opportunity CRISP provided to discuss healthy and unhealthy behaviors with their patients, but many GPs challenged the screening recommendation generated by CRISP; 3) Collective Action: CRISP disrupted clinician-patient flow if the GP was less comfortable with computers. GP consultation time was a major implementation barrier and overall consensus was that PNs have more capacity and time to use CRISP effectively; 4) Reflexive monitoring: Limited systematic monitoring of new interventions is a potential barrier to the sustainable embedding of CRISP. CONCLUSIONS: CRISP has the potential to improve risk-appropriate CRC screening in primary care but was considered more likely to be successfully implemented as a nurse-led intervention.

The role of asymmetric dimethylarginine alone and in combination with N-terminal pro-B-type natriuretic peptide as a screening biomarker for systemic sclerosis-related pulmonary arterial hypertension: a case control study.

OBJECTIVES: Asymmetric dimethylarginine (ADMA) is a novel biomarker of endothelial cell dysfunction. In this proof of concept study, we sought to evaluate the role of ADMA as a screening biomarker for incident systemic sclerosis-related pulmonary arterial hypertension (SSc-PAH). METHODS: ADMA levels were measured using high performance liquid chromatography in 15 consecutive treatment-naive patients with newly-diagnosed SSc-PAH and compared with 30 SSc-controls without PAH. Logistic regression models were used to evaluate the independent association of ADMA with PAH. The optimal cut-point of ADMA for SSc-PAH screening was determined. NT-proBNP levels were previously measured in the same patients and the optimal cut-point of NT-proBNP of ≥210ng/mL was coupled with the optimal cut-point of ADMA to create a screening model that combined the two biomarkers. RESULTS: The PAH group had significantly higher mean ADMA levels than the control group (0.76±0.14 µM versus 0.59±0.07 µM; p<0.0001). ADMA levels remained significantly associated with PAH after the adjustment for specific disease characteristics, cardiovascular risk factors and other SSc-related vascular complications (all p<0.01). An ADMA level ≥0.7 µM had a sensitivity of 86.7%, specificity of 90.0% and AUC of 0.86 for diagnosing PAH. A screening model that combined an NT-proBNP ≥210ng/mL and/ or ADMA ≥0.7 ng/mL resulted in a sensitivity of 100% and specificity of 90% for the detection of SSc-PAH. CONCLUSIONS: In this small study, use of ADMA in combination with NT-proBNP produced excellent sensitivity and specificity for the non-invasive identification of SSc-PAH. The role of ADMA as a screening biomarker for SSc-PAH merits further evaluation.

Active Foot Synovitis in Patients With Rheumatoid Arthritis: Unstable Remission Status, Radiographic Progression, and Worse Functional Outcomes in Patients With Foot Synovitis in Apparent Remission.

OBJECTIVE: To determine whether foot synovitis is associated with adverse radiographic and functional outcomes after 3 years in an inception rheumatoid arthritis (RA) cohort receiving treat-to-target combination disease-modifying antirheumatic drug therapy. METHODS: Disease activity was assessed in early RA patients (n = 266) using the Disease Activity Score in 28 joints, Clinical Disease Activity Index (CDAI), and Simplified Disease Activity Index (SDAI). Radiographic outcomes were assessed with annual hand and feet radiographs and quality of life with the Short Form 36 (SF-36). The prevalence of remission and foot synovitis was calculated using marginal binomial generalized estimating equations, transition between remission and nonremission states by a multistate Markov model, and changes in radiographic scores by a negative binomial mixed regression log-link model. Population-matched SF-36 data were analyzed by mixed-effects linear regression. RESULTS: Disease activity scores that omit foot joints were modest in their ability to capture foot synovitis. Despite the relative stringency of the SDAI and CDAI for remission, 25-36% of patients in remission had foot synovitis. In patients in remission, foot synovitis predicted transition from remission into relapse by up to 2-fold. The sustainability of remission markedly influenced the progression of erosion scores (P = 0.006). After adjusting for disease activity, foot synovitis was associated with worse SF-36 physical functioning scores (P = 0.025). CONCLUSION: Disease activity measures that omit foot joints capture foot synovitis poorly. When it is used to define remission, foot synovitis is found in a substantial proportion of patients, which predicts relapse and worse physical function. Foot synovitis influences the sustainability of remission, which in turn markedly influences radiographic progression. Regardless of remission status, persistent foot synovitis should prompt therapy escalation in order to improve long-term outcomes.

The inclusion of N-terminal pro-brain natriuretic peptide in a sensitive screening strategy for systemic sclerosis-related pulmonary arterial hypertension: a cohort study.

INTRODUCTION: Pulmonary arterial hypertension (PAH) is a major cause of mortality in systemic sclerosis (SSc). Screening guidelines for PAH recommend multiple investigations, including annual echocardiography, which together have low specificity and may not be cost-effective. We sought to evaluate the predictive accuracy of serum N-terminal pro-brain natriuretic peptide (NT-proBNP) in combination with pulmonary function tests (PFT) ('proposed' algorithm) in a screening algorithm for SSc-PAH. METHODS: We evaluated our proposed algorithm (PFT with NT-proBNP) on 49 consecutive SSc patients with suspected pulmonary hypertension undergoing right heart catherisation (RHC). The predictive accuracy of the proposed algorithm was compared with existing screening recommendations, and is presented as sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). RESULTS: Overall, 27 patients were found to have pulmonary hypertension (PH) at RHC, while 22 had no PH. The sensitivity, specificity, PPV and NPV of the proposed algorithm for PAH was 94.1%, 54.5%, 61.5% and 92.3%, respectively; current European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines achieved a sensitivity, specificity, PPV and NPV of 94.1%, 31.8%, 51.6% and 87.5%, respectively. In an alternate case scenario analysis, estimating a PAH prevalence of 10%, the proposed algorithm achieved a sensitivity, specificity, PPV and NPV for PAH of 94.1%, 54.5%, 18.7% and 98.8%, respectively. CONCLUSIONS: The combination of NT-proBNP with PFT is a sensitive, yet simple and non-invasive, screening strategy for SSc-PAH. Patients with a positive screening result can be referred for echocardiography, and further confirmatory testing for PAH. In this way, it may be possible to shift the burden of routine screening away from echocardiography. The findings of this study should be confirmed in larger studies.

A tale of two trails: exploring different paths to success.

BACKGROUND: This comparative case study investigates 2 successful community trail initiatives, using the Active Living By Design (ALBD) Community Action Model as an analytical framework. The model includes 5 strategies: preparation, promotion, programs, policy, and physical projects. METHODS: Key stakeholders at 2 sites participated in in-depth interviews (N=14). Data were analyzed for content using Atlas Ti and grouped according to the 5 strategies. RESULTS: PREPARATION: Securing trail resources was challenging, but shared responsibilities facilitated trail development. PROMOTIONS: The initiatives demonstrated minimal physical activity encouragement strategies. PROGRAMS: Community stakeholders did not coordinate programmatic opportunities for routine physical activity. POLICY: Trails' inclusion in regional greenway master plans contributed to trail funding and development. Policies that were formally institutionalized and enforced led to more consistent trail construction and safer conditions for users. PHYSICAL PROJECTS: Consistent standards for wayfinding signage and design safety features enhanced trail usability and safety. CONCLUSIONS: Communities with different levels of government support contributed unique lessons to inform best practices of trail initiatives. This study revealed a disparity between trail development and use-encouragement strategies, which may limit trails' impact on physical activity. The ALBD Community Action Model provided a viable framework to structure cross-disciplinary community trail initiatives.

Discordance between patient and physician assessments of disease severity in systemic sclerosis.

OBJECTIVE: To describe the magnitude and correlates of discordance between patient and physician assessments of disease severity in patients with systemic sclerosis (SSc). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

The association between disease activity and duration in systemic sclerosis.

OBJECTIVE: The absence of a standardized disease activity index has been an important barrier in systemic sclerosis (SSc) research. We applied the newly derived Valentini Scleroderma Disease Activity Index (SDAI) among our cohort of patients with SSc to document changes in disease activity over time and to assess possible differences in activity between limited and diffuse disease. METHODS: Cross-sectional study of a national cohort of patients enrolled in the Canadian Scleroderma Research Group Registry. Disease activity was measured using the SDAI. Depression scores were measured using the Centre for Epidemiologic Studies Depression Scale (CES-D). RESULTS: A total of 326 out of 639 patients had complete datasets at the time of this analysis; 87% were female, of mean age 55.6 years, with mean disease duration 14.1 years. SDAI declined steeply in the first 5 years after disease onset and patients with diffuse disease had 42% higher SDAI scores than patients with limited disease with the same disease duration and depression scores (standardized relative risk 1.42, 95% CI 1.21, 1.65). Patients with higher CES-D scores had higher SDAI scores relative to patients with the same disease duration and disease subset (standardized RR 1.22, 95% CI 1.14, 1.31). Among the 10 components that make up the SDAI, only skin score (standardized OR 0.59, 95% CI 0.43, 0.82) and patient-reported change in skin (standardized OR 0.64, 95% CI 0.45, 0.92) decreased with increasing disease duration. High skin scores (standardized OR 32.2, 95% CI 15.8, 72.0) were more likely and scleredema (standardized OR 0.58, 95% CI 0.37, 0.92) was less likely to be present in patients with diffuse disease. High depression scores were associated with positive responses for patient-reported changes in skin and cardiopulmonary function. CONCLUSION: Disease activity declined with time and patients with diffuse disease had consistently higher SDAI scores. Depression was found to be associated with higher patient activity scores and strongly associated with patient self-response questions. The role of depression should be carefully considered in future applications of the SDAI, particularly as several components of the score rely upon patient recall.

Hypocomplementemia in systemic sclerosis--clinical and serological correlations.

OBJECTIVE: Although complement fixation is not commonly thought to be part of the pathogenesis of systemic sclerosis (SSc), hypocomplementemia has been associated with SSc. We hypothesized that hypocomplementemia in SSc might indicate the presence of overlap disease. We investigated if SSc patients with hypocomplementemia had more features of overlap disease than those with normal complement levels. METHODS: Study subjects consisted of those enrolled in the Canadian Scleroderma Research Group Registry. Patients were divided into 2 groups: those with normal complement levels (normal C3 and C4) and those with hypocomplementemia (low C3 or C4). Evidence of overlap disease was defined as physician reports of other specific rheumatic conditions. Autoantibodies were assayed. Differences in rates of concomitant diseases and in antibody profiles were compared between groups. RESULTS: Our study included 321 patients (88% women, mean age 56 +/- 13 yrs, mean disease duration 11 +/- 9 yrs). Of these, 276 (86%) had normal complements and 45 (14%) had hypocomplementemia. Patients with hypocomplementemia were significantly more likely to have physician-reported inflammatory myositis (27% vs 12%; p < 0.008) and vasculitis (11% vs 2%; p < 0.011) than those with normal complement. There was also a trend toward more antichromatin antibodies (18% vs 9%; p = 0.051) in patients with hypocomplementemia compared to normals. CONCLUSION: Hypocomplementemia may identify a particular subgroup of SSc patients who have overlap disease.

Update on autoantibodies in systemic sclerosis.

PURPOSE OF REVIEW: This is a review of autoantibodies described in systemic sclerosis with an emphasis on recently published studies. In the past, most, if not all of the discussion on this topic focused on antinuclear antibodies, but it is now appreciated that autoantibodies to cytoplasmic, cell surface, intercellular and plasma components are also important in the context of systemic sclerosis. RECENT FINDINGS: A number of recent studies have highlighted the disease associations of autoantibodies and the potential pathogenic role of the more traditional autoantibodies, such as antitopoisomerase I and anticentromere antibodies. The recent identification of autoantibodies directed to the platelet-derived growth factor receptor is of particular interest because of its possible association with the pathogenesis of systemic sclerosis. SUMMARY: Autoantibodies in systemic sclerosis are associated with demographic, diagnostic, pathological, and prognostic features of the disease. Emerging research on the pathogenic roles of newer autoantibodies provides valuable insights into disease pathogenesis and potential therapeutic targets.