Background: Survival of scleroderma has changed since the renal crisis treatment has become possible. Aims: To document the changes in survival and organ system causes of mortality in systemic ...sclerosis (SSc) over the past 25 years in patients from a single medical centre. Methods: Consecutive patients evaluated at the University of Pittsburgh, Pittsburgh, Pennsylvania, USA between 1 January 1972 and 31 December 1996 were studied. Survival was determined in five 5-year time periods between 1972 and 1997. Causes of death included scleroderma-related (scleroderma renal crisis, pulmonary arterial hypertension, pulmonary fibrosis (PF), gastrointestinal (GI), heart and multiorgan failure) and non-scleroderma-related (cancer, atherosclerotic cardiovascular or cerebrovascular disease, infection, sudden death, other and unknown) causes. Results: The 10-year survival improved steadily from 54% to 66% during each of the time intervals. There was a significant improvement in survival for patients during 1982–91 compared with those during 1972–81 (p<0.001), even when patients with renal crisis were excluded (p<0.005). The frequency of deaths due to renal crisis significantly decreased over the 30-year time period, from 42% to 6% of scleroderma-related deaths (p<0.001), whereas the proportion of patients with scleroderma who died of PF increased from 6% to 33% (p<0.001). The frequency of pulmonary hypertension, independent of PF, also significantly increased during this time period (p<0.05). There were no changes in scleroderma GI- and heart-related deaths, nor in any of the non-scleroderma-related causes, although patients with scleroderma were less likely to die from scleroderma-related problems in the past 15 years. Conclusion: The change in the pattern of scleroderma-related deaths over the past 30 years demonstrates that the lung (both pulmonary hypertension and PF) is the primary cause of scleroderma-related deaths today. It is important that aggressive searches continue to develop better therapies for these severe pulmonary complications of SSc.
Objective. To develop and assess the psychometric properties of the Localized Scleroderma (LS) Skin Damage Index (LoSDI) and Physician Global Assessment of disease Damage (PGA-D). Methods. Damage was ...defined as irreversible/persistent changes (>6 months) due to previous active disease/complications of therapy. Eight rheumatologists assessed the importance of 17 variables in formulating the PGA-D/LoSDI. LS patients were evaluated by two rheumatologists using both tools to assess their psychometric properties. LoSDI was calculated by summing three scores for cutaneous features of damage dermal atrophy (DAT), subcutaneous atrophy (SAT) and dyspigmentation (DP) measured at 18 anatomic sites. Patient GA of disease severity (PtGA-S), Children's Dermatology Life Quality Index (CDLQI) and PGA-D were recorded at the time of each examination. Results. Thirty LS patients (112 lesions) and nine patient-visit pairs (18 lesions) were included for inter- and intra-rater reliability study. LoSDI and its domains DAT, SAT, DP and PGA-D demonstrated excellent inter- and intra-rater reliability (reliability coefficients 0.86–0.99 and 0.74–0.96, respectively). LoSDI correlated moderately with PGA-D and poorly with PtGA-S and CDLQI. PGA-D correlated moderately with PtGA-S, but poorly with CDLQI. Conclusions. To complete the LS Cutaneous Assessment Tool (LoSCAT), we developed and evaluated the psychometric properties of the LoSDI and PGA-D in addition to the LS Skin Severity Index (LoSSI). These instruments will facilitate evaluation of LS patients for individual patient management and clinical trials. LoSDI and PGA-D demonstrated excellent reliability and high validity. LoSCAT provides an improved understanding of LS natural history. Further study in a larger group of patients is needed to confirm these preliminary findings.
Ischaemic digital ulcers (DUs) are common in patients with systemic sclerosis (SSc) and are a cause of disease-related morbidity. In an earlier trial, treatment with bosentan, an oral endothelin ...receptor antagonist, reduced the occurrence of new DUs by 48%. The present study (RAPIDS-2, for 'RAndomized, double-blind, Placebo-controlled study with bosentan on healing and prevention of Ischemic Digital ulcers in patients with systemic Sclerosis') was conducted to more fully evaluate the effects of bosentan treatment on DUs associated with SSc.
This double-blind, placebo-controlled trial conducted at 41 centres in Europe and North America randomised 188 patients with SSc with at least 1 active DU ('cardinal ulcer') to bosentan 62.5 mg twice daily for 4 weeks and 125 mg twice daily thereafter for 20 weeks (n=98) or matching placebo (n=90; total 24 weeks). The two primary end points were the number of new DUs and the time to healing of the cardinal ulcer. Secondary end points included pain, disability and safety.
Over 24 weeks, bosentan treatment was associated with a 30% reduction in the number of new DUs compared with placebo (mean ± standard error: 1.9±0.2 vs 2.7±0.3 new ulcers; p=0.04). This effect was greater in patients who entered the trial with more DUs. There was no difference between treatments in healing rate of the cardinal ulcer or secondary end points of pain and disability. Peripheral oedema and elevated aminotransferases were associated with bosentan treatment.
Bosentan treatment reduced the occurrence of new DUs in patients with SSc but had no effect on DU healing. Bosentan was well tolerated and may be a useful adjunct in the management of patients with SSc with recurrent DUs.
Objective
To assess cumulative survival rates and identify independent predictors of mortality in patients with incident systemic sclerosis (SSc)–associated pulmonary arterial hypertension (PAH) who ...had undergone routine screening for PAH at SSc centers in the US.
Methods
The Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma registry is a prospective registry of SSc patients at high risk for PAH or with definite pulmonary hypertension diagnosed by right‐sided heart catheterization within 6 months of enrollment. Only patients with World Health Organization group I PAH (mean pulmonary artery pressure ≥25 mm Hg and pulmonary capillary wedge pressure ≤15 mm Hg without significant interstitial lung disease) were included in these analyses.
Results
In total, 131 SSc patients with incident PAH were followed for a mean ± SD of 2.0 ± 1.4 years. The 1‐, 2‐, and 3‐year cumulative survival rates were 93%, 88%, and 75%, respectively. On multivariate analysis, age >60 years (hazard ratio HR 3.0, 95% confidence interval 95% CI 1.1–8.4), male sex (HR 3.9, 95% CI 1.1–13.9), functional class (FC) IV status (HR 6.5, 95% CI 1.8–22.8), and diffusing capacity for carbon monoxide (DLco) <39% predicted (HR 4.2, 95% CI 1.3–13.8) were significant predictors of mortality.
Conclusion
This is the largest study describing survival in patients with incident SSc‐associated PAH followed up at multiple SSc centers in the US who had undergone routine screening for PAH. The survival rates were better than those reported in other recently described SSc‐associated PAH cohorts. Severely reduced DLco and FC IV status at the time of PAH diagnosis portended a poor prognosis in these patients.
To develop and evaluate a Localized Scleroderma (LS) Skin Severity Index (LoSSI) and global assessments' clinimetric property and effect on quality of life (QOL).
A 3-phase study was conducted. The ...first phase involved 15 patients with LS and 14 examiners who assessed LoSSI surface area (SA), erythema (ER), skin thickness (ST), and new lesion/extension (N/E) twice for inter/intrarater reliability. Patient global assessment of disease severity (PtGA-S) and Children's Dermatology Life Quality Index (CDLQI) were collected for intrarater reliability evaluation. The second phase was aimed to develop clinical determinants for physician global assessment of disease activity (PhysGA-A) and to assess its content validity. The third phase involved 2 examiners assessing LoSSI and PhysGA-A on 27 patients. Effect of training on improving reliability/validity and sensitivity to change of the LoSSI and PhysGA-A was determined.
Interrater reliability was excellent for ER intraclass correlation coefficient (ICC) 0.71, ST (ICC 0.70), LoSSI (ICC 0.80), and PhysGA-A (ICC 0.90) but poor for SA (ICC 0.35); thus, LoSSI was modified to mLoSSI. Examiners' experience did not affect the scores, but training/practice improved reliability. Intrarater reliability was excellent for ER, ST, and LoSSI (Spearman's rho = 0.71-0.89) and moderate for SA. PtGA-S and CDLQI showed good intrarater agreement (ICC 0.63 and 0.80). mLoSSI correlated moderately with PhysGA-A and PtGA-S. Both mLoSSI and PhysGA-A were sensitive to change following therapy.
mLoSSI and PhysGA-A are reliable and valid tools for assessing LS disease severity and show high sensitivity to detect change over time. These tools are feasible for use in routine clinical practice. They should be considered for inclusion in a core set of LS outcome measures for clinical trials.
To examine the association of skin thickness progression rate (STPR) with mortality, and as a predictor of future internal organ involvement in an inception cohort of diffuse cutaneous systemic ...sclerosis (SSc) patients.
Diffuse cutaneous SSc patients older than 16 years of age evaluated at the University of Pittsburgh within 2 years of the first evidence of skin thickening between 1980 and 2005 were eligible. The authors calculated the STPR on these patients, and examined the relationship of this variable to the development of early internal organ involvement and short-term mortality using logistic regression.
826 patients were included in the analysis. Patients with a rapid STPR experienced significantly reduced short-term survival at 1 and 2 years from the time of first Pittsburgh evaluation (p=0.002). Patients with a rapid STPR were more likely to develop renal crisis within 1-2 years of follow-up. Rapid STPR was found to be an independent predictor of both mortality (OR 1.72; 95% CI 1.13 to 2.62; p=0.01) and 'renal crisis' (OR 2.05, 95% CI 1.10 to 3.85; p=0.02) within 2 years from first evaluation.
The STPR is an easy measure to perform at the time of initial evaluation for identifying those diffuse cutaneous SSc patients who are at increased risk of mortality and the development of renal crisis during the following 2 years.
Loss of CD28 expression by CD8+ T cells occurs with age and during chronic inflammatory conditions. CD8+CD28– T cells are a heterogeneous cell subpopulation whose function ranges from ...immunosuppressive to effector. Here we analyzed the role of CD8+CD28– T cells in the pathogenesis of systemic sclerosis (SSc), a connective tissue disorder characterized by autoimmunity, vasculopathy, and extensive cutaneous and visceral fibrosis. We show that the frequency of CD8+CD28– T cells is increased in the blood and affected skin of SSc patients, independent of patient age, and correlates with the extent of skin fibrosis. We found that most skin-tropic CD8+CD28– T cells are resident in the skin lesions of patients in the early stage of the disease, exhibit an effector memory phenotype, and present a strong cytolytic activity ex vivo. Skin-resident and circulating SSc CD8+CD28– T cells produce high levels of the profibrotic cytokine IL-13, which induces collagen production by normal and SSc dermal fibroblasts. Thus, our findings indicate that CD8+CD28– T cells represent a pathogenic T-cell subset in SSc and likely play a critical role in the early stage of SSc skin disease.
Systemic sclerosis (SSc) is a female-predominant disease, characterized by excessive extracellular matrix deposition (ECM) with dermal and internal organ fibrosis. Considering the sex-based disparity ...in disease incidence, estradiol (E2), an estrogen form with pro-fibrotic effects, may play a role in SSc. We reported that post-menopausal women with diffuse cutaneous (dc)SSc have higher serum E2 levels compared to similar aged, healthy controls. Since males with SSc tend to have more severe disease, we examined serum E2 in dcSSc males in relation to disease characteristics and survival.
We measured serum E2 in 83 dcSSc men > 50 years old from the University of Pittsburgh Scleroderma Center and similar aged healthy controls. Using statistical modeling, we examined the associations between serum E2, internal organ involvement, autoantibody profiles, and survival.
Male dcSSc patients had significantly higher serum E2 levels compared to healthy males and similar aged dcSSc post-menopausal women. Male dcSSc patients with high serum E2 had significantly more heart involvement, a trend for higher skin thickness progression rate, and worse survival. Using Cox regression modeling, increased serum E2 levels in anti-Scl-70 antibody-positive dcSSc males were associated with an increased risk of death.
dcSSc males > 50 years old have higher levels of serum E2 compared to healthy controls and dcSSc post-menopausal women. Elevated serum E2 levels in dcSSc males are associated with heart involvement, trend to progression of dermal fibrosis, and, if anti-Scl-70 antibody positive, worse survival. Our study expands on previous work implicating E2 in dermal fibrosis in SSc and associates E2 levels with internal organ involvement and survival. These data suggest a role for estrogen imbalance in dcSSc.
Gerald P Rodnan Steen, Virginia D; Medsger, Thomas A
Rheumatic diseases clinics of North America,
02/2024, Letnik:
50, Številka:
1
Journal Article
Recenzirano
Dr Gerald Rodnan was a man of many talents who developed a single-minded fascination with the disease systemic sclerosis. His passion and vision led to numerous important research contributions to ...our understanding of the natural history of this disease and his extensive travel and teaching stimulated many other investigators in the United States and throughout the world to devote their careers to this uncommon but serious disorder. He indeed was a "Giant" in rheumatology and those of us who had the opportunity to train under him have been inspired to carry it forward.
Objective
To identify and characterize a novel systemic sclerosis (SSc)–related autoantibody directed against a complex consisting of RuvBL1 and RuvBL2 (RuvBL1/2) and to assess its clinical ...correlations.
Methods
We first analyzed 316 consecutive patients with SSc who were evaluated at Kanazawa University Hospital. Controls included 290 patients with other connective tissue diseases, interstitial lung disease alone, or autoimmune hepatitis, and 50 healthy subjects. Autoantibody specificities were analyzed using RNA and protein immunoprecipitation assays. Autoimmune targets were affinity purified using patients' sera and subjected to liquid chromatography mass spectrometry. SSc patients in another institution in Japan and the University of Pittsburgh cohort were also included in analysis for evaluating clinical correlations.
Results
By protein immunoprecipitation assay, 6 SSc sera (1.9%) reacted with doublets with molecular weights of ∼50 kd. Liquid chromatography mass spectrometry of the partially purified autoantigen and additional immunoblot‐based analyses revealed that this antibody specificity recognized RuvBL1/2. Anti‐RuvBL1/2 antibody was exclusively detected in SSc patients. SSc patients with anti‐RuvBL1/2 in both the Japanese and Pittsburgh cohorts consistently had higher frequencies of SSc in overlap with myositis and diffuse skin thickening than those without anti‐RuvBL1/2. Compared with other autoantibodies related to SSc/myositis overlap (anti–PM‐Scl and anti‐Ku), anti‐RuvBL1/2 was distinctive in terms of its associations with older age at SSc onset, male sex, and a high frequency of diffuse cutaneous involvement.
Conclusion
Anti‐RuvBL1/2 antibody is a novel SSc‐related autoantibody associated with a unique combination of clinical features, including myositis overlap and diffuse cutaneous involvement.
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