SSc is known as the most severe connective tissue disorder, and to be associated with a high mortality risk. Some improvements in therapy for SSc have been achieved in recent years and some ...preliminary data have suggested an improvement in patient survival. Thus, we set out to determine whether mortality rate in SSc patients has decreased over the past 40 years through a meta-analysis of cohort studies.
We performed a systematic review and a meta-analysis of literature in MEDLINE and Embase databases from January 1960 to June 2010. All cohort studies reporting on SSc mortality were analysed. We then calculated pooled standardized mortality ratios (SMRs) of SSc mortality and calculated their changes over time using meta-regression analysis.
Nine studies were included, corresponding to a total of 2691 SSc patients. The pooled SMR was 3.53 95% CI 3.03, 4.11, P < 0.0001; I(2 )= 93%, P(het) = 0.001. Mid-cohort year ranged from 1977 to 1995 (before 1980: two studies; 1980-90: five studies; and after 1990: two studies): adjusted meta-regression analysis did not show significant change in SMR over time (P = 0.523). Among 732 deaths, heart involvement was the most frequent cause of deaths (29%) followed by lung involvement.
Our results confirm that SSc is a devastating condition as reflected by a pooled SMR of 3.5. Additionally, SMR has not significantly changed over the past 40 years. Further studies are needed to assess the effect of the most recent available therapies on mortality in SSc.
To determine the predictive value of functional autoantibodies against vascular receptors for the development of ischemic digital ulcers (DU) in patients with systemic sclerosis (SSc).
Angiotensin II ...Type 1 receptor (AT1R) and endothelin 1 Type A receptor (ETAR) autoantibodies were measured at baseline in a prospective cohort of 90 patients with SSc together with 5 validated angiogenic markers. The primary outcome was the occurrence of at least 1 new ischemic DU during the 5-year followup.
Twenty-four patients developed at least 1 new DU during the followup period. Univariate Cox analysis revealed that concentrations above the median value of anti-AT1R and anti-ETAR antibodies were predictive of the occurrence of ischemic DU (HR 2.85, 95% CI 1.19-6.84 and HR 3.39, 95% CI 1.35-8.50, respectively). A first multivariate Cox analysis including functional autoantibodies and clinical predictors of new DU confirmed anti-ETAR autoantibodies as independent predictors of the occurrence of new ischemic DU (HR 3.15, 95% CI 1.22-8.13) together with a history of DU at baseline. In a second model implemented with angiogenic markers, anti-ETAR autoantibodies remained an independent predictor of the occurrence of new ischemic DU (HR 9.59, 95% CI 1.75-52.64) together with the presence at baseline of active DU or history of DU.
Anti-ETAR autoantibodies can be used together with the presence of current or past DU to identify patients with SSc who are at risk for the development of subsequent DU. These autoantibodies may allow for earlier management and therapeutic intervention.
To measure the prevalence of different types of pulmonary hypertension (PH) and to identify patients with systemic sclerosis (SSc) at highest risk in a multicenter European sample, with a ...metaanalysis of relevant studies.
Consecutive patients with SSc recruited at 11 French and Italian centers underwent detailed evaluations, including Doppler echocardiography, chest computed tomography, pulmonary function tests, and right-heart catheterization (RHC), to detect the presence and causes of PH. A metaanalysis was performed, including data from 4 other studies.
Among 206 patients in whom it was suspected, PH was confirmed by RHC in 83 patients (7%). Precapillary PH was found in 64 patients (5%), of whom 42 had pulmonary arterial hypertension (PAH) and 22 had PH secondary to interstitial lung disease (ILD). RHC identified 17 patients (1%) with postcapillary PH secondary to left-heart disease. Patients with DLCO/alveolar volume < 70% were more likely to have precapillary PH (87.5% vs 42%; p < 0.0001). Precapillary and postcapillary PH were associated with advanced age (68 ± 14 vs 59 ± 12 yrs, p < 0.0001, and 74 ± 16 vs 61.5 ± 10 yrs, p < 0.0001, respectively). The metaanalysis of 3818 patients showed a prevalence of precapillary PH of 9% (95% CI 6%-12%) and identified advanced age, longer disease duration, and limited cutaneous disease subset as risk factors for this condition.
The prevalence of precapillary PH in our multicenter study of SSc was 5%, and in the metaanalysis 9%. Our observations support use of RHC to confirm the presence of precapillary PH suspected by noninvasive testing. We also identified patients at high risk who should be carefully monitored.
Objective
To measure plasma concentrations of high‐sensitivity cardiac troponin T (HS‐cTnT) and N‐terminal pro–brain natriuretic peptide (NT‐proBNP) in patients with systemic sclerosis (SSc; ...scleroderma) and age‐ and sex‐matched healthy control subjects, and to examine the contribution of traditional cardiovascular risk factors and SSc features to the concentrations of these 2 cardiac biomarkers.
Methods
Plasma HS‐cTnT and NT‐proBNP concentrations were measured using the electrochemiluminescence method and sandwich immunoassay, respectively.
Results
The study group comprised 161 unrelated patients with SSc and 213 matched control subjects. HS‐cTnT and NT‐proBNP plasma levels were significantly increased in SSc patients compared with controls (both P < 0.001). Similar results were observed in the subgroup of patients with SSc who had no cardiovascular risk factors (n = 72). Multivariate logistic regression analysis confirmed diabetes mellitus (P = 0.006), high blood pressure (P = 0.021), precapillary pulmonary hypertension (P = 0.039), and the diffuse cutaneous SSc (P = 0.004) as factors independently associated with an HS‐cTnT level of >14 ng/liter. Increased NT‐proBNP concentrations were associated only with the presence of precapillary pulmonary hypertension (P < 0.001). Normal concentrations of both HS‐cTnT and NT‐proBNP had a high negative predictive value for precapillary pulmonary hypertension (92%), and the combination of increased values of these 2 markers had the highest strength of association with precapillary pulmonary hypertension in logistic regression analysis.
Conclusion
HS‐cTnT and NT‐proBNP concentrations are increased in patients with SSc, even in those who are free of cardiovascular risk factors. These easily obtained biomarkers may be useful for systematic evaluation and stratification of SSc patients, especially to identify those at risk of pulmonary hypertension.
Abstract Objective To determine the merit of nailfold videocapillaroscopy (NVC) to detect meaningful microvascular changes over time in patients with systemic sclerosis (SSc) and whether these ...changes are associated with overall disease progression and organ involvements. Methods A prospective cohort of 140 SSc patients was recruited over a 12-month period and was followed up on an annual basis for 3 years. Detailed NVC analysis was performed at inclusion and repeated annually. Disease progression and organ damage were defined according to validated definitions. Results Significant NVC changes were detected in 72 SSc patients (51%) during the follow-up period. Patients with incident or increased number of giant capillaries were less at risk to develop new digital ulcers (DU) (Hazard Ratio, HR: 0.53, 95% confidence interval, CI: 0.07–0.93). Loss of capillaries over time was confirmed as a robust and independent marker of organ progression. The reduction of the number of capillaries was associated with overall disease progression (HR: 4.35, 95% CI 1.87–10.12), occurrence of new DU (HR: 5.33, 95% CI 1.69–16.71), lung vascular progression (HR: 18.53, 95% CI 1.28–78.33), progression of skin fibrosis (HR: 4.22, 95% CI 1.24–14.36) and worsening of the Medsger severity score (HR: 5.26, 95% CI 1.78–15.52). Conclusion Significant NVC changes are observed in almost half of patients with SSc during a follow-up of 3 years. Sequential NVC examinations have responsiveness to detect disease progression. Sequential NVC is confirmed of value to monitor SSc, as well as progressive loss of capillaries over time as a potential surrogate marker for disease progression.
Context:
It is unclear whether bone mineral density (BMD) improves in patients with normocalcemic primary hyperparathyroidism (PHPT) after parathyroidectomy (PTX).
Objective:
The objective of the ...study was to evaluate and compare the impact of PTX on BMD change at 1 year in normocalcemic vs hypercalcemic PHPT.
Design:
This was a longitudinal cohort study.
Setting:
The study took place at a referral center.
Patients:
We included 60 PHPT patients (mean age 64.0 ± 10.1 years), successfully treated by PTX by the same surgeon. Two groups were individualized according to baseline serum total (albumin corrected) calcium: 39 patients with normal baseline serum total calcium (normocalcemic group) and 21 patients with hypercalcemia at baseline (hypercalcemic group).
Main Outcome Measure:
BMD changes 1 year after PTX were measured.
Results:
In the normocalcemic group, BMD increased significantly by +2.3 ± 5.0% at the spine (P = .016) and +1.9 ± 5.7% at the hip (P = .048). In the hypercalcemic group, BMD increased significantly by +4.0 ± 3.8% at the spine (P = .0003) and +3.2 ± 4.2% at the hip (P = .003). There was no difference in these BMD gains between both groups (P > .1). The presence of multiple adenomas or hyperplasia was more frequent in the normocalcemic group than in the hypercalcemic group (P = .04).
Conclusion:
Our results indicate for the first time that successful PTX in normocalcemic PHPT patients with osteoporosis is followed with mild but significant BMD improvement at the spine and hip at 1 year, comparable with that observed in hypercalcemic PHPT, suggesting that PTX may be beneficial in normocalcemic PHPT.
Abstract Systemic sclerosis is an orphan connective tissue disease characterized by alterations of the microvasculature, disturbances of the immune system and massive deposition of collagen and other ...matrix substances in the skin and internal organs. A major achievement of the recent years has been the validation of new classification criteria, allowing earlier diagnosis and earlier treatment of systemic sclerosis, before irreversible fibrosis and organ damage appeared (“window of opportunity”). Raynaud's phenomenon is usually the first sign of the disease and is considered as the main sentinel sign for the identification of very early systemic sclerosis. Systemic sclerosis is clinically heterogeneous and disease course remains unpredictable. Its prognosis depends on cardiopulmonary involvement and recent studies aim to identify serum or genetic biomarkers predictive of severe organ involvement. Moreover, the prospective follow-up of large cohorts has provided and will offer critical material to identify strong prognostic factors. Whereas the outcomes of vascular manifestations of the disease has been recently improved due to targeted therapy, recent data have highlighted that mortality has not changed over the past 40 years. This reflects the absence of efficacy of current available drugs to counteract the fibrotic process. Nevertheless, several targeted immunity therapies, commonly with proven efficacy in other immune diseases, are about to be investigated in systemic sclerosis. Indeed, promising results in small and open studies have been reported. This article deals with recent insights into classification criteria, pathogenesis, organ involvements, outcome and current and possible future therapeutic options in systemic sclerosis.
Treatment for fibrosis represents a critical unmet need, because fibrosis is the leading cause of death in industrialized countries, and there is no effective therapy to counteract the fibrotic ...process. The development of fibrosis relates to the interplay between vessel injury, immune cell activation, and fibroblast stimulation, which can occur in various tissues. Immunotherapies have provided a breakthrough in the treatment of immune diseases. The glycoprotein OX40–OX40 ligand (OX40L) axis offers the advantage of a targeted approach to costimulatory signals with limited impact on the whole immune response. Using systemic sclerosis (SSc) as a prototypic disease,we report compelling evidence that blockade of OX40L is a promising strategy for the treatment of inflammation-driven fibrosis. OX40L is overexpressed in the fibrotic skin and serum of patients with SSc, particularly in patients with diffuse cutaneous forms. Soluble OX40L was identified as a promising serum biomarker to predict the worsening of lung and skin fibrosis, highlighting the role of this pathway in fibrosis. In vivo, OX40L blockade prevents inflammation-driven skin, lung, and vessel fibrosis and induces the regression of established dermal fibrosis in different complementary mouse models. OX40L exerts potent profibrotic effects by promoting the infiltration of inflammatory cells into lesional tissues and therefore the release of proinflammatory mediators, thereafter leading to fibroblast activation.
Summary Heart involvement, including primary myocardial involvement, is very common in systemic sclerosis. There is strong evidence that primary myocardial involvement is related to repeat focal ...ischaemic injury causing subsequent irreversible myocardial fibrosis. Clinically evident cardiac involvement is recognized to be a poor prognostic factor; thus preclinical identification is highly encouraged. The severity of heart involvement has been confirmed recently. Echocardiography, including pulsed tissue Doppler echocardiography, is the cornerstone of routine heart assessment. Myocardial perfusion may be assessed by single photon emission computed tomography. If available, cardiac magnetic resonance imaging should be considered as it allows simultaneous measurement of ventricular volumes and function and myocardial perfusion, and assessment of possible inflammation and/or fibrosis. Biological variables, such as B-type natriuretic peptides, are highly relevant, valuable markers of global heart involvement in systemic sclerosis and should be considered for screening of patients and/or research purposes.
Specific cardiac involvement in granulomatosis with polyangiitis (GPA) is probably underestimated since many of these conditions are subclinical. The objective of this study was to assess the ...prevalence and patterns of cardiac abnormalities detected by cardiac MRI (CMRI) in patients with GPA.
Thirty-one consecutive patients with newly diagnosed or relapsing GPA underwent CMRI to assess morphological, functional, perfusion at rest and delayed enhancement abnormalities.
At least one abnormality was observed on CMRI for 19 of 31 patients (61%). Four patients (13%) had an impaired left ventricle ejection fraction (LVEF). LV regional wall motion abnormalities were found in 11 patients (35%). Late gadolinium enhancement (LGE) was detected in 10 of 31 patients (32%). LGE was mostly nodular ( n = 9). Myocardial early contrast enhancement was detected in 5 of the 31 patients (16%), which was systematically associated with LGE in the same territory. CMRI detected pericarditis in eight patients (26%). GPA with <18 months duration was associated with a higher LVEF ( P = 0.03), fewer CMRI abnormalities ( P = 0.04) and less LV hypokinesia ( P = 0.04) than GPA with a longer duration. Patients with recent-onset GPA had a higher LVEF ( P = 0.01) and less LV hypokinesia ( P = 0.006) than patients experiencing a relapse ( P = 0.02).
CMR is an accurate technique for detecting heart involvement in GPA. This unique non-invasive technique may provide information with important clinical implications for the accurate early assessment of cardiac lesions in GPA patients and for detecting cumulative, irreversible damage. It may also have prognostic implications.
PDF
