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.
Objectives To assess the prevalence and characteristics of severe pyogenic, nonpyogenic, and opportunistic infections in polymyositis and dermatomyositis (PM/DM) patients and to evaluate the ...predictive values for infections on clinical presentation and biochemical findings of PM/DM to detect patients at risk for such infections. Methods The medical records of 279 consecutive PM/DM patients in 3 medical centers were reviewed. Results One hundred four severe infections occurred in our patients (37.3%), ie, pyogenic ( n = 71) and nonpyogenic/opportunistic infections ( n = 33). Pyogenic infections were mainly due to aspiration pneumonia ( n = 46) and calcinosis cutis infection. Thirty-three PM/DM patients developed nonpyogenic/opportunistic infections that were due to the following: Candida albicans , Pneumocystis jiroveci , Aspergillus fumigatus , Geotrichum capitatum , Mycobacterium ( avium-intracellulare complex, xenopi , marinum , peregrinum , tuberculosis ), Helicobacter heilmanii , cytomegalovirus, herpes simplex and zoster virus, hepatitis B and C, JC virus, Leishmania major , Strongyloides stercoralis . Esophageal dysfunction, ventilatory insufficiency, malignancy, and lymphopenia were significantly more frequent in the group of PM/DM patients with infections. Conclusion Our study underscores the high frequency of infections in PM/DM, resulting in an increased mortality rate. Our results suggest that prophylaxis against pyogenic infections should be routinely recommended for patients with PM/DM, including regular physical examination of lungs to depict aspiration pneumonia as well as risk factors of aspiration pneumonia. Finally, because a great variety of micro-organisms may be responsible for opportunistic infections, it seems difficult to initiate primary prophylaxis in PM/DM patients exhibiting risk factors for opportunistic infections.
Systemic sclerosis (SSc) is an orphan, complex, inflammatory disease affecting the immune system and connective tissue. SSc stands out as a severely incapacitating and life-threatening inflammatory ...rheumatic disease, with a largely unknown pathogenesis. We have designed a two-stage genome-wide association study of SSc using case-control samples from France, Italy, Germany, and Northern Europe. The initial genome-wide scan was conducted in a French post quality-control sample of 564 cases and 1,776 controls, using almost 500 K SNPs. Two SNPs from the MHC region, together with the 6 loci outside MHC having at least one SNP with a P<10(-5) were selected for follow-up analysis. These markers were genotyped in a post-QC replication sample of 1,682 SSc cases and 3,926 controls. The three top SNPs are in strong linkage disequilibrium and located on 6p21, in the HLA-DQB1 gene: rs9275224, P = 9.18×10(-8), OR = 0.69, 95% CI 0.60-0.79; rs6457617, P = 1.14×10(-7) and rs9275245, P = 1.39×10(-7). Within the MHC region, the next most associated SNP (rs3130573, P = 1.86×10(-5), OR = 1.36 1.18-1.56) is located in the PSORS1C1 gene. Outside the MHC region, our GWAS analysis revealed 7 top SNPs (P<10(-5)) that spanned 6 independent genomic regions. Follow-up of the 17 top SNPs in an independent sample of 1,682 SSc and 3,926 controls showed associations at PSORS1C1 (overall P = 5.70×10(-10), OR:1.25), TNIP1 (P = 4.68×10(-9), OR:1.31), and RHOB loci (P = 3.17×10(-6), OR:1.21). Because of its biological relevance, and previous reports of genetic association at this locus with connective tissue disorders, we investigated TNIP1 expression. A markedly reduced expression of the TNIP1 gene and also its protein product were observed both in lesional skin tissue and in cultured dermal fibroblasts from SSc patients. Furthermore, TNIP1 showed in vitro inhibitory effects on inflammatory cytokine-induced collagen production. The genetic signal of association with TNIP1 variants, together with tissular and cellular investigations, suggests that this pathway has a critical role in regulating autoimmunity and SSc pathogenesis.
Screening is important to determine whether patients with systemic sclerosis (SSc) have pulmonary hypertension because earlier pulmonary hypertension treatment can improve survival in these patients. ...Although decreased transfer factor of the lung for carbon monoxide (
) is currently considered the best pulmonary function test for screening for pulmonary hypertension in SSc, small series have suggested that partitioning
into membrane conductance (diffusing capacity) for carbon monoxide (
) and alveolar capillary blood volume (
) through combined measurement of
and transfer factor of the lung for nitric oxide (
) is more effective to identify pulmonary hypertension in SSc patients compared with
alone. Here, the objective was to determine whether combined
-
partitioned with recently refined equations could more accurately detect pulmonary hypertension than
alone in SSc.For that purpose, 572 unselected consecutive SSc patients were retrospectively recruited in seven French centres.Pulmonary hypertension was diagnosed with right heart catheterisation in 58 patients.
,
and
were all lower in SSc patients with pulmonary hypertension than in SSc patients without pulmonary hypertension. The area under the receiver operating characteristic curve for the presence of pulmonary hypertension was equivalent for
(0.82, 95% CI 0.79-0.85) and
(0.80, 95% CI 0.76-0.83), but lower for
(0.75, 95% CI 0.71-0.78) and
(0.66, 95% CI 0.62-0.70).Compared with
alone, combined
-
does not add capability to detect pulmonary hypertension in unselected SSc patients.
Myopathy related to systemic sclerosis (Myo-SSc) is a disabling and unpredictable complication of SSc. We assessed the predictive value of serum aldolase, creatine kinase (CK), alanine transaminase ...(ALT), aspartate transaminase (AST) and C-reactive protein (CRP) to estimate the risk of developing Myo-SSc.
We enrolled 137 SSc patients without proximal muscle weakness in a prospective monocentric study to follow them longitudinally over a four-year period. The risk of occurrence of Myo-SSc was ascertained according to the European NeuroMuscular Centre criteria and was analyzed according to levels of plasma aldolase, CK, transaminase enzymes and CRP at inclusion. Performance of each parameter to predict Myo-SSc occurrence was assessed and compared with the others.
The area under the receiver operating characteristic curves (ROC) of plasma aldolase for Myo-SSc occurrence prediction was 0.80 (95% CI: 0.67 to 0.94, P < 0.001), which was higher than that of plasma CK (0.75, P = 0.01), and that of ALT (0.63, P = 0.04). AST and CRP had no predictive value for Myo-SSc occurrence. The best cut-off of aldolase for prediction of Myo-SSc occurrence within three years after inclusion was 9 U/L and higher than the upper normality limit (7 U/L), unlike that of CK and ALT. Myo-SSc occurred more frequently in patients whose plasma aldolase was higher than 9 U/L. Adjusted Hazard Ratio for patients with aldolase > 9 U/L was 10.3 (95% CI: 2.3 to 45.5), P < 0.001.
Increased plasma aldolase level accurately identified SSc patients with high risk to develop subsequent Myo-SSc. This could help initiate appropriate treatment when the disabling muscle damage is still in a reversible stage.
Respiratory failure is a life-threatening and unpredictable complication of systemic sclerosis (SSc). A study was undertaken to assess the value of alveolar nitric oxide (NO) in predicting the risk ...of lung function deterioration leading to respiratory failure or death in patients with SSc.
105 patients with SSc were enrolled in this prospective cohort and were followed longitudinally over a 3-year period during which the risk of occurrence of deleterious events was analysed according to alveolar concentration (C(A)NO), conducting airway output (J'(aw)NO) and fractional concentration (F(E)NO(0.05)) of exhaled NO measured at inclusion. Comparison was made between each NO parameter to predict the occurrence of deleterious events, defined as a 10% decrease in total lung capacity or forced vital capacity from baseline, or death.
The area under the receiver operating characteristic curve of C(A)NO to predict the occurrence of the combined events was 0.84 (95% CI 0.76 to 0.92; p<0.001), which was significantly higher than those of J'(aw)NO and F(E)NO(0.05) (p<0.001). A cut-off of C(A)NO of 5.3 ppb had a sensitivity of 88% and a specificity of 62% for the prediction of the occurrence of combined events during follow-up, and was validated in an independent cohort of patients with SSc. Combined events occurred more frequently in patients whose C(A)NO was >5.3 ppb. The adjusted HR for patients with C(A)NO >5.3 ppb was 6.06 (95% CI 2.36 to 15.53; p<0.001). C(A)NO accurately predicted the occurrence of combined events irrespective of forced vital capacity values or the presence of interstitial lung disease at baseline.
Increased C(A)NO accurately identifies patients with SSc with a high risk of developing lung function deterioration and may help to initiate early appropriate treatment.
Background: Systemic sclerosis (SSc) is a connective-tissue disease characterized by vascular injury, immune-system disorders, and excessive fibrosis of the skin and multiple internal organs. Recent ...reports found that RhoA/Rho-kinase (ROCK) pathway is implicated in various fibrogenic diseases. Intradermal injection of hypochlorous acid (HOCl)-generating solution induced inflammation, autoimmune activation, and fibrosis, mimicking the cutaneous diffuse form of SSc in humans. Our study aimed firstly to describe pulmonary inflammation and fibrosis induced by HOCl in mice, and secondly to determine whether fasudil, a selective inhibitor of ROCK, could prevent lung and skin fibroses in HOCl-injected mice. Methods: Female C57BL/6 mice received daily intradermal injection of hypochlorous acid (HOCl) for 6 weeks to induce SSc, with and without daily treatment with fasudil (30 mg·kg
−1
·day
−1
) by oral gavage. Results: HOCl intoxication induced significant lung inflammation (macrophages and neutrophils infiltration), and fibrosis. These modifications were prevented by fasudil treatment. Simultaneously, HOCl enhanced ROCK activity in lung and skin tissues. Inhibition of ROCK reduced skin fibrosis, expression of α-smooth-muscle actin and 3-nitrotyrosine, as well as the activity of ROCK in the fibrotic skin of HOCl-treated mice, through inhibition of phosphorylation of Smad2/3 and ERK1/2. Fasudil significantly decreased the serum levels of anti-DNA-topoisomerase-1 antibodies in mice with HOCl-induced SSc. Conclusions: Our findings confirm HOCl-induced pulmonary inflammation and fibrosis in mice, and provide further evidence for a key role of RhoA/ROCK pathway in several pathological processes of experimental SSc. Fasudil could be a promising therapeutic approach for the treatment of SSc.
Digital ulcers are the most frequent vascular manifestations of systemic sclerosis (SSc). Clinical features of patients with prior or current digital ulcers have not been extensively described. This ...cross-sectional analysis of a large multicenter cohort compared the characteristics of SSc patients with prior or current digital ulcers with those never affected.
Patients with prior/current digital ulcers or never affected were identified in the cohort of SSc patients enrolled in the French ItinérAIR-Sclérodermie registry. Rodnan skin scores, pulmonary function test results, and clinical and immunological data were analyzed to identify digital ulcerassociated clinical features.
Of 599 SSc patients, 317 had prior or current digital ulcers. These patients were more frequently male, with impaired diffusing capacity for carbon monoxide (DLCO), and higher Rodnan skin scores than patients never affected by digital ulcers. In a multivariate analysis, male gender, early onset of SSc, increased duration of SSc, high Rodnan skin score, and presence of anti-topoisomerase I antibodies (anti-topo I) were associated with prior or current digital ulcers. Comparison of patients with current digital ulcers versus patients never affected indicated that affected patients had increased duration of SSc, impaired DLCO, increased Rodnan score, and younger age at onset of SSc.
Male patients with early onset SSc, more severe skin fibrosis, impaired DLCO, and anti-topo I were most likely to exhibit prior or current digital ulcers. Confirmation of these results in a prospective longitudinal study may enable identification of patients at greatest risk of developing digital ulcers, facilitating management of this disabling complication.
Fibrocytes are circulating precursors for fibroblasts. Blood fibrocytes are increased in patients with idiopathic pulmonary fibrosis (IPF). The aim of this study was to determine whether alveolar ...fibrocytes are detected in broncho-alveolar lavage (BAL), to identify their prognostic value, and their potential association with culture of fibroblasts from BAL.
We quantified fibrocytes in BAL from 26 patients with IPF, 9 patients with Systemic Sclerosis(SSc)-interstitial lung disease (ILD), and 11 controls. BAL cells were cultured to isolate alveolar fibroblasts.
Fibrocytes were detected in BAL in 14/26 IPF (54%) and 5/9 SSc patients (55%), and never in controls. Fibrocytes were in median 2.5% 0.4-19.7 and 3.0% 2.7-3.7 of BAL cells in IPF and SSc-ILD patients respectively. In IPF patients, the number of alveolar fibrocytes was correlated with the number of alveolar macrophages and was associated with a less severe disease but not with a better outcome. Fibroblasts were cultured from BAL in 12/26 IPF (46%), 5/9 SSc-ILD (65%) and never in controls. The detection of BAL fibrocytes did not predict a positive culture of fibroblasts.
Fibrocytes were detected in BAL fluid in about half of the patients with IPF and SSc-ILD. Their number was associated with less severe disease in IPF patients and did not associate with the capacity to grow fibroblasts from BAL fluid.
To assess the prevalence and potential associations with the systemic sclerosis (SSc) phenotype of additional autoimmune diseases (AID).
A multicenter study was performed in France and Italy to ...recruit consecutive European Caucasian patients with SSc systematically assessed for the coexistence of predefined AID known to occur with connective tissue diseases.
We recruited 585 French and 547 Italian patients with SSc. Specific AID were found in 114/585 (19%) French and 179/547 (33%) Italians with SSc (p < 0.0001). Sjögren's syndrome and thyroiditis were the predominant AID in both cohorts (12% for Sjögren's syndrome and 6% for thyroiditis in the combined populations). The frequency of myositis, primary biliary cirrhosis, rheumatoid arthritis, and systemic lupus erythematosus was low (< 4%) and similar in both cohorts. The coexistence of at least 1 of the AID in the whole cohort was associated in multivariate analysis with the limited cutaneous subtype, the presence of antinuclear antibodies, and a lower prevalence of digital ulcers.
Our study shows that 21% of this large series of European Caucasian patients with SSc have developed at least 1 AID. This latter condition identified a subset of patients with milder disease. Thus, associations of AID and autoimmune background in SSc have to be considered for further therapeutic and biological investigations in SSc.
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