Giovanna Cuomo

Inappropriate exercise-induced increase in pulmonary artery pressure in patients with systemic sclerosis

Background Recent data show that there is an unexpectedly high prevalence of ‘inappropriate’ pulmonary responses to exercise among patients with systemic sclerosis (SS). However, no consensus exists as to which threshold of pulmonary artery systolic pressure (PASP) can be considered diagnostically relevant. Aim To evaluate pulmonary vascular reserve and right ventricular function changes induced by exercise in SS patients without overt pulmonary arterial hypertension. Methods and results The study enrolled 172 consecutive SS patients in NYHA class I–II, with a peak tricuspid regurgitant jet velocity at echocardiography not greater than 3 m/s, and 88 control subjects. Echocardiography was performed at rest and at the end of a maximal exercise test. SS patients showed a higher exercise-induced PASP than control subjects (36.9±8.7 vs 25.9±3.3 mm Hg, p=0.00008). The response to effort was higher in the presence of moderate interstitial lung disease (39.7±9.3 vs 36.0±8.4 mm Hg, p=0.016) or subclinical left ventricular diastolic dysfunction (42.3±5.8 vs 37.0±8.6 mm Hg, p=0.015). In control subjects, PASP values were normally distributed at rest and after exercise. In SS patients, the distribution was normal at rest but bimodal after exercise, with a second peak at 52.2 mm Hg including 13% of the total SS population. Patients in this subgroup showed subtle abnormalities of right ventricular function at rest and, most importantly, a blunted increase in right ventricular systolic function with exercise. Conclusion Exercise echocardiography may identify a subset of SS patients with an inappropriate exercise-induced increase in PASP and early signs of right ventricular dysfunction.

To be or not to be, ten years after: evidence for mixed connective tissue disease as a distinct entity.

OBJECTIVES To determine if mixed connective tissue disease (MCTD) can be considered an independent clinical entity, to compare 3 different classification criteria for MCTD (Kasukawa, Alarcón-Segovia, and Sharp), and to define predictors (clinical features and autoantibodies) of potential evolution toward other connective tissue diseases (CTDs). METHODS One hundred sixty-one MCTD patients were evaluated retrospectively at the diagnosis and in 2008. They were classified, at the diagnosis, according to the 3 classification criteria of MCTD (Sharp, Alarcón-Segovia, and Kasukawa) and reclassified in 2008 according to their evolution. Statistical analyses were performed to find out predictors (clinical features and autoantibodies) of evolution into other CTDs. RESULTS After a mean of 7.9 years of disease, 57.9% of patients still satisfied MCTD classification criteria of Kasukawa; 17.3% evolved into systemic sclerosis, 9.1% into systemic lupus erythematosus, 2.5% into rheumatoid arthritis, 11.5% was reclassified as affected by undifferentiated connective tissue disease, and 1.7% as suffering from overlap syndrome. Kasukawas criteria were more sensitive (75%) in comparison to those of Alarcón-Segovia (73%) and Sharp (42%). The presence of anti-DNA antibodies (P = 0.012) was associated with evolution into systemic lupus erythematosus; hypomotility or dilation of esophagus (P < 0.001); and sclerodactyly (P = 0.034) with evolution into systemic sclerosis. CONCLUSIONS MCTD is a distinct clinical entity but it is evident that a subgroup of patients may evolve into another CTD during disease progression. Initial clinical features and autoantibodies can be useful to predict disease evolution.

Peripheral Blood T Lymphocytes from Systemic Sclerosis Patients Show Both Th1 and Th2 Activation

Our objective was to investigate the phenotype of helper T cells in the peripheral blood of patients with systemic sclerosis (SSc). PBMC from 15 patients with SSc and 15 sex- and age-matched controls were investigated for lymphocyte subpopulations (CD3, CD4, CD8, CD19, CD16/CD56, CD3-DR); IL-2, IL-4, and IFN-γ mRNAs; and the relative cytokines in their cytoplasm. The last assay was carried out both in unstimulated and in PMA-activated PBMC. SSc patients presented a higher percentage of activated T cells, CD3+ DR+ (19.7 ± 9.9 vs 5.1 ± 2.5%; P < 0.0001); 12 of them presented IFN-γ mRNA-positive cells; and none IL-2 or IL-4 mRNAs. Under basal conditions, PBMC from six SSc patients contained IL-2, IL-4, and IFN-γ (i.e., they showed both Th1 and Th2 activation), and 1 IFN-γ only. PMA-stimulated PBMC of patients differed from those of controls only in the increased percentage of IFN-γ positive cells (52 ± 12 vs 37 ± 11%; P < 0.01). Our study demonstrates that Th1 activation occurs in the peripheral blood of SSc patients. This evidence must be faced with from both a pathogenetic and a therapeutical point of view.

Ultrasonographic features of the hand and wrist in systemic sclerosis

OBJECTIVES To investigate ultrasonographic hand and wrist features in patients with SSc and their correlation with clinical and X-ray examinations. METHODS All the patients and controls underwent clinical examination, X-ray and ultrasonography (US) evaluations of the hands and wrists. Forty-five SSc patients all of whom satisfied the ACR criteria and 45 controls-15 patients with RA, 15 patients with FM syndrome and 15 healthy subjects were assessed. US was performed by a General Electric Logiq-5 PRO using a 7-12 MHz linear array transducer. RESULTS Joint effusion was found in 22 (49%) SSc patients; synovial proliferation in 19 (42%), which was associated with a power Doppler signal in 11 of them; marginal bone erosions in 5 (11%); joint space narrowing in 8 (18%); periarticular calcinosis in 12 (27%); and osteophytosis in 26 (59%). In SSc patients, the prevalence of synovitis as detected by US (i.e. effusion and/or synovial proliferation) was found to be significantly higher than that found by clinical examination (i.e. tenderness and/or swelling) (26 vs 15 out of 45 cases; P = 0.03). US indicated a significantly higher number of joints with osteophytes than X-rays (59 vs 27%; P < 0.005). CONCLUSIONS Our study depicts the main sonographic abnormalities of the SSc hand. Using US, we found an unexpectedly high prevalence of joint pathology in SSc without clinically involved hands. The clinical usefulness of US in the assessment of SSc articular involvement either in clinical practice or in therapeutic trials is yet to be defined.

Early systemic sclerosis: assessment of clinical and pre-clinical organ involvement in patients with different disease features

OBJECTIVE To assess internal organ involvement in early SSc at presentation. METHODS One hundred and fifteen patients admitted to a tertiary centre because of RP, who did not present any routinely detectable scleroderma-related internal organ involvement, were investigated for ANA and videocapillaroscopy, and underwent history and physical examination to detect symptoms/signs suggestive of SSc. Patients were then subdivided into three groups: (i) early SSc, constituted by patients without clinical manifestations other than RP, but with scleroderma marker autoantibodies and/or typical capillaroscopic abnormalities; (ii) probable SSc, constituted by patients with the same autoantibody and/or capillaroscopic status as early SSc patients, but with any of the following manifestations: digital ulcers/scars, puffy fingers, arthritis, telangiectasia, dysphagia/heartburn, shortness of breath; (iii) UCTD, constituted by patients with a specific (i.e. disease antibody marker) ANA and capillaroscopic findings plus any disease manifestation. All patients were investigated by lung functional study and B-mode echo-Doppler-cardiography. Patients who consented underwent oesophageal manometry. RESULTS An inverted mitral E : A ratio (i.e. early scleroderma cardiac involvement) and/or a diffusing lung capacity for CO <80% of the predictive value (i.e. early lung involvement) and/or basal low oesophageal sphincter pressure <15 mmHg (i.e. early oesophageal involvement) were detected in 37/51 probable SSc patients (72%), 8/19 early SSc patients (42%) and 12/45 UCTD patients (27%). CONCLUSION A scleroderma-related internal organ involvement was detected in patients from each group and, more importantly, was pre-clinical in a number of cases.

Association of a functional polymorphism in the matrix metalloproteinase-12 promoter region with systemic sclerosis in an Italian population.

Objective. To investigate the possible implication of the matrix metalloproteinase-12 (MMP-12) gene in the genetic predisposition to systemic sclerosis (SSc) susceptibility and clinical phenotype. Methods. The MMP-12 rs2276109 A/G functional polymorphism was selected as a genetic marker and genotyped by polymerase chain reaction-restriction fragment length polymorphism assay in 513 unrelated subjects of Italian white ancestry: 250 patients with SSc [146 limited cutaneous SSc (lcSSc), 104 diffuse cutaneous SSc (dcSSc)] and 263 healthy individuals. Results. A significant difference was observed in MMP-12 rs2276109 genotype distribution between patients with SSc and controls (p = 0.0003), and between lcSSc and dcSSc (p = 0.003). The A allele frequency was significantly higher in patients with SSc than in controls (p = 0.0002), and higher in dcSSc than in lcSSc (p = 0.003). After adjustment for age and sex, the homozygosity for the A allele significantly influenced the predisposition to SSc and to dcSSc (OR 2.44, 95% CI 1.61–3.71, p < 0.0001; OR 4.69, 95% CI 2.36–9.33, p < 0.0001, respectively). A trend toward an association between the AA genotype and lcSSc was observed (p = 0.06). The homozygosity for the A allele was also significantly and independently associated with antitopoisomerase I antibody positivity (OR 6.39, 95% CI 2.18–18.76, p = 0.001) and interstitial lung disease (OR 2.94, 95% CI 1.25–6.95, p = 0.01). Conclusion. The MMP-12 rs2276109 gene polymorphism may contribute to susceptibility to SSc, and in particular to dcSSc and pulmonary fibrosis.

Brief report: successful pregnancies but a higher risk of preterm births in patients with systemic sclerosis: an Italian multicenter study

OBJECTIVE To assess fetal and maternal outcomes in women with systemic sclerosis (SSc). METHODS Prospectively collected data on 99 women with SSc from 25 Italian centers were analyzed retrospectively. Women with SSc were observed during 109 pregnancies (from 2000 to 2011), and outcomes were compared to those in the general obstetric population (total of 3,939 deliveries). The maternal age at conception was a mean ± SD 31.8 ± 5.3 years, and the median disease duration at conception was 60 months (range 2-193 months). RESULTS SSc patients, compared to the general obstetric population, had a significantly increased frequency of preterm deliveries (25% versus 12%) and severe preterm deliveries (<34 weeks of gestation) (10% versus 5%), intrauterine growth restriction (6% versus 1%), and babies with very-low birth weight (5% versus 1%). Results of multivariable analysis showed that corticosteroid use was associated with preterm deliveries (odds ratio [OR] 3.63, 95% confidence interval [95% CI] 1.12-11.78), whereas the use of folic acid (OR 0.30, 95% CI 0.10-0.91) and presence of anti-Scl-70 antibodies (OR 0.26, 95% CI 0.08-0.85) were protective. The disease remained stable in most SSc patients, but there were 4 cases of progression of disease within 1 year from delivery, all in anti-Scl-70 antibody-positive women, 3 of whom had a disease duration of <3 years. CONCLUSION Women with SSc can have successful pregnancies, but they have a higher-than-normal risk of preterm delivery, intrauterine growth restriction, and babies with very-low birth weight. Progression of the disease during or after pregnancy is rare, but possible. High-risk multidisciplinary management should be standard for these patients, and pregnancy should be avoided in women with severe organ damage and postponed in women with SSc of recent onset, particularly if the patient is positive for anti-Scl-70 antibodies.

Stress Doppler Echocardiography in Systemic Sclerosis: Evidence for a Role in the Prediction of Pulmonary Hypertension

OBJECTIVE Patients with systemic sclerosis (SSc) in whom pulmonary hypertension (PH) is not suspected have been reported to develop an inappropriate increase of pulmonary artery systolic pressure as estimated by Doppler echocardiography under conditions of exercise (pulmonary artery systolic pressure under exercise). We undertook this study to investigate whether this increase or any other parameter detectable by stress Doppler echocardiography has utility in predicting the development of PH in SSc. METHODS We enrolled a total of 170 patients with SSc previously investigated using standard and stress Doppler echocardiography and tissue Doppler imaging. Each patient was evaluated at baseline and yearly for skin and internal organ involvement. Right-sided heart catheterization was carried out when PH was suspected. The baseline Cochin Risk Prediction Score was calculated retrospectively. RESULTS During followup, 6 patients (3.5%) developed PH. Compared with patients without any feature suggesting PH, the Cochin Risk Prediction Score was higher in this group (mean ± SD 4.2 ± 0.9 versus 3.4 ± 0.9; P < 0.05), as was the difference between pulmonary artery systolic pressure under exercise and pulmonary artery systolic pressure (Δpulmonary artery systolic pressure) (18.2 ± 7 mm Hg versus 9.4 ± 6.5 mm Hg; P < 0.001), even when adjusted for cardiac index changes. In multivariate analysis, Δpulmonary artery systolic pressure (hazard ratio [HR] 3.4 [95% confidence interval 1.4-8], P < 0.01) and Cochin Risk Prediction Score within the fifth quintile of the values registered in our series (HR 9.3 [95% confidence interval 1.4-63.7], P < 0.05) were the only factors independently predictive of PH during followup. A Δpulmonary artery systolic pressure cutoff of >18 mm Hg, identified by receiver operating characteristic curve analysis, had a sensitivity of 50% and a specificity of 90% for the development of PH during followup. CONCLUSION An inappropriate response to exercise among patients with SSC is detectable by stress Doppler echocardiography. Independently of other clinical associations, increased Δpulmonary artery systolic pressure heralds PH. Stress Doppler echocardiography may represent an additional screening tool for this severe complication.

Early Systemic Sclerosis: Serum Profiling of Factors Involved in Endothelial, T-cell, and Fibroblast Interplay is Marked by Elevated Interleukin-33 Levels

PurposeTo assess the serum profile of factors involved in endothelial, T-cell, and fibroblast interplay in patients with Raynaud’s phenomenon (RP) associated with nailfold vodeocapillaroscopy (NVC) scleroderma findings and/or systemic sclerosis (SSc) marker autoantibodies, recently labeled as early SSc patients.MethodsSerum levels of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), CCL2, CXCL8, IL-13, IL-33, and transforming growth factor-β (TGF-β) were measured in 24 early SSc patients, 48 definite SSc patients, and 24 osteoarthritis/fibromyalgia controls by multiplex suspension immunoassay. All SSc patients were investigated for the presence/absence of preclinical and clinical organ involvement, SSc marker autoantibodies, and NVC abnormalities.ResultsSerum sICAM-1, CCL2, CXCL8, and IL-13 were increased in all SSc patients as compared to controls, and paralleled the severity of the disease subset (early SSc < limited cutaneous SSc < diffuse cutaneous SSc; p < 0.0001). Surprisingly, IL-33 was significantly higher in early SSc patients as compared to both controls (p < 0.01) and definite SSc patients (p < 0.05). In early SSc there were no differences in the investigated markers according to the functional and serological features assessed.ConclusionsOur study suggests that an endothelial, T-cell and fibroblast activation can be present in patients with early SSc and it is associated with a distinct profile of circulating factors involved in the cross-talk of these cells. The marked increase of IL-33 in early SSc patients suggests new routes of investigation of cell-cell dynamics in target tissues predating overt disease manifestations, thus opening to new therapeutic approaches.

The enhanced liver fibrosis test: a clinical grade, validated serum test, biomarker of overall fibrosis in systemic sclerosis

Objectives The absence of a serological surrogate outcome measure of fibrosis in systemic sclerosis (SSc) is a major deficiency for intervention studies and clinical management. An algorithm including the serum concentration of procollagen-III aminoterminal-propeptide, tissue inhibitor of matrix metalloproteinase-1 and hyaluronic acid, has recently been validated as predictive of severity and clinical outcome in chronic liver diseases (enhanced liver fibrosis (ELF) test) and implemented as a clinical grade test available for physicians. We evaluated the ELF test as a surrogate outcome measure in SSc. Methods The ELF score was determined blindly in 210 patients with SSc. Results were correlated with clinical, functional and instrumental variables including disease severity, activity and disability. Results The ELF test was above normal range in 83% of SSc patients (175/210). The ELF score showed a significant correlation (p<0.0001) with extent of skin involvement (r=0.28), diffusing lung capacity of carbon monoxide (DLCO) (r=−0.32), health assessment questionnaire–disability index (HAQ-DI) (r=0.32), disease severity score (r=0.3) and age (r=0.41). In addition, ELF correlated with disease activity (r=0.23; p=0.02). Using regression analysis, the extent of skin involvement, age, DLCO and gender were independently associated with the ELF score. The ELF score did not correlate with the presence of pulmonary artery hypertension, digital ulcers or any other measure of vasculopathy. Conclusions The ELF test is a clinical-grade serum test that significantly correlates with several measures of fibrosis in SSc and with overall disease activity, severity and HAQ-DI. The specific correlation with fibrosis and its face validity, together with the feasibility of the test, warrant its further development as a surrogate outcome measure of fibrosis in SSc.