Value of systolic pulmonary arterial pressure as a prognostic factor of death in the systemic sclerosis EUSTAR population.

OBJECTIVE: The aim of this study was to assess the prognostic value of systolic pulmonary artery pressure (sPAP) estimated by echocardiography in the multinational European League Against Rheumatism Scleroderma Trial and Research (EUSTAR) cohort. METHODS: Data for patients with echocardiography documented between 1 January 2005 and 31 December 2011 were extracted from the EUSTAR database. Stepwise forward multivariable statistical Cox pulmonary hypertension analysis was used to examine the independent effect on survival of selected variables. RESULTS: Based on our selection criteria, 1476 patients were included in the analysis; 87% of patients were female, with a mean age of 56.3 years (s.d. 13.5) and 31% had diffuse SSc. The mean duration of follow-up was 2.0 years (s.d. 1.2, median 1.9). Taking index sPAP of <30 mmHg as reference, the hazard ratio (HR) for death was 1.67 (95% CI 0.92, 2.96) if the index sPAP was between 30 and 36 mmHg, 2.37 (95% CI 1.14, 4.93) for sPAP between 36 and 40 mmHg, 3.72 (95% CI 1.61, 8.60) for sPAP between 40 and 50 mmHg and 9.75 (95% CI 4.98, 19.09) if sPAP was >50 mmHg. In a multivariable Cox model, sPAP and the diffusing capacity for carbon monoxide (DLCO) were independently associated with the risk of death [HR 1.833 (95% CI 1.035, 3.247) and HR 0.973 (95% CI 0.955, 0.991), respectively]. sPAP was an independent risk factor for death with a HR of 3.02 (95% CI 1.91, 4.78) for sPAP ≥36 mmHg. CONCLUSION: An estimated sPAP >36 mmHg at baseline echocardiography was significantly and independently associated with reduced survival, regardless of the presence of pulmonary hypertension based on right heart catheterization.

Reliability and validity of the Italian version of the UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument in patients with systemic sclerosis.

OBJECTIVES: To test the acceptability, feasibility, reliability and validity of the Italian translated version of the UCLA Scleroderma Clinical Trial Consortium GIT (UCLA-SCTC GIT) 2.0. Gastrointestinal tract (GIT) involvement is frequent in systemic sclerosis (SSc). The UCLA-SCTC GIT 2.0 is a validated instrument for measuring the presence and impact of GIT symptoms in SSc patients. METHODS: Acceptability and feasibility of the questionnaire were evaluated based on the input from the patients. Internal consistency was evaluated by Cronbach's alpha. External consistency was measured by comparing with the Short Form (SF)-36 and EQ-5D by Spearman's rho, meaningful if ≥0.30. RESULTS: Sixty-two consecutive SSc patients (mean age 60.6) were recruited, 88.5% were female. The UCLA-SCTC GIT 2.0 was well accepted. Percentage of missing data in UCLA-SCTC GIT total score was 2 %. Internal consistency was acceptable (alpha≥0.70) for all domains. Cronbach's alpha was ≥0.70 for all domains. UCLA-SCTC GIT 2.0 discriminated between patients with or without gastroesophageal reflux disease whether diagnosed clinically or by objective testing (p<0.01 for both). UCLA-SCTC GIT emotional well-being was correlated with the conceptually equivalent SF-36 mental health domains (correlation coefficient>0.35) and with the EQ-5D usual activities domain (0.38), thus reflecting the impact on everyday activities. The distention/bloating domain strongly correlated with the EQ-5D anxiety/depression domain (0.51) and reflux domain with role emotional of SF-36 (0.44). CONCLUSIONS: This is the first validation study of the Italian version of UCLA-SCTC GIT 2.0. Our data support its feasibility, reliability, and validity in Italian SSc patients.

Interleukin-17A+ cell counts are increased in systemic sclerosis skin and their number is inversely correlated with the extent of skin involvement.

OBJECTIVE: Levels of interleukin-17A (IL-17A) have been found to be increased in synovial fluid from individuals with systemic sclerosis (SSc). This study was undertaken to investigate whether IL-17A-producing cells are present in affected SSc skin, and whether IL-17A exerts a role in the transdifferentiation of myofibroblasts. METHODS: Skin biopsy samples were obtained from the involved skin of 8 SSc patients and from 8 healthy control donors undergoing plastic surgery. Immunohistochemistry and multicolor immunofluorescence techniques were used to identify and quantify the cell subsets in vivo, including IL-17A+, IL-4+, CD3+, tryptase-positive, α-smooth muscle actin (α-SMA)-positive, myeloperoxidase-positive, and CD1a+ cells. Dermal fibroblast cell lines were generated from all skin biopsy samples, and quantitative polymerase chain reaction, Western blotting, and solid-phase assays were used to quantify α-SMA, type I collagen, and matrix metalloproteinase 1 (MMP-1) production by the cultured fibroblasts. RESULTS: IL-17A+ cells were significantly more numerous in SSc skin than in healthy control skin (P = 0.0019) and were observed to be present in both the superficial and deep dermis. Involvement of both T cells and tryptase-positive mast cells in the production of IL-17A was observed. Fibroblasts positive for α-SMA were found adjacent to IL-17A+ cells, but not IL-4+ cells. However, IL-17A did not induce α-SMA expression in cultured fibroblasts. In the presence of IL-17A, the α-SMA expression induced in response to transforming growth factor ß was decreased, while MMP-1 production was directly enhanced. Furthermore, the frequency of IL-17A+ cells was higher in the skin of SSc patients with greater severity of skin fibrosis (lower global skin thickness score). CONCLUSION: IL-17A+ cells belonging to the innate and adaptive immune system are numerous in SSc skin. IL-17A participates in inflammation while exerting an inhibitory activity on myofibroblast transdifferentiation. These findings are consistent with the notion that IL-17A has a direct negative-regulatory role in the development of dermal fibrosis in humans.

Improving outcome prediction of systemic sclerosis from isolated Raynaud's phenomenon: role of autoantibodies and nail-fold capillaroscopy.

OBJECTIVE: A simple weighted prognostic algorithm, based on capillaroscopy and autoantibodies, is developed to classify patients at different risk of transition from isolated RP to SSc within 5 years from the screening visit. METHODS: Two hundred and eighty-eight of 768 patients with isolated RP who underwent capillaroscopy were recruited. The prognostic contributions of capillaroscopic findings (giant loops, haemorrhages and the number of capillaries) and SSc-associated autoantibodies (ACAs, anti-topo I and ANAs) were assessed in a semi-parametric regression models suitable for competing risks. A prognostic index was built by a bagging technique. A structured tree approach was used to extract simple classificatory rules that can be directly interpreted. RESULTS: Thirty-four transitions from isolated RP to SSc and 42 to other CTDs were observed. All of the chosen variables had a substantial prognostic impact. A complex non-linear prognostic pattern was observed for capillaries, with the risk of developing SSc increasing as the number of loops decreased. The presence of ANAs had a strong impact on prognosis [hazard ratio (HR) = 9.70], which was increased by the presence of ACA (HR = 3.94; P < 0.001). A weighted prognostic classification for the development of SSc was constructed using capillary number, giant loops and ANAs. The prognostic discrimination was satisfactory (Harrell's C-index = 0.86). CONCLUSION: Our prognostic model is based on easy-to-obtain features (i.e. the number of capillaries, giant loops and ANAs) and could be used to facilitate clinical decision making in the screening phase, and may also have important implications for stratifying patients into risk groups for future clinical assessment.

Reliability and validity of the Italian version of the hand functional disability scale in patients with systemic sclerosis.

The English version of hand functional disability scale is a validated instrument for measuring hand involvement in patients with systemic sclerosis (SSc). Because validation of multiple-language versions of existing validated questionnaires plays a key role in standardizing the outcome measurement and increasing the statistical power of clinical studies, this study aims to validate a translated Italian version of hand functional disability scale which is not available at the moment. The Italian version of hand functional disability scale was tested on 50 patients with SSc. To determine test-retest reliability, 40 SSc patients were asked to complete the questionnaire a second time within 2 weeks of the initial testing session. The test-retest reliability and internal consistency were determined by intra-class correlation coefficient (ICC) and Cronbach's alpha. External consistency was measured by comparing with an already validated test, the Health Assessment Questionnaire (HAQ), and clinical measurements. To explore the relationships among these variables, multiple correspondence analysis (MCA) was adopted. The statistical analysis of each domain and the total score revealed a good test-retest reliability (ICCs > 0.75) and internal consistency (Cronbach's alpha > 0.7). Furthermore, a good external consistency was confirmed by evaluating the differences between the distributions of hand functional disability scale score for SSc patients with or without hand involvement (arthralgias, arthritis, flexion contractures, and digital ulcers) and comparing results with those obtained for HAQ. Finally, MCA demonstrates a strong correlation among functional disability scale areas and HAQ scores. The hand functional disability scale is a self-administered questionnaire and it has been specially developed to measure hand impairment in patients with hand disorders. Our data support its validity and reliability in Italian SSc patients.

X monosomy in female systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease, predominantly occurring in women of childbearing age. SLE, like several other autoimmune diseases, is characterized by a striking female predominance and, although sex hormone influences have been suggested as an explanation for this phenomenon, definitive data are still unavailable. Our group recently reported an increased X monosomy in lymphocytes of women, affected with primary biliary cirrhosis (PBC), systemic sclerosis (SSc), and autoimmune thyroiditis (AITD) in comparison to healthy women, thus suggesting the involvement of this chromosome in female predominance and in the deregulation of the immune system that characterizes autoimmunity. We have now evaluated X monosomy rates in SLE using fluorescence in situ hybridization (FISH) on peripheral mononuclear white blood cells (PBMCs) from female patients compared to healthy age-matched controls. In addition, because of a previous finding of microchimerism as a pathogenetic cause of a number of autoimmune diseases, we investigated the presence of cells carrying the Y chromosome. We did not identify an increased X monosomy in women with SLE compared to controls (P = 0.3960, SLE vs. HCs, Student's t-test), thus suggesting that a different mechanism of immune deregulation might be predominant in the female population of patients with SLE.

Bilateral vocal fold immobility in a patient with overlap syndrome rheumatoid arthritis/systemic sclerosis.

Bilateral vocal fold immobility (BVFI) can be the result of a primary disorder or as an iatrogenic complication of surgery or intubation. Laryngeal involvement can be a rare complication of connective tissue disorders and it usually occurs in association with other symptoms and signs that indicate active disease. We present a case of BVFI in a patient with an overlap syndrome rheumatoid arthritis/systemic sclerosis, referred to our division because of dysphonia and dyspnea. The video-laryngostroboscopy showed the presence of BVFI. Physical examination, blood tests, lung and neck high resolution computed tomography scans did not demonstrate significant abnormalities. She was treated with pulses of intravenous methylprednisolone with slow improvement.

Use of antibodies recognizing cyclic citrullinated peptide in the differential diagnosis of joint involvement in systemic sclerosis.

OBJECTIVE: To determine the prevalence of anti-cyclic citrullinated peptide (CCP) antibodies in systemic sclerosis (SSc) and to assess any association between the presence of anti-CCP, radiographic features, and clinical manifestations. MATERIALS AND METHODS: Anti-CCP antibodies and rheumatoid factor (RF) were tested in serum samples from 75 patients with SSc (64 women and 11 men), with a mean age of 59.4 years (range 24-85) with either diffuse (dcSSc) and limited (lcSSc) cutaneous involvement. As a control group, 22 age- and sex-matched healthy controls (HCs) were examined. Standard radiographs of the hands and wrists were examined in each patient. RESULTS: The presence of anti-CCP was found in sera of 10.6% (8/75) patients with SSc (lcSSc 3 of 44, 6.8%; dcSSc 5 of 31, 16.1%). None of the HCs was positive for anti-CCP. The positivity of RF was observed in 19 of 75 (25.3%) SSc patients (lcSSc 10 of 44, 22.7%; dcSSc 9 of 31, 29%). Statistically significant association was found between anti-CCP positivity and the presence of arthritis (p<0.0001) and marginal erosions (p=0.001). CONCLUSION: Our data show that joint involvement is a common presenting feature of SSc. In this report, we show that anti-CCP antibodies can be detected also in patients with SSc, but they are generally less commonly present than in adults with rheumatoid arthritis (RA). Thus, the finding of high titers of anti-CCP antibodies may help to define the diagnosis of overlap syndrome SSc/RA and facilitate diagnosis and appropriate treatment.

Interstitial lung disease outcomes by high-resolution computed tomography (HRCT) in Anti-Jo1 antibody-positive polymyositis patients: a single centre study and review of the literature.

Interstitial lung disease (ILD) is a frequent complication of inflammatory myopathies with high rates of morbidity and mortality. Antibodies against aminoacyl-tRNA-synthetases are the strongest predictive factors in ILD. In this study, we reviewed the literature and we retrospectively analysed high-resolution computed tomography (HRCT) findings in a cohort of 131 consecutive subjects: 75 with polymyositis (PM), 43 with dermatomyositis (DM), one with amyophatic PM, two with paraneoplastic syndromes, and 10 with overlapping syndromes. The inclusion criteria were PM/DM, anti-Jo1 antibody positivity, and HRCT-assessed ILD. The effect of 12 months' treatment with cyclophosphamide (CYC) or cyclosporin A (CsA) plus steroids was assessed by comparing baseline and follow-up HRCT scans for evidence of stability, improvement or worsening. Fifteen patients (11.5%) had ILD and were Jo-1 positive. They were all women with PM, and had a mean age of 47.33 years and a median duration of symptoms of 7.26 months. At baseline, HRCT showed ground-glass attenuations in eight cases, septal thickening in seven, and honeycombing in four. Twelve months after diagnosis, ILD had worsened in nine patients (60%; exact confidence interval [ECI] 32-84) and was stable in four (two patients were lost to follow-up). Seven of the 15 patients were treated with CsA, and 12-month HRCT revealed a worsening in ILD in five cases (71%; ECI 0.29-0.96); ILD also worsened (ECI 16-84) in four of the eight patients treated with CYC pulses (50%). The evolution of the HRCT findings was not significantly different between the two groups. Our findings confirm that ILD is a common early manifestation in patients with Jo1-positive PM. Over twelve months, HRCT showed worsening ILD in most of our patients, with no difference in the HRCT changes between those treated with CYC or CsA.

N-TproBNP as biomarker in systemic sclerosis.

Systemic sclerosis (SSc) is a connective tissue disorder characterized by tissue fibrosis affecting the skin and internal organs, fibroproliferative vasculopathy, and autoimmune activation. SSc still heralds a poor prognosis with significant morbidity and mortality. Early detection of organ involvement is critical as currently available treatments are most effective when started early. Many candidate biomarkers have been investigated in the past two decades. However, despite the enormous efforts, no accurate tool to predict the pattern of organ involvement and to assess disease activity has been yet identified. The N-terminal fragment of probrain natriuretic peptide (N-TproBNP) is a neurohormone released by ventricular myocytes in response to pressure overload. N-TproBNP is highly relevant for diagnosis, prognosis, and prediction of pulmonary arterial hypertension in SSc. Moreover, several studies support its potential benefit for cardiac assessment of scleroderma patients. Conversely, the role of N-TproBNP as surrogate marker of pulmonary fibrosis and skin involvement is much less clear. We provide an extensive review of the studies that have previously investigated the role of N-TproBNP as candidate biomarker in scleroderma manifestations, presenting also the findings of a recent study we conducted in a cohort of 87 SSc patients.

Feasibility of different capillaroscopic measures for identifying nailfold microvascular alterations.

OBJECTIVE: To ascertain the most reliable and relevant capillaroscopic measurements of nailfold videocapillaroscopy (NVC) by analyzing their inter- and intraobserver agreement and predictive value. METHODS: We studied 217 subjects (110 with Raynaud's phenomenon under ongoing evaluation, and 107 with connective tissue diseases) by evaluating the number of capillaries, intercapillary distances, avascular areas, capillary disorganization, capillary loop length, capillary width, percentage of minor abnormalities (tortuous, crossed, or enlarged capillaries), and major abnormalities (giant, bushy, meandering, or branching capillaries), microhemorrhage, skin transparency, and subpapillary plexus visibility. Every finger of both hands was examined. All of the measurements were made by 2 observers under blinded conditions. RESULTS: A total of 877 nailfold images were analyzed. The number of capillaries/mm, interpeak distance, and avascular areas were poorly discriminant, with no statistical differences between their areas under the receiver operating characteristic curve; their reproducibility and repeatability were good, except for the intercapillary distance. Minor abnormalities were observed in 75% of the cases and major abnormalities in 34%; the inter- and intraobserver agreement concerning the major abnormalities was almost perfect. There was very good inter- and intraobserver agreement regarding the analysis of capillary disorganization and hemorrhages. CONCLUSIONS: This study shows that NVC can be useful in quantitatively and reproducibly recording various parameters. We suggest that combining the parameters showing the greatest reliability and prognostic value may be the best means of analyzing NVC images.

Prognostic model based on nailfold capillaroscopy for identifying Raynaud's phenomenon patients at high risk for the development of a scleroderma spectrum disorder: PRINCE (prognostic index for nailfold capillaroscopic examination).

OBJECTIVE: To construct a prognostic index based on nailfold capillaroscopic examinations that is capable of predicting the 5-year transition from isolated Raynaud's phenomenon (RP) to RP secondary to scleroderma spectrum disorders (SSDs). METHODS: The study involved 104 consecutive adult patients with a clinical history of isolated RP, and the index was externally validated in another cohort of 100 patients with the same characteristics. Both groups were followed up for 1-8 years. Six variables were examined because of their potential prognostic relevance (branching, enlarged and giant loops, capillary disorganization, microhemorrhages, and the number of capillaries). RESULTS: The only factors that played a significant prognostic role were the presence of giant loops (hazard ratio [HR] 2.64, P = 0.008) and microhemorrhages (HR 2.33, P = 0.01), and the number of capillaries (analyzed as a continuous variable). The adjusted prognostic role of these factors was evaluated by means of multivariate regression analysis, and the results were used to construct an algorithm-based prognostic index. The model was internally and externally validated. CONCLUSION: Our prognostic capillaroscopic index identifies RP patients in whom the risk of developing SSDs is high. This model is a weighted combination of different capillaroscopy parameters that allows physicians to stratify RP patients easily, using a relatively simple diagram to deduce the prognosis. Our results suggest that this index could be used in clinical practice, and its further inclusion in prospective studies will undoubtedly help in exploring its potential in predicting treatment response.

Evaluation of nailfold videocapillaroscopic abnormalities in patients with systemic lupus erythematosus.

OBJECTIVE: Nailfold capillaroscopy (NFC) has been shown to have a remarkable value in the differential diagnosis of connective tissue diseases. In fact, NFC patterns reflect the microvascular changes that may play a significant role in pathogenesis. The aims of this study were to determine in patients with systemic lupus erythematosus (SLE) the prevalence of NFC patterns, to evaluate any association with clinical features and laboratory parameters. MATERIALS AND METHODS: One hundred twenty-three patients with SLE were included in this retrospective study. Video NFC parameters were analyzed in each patient. In all cases, the following parameters were evaluated: capillary arrangement, density, size, and shape. RESULTS: In patients with SLE, major capillary abnormalities were frequently observed (44 of 123 = 35.8%); however, no specific pattern was noted. There was a significant correlation between the SLEDAI index and the severity of capillary abnormalities (P < 0.0001). Pathologic capillary abnormalities were also significantly increased in SLE with positive anti-U1-RNP antibodies (P < 0.05). CONCLUSION: NFC may be a useful method to evaluate the microvascular changes in patients with SLE, and the presence of major capillary abnormalities seems to herald a more severe clinical course of the illness.

X chromosome monosomy: a common mechanism for autoimmune diseases.

The majority of human autoimmune diseases are characterized by female predominance. Although sex hormone influences have been suggested to explain this phenomenon, the mechanism remains unclear. In contrast to the role of hormones, it has been suggested, based on pilot data in primary biliary cirrhosis, that there is an elevation of monosomy X in autoimmune disease. Using peripheral white blood cells from women with systemic sclerosis (SSc), autoimmune thyroid disease (AITD), or healthy age-matched control women, we studied the presence of monosomy X rates using fluorescence in situ hybridization. We also performed dual-color fluorescence in situ hybridization analysis with a chromosome Y alpha-satellite probe to determine the presence of the Y chromosome in the monosomic cells. In subsets of patients and controls, we determined X monosomy rates in white blood cell subpopulations. The rates of monosomy X increased with age in all three populations. However, the rate of monosomy X was significantly higher in patients with SSc and AITD when compared with healthy women (6.2 +/- 0.3% and 4.3 +/- 0.3%, respectively, vs 2.9 +/- 0.2% in healthy women, p < 0.0001 in both comparisons). Importantly, X monosomy rate was more frequent in peripheral T and B lymphocytes than in the other blood cell populations, and there was no evidence for the presence of male fetal microchimerism. These data highlight the thesis that chromosome instability is common to women with SSc and AITD and that haploinsufficiency for X-linked genes may be a critical factor for the female predominance of autoimmune diseases.