C. Lubatti

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 Raynauds 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.

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 (Harrells 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.

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 Raynauds 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.

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.

Combined pulmonary fibrosis and emphysema syndrome in systemic sclerosis

Dear Editor, Combined pulmonary fibrosis and emphysema (CPFE) is a described syndrome observed in patients affected by connective tissue diseases (CTDs) and by smokinginduced chronic lung disease. We have observed two patients with systemic sclerosis (SSc) and pulmonary alterations consistent with CPFE. The first was a 67-year-old man with limited cutaneuos SSc (lcSSc) who had been a heavy smoker for more than 30 years. High-resolution computed tomography (HRCT) revealed diffuse subpleural linear thickening and centrilobular emphysema with large bullae in the apex, bronchiectasis and honeycomb lesions at the base. There were no other signs of disease activity. Five years later, he suddenly developed symmetric erosive polyarthritis, worsening HRCT lesions (subpleural, apical and intraparenchymal emphysematous bullae, diffuse honeycombing, multiple mediastinic lymph nodes, and subpleural interstitial thickening: Fig. 1a), reduced forced vital capacity (76%) and diffusion capacity of carbon monoxide (DLCO: 60%), and high systolic pulmonary artery pressure (sPAP) as revealed by Doppler echocardiography (36 mmHg). The second patient was a 70-year-old woman who rapidly developed diffuse cutaneous SSc (dcSSc) with neurological, esophageal and pulmonary involvement. Pulmonary function tests showed severely reduced DLCO (46%), and HRCT revealed diffuse interstitial reticulo-nodular alterations, multiple cysts and small mediastinic lymph nodes (Fig. 1b). Smoking, exposure to chemical substances, infection and rare neoplasms such as Langherhans cell histiocytosis were excluded. As they were found in our SSc patients at the time of diagnosis, interstitial fibrosis with diffuse pulmonary cystic lesions may be a not so uncommon manifestation of interstitial lung disease that requires specific investigations in order to exclude infections and cancer. Our cases strengthen the hypothesis of Cottin et al. that CTDsmay be a co-factor in the pathogenesis of CPFE. The presence of CPFE in SSc patients may increase the risk of severe visceral complications such as pulmonary hypertension and reduced alveolar diffusion capacity. Furthermore, in the absence of other signs of disease activity, pulmonary damage due to tobacco smoking may hamper the recognition of lung involvement due to SSc at the time of diagnosis.

Successful pregnancies but a higher risk of preterm births in systemic sclerosis : an Italian multicentric 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.

Fibrosis biomarkers in isolated Raynaud's phenomenon: too little, too soon?

Raynauds phenomenon (RP) can be the first manifestation or may be present before the development of an overt systemic sclerosis (SSc).1 Enhanced liver fibrosis (ELF) test, an algorithm combining tissue inhibitors of matrix metalloproteinases (TIMP-1), hyaluronic acid (HA) and aminoterminal propeptide of type III procollagen (PIIINP), has been related to several measures of fibrosis in SSc patients.2–⇓4 We evaluated whether these biomarkers could discriminate between primary and secondary RP. Consecutive adult patients with RP at the first rheumatologic evaluation were recruited from February 2011 to May 2012 with ethics committee approval. Exclusion criteria were history of any fibrosing disorder, organ transplantation, hepatocellular carcinoma or treatment with interferon. One patient was excluded for interferon treatment. Fifteen limited cutaneous SSc and 15 diffuse …

AB1085 Empirical Approach to Investigate Raynaud's Phenomenon: The Pearl Study

Background An early diagnosis of connective tissue disease (CTD) provides a window of opportunity for monitoring and treating patients. Objectives We examined the role of history, capillaroscopy and autoantibodies to differentiate between patients with primary Raynauds phenomenon (RP) and secondary RP due to a CTD at their first medical evaluation. Methods One hundred fifteen consecutive adults with RP were studied. Patient profiles based on history, physical examination, capillaroscopy and laboratory investigations were examined. Logistic regression models were used in the statistical analysis. Results RP was bilateral in 92.7% of patients. The middle finger was significantly more affected. A lack of association between fingers affected by RP and fingers with capillary abnormalities was observed OR=0.75 (0.34-1.66). Fingers affected by RP with the cyanotic phase had a higher risk to have hemorrhages at capillaroscopy OR=4.46 (1.50-13.30) and giant capillaries OR=24.85 (1.48-41.74). None of the variables can discriminate between primary and secondary RP. Among these, thumb involvement and the presence of three colour phases have an OR of 1.48 and 1.85 respectively. Patients with SSc had a greater value of VAS pain (p=0.011). The presence of anti-centromere antibodies was significantly associated with a higher risk of SSc (p<0.001). Conclusions Markers of a potential development of a CTD in patients with RP include: severe RP symptoms (high VAS pain), positive autoantibodies and capillary abnormalities. The presence of three colour changes and the involvement of thumb may also be a warning for secondary forms. Disclosure of Interest None declared

AB1013 Systemic Sclerosis and Myositis Extractable Nuclear Antigen (ENA) Analysis: Profile of A Cohort of Subjects with Isolated Raynaud's Phenomenon

Background Raynauds phenomenon (RP) may predate an overt Connective Tissue Disease (CTD) of the “Scleroderma spectrum” such as Systemic sclerosis (SSc). The predictive role of auto-antibodies (auto-Abs) such as ANA for the development of a CTD in patients with isolated RP (i.e. with no other signs or symptoms of CTD) is well known, whereas data regarding the prevalence of anti-ENA in such patients are lacking. Objectives Our aim was to evaluate the profile of anti-ENA in patients with isolated RP. Methods Sera were analyzed for anti-ENA by EUROLINE “Scleroderma profile” (antigens: Scl70, CENP A, CENP B, RP11, RP155, fibrillarin (Fib), NOR90, Th/To, PM-Scl100, PM-Scl75, Ku, PDGFR, Ro-52) and “Myosites profile” (antigens: Mi-2, Ku, PM-Scl100, PM-Scl75, Jo-1, SRP, PL-7, PL-12, EJ, OJ, Ro-52) [EUROIMMUN AG Leuback, Germany]. Results A total of 115 adults (105 females and 10 males) with isolated RP were enrolled in two Italian Rheumatology Centers (G. Pini Institute, Milan and Moriggia-Pelascini Hospital, Gravedona) from March 2011 to September 2013. Forty-four of 115 (38.0%) subjects were positive for at least one anti-ENA; 71 out of 110 (61.7%) were negative both for Scleroderma and Myosites profiles (see table 1 and 2). Conclusions Up to 38% of RP subjects were positive for at least one anti-ENA. The detection of anti-ENA since the first Rheumatologic evaluation may aid the specialist in achieving an earlier diagnosis. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5955

FRI0403 How early starts increased collagen synthesis in systemic sclerosis

Background One of the hallmarks of overt Systemic Sclerosis (SSc) is the interstitial and perivascular fibrosis resulting in functional impairment of affected organs. During the fibrotic process, the increased collagen synthesis has been correlated to the increase of some biomarkers of collagen metabolism, but it is not know how early these biomarkers can be detected during the disease course. Objectives To evaluate the ongoing fibrotic process based on collagen biomarkers in a cohort of patients in different phases of the disease: from isolated Raynaud’s phenomenon (RP) to overt SSc. For this purpose tissue inhibitor of matrix metalloproteinases-1 (TIMP-1), hyaluronic acid (HA), aminoterminal propeptide of type III procollagen (PIIINP) and Enhanced Liver Fibrosis (ELF) test were chosen. Methods 140 consecutive adult subjects referring in approximately 6 months time were enrolled. They were classified as: 1) primary RP (pRP) [1]; 2) RP suspected secondary to SSc; 3) very early SSc [2]; 4) limited cutaneous (lc)-SSc; and 5) diffuse cutaneous (dc)-SSc. Patients with any other fibrosing disorder or treated with interferon were excluded. TIMP-1, HA, PIIINP and ELF score (derived from an algorithm of the above mentioned biomarkers) were blindly determined by an independent commercial service (iQur, UK). Statistical analysis was performed by regression modelling and ROC curve analysis adjusting for age. Results The study population consisted in 50 pRP (47 women, median age 44.5 yrs), 43 RP suspected secondary to SSc (43 women, median age 43 yrs), 16 very early SSc (16 women, median age 57.5 yrs),15 lc-SSc (14 women, median age 67 yrs), and 15 dc-SSc (13 women, median age 65 yrs). 1 patient was excluded for a recent treatment with interferon. The ELF test and HA were significantly higher in patients with very early SSc compared to subjects with RP suspected secondary to SSc (ELF test: median 8,46 vs 7,84 ng/ml, p= 0.0286; HA: median 30,62 vs 13,6 ng/ml, p= 0.03). PIIINP was significantly higher in patients with dc-SSc compared to very early SSc (median 7,23 vs 5,42 ng/ml; p= 0.006). These differences were not confirmed when these results were weighted for age. When patients with overt SSc were studied an increase of these biomarkers was observed as a trend, but only PIIINP reached a statistical significance. This last result was also confirmed once being weighed for age. Conclusions In our study, the selected biomarkers were not able to distinguish among subjects between pRP, suspected secondary RP, and patients with very early SSc. Nevertheless, these fibrosis biomarkers showed an increasing trend in different subgroups and with age, with no relation to RP duration. These data support the hypothesis that the immune perturbations and vascular injury precede the development of fibrosis, which, in turn, further exacerbates vascular and immune damage. References LeRoy EC, Medsger TA, Jr. Clin Exp Rheumatol. 1992;10:485-8. Avouac J, Fransen J, Walker UA, Riccieri V, Smith V, Muller C, et al. Ann Rheum Dis. 2011;70:476-81. Disclosure of Interest None Declared