Bianca Marasini’s research while affiliated with Istituto Clinico Humanitas IRCCS and other places

Objective: Systemic sclerosis (SSc) is a heterogeneous connective tissue disease that is typically subdivided into limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) depending on the extent of skin involvement. This subclassification may not capture the entire variability of clinical phenotypes. The European Scleroderma Trials and Research (EUSTAR) database includes data on a prospective cohort of SSc patients from 122 European referral centers. This study was undertaken to perform a cluster analysis of EUSTAR data to distinguish and characterize homogeneous phenotypes without any a priori assumptions, and to examine survival among the clusters obtained. / Methods: A total of 11,318 patients were registered in the EUSTAR database, and 6,927 were included in the study. Twenty‐four clinical and serologic variables were used for clustering. / Results: Clustering analyses provided a first delineation of 2 clusters showing moderate stability. In an exploratory attempt, we further characterized 6 homogeneous groups that differed with regard to their clinical features, autoantibody profile, and mortality. Some groups resembled usual dcSSc or lcSSc prototypes, but others exhibited unique features, such as a majority of lcSSc patients with a high rate of visceral damage and antitopoisomerase antibodies. Prognosis varied among groups and the presence of organ damage markedly impacted survival regardless of cutaneous involvement. / Conclusion: Our findings suggest that restricting subsets of SSc patients to only those based on cutaneous involvement may not capture the complete heterogeneity of the disease. Organ damage and antibody profile should be taken into consideration when individuating homogeneous groups of patients with a distinct prognosis.

Purpose: The most common adverse reaction to zoledronic acid (ZOL) infusion is the acutephase reaction (APR), characterized by transient, usually mild, flu-like symptoms. Previous treatment with oral aminobisphosphonates (BPs) was reported as an independent protective factor for APR, and an association between APR and 25-hydroxyvitamin D (25[OH]D) levels in BP-naïve patients treated with ZOL was identified. The aim of our study was to confirm this association and to see if the association was different in patients previously treated with oral BPs compared with BP-naïve patients, and to investigate the role of 25(OH)D for the time of APR onset. Methods: We included 153 consecutive patients with postmenopausal osteoporosis undergoing their first ZOL infusion. Sixty-eight had been previously treated with oral BPs. Clinical, demographic and serological data were recorded. Results: 25(OH)D levels were significantly lower in patients experiencing APR compared to patients without APR (26.3±12.7 vs 37.0±13.5ng/mL, respectively; p<0.0001). Patients with 25(OH)D <30ng/mL had a significantly higher risk of APR (odds ratio [OR] 4.2 [95% confidence interval [CI] 2.1-8.2]) occurring in 65%. APR was significantly less frequent in patients previously treated with oral BPs than in BP-naïve subjects (33.8% [23/68] vs 52.9% [45/85], p=0.018), but only a weak association remained after correction for 25(OH)D (OR 0.5, 95% CI 0.3-1.1, p=0.08). Conclusions: Higher baseline 25(OH)D levels appear to be protective for APR post-ZOL infusion. The role of previous treatment with oral BPs as an independent protective factor for APR should be evaluated in a larger cohort. Abbreviations: ZOL = zoledronic acid; APR = acute-phase reaction; BPS = amino-bisphosphonates; 25[OH]D = 25-hydroxyvitamin D; OR = odds ratio; CI = confidence interval; OP = osteoporosis; PTH = parathyroid hormone; ROC = receiver operating characteristic.

Purpose Nailfold videocapillaroscopy (NVC) identifies the microvascular hallmarks of systemic sclerosis (SSc) and vascular endothelial growth factor (VEGF) and may play a pivotal role in the associated vasculopathy. The aim of the present study was to compare NVC alterations with clinical subsets, internal organ involvement, and serum VEGF levels in a cohort of selected SSc cases. Methods We studied 44 patients with SSc who were evaluated within 3 months from enrollment by NVC, skin score, severity index, pulmonary function tests, carbon monoxide diffusing capacity (DLCO), echocardiography, pulmonary high-resolution computed tomography (HRCT), gastroesophageal (GE) endoscopy or manometry or X-ray, and serum autoantibodies. Serum VEGF-A levels were determined by ELISA in 72 SSc patients and 31 healthy controls. Results Giant capillaries were inversely correlated with age (p = 0.034, r = −0.34) and to the extent of reticular pattern at HRCT (p = 0.04, r = −0.5). Avascular areas were directly correlated with capillaroscopy skin ulcer risk index (CSURI) (p = 0.006, r = +0.4) and severity index (p = 0.004, r = +0.5). The mean capillary density was directly correlated to the ulcer number (p = 0.02, r = +0.4) and to DLCO/alveolar volume (p = 0.02, r = +0.4) and inversely correlated with severity index (p = 0.01, r = −0.4) and skin score (p = 0.02, r = −0.4). Serum VEGF levels were higher in the SSc population vs controls (p = 0.03) and inversely correlated with DLCO (p = 0.01, r =−0.4) and directly with ground-glass and reticular pattern at HRCT (p = 0.04, r = +0.4 for both). Conclusions Our data suggest the importance of NVC not only for the diagnosis, but also for the global evaluation of SSc patients. Of note, serum VEGF levels may act as a biomarker of interstitial lung involvement.

Background Carpometacarpal osteoarthritis (CMC OA) is highly prevalent in older adults, and is often unresponsive to medical treatment. Intra-articular hyaluronic acid (HA) has been widely shown to improve pain and function in patients with knee OA and it seems to be a promising therapy also for CMC OA. To date no studies compared the efficacy of different HA compounds in CMC OA. Objectives To investigate the three-month efficacy of two different HA compounds on pain relief in CMC OA. Methods Eighty female patients affected by symptomatic CMC OA (aged 65±8 years, mean ± SD) were treated with three once-weekly intra-articular injections of HA (Hyalgan 1ml, MW 500-700 kDalton, or Jointex 1ml, MW 800-1200 kDalton). All subjects met ACR criteria for hand OA and had CMC OA grade 1-4 according to Kellgren and Lawrence on standard X-ray performed within 6 months before the inclusion. Fourty patients (aged 64±8 years, mean ± SD) were treated with Hyalgan while 40 patients (aged 67±8 years, mean ± SD) were treated with Jointex. All the patients were followed for a 3-month period after the last injection. Treatment efficacy was assessed through visual analogue scale (VAS) pain quantification (baseline; 2nd and 3rd injection; one and three months after the last injection). Side effects were recorded. Results In both groups VAS was significantly reduced after the first injection and reached the slowest score one month after the last injection (Hyalgan: 2nd injection vs baseline, p=0.0019; 3rd injection vs baseline, p<0.0001; 3rd injection vs 2nd injection, p=0.057; Jointex: 2nd injection vs baseline, p=0.0008; 3rd injection vs baseline, p<0.0001; 3rd injection vs 2nd injection, p=0.0096). The efficacy was maintained for all the whole follow-up period (Hyalgan and Jointex: one month vs baseline, p<0.0001; three months vs baseline, p<0.0001 - one month vs 3rd injection, p=n.s.;three months vs 3rd injection, p=n.s.). No significant differences in VAS score were found between the two groups at baseline and during the follow-up period (Hyalgan vs Jointex: baseline 7.05±2.33 vs 7.08±2.07; 3rd injection 4.35±2.85 vs 4.30±2.29; 1month 3.75±2.65 vs 3.25±2.22; 3months 4.23±2.90 vs 4.03±2.56; p=n.s.). Only minor side effects were observed in both treatment groups (mild pain and/or ecchymosis in injection site). Conclusions Our study supports viscosupplementation with HA as a safe and efficacious approach for symptomatic CMC OA. In our preliminary study no significant differences were found between intra-articular Hyalgan and Jointex for pain relief. Further studies are needed to determine the long-term efficacy and the optimal treatment schedule. Disclosure of Interest None Declared

Background Anticentromere antibody (ACA) are considered a serological marker of systemic sclerosis (SSc), in particular of its limited form (lcSSc). They are rarely observed in other connective tissue diseases, but seldom are found associated with primary biliary cirrhosis (PBC). Objectives To evaluate the clinical heterogeneity of patients with anticentromere antibodies (ACA). Methods One hundred of patients sent to our Center because of ACA positivity, were retrospectively analyzed. There were 99 females with a follow-up period of at least 5 years. Results All patients had an autoimmune disease. Eighty-four had systemic sclerosis (SSc): 71 had lcSSc, 8 diffuse SSc (dcSSc) and 5 SSc sine scleroderma. In 17 patients (20.2%) SSc was associated with other autoimmune diseases, mostly with PBC (12 patients, 9 with lcSSc) and autoimmune thyroiditis (7 patients, 6 lcSSc). Two patients had SSc in overlap with rheumatoid arthritis (RA) and Sjögren’s syndrome (SS), respectively. Sixteen patients did not have SSc, but other rheumatic diseases: 9 had Undifferentiated Connective Tissue Disease, 2 Systemic Lupus Erythematosus, 2 SS and 2 RA in overlap with SS. Conclusions The presence of ACA does indicate an autoimmune disorder, mainly lcSSc, often in overlap with PBC. Therefore, the presence of ACA should deserve further examination, because marker of autoimmune disease. Disclosure of Interest None Declared

Systemic sclerosis (SSc) is a rare disease requiring multicentre collaboration to reveal comprehensive details of disease-related causes for morbidity and mortality. The European League Against Rheumatism (EULAR) Scleroderma Trials and Research (EUSTAR) group initiated a database to prospectively gather key data of patients with SSc using a minimal essential dataset that was reorganised in 2008 introducing new items. Baseline visit data of patients who were registered between 2004 and 2011 were analysed using descriptive statistics. In June 2011, 7655 patients (2838 with diffuse cutaneous (dc) and 4481 with limited cutaneous (lc) SSc who fulfilled the American College of Rheumatology diagnostic criteria had been registered in 174 centres, mainly European. The most prominent hallmarks of disease were Raynaud's phenomenon (96.3%), antinuclear antibodies (93.4%) and a typical capillaroscopic pattern (90.9%). Scleroderma was more common on fingers and hands than on any other part of the skin. Proton pump inhibitors (65.2%), calcium channel blockers (52.7%), and corticosteroids (45.3%) were most often prescribed. Among the immunosuppressant agents, cyclophosphamide was used more often in dcSSc than in lcSSc. The EUSTAR database provides an abundance of information on the true clinical face of SSc that will be helpful in improving the classification of SSc and its subsets and for developing more specific therapeutic recommendations.

Tenofovir is widely used as first-line treatment of HIV infection, although its use is sometimes complicated by a reversible proximal renal tubulopathy. We report the case of a 45-year-old woman with chronic HIV infection and personality disorder, who after 12 months of tenofovir, complained of fatigue, diffuse bone pain and gait disturbances. The elevated level of alkaline phosphatase, hypophosphatemia and inappropriate phosphaturia suggested the diagnosis of hypophosphatemic osteomalacia secondary to proximal renal tubulopathy. A dual-energy x-ray absorptiometry showed a bone mineral density below the expected range for age (lumbar spine Z-score −3.3, femoral neck Z-score −2.1). A whole body 99mTc-methylene diphosphonate bone scan showed multiple areas of increased focal activity in the lumbar and thoracic spine and in sacroiliac and hip joints consistent with pseudofractures. Two months after tenofovir discontinuation and administration of vitamin D and phosphate, osteomalacia-related symptoms disappeared. Eleven months later, bone and mineral metabolism data were normal and bone scintigraphy did not show any pathological findings. This report highlights the importance of considering the diagnosis of osteomalacia in patients treated with tenofovir and emphasizes the need for monitoring alkaline phosphatase, blood and urinary phosphate and creatinine, especially in patients with risk factors for bone disease.

Chronic inflammatory rheumatic diseases are associated with an increased risk of cardiovascular (CV) atherosclerotic events. The inflammatory state, which is the hallmark of chronic rheumatic diseases, is the important driving force for accelerated atherogenesis. Since the control of traditional risk factors alone is insufficient in reducing the risk, much attention has been directed towards the potential use of statins. Statins, a family of drugs that suppress cholesterol biosynthesis by inhibiting the hydroxymethyl glutaryl coenzyme A reductase, have been shown to significantly reduce CV-related morbidity and mortality. In addition to lower lipid levels, several non-lipid lowering pleiotropic effects, including anti-inflammatory and immunomodulatory activities, make statins potential therapeutic agents in chronic rheumatic diseases. However, lipid metabolism in chronic rheumatic diseases is complex, since inflammatory states can induce alterations in lipid levels and function, so that cholesterol target levels from general guidelines may not be adequate in chronic inflammatory rheumatic diseases. Larger trials are needed to refine the precise benefits and health-utility associated with this therapy.

Pulmonary hypertension is a severe and rapidly progressive disease, particularly frequent in patients with rheumatic diseases. The aims of this study were the following: to determine the prevalence of pulmonary hypertension in Italian patients with autoimmune rheumatic diseases, and to evaluate if the presence of a rheumatic disease in general, or of a specific autoimmune rheumatic disease, is a risk factor for the development of pulmonary hypertension. One hundred and thirteen Italian patients with connective tissue diseases (105 females, 8 males), aged 19 to 83 yrs, entered the study. Fifty-one had systemic sclerosis (SSc): 49 were females, 2 males, aged 34 to 83 yrs; 41 had limited cutaneous SSc, 8 diffuse cutaneous SSc, and 2 SSc sine scleroderma. Thirty-three patients had systemic lupus erythematosus (SLE): all but one were females, their age ranged from 19 to 82 yrs. Twenty-five had rheumatoid arthritis (RA): 21 females, 4 males, aged 26 to 45 yrs. Three females and one male, 51-77 yrs, had mixed connective tissue disease (MCTD). Systolic pulmonary arterial pressure (SPAP) was assessed by Doppler echocardiography. Twenty three patients had pulmonary hypertension, which was more frequent in MCTD than in SLE (75% vs 6.1%, p=0.0002) or in AR (20%, p=0.0313). Pulmonary hypertension was more frequent in SSc than in SLE (25.5% vs 6.1%, p=0.0028) and in limited than in diffuse SSc (21.6% vs 3.9%). SPAP was significantly related to age (r=0.35, p=0.0275), with patients with pulmonary hypertension older than patients with normal SPAP (66+/-13 vs 52+/-16 yrs, p=0.0003). These data show a significant association between pulmonary hypertension and autoimmune rheumatic diseases. Therefore, pulmonary hypertension assessment seems mandatory, at least in MCTD and SSc. However, more studies are needed to clarify the relationship between age and pulmonary hypertension and to verify whether the low prevalence of pulmonary hypertension we found in our SLE patients is related or not to their lower age.