Paraneoplastic rheumatic disorders: a narrative review.

Paraneoplastic syndromes (PS) are a heterogeneous group of diseases related to a neoplasm, indirectly dependent on it. Diagnosis and the treatment are often a challenge for clinicians, not least because the pathogenetic mechanisms are highly complex and not entirely known. Nonetheless, in most cases, PS precede the diagnosis of malignancies, thus their identification is particularly important in addressing physicians' diagnostic work-up with regard to early cancer diagnosis. Among paraneoplastic syndromes, those of rheumatologic interest represent a large component. In this paper, we review the main rheumatic PS.

Micro and nanoparticles as possible pathogenetic co-factors in mixed cryoglobulinemia.

BACKGROUND: Mixed cryoglobulinemia (MC) is a rare multisystem disease whose aetiopathogenesis is not completely understood. Hepatitis C virus (HCV) infection may have a causative role, and genetic and/or environmental factors may also contribute. AIMS: To investigate the presence and possible role of environmental agents in MC. METHODS: We recruited 30 HCV-infected MC patients with different clinical manifestations and a control group of 30 healthy, sex-/age-matched volunteers. We collected serum samples from each patient and incubated at 4°C for 7 days to obtain cryoprecipitate samples. We used environmental scanning electron microscopy (ESEM) and energy dispersive X-ray spectroscopy microanalysis to verify the presence of microparticles (MPs) and nanoparticles (NPs) in serum and cryoprecipitate samples. We evaluated environmental exposure using a medical and occupational history questionnaire for each subject. RESULTS: MC patients had a significantly higher risk of occupational exposure (OR 5.6; 95% CI 1.84-17.50) than controls. ESEM evaluation revealed a significantly higher concentration, expressed as number of positive spots (NS), of serum inorganic particles in MC patients compared with controls (mean NS 18, SD = 16 versus NS 5.4, SD = 5.1; P < 0.05). Cryoprecipitate samples of MC patients showed high concentrations of inorganic particles (mean NS 49, SD = 19). We found a strong correlation between NS and cryocrit (i.e. percentage of cryoprecipitate/total serum after centrifugation at 4°C) levels (P < 0.001). CONCLUSIONS: In addition to HCV infection, MPs and NPs might play an important role in the aetiopathogenesis of MC.

Predictive value of isolated DLCO reduction in systemic sclerosis patients without cardio-pulmonary involvement at baseline.

Impaired diffusing capacity of the lung for carbon monoxide (DLCO) was frequently observed in systemic sclerosis (SSc) patients, generally related to the presence of interstitial lung disease (ILD) and/or pulmonary arterial hypertension (PAH). However, in clinical practice abnormally low DLCO values may be found also in the absence of these SSc complications. The objective was to investigate the prospective clinical relevance of isolated DLCO reduction at baseline in SSc patients. Ninety-seven SSc female patients (age at the diagnosis: 51.3±14.5 years; disease duration: 10.4±6.6 years; limited/diffuse skin subsets: 92/5), without any clinical, radiological (high resolution computed tomography), and echocardiographic manifestations of ILD or PAH at baseline, nor other lung or heart diseases able to affect DLCO, were recruited at our Rheumatology Centre. Patients with DLCO <55% (15 patients; group A) were compared with those with normal DLCO (82 patients; group B), at baseline and at the end of follow-up. At baseline, patients of group A showed significantly higher percentage of anticentromere autoantibodies compared to group B (13/15, 86.6% vs 48/82, 58.5%; p=0.044). More interestingly, at the end of long-lasting clinical follow-up (11.6±6.7 years), pre-capillary PAH (right heart catheterization) solely developed in some patients of group A (3/15, 20% vs 0/82; p=0.003). In SSc patients, the presence at baseline of isolated, marked DLCO reduction (<55% of predicted) and serum anticentromere autoantibodies might characterize a peculiar SSc subset that may precede the development of PAH. Therefore, careful clinical follow-up of patients with isolated moderate-severe DLCO reduction should be mandatory.

IP-10 in autoimmune thyroiditis.

The interferon-γ-inducible protein 10 (IP-10) was initially identified as a chemokine that is induced by interferon (IFN)-γ. IP-10 exerts its function through binding to chemokine (C-X-C motif) receptor 3 (CXCR3). IP-10 and its receptor, CXCR3, appear to contribute to the pathogenesis of many autoimmune diseases, organ specific (such as type 1 diabetes, Graves' disease and ophthalmopathy), or systemic (such as systemic lupus erythematosus, mixed cryoglobulinemia, Sjogren syndrome, or systemic sclerosis). The secretion of IP-10 by (CD)4+, CD8+, and natural killer is dependent on IFN-γ. Under the influence of IFN-γ, IP-10 is secreted by thyrocytes. Determination of high level of IP-10 in peripheral fluids is therefore a marker of a T helper 1 orientated immune response. High levels of circulating IP-10, have been shown in patients with autoimmune thyroiditis (AT). Among patients with AT, IP-10 levels were significantly higher in those with a hypoechoic ultrasonographic pattern, which is a sign of a more severe lympho-monocytic infiltration, and in those with hypothyroidism. For these reasons, it has been postulated that IP-10 could be a marker of a stronger and more aggressive inflammatory response in the thyroid, subsequently leading to thyroid destruction and hypothyroidism. Further studies are needed to investigate whether IP-10 is a novel therapeutic target in AT.

Lung involvement in systemic sclerosis: role of high resolution computed tomography and its relationship with other pulmonary and clinico-serological features.

The study investigated the characteristic of interstitial lung disease in a large series of systemic sclerosis (SSc) patients by means of HRCT and the correlations between functional lung parameters, serological features and the extent of lung involvement evaluated by high-resolution computed tomography (HRCT). One hundred and seven SSc patients, consecutively investigated by means of HRCT, standard chest X-ray, and pulmonary function tests, were retrospectively evaluated. Chest radiogram and HRCT scores were strongly associated (Pearson’'s r=0.82, p < .0001); moreover, the first significantly correlated with spirometric parameters, even if weakly. Anti-Scl70 and anti-centromere antibodies were associated with higher (p=0.01) and lower HRCT score (p=0.0002), respectively. The extension of interstitial lung involvement in SSc evaluated with HRCT is directly proportional to functional lung parameters. HRCT, spirometry and DLco should be considered essential in the core-set of non-invasive diagnostic tools for the first-line assessment of scleroderma lung involvement.

Peroxisome proliferator-activated receptor γ agonists reduce cell proliferation and viability and increase apoptosis in systemic sclerosis fibroblasts.

BACKGROUND: No study has evaluated the effect of the peroxisome proliferator-activated receptor γ (PPARγ) agonists on cell viability, proliferation and apoptosis in cultured systemic sclerosis (SSc) fibroblasts. OBJECTIVES: The effects of two pure PPARγ agonists (rosiglitazone and pioglitazone) in cultured SSc fibroblasts were evaluated and compared with effects in normal fibroblasts. METHODS: The study included evaluation of cell viability and proliferation (based on the cleavage of tetrazolium salts and measurement of absorbance of the cell proliferation reagent WST-1), and determination of cell apoptosis (by means of the Hoechst dye uptake). RESULTS: Rosiglitazone or pioglitazone (20µmolL(-1) ) significantly reduced cell proliferation (cell count of 75% and 83% compared with baseline, respectively, after 2h) and cell viability (absorbance reductions of 25% and 22% compared with baseline, respectively, after 2 h), and increased apoptosis (apoptotic cell percentages 9·9% and 8·6%, respectively, after 48h of incubation) in SSc fibroblasts, whereas they did not present a significant influence on control fibroblasts. CONCLUSIONS: The effects of rosiglitazone or pioglitazone shown on SSc fibroblasts raise the hypothesis of a therapeutic role for PPARγ agonists in patients affected by SSc.

High circulating chemokines (C-X-C motif) ligand 9, and (C-X-C motif) ligand 11, in hepatitis C-associated cryoglobulinemia.

(C-X-C motif) ligand 9 and (C-X-C motif) ligand 11 (CXCL9 and CXCL11), are potent chemoattractants for activated T cells, and play an important role in T helper 1 (Th)1 cell recruitment in chronic hepatitis C. No study has evaluated CXCL9, together with CXCL11, circulating levels in patients with mixed cryoglobulinemia and hepatitis C (MC+HCV-p). The aim of the present study therefore was to measure serum CXCL9, and CXCL11 levels, in MC+HCV-p, and to relate the findings to the clinical phenotype. Serum CXCL9 and CXCL11 were measured in 71 MC+HCV-p and in matched controls. MC+HCV-p showed significantly higher mean CXCL9 and CXCL11 levels than controls (P less than 0.001, for both), in particular, in 32 patients with active vasculitis (P less than 0.001). By defining high CXCL9 or CXCL11 level as a value of at least 2 SD above the mean value of the control group ( greater than 100 pg/mL): 89 percent MC+HCV-p and 5 percent controls had high CXCL9 (P less than 0.0001, chi-square); 90 percent MC+HCV-p and 6 percent controls had high CXCL11 (P less than 0.0001, chi-square). In a multiple linear regression model of CXCL9 vs age, ALT, CXCL11, only CXCL11 was significantly (r = 0.452, P less than 0.0001) and independently related to CXCL9. Our study demonstrates in MC+HCV-p vs controls: (i) high serum CXCL9, and CXCL11, significantly associated with the presence of active vasculitis; (ii) a strong relationship between circulating CXCL9 and CXCL11. Future studies on a larger cohort of patients are needed to evaluate the relevance of serum CXCL9 and CXCL11 determination as clinico-prognostic marker of MC+HCV.

Systematic review of 2008-2012 literature and update of recommendations for the use of methotrexate in rheumatic diseases, with a focus on rheumatoid arthritis.

The objective of this review is to update the recommendations of the 2010 Italian Consensus on the use of methotrexate (MTX) in rheumatoid arthritis (RA) and other rheumatic diseases. The literature published between 2008 and 2012 was systematically reviewed and updated recommendations on MTX use in rheumatic diseases, particularly RA, were formulated. These recommendations were approved by a panel of expert Italian Rheumatologists. A total of 10,238 references were identified, among which 70 studies were selected for critical evaluation. Sufficient evidence had accumulated to warrant changes to several of the recommendations in the new version. A new recommendation for patients with RA who are in MTX-induced clinical remission was also proposed and approved by the panel. Updated recommendations for the use of MTX in patients with RA or other rheumatologic disease are proposed.

Predictive role of capillaroscopic skin ulcer risk index in systemic sclerosis: a multicentre validation study.

UNLABELLED: Introduction The early detection of systemic sclerosis (SSc) patients at high risk of developing digital ulcers could allow preventive treatment, with a reduction of morbidity and social costs. In 2009, a quantitative score, the capillaroscopic skin ulcer risk index (CSURI), calculated according to the formula 'D×M/N(2'), was proposed, which was highly predictive of the appearance of scleroderma digital ulcers within 3 months of capillaroscopic evaluation. OBJECTIVES: This multicentre study aims to validate the predictive value and reproducibility of CSURI in a large population of SSc patients. METHODS: CSURI was analysed in 229 unselected SSc patients by nailfold videocapillaroscopy (NVC). All patients were re-evaluated 3 months later with regard to the persistence and/or appearance of new digital ulcers. RESULTS: 57 of 229 patients presented with digital ulcers after 3 months. The receiver operating characteristic curve analysis showed an area under the curve of 0.884 (95% CI 0.835 to 0.922), with specificity and sensitivity of 81.4% (95% CI 74.8 to 86.89) and 92.98% (95% CI 83.0 to 98.0), respectively, at the cut-off value of 2.96. The reproducibility of CSURI was validated on a random sample of 81 patients, with a κ-statistic measure of interrater agreement of 0.8514. CONCLUSIONS: The role of CSURI was confirmed in detecting scleroderma patients with a significantly high risk of developing digital ulcers within the first 3 months from NVC evaluation. CSURI is the only method validated to predict the appearance of digital ulcers and its introduction into routine clinical practice might help optimise the therapeutic strategy of these harmful SSc complications.

Aortic pulse wave velocity measurement in systemic sclerosis patients.

BACKGROUND: Systemic sclerosis (SSc) is characterized by endothelial dysfunction and widespread microangiopathy. However, a macrovascular damage could be also associated. Aortic pulse wave velocity (aPWV) is known to be a reliable indicator of arterial stiffness and a useful prognostic predictor of cardiovascular events. Moreover, aPWV may be easily measured by non-invasive, user-friendly tool. Aim of our study was to evaluate aPWV alterations in a series of SSc patients. METHODS: The aPWV was evaluated in 35 consecutive female SSc patients and 26 sex- and age-matched healthy controls. aPWV alterations were correlated with cardiopulmonary involvement. RESULTS: A significant increase of aPWV was observed in SSc patients compared to controls (9.4 ± 3.2 m/s vs 7.3 ± 1 m/s; P = 0.002). In particular, 14/35 (40%) SSc patients and only 1/26 (4%) controls (P=0.0009) showed increased aPWV (>9 m/s cut-off value). Moreover, echocardiography evaluation showed an increased prevalence of right atrial and ventricular dilatation (atrial volume: 23.6 ± 6.2 mL vs 20.3 ± 4.3 mL, P=0.026; ventricular diameter 19.5 ± 4.9 mm vs 15.9 ± 1.6 mm; P=0.001) associated to higher values of pulmonary arterial systolic pressure (PAPs) in SSc patients (31.5 ± 10.4 mmHg vs 21.6 ± 2.9 mmHg; P<0.0001; 40% of SSc patients showed an abnormal PAPs). Clinically, SSc patients presented a reduction of six-minute walking test (413 ± 96 m vs 491 ± 49 m; P=0.001), not correlated with pulmonary function tests. Increased aPWV values were evidenced only in SSc patients >50 years old. Furthermore, altered aPWV was more frequently associated with limited cutaneous pattern, longer disease duration (≥ 5 years), and/or presence of anticentromere antibody (ACA). CONCLUSIONS: A significantly higher prevalence of abnormally increased aPWV was evidenced in SSc patients compared to healthy controls. The possibility of more pronounced and diffuse vascular damage in a particular SSc subset (ACA-positive subjects with limited cutaneous scleroderma and longer disease duration) might be raised.

IFN-γ and TNF-α induce a different modulation of interleukin-6 in systemic sclerosis fibroblasts compared to healthy controls.

BACKGROUND: To our knowledge, no previous study has evaluated the effect of interferon (IFN)-γ, tumour necrosis factor (TNF)-α, or their combination on the prototype proinflammatory cytokine interleukin (IL)-6 in primary cultured fibroblasts from patients with systemic sclerosis (SSc) at an early stage of the disease. METHODS: Fibroblast cultures from five SSc patients (disease duration < 2 years) and five healthy controls were evaluated for the basal production of IL-6, and after stimulation with TNF-α or IFN-γ, alone or combined. RESULTS: The fibroblasts from SSc patients produced higher levels of IL-6 in basal condition than controls [617 ± 173 vs. 213 ± 123 pg/mL; analysis of variance (ANOVA), p < 0.001]. TNF-α was able to dose-dependently induce IL-6 in SSc (609 ± 184, 723 ± 243, 1079 ± 297, 1436 ± 326 pg/mL, with TNF-α 0, 1, 5, 10 ng/mL, respectively) but not in control fibroblasts, whereas IFN-γ was unable to induce IL-6. Furthermore, the combination of IFN-γ and TNF-α induced a stronger secretion of IL-6 in SSc fibroblasts (ANOVA, p < 0.0001), without effect in controls. CONCLUSIONS: SSc fibroblasts participate in the self-perpetuation of inflammation by releasing IL-6, under the influence of TNF-α and/or IFN-γ.

High levels of circulating N-terminal pro-brain natriuretic peptide in patients with hepatitis C.

Many patients chronically infected by hepatitis C virus (HCV) experience symptoms like fatigue, dyspnea and reduced physical activity. However, in many patients, these symptoms are not proportional to the liver involvement and could resemble symptoms of chronic heart failure. To our knowledge, no study evaluated serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) in a large series of patients with HCV chronic infection (HCV+). Serum NT-proBNP was assayed in 50 patients HCV+ and in 50 sex- and age-matched controls. HCV+ patients showed significantly higher mean NT-proBNP level than controls (P = 0.001). By defining high NT-proBNP level as a value higher than 125 pg/mL (the single cut-off point for patient under 75 years of age), 34% HCV+ and 6% controls had high NT-proBNP (Fisher exact test; P < 0.001). With a cut-off point of 300 pg/mL (used to rule out chronic heart failure in patients under 75 years of age) 10% HCV+ and 0 controls had high NT-proBNP (Fisher exact test; P = 0.056). With a cut-off point of 900 pg/mL (used for ruling in chronic heart failure in patients with age 50-75) 8% HCV+ patients and 0 controls had high NT-proBNP (Fisher exact test; P = 0.12). The study demonstrates high levels of circulating NT-proBNP in HCV+ patients compared to healthy controls. The increase of NT-proBNP may indicate the presence of a sub-clinical cardiac dysfunction. Further prospective studies quantifying these symptoms in correlation with echocardiography are needed to confirm this association.

Bronchoalveolar lavage and response to cyclophosphamide in scleroderma alveolitis.

OBJECTIVES: Systemic sclerosis (SSc) is characterized by abnormal fibrosis of the skin and internal organs, particularly the lungs. Recent reports have revealed a lack of correlation between bronchoalveolar lavage (BAL) variations and response to cyclophosphamide (CYC) in patients with scleroderma-related alveolitis. Our study aimed to evaluate whether the normalization of BAL cellularity correlates with long-term response to CYC. METHODS: We retrospectively studied 26 consecutive SSc patients with alveolitis diagnosed by BAL and treated with CYC therapy (cumulative dosage 26.5 +/- 11.7 g; 21.1 +/- 8.9 months of treatment). We evaluated high-resolution computed tomography (HRCT), forced vital capacity (FVC), and carbon monoxide diffusing capacity (DLCO) variations before and after CYC. Radiological and functional parameters were re-evaluated in 23 patients after 1-year follow-up. RESULTS: BAL cellularity normalized after CYC therapy in 12/26 (46.2%) patients (group 1), while it remained abnormal in 14/26 (53.8%) (group 2). FVC and DLCO of group 1 slightly increased after CYC (p = 0.014 and p = 0.07, respectively) and remained stable at follow-up, whereas in group 2 they did not change after CYC and at follow-up (p = not significant). Moreover, at the end of CYC, FVC and/or DLCO showed a clinical improvement/stabilization in all patients of group 1 versus 8/14 of group 2, while at the re-evaluation 1 year after completing CYC, 2/11 patients of group 1 worsened versus 5/12 of group 2. HRCT progression was observed in 1/11 of group 1 and 8/12 of group 2 (p = 0.009). CONCLUSIONS: BAL fluid normalization after CYC therapy correlated with long-term response to treatment, contrary to what is observed in individuals with persistent alveolitis.

Recombinant human erythropoietin stimulates vasculogenesis and wound healing in a patient with systemic sclerosis complicated by severe skin ulcers.

Systemic sclerosis (SSc) is often complicated by severe skin ulcers that are unresponsive to traditional treatments. Vascular alterations are responsible for the ischaemic features of the disease in both the skin and visceral organs. Defective neoangiogenesis correlates with an abnormally reduced quantity of circulating endothelial progenitor cells (EPCs) caused by impaired maturation potential and proliferative capacity of bonemarrow endothelial stem cells. We report a patient with nonhealing cutaneous ulcers successfully treated with recombinant human erythropoietin (rHuEPO). The possible biological effects of this drug were also investigated. Before rHuEPO treatment, the bone-marrow sample contained reduced numbers of EPCs, which were functionally impaired. After a 6-month rHuEPO cycle, a marked increase in endothelial progenitor markers was seen, along with a significant reduction in their apoptotic rates. The clinical and laboratory data variations before and after rHuEPO treatment give new insights into the pathogenetic role of impaired endothelial stem-cell maturation and defective neoangiogenesis in patients with SSc.

CXCL10 (alpha) and CCL2 (beta) chemokines in systemic sclerosis--a longitudinal study.

OBJECTIVES: To measure serum levels of CXCL10 and CCL2 chemokines in patients with SSc, and relate the findings to clinical phenotype and disease progression. METHODS: Serum CXCL10 and CCL2 were assayed in 72 consecutive newly diagnosed SSc patients and in 72 sex- and age-matched controls. In 37 SSc and 37 controls, serum CXCL10 and CCL2 were re-evaluated 5 yrs later. RESULTS: SSc at onset showed significantly higher CXCL10 serum levels than controls (216 +/- 126 vs 92 +/- 53 pg/ml; P < 0.0001), as well as CCL2 (388 +/- 172 vs 318 +/- 120 pg/ml; P = 0.01). CXCL10 was significantly increased in SSc with interstitial lung involvement or with kidney involvement (P = 0.01 and P = 0.02, respectively). A significant decrease of CXCL10 was observed from the baseline after 5 yrs in SSc (137 +/- 112 vs 270 +/- 122 pg/ml, respectively; P < 0.0001), while no significant change was observed for CCL2 (418 +/- 176 vs 405 +/- 164 pg/ml; P = NS); the CCL2/CXCL10 ratio significantly increased at the fifth year (1.7 +/- 0.8 vs 3.5 +/- 2.5; P < 0.0001). No significant variations were observed in controls from the basal to the 5-yr evaluation with regards to CXCL10, CCL2 or CCL2/CXCL10 ratio. CONCLUSIONS: Our study demonstrates high serum levels of CXCL10 (Th1) and CCL2 (Th2) chemokines in newly diagnosed SSc. High values of CXCL10 are associated with a more severe clinical phenotype (lung and kidney involvement). CXCL10 declined during the follow-up, while CCL2 remained unmodified, suggesting that the disease progresses from the early Th1 inflammatory condition to the advanced Th2-like stage.

Cardiovascular risk and prostanoids in systemic sclerosis.

OBJECTIVE: Systemic sclerosis (SSc) is characterized by Raynaud's phenomenon and frequent cutaneous ulcers. In patients resistant to oral treatments, i.v. prostanoids are usefully employed. Some anecdotal reports underlined the potential risk to develop cardiovascular ischemic complications in prostanoid-treated SSc patients. METHODS: Fifty SSc patients (group 1: 44 female and 6 male, mean age 60.4 +/- 13.8SD) undergoing long-term prostanoid therapy (iloprost or alprostadil) and 42 control patients (group 2), treated with only oral drugs, were retrospectively evaluated for the cardiovascular risk and incidence of ischemic events. RESULTS: Ischemic cardiovascular complications, i.e., myocardial infarction or stroke, were recorded in a significantly higher number of patients undergoing prostanoid treatment compared to controls (group 1: 7/50, 14% vs. group 2: 1/42, 2.4%; p=0.041). Interestingly, these events were significantly more frequent in the subgroup of patients with high cardiovascular risk (group 1: 6/10, 60% vs. group 2: 1/19, 5.2%; p=0.0026). CONCLUSION: The present study suggests a possible role of prostanoid treatment in the pathogenesis of ischemic cardiovascular complications in SSc patients non-responders to oral vasodilators and high cardiovascular risk. Since prostanoids represent the first choice treatment of the most severe scleroderma ischemic cutaneous lesions, cardiovascular risk should be carefully evaluated in all patients before therapy.

[Correlation of a quantitative videocapillaroscopic score with the development of digital skin ulcers in scleroderma patients]. / Correlazione di uno score quantitativo capillaroscopico con lo sviluppo di ulcere ischemiche digitali nei pazienti con sclerosi sistemica.

BACKGROUND: Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and visceral organs. The microangiopathy is early detectable in the course of the disease by nailfold videocapillaroscopy (NVC), a non-invasive technique with a high diagnostic value. OBJECTIVE: Aim of our study was to evaluate the feasibility of a quantitative score and its correlation with the digital skin ulcers, which frequently complicate SSc microangiopathy. METHODS: We retrospectively analysed the NVC of 65 SSc patients, performed by 200x videocapillaroscopy connected to image analyse software (Videocap; DS MediGroup, Milan, Italy). The analysis of NVC images included: total number of capillaries in the distal row (N), maximum diameter (D) and number of giant capillaries (M), M/N ratio and percentage of M, presence/absence of micro-haemorrhages and tortuosity. RESULTS: 21/65 SSc patients experienced digital ulcers within three months after the NVC examination. The N, D, M/N, and percentage of M significantly correlated with the appearance of ischemic ulcers. A multiple regression analysis showed a statistically significant correlation for N, M/N and D, while sensitivity and specificity of these parameters were unsatisfactory. A capillaroscopic score, according to the formula D x M/N2, showed a high specificity and sensibility (93.2% and 85.7% respectively; area under ROC curve: 0.918) to predict the appearance of digital ulcers. CONCLUSIONS: This capillaroscopic score may represent a feasible and simple tool in SSc patients' assessment. The routinely use of this parameter might permit to recognize and to preventively treat SSc patients at high risk to develop digital ulcers.

The safety of iloprost in systemic sclerosis in a real-life experience.

Iloprost (ILO) is employed intravenously for the treatment of severe Raynaud phenomenon (RP) and digital ulcers (DU) in systemic sclerosis (SSc). The aim of this study was to evaluate the safety and tolerability of the intravenous treatment with ILO in different phases of SSc. Eighty-one consecutive non-selected SSc patients, all on nifedipine, with moderate RP, treated with ILO infusion, were retrospectively evaluated. Patients were sub classified according to the edematous or fibrotic/atrophic cutaneous phase of the disease. ILO was infused with a progressive increase of the dosage up to the achievement of patient's tolerance, 1 day/week. In cases of slower infusion regimen due to adverse events (AE) at the beginning of the administration, patients received a lower dose of the drug (not possible to quantify precisely the final cumulative dosage). 16/81 SSc patients presented digital edema, 5 developed diarrhea, and 9 developed transient hypotension during the infusion at 20 ml/h that ameliorated when the drug was withdrawn. Moreover, 10/16 edematous patients experienced significant and painful digital swelling, unlike patients in the fibrotic group (p < 0.0001); 11/16 patients reported flushing and 7/16 headache, always controlled with dose tapering below 10 ml/h. In the atrophic/fibrotic phase patients (65/81), 10 developed diarrhea and 24 hypotension at infusion rate of 20 ml/h that led to temporary withdrawal of the drug. When ILO was restarted and kept below 10 ml/h, no side effects were experienced. 23/65 patients experienced flushing and 8/65 headache, all controlled with infusion reduction below 10 ml/h. In these patients, adverse events were significantly less frequent than in the edematous group (p = 0.023 and p = 0.008, respectively). Our data suggest that calcium channel blockers should be transitorily stopped while using ILO and that a pre-treatment approach might reduce or control adverse events. In patients with digital edema, ILO infusion should be carefully employed after the evaluation of patient's drug tolerance.

Haematological Malignancies in Systemic Sclerosis Patients: Case Reports and Review of the World Literature.

Background. The association of systemic sclerosis (SSc) and haematological cancers was reported in a large number of case reports and cohort studies, describing SSc patients with highly heterogeneous clinical pictures. Objective. We reviewed the literature to better describe SSc patients with haematological malignancies. Methods. SSc cases complicated by haematological malignancies described in the world literature were collected; other 2 cases referred to our centre were reported. Results. One hundred-thirty SSc subjects were collected from 1954 up to date. The mean age of patients at cancer diagnosis was 56.1 ± 16.7 years; 72% of patients were females. In 60% of cases, the diagnosis of haematological malignancy was described within 5 years of SSc diagnosis. In 7.8% of cases, coexistence of Sjögren's syndrome or other autoimmune disorders was cited. Sixty-six cases with lymphoma (in the majority of cases B-cell neoplasms), 28 with leukaemia (chronic lymphocytic form in 9), 14 with multiple myeloma plus one solitary IgM plasmocytoma, and 16 with myeloproliferative disorders were found. No specific SSc subsets seem to be related to haematological malignancies. Conclusions. We remarked the importance of clinical work-up in SSc, in order to early diagnose and treat eventual occult haematological malignancies, especially during the first years of the disease.

Serum 25-OH vitamin D levels in systemic sclerosis: analysis of 140 patients and review of the literature.

Hypovitaminosis D is increasingly reported in autoimmune diseases. We investigated the 25-OH-vitamin D (25-OH-vitD) levels in systemic sclerosis (SSc) patients, in correlation with disease's features. We measured the 25-OH-vitD serum levels in 140 consecutive patients (F/M 126/15; mean age 61 ± 15.1 years), 91 without (group A) and 49 with (group B) 25-OH-cholecalciferol supplementation. Patients of group A invariably showed low 25-OH-vitD levels (9.8 ± 4.1 ng/ml vs. 26 ± 8.1 ng/ml of group B); in particular, 88/91 (97%) patients showed vitamin D deficiency (<20 ng/ml), with very low vitamin D levels (<10 ng/ml) in 40 (44%) subjects. Only 15/49 (30.6%) patients of group B reached normal levels of 25-OH-vitD (≥30 ng/ml), whereas vitamin D deficiency persisted in 12/49 (24.5%) individuals. Parathormone levels inversely correlated with 25-OH-vitD (r = -0.3, p < 0.0001). Of interest, hypovitaminosis D was statistically associated with autoimmune thyroiditis (p = 0.008), while calcinosis was more frequently observed in patients of group A (p = 0.057). Moreover, we found significantly higher percentage of serum anticentromere antibodies in group B patients with 25-OH-vitD level ≥30 ng/ml (8/15 vs. 6/34; p = 0.017). In literature, hypovitaminosis D is very frequent in SSc patients. An association with disease duration, calcinosis, or severity of pulmonary involvement was occasionally recognized. Hypovitaminosis D is very frequent in SSc and severe in a relevant percentage of patients; furthermore, less than one third of supplemented subjects reached normal levels of 25-OH-vitD. The evaluation of 25-OH-vitD levels should be included in the routine clinical work-up of SSc. The above findings expand previous observations and may stimulate further investigations.