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Reconstructive microsurgery is performed to reattach, transfer, or transplant body tissues. Venous congestion is a complication that threatens the viability of the affected tissue and is often treated with medicinal leeches. Leech therapy has two phases: active bloodletting and passive bleeding from the leech wound after detachment, which can last for several hours. Unfortunately, the small blood volumes removed by medicinal leeches are generally ineffective in decongesting tissue. Our goal was to develop a device to augment blood removal during the passive-bleeding phase of leech therapy with the use of a porcine model of venous congestion. Results indicated that the use of the device resulted in significant increases in blood retrieval relative to reports of passive bleeding alone (141%, 156%, and 155% in 1, 2, and 3 hours, respectively). These results are an encouraging first step toward development of a mechanical device that completely replaces the use of medicinal leeches in modern medicine. [ABSTRACT FROM AUTHOR]

Medicinal leeches are used to treat venous congestion, a complication of reconstructive surgery. Despite substantial drawbacks of leeching, little progress has been made to develop a device that would replace the leech for this purpose. The goal of this study was to develop and test mechanical prototypes for the treatment of venous congestion. We tested four prototypes (1, 2, 3a, and 3b) using congested fasciocutaneous flaps in swine. Blood removed by each prototype was measured for up to 4 hours. On average, the four prototypes removed 609%, 644%, 853%, and 811% more blood, respectively, from congested flaps versus a leech. Prototypes 3a and 3b, which allowed for innovative subcutaneous chemical (3a and 3b) and mechanical (3b) anticoagulation at the bleeding wound, sustained high levels of blood removal for up to 4 hours. Thus, a mechanical device can potentially replace the use of leeches for treating venous congestion. [ABSTRACT FROM AUTHOR]

Patients and health workers were at high risk of infection during the Sars-Cov-2 pandemic lockdown. For this reason, other medical and clinical approaches such as Telemedicine were necessary. Despite Telemedicine was born before COVID-19, the pandemic was the opportunity to accelerate a process already underway for at least a decade and to blow all the barriers away. Our aim is to describe the experience of Telemedicine during and immediately after the first lockdown to assure the follow-up in a 'virtual' outpatient clinic dedicated to Rheumatic and Musculoskeletal Diseases (RMDs) and to give an overview of Telemedicine in the rheumatology field. We retrospectively evaluated the patient flow to our rheumatology division from March to September 2020 and, in accordance with local restrictions, three periods were selected. In the 1st period, 96.96% of the outpatient clinic cases were shifted to Telemedicine; these decreased to 52.45% in the 2nd period, while the 3rd period was characterized by the return of the patients at the clinic (97.6%). Diagnostic procedures were postponed during the 1st period, reduced drastically during the 2nd and performed regularly during the third period. Intravenous infusions were maintained as much as possible during the three periods, to assure therapeutic continuity. Shifting stable patients to Telemedicine has the potential to allow continuity of care, while reducing the risk of contagion during a pandemic. In the next future, the integration of Telemedicine as standard of care for specific clinical applications might assure assistance for RMDs patients also in non-pandemic conditions., (© 2021. International League of Associations for Rheumatology (ILAR).)

Background: A high percentage of patients with systemic sclerosis (SSc) develop interstitial lung disease (ILD) during the course of the disease. Promising data have recently shown that lung ultrasound (LUS) is able to detect ILD by the evaluation of B-lines (previously called ultrasound lung comets), the sonographic marker of pulmonary interstitial syndrome., Objective: To evaluate whether LUS is reliable in the screening of ILD in patients with SSc., Methods: Fifty-eight consecutive patients with SSc (54 women, mean age 51±14 years) who underwent a high resolution CT (HRCT) scan of the chest were also evaluated by LUS for detection of B-lines. Of these, 32 patients (29 women, mean age 51±15 years) fulfilled the criteria for a diagnosis of very early SSc., Results: At HRCT, ILD was detected in 88% of the SSc population and in 41% of the very early SSc population. A significant difference in the number of B-lines was found in patients with and without ILD on HRCT (57±53 vs 9±9; p<0.0001), with a concordance rate of 83%. All discordant cases were false positive at LUS, providing a sensitivity and negative predictive value of 100% in both SSc and very early SSc., Conclusions: ILD may be detected in patients with very early SSc. The presence of B-lines at LUS examination correlates with ILD at HRCT. LUS is very sensitive for detecting ILD even in patients with a diagnosis of very early SSc. The use of LUS as a screening tool for ILD may be feasible to guide further investigation with HRCT.

Objective: Systemic sclerosis (SSc) is characterized by early perivascular inflammation, microvascular endothelial cell (MVEC) activation/damage, and defective angiogenesis. Junctional adhesion molecules (JAMs) regulate leukocyte recruitment to sites of inflammation and ischemia-reperfusion injury, vascular permeability, and angiogenesis. This study was undertaken to investigate the possible role of JAMs in SSc pathogenesis., Methods: JAM-A and JAM-C expression levels in skin biopsy samples from 25 SSc patients and 15 healthy subjects were investigated by immunohistochemistry and Western blotting. Subcellular localization of JAMs in cultured healthy dermal MVECs and SSc MVECs was assessed by confocal microscopy. Serum levels of soluble JAM-A (sJAM-A) and sJAM-C in 64 SSc patients and 32 healthy subjects were examined by enzyme-linked immunosorbent assay., Results: In control skin, constitutive JAM-A expression was observed in MVECs and fibroblasts. In early-stage SSc skin, JAM-A expression was strongly increased in MVECs, fibroblasts, and perivascular inflammatory cells. In late-stage SSc, JAM-A expression was decreased compared with controls. JAM-C was weakly expressed in control and late-stage SSc skin, while it was strongly expressed in MVECs, fibroblasts, and inflammatory cells in early-stage SSc. Surface expression of JAM-A was higher in early-stage SSc MVECs and increased in healthy MVECs stimulated with early-stage SSc sera. JAM-C was cytoplasmic in resting healthy MVECs, while it was recruited to the cell surface upon challenge with early-stage SSc sera. Early-stage SSc MVECs exhibited constitutive surface JAM-C expression. In SSc, increased levels of sJAM-A and sJAM-C correlated with early disease and measures of vascular damage., Conclusion: Our findings indicate that JAMs may participate in MVEC activation, inflammatory processes, and impaired angiogenesis in different stages of SSc., (Copyright © 2013 by the American College of Rheumatology.)

Objective: To determine serum concentrations and tissue expression of matrix metalloproteinase-12 (MMP-12) and their correlation with clinical features in patients with systemic sclerosis (SSc)., Methods: Serum MMP-12 levels from 72 patients with SSc and 42 healthy volunteers were examined by ELISA. Immunohistochemical expression of MMP-12 was analysed in skin biopsies from 20 patients with SSc and 13 healthy subjects and lung biopsies from three patients with SSc-related interstitial lung disease (ILD) and five controls., Results: Circulating levels of MMP-12 were significantly increased in patients with SSc compared with healthy controls. Serum MMP-12 levels were significantly higher in both patients with limited cutaneous SSc and those with diffuse cutaneous SSc than in healthy controls, and correlated positively with the extent of skin involvement. MMP-12 levels were raised in SSc patients with ILD compared with patients without ILD, and correlated with severity of lung restriction. Increased serum levels of MMP-12 were also associated with the presence of digital ulcers and severity of nailfold capillary abnormalities. In contrast to almost undetectable MMP-12 expression in healthy skin, MMP-12 was strongly expressed in keratinocytes, dermal endothelial cells, fibroblasts/myofibroblasts and inflammatory cells in the skin of patients with SSc. Affected lung tissue from patients with SSc-related ILD showed strong MMP-12 expression in capillary vessels, inflammatory cells, alveolar macrophages and fibroblasts in the thickened alveolar septa, while faint expression was observed in normal lung tissue., Conclusions: MMP-12 levels are increased in patients with SSc and are associated with severity of skin and pulmonary fibrosis and peripheral vascular damage.

Objective: Dysfunctional angiogenesis is a pathogenetic marker of SSc. Circulating levels of endothelial progenitor cells are reduced, and mesenchymal stromal cells show a reduced differentiation into endothelial cells and capacity to form capillaries. This suggests that pathophysiologically relevant changes may already exist in SSc bone marrow (BM) stromal cells that may affect downstream angiogenesis. The aim of this study is to evaluate, in SSc BM, angiogenesis, cellular immune system and fibrosis., Methods: Eight SSc patients affected by a severe dcSSc and screened for autologous haematopoietic stem cells transplantation (HSCT) underwent a BM biopsy. BM biopsies were compared with six healthy controls. To evaluate angiogenesis and cellular immunity, the following antibodies were used: vascular endothelial growth factor (VEGF), kinase insert domain-containing receptor/fetal liver kinase-1 (KDR/flk-1), MMP-9 and CD34. To evaluate fibrosis, silver impregnation for reticulum was used. The number of vessels, the mean area of vascularization, the perimeter and microvessel density (MVD) were measured with a multiparametric computerized imaging analysis., Results: A significant reduction in BM vascularity was found, while VEGF expression was much higher in SSc BM samples. Two patients had a Grade 2, whereas another two had a Grade 1 fibrosis., Conclusion: In SSc, BM is characterized by a reduction of microvascular density and number of vessels and a significant increase of VEGF. This indicates that BM may be involved in the process of loss of angiogenesis, despite the presence of high local and systemic levels of VEGF.

Objective: To characterise bone marrow-derived mesenchymal stem cells (MSCs) from patients with systemic sclerosis (SSc) for the expression of factors implicated in MSC recruitment at sites of injury, angiogenesis and fibrosis. The study also analysed whether the production/release of bioactive mediators by MSCs were affected by stimulation with cytokines found upregulated in SSc serum and tissues, and whether MSCs could modulate dermal microvascular endothelial cell (MVEC) angiogenesis., Methods: MSCs obtained from five patients with early severe diffuse SSc (SSc-MSCs) and five healthy donors (H-MSCs) were stimulated with vascular endothelial growth factor (VEGF), transforming growth factor β (TGFβ) or stromal cell-derived factor-1 (SDF-1). Transcript and protein levels of SDF-1 and its receptor CXCR4, VEGF, TGFβ(1) and receptors TβRI and TβRII were evaluated by quantitative real-time PCR, western blotting and confocal microscopy. VEGF, SDF-1 and TGFβ(1) secretion in culture supernatant was measured by ELISA. MVEC capillary morphogenesis was performed on Matrigel with the addition of MSC-conditioned medium., Results: In SSc-MSCs the basal expression of proangiogenic SDF-1/CXCR4 and VEGF was significantly increased compared with H-MSCs. SSc-MSCs constitutively released higher levels of SDF-1 and VEGF. SDF-1/CXCR4 were upregulated after VEGF stimulation and CXCR4 redistributed from the cytoplasm to the cell surface. VEGF was increased by SDF-1 challenge. VEGF, TGFβ and SDF-1 stimulation upregulated TGFβ(1), TβRI and TβRII in SSc-MSCs. TβRII redistributed from the cytoplasm to focal adhesion contacts. SSc-MSC-conditioned medium showed a greater proangiogenic effect on MVECs than H-MSCs. Experiments with blocking antibodies showed that MSC-derived cytokines were responsible for this potent proangiogenic effect., Conclusion: SSc-MSCs constitutively overexpress and release bioactive mediators/proangiogenic factors and potentiate dermal MVEC angiogenesis.

Objective: Cardiac involvement means a poor prognosis in systemic sclerosis (SSc). Conduction defects and arrhythmias are frequent in patients with SSc, and may result in sudden cardiac death. We tested whether electrophysiologic studies and implantation of cardioverter defibrillators are recommended when ventricular arrhythmias are present., Method: A cardioverter defibrillator was implanted in 10 patients with SSc who had heart involvement., Result: After 36 months, analysis of the device showed several episodes of ventricular tachycardia in 3 patients, which were promptly reverted by electrical shock delivery., Conclusion: In patients with SSc who are affected by ventricular arrhythmias, the implantation of a cardioverter defibrillator may prevent sudden cardiac death.

Rationale: Systemic sclerosis (SSc) is characterized by widespread microangiopathy, fibrosis, and autoimmunity. Despite the lack of angiogenesis, the expression of vascular endothelial growth factor A (VEGF) was shown to be upregulated in SSc skin and circulation; however, previous studies did not distinguish between proangiogenic VEGF(165) and antiangiogenic VEGF(165)b isoforms, which are generated by alternative splicing in the terminal exon of VEGF pre-RNA., Objective: We investigated whether VEGF isoform expression could be altered in skin and circulation of patients with SSc., Methods and Results: Here, we show that the endogenous antiangiogenic VEGF(165)b splice variant is selectively overexpressed at both the mRNA and protein levels in SSc skin. Elevated VEGF(165)b expression correlated with increased expression of profibrotic transforming growth factor-β1 and serine/arginine protein 55 splicing factor in keratinocytes, fibroblasts, endothelial cells, and perivascular inflammatory cells. Circulating levels of VEGF(165)b were significantly higher in patients with SSc than in control subjects. Microvascular endothelial cells (MVECs) isolated from SSc skin expressed and released higher levels of VEGF(165)b than healthy MVECs. Transforming growth factor-β1 upregulated the expression of VEGF(165)b and serine/arginine protein 55 in both SSc and healthy MVECs. In SSc MVECs, VEGF receptor-2 was overexpressed, but its phosphorylation was impaired. Recombinant VEGF(165)b and SSc-MVEC-conditioned medium inhibited VEGF(165)-mediated VEGF receptor-2 phosphorylation and capillary morphogenesis in healthy MVECs. The addition of anti-VEGF(165)b blocking antibodies abrogated the antiangiogenic effect of SSc-MVEC-conditioned medium. Capillary morphogenesis was severely impaired in SSc MVECs and could be ameliorated by treatment with recombinant VEGF(165) and anti-VEGF(165)b blocking antibodies., Conclusions: In SSc, a switch from proangiogenic to antiangiogenic VEGF isoforms may have a crucial role in the insufficient angiogenic response to chronic ischemia.

In Systemic Sclerosis (SSc), face involvement causes functional loss as well as aesthetic changes and loss of the self-image. The aim of the work is to evaluate the efficacy of a rehabilitation program based on the combination of Kabat's technique, connective massage and kinesitherapy specifically conceived for the face of SSc patients. Forty SSc patients were enrolled: 20 patients (interventional group) were treated for 9 weeks (twice a week, 1 h per session) with a combined connective tissue massage, Kabat's technique, kinesitherapy and home exercise program, and 20 patients (control group) were assigned only home exercise program. All patients were assessed at baseline (T0), at the end of the treatment (T1) and after 9 weeks of follow-up (T2). They were evaluated with SF-36, HAQ, modified Rodnan skin score, mouth opening in centimeters and Mouth Handicap in Systemic Sclerosis (MHISS) scale. At T1, both groups improved in mouth opening (P < 0.05), but the improvement was maintained at T2 only in interventional group. In interventional group, facial skin score ameliorated at T1 and maintained at T2 (P < 0.05 vs. T0), while no change was observed in controls. In both groups, SF-36 and HAQ were not affected by the treatment. MHISS scale improved significantly in interventional group at T1 (P < 0.001), while no change was found in controls. The combination of connective tissue massage, Kabat's technique, kinesitherapy and home-based exercises is more effective than a home exercise program alone in the rehabilitative treatment of SSc facial involvement.

Week Hospital is an innovative inpatient health care organization and management, by which hospital stay services are planned in advance and delivered on week-time basis to elective patients. In this context, a strategic decision is the optimal clinical management of patients, and, in particular, devising efficient and effective admission and scheduling procedures, by tackling different requirements such as beds' availability, diagnostic resources, and treatment capabilities. The main aim is to maximize the patient flow, by ensuring the delivery of all clinical services during the week. In this paper, the optimal management of Week Hospital patients is considered. We have developed and validated an innovative integer programming model, based on clinical resources allocation and beds utilization. In particular, the model aims at scheduling Week Hospital patients' admission/discharge, possibly reducing the length of stay on the basis of an available timetable of clinical services. The performance of the model has been evaluated, in terms of efficiency and robustness, by considering real data coming from a Week Hospital Rheumatology Division. The experimental results have been satisfactory and demonstrate the effectiveness of the proposed approach.

Objectives: To investigate carpal tunnel syndrome (CTS) with ultrasound (US) in asymptomatic SSc patients and to seek out the relationship between CTS and SSc clinical variables, Methods: In 64 SSc patients (55 women and 9 men, mean age 57±14 years) and in 30 healthy controls, area (MNA), transverse (MNT) and anteroposterior (MNAP) diameters of MN at carpal tunnel were studied with US (My Lab 25 XVG US Esaote 18 MHz). MN flattening ratio (MNFR) was calculated. Duration of disease, subset (limited, diffuse), phase of skin involvement (oedematous, atrophic, fibrotic), modified Rodnan skin score (mRSS) and friction tendon rub were also recorded., Results: MNA (p<0.001), MNT (p<0.005) and MNFR (p<0.005) were significantly higher in the SSc patients than in controls, while no difference in MNAP was found. There was no correlation between median nerve (MN) and SSc clinical features (only lower MNAP correlated inversely with longer disease duration; Spearman coefficient -0.2)., Conclusions: MN involvement is frequently present in all phases of asymptomatic SSc patients, independently to clinical variables.

Objective: To evaluate in SSc, the frequency of digital lesions and the morphology, characteristics, natural course and time to healing of 1614 digital ulcers (DUs)., Methods: One hundred SSc patients were followed up for 4 years. In the first step, the digital lesions were observed and classified at the time of presentation [digital pitting scar (DPS); DU; calcinosis; gangrene]. In the second step, DUs were divided into subsets according to their origin and main features. In the third step, the time to healing was recorded for each DU and the influence of DU main characteristics on time to healing was also evaluated., Results: In the first step, 1614 digital lesions were observed: DPS, 712 (44.1%) lesions; DU, 785 (48.6%); calcinosis, 110 (6.8%); and gangrene, 7 (0.8%). In the second step, DUs were subsetted as follows: DU developed on DPS (8.8%), pure DU; DU developed on calcinosis (60%); DU derived from gangrene. In the third step, the mean time to healing was 25.6 (15.6) days in DPS, 76.2 (64) days in pure DU, 93.6 (59.2) days in calcinosis ulcers and 281.1 (263.3) in gangrene., Conclusions: In SSc, digital lesions are represented by DPS, DU, calcinosis and gangrene, and provide an evidence-based DU subsetting according to their origin and main characteristics. Subsetting may be helpful for a precise DU evaluation and staging, and in randomized controlled trials for a precise identification of those DUs that are to be included in therapeutic studies.

Background: Currently, assessment of dermal thickness in systemic sclerosis (SSc) is performed by palpation and assessment using the modified Rodnan skin score (mRSS)., Objective: To verify whether high frequency ultrasound (US) may be a reliable and a reproducible method to measure digital dermal thickness., Methods: In 70 patients with SSc, skin thickness was evaluated with US by 2 observers at 2 different sites on the second digit of the dominant limb to determine the interobserver variability. Patients and controls were examined twice by the first observer for intraobserver variability. Patients were divided into three subgroups according to the phase of the disease (oedematous, fibrotic or atrophic)., Results: At both examined areas, US showed a significant dermal thickening (p<0.001) in the whole group of patients with SSc. A low intraobserver and interobserver variability was found. A highly significant correlation between the global mRSS and the local dermal thickness at the two examined sites (p=0.032, p=0.021) was detected. Skin thickness was significantly higher in the oedematous than in the fibrotic group (p<0.001) and significantly higher in the fibrotic and the oedematous group (p<0.001) than in the atrophic group (p<0.002)., Conclusions: US is a reliable tool giving reproducible results, and is able to detect digital dermal thickening in SSc.

Background: Early endothelial cell (EC) activation/damage and profibrotic Th2-associated cytokines play a pivotal role in systemic sclerosis (SSc). Interleukin 33 (IL33) is a novel member of the IL1 family that promotes Th2 responses and inflammation through the ST2 receptor. IL33 is also a chromatin-associated transcriptional regulator in ECs., Objective: To investigate the role of the IL33/ST2 axis in SSc., Methods: Skin biopsies were obtained from 30 patients with SSc (15 early/15 late stage) and 10 healthy subjects. Lung, kidney, heart, oesophagus, stomach, placenta biopsies and bronchoalveolar lavage cells from patients with SSc and controls were also analysed. IL33/ST2 expression was investigated by immunohistology, confocal immunofluorescence microscopy, western blotting and RT-PCR., Results: In skin biopsies from control subjects, constitutive nuclear IL33 protein expression was found in dermal ECs and keratinocytes, while ST2 was weakly expressed in ECs and fibroblasts. In skin biopsies from patients with early SSc, IL33 protein was downregulated or absent in ECs and epidermis while IL33 mRNA was normally expressed or even upregulated. Moreover, ECs, perivascular infiltrating mast cells, CD68-positive macrophages, CD3-positive T cells, CD20-positive B cells and activated fibroblasts/myofibroblasts exhibited strong ST2 expression. In skin biopsies from patients with late SSc, IL33 was constitutively found in most ECs while ST2 immunostaining was weaker. In early SSc, the loss of endothelial IL33 protein and the overexpression of ST2 involved all affected organs. Dermal and pulmonary fibroblasts showed IL33 expression in SSc., Conclusion: IL33 and ST2 are abnormally expressed in SSc. In early SSc, upon EC activation/damage IL33 may be mobilised from ECs to signal through ST2 in key profibrotic players such as inflammatory/immune cells and fibroblasts/myofibroblasts.

Rehabilitation may contribute to the management of systemic sclerosis (SSc) dealing with disabilities due to hand involvement. The aim of this study is to evaluate the efficacy of a rehabilitation programme based on the combination of connective tissue massage and Mc Mennell joint manipulation specifically conceived for SSc patients' hands. Forty SSc patients were enrolled: 20 (interventional group) were treated for a 9-week period (twice a week, 1 h per session) with a combination of connective tissue massage, Mc Mennell joint manipulation and home exercise programme, and 20 (control group) were assigned only to home exercise programme. Patients of both groups were assessed at baseline (T0), after 9 week (T1) and at a 9 weeks follow-up (T2). They were evaluated for quality of life by SF-36 and Health Assessment Questionnaire (HAQ), hands involvement by Hand Mobility in Scleroderma (HAMIS) test, Cochin hand functional disability scale and the measurements of ROM. In the interventional group, fist closure, HAMIS test and Cochin hand functional disability scale improved at the end of the treatment (p < 0.0001) as well as HAQ, Physical Synthetic Index (PSI) and Mental Synthetic Index (MSI) of SF-36 scores (HAQ and PSI, p < 0.0001; MSI, p < 0.001). In the control group, the programme of home daily exercises improved only fist closure at the end of the treatment (p < 0.0001). The combination of connective tissue massage, Mc Mennell joint manipulation and home exercise programme is effective in the rehabilitative treatment of SSc hands. This combined treatment may lead to an improvement of hand function and quality of life.

Objectives: To investigate joint involvement in SSc and its relationship with autoantibody to the hnRNP and to anti-cyclic citrullinated peptide (anti-CCP)., Methods: Sera from 55 SSc patients were investigated. Joint involvement was determined by clinical, radiological and ultrasonographical evaluation. Anti-hnRNP proteins A1 and A2 (anti-hnRNP-A1/A2) antibodies were determined by immunoblotting. Anti-CCP, ACA, anti-topo I (ATA), Sm, U1-RNP, ribosomal RNP, Ro/SSA, La/SSB autoantibody and RF were determined., Results: Six patients were positive for anti-hnRNP-A2 autoantibody and two were anti-A1 positive. Eight patients had joint erosions: seven of the eight patients positive for anti-hnRNP-A2 or A1 presented articular involvement (P < 0.04) and five of the eight erosive patients were positive for either of the two autoantibodies (P < 0.02). Of the four patients positive for anti-CCP, none had anti-hnRNP but three had erosive aspects. ATAs were found in 10 patients, six of which were also positive for anti-hnRNP (P < 0.05). RF was positive in 16 patients and in seven among those with articular involvement (P < 0.04). RF was significantly associated with anti-hnRNP in patients with erosive arthritis (P < 0.02), but not with the presence of anti-hnRNP alone. Epitope mapping of the three strongest anti-hnRNP-A2-positive sera recognized the same major epitope as patients with RA. SSc patients have higher incidence of erosions and anti-hnRNP-A2/A1 positivity. RF test and anti-hnRNP had a statistically significant diagnostic value for articular involvement., Conclusions: These parameters might suggest that autoantibody to both hnRNP antigens might become a non-specific but useful marker for joint involvement in SSc patients and identify SSc patients prone to develop joint damage.

Background: In systemic sclerosis (SSc), digital ulcers (DU) are painful, difficult to heal and frequently infected, thus greatly affecting quality of life and increasing SSc-related disability. Vitamin E has been previously used in cutaneous lesions for its antioxidant and anti-inflammatory effects., Objectives: To study the healing effect of D-alpha-tocopheryl acetate (acetic ester of alpha-tocopherol) (VE) gel on DU of SSc patients., Methods: 27 SSc patients with a total of 86 DU were enrolled in an open pilot study. The patients were randomly assigned to two groups: 15 patients were treated until DU healing with the local standard ulcer care protocol with the application of vitamin E gel (experimental group), while 12 patients were treated with standard ulcer care protocol only (control group). In both groups, DU were treated twice a week and pain was scored by a NRS (numeric rating scale). In both groups the cost of medications was analysed., Results: VE induced a faster healing of DU in respect to controls (13.22+/-2.72 weeks, versus 20.94+/-3.65; p<0.0001) with a lower number of medications (26.18+/-5.63 vs. 41.88+/-7.31; p<0.0001). Resolution of pain was faster in experimental (17.82+/-4,59 medications) than in controls (26.26+/-19.16 medications) (p=0.0022). In the experimental group, the cost of medications was significantly lower (6,919.15 euros/patient) than in the control group (11,056.32 euros/patient)., Conclusion: The application of VE reduces time of healing and has a faster resolution of pain, with a significant reduction of costs. Topical VE may improve the management of DU in SSc.

Introduction: Rehabilitation may contribute to the management of Systemic Sclerosis (SSc) dealing with disabilities due to skin and joint involvement., Aim: to evaluate the efficacy of a district specific and global rehabilitation program tailored for SSc patients., Materials and Methods: 20 SSc patients were enrolled and randomly assigned to 2 groups. Interventional group (10 pts) was treated that included hand and face specific rehabilitation and at least a global rehabilitation technique such as hydrokinesytherapy or land-based program, also comprising respiratory exercises. Hand lymphatic drainage was added when necessary. Observational group (10 patients) was only provided with educational advices and medical information about SSc. Patients were evaluated at baseline (T0) and after the 9 weeks treatment period (T1). Interventional group was also assessed after a 9 weeks follow-up (T2). Patients were evaluated by SF-36, HAQ and a purpose-built-questionnaire for global health condition and with Hamis test, Duruöz scale, range of motion, water volumetric test, mouth opening and a purpose-built-questionnaire for hand and face involvement., Results: At the end of the treatment, patients of interventional group improved in all the parameters evaluated. At follow-up, mouth mobility and functionality such as global health status was partially lost, only hand mobility and functionality parameters were maintained. No changes were observed in controls., Conclusion: The association and of district-specific and global rehabilitative techniques conceived and tailored for SSc patients improves disability, HRQoL, hand and face disability and functionality, with its effects partially maintained at the follow-up.

Background: Induced sputum (IS) is a noninvasive tool, which can be used to collect cellular and soluble materials from lung airways., Objective: To evaluate if IS may be a useful and safe tool for the detection of airway inflammation in patients with interstitial lung disease (ILD) in systemic sclerosis (SSc)., Methods: Sixty-eight patients with SSc and ILD as well as 18 healthy individuals (controls) were selected and submitted to IS examination. In 34 of 68 patients with SSc, bronchoalveolar lavage (BAL) was also performed. Safety of IS was assessed by comparison of forced expiratory volume in the first second (FEV(1)), FEV(1)/forced vital capacity ratio and peak expiratory flow before and after the IS procedure. Cell composition in samples collected by BAL and IS was correlated, and IS total and differential cell count in SSc patients and controls were compared., Results: The total number of cells was significantly higher in IS samples of SSc patients compared to those of healthy controls. Mean percentage of neutrophils was also higher in SSc patients (41.79 +/- 23.89 vs. 27.37 +/- 17.90), as well as lymphocytes (17.42 +/- 19.70 vs. 3.13 +/- 2.28) and eosinophils (2.35 +/- 4.43 vs. 0.41 +/- 0.46). On the other hand, mean percentage of macrophages was higher in healthy individuals (69.10 +/- 19.15 vs. 36.96 +/- 20.68). In fluid recovered by BAL, the most frequent cells were macrophages (67.89% +/- 17.26), while neutrophils (14.77 +/- 17.18%) and lymphocytes (15.62 +/- 13.46%) were less frequent and eosinophils (1.66 +/- 2.08%) were rare. A similar pattern of cell composition was found in IS samples (41.15 +/- 21.67% of macrophages, 39.72 +/- 23.15% of neutrophils, 15.28 +/- 19.46% of lymphocytes and 2.56 +/- 5.03% of eosinophils). Strength of correlation between BAL and IS was significant for macrophages and neutrophils. After IS procedure was performed, improvement of FEV(1) (mean value before IS was 85.09 +/- 14.44 and 88.93 +/- 16.40 after IS) and FEV(1)/forced vital capacity (mean value before IS was 98.53 +/- 12.11 and 105.22 +/- 10.78 after IS) was observed., Conclusion: The IS method may allow a noninvasive assessment of cell composition in airway fluid and may contribute to the better understanding of upper/medium airway inflammation in SSc. Future studies are needed to verify whether IS can replace invasive procedures for the detection and monitoring of lung inflammation in SSc., (Copyright 2008 S. Karger AG, Basel.)

Background: In systemic sclerosis (SSc), joint involvement may reduce the functional capacity of the hands. Intravenous immunoglobulins have previously been shown to benefit patients with SSc., Aim: To verify the efficacy of intravenous immunoglobulins on joint involvement and function in SSc., Patients and Methods: 7 women with SSc, 5 with limited and 2 with diffuse SSc, with a severe and refractory joint involvement were enrolled in the study. Methotrexate and cyclophosphamide pulse therapy did not ameliorate joint symptoms. Hence, intravenous immunoglobulins therapy was prescribed at a dosage of 2 g/kg body weight during 4 days/month for six consecutive courses. The presence of joint tenderness and swelling, and articular deformities (due to primary joint involvement and not due to skin and subcutaneous changes) were evaluated. Before and after 6 months of treatment, patients were subjected to (1) Ritchie Index (RI) evaluation of joint involvement; (2) Dreiser Algo-Functional Index (IAFD) evaluation of hand joint function; (3) pain visual analogue scale (VAS) to measure joint pain; (4) Health Assessment Questionnaire (HAQ) to evaluate the limitations in everyday living and physical disability; and (5) modified Rodnan Skin Score for skin involvement., Results: After 6 months of intravenous immunoglobulins therapy, joint pain and tenderness, measured with the VAS, decreased significantly (p<0.03), and hand function (IAFD) improved significantly (p<0.02), together with the quality of life (HAQ; p<0.03). All patients significantly improved, except for one. The skin score after 6 months of intravenous immunoglobulins therapy was significantly reduced (p<0.003)., Conclusion: This pilot study suggests that intravenous immunoglobulins may reduce joint pain and tenderness, with a significant recovery of joint function in patients with SSc with severe and refractory joint involvement. The cost of intravenous immunoglobulins might limit their use only to patients who failed disease-modifying antirheumatic drugs.

Increased evidence suggests an accelerated macrovascular disease in systemic sclerosis (SSc). Brachial artery flow-mediated vasodilation (FMD) and carotid intima-media thickness (IMT) are two indicators of subclinic cardiovascular disease and are frequently used as surrogate measures of subclinic atherosclerosis. The aim of this study was to evaluate macrovascular involvement in SSc. We studied 35 SSc patients (6 males and 29 females; 11 with diffuse and 24 with limited disease) and 20 healthy controls. Brachial artery FMD was assessed by method described by Celermajer in all patients and 13 control subjects. IMT was measured using high-resolution B-mode ultrasonography in patients and controls. Traditional risk factors for atherosclerosis (hypertension, dyslipidemia, and smoke) were also assessed. FMD was significantly impaired (3.41% +/- 4.56% versus 7.66% +/- 4.24%; P < 0.037) and IMT was significantly elevated compared with healthy controls (0.93 +/- 0.29 mm versus 0.77 +/- 0.13 mm; P < 0.005). FMD was not significantly different in SSc with increased IMT compared with those with normal IMT). No correlation was found between risk factors for atherosclerosis and the impairment of FMD or IMT in SSc patients. The impairment of endothelial function and structural changes of large vessels are evident in SSc, but do not seem associated with traditional risk factors for atherosclerosis. Prospective studies including also clinical outcomes are needed to assess the features and significance of macrovacular involvement in SSc.

Autoimmune diseases are characterized by enhanced atherosclerosis. Humoral immune responses to mycobacterial HSP-65, human HSP-60, and to oxLDL have been established in a number of human autoimmune diseases and are considered to be associated with atherosclerosis. The aim of this study was to evaluate carotid artery intima-media thickness (IMT) in patients having systemic sclerosis (SSc) and to find out whether early atherosclerosis is associated with these autoantibodies. Forty-four patients having SSc underwent clinical evaluation and carotid artery IMT measurement. Several autoantibodies were tested among patients and a control group. The antibodies against human HSP-60 were measured by antihuman (IgG/IgM) HSP-60 ELISA kit. IgGs and IgMs antimycobacterial HSP-65 were determined using an ELISA with mycobacterial recombinant HSP-65 antigens. Similarly, anti-oxLDL antibodies were measured by an ELISA kit. Abnormal IMT levels were significantly more common in SSc patients compared with control subjects. Age was found as the sole most significant clinical parameter associated with carotid artery IMT in SSc. Disease duration, type of SSc, lung function tests, and cardiovascular risk factors were not associated with IMT in these patients. Levels of HSP-60, HSP-65, and oxLDL autoantibodies were similar among patients compared with controls, and in patients having "positive" IgM anti-HSP-65, higher IMT values were found. Abnormal carotid IMT is more prevalent in SSc than in normal subjects. Age rather than other clinical parameters is associated with early atherosclerotic changes in SSc. Autoantibodies to oxLDL, HSP-60, and HSP-65 are not elevated in SSc and there is only a borderline association with carotid artery IMT.

In systemic sclerosis (SSc), the involvement of the interstitium or vascular system of the lung may lead to pulmonary arterial hypertension (PAH). PAH is often asymptomatic or oligosymptomatic in early SSc and, when it becomes symptomatic, pulmonary vascular system is already damaged. Exercise echocardiography (ex-echo), measuring pulmonary artery pressure (PAP) during exercise and allowing to differentiate physiologic from altered PAP responses, may identify subclinical PAH. Our aims were (a) to evaluate by ex-echo the change of PAP in patients with SSc without lung involvement; and (b) to correlate PAP during exercise (ex-PAP) values to clinical and biohumoral parameters of PAH. Twenty-seven patients with limited SSc (ISSc) without interstitial lung involvement were studied. Patients underwent rest and exercise two-dimensional and Doppler echocardiography by supine cycloergometer. Systolic PAP was calculated using the maximum systolic velocity of the tricuspid regurgitant jet at rest and during exercise values of systolic PAP exceeding 40 mmHg at ex-echo were considered as abnormal, and biohumoral markers potentially related to PAH were assessed. Eighteen of 27 SSc patients presented an ex-PAP > 40 mmHg, while in 9 of 27 patients ex-PAP values remained < 40 mmHg (48.8 +/- 4.5 mmHg versus 36.2 +/- 3.1 mmHg; P < 0.001). Other echocardiographic and ergometric parameters, clinical tests, and biohumoral markers were not different in the two groups. Ex-PAP significantly correlated with D-dimer (P = 0.0125; r2 = 0.2029). Ex-echo identifies a cluster of SSc patients with subclinical PAH that may develop PAH. This group should be followed up and may be considered for specific therapies to prevent disease evolution.

Objective: Systemic sclerosis (SSc) is characterized by microvascular and macrovascular alterations. The D allele of the ACE I/D polymorphism is known to be associated with an increased incidence of atherosclerosis and has been recently proposed as associated with increased risk of SSc. This study evaluates the relationship between intima-media thickness (IMT), ankle-brachial pressure measurements (ABPI) and ACE I/D polymorphism in SSc patients., Methods: According to the presence of ACE D allele (analysed by PCR), 53 SSc patients (47 females and 6 males; median age was 60.4 +/- 10.68 yrs; range 40-75 yrs) were divided in carriers of the D allele (DD + ID) (n = 46) and carriers of the I allele (II) (n = 7). In these patients, IMT and ABPI [calculated as the posterior tibial artery pressure (mmHg) divided by the brachial pressure] were obtained. Forty-three healthy controls (40 women and 13 men; median age 56.3 +/- 10.23; range 40-70 yrs) of the same ethnicity were recruited., Results: SSc patients had IMT significantly higher than controls (0.85 +/- 0.03 vs 0. 68 +/- 0.01; P < 0.03). No significant differences (P > 0.3) in ABPI values between patients (1.018 +/- 0.10) and controls (1.091 +/- 0.11) were found. SSc patients with ACE DD and ID genotype showed an IMT significantly greater (0.89 +/- 0.03) than those carrying the II genotype (0.61 +/- 0.01) (P < 0.04). ABPI was not different among ACE gene genotypes., Conclusion: Our findings confirm an increased prevalence of macrovascular disease in SSc patients and show that IMT is greater in patients carrying the ACE DD and ID genotype in comparison with II homozygotes. This suggests that, in SSc, the presence of ACE D allele may predispose to an involvement of the macrovascular system.

Background: To ascertain if analysis of lung density histograms in thin-section CT was more reproducible than visual assessment of lung changes in systemic sclerosis (SSc), and if such density histogram parameters as mean lung attenuation (MLA), skewness, and kurtosis could more closely reflect pulmonary function as well as exercise and quality of life impairment., Methods: The intraoperator and interoperator reproducibility of visual and densitometric lung CT analysis in 48 SSc patients examined with CT were evaluated by means of weighted kappa statistics. Univariate and multivariate regression analyses were applied to evaluate the relationship of visual and densitometric CT measurements with functional parameters including functional residual capacity (FRC), FVC, FEV(1), diffusion capacity of the lung for carbon monoxide (Dlco), 6-min walking testing (6MWT), and health-related quality of life questionnaire (QLQ) parameters., Results: The intraoperator and interoperator reproducibility of MLA (intraobserver weighted kappa = 0.97; interobserver weighted kappa = 0.96), skewness (intraobserver weighted kappa = 0.89; interobserver weighted kappa = 0.88), and kurtosis (intraobserver weighted kappa = 0.89; interobserver weighted kappa = 0.88) were higher than those of visual assessment (intraobserver weighted kappa = 0.71; interobserver weighted kappa = 0.69). In univariate analysis, only densitometric measurements were correlated with some exercise and QLQ parameters. In multivariate analysis, MLA (square regression coefficient corrected [R(2)c] = 0.70), skewness (R(2)c = 0.78), and kurtosis (R(2)c = 0.77) were predicted by FRC, FVC, Dlco, 6MWT, and QLQ parameters, while visual assessment was associated only with FRC and FVC (R(2)c = 0.40)., Conclusions: In SSc, densitometric analysis is more reproducible than visual assessment of lung changes in thin-section CT and more closely correlated to pulmonary function testing, 6MWT, and QLQ. Density histogram parameters may be useful for cross-sectional and longitudinal studies of lung involvement in SSc.

Objective: Advanced glycation endproducts (AGEs), including Nepsilon-(carboxymethyl)lysine-protein adducts (CML) are involved in micro/macrovascular changes and are co-localized with adhesion molecules in inflamed tissues. Serum levels of CML were investigated in systemic sclerosis (SSc) characterized by microvascular modifications and correlated with indices of micro/macrovascular damage., Methods: In 66 SSc patients (limited SSc, n = 55; diffuse SSc, n = 11) and 20 controls, CML serum levels were measured by enzyme-linked immunosorbent assay. Nailfold capillaroscopy, intima-media thickness (IMT) and the ankle-brachial index (ABI) were also recorded, to characterize micro/macrovascular involvement., Results: CML levels were significantly higher in SSc (79.2 +/- 39 mg/ml vs 49.6 +/- 26.1 mg/ml, mean +/- s.d.; P<0.01), without significant differences between SSc subsets. CML levels were significantly higher in all capillaroscopic patterns: the 'early' pattern showed higher levels than 'active' and 'late' patterns. IMT was significantly higher in SSc (P<0.01) than in controls, whilst ABI was no different from controls., Conclusions: These data indicate that although both CML formation and macrovascular involvement are increased in SSc, there is no correlation between these two parameters. However, the characteristic early nailfold capillaroscopy changes of SSc are associated with proportionally greater CML formation, suggesting that AGEs are involved in SSc microangiopathy.

Heart involvement is a frequent cause of morbidity and mortality in autoimmune diseases. All cardiac structures can be involved: pericardium, endocardium, myocardium, coronary circle, and conduction system. In the last decade many patients affected by autoimmune diseases have been treated with hematopoietic stem cell transplantation; the vast majority of these transplants have been autologous, and most have been within the context of phase I and II clinical trials; now, phase III trials are ongoing. Patients affected by autoimmune disease often have cardiac involvement which potentially puts them at higher risk from acute cardiotoxicity due to alkylating agents such as cyclophosphamide. The authors propose an algorithm for cardiac assessment before stem cell transplantation in order to identify those patients at highest risk, prior to administering any drug, to avoid further worsening of heart involvement and possible organ failure.A baseline assessment includes physical examinations, ECG to highlight arrhythmias and conduction abnormalities, chest X-ray to evaluate the presence of pericardial effusion and cardiothoracic ratio.A second-step evaluation includes echocardiography (which assesses the following parameters: left ventricular ejection fraction, diastolic function, tricuspid gradient, pulmonary acceleration time, right ventricular diameter and pericardial effusion, wall motion), Holter ECG that may highlight the presence of arrhythmias and biohumoral parameters such as brain natriuretic peptide and troponin I. If these parameters show abnormalities, a further step is required before transplantation. Cardiac catheterization allows to identify ischemic coronary diseases and pulmonary artery hypertension. Intensive monitoring with life card assessment before inclusion might establish ischemic coronary diseases or complex arrhythmias requiring pacing. Magnetic resonance imaging and single-photon emission computed tomography with dipyridamole are useful tools to evaluate the coronary flow. Treatment of ischemic coronary disease (assessment for revascularization), cardiac failure, pulmonary artery hypertension and arrhythmias constitutes the final step. The aim is to optimize cardiac status in order to allow intense immunosuppressive treatments.

Chronic sarcoidosis (CS) is often unresponsive to usual treatments. Melatonin, an immunoregulatory drug, was employed in CS patients in whom usual treatments were ineffective or induced severe side effects. Melatonin was given for 2 yr (20 mg/day in the first year, 10 mg/day in the second year) to 18 CS patients. Pulmonary function tests, chest X rays, pulmonary computed tomography, Ga(67) scintigraphy and angiotensin-converting enzyme (ACE) were assayed at baseline and in the follow-up. Normalization of ACE, improvement of pulmonary parameters and resolution of skin involvement were found in the patients given melatonin. After 24 months of melatonin therapy, hylar adenopathy completely resolved in eight patients and parenchymal lesions were markedly improved in all patients; in the five patients with reduced diffusion capacity of the lung for carbon monoxide, the values normalized after 6 months of therapy and remained stable until month 24. After 24 months, Ga(67) pulmonary and extra-pulmonary uptake was totally normalized in seven patients and, at month 12 months, ACE was normalized in six patients in which the values were high at the baseline. Skin lesions, present in three patients, completely disappeared at month 24 months. No side effects were experienced and no disease relapse was observed during melatonin treatment. Melatonin may be an effective and safe therapy for CS when other treatments fail or cause side effects.

Objective: Microvascular disorders are relevant in systemic sclerosis (SSc). Hyperviscosity, due to alterations of blood cells and plasma components, may play a role in the pathogenesis of microcirculatory disorders. An impaired availability of nitric oxide, related to polymorphisms in NOS3, the gene for endothelial cell nitric oxide synthase, might influence erythrocyte deformability. We undertook this study to investigate the hemorheologic profile in SSc and the role of NOS3 polymorphisms in modulating the hemorheologic status of SSc patients., Methods: We studied 113 consecutive SSc patients (75 with limited cutaneous SSc [lcSSc] and 38 with diffuse cutaneous SSc [dcSSc]) and 113 healthy controls. The hemorheologic profile was obtained by assessing whole blood viscosity (WBV; at shear rates of 0.512 and 94.5 seconds(-1)), plasma viscosity (PLV; at a shear rate of 94.5 seconds(-1)), and erythrocyte deformability index (DI). We determined NOS3 polymorphisms by molecular analysis., Results: A marked alteration of hemorheologic parameters was found both in patients with lcSSc and in those with dcSSc compared with controls (P < 0.0001). In multivariate analysis, rheologic variables were significantly associated with the disease (for WBV at a shear rate of 94.5 seconds(-1), odds ratio [OR] 5.4, 95% confidence interval [95% CI] 1.4-19.9, P = 0.01; for PLV, OR 2.8, 95% CI 1.2-6.5, P = 0.01; for DI, OR 3.9, 95% CI 1.4-10.8, P = 0.007), and NOS3 -786C and 894T alleles significantly affected the DI (for -786C allele, OR 2.3, 95% CI 1.01-5.4, P = 0.04; for 894T allele, OR 2.2, 95% CI 1.01-4.8, P = 0.04). The simultaneous presence of the -786C and 894T alleles represented a susceptibility factor for SSc (OR 2.8, 95% CI 1.4-5.7, P = 0.004)., Conclusion: Our findings document an altered rheologic profile in SSc and demonstrate a relationship between this alteration and NOS3 polymorphisms, thus shedding light on a potential novel mechanism influencing the microcirculation in this disease.

Background: Venous outflow obstruction is the most common cause of tissue failure after microvascular reconstructive surgery. If it is not recognized early, there is an increased risk of tissue damage and loss. Currently, however, there are no adequate models for the study of this clinical problem. The purpose of this study was to develop a partial congestion model for the study of skin flap physiology in response to varying levels of occluded venous outflow., Methods: Nine mixed-breed pigs were equally divided into three experimental groups (0 percent, 20 percent, and 50 percent venous outflow) to determine the effects of varying venous outflow on cutaneous flap color, oxygen tension, and edema. A cutaneous pedicle flap model and a partial congestion system were used to observe changes in variable venous obstruction., Results: Only 0 percent venous outflow resulted in progressive color change across time. In addition, 0 percent venous outflow demonstrated significantly different oxygen tension levels relative to the other groups. Twenty percent venous outflow resulted in significant edema formation relative to the other groups. The 50 percent group showed an increase in oxygen tension from the second hour of venous obstruction to the end of the experiment., Conclusions: Tissue flap color is the clinical standard on which flap health is measured. After 8 hours, only complete venous occlusion resulted in significant color change. However, physiological changes that could affect tissue flap health were noted with only partial venous occlusion, including the development of edema formation. Accordingly, subtle color change could indicate partial venous congestion and may warrant intervention by the surgeon.

Objective: . Involvement of the central nervous system (CNS) in systemic sclerosis (SSc) is rare. Proton magnetic resonance spectroscopy (1H-MRS) assesses in vivo cerebral metabolites. We investigated the biochemical modifications of the CNS in SSc., Methods: N-acetylaspartate/creatine ratio (NAA/Cr) and choline/creatine ratio (Cho/Cr) at right centrum semiovale (RCS) and at right basal ganglia (RBG) were evaluated by 1H-MRS in 12 patients with limited (lSSc) and 8 patients with diffuse SSc (dSSc) and 20 control subjects., Results: With 1H-MRS, a significant reduction of NAA/Cr ratio at RBG (p < 0.02) and at RCS (p < 0.002) was detected in SSc patients. Cho/Cr ratio was increased (p < 0.02) in the RCS, but not in RBG. In patients with lSSc, a significant reduction of NAA/Cr was detected in RCS but not in RBG., Conclusion: Evidence of neuroaxonal damage strongly suggests the existence of CNS involvement in SSc.

Background: In systemic sclerosis (SSc) the lack of an angiogenic response to hypoxia may be due to inappropriate synthesis of angiogenic and angiostatic factors. Tissue kallikrein (t-kallikrein), regulating the kallikrein-kinin system and acting on the microcirculation, is a potent angiogenic agent, and kallistatin is its natural inhibitor., Objective: To evaluate, in patients with SSc, t-kallikrein and kallistatin levels and their correlation with clinical features and measures of microvascular involvement., Patients and Methods: Serum levels of t-kallikrein and kallistatin (ELISA) and t-kallikrein skin expression (immunohistochemistry) were studied in patients with SSc, and evaluated for subset (dSSc or lSSc), clinical and immunological features, and microvascular involvement (ulcers, telangiectasias, nailfold videocapillaroscopy)., Results: Circulating levels of t-kallikrein were higher in SSc than in controls (p<0.001). T-kallikrein did not differ between lSSc and dSSc, although it was higher in lSSc than in controls (p<0.001).T-kallikrein levels were higher in patients with early and active capillaroscopic pattern than in those with late pattern (p = 0.019 and 0.023). Patients with giant capillaries and capillary microhaemorrhages had higher t-kallikrein concentrations than patients with architectural derangement (p = 0.04). No differences in kallistatin levels were detected between patients with SSc and controls, or between lSSc and dSSc. In early SSc skin, the presence of t-kallikrein was found in endothelial and in perivascular inflammatory cells, while no staining in skin of advanced SSc was detected., Conclusion: T-kallikrein levels are increased in patients with SSc, particularly in lSSc, and are associated with early and active capillaroscopic patterns. T-kallikrein may play a part in SSc microvascular changes.

Our objective was to observe whether dysfunctional psychological dimensions of pain could be detected in fibromyalgia patients through the development of a new questionnaire. An original questionnaire composed of 51 items was given to 250 patients (185 females and 65 males, mean age 55+/-12.8 years) suffering from chronic fibromyalgia according to the criteria of the Multicenter Criteria Committee of the American College of Rheumatology. A Varimax computerized program of factorial analysis with orthogonal and oblique rotation of the axes was used to analyze the data. Five strong independent factors were identified: 1) catastrophizing and 2) external control beliefs (cognitive); 3) alexithymia (emotional); 4) restless behavior (behavioral); and 5) need for support (relational). Our questionnaire is a preliminary development of an Italian language psychological characterization of FM patients which may be a relevant and useful tool for the evaluation of the outcome of clinical/psychological treatment of FM.