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Roberto Giacomelli - Top 30 Publications

Macrophage activation syndrome in Still's disease: analysis of clinical characteristics and survival in paediatric and adult patients.

Macrophage activation syndrome (MAS) is a reactive form of hemophagocytic lymphohistiocytosis, complicating Still's disease, both in paediatric and adult patients. In this work, we aimed to investigate clinical picture and outcome of Still's disease patients developing MAS. We performed a retrospective analysis of patients, both paediatrics and adults, affected by Still's disease attending our department. During the follow-up, each patient was investigated for MAS occurrence and possible predictors, clinical and laboratory factors, were analysed. We evaluated 50 patients affected by Still's disease, 21 paediatric and 29 adult patients. Ten patients experienced MAS (five adult and five paediatric patients) and its development significantly reduced the survival rate when compared with patients without this complication (p < 0.0001). The analysis of possible predictors showed that high-value systemic score (p = 0.03) and high levels of serum ferritin (p = 0.002) were independently associated with an increased likelihood of MAS. MAS occurrence significantly reduced survival rate in both paediatric and adult patients affected by Still's disease. The high levels of serum ferritin and an elevated systemic score, at the time of diagnosis, were significantly associated with MAS.

Biologic drugs in adult onset Still's disease: a systematic review and meta-analysis of observational studies.

Biological drugs, mainly interleukin (IL)-1 and IL-6 antagonists, but also tumor necrosis factor (TNF) inhibitors, have been used in the treatment of adult onset Still's disease patients (AOSD).

Advances in immunopathogenesis of macrophage activation syndrome during rheumatic inflammatory diseases: toward new therapeutic targets?

Macrophage activation syndrome (MAS) is a severe, hyperinflammatory life-threatening syndrome, generally complicating different rheumatic diseases. Despite the severity of the disease, little is known about the pathogenic mechanisms and, thus, possible targeted therapies in the management of these patients. Areas covered: In this review, we aimed to update the current pathogenic knowledge of MAS, during rheumatic diseases, focusing mainly on immunologic abnormalities and on new possible therapeutic strategies. Expert commentary: The difficult pathogenic scenario of MAS, in which genetic defects, predisposing diseases, and triggers are mixed together with the high mortality rate, make it difficult to manage these patients. Although most efforts have been focused on investigating the disease in children, in recent years, several studies are trying to elucidate the possible pathogenic mechanism in adult MAS patients. In this context, genetic and immunological studies might lead to advances in the knowledge of pathogenic mechanisms and possible new therapeutic targets. In the future, the results of ongoing clinical trials are awaited in order to improve the management and, thus, the survival of these patients.

Prevalence of type 2 diabetes and impaired fasting glucose in patients affected by rheumatoid arthritis: Results from a cross-sectional study.

Although the better management of rheumatoid arthritis (RA) has significantly improved the long-term outcome of affected patients, a significant proportion of these may develop associated comorbidities including cardiometabolic complications. However, it must be pointed out that a comprehensive cardiometabolic evaluation is still poorly integrated into the management of RA patients, due to a limited awareness of the problem, a lack of appropriate clinical studies, and optimal strategies for cardiovascular (CV) risk reduction in RA. In addition, although several studies investigated the possible association between traditional CV risk factors and RA, conflicting results are still available.On this basis, we planned this cross-sectional study, aimed at investigating the prevalence of type 2 diabetes (T2D) and impaired fasting glucose (IFG) in RA patients compared with age- and gender- matched control individuals. Furthermore, we analyzed the role of both traditional and RA-related CV risk factors in predicting T2D and IFG.We observed an increased prevalence of T2D in RA patients when compared with age- and gender-matched controls. Regression analyses demonstrated that the presence of high blood pressure (HBP), a longer disease duration, and exposure to corticosteroids (CCS) were significantly associated with an increased likelihood of being classified as T2D. In addition, we observed an increased prevalence of IFG in RA patients when compared with age- and gender-matched controls. Regression analyses demonstrated that a higher body mass index (BMI), the presence of metabolic syndrome (MetS), higher levels of total cholesterol, the presence of radiographic damage, and higher serum levels of C-reactive protein (CRP) were significantly associated with an increased likelihood of presenting IFG.In this cross-sectional study, we observed an increased prevalence of T2D and IFG in an Italian cohort of RA patients when compared with age- and gender-matched control individuals. Interestingly, both RA-specific features, such as disease duration, CCS exposure, and radiographic damage, and traditional CV risk factors, such as HBP and MetS, were significantly associated with glucose metabolism abnormalities.

The challenge to interpret conflicting results and the need of a univocal definition for germinal centres in primary Sjögren's syndrome.

Computed Tomography and MR Imaging in Rheumatoid Arthritis.

The clinical diagnosis of rheumatoid arthritis is supported by imaging findings. MR imaging, in particular, can allow an early diagnosis to determine a target therapy that can stop or at least slow the disease progression.

International consensus: What else can we do to improve diagnosis and therapeutic strategies in patients affected by autoimmune rheumatic diseases (rheumatoid arthritis, spondyloarthritides, systemic sclerosis, systemic lupus erythematosus, antiphospholipid syndrome and Sjogren's syndrome)?: The unmet needs and the clinical grey zone in autoimmune disease management.

Autoimmune diseases are a complex set of diseases characterized by immune system activation and, although many progresses have been done in the last 15years, several unmet needs in the management of these patients may be still identified. Recently, a panel of international Experts, divided in different working groups according to their clinical and scientific expertise, were asked to identify, debate and formulate a list of key unmet needs within the field of rheumatology, serving as a roadmap for research as well as support for clinicians. After a systematic review of the literature, the results and the discussions from each working group were summarised in different statements. Due to the differences among the diseases and their heterogeneity, a large number of statements was produced and voted by the Experts to reach a consensus in a plenary session. At all the steps of this process, including the initial discussions by the steering committee, the identification of the unmet needs, the expansion of the working group and finally the development of statements, a large agreement was attained. This work confirmed that several unmet needs may be identified and despite the development of new therapeutic strategies as well as a better understanding of the effects of existing therapies, many open questions still remain in this field, suggesting a research agenda for the future and specific clinical suggestions which may allow physicians to better manage those clinical conditions still lacking of scientific clarity.

Poor clinical response in rheumatoid arthritis is the main risk factor for diabetes development in the short-term: A 1-year, single-centre, longitudinal study.

Despite of the European League Against Rheumatism (EULAR) provided different sets of recommendations for the management of cardiovascular risk in inflammatory arthritis patients, it must be pointed out that cardiometabolic comorbidity, such as type 2 diabetes (T2D), remains still underdiagnosed and undertreated in patients affected by rheumatoid arthritis (RA).

Prevalence and significance of anti-saccharomyces cerevisiae antibodies in primary Sjögren's syndrome.

Saccharomyces cerevisiae is a common yeast used in the food industry. IgG and IgA antibodies against the phosphopeptidomannan of the S. cerevisiae cell wall (ASCA) are a well known marker of disease severity in Crohn's disease. Moreover, a number of studies assessed ASCA in several systemic and organ-specific autoimmune diseases postulating molecular mimicry as a possible link between ASCA and autoimmunity. However, since they have never been tested in primary Sjögren's syndrome (pSS), the purpose of this study was to investigate these antibodies in a large cohort of pSS patients, compared to healthy donors (HD), and their significance as potentially helpful biomarker in a clinical setting.

Response to Interleukin-1 Inhibitors in 140 Italian Patients with Adult-Onset Still's Disease: A Multicentre Retrospective Observational Study.

Background: Interleukin (IL)-1 plays a crucial role in the pathogenesis of Adult onset Still's disease (AOSD). Objectives: To evaluate the efficacy and safety of anakinra (ANA) and canakinumab (CAN) in a large group of AOSD patients. Methods: Data on clinical, serological features, and concomitant treatments were retrospectively collected at baseline and after 3, 6, and 12 months from AOSD patients (Yamaguchi criteria) referred by 18 Italian centers. Pouchot's score was used to evaluate disease severity. Results: One hundred forty patients were treated with ANA; 4 were subsequently switched to CAN after ANA failure. The systemic pattern of AOSD was identified in 104 (74.2%) of the ANA-treated and in 3 (75%) of the CAN-treated groups; the chronic-articular type of AOSD was identified in 48 (25.8%) of the ANA-treated and in 1 (25%) of the CAN-treated groups. Methotrexate (MTX) was the most frequent disease modifying anti-rheumatic drug (DMARD) used before beginning ANA or CAN [91/140 (75.8%), 2/4 (50%), respectively]. As a second-line biologic DMARD therapy in 29/140 (20.7%) of the patients, ANA was found effective in improving all clinical and serological manifestations (p < 0.0001), and Pouchot's score was found to be significantly reduced at all time points (p < 0.0001). No differences in treatment response were identified in the ANA-group when the patients were stratified according to age, sex, disease pattern or mono/combination therapy profile. ANA primary and secondary inefficacy at the 12-month time point was 15/140 (10.7%) and 11/140 (7.8%), respectively. Adverse events (AEs) [mainly represented by in situ (28/47, 59.5%) or diffuse (12/47, 25.5%) skin reactions and infections (7/47, 14.8%)] were the main causes for discontinuation. Pouchot's score and clinical and serological features were significantly ameliorated at all time points (p < 0.0001) in the CAN-group, and no AEs were registered during CAN therapy. Treatment was suspended for loss of efficacy only in one case (1/4, 25%). Conclusion: This is the largest retrospective observational study evaluating the efficacy and safety of IL-1 inhibitors in AOSD patients. A good response was noted at 3 months after therapy onset in both the ANA- and CAN-groups. Skin reaction may nevertheless represent a non-negligible AE during ANA treatment.

What could we learn from the sub-analysis of a single nation cohort in a worldwide study? Lessons from the results observed in the Italian cohort of the GO-MORE trial.

GO-MORE Trial investigated the use of Golimumab (GLM) in 3280 rheumatoid arthritis (RA) patients worldwide. At present, the burden of arthritis is greater in poorer countries than in developed countries due to socioeconomic disparities, thus suggesting the usefulness of subgroup investigations. We aimed to evaluate GLM as add-on therapy for RA patients in the Italian cohort of GO-MORE trial and compared the clinical characteristics between Italian patients and the enrolled patients worldwide.

Pharmacological stress, rest perfusion and delayed enhancement cardiac magnetic resonance identifies a very early cardiac involvement in systemic sclerosis patients of recent onset.

To evaluate occult cardiac involvement in asymptomatic systemic sclerosis (SSc) patients by pharmacological stress, rest perfusion and delayed enhancement cardiac magnetic resonance (CMR), for a very early identification of patients at higher risk of cardiac-related mortality.

Cryoglobulinemia in Sjögren Syndrome: A Disease Subset that Links Higher Systemic Disease Activity, Autoimmunity, and Local B Cell Proliferation in Mucosa-associated Lymphoid Tissue.

To compare systemic disease activity by validated tools, i.e., the European League Against Rheumatism Sjögren Syndrome Disease Activity Index (ESSDAI) and the Clinical ESSDAI (ClinESSDAI) scores, between primary Sjögren syndrome (pSS) with positive serum cryoglobulins and pSS without serum cryoglobulins.

Correlation between ESSDAI and ClinESSDAI in a real-life cohort of patients with Sjögren's syndrome.

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Phenotypical and Functional Characteristics of In Vitro-Expanded Adipose-Derived Mesenchymal Stromal Cells From Patients With Systematic Sclerosis.

Mesenchymal stromal cells (MSCs) have received attention as an ideal source of regenerative cells because of their multipotent differentiation potential. Adipose tissue is an attractive source of MSCs. Recent studies have shown that autologous fat grafting may be effective in the treatment of systemic sclerosis (SSc), but no specific study exists that aimed at investigating whether adipose tissue-derived stromal cells (ADSCs) from SSc patients maintain normal phenotypic and functional characteristics. The purpose of the current study was to investigate whether ADSCs from patients with SSc (SSc-ADSCs) are phenotypically and functionally identical to those from healthy controls (HC-ADSCs). Adipose tissue samples were obtained from 10 patients with SSc and from 8 HCs. Both MSC populations were evaluated for their capacity to (a) express specific MSC surface antigens by flow cytometry analysis, (b) proliferate, (c) differentiate along the adipogenic and osteogenic lineages, (d) suppress in vitro lymphocyte proliferation induced by a mitogenic stimulus, and (e) support endothelial cell (EC) tube formation. ADSCs from SSc patients and HCs showed similar surface phenotype and multilineage differentiation capabilities. In PBMC proliferation inhibition assays, no significant differences were observed between SSc- and HC-ADSCs. Using ADSC/EC cocultures, both SSc- and HC-ADSCs improved tube formation by both HC- and SSc-ECs. This effect was enhanced under hypoxic conditions in all of the cocultures. SSc-ADSCs exhibited the same phenotypic pattern, proliferation and differentiation potentials, and immunosuppressive properties as those from HCs. The proangiogenic activity shown by SSc-ADSCs, namely, under hypoxic conditions, suggests that autologous ADSC grafting may represent a possible therapeutic option for SSc.

Increased Cardiovascular Events and Subclinical Atherosclerosis in Rheumatoid Arthritis Patients: 1 Year Prospective Single Centre Study.

Several studies showed the close relationship between Rheumatoid Arthritis (RA) and cerebro-cardiovascular events (CVEs) and subclinical atherosclerosis. In this study, we investigated the occurrence of CVEs and subclinical atherosclerosis during the course of RA and we evaluated the possible role of both traditional cardiovascular (CV) and disease related risk factors to predict the occurrence of new CVEs and the onset of subclinical atherosclerosis.

Interstitial lung disease in systemic sclerosis: current and future treatment.

Systemic sclerosis (SSc) has the highest fatality rate among connective tissue diseases and is characterized by vascular damage, inflammation and fibrosis of the skin and various internal organs. Interstitial lung disease (ILD) frequently complicates SSc and can be a debilitating disorder with a poor prognosis. ILD is the most frequent cause of death in SSc, and the management of SSc-ILD patients is a great challenge. Early detection of pulmonary involvement based on a recent decline of lung function tests and on the extent of lung involvement at high-resolution computed tomography is critical for the best management of these patients. This article summarizes classification, pathogenesis, diagnosis, prognosis, survival and finally current and future treatment options in SSc-ILD.

Anti-TNF treatment response in rheumatoid arthritis patients with moderate disease activity: a prospective observational multicentre study (MODERATE).

Rheumatoid arthritis (RA) patients with moderate disease activity show progression of joint damage and have impaired quality of life, physical function, work and daily activities. Little is known about management of patients with moderate RA. The aim of the study was to assess the 1-year response to anti-TNF in biologic-naïve RA patients with moderate (3.2 <DAS28 ≤5.1) disease activity despite DMARD treatment, in the Italian clinical practice.

Adult-onset Still's disease: evaluation of prognostic tools and validation of the systemic score by analysis of 100 cases from three centers.

Adult-onset Still's disease (AOSD) is rare inflammatory disease of unknown etiology that usually affects young adults. The more common clinical manifestations are spiking fevers, arthritis, evanescent rash, elevated liver enzymes, lymphadenopathy, hepatosplenomegaly, and serositis. The multi-visceral involvement of the disease and the different complications, such as macrophage activation syndrome, may strongly decrease the life expectancy of AOSD patients.

Influence of geolocation and ethnicity on the phenotypic expression of primary Sjögren's syndrome at diagnosis in 8310 patients: a cross-sectional study from the Big Data Sjögren Project Consortium.

To analyse the influence of geolocation and ethnicity on the clinical presentation of primary Sjögren's syndrome (SjS) at diagnosis.

Biologic therapies and infections in the daily practice of three Italian rheumatologic units: a prospective, observational study.

Since the introduction of biologics, many concerns about the increased risk of infections have been reported and, to date, the real impact of infections on the daily practice in the rheumatologic centers is still largely unknown. In this work, we evaluated the infection rates associated with the use of biologics in a large cohort of patients. A prospective study, between January 2010 and December 2013, enrolling 731 rheumatic patients, was performed. Demographic and disease characteristics, therapies, comorbidities, and infectious events were recorded and statistically analyzed by multivariate analysis. Two-hundred thirty-five infectious episodes were observed in 28.4 % of patients. About total infections, bacteria were identified in 70.6 % of total cases and viruses in 18.3 %. The most common site of not-serious infection was the urinary tract. Duration of disease, longer follow-up, concomitant steroid therapy, and comorbidities were significantly associated with not-serious infection. In our cohort, 17 episodes fulfilled the criteria of serious infection and occurred in 17 different patients (2.3 %), the majority involving the lower respiratory tract. Serious infections were associated with the beginning of biologics in older age. Our prospective, observational study showed that, in daily practice, a lesser rate of serious as well as not-serious infections may be observed in rheumatic patients treated with biologics than those reported in previous papers. The most common sites of not-serious infections are both the urinary and the respiratory tracts, and for serious infections, the respiratory tract. When pathogens were isolated, we did not find any multidrug-resistant organism.

Endothelial progenitor cells: Are they displaying a function in autoimmune disorders?

Endothelial Progenitor Cells (EPCs) are bone marrow derived cells able to differentiate in mature endothelial cells (EC) contributing to the generation of new vessels, connecting to fibronectin, and forming colonies and/or colony forming units. Since circulating EPCs can be actively considered part of endothelial damage in several cardiovascular diseases and autoimmune disorders the possibility to have a measure for endothelium damage should be considered of interest to predict the patient out-come. At the same time the EPCs proliferative and regenerative role could be considered for therapeutic applications. Studies have been performed to elucidate the role of EPCs in Systemic Sclerosis and many review and articles published on this topic. In the present paper we aimed to review the role of EPCs in other autoimmune disorders.

Prognostic factors of macrophage activation syndrome, at the time of diagnosis, in adult patients affected by autoimmune disease: Analysis of 41 cases collected in 2 rheumatologic centers.

Macrophage activation syndrome (MAS) is a rare, life-threatening disease in which early diagnosis and aggressive therapeutic strategy may improve the outcome. Due to its rarity, epidemiologic data are still lacking. Hyperferritinemia is frequently associated with MAS and might modulate the cytokine storm, which is involved in the development of multiple organ failure. In this paper, we investigated clinical data, treatments, and outcome of a homogeneous cohort of 41 adult MAS patients, complicating autoimmune rheumatic diseases. MAS-related death occurred in 17 patients (42.5%) during the follow-up, and older age and increased serum ferritin levels, at the time of diagnosis, were significantly associated with mortality. In conclusion, adult MAS is associated with high mortality rate. Some clinical features at diagnosis may be predictive of MAS-associated death.

Persistence of focal lymphocytic sialadenitis in patients with primary Sjögren's syndrome treated with rituximab: a possible role for glandular BAFF.

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Searching for a good model for systemic sclerosis: the molecular profile and vascular changes occurring in UCD-200 chickens strongly resemble the early phase of human systemic sclerosis.

Vascular injury and endothelial cell (EC) apoptosis are the earliest events in systemic sclerosis (SSc), before the onset of fibrosis, and stromal cell-derived factor 1 (SDF-1), vascular endothelial growth factor (VEGFA), endothelin-1 (ET-1) and platelet-derived growth factors (PDGF-BB) represent the key molecules to study the link between vascular injury and fibrosis during SSc. The University of California at Davis line 200 (UCD-200) chickens display the same hallmarks of human SSc: vascular occlusion, perivascular lymphocytic infiltration and fibrosis of skin and internal organs. In this study we assessed both cytokines and growth factors involved in the early phases of the UCD-200 chickens' skin lesions, to determine whether these animals might represent an appropriate experimental model to study the pathogenesis of SSc.

Perivascular Cells in Diffuse Cutaneous Systemic Sclerosis Overexpress Activated ADAM12 and Are Involved in Myofibroblast Transdifferentiation and Development of Fibrosis.

Microvascular damage is pivotal in the pathogenesis of systemic sclerosis (SSc), preceding fibrosis, and whose trigger is not still fully understood. Perivascular progenitor cells, with profibrotic activity and function, are identified by the expression of the isoform 12 of ADAM (ADAM12) and this molecule may be upregulated by transforming growth factor-β (TGF-β). The goal of this work was to evaluate whether pericytes in the skin of patients with diffuse cutaneous SSc (dcSSc) expressed ADAM12, suggesting their potential contribution to the fibrotic process, and whether TGF-β might modulate this molecule.

Mesenchymal Stem Cell Transplantation in Systemic Sclerosis: Comment on the Article by Maria et al.

Adult-onset Still's disease: an Italian multicentre retrospective observational study of manifestations and treatments in 245 patients.

Adult-onset Still's disease (AOSD) is a systemic inflammatory condition of unknown aetiology characterized by typical episodes of spiking fever, evanescent rash, arthralgia, leukocytosis and hyperferritinemia. Given the lack of data in Italian series, we promote a multicentric data collection to characterize the clinical phenotype of Italian patients with AOSD. Data from 245 subjects diagnosed with AOSD were collected by 15 centres between March and May 2013. The diagnosis was made following Yamaguchi's criteria. Data regarding clinical manifestations, laboratory features, disease course and treatments were reported and compared with those presented in other published series of different ethnicity. The most frequent features were the following: arthritis (93 %), pyrexia (92.6 %), leukocytosis (89 %), negative ANA (90.4 %) and neutrophilia (82 %). As compared to other North American, North European, Middle Eastern and Far Eastern cohorts, Italian data show differences in clinical and laboratory findings. Regarding the treatments, in 21.9 % of cases, corticosteroids and traditional DMARDs have not been able to control the disease while biologics have been shown to be effective in 48 to 58 patients. This retrospective work summarizes the largest Italian multicentre series of AOSD patients and presents clinical and laboratory features that appear to be influenced by the ethnicity of the affected subjects.

IL-1β at the crossroad between rheumatoid arthritis and type 2 diabetes: may we kill two birds with one stone?

Although in the past the prevention of joint destruction in rheumatoid arthritis (RA) was strongly emphasized, now a great interest is focused on associated comorbidities in these patients. Multiple data suggest that a large percentage of RA patients are affected by Type 2 Diabetes (T2D), whose incidence has reached epidemic levels in recent years, thus increasing the health care costs. A better knowledge about the pathogenesis of these diseases as well as the mechanisms of action of drugs may allow both policy designers and physicians to choose the most effective treatments, thus lowering the costs. This review will focus on the role of Interleukin (IL)-1β in the pathogenesis of both the diseases, the efficacy of IL-1 blocking molecules in controlling these diseases, and will provide information suggesting that targeting IL-1β, in patients affected by both RA and T2D, may be a promising therapeutic choice.

Interleukin-9 Overexpression and Th9 Polarization Characterize the Inflamed Gut, the Synovial Tissue, and the Peripheral Blood of Patients With Psoriatic Arthritis.

To investigate the expression and tissue distribution of Th9-related cytokines in patients with psoriatic arthritis (PsA).