Publications by authors named "Francesco Ferro"

65 Publications

Characterization of Extracellular Vesicle Cargo in Sjögren's Syndrome through a SWATH-MS Proteomics Approach.

Int J Mol Sci 2021 May 4;22(9). Epub 2021 May 4.

Department of Clinical and Experimental Medicine, Rheumatology Unit, University of Pisa, 56126 Pisa, Italy.

Primary Sjögren's syndrome (pSS) is a complex heterogeneous disease characterized by a wide spectrum of glandular and extra-glandular manifestations. In this pilot study, a SWATH-MS approach was used to monitor extracellular vesicles-enriched saliva (EVs) sub-proteome in pSS patients, to compare it with whole saliva (WS) proteome, and assess differential expressed proteins between pSS and healthy control EVs samples. Comparison between EVs and WS led to the characterization of compartment-specific proteins with a moderate degree of overlap. A total of 290 proteins were identified and quantified in EVs from healthy and pSS patients. Among those, 121 proteins were found to be differentially expressed in pSS, 82% were found to be upregulated, and 18% downregulated in pSS samples. The most representative functional pathways associated to the protein networks were related to immune-innate response, including several members of S100 protein family, annexin A2, resistin, serpin peptidase inhibitors, azurocidin, and CD14 monocyte differentiation antigen. Our results highlight the usefulness of EVs for the discovery of novel salivary-omic biomarkers and open novel perspectives in pSS for the identification of proteins of clinical relevance that could be used not only for the disease diagnosis but also to improve patients' stratification and treatment-monitoring. Data are available via ProteomeXchange with identifier PXD025649.
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http://dx.doi.org/10.3390/ijms22094864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124455PMC
May 2021

One year in review 2021: systemic vasculitis.

Clin Exp Rheumatol 2021 Mar-Apr;39 Suppl 129(2):3-12. Epub 2021 May 19.

Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Italy.

Large- and small-vessel vasculitis are complex potentially life-threatening systemic autoimmune diseases that have recently been subjected to considerable immunologic and clinical research. Following the other reviews of this series, here we aim to summarise some of the most significant studies that have been recently published on the pathogenesis, clinical features and novel treatments of systemic vasculitis.
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May 2021

Peripheral Nervous System Involvement in Sjögren's Syndrome: Analysis of a Cohort From the Italian Research Group on Sjögren's Syndrome.

Front Immunol 2021 24;12:615656. Epub 2021 Mar 24.

Rheumatology Unit, Department of Medicine, University of Perugia, Perugia, Italy.

Purpose: The prevalence of peripheral nervous system (PNS) involvement in primary Sjögren's syndrome (pSS) has been reported to range from 2% to over 50%. Bias in study designs, including low number of patients and unclearly defined rheumatological and neurological diagnosis could explain such variability. Consequently, the exact depiction of PNS involvement in pSS is still lacking. This study aimed at analyzing the prevalence and the clinical and laboratory factors associated with PNS involvement in a very large cohort of well-characterized pSS patients with a clearly defined neurological diagnosis.

Methods: Clinical and serological data of 1,695 pSS patients with specific and accurate information on PNS involvement were analyzed. Comparisons between patients with and without PNS involvement and between patients with distinct subsets of PNS manifestations were performed.

Results: Prevalence of PNS involvement was 3.7%. The most frequent types observed were pure sensory neuropathies and axonal sensorimotor polyneuropathies (SMP). Patients with PNS involvement exhibited a more active disease profile and were more frequently treated with immunosuppressants. Intriguingly, clinical and serological negative prognostic factors, including purpura, extra-glandular manifestations, leukopenia, low complement and cryoglobulinemia, principally characterized patients with SMP, while subjects with pure sensory neuropathy displayed a milder phenotype.

Conclusion: Our results highlight that PNS involvement is rather rare, but prognostically relevant in pSS. Main adverse prognostic features characterize patients with SMP, while pure sensory neuropathies are usually associated with a mild clinical picture. These findings, useful for patient stratification, may suggest protean pathogenic pathways underlying different types of PNS manifestations in pSS.
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http://dx.doi.org/10.3389/fimmu.2021.615656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024688PMC
March 2021

COVID-19: the new challenge for rheumatologists. One year later.

Clin Exp Rheumatol 2021 Jan-Feb;39(1):203-213. Epub 2021 Feb 5.

University of Pisa, Italy.

At the beginning of COVID-19, we underlined that this pandemic was a new challenge for rheumatologists. On the one hand, it was necessary to clarify the impact of this new viral disease on the natural history of many rheumatic diseases and, on the other hand, to define the beneficial or harmful effects of the synthetic or targeted therapies used for their treatment. In addition, we have postulated that in view of the common pathogenetic mechanisms involved, the therapeutic armamentarium currently employed in the management of viral or idiopathic systemic autoimmune rheumatic diseases could be useful to control the "cytokine storm" induced by SARS-COV-2. One year later, in the present review we have analysed the progress of the knowledge on both these aspects and updated the algorithms initially proposed for a rational use of the synthetic and targeted anti-inflammatory and immunomodulatory agents in the management of COVID-19.
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February 2021

Ultra-high frequency ultrasonography (UHFUS)-guided minor salivary gland biopsy: A promising procedure to optimize labial salivary gland biopsy in Sjögren's syndrome.

J Oral Pathol Med 2021 May 15;50(5):485-491. Epub 2021 Feb 15.

Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, Unit of Dentistry and Oral Surgery, University of Pisa, Pisa, Italy.

Background: Sjögren's syndrome (SS) is an autoimmune disease characterized by an inflammatory infiltrate of exocrine salivary and lachrymal glands. Diagnosis is complex, and minor salivary gland biopsy and subsequent focus score (FS) calculation appear of extreme importance in the diagnostic work-up of the disease. Ultra-high frequency ultrasonography (UHFUS) is a recently introduced diagnostic technique, which is gaining an increasingly important role in intraoral imaging. This study aims at exploring the usefulness of UHFUS for obtaining valuable labial salivary gland samples to assess the histopathological features of SS patients.

Methods: Patients with clinical suspect of SS and eligible for minor salivary gland biopsy were enrolled. UHFUS scan of the lower lip was performed. Glandular echostructure was classified according to Outcome Measures in Rheumatology (OMERACT) scoring system. The glands to be sampled were selected on the basis of UHFUS evaluation and biopsied. The areas of the samples were recorded and compared with those obtained without UHFUS guidance. The correlation between UHFUS grade and labial gland FS was also assessed.

Results: The areas of the samples obtained with UHFUS guidance were significantly higher (7.25 ± 3.98 mm ) than those obtained by conventional procedures (5.79 ± 3.49 mm , P = .02). UHFUS correlated significantly with the salivary gland FS (r = .532, P = .001).

Conclusion: UHFUS seems a promising tool in SS diagnostic algorithm, being able to provide a valuable support to the biopsy procedure. Further studies are mandatory to confirm the role of UHFUS in SS.
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http://dx.doi.org/10.1111/jop.13162DOI Listing
May 2021

Ultra-high frequency ultrasound (UHFUS) applications in Sjogren syndrome: narrative review and current concepts.

Gland Surg 2020 Dec;9(6):2248-2259

Diagnostic and Interventional Radiology, Department of Translational Research and of New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.

Primary Sjogren's syndrome (SS) is a systemic autoimmune chronic inflammatory disease with predominant involvement of the exocrine glands, particularly the salivary glands (SGs). The role of salivary glands ultrasound (SGUS) in the work-up of patients with primary Sjogren syndrome (SS) is progressively increasing due to its useful support in diagnosis and follow-up as a widely available, repeatable, non-invasive and safe technique. Although SGUS is not yet included in the dominant primary SS classification, several studies supported its inclusion in the American College of Rheumatology/European League Against Rheumatism criteria. In this context, a novel imaging technique, ultra-high frequency ultrasound (UHFUS), is being explored. Compared to the frequencies used in conventional ultrasound (US) (up to 22 MHz), UHFUS operates with higher frequencies (30-100 MHz) allowing for outstanding image resolution, up to 30 µm. UHFUS permits the scan of both major and minor SGs, opening new avenues for the integration of tissue and imaging biomarkers. Although further studies are needed to confirm its role, this novel imaging technique might lead to several potential improvements, including earlier diagnosis, reduction of unnecessary and inadequate biopsies and better management and follow-up of patients with primary SS.
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http://dx.doi.org/10.21037/gs-20-529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804531PMC
December 2020

Impact of first wave of SARS-CoV-2 infection in patients with Systemic Lupus Erythematosus: Weighting the risk of infection and flare.

PLoS One 2021 13;16(1):e0245274. Epub 2021 Jan 13.

Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Introduction: The aim of this study was to investigate the incidence and clinical presentation of SARS-CoV-2 infections in a Systemic Lupus Erythematosus (SLE) cohort; to assess correlations with disease characteristics and rheumatic therapy; and to evaluate the occurrence of treatment discontinuation and its impact on disease activity.

Materials And Methods: SLE patients monitored by a single Italian centre were interviewed between February and July 2020. Patients were considered to be positive for SARS-CoV-2 infections in case of 1) positive nasopharyngeal swab; 2) positive serology associated with COVID19 suggesting symptoms. The following data were also recorded: clinical symptoms, adoption of social distancing measures, disease activity and treatment discontinuation.

Results: 332 patients were enrolled in the study. Six patients (1.8%) tested positive for SARS-CoV-2 infection, with the incidence being significantly higher in the subgroup of patients treated with biological Disease-Modifying Anti-Rheumatic Drugs (p = 0.005), while no difference was observed for other therapies, age at enrollment, disease duration, type of cumulative organ involvement or adoption of social isolation. The course of the disease was mild. Thirty-six patients (11.1%) discontinued at least part of their therapy during this time period, and 27 (8.1%) cases of disease flare were recorded. Correlation between flare and discontinuation of therapy was statistically significant (p<0.001). No significant increase of rate of flare in a subgroup of the same patients during 2020 was observed.

Conclusion: Treatment discontinuation seems to be an important cause of disease flare. Our findings suggest that abrupt drug withdrawal should be avoided or evaluated with caution on the basis of individual infection risk and comorbidities.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245274PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806138PMC
January 2021

Myeloid neoplasms and autoimmune diseases: markers of association.

Clin Exp Rheumatol 2021 Jan 6. Epub 2021 Jan 6.

Department of Clinical and Experimental Medicine, University of Pisa, Italy.

Objectives: To investigate the prognostic significance of concomitant autoimmune diseases (ADs) in myeloproliferative neoplasms (MPNs).

Methods: 435 subjects with a diagnosis of MPNs were included in this observational single institution longitudinal study. Of them, 34 patients presented an overt AD at diagnosis of MPN. Clinical presenting features, progression-free and overall survival were compared between MPN subgroups in relation to co-existence of AD at diagnosis of MPN.

Results: Compared to cases without ADs, the subjects with ADs were significantly younger, had lower haemoglobin and haematocrit levels and more frequently presented with splenomegaly. The clinical and biological features associated to progression-free and overall survival were: age, presence of splenomegaly, histotype (MF vs. PV vs. ET), anaemia, high platelet count and presence of any AD at diagnosis of MPN. The age-adjusted hazard ratio (HR) of progression for the presence of AD at diagnosis of MPN was 2.76. Overall survival was not significantly associated to AD at diagnosis, but the HR of progression for the presence of AD at diagnosis of MPN was 2.18.

Conclusions: A possible common genetic predisposition, the inflammatory bone marrow microenvironment and the activation of theJAK/STAT pathway could be considered as responsible for the observed association between MPNs and ADs.
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January 2021

How do systemic lupus erythematosus patients with very-long disease duration present? Analysis of a monocentric cohort.

Lupus 2021 Mar 7;30(3):439-447. Epub 2021 Jan 7.

Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Objective: to describe the disease path and the very long-term outcome in a monocentric cohort of patients with Systemic Lupus Erythematosus (SLE).

Methods: SLE patients with a disease duration of at least 15 years from diagnosis were enrolled. The number of hospitalizations, the disease flares occurred over the disease course and the organ damage accumulation were evaluated at 1, 2, 3, 4, 5, 10 years from diagnosis and at last observation in 2019 as well. Disease state, ongoing therapies and quality of life measures were also assessed at last visit.

Results: 126 Caucasian SLE patients were included in the analysis (95% female, median age 47.5 IQR 41-53, median disease duration 21 IQR19-26). At last visit, the majority of the patients (78.6%) was on LLDAS (remission included), 53.4% were on GC treatment and 35.7% on immunosuppressant. Furthermore, 53.2% had at least one organ damage. The majority of patients (66.7%) presented a relapsing-remitting course, for a total of 158 flares during the disease course (incidence rate: 0.79/patient-year); moreover, 84.9% of the cohort experienced at least one hospital admission, amounting to a total of 328 hospitalizations (incidence rate: 0.85/patient-year). The main reason for admission was disease activity, while the percentage of hospitalizations due to other causes has been growing over the 10 years of follow-up.

Conclusion: after a very long period of disease, most of the patients with SLE are in remission and are not taking GC therapy; however, the risk of incurring in disease flare remains a real problem.
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http://dx.doi.org/10.1177/0961203320984230DOI Listing
March 2021

Salivary Gland Ultrasonography in Sjögren's Syndrome: A European Multicenter Reliability Exercise for the HarmonicSS Project.

Front Med (Lausanne) 2020 23;7:581248. Epub 2020 Nov 23.

Rheumatology Clinic, Department of Medical Area, Academic Hospital S. Maria della Misericordia, University of Udine, Udine, Italy.

Salivary gland ultrasonography (SGUS) is increasingly applied for the management of primary Sjögren's syndrome (pSS). This study aims to: (i) compare the reliability between two SGUS scores; (ii) test the reliability among sonographers with different levels of experience. In the reliability exercise, two four-grade semi-quantitative SGUS scoring systems, namely De Vita et al. and OMERACT, were tested. The sonographers involved in work-package 7 of the HarmonicSS project from nine countries in Europe were invited to participate. Different levels of sonographers were identified on the basis of their SGUS experience and of the knowledge of the tested scores. A dedicated atlas was used as support for SGUS scoring. Twenty sonographers participated in the two rounds of the reliability exercise. The intra-rater reliability for both scores was almost perfect, with a Light's kappa of 0.86 for the De Vita et al. score and 0.87 for the OMERACT score. The inter-rater reliability for the De Vita et al. and the OMERACT score was substantial with Light's Kappa of 0.75 and 0.77, respectively. Furthermore, no significant difference was noticed among sonographers with different levels of experience. The two tested SGUS scores are reliable for the evaluation of major salivary glands in pSS, and even less-expert sonographers could be reliable if adequately instructed.
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http://dx.doi.org/10.3389/fmed.2020.581248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719819PMC
November 2020

Primary Sjögren's Syndrome of Early and Late Onset: Distinct Clinical Phenotypes and Lymphoma Development.

Front Immunol 2020 19;11:594096. Epub 2020 Oct 19.

Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

Objectives: To study the clinical, serological and histologic features of primary Sjögren's syndrome (pSS) patients with early (young ≤35 years) or late (old ≥65 years) onset and to explore the differential effect on lymphoma development.

Methods: From a multicentre study population of 1997 consecutive pSS patients, those with early or late disease onset, were matched and compared with pSS control patients of middle age onset. Data driven analysis was applied to identify the independent variables associated with lymphoma in both age groups.

Results: Young pSS patients (19%, n = 379) had higher frequency of salivary gland enlargement (SGE, lymphadenopathy, Raynaud's phenomenon, autoantibodies, C4 hypocomplementemia, hypergammaglobulinemia, leukopenia, and lymphoma (10.3% vs. 5.7%, p = 0.030, OR = 1.91, 95% CI: 1.11-3.27), while old pSS patients (15%, n = 293) had more frequently dry mouth, interstitial lung disease, and lymphoma (6.8% vs. 2.1%, p = 0.011, OR = 3.40, 95% CI: 1.34-8.17) compared to their middle-aged pSS controls, respectively. In young pSS patients, cryoglobulinemia, C4 hypocomplementemia, lymphadenopathy, and SGE were identified as independent lymphoma associated factors, as opposed to old pSS patients in whom SGE, C4 hypocomplementemia and male gender were the independent lymphoma associated factors. Early onset pSS patients displayed two incidence peaks of lymphoma within 3 years of onset and after 10 years, while in late onset pSS patients, lymphoma occurred within the first 6 years.

Conclusion: Patients with early and late disease onset constitute a significant proportion of pSS population with distinct clinical phenotypes. They possess a higher prevalence of lymphoma, with different predisposing factors and lymphoma distribution across time.
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http://dx.doi.org/10.3389/fimmu.2020.594096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604905PMC
October 2020

Validation of thymic stromal lymphopoietin as a biomarker of primary Sjögren's syndrome and related lymphoproliferation: results in independent cohorts.

Clin Exp Rheumatol 2020 Jul-Aug;38 Suppl 126(4):189-194. Epub 2020 Oct 23.

Rheumatology Clinic, Udine University Hospital, Department of Medical Area, University of Udine, Italy.

Objectives: Thymic stromal lymphopoietin (TSLP) has been implicated in primary Sjögren's syndrome (pSS) and related B-cell lymphoproliferation and lymphoma (NHL) by studies on salivary pathologic tissues and serum. The purpose of this work was to validate serum TSLP as biomarker of pSS and related lymphoproliferation by the study of two additional independent cohorts.

Methods: Serum TSLP was measured by ELISA in the original published Cohort-1 from Udine, Italy, including 91 patients. Two additional cohorts were then studied for validation: Cohort-2, including 4 sub-cohorts comprising 125 patients from the Universities of Roma, L'Aquila, Pisa and Perugia, belonging to the Italian SS Study Group (GRISS), and Cohort-3, including 59 patients from the University of Athens, Greece. Overall, 159 control subjects were enrolled. Active pSS-NHL, as well as pre-lymphomatous conditions, i.e. persistent salivary gland swelling and mixed cryoglobulinaemia, were investigated in detail. In addition, serum samples from pSS-NHL in complete remission were analysed (n=27).

Results: TSLP serum levels were confirmed to be significantly higher in pSS compared to controls in both Cohort-2 and Cohort-3, in particular in patients with lymphoproliferation. Serum TSLP was much higher in pSS pre-lymphomatous conditions. Finally, active NHL showed the highest TSLP serum levels, while in NHL in remission TSLP resulted undetectable or significantly lower than in benign pSS.

Conclusions: By the study of independent cohorts, it was again demonstrated that serum TSLP levels are increased in pSS, above all in more advanced B-cell lymphoproliferation and NHL. Serum TSLP can therefore represent a novel biomarker for pSS-related lymphoproliferation.
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October 2020

Total area of inflammatory infiltrate and percentage of inflammatory infiltrate identify different clinical-serological subsets of primary Sjögren's syndrome better than traditional histopathological parameters.

Clin Exp Rheumatol 2020 Jul-Aug;38 Suppl 126(4):195-202. Epub 2020 Oct 23.

Rheumatology Unit, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.

Objectives: Recently, the total area of the inflammatory infiltrate and the percentage of inflammatory infiltrate have been proposed as novel histopathological parameters to improve the stratification of patients with Sjögren's syndrome (SS) in clinical trials. Both these parameters provide a more accurate assessment of the extent of the infiltrate in minor salivary gland biopsies (MSGBs) and may overcome the bias related to the Focus score (FS). To date, however, only few studies have investigated their clinical value and feasibility. In this study we revised consecutive MSGBs obtained routinely in a real-life clinical setting and correlated the total area of the inflammatory infiltrate and the percentage of inflammatory infiltrate both with the other MSGB histopathological parameters and with patients' clinical features in order to explore their usefulness in SS diagnostic work-up.

Methods: We assessed the area of the inflammatory infiltrate and the percentage of the inflammatory infiltrate in consecutive MSGBs and correlated these parameters with the number of foci, the FS and the presence of ectopic lymphoid structures (ELS). We also correlated these additional parameters with patients' clinical and biological data.

Results: We revised 69 MSGB samples: 46 from patients with a diagnosis of SS and 23 from subjects with no SS. The total area of inflammatory infiltrate and the percentage of inflammatory infiltrate appeared significantly higher in patients fulfilling the ACR/EULAR classification criteria for SS and correlated significantly with both the number of foci (p<0.001) and the FS (p<0.001). Particularly, they correlated better with the ELS in MSGBs than the number of foci and the FS. When we limited the analysis to the 32/69 patients with a FS<1, both the total area of the inflammatory infiltrate (p=0.02) and the percentage of the inflammatory infiltrate (p=0.03), but not the number of foci (p=0.12) remained significantly higher in the 10/32 anti-Ro/SSA positive patients fulfilling the ACR/EULAR classification criteria. Finally, the total area of inflammatory infiltrate and the percentage of inflammatory infiltrate correlated significantly with several biological and haematological SS-related abnormalities including hypergammaglobulinaemia, C4 levels, total number of white blood cells and the number of circulating lymphocytes.

Conclusions: The total area of the inflammatory infiltrate and the percentage of the inflammatory infiltrate in SS referral centres, and particularly for selected cases, may maximise the information on disease activity at tissue level, ultimately improving SS patients' assessment.
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October 2020

Ultra-high frequency ultrasonography of labial glands is a highly sensitive tool for the diagnosis of Sjögren's syndrome: a preliminary study.

Clin Exp Rheumatol 2020 Jul-Aug;38 Suppl 126(4):210-215. Epub 2020 Oct 23.

Rheumatology Unit, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.

Objectives: Ultra-high frequency ultrasonography (UHFUS) has been recently introduced in oral medicine due to its ability to image small anatomical structures including labial salivary glands (LSG). To date no ultrasonography morphological studies of labial salivary glands (LSG) have been carried out in SS. In this pilot study we aimed at analysing the distribution of UHFUS findings in LSG of patients with suspected SS, focusing in particular on the association with patients' oral dysfunction, antibody profiles and histopathology.

Methods: Consecutive patients undergoing a LSG biopsy for clinically suspected SS were included in this study between January 2018 and January 2020. Intraoral UHFUS scan of the lip mucosa was performed with Vevo MD equipment, using a 70 MHz probe with a standardised protocol. LSG were assessed by using a four-grade semiquantitative scoring system (0-3), similar to the OMERACT scoring system used for major salivary glands. The distribution of UHFUS grades was compared in patients stratified according their final diagnosis, patients antibody profiles and LSG histopathology.

Results: We included 128 patients with suspected SS: out of them, 54 (42.2%) received a final diagnosis of SS, made according to the ACR 2016 criteria and 74 (57.8%) were diagnosed as no-SS sicca controls. We found that LSG inhomogeneity was significantly greater in patients with SS than in no-SS subjects (p<0.0001). We also found that higher UHFUS pattern of inhomogeneity (i.e. grade 2 and 3) were significantly more frequent in both SSA+/SSB- and SSA+/SSB+ patients (p=0.001). A normal UHFUS pattern, by contrast, was significantly more common in SSA-/SSB- subjects (i.e. 15/83 (18.1%) vs. 1/33 (3%) vs. 0/12 (0%), p=0.001). Finally, LSG inhomogeneity was significantly associated with both the number of foci (p<0.001) and focus score (p<0.001). Particularly, we found that both the number of foci and the FS were significantly higher in patients presenting a UHFUS grading of 2 and 3 with respect to those presenting a UHFUS grading of 0 and 1 (p=0.01).

Conclusions: This preliminary study demonstrates the optimal feasibility of UHFUS and its high sensitivity in identifying negative patients on subsequent lip biopsy, thus avoiding invasive procedures in selected cases. Further studies are in progress to define the clinical and predictive role of the various patterns observed and their added value with respect to traditional salivary gland ultrasonography.
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October 2020

Significance of anti-La/SSB antibodies in primary Sjögren's syndrome patients with combined positivity for anti-Ro/SSA and salivary gland biopsy.

Clin Exp Rheumatol 2020 Jul-Aug;38 Suppl 126(4):53-56. Epub 2020 Oct 22.

Rheumatology Unit, Department of Medicine, University of Perugia, Italy.

Objectives: Immunological parameters exert a relevant diagnostic and prognostic role in primary Sjögren's syndrome (pSS) and may identify specific disease phenotypes. Among disease-associated immunological features, anti-La/SSB are rarely found without concomitant anti-Ro/SSA and their clinical significance in patients with pSS has been poorly investigated. Thus, we aimed to characterise the value of anti-La/SSB analysing clinical and serologic features of a wide cohort of pSS patients with both circulating anti-Ro/SSA and positive salivary gland biopsy (SGB).

Methods: Clinical and serological data of 600 pSS patients with both anti-Ro/SSA and SGB positivity and categorised according to anti-La/SSB status were retrospectively analysed. Comparisons between patients with and without circulating anti-La/SSB were performed.

Results: Among the whole cohort, 319 (53%) of patients were anti-La/SSB negative and 281 (47%) were anti-La/SSB positive. Anti-La/SSB positive patients were younger at disease diagnosis and had a longer disease duration. Moreover, anti-La/SSB positive patients had a higher prevalence of hypergammaglobulinaemia and circulating rheumatoid factor and of lymphoproliferative disorders in comparison to seronegative group. At multivariate analysis, hypergammaglobulinaemia (OR=1,7; 95% CI 1.17, 2.43), rheumatoid factor (OR=2.3; 95% CI 1.6, 3.3) and lymphoma (OR=2.6; 95% CI 1.12, 5.96) were identified as independent variables significantly associated with anti-La/SSB positivity.

Conclusions: In patients with pSS and concomitant anti-Ro/SSA and SGB positivity, the presence of anti-La/SSB may help in identifying a disease subset with distinct prognostic features, especially in terms of higher risk of lymphoproliferative complications.
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October 2020

Articular involvement, steroid treatment and fibromyalgia are the main determinants of patient-physician discordance in systemic lupus erythematosus.

Arthritis Res Ther 2020 10 14;22(1):241. Epub 2020 Oct 14.

Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, Pisa, Italy.

Background: Remission or the lowest possible disease activity is the main target in the management of systemic lupus erythematosus (SLE). Anyway, conflicting data are present in the literature regarding the correlation between physician-driven definitions and patient perception of the disease. The objective of this study is to evaluate the relationship between the definition of lupus low disease activity state (LLDAS) and patient's health-related quality of life (HRQoL).

Methods: This is a cross-sectional, monocentric study. Adult SLE patients were included. For each patient, demographics, disease duration, medications, comorbidities, organ damage, active disease manifestations and SELENA-SLEDAI were assessed. Patients have been categorised as follows: LLDAS, remission and active disease. Each patient completed the following patient-reported outcomes (PROs): SF-36, LIT, FACIT-Fatigue and SLAQ. A SLAQ score < 6 (25° percentile of our cohort) was used as the cut-off value to define a low disease activity state according to patient self-evaluation.

Results: We enrolled 259 consecutive SLE patients (mainly female and Caucasian, mean age 45.33 ± 13.14 years, median disease duration 14 years). 80.3% were in LLDAS, of whom 82.2% were in remission; 19.7% were active. No differences emerged for any of the PROs used between the LLDAS and the active group. Considering the LLDAS subgroup, we identified 56 patients with a subjective low disease activity (SLAQ < 6) and we defined them as "concordant"; the remaining 152 patients in LLDAS presented a subjective active disease (SLAQ ≥ 6) and were defined "discordant". Discordant patients presented more frequently ongoing and past joint involvement (p < 0.05) and a diagnosis of fibromyalgia (p < 0.01); furthermore, they were more likely to be on glucocorticoid therapy (p < 0.01). Discordant patients showed a significantly poorer HRQoL, assessed by all PROs (p < 0.0001).

Conclusions: Joint involvement, glucocorticoid therapy and comorbid fibromyalgia resulted to be the most important variables determining the poor concordance between patient and physician perspective on the disease.
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http://dx.doi.org/10.1186/s13075-020-02334-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559765PMC
October 2020

One year in review 2020: pathogenesis of primary Sjögren's syndrome.

Clin Exp Rheumatol 2020 Jul-Aug;38 Suppl 126(4):3-9. Epub 2020 Sep 29.

Rheumatology Unit, Department of Clinical and Experimental Rheumatology, University of Pisa, Italy.

The pathogenesis of primary Sjögren's syndrome (pSS) remains poorly understood. However, important efforts have been made during the last few months. In this review, following the others of this series we will summarise the most recent literature on pSS pathogenesis focusing in particular on new insights into pSS animal models, genetics and epigenetics, innate and adaptive immune system abnormalities and tertiary lymphoid structures. Hopefully, novel insights into pSS pathogenesis will pave the way to new therapeutic approaches to the disease improving patients' management and prognosis.
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October 2020

Symmetric peripheral polyarthritis developed during SARS-CoV-2 infection.

Lancet Rheumatol 2020 Sep 13;2(9):e518-e519. Epub 2020 Jul 13.

Rheumatology Unit, Azienda Ospedaliero Universitaria Pisana, 56126 Pisa, Italy.

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http://dx.doi.org/10.1016/S2665-9913(20)30216-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357970PMC
September 2020

Sjögren's Syndrome: The Clinical Spectrum of Male Patients.

J Clin Med 2020 Aug 12;9(8). Epub 2020 Aug 12.

Pathophysiology Department, Athens School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece.

Background: To compare the clinical, serological and histologic features between male and female patients with Sjögren's syndrome (SS) and explore the potential effect of gender on lymphoma development.

Methods: From a multicenter population (Universities of Udine, Pisa and Athens, Harokopion and Ioannina (UPAHI)) consisting of consecutive SS patients fulfilling the 2016 ACR/EULAR criteria, male patients were identified, matched and compared with female controls. Data-driven multivariable logistic regression analysis was applied to identify independent lymphoma-associated factors.

Results: From 1987 consecutive SS patients, 96 males and 192 matched female controls were identified and compared. Males had a higher frequency of lymphoma compared to females (18% vs. 5.2%, OR = 3.89, 95% CI: 1.66 to 8.67; = 0.0014) and an increased prevalence of serum anti-La/SSB antibodies (50% vs. 34%, OR = 1.953, 95% CI: 1.19 to 3.25; = 0.0128). No differences were observed in the frequencies of lymphoma predictors between the two genders. Data-driven multivariable logistic regression analysis revealed negative association of the female gender with lymphoma and positive association with lymphadenopathy.

Conclusion: Male SS patients carry an increased risk of lymphoma development. Although statistics showed no difference in classical lymphoma predictors compared to females, data-driven analysis revealed gender and lymphadenopathy as independent lymphoma-associated features.
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http://dx.doi.org/10.3390/jcm9082620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463756PMC
August 2020

Ultra-High Frequency Ultrasound, A Promising Diagnostic Technique: Review of the Literature and Single-Center Experience.

Can Assoc Radiol J 2020 Jul 28:846537120940684. Epub 2020 Jul 28.

Unit of Dentistry and Oral Surgery, Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy.

Objectives: Ultra-high frequency ultrasonography (UHFUS) is a recently introduced diagnostic technique which finds several applications in diverse clinical fields. The range of frequencies between 30 and 100 MHz allows for high spatial resolution imaging of superficial structures, making this technique suitable for the imaging of skin, blood vessels, musculoskeletal anatomy, oral mucosa, and small parts. However, the current clinical applications of UHFUS have never been analyzed in a consistent multidisciplinary manner. The aim of this study is to revise and discuss the current applications of UHFUS in different aspects of research and clinical practice, as well as to provide some examples of the current work-in-progress carried out in our center.

Materials And Methods: A literature search was performed in order to retrieve articles reporting the applications of UHFUS both in research and in clinical settings. Inclusion criteria were the use of frequencies above 30 MHz and study design conducted in vivo on human subjects.

Results: In total 66 articles were retrieved. The majority of the articles focused on dermatological and vascular applications, although musculoskeletal and intraoral applications are emerging fields of use. We also describe our experience in the use of UHFUS as a valuable diagnostic support in the fields of dermatology, rheumatology, oral medicine, and musculoskeletal anatomy.

Conclusion: Ultra-high frequency ultrasonography application involves an increasing number of medical fields. The high spatial resolution and the superb image quality achievable allow to foresee a wider use of this novel technique, which has the potential to bring innovation in diagnostic imaging.
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http://dx.doi.org/10.1177/0846537120940684DOI Listing
July 2020

Translation, cultural adaptation and validation of the Italian version of the Brief Index of Lupus Damage: the BILDit.

Lupus 2020 Sep 13;29(10):1198-1205. Epub 2020 Jul 13.

Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Objectives: The Brief Index of Lupus Damage (BILD) is an instrument of self-evaluation of organ damage for systemic lupus erythematosus (SLE) patients. The objectives of this study were the translation, cultural adaptation and validation of the Italian version of the BILD (BILDit).

Methods: The process of translation and cultural adaptation followed published guidelines. The BILDit was pretested in a pilot study with 30 SLE patients in order to evaluate acceptability, reliability, comprehension and feasibility, and then validated in consecutive SLE patients attending our clinic.

Results: A total of 167 SLE patients were enrolled. In the pilot study, the BILDit demonstrated good acceptability, feasibility and comprehensibility and a very high degree of reliability (Cronbach's α = 1). In the validation cohort, the BILDit showed a significant positive correlation with the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI; ρ = 0.69;  < 0.001). Analysing the item-by-item correlation between the BILDit and the SDI, a good correlation ( < 0.001) was found for 73.1% of the items. In the multivariate analysis, the BILDit showed a significant positive correlation with age and disease duration ( < 0.01).

Conclusions: The BILDit seems to be an acceptable and reliable instrument for patient self-evaluation of disease damage, with a good correlation with the SDI. It can be considered as a screening tool for the evaluation of organ damage starting from the patient's perceptive.
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http://dx.doi.org/10.1177/0961203320940012DOI Listing
September 2020

Are patients with systemic lupus erythematosus more prone to result false-positive for SARS-CoV2 serology?

Clin Exp Rheumatol 2020 May-Jun;38(3):577. Epub 2020 May 27.

Rheumatology Unit, University of Pisa, Italy.

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September 2020

The CoV-2 outbreak: how hematologists could help to fight Covid-19.

Pharmacol Res 2020 07 6;157:104866. Epub 2020 May 6.

Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

COVID-19 is a medical emergency, with 20 % of patients presenting with severe clinical manifestations. From the pathogenetic point of view, COVID-19 mimics two other well-known diseases characterized by cytokine storm and hyper-activation of the immune response, with consequent organ damage: acute graft-versus-host disease (aGVHD) and macrophage activation syndrome (MAS). Hematologists are confident with these situations requiring a prompt therapeutic approach for switching off the uncontrolled cytokine release; here, we discuss pros and cons of drugs that are already employed in hematology in the light of their possible application in COVID-19. The most promising drugs might be: Ruxolitinib, a JAK1/2 inhibitor, with a rapid and powerful anti-cytokine effect, tyrosine kinase inhibitors (TKIs), with their good anti-inflammatory properties, and perhaps the anti-Cd26 antibody Begelomab. We also present immunological data from gene expression experiments where TKIs resulted effective anti-inflammatory and pro-immune drugs. A possible combined treatment algorithm for COVID-19 is here proposed.
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http://dx.doi.org/10.1016/j.phrs.2020.104866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202852PMC
July 2020

One year in review 2020: vasculitis.

Clin Exp Rheumatol 2020 Mar-Apr;38 Suppl 124(2):3-14. Epub 2020 Apr 28.

Clinic of Rheumatology, Department of Medicine, University of Udine, Italy.

Systemic vasculitides are a group of diseases that could potentially affect any organ with heterogeneous clinical manifestations that usually depend on the size of the most involved vessels. These diseases could be associated with a relevant burden of mortality and morbidity if not early recognised and treated. Moreover, even if they are usually rare diseases, their incidence and prevalence seem to be increasing in the last decade, partially because of improved awareness and management of vasculitis from physicians. Like in the previous annual reviews of this series, in this paper we revised the most recent literature on pathogenesis, clinical manifestations and treatment options in small- and large-vessel vasculitis.
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September 2020

Patients with Interstitial Lung Disease Secondary to Autoimmune Diseases: How to Recognize Them?

Diagnostics (Basel) 2020 Apr 9;10(4). Epub 2020 Apr 9.

Regional Referral Centre for Rare Lung Diseases, A. O. U. "Policlinico-Vittorio Emanuele" Dept. of Clinical and Experimental Medicine, University of Catania, via S. Sofia 68, pavillon 3 floor 1, 95123 Catania, Italy.

The diagnostic assessment of patients with Interstitial Lung Disease (ILD) can be challenging due to the large number of possible causes. Moreover, the diagnostic approach can be limited by the severity of the disease, which may not allow invasive exams. To overcome this issue, the referral centers for ILD organized Multidisciplinary Teams (MDTs), including physicians and experts in complementary discipline, to discuss the management of doubtful cases of ILD. MDT is currently considered the gold standard for ILD diagnosis, but it is not often simple to organize and, furthermore, rheumatologists are still not always included. In fact, even if rheumatologic conditions represent a common cause of ILD, they are sometimes difficult to recognize, considering the variegated clinical features and their association with all possible radiographic patterns of ILD. The first objective of this review is to describe the clinical, laboratory, and instrumental tests that can drive a diagnosis toward a possible rheumatic disease. The secondary objective is to propose a set of first-line tests to perform in all patients in order to recognize any possible rheumatic conditions underlying ILD.
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http://dx.doi.org/10.3390/diagnostics10040208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235942PMC
April 2020

COVID-19: the new challenge for rheumatologists.

Clin Exp Rheumatol 2020 Mar-Apr;38(2):175-180. Epub 2020 Mar 24.

University of Pisa, Italy.

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March 2020

Impact of fatigue on health-related quality of life and illness perception in a monocentric cohort of patients with systemic lupus erythematosus.

RMD Open 2020 02;6(1)

Department of Clinical and Experimental Medicine, Rheumatology Unit, University of Pisa, Pisa, Italy

Background: Fatigue is a very common and debilitating symptom in patients with systemic lupus erythematosus (SLE), even among those with a mild or inactive disease. The objective of this study is to define fatigue determinants and describe the impact of fatigue on health-related quality of life (HRQoL) and illness perception in a monocentric cohort of patients with SLE.

Methods: This is a cross-sectional study. Adult patients with SLE were included. For each patient, demographics, medications, comorbidities, organ damage (Systemic Lupus International Collaborating Clinics Damage Index), active disease manifestations and Systemic Lupus Disease Activity Index scores were collected. It was evaluated if each patient met the definitions of remission and low disease activity. At enrolment, each patient completed the Short Form-36 (SF-36), Functional Assessment Chronic Illness Therapy-Fatigue (FACIT-F), Lupus Impact Tracker (LIT), Systemic Lupus Activity Questionnaire (SLAQ) and Brief Index of Lupus Damage (BILD). The FACIT-F questionnaire was also administered to a group of healthy controls.

Results: 223 patients were included (mean age 44.9±13.2 years, median disease duration 13 years). 18.2% had an active disease, 43.5% met the definition of remission on treatment, and 11.8% had a concomitant fibromyalgia. The median FACIT-F score of our cohort was significantly lower compared with that of healthy controls (40 vs 47; p<0.001). FACIT-F scores were irrespective of age, disease duration, disease activity and damage. FACIT-F score was significantly lower in patients with fibromyalgia (p<0.01). FACIT-F scores demonstrated a significant correlation with all other patient-reported outcomes: SF-36 (r=0.53-0.77), LIT (r=-0.78), SLAQ (r=-0.72) and BILD (r=-0.28).

Conclusions: Fatigue in patients with SLE has a strong negative impact on HRQoL and patient perception of the disease burden. Fatigue seems irrespective of disease activity but significantly influenced by the presence of fibromyalgia.
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http://dx.doi.org/10.1136/rmdopen-2019-001133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046978PMC
February 2020

Alveolar haemorrhage in ANCA-associated vasculitis: Long-term outcome and mortality predictors.

J Autoimmun 2020 03 9;108:102397. Epub 2020 Jan 9.

Rheumatology Section, Department of Medicine, University of Verona, Verona, Italy.

Introduction: Alveolar haemorrhage (AH) is considered an important cause of morbidity and early mortality in anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV).

Objectives: The aim of this study was to identify predictors of outcome in patients with AH-AAV and to evaluate outcome and causes of death in this subset.

Materials And Methods: A multicenter retrospective study was conducted in 29 Italian Centers. Clinicians were asked to recruit all patients diagnosed with AAV-associated AH during the last 10 years, from 2007 to 2016. Univariate and multivariable analysis were performed.

Results: One-hundred and six patients were included (median age at onset of 55 years [IQR 42-67]). The majority were ANCA-positive (PR3 57.1%, MPO 33.7%) and 72.6% had also renal involvement. At presentation, anaemia was shown in 97 (92.4%) patients, hemoptysis in 54 (51.9%), respiratory failure in 68 (66.7%), of whom 48 (70.6%), requiring respiratory support. At the end of the 37 months [IQR 13-77] follow-up, 19/106 (17.9%) patients were dead. The main causes of death were active disease and infections. By stepwise regression analysis, age >65 years (HR 3.66 [95% CI 1.4-9.51], p = 0.008) and the need for respiratory support (HR 4.58 [95% CI 1.51-13.87], p = 0.007) at AH onset were confirmed to be predictive of mortality.

Conclusions: Predictors of outcome in AAV-AH were determined. Factors related to the patient's performance status and the severity of the lung involvement strongly influenced the outcome. Balancing harms and benefits for the individual patient in induction and maintenance treatment strategies is crucial.
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http://dx.doi.org/10.1016/j.jaut.2019.102397DOI Listing
March 2020