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Objective To investigate the gene expression profile in patients with Sjogren's syndrome that is characterized by different clinical phenotypes. Methods RNA from peripheral blood mononuclear cells was purified in 8 patients with glandular features (GFs) and widespread pain (WP) and 11 with extraglandular manifestations (EGMs) and then was analyzed by hybridization on a human gene chip exploring more than 40,000 human genes. Differentially expressed genes (DEGs) in the two subgroups (ie, those with false discovery rate-corrected P values ≤ 0.01) with respect to 20 healthy controls have been submitted to functional classification using a Gene Ontology database and were mapped to define the networks of protein to protein interactions (PPIs). Results The enriched pathway analyses of DEGs and of the highly interconnected modules identified in the PPI networks showed that the pathological processes characterizing the two subgroups were substantially different. The predominant pathways in patients with EGMs are related to T- and B-cell activation, Toll-like receptor, interferon signaling, and apoptosis. Conversely, pathological processes related to pain transmission and modulation are preferentially operative in patients with GFs and WP. These data suggest that a neuroinflammatory pathway driven by cytokines and chemokines may play a central role in triggering WP features in this phenotype of patients. Conclusion The present study supports the hypothesis that different biological pathways are operative in patients with primary Sjogren's syndrome with different clinical phenotypes. A better knowledge of these specific processes might help in tailoring more effective target therapies.

Background In previous studies, we demonstrated that the NEMO score, i.e. the cumulative number of microhaemorrhages (MHEs) and microthromboses (MTs), observed in nailfold videocapillaroscopy was a good indicator of the steady state level of disease activity (DA) in patients with systemic sclerosis (SSc) when the European Scleroderma Study Group (EScSG) index was considered the gold standard. Aim of the study To verify whether the NEMO score could be (i) a valid tool to assess DA, even when the modified European Scleroderma Trials and Research (EUSTAR) index was considered to be the comparator, and (ii) a sensitive method to capture the DA overtime changes. Patients and methods The NEMO score and the EScSG and EUSTAR indices were contemporarily assessed at baseline (T0) and after a follow-up of 4–56 months (T1) in 98 patients with SSc. The differences (Δ) between the T1 and T0 values of the NEMO score and the EScSG and EUSTAR indices were calculated and compared to each other. Results NEMO score values were very closely correlated with the corresponding values of the EScSG and EUSTAR indices both at T0 and T1 observations (p p p Receiver operating characteristic (ROC) curve analysis showed the NEMO score had a good sensitivity and specificity in classifying patients with a predefined level of DA (scores ≥ 3.0 and ≥ 2.5 for the EScSG and EUSTAR indices, respectively, p Δ values of the NEMO score were significantly correlated with the corresponding values of both the EScSG and EUSTAR indices. Weighted Cohen’s k level of agreement between Δ values of the NEMO score and those of the EScSG and EUSTAR indices was moderate (0.55 and 0.59, respectively). Conclusions NEMO score proves to be a feasible, non-invasive, and valid tool to assess steady state levels and changes over time of DA in patients with SSc. Thus, it can represent an alternative or complementary method to measure this disease status entity in this disorder.

Primary Sjogren's syndrome (SjS) is a systemic autoimmune disease most commonly diagnosed in middle-aged women. Although the disease can occur at all ages, it is diagnosed between 30 and 60 years of age in two-thirds of patients. In more than 20% of cases, the people are older than 65 years. In this review, we focus on the therapeutic management of primary SjS in older patients, following the recently published 2020 European League Against Rheumatism (EULAR) recommendations for the management of the disease with topical and systemic therapies. These recommendations are applicable to all patients with primary SjS regardless of age at diagnosis, although the therapeutic management in older patients requires additional considerations. Older patients are more likely to have pulmonary, liver, kidney, or heart-related comorbidities (even cognitive disturbances); caution is required when most drugs are used, including muscarinic agents, systemic corticosteroids and synthetic immunosuppressants. It is also important to monitor the use of eye drops containing steroids due to the increased risk of developing cataracts, a frequent ocular complication in the older population. In contrast, the majority of drugs that can be used topically (pilocarpine rinses, eye drops containing topical non-steroidal anti-inflammatory drugs (NSAIDs) or cyclosporine A, topical dermal formulations of NSAIDs) have shown an acceptable safety profile in older patients, as well as rituximab. A rigorous evaluation of the medical history of older patients is essential when drugs included in the EULAR guidelines are prescribed, with special attention to factors frequently related to ageing, such as polypharmacy, the existence of organ-specific comorbidities, or the enhanced susceptibility to infections.

There is a great deal of evidence pointing to interferons (IFNs) as being key cytokines in the pathogenesis of different systemic autoimmune diseases, including primary Sjögren’s syndrome (pSS). In this disease, a large number of studies have shown that an overexpression of type I IFN, the ‘so-called’ type I IFN signature, is present in peripheral blood mononuclear cells, and that this finding is associated with the development of systemic extra-glandular manifestations, and a substantial production of autoantibodies and inflammatory cytokines. In contrast, the absence or a milder expression of type I IFN signature and low level of inflammatory cytokines characterizes patients with a different clinical phenotype, where the disease is limited to glandular involvement and often marked by the presence of widespread pain and depression. The role of type II (IFNγ) in this subset of pSS patients, together with the potentially related activation of completely different immunological and metabolic pathways, are emerging issues. Expression of both types of IFNs has also been shown in target tissues, namely in minor salivary glands where a predominance of type II IFN signature appeared to have a certain association with the development of lymphoma. In view of the role played by IFN overexpression in the development and progression of pSS, inhibition or modulation of IFN signaling has been regarded as a potential target for the therapeutic approach. A number of therapeutic compounds with variable mechanisms of action have been tested or are under consideration for the treatment of patients with pSS.

Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disorder characterized by very heterogeneous features. The spectrum of this disorder may vary from benign but disabling symptoms such as dryness, due to lachrymal and salivary involvement, pain and fatigue, to systemic, potentially severe, manifestations that may involve any organ. In recent decades, the arrival of biotechnological therapy has offered new opportunities for the treatment of this—until now—orphan disease. Currently, the possible use of these new drugs in therapeutic trials has made it necessary to have reliable outcome measures to evaluate their efficacy in this disease. A great effort has been made in multicenter, often multinational, studies to develop and validate instruments capable of assessing the different disease-related features. The adoption in therapeutic trials of the newly developed outcome measures aimed at assessing systemic features and patient reported symptoms has often yielded disappointing results. These negative data have been ascribed, on the one hand, to the trial design not being completely appropriate, and, on the other hand, to the fact that a single instrument may be not sufficient to cover the great clinical heterogeneity of the disease features. There is now growing belief that composite end points that include instruments that are able to assess the various aspects of the disease may be more properly and successfully used in future therapeutic trials.

BackgroundNailfold videocapillaroscopy (NVC) is a feasible method that allows the observation of the microvascular changes that mark the course of systemic sclerosis (SSc). In previous studies we demonstrated that the NEMO score, i.e., the cumulative number of microhaemorrhages and microthromboses, is a good indicator of the steady state level and overtime changes of disease activity (DA) in SSc.ObjectivesTo verify whether high NEMO scores, which mirror a very active microvascular derangement in the fingers, may predict the subsequent development of ischemic digital ulcers (IDUs).Methods The NEMO score was assessed at baseline (T0) in 98 patients with SSc, all classified according to the ACR-EULAR criteria. Of them, 90 were females, 48 had the limited and 50 the diffuse cutaneous variant of SSc. Afterwards, the patients were closely followed up for two years, and the appearance of new IDUs recorded at any time of the follow up.The T0-NEMO score values of patients who developed IDUs were compared to those of patients who did not. A receiver operating curve (ROC) was constructed, and the area under the curve (AUC) calculated by plotting the sensitivity and 1-specificity of the different NEMO score values in predicting the subsequent development of IDUs.Results During the follow-up 38 out of 98 patients developed one or more IDUs. The NEMO score at T0 was significantly higher in those who developed IDUs with respect to those who did not [median 14.5 (95%CI 11.0-21.5), and 4.5 (95%CI 4.0-6.0), respectively, pConclusionsBeing a valid tool to measure DA levels in SSc, the NEMO score also appears to be good predictive instrument to predict future development of IDUs in this disease.

To assess the efficacy and safety of a new deformity correction philosophy treatment for AIS called apical vertebral derotation and translation (AVDT). It is a retrospective study of prospectively collected data concerning two different scoliosis correction techniques used in our department. A total of 81 patients (22M, 59F) with a mean age of 15.5 years and minimum follow-up of 2 years were reviewed. Patients were divided into two groups according to the correction technique: 36 patients underwent single-rod derotation using all screws construct (AS), while 45 patients underwent apical vertebral derotation and translation using screws and sublaminar bands (SB). The mean improvement of the MT curve was 70% in the AS group and 60.6% in the SB group, while the mean improvement of the TL/L curve was 65.5 and 72.4%, respectively. PT increased in both groups after surgery with a mean amount of 2.5° in the AS group and only 1° in the SB group. We observed also a greater amount of cervical lordosis reduction in the AS group (4.5°) compared with the SB group (only 1°). The SB group had less operative time and less blood loss. There was no significant difference between the two groups at the final follow-up and both techniques led to an excellent correction in the frontal plane; in the sagittal plane, the AVDT technique seemed to give less sagittal imbalance with better cervical profile; the surgical procedure is easy with less operative time, less blood loss and less risk of potential complications. These slides can be retrieved under Electronic Supplementary Material.

Systemic sclerosis (SSc) is one of the most complex connective tissue diseases. Although significant progress in the knowledge of pathogenic mechanisms and timely diagnosis, therapeutic options remain limited. The attempt to find new treatments for SSc has led researchers to investigate the potential of cellular therapies using autologous and allogeneic stem cells. Multipotent mesenchymal stromal cells (MSCs) are considered an attractive candidate for cell-based therapies. MSCs comprise a heterogeneous population of cells with multilineage differentiation potential that are preferentially able to home to the sites of damage, and secrete various cytokines and growth factors that can have immunomodulatory, angiogenic, anti-inflammatory and anti-apoptotic effects. MSCs from bone-marrow have been first extensively characterized. Adipose tissue represents an additional abundant and accessible source of stem cells. Compared with BM-MSCs, adipose-derived stromal/stem cells (ASCs) offer several advantages, including ease of isolation, less donor morbidity, relative abundance, and rapidity of expansion. For all these reasons, at present ASCs are one of the most attractive and promising sources of adult stem cells for cell therapy, finding a field of application in the treatment of SSc, too. This review will focus on the current applications and possible future perspectives of adipose tissue-cell therapies in SSc.

Primary Sj&ouml, gren&rsquo, s syndrome (pSjS) is a chronic systemic autoimmune disorder, primarily affecting exocrine glands, its pathogenesis is still unclear. Long non-coding RNAs (lncRNAs) are thought to play a role in the pathogenesis of autoimmune diseases and a comprehensive analysis of lncRNAs expression in pSjS is still lacking. To this aim, the expression of more than 540,000 human transcripts, including those ascribed to more than 50,000 lncRNAs is profiled at the same time, in a cohort of 16 peripheral blood mononuclear cells PBMCs samples (eight pSjS and eight healthy subjects). A complex network analysis is carried out on the global set of molecular interactions among modulated genes and lncRNAs, leading to the identification of reliable lncRNA-miRNA-gene functional interactions. Taking this approach, a few lncRNAs are identified as targeting highly connected genes in the pSjS transcriptome, since they have a major impact on gene modulation in the disease. Such genes are involved in biological processes and molecular pathways crucial in the pathogenesis of pSjS, including immune response, B cell development and function, inflammation, apoptosis, type I and gamma interferon, epithelial cell adhesion and polarization. The identification of deregulated lncRNAs that modulate genes involved in the typical features of the disease provides insight in disease pathogenesis and opens avenues for the design of novel therapeutic strategies.

Aims: The therapeutic management of Sjogren syndrome (SjS) has not changed substantially over the past decades: treatment decisions remain challenging in clinical practice, without a specific therapeutic target beyond the relief of symptoms as the most important goal. In view of this scenario, the European League Against Rheumatism (EULAR) promoted and supported an international collaborative study (EULAR SS Task Force) aimed to develop the first EULAR evidence-, consensus-based recommendations for the management of patients with SjS with topical and systemic medications. The aim was to develop a rational therapeutic approach to SjS patients useful for healthcare professionals, doctors in specialist training, medical students, pharmaceutical industries and drug regulatory organizations following the 2014 EULAR standardized operating procedures. Methods: The Task Force included rheumatologists, specialists in internal medicine, oral care specialists, ophthalmologists, gynaecologists, dermatologists, epidemiologists, statisticians, GPs, nurses and patient representatives from 30 countries of the 5 continents. Evidence was collected from studies including primary SjS patients fulfilling the 2002/2016 criteria; when no evidence was available, evidence from studies including associated SjS or patients fulfilling previous sets of criteria was considered and extrapolated. On the basis of the research questions, a systematic literature search between January 1986 and December 2017 was carried out. Summary-of-findings tables were generated and levels of evidence were determined according to the study design using the standards of the Oxford CEBM. A web-based Delphi procedure was carried out in order to reach consensus. For each statement, the grade of recommendation was based on the maximum level of evidence achieved in the SLR using the 4-point scale CEBM categorization. Consensus for endorsement was defined as an agreement score of at least 8 on a 0-10 scale by more than 80% of participants. Results: The Task Force endorsed the presentation of general principles for the management of patients with SjS as 3 overarching, general consensus-based recommendations and 12 specific recommendations that form a logical sequence starting with the management of the central triplet of symptoms (dryness, fatigue and pain) followed by the management of systemic, extraglandular disease (Table 1). Conclusion: The 2019 EULAR recommendations are based on the evidence collected in the last 16 years in the area of management of primary 2002 SjS patients and on discussions by a large and broadly international Task Force. The recommendations synthesise the current thinking on approaching SjS treatment in a set of overarching principles and recommendations. We hope that the current recommendations will be broadly applied in clinical practice and/or serve as a template for national societies to develop local recommendations. Disclosure of Interests: None declared

Autoimmune rheumatic diseases are characterised by an abnormal immune system response, complement activation, cytokines dysregulation and inflammation. In last years, despite many progresses in managing these patients, it has been shown that clinical remission is reached in less than 50% of patients and a personalised and tailored therapeutic approach is still lacking resulting in a significant gap between guidelines and real-world practice. In this context, the need for biomarkers facilitating early diagnosis and profiling those individuals at the highest risk for a poor outcome has become of crucial interest. A biomarker generally refers to a measured characteristic which may be used as an indicator of some biological state or condition. Three different types of medical biomarkers has been suggested: i. mechanistic markers; ii. clinical disease markers; iii. therapeutic markers. A combination of biomarkers from these different groups could be used for an ideal more accurate diagnosis and treatment. However, although a growing body of evidence is focused on improving biomarkers, a significant amount of this information is not integrated on standard clinical care. The overarching aim of this work was to clarify the meaning of specific biomarkers during autoimmune diseases; their possible role in confirming diagnosis, predicting outcome and suggesting specific treatments.

We retrospectively evaluated the efficacy of autologous hematopoietic stem cell transplantation (AHSCT) in 18 patients with rapidly progressive diffuse cutaneous systemic sclerosis (rp-dcSSc), and compared their disease outcomes with those of 36 demographically- and clinically-matched patients treated with conventional therapies. Cutaneous involvement, by performing modified Rodnan skin score (mRss), lung diffusion capacity, by measuring diffusing capacity of lung for carbon monoxide (DLCO), and disease activity, by applying the European Scleroderma Study Group (ESSG) scoring system, were the outcome variables measured at the baseline time and then every 12 months for the following 60 months in both the AHSCT-treated patients and the control group. In the AHSCT group, treatment-related mortality was 5.6%. In this group, both mRss and ESSG scores showed a significant reduction 1 year after AHSCT (P

Background:Nailfold videocapillaroscopy (NVC) is a feasible method that allows the observation and follow-up of the microvascular changes that mark the course of Systemic Sclerosis (SSc). In previous studies, we demonstrated that the NEMO score, namely the cumulative Number of microhaEMOrrhages and microthromboses, is a good indicator of the steady state level and over time changes of disease activity (DA) in SSc (1-3).Objectives:To verify whether a high NEMO score, and then a high level of active microvascular derangement in the fingers may be predictive of the subsequent development of ischemic digital ulcers (IDUs).Methods:The NEMO score was assessed at baseline (T0) in 98 patients affected by SSc, according to the ACR-EULAR criteria. Out of them, 90 were females, 48 had the limited form and 50 the diffuse cutaneous variant of SSc. ACA and anti-Scl-70 antibodies were positive in 42 and 50 patients, respectively. The NVC pattern was early, active and late in 16, 42 and 40 patients, respectively.Afterwards, patients were closely followed up for 3 years, and the appearance of new IDUs was recorded in any time of the follow up.The T0-NEMO score values of patients who developed IDUs were compared to those of patients who did not. A receiver operating curve (ROC) was constructed, and the area under the curve (AUC) calculated, by plotting the sensitivity and 1-specificity of the different NEMO score values in predicting the development of IDUs.Results:During the follow up, 38 out of 98 patients developed one or more DUs. The NEMO score at T0 was significantly higher in those who developed IDUs with respect to those who did not [median 14.5 (CI 11.0-21.5), and 4.5 (CI 4.0-6.0), respectively, pConclusion:NEMO score is not only a valid tool to assess the level of DA in the course of SSc, but this NVC parameter could also be used as a good predictor of the future development of IDUs in patients with this disease.References:[1]Sambataro et al. Arthritis Res Ther 2014;16:462-69[2]Andracco et al. Arthritis Res Ther 2017;19:133-41[3]Pignataro et al. Arthritis Res Ther. 2019;21(1):258Disclosure of Interests:Nicoletta Del Papa: None declared, Francesca Pignataro: None declared, Wanda Maglione: None declared, Antonina Minniti: None declared, Domenico Sambataro: None declared, Gianluca Sambataro: None declared, Gabriele Valentini Grant/research support from: BMS, MSD, NOVARTIS, LILLY, PFIZER, ABBVIE, CELGENE, Claudio Vitali: None declared, Roberto Caporali Consultant of: AbbVie; Gilead Sciences, Inc.; Lilly; Merck Sharp & Dohme; Celgene; Bristol-Myers Squibb; Pfizer; UCB, Speakers bureau: Abbvie; Bristol-Myers Squibb; Celgene; Lilly; Gilead Sciences, Inc; MSD; Pfizer; Roche; UCB

Background:It is well known that Sjögren’s syndrome (SjS) is characterized by an upregulation of interferon (IFN)-induced genes. Namely, IFN type I signature has been reported in peripheral blood mononuclear cells (PBMCs) and in salivary glands of patients with this disease. However, few data are available on possible variability of IFN-induced gene upregulation in different clinical phenotypes of SjS.Objectives:To verify whether upregulation of IFN-induced genes is comparable in patients with SjS characterized by different clinical phenotypes, i.e., patients with systemic extraglandular manifestations (EGMs) versus patients with a disease limited to glandular features (GFs) and with widespread pain (WP).Methods:The study population was composed by 11 patients with SjS and EGMs (1 male, age range 18-78 years), and 10 patients with only GFs and WP (all females, age range 46-81 years), all classified according to ACR-EULAR criteria. The prevalence of anti-SSA(Ro) antibodies was 11/11 and 8/10, respectively. Lip biopsy was positive in all cases. Six healthy normal subjects were also included in the study as control population.Four IFN type I- and 5 IFN type II-induced genes were chosen for the study on the basis of previous literature data. Total RNA from each patient and control was isolated from purified PBMCs, followed by cDNA preparation and real time quantitative-PCR (RQ-PCR) analysis, using specific primer/probe sets. For calculation of relative expression, all samples were normalised against expression of a household gene (beta actin). A further normalization was performed against the mean value of relative expression obtained in the normal controls. Final fold change values were determined from the double-normalised values using the 2−ΔΔCT method (Applied Biosystems).Results:Fold change values of gene expression of both IFN type I- and type II-induced genes in PBMCs were different in the two clinical phenotypes of SjS. Fold change values of IFN type I-induced genes appeared strongly higher in patients with EGM, and some of them only moderately increased in those with only GF and WP. The expression of some of IFN type II-induced genes were slightly increased in patients belonging to both clinical phenotypes. Results are detailed in the table.Table.Fold change values of gene expression in patients with SjS plus EGMs, in patients with disease limited to GF and WP, and in controls.GeneMX1IFIT1IFT3IFI44IDO1GRP1MIGIP-10P2RY14SjS-EGMs85.938.524.440.425.18.34.51.55.5SJS-GF-WP4.21.72.04.84.11.20.60.31.3Controls2.11.61.11.51.41.31.51.31.4Legend. IFN type I-induced genes: MIX, IFN-induced GTP binding protein 1; IFIT1, IFN-induced protein with tetratricopeptide repeats 1; IFIT3, IFN-induced protein with tetratricopeptide repeats 3; IFI44, IFN-induced protein 44.IFN type II-induced genes: IDO1, indolamine-deoxygenase 1; GBP1, guanylate binding protein 1; MIG, C-X-C chemokine 9 (CXCL9); IP-10, C-X-C chemokine 10 (CXCL10); P2RY14, purinergic receptor 14.Conclusion:The present data indicate that IFN type I- and, to a lesser degree, type II-induced genes are upregulated in patients with SjS, but this phenomenon is consistently stronger in patients with systemic EGMs. In patients with only GFs IFN-induced gene upregulation is milder in PBMCs, and then probably more restricted to the exocrine target tissues.Disclosure of Interests:Nicoletta Del Papa: None declared, Claudio Vitali: None declared, Maurizio Lorini: None declared, Vincenzo Carbonelli: None declared, Wanda Maglione: None declared, Francesca Pignataro: None declared, Antonina Minniti: None declared, Nicola Montano: None declared, Roberto Caporali Consultant of: AbbVie; Gilead Sciences, Inc.; Lilly; Merck Sharp & Dohme; Celgene; Bristol-Myers Squibb; Pfizer; UCB, Speakers bureau: Abbvie; Bristol-Myers Squibb; Celgene; Lilly; Gilead Sciences, Inc; MSD; Pfizer; Roche; UCB

Background: Mortality rate in patients infected by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) can be related to the presence of comorbidities like diabetes, cardiovascular and pulmonary diseases. On the contrary, few data exist on the impact of CoronaVirus Disease 2019 (COVID-19) on patients with rheumatic disorders, namely in those having pulmonary involvement and treated with immunosuppressive agents. The present survey is aimed at knowing the impact of COVID-19 in a cohort of patients with systemic sclerosis (SSc). Methods: Telephone interviews were carried out during the COVID-19 outbreak in patients with SSc followed in a Rheumatic Disease Unit in Italy. Patients were asked for confirmed SARS-CoV-2 infection, symptoms suggestive of COVID-19, and modification of their therapy. Results: A total number of 526 patients with SSc were contacted and interviewed. Of them, 270 and 256 had limited cutaneous and diffuse cutaneous SSc, respectively. Interstitial lung disease (ILD) was present in 45% of patients and most of them (68.2%) were treated with immunosuppressive therapy. Only two patients were hospitalized for COVID-19-related pneumonia, and one of them died despite invasive ventilator support. An additional 11 patients reported flu-like symptoms compatible with a mild form of COVID-19. Nobody modified the therapy during the COVID-19 outbreak. Conclusion: Despite the large prevalence of ILD and immunosuppressive therapies, which can be considered risk factors for the occurrence and severity of incidental viral infections, the impact of COVID-19, in terms of mortality rate and morbidity, does not appear particularly severe in this large cohort of patients with SSc. Possible mechanisms influencing this figure are discussed.

Background A randomized controlled trial (RCT) was performed to confirm preliminary uncontrolled data indicating that regional adipose tissue (AT) grafting (G) is effective in inducing ischemic digital ulcer (IDU) healing in patients with systemic sclerosis (SSc). Patients and methods SSc patients with IDUs were randomized to be blindly treated with AT-G or a sham procedure (SP). AT-G consisted of injection, at the base of the finger with the IDU, of 0.5–1 ml AT after centrifugation of fat aspirate. The SP consisted of false liposuction and local injection of saline solution. The primary endpoint was to compare the cumulative prevalence of healed IDUs in the two groups within the following 8 weeks. Results AT-G and the SP were carried out in 25 and 13 patients, respectively. The two groups were comparable for age, gender, disease duration, and SSc subtypes. IDU healing was observed in 23/25 and 1/13 patients treated with AT-G and the SP, respectively (p

Background Different phenotypes characterise the clinical spectrum of primary Sjogren’s syndrome (SjS). Patients with a clinical expression limited to glandular features (GFs) are classically distinguished from patients with extra-glandular manifestations (EGMs). The former patients often complain higher level of fatigue and widespread pain (WP). (Segal et al. 2013) This suggests that gene expression pattern may be different in the two subgroups. Objectives To investigate the differences of gene expression in SjS patients with GFs and in those with EGMs. Methods Nineteen patients with SjS were selected for the study. Gene expression in peripheral blood mononuclear cells (PBMCs) was analysed in 4 patients with EGMs and 4 patients with GFs alone using Clariom D human Affymetrix gene chip (Affymetrix, Santa Clara, CA, USA), and compared to that found in healthy controls. Differences in gene expression were evaluated by analysis of variance (ANOVA) and Step-Up FDR-controlling procedure, being FDR corrected p value≤0.01 and fold change >2 considered as statistically significant. Validation of the gene overexpression was performed by quantitative Real Time(qRT)-PCR in PBMCs from all the selected SjS patients, using the ΔΔCt method for comparing relative fold expression differences. Results All the enrolled SjS patients (18 females and 1 male) had a positive lip biopsy, while anti-SSA/Ro antibodies were detected in 10/11 and 6/8 of the patients with EGMs and with GFs alone, respectively. ESSDAI value ranged from 7 to 55 in patients with EGMs (median 17), and from 0 to 2 in patients with GFs alone (median 1). In both types of patients, the functional analysis of the two transcriptomes showed a large number (>1000) of modulated genes that are involved in the well-known pathological processes of SjS, i.e., apoptosis, inflammatory response, immune response, type I and type II interferons, and Toll-like receptors signalling. Genes modulated only in patient with EGMs showed a significant enrichment of the biological processes associated with immune response (79% of all enriched processes) and, namely, of the molecular pathways related to B cell activation. The analysis of the transcripts expressed only in patients with GFs alone showed instead a preponderant enrichment in different metabolic processes (43%) and in processes associated with the central perception of the stimuli. Indeed, genes involved in sensory perception and in nociceptive signals (i.e., ANPEP, TNRF1, P2RY1, IFNG) were modulated exclusively in patients with GFs alone. The significant differential expression of selected genes in the two SjS subgroups was confirmed by the qRT-PCR analysis. Conclusions These data indicate that in SjS patients with GFs alone a dysregulation of pain pathways (namely beta-adrenergic receptor and Notch signalling) may play a role in the development of WP that is common in this subset of patients. The biological mechanisms triggering the activation of these genes remain to be completely clarified. Disclosure of Interest None declared

For many years primary Sjögren’s syndrome (pSS) has been considered an orphan disease, since no specific therapies were recognized as being capable of contrasting the development and progression of this disorder. The treatment of oral and ocular features, as well as of the systemic organ involvement, has been entrusted to the joint management of different subspecialty physicians, like ophthalmologists, otolaryngologists, dentists and rheumatologists. These latter subspecialty doctors are usually more involved in the treatment of systemic extraglandular involvement and, to do it, they have long been using the conventional therapies borrowed by the treatment schedules adopted in other systemic autoimmune diseases. The increasing knowledge of the biological pathways that are operative in patients with pSS, and the parallel development of molecular biology technology, have allowed the production and availability of a number of biological agents able to positively act on different disease mechanisms, and thus are candidates for testing in therapeutic trials. Meanwhile, the scientific community has made a great effort to develop new accurate and validated classification criteria and outcome measures to be applied in the selection of patients to be included and monitored in therapeutic studies. Some of the new-generation biotechnological agents have been tested in a number of open-label and randomized controlled trials that have produced in many cases inconclusive or contradictory results. Behind the differences in trial protocols, adopted outcome measures and predefined endpoints, reasons for such unsatisfactory results can be found in the large heterogeneity of clinical subtypes in the examined cohorts. The future challenge for a substantial advancement in the therapeutic approach to pSS could be to identify the pathologic mechanisms, outcome tools and biomarkers that characterize the different subsets of the disease in order to test carefully selected target therapies with the highest probability of success in each different clinical phenotype.

Digital ulcers (DUs) are a rather frequent and invalidating complication in systemic sclerosis (SSc), often showing a very slow or null tendency to heal, in spite of the commonly used systemic and local therapeutic procedures. Recently, stem cell therapy has emerged as a new approach to accelerate wound healing. In the present study, we have tentatively treated long-lasting and poorly responsive to traditional therapy SSc-related DUs by implantation of autologous adipose tissue-derived cell (ATDC) fractions. Fifteen patients with SSc having a long-lasting DU in only one fingertip who were unresponsive to intensive systemic and local treatment were enrolled in the study. The grafting procedure consisted of the injection, at the basis of the corresponding finger, of 0.5-1 ml of autologous ATDC fractions, separated by centrifugation of adipose tissue collected through liposuction from subcutaneous abdominal fat. Time to heal after the procedure was the primary end point of the study, while reduction of pain intensity and of analgesic consumption represented a secondary end point. Furthermore, the posttherapy variation of the number of capillaries, observed in the nailfold video capillaroscopy (NVC) exam and of the resistivity in the digit arteries, measured by high-resolution echocolor-Doppler, were also taken into account. A rather fast healing of the DUs was reached in all of the enrolled patients (mean time to healing 4.23 weeks; range 2-7 weeks). A significant reduction of pain intensity was observed after a few weeks ( p < 0.001), while the number of capillaries was significantly increased at 3- and 6-month NVC assessment ( p < 0.0001 in both cases). Finally, a significant after-treatment reduction of digit artery resistivity was also recorded ( p < 0.0001). Even with the limitations related to the small number of patients included and to the open-label design of the study, the observed strongly favorable outcome suggests that local grafting with ATDCs could represent a promising option for the treatment of SSc-related DUs unresponsive to more consolidated therapies.

Joint and muscle pain are commonly observed in patients with primary Sjögren's syndrome (pSS). Different types of pain can be distinguished, that is, articular pain, neuropathic pain and widespread pain. Articular pain is due to more or less evident synovitis, usually involving peripheral joints such as hand joints, wrists, knees and ankles. Drugs used to treat rheumatoid arthritis, or lupus synovitis, are also employed for articular involvement in pSS. Pure sensory neuropathies and, more often, small fibre neuropathies are responsible for neuropathic pain in pSS. This is usually localised in the legs and arms with a characteristic glove or sock distribution. Widespread pain, often assuming the features of fibromyalgia, has also been reported in patients with pSS. The pathological mechanisms underlying both neuropathic pain and widespread (fibromyalgia) pain in pSS have not been so far completely clarified.

Labial salivary gland (LSG) biopsy is used in the classification of primary Sjögren's syndrome (PSS) and in patient stratification in clinical trials. It may also function as a biomarker. The acquisition of tissue and histological interpretation is variable and needs to be standardised for use in clinical trials. A modified European League Against Rheumatism consensus guideline development strategy was used. The steering committee of the ad hoc working group identified key outstanding points of variability in LSG acquisition and analysis. A 2-day workshop was held to develop consensus where possible and identify points where further discussion/data was needed. These points were reviewed by a subgroup of experts on PSS histopathology and then circulated via an online survey to 50 stakeholder experts consisting of rheumatologists, histopathologists and oral medicine specialists, to assess level of agreement (0-10 scale) and comments. Criteria for agreement were a mean score ≥6/10 and 75% of respondents scoring ≥6/10. Thirty-nine (78%) experts responded and 16 points met criteria for agreement. These points are focused on tissue requirements, identification of the characteristic focal lymphocytic sialadenitis, calculation of the focus score, identification of germinal centres, assessment of the area of leucocyte infiltration, reporting standards and use of prestudy samples for clinical trials. We provide standardised consensus guidance for the use of labial salivary gland histopathology in the classification of PSS and in clinical trials and identify areas where further research is required to achieve evidence-based consensus.

Autoimmune diseases are a complex set of diseases characterized by immune system activation and, although many progresses have been done in the last 15 years, 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.

Background Some abnormalities in nailfold videocapillaroscopy (NVC), such as the presence of micro-haemorrhages (MHEs), micro-thromboses (MTs), giant capillaries (GCs) and reduction in the number of capillaries (nCs), suggest a disease activity (DA) phase in systemic sclerosis (SSc). In a previous paper, we showed that the number of micro-haemorrhages and micro-thromboses (the so-called NEMO score) was the NVC feature more closely associated with DA. The present study was aimed at validating the NEMO score as a measure of DA in patients with SSc. Methods Two cohorts of 122 and 97 patients with SSc who were referred to two different rheumatology units, one in Milan and one in Naples, respectively, constituted the validation cohorts. The NEMO score, the total number of GCs and the mean nCs per digit were the parameters defined in each patient by eight-finger NVC. An expert operator analysed the NVCs in each of the participating units. The European Scleroderma Study Group (ESSG) index was used to define the DA level in each patient at the time of NVC examination. Results The NEMO score was the NVC parameter more strictly correlated with the ESSG score in both the Milan and Naples cohorts (p

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.

Background Osteoporotic vertebral fractures (VFs) are often misdiagnosed because asymptomatic and occurring in the absence of specific trauma. Further, diagnostic assessment of VFs may be suboptimal. Aim of the study To assess the misdiagnosis of vertebral fractures on local radiographic readings in the cohort of patients enrolled in the POINT study. Methods We enrolled hospitalised patients, admitted for any cause to the Internal Medicine Units of 37 hospitals participating to the cross-sectional previously published POINT study. The assessment of VFs was performed both by local radiologists and by two expert skeletal radiologists, by using semiquantitative method (SQ). To better evaluate mild vertebral deformities, the two central radiologists also used the algorithm-based qualitative assessment (ABQ). Results The radiographs of 661 patients (401 females; mean age 75.8 ± 8.0) were evaluated. The inter-reader percent agreement between two central expert radiologists per-vertebra assessment was excellent (99.78%; k = 0.984; 95% CI, 0.977–0.991). Central reading identified 318/661 (48.1%) patients with at least one VF. Local and central readings agreed in 502/661 (75.9%) patients, resulting in a fair reproducibility (k = 0.52; 95% confidence interval 0.44–0.59). Diagnostic performance parameters of local readings were: sensitivity 76.1%; specificity 75.8%; PPV 74.46%; NPV 77.38%). By examining 9254 vertebrae, central and local readers diagnosed 665 (7.2%) and 562 (6.1%) VFs respectively. Misdiagnosis (102 false positives and 205 false negatives) mainly occurred for mild VFs. Local readings identified correctly 460 out 665 VFs diagnosed by central readings, resulting in sensitivity of 69.2% and PPV of 81.8%. Conclusions Following a standardized protocol of acquisition techniques and of interpretation criteria, an excellent agreement between local and central readings for moderate and severe vertebral fractures resulted. However a significant amount of mild vertebral fractures, that are the most of VFs, were misdiagnosed by local radiologists. In order to improve VFs assessment, the radiologists should be trained and sensitized in relation to the relevant clinical significance of osteoporotic VFs identification.

ObjectiveTo evaluate current evidence on the efficacy and safety of topical and systemic medications in patients with primary Sjögren syndrome (SjS) to inform European League Against Rheumatism treatment recommendations.MethodsThe MEDLINE, EMBASE and Cochrane databases were searched for case-control/prospective cohort studies, randomised controlled trials (RCTs) and systematic reviews.ResultsCurrent evidence in primary SjS patients fulfilling the 2002 criteria is based on the data from 9 RCTs, 18 prospective cohort studies and 5 case-control studies. Two Cochrane systematic literature reviews (SLRs) have reported that topical treatments for dry mouth and dry eye are safe and effective. Ocular cyclosporine A was safe and effective in two RCTs including 1039 patients with dry eye syndrome. Two Cochrane SLRs on serum tear drops and plugs showed inconsistency in possible benefits, both for symptoms and objective measures. Five RCTs reported significant improvements in oral dryness and salivary flow rates for pilocarpine and cevimeline. An RCT showed no significant placebo-differences for hydroxychloroquine 400 mg/day for the primary outcome (visual analogue scale (VAS) composite of dryness, fatigue and pain). We identified seven RCTs carried out in primary SjS patients. RCTs using infliximab, anakinra and baminercept found no placebo-differences for the primary outcomes. The two largest RCTs randomised 255 patients to receive rituximab or placebo and reported no significant results in the primary outcome (VAS composite), while prospective studies suggested efficacy in systemic disease.ConclusionThe current evidence supporting the use of the main topical therapeutic options of primary SjS is solid, while limited data from RCTs are available to guide systemic therapies.

Sjögren's syndrome (SjS) is a systemic autoimmune disease that mainly affects the exocrine glands, leading to generalized mucosal dryness. However, primary SjS may initially present with non-sicca (systemic) manifestations. When these features appear before the onset of an overt sicca syndrome, we may talk of an underlying 'occult' SjS. The European League Against Rheumatism (EULAR) has promoted and supported an international collaborative study group (EULAR-SS Task Force) aimed at developing consensual recommendations to provide a homogeneous approach to the patient with primary SjS presenting with systemic involvement. This review summarizes the key factors that should be taken into account in the diagnostic approach in a patient with suspected SjS according to the main clinical patterns of presentation, and is especially focused on organ-specific systemic disease presentations, including a consensus set of recommendations in order to reach an early diagnosis. Close collaboration with the different specialties involved through a comprehensive multidisciplinary approach is essential in SjS patients presenting with systemic involvements.

Most rheumatic diseases are multisystem disorders that are heterogeneous in their presentation, course and outcome. These conditions still lack a single clinical, laboratory, pathological or radiological feature that could serve as a ‘gold standard’ in support of diagnosis and/or classification. Thus, the development of criteria for use in clinical care and research studies has been an important challenge in these disorders.1 From the theoretical and methodological point of view, classification and diagnostic criteria are quite different. Classification criteria are standardised tools that are aimed at selecting well-defined and homogenous groups of patients for research and at guaranteeing comparability across studies. They are not designed to be used for the clinical diagnosis in individual patients and may be defective in capturing some cases with a less common clinical presentation or course.2 Diagnostic criteria are generally less stringent and usually include a wider variety of disease features. Their aim is to accurately identify as many people with that condition as possible.1 Given the complexity of systemic rheumatic disorders, the development of diagnostic criteria in these diseases is certainly difficult. Therefore, optimal diagnostic criteria have not been defined for most of the rheumatic diseases and the diagnosis, given the suspicion of one of these disorders, is commonly based on a decision-making process by physicians who have to evaluate a complex combination of symptoms, signs, diagnostic tests and rule out other confounding or similar diseases. As a consequence of these theoretical assumptions, the diagnostic criteria are commonly characterised by high sensitivity and negative predictive value, whereas the classification criteria classically possess high specificity and positive predictive value to minimise the risk of classifying false positive patients as having the …

We report here a case of a 62-year-old Caucasian woman, suffering from diffuse cutaneous systemic sclerosis (SSc), who developed a tumoural calcinosis (TC) localised in the left side of the neck around the cervical spine that caused severe pain and motion impairment, without involvement of regional neurological structures. A review of the literature on this issue (based on PubMed database) allowed us to identify 35 previously described cases of TC in para-vertebral area in the course of SSc. The main characteristics of these patients have been summarised.