Search

Objective To describe early prosthesis implantations in a cohort of patients with juvenile idiopathic arthritis (JIA) followed in a tertiary referral hospital and to analyze possible factors influencing implant survival. Methods This was a retrospective cohort study. Charts of all patients with JIA who underwent total joint replacement at Gaetano Pini Hospital, Milan, Italy from January 1992 to June 2019 were retrieved, and relevant data were analyzed. Results Eighty-five patients met the inclusion criteria for this study, with a median follow-up period of 17.2 years. The median age at first prosthesis was 22.7 years. The total number of replaced joints was 198 over a period of 27 years. The hip was the most frequently replaced joint, accounting for almost two-thirds of the total number of implants; the other one-third refers mostly to knee implants. Polyarticular JIA and systemic JIA were the most represented JIA categories in the study cohort. A significant upward trend of the age at arthroplasty and of disease duration before arthroplasty over decades was found. The rates of implant survival at 5, 10, and 15 years were comparable (from 84% to 89%); 50% of implants lasted ≥20 years. Conclusion We reported retrospective data on early joint replacement in a cohort of patients with JIA. We observed a progressive and significant upward trend of both age at arthroplasty and disease duration before the first arthroplasty over time. The JIA category, year of implant, and presence of complications significantly affected implant survivorship.

Beta-2 Glycoprotein I (β2-GPI) is the main target of anti-phospholipid antibodies (aPL) in the autoimmune anti-phospholipid syndrome, characterized by increased risk of stroke. We here investigated the antibody independent role of β2-GPI after ischemia/reperfusion, modeled in vivo by transient middle cerebral artery occlusion (tMCAo) in male C57Bl/6J mice; in vitro by subjecting immortalized human brain microvascular endothelial cells (ihBMEC) to 16 h hypoxia and 4 h re-oxygenation. ApoH (coding for β2-GPI) was upregulated selectively in the liver at 48 h after tMCAo. At the same time β2-GPI circulating levels increased. β2-GPI was detectable in brain parenchyma and endothelium at all time points after tMCAo. Parenchymal β2-GPI recognized apoptotic neurons (positive for annexin V, C3 and TUNEL) cleared by CD68+ brain macrophages. Hypoxic ihBMEC showed increased release of IL-6, over-expression of thrombomodulin and IL-1α after re-oxygenation with β2-GPI alone. β2-GPI interacted with mannose-binding lectin in mouse plasma and ihBMEC medium, potentially involved in formation of thrombi. We show for the first time that brain ischemia triggers the hepatic production of β2-GPI. β2-GPI is present in the ischemic endothelium, enhancing vascular inflammation, and extravasates binding stressed neurons before their clearance by phagocytosis. Thus β2-GPI may be a new mediator of brain injury following ischemic stroke.

Highlights • Systemic lupus erythematosus (SLE) associates with infection susceptibility. • COVID-19 is a pandemic infectious disease with high morbidity and mortality. • The impact of COVID-19 in SLE is poorly characterised. • A web-based survey amongst patients with SLE suggest a moderate increase in morbidity due to COVID-19. • Hydroxychloroquine does not seem able to prevent COVID-19 in patients with SLE., Background Systemic lupus erythematosus (SLE) is a chronic disease characterised by autoimmunity and increased susceptibility to infections. COVID-19 is a systemic viral disease currently spreading as a pandemic. Little is known about the impact of COVID-19 in patients with SLE. Objective to acquire information on the impact of COVID-19 in SLE. Methods A 26-item anonymous questionnaire investigating demographics, SLE clinical features, COVID-19 diagnoses and changes in treatments and daily habits was administered to patients with SLE from three referral centres through www.surveymonkey.com over 10 days. Data from the survey were compared to those from published estimates about the general population. Results Four-hundred-seventeen patients responded to the survey. More than 60% of subjects complained of symptoms that are also associated to COVID-19. Fourteen COVID-19 diagnoses (five confirmed by polymerase chain reaction) were reported, in contrast to a 0.73% prevalence of confirmed cases in Lombardy. One hospitalisation was reported. Fever, anosmia, dry cough, a self-reported history of neuropsychiatric SLE and a recent contact with confirmed COVID-19 cases were more strongly associated with COVID-19, as were symptoms and lower compliance to behavioural preventive measures in patients’ contacts. No protective effect was seen in subjects on hydroxychloroquine. Conclusion COVID-19 morbidity might only moderately be increased in most patients with SLE, although limited information can be inferred on more severe cases. Hydroxychloroquine apparently seems not to confer protection to infection per se, although other beneficial roles cannot be excluded. Containment policies and behavioural preventive measures could have a major role in limiting the impact of COVID-19 in patients with SLE.

OBJECTIVE: Clinical heterogeneity, a hallmark of systemic autoimmune diseases, impedes early diagnosis and effective treatment, issues that may be addressed if patients could be classified into groups defined by molecular pattern. This study was undertaken to identify molecular clusters for reclassifying systemic autoimmune diseases independently of clinical diagnosis. METHODS: Unsupervised clustering of integrated whole blood transcriptome and methylome cross-sectional data on 955 patients with 7 systemic autoimmune diseases and 267 healthy controls was undertaken. In addition, an inception cohort was prospectively followed up for 6 or 14 months to validate the results and analyze whether or not cluster assignment changed over time. RESULTS: Four clusters were identified and validated. Three were pathologic, representing "inflammatory," "lymphoid," and "interferon" patterns. Each included all diagnoses and was defined by genetic, clinical, serologic, and cellular features. A fourth cluster with no specific molecular pattern was associated with low disease activity and included healthy controls. A longitudinal and independent inception cohort showed a relapse-remission pattern, where patients remained in their pathologic cluster, moving only to the healthy one, thus showing that the molecular clusters remained stable over time and that single pathogenic molecular signatures characterized each individual patient. CONCLUSION: Patients with systemic autoimmune diseases can be jointly stratified into 3 stable disease clusters with specific molecular patterns differentiating different molecular disease mechanisms. These results have important implications for future clinical trials and the study of nonresponse to therapy, marking a paradigm shift in our view of systemic autoimmune diseases. ispartof: ARTHRITIS & RHEUMATOLOGY vol:73 issue:6 pages:1073-1085 ispartof: location:United States status: published

Background Clinical heterogeneity, a hallmark of systemic autoimmune diseases (SADs) impedes early diagnosis and effective treatment, issues that may be addressed if patients could be grouped into a molecular defined stratification. Methods With the aim of reclassifying SADs independently of the clinical diagnoses, unsupervised clustering of integrated whole blood transcriptome and methylome cross-sectional data of 918 patients with 7 SADs and 263 healthy controls was undertaken. An inception cohort prospectively followed for 6 and 14 months was studied to validate the results in early cases and analyze if cluster assignment was modified with time. Results Four clusters were identified Three aberrant clusters were ‘acute phase inflammatory’, ‘T cell immunity’, and ‘interferon’, each including all diagnoses, were defined by genetic, clinical, serological and cellular features. A fourth cluster showed no specific molecular pattern, to which 74% of healthy controls clustered with patients. The inception cohort showed that most patients were either assigned always to the same cluster or moved from the healthy-like cluster to a single aberrant cluster resembling the relapsing-remitting dynamic of these diseases, showing that single aberrant molecular signatures characterize each individual patient. Conclusions Patients with SADs share molecular signatures and can be therefore stratified into three disease clusters differentiating each patient into a specific molecular disease pathway. Such assignment is stable with time. These results have important implications for understanding disease progression and therapy design marking a paradigm shift in our view of SADs. Acknowledgment This work has been supported through a grant from the Innovative Medicines Initiative Joint Undertaking No. 115565 and in-kind and in-cash contributions from the EFPIA partners. G.B. is supported by the Instituto de Salud Carlos III (ISCIII, Spanish Health Ministry), through the Sara Borrell subprogram (CD18/00153). The authors would like to particularly express their gratitude to the patients, nurses and many others who helped directly or indirectly in the consecution of this study.

SUMMARYBackgroundClinical heterogeneity, a hallmark of systemic autoimmune diseases (SADs) impedes early diagnosis and effective treatment, issues that may be addressed if patients could be grouped into a molecular defined stratification.MethodsWith the aim of reclassifying SADs independently of the clinical diagnoses, unsupervised clustering of integrated whole blood transcriptome and methylome cross-sectional data of 918 patients with 7 SADs and 263 healthy controls was undertaken. In addition, an inception cohort was prospectively followed for 6 and 14 months to validate the results and analyze if cluster assignment changed or not with time.ResultsFour clusters were identified. Three clusters were aberrant, representing ‘inflammatory’, ‘lymphoid’, and ‘interferon’ patterns each including all diagnoses and defined by genetic, clinical, serological and cellular features. A fourth cluster showed no specific molecular pattern and accumulated also healthy controls. An independent inception cohort showed that with time, the molecular clusters remain stable, showing that single aberrant molecular signatures characterize each individual patient.ConclusionsPatients with SADs can be jointly stratified into three stable disease clusters with specific molecular patterns differentiating different molecular disease mechanisms. These results have important implications for future clinical trials and the study of therapy non-responsiveness marking a paradigm shift in the view of SADs.

Biological agents have radically changed the prognosis of rheumatic patients. Current evidence demonstrates that tight disease control during pregnancy is mandatory to minimize adverse outcome risk. As the new therapeutic tools are pivotal to maintain appropriate disease activity, it is timely to review available evidence about the safety of biologics and small molecules in pregnancy. Areas covered: A comprehensive literature review has been performed, reporting available data about the passage into breast milk, rate of pregnancy loss and fetal malformations, and long-term complications due to in utero exposure to biological agents and small molecules. Expert commentary: Data about the safety of agents against tumor necrosis factor in pregnancy are reassuring. Even rituximab, tocilizumab, belimumab, ustekinumab, secukinumab, and abatacept have not been associated with an increased rate of fetal abnormalities or adverse pregnancy outcome. Experience with small molecules is too small to draw any conclusion. Even if further data are warranted to define the possible long-term effects of in utero biologic exposure on the infant immune system development, it is reasonable to speculate that in the next future the use of biologics during pregnancy will continue to expand, at least when maternal benefit justifies the potential risk to the fetus.

Background:Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic condition in childhood. New therapies acting on specific targets have led to a significant improvement in the management of JIA. However, when medical therapy fails, total joint replacement represents the standard treatment to obtain pain relief and improve functional outcomes.Objectives:To describe early prosthesis in a JIA cohort followed in a tertiary referral hospital and to analyze any possible factors influencing implant survival, including surgical improvements over time.Methods:This is a monocentric retrospective cohort study; patients were enrolled from January 1992 to June 2019. All patients who underwent total joint replacement and were followed in our institute were included.Results:Eighty-five patients met the inclusion criteria, with a median follow-up of 17.2 years. The total number of replaced joints over 27 years was 198 (Figure 1). Clinical features and implant data are reported in Table 1.Table 1.Patients’ clinical features and implants dataTotal number of patients/ implants85/198JIA categories16 Oligoarticular37 Polyyarticular (7 RF postive)24 Systemic8 otherAge at first arthroplasty median (mean+SD; range)22.7 y (25.1±6.9;14.3-46.5)Disease duration at I arthroplasty median (mean+SD; range)17.4 y (18.6±8.1;1.88-43.7)Location of arthroplasty121 Hips66 Knees11 AnklesType of arthroplasty156 Regular6 Custom31 Hybrid implant5 unknownArthroplasty complications8 Intraoperative fracture3 Infections14 Aseptic mobilizationRevisions13 (9 hips, 4 knees)Figure 1.Numbers of arthroplasties performed for each year.We grouped all arthroplasties by the year of surgical procedure: before 2000 (group A; 28 implants), between 2000 and 2010 (group B; 94 implants) and after 2010 (group C; 76 implants).A significant difference of age at arthroplasty was found between group A and group B (21.93 y vs 26.82; p = 0.03) and between group A and group C (21.93 y vs 27.81 y; p = 0.00).The same upward trend was found with regard to disease duration before arthroplasty: a significant difference between group A and group B (16.98 y vs 21.66 y; p = 0.03) and between group A and group C (16.98 y vs 22.93 y; p= 0.00).The rate of implant survival at 5, 10 and 15 years were comparable (from 84% to 89%); whereas 50% of eligible implants lasted 20 years or more (Figure 2).Figure 2.Kaplan Meier survival curve of implants.The year of surgery was found to be significantly related to implant survival [Hazard Ratio (HR) 1.001, confidence interval (CI) 1.0001-1.0006; p< 0.001] as well as the presence of complications (HR 3.69, CI 1.82-7.48; p < 0.001) in multivariate analysis. Furthermore, prostheses of polyarticular RF-neg patients had more possibilities to last longer than those of S-JIA patients (HR 0.23, CI 0.09-0.53; p= 0.00) as well as implants of all polyarticular JIA (RF-pos and neg together) (p < 0.001).Conclusion:We observed an upward trend of both age at arthroplasty and disease duration before the first arthroplasty over time. JIA category, year of implants and the presence of complications significantly affected implant survival. Future researches should assess functional outcome and survival of implants according to medical therapy and different surgical approaches.Disclosure of Interests:None declared

Background Juvenile idiopathic arthritis (JIA) includes all forms of inflammatory arthritis, with onset before the 16th birthday, lasting more than 6 weeks. Although conservative management with nonsteroidal anti-inflammatory drugs and disease-modifying antirheumatic drugs can be effective, a significant number of young adults affected by JIA requires a major surgical procedure, including different types of prosthetic devices. Objectives This article presents a monocentric experience of an interdisciplinary team of rheumatologists and orthopedic surgeons for JIA and the outcome of patients subjected to prosthesis implantation. Methods Data were collected through a retrospective analysis of 583 patients attending to our transitional care center for JIA between 1999 and 2018, in the context of a once-week rheumatologic counseling with the orthopedic surgeons. Descriptive statistics were used to evaluate the baseline and follow-up data. Results On a total of 257 prosthesis implantations, 137 were total hip prosthesis, 101 total knee prosthesis and 19 total ankle prosthesis. The 10-year implant survival rate was 97%, with good results in term of function and comfort for the patients. Complications were observed in 9% of patients, including intraoperative fractures, periprosthetic joint infections and wound dehiscence. The majority of patients were treated with biologic therapy before surgery. Conclusion Prosthesis implantation in JIA patients is a complicated and difficult procedure, related to the management of the biologic therapy, the low quality of bone, the remarkable stiffness and deformity of the joints. Long-term results were good, even in patients with severe arthritis, showing drastic reduction of joint pain and an improvement of functionality. The risk of complications results to be modest compared to a great survival rate and a valid recovery of joint range of motion. The interdisciplinary team composed by rheumatologists and orthopedic surgeons for the all follow-up of these patients is a cornerstone to obtain the perfect schedule for prosthetic implantation. References [1] C. Mertelsmann-Voss et al. US Trends in Rates of Arthroplasty for Inflammatory Arthritis Including Rheumatoid Arthritis, Juvenile Idiopathic Arthritis, and Spondyloarthritis. Arthritis & Rheumatology, June 2014. [2] M. P. Abdel et al. Surgical Management of the Juvenile Idiopathic Arthritis Patient with Multiple Joint Involvement. Orthopedic Clinics of North America, 2014-10-01. Disclosure of Interests None declared

The etiology of autoimmune diseases is the result of a complex interaction of the immune system with environmental and genetic factors, although the underlying mechanisms are not completely understood. A number of autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, show a striking female predominance. Sexual dimorphism in autoimmunity can be explained at least in part by the role of sex hormones in the regulation of the immune system, whose cells express estrogen and androgen receptors. Furthermore, other mechanisms such as epigenetics may be involved in this multifaceted scenario. The rupture of this complex balance may contribute to the development of autoimmune diseases. In this chapter, we will focus on the effects of sex hormones and prolactin on the pathogenesis and development of autoimmunity.

Background There are many differences in clinical manifestations, assessment and management of Juvenile Idiopathic Arthritis (JIA) between childhood and adults9 arthritis onset. The transition from pediatric to the adult care emphasizes a lot of aspects that need to be addressed. Objectives To describe the long-term outcome of JIA. Methods Two-hundred and forty patients affected by JIA and referred to a transition care rheumatology tertiary centre were considered between 1999 and 2016. The outcome assessment included disease activity, medications, number of prosthesis implantation, pregnancy, mortality, social integration (mobility, employment status and educational level). Results Seventy-four (30.8%) males and 166 (69.2%) females were included; 53 (22.1%) patients were lost in follow up. Subtypes of JIA at disease onset included 101 oligoarthirtis (42.1%), 67 polyarthritis (27.9%), 43 systemic arthritis (17.9%), 7 psoriatic arthritis (2.9%), 22 enthesitis related arthritis (9.2%). Forty-eight (20%) patients had persistent uveitis. Ninety-three implant prosthesis and 14 arthodesis were recordered. The average disease duration was 20 years, the median age of the patients was 27 (18–57) years. Five deaths (2.1%) occurred in this cohort. At follow up 117 (48.7%) had low active disease activity, 70 (29.2%) had moderate disease activity, 14 (5.8%) had a high disease activity, 24 (10%) were on remission ON medication and 15 (6.3%) OFF medication. Among patients still on medication, 59 (24.6%) were treated with oral steroids, 18 (7.5%) with csDMARDs and 169 (70.4%) with bDMARDs. Seventy-five (31.3%) patients had a higher educational level (university), 195 (81.3%) had an employment, 128 (53.3%) had a driving license. Twenty-one (8.8%) pregnancies were registered. The transition age was considered after age of sixteen years old. In this contest, it was important the multidisciplinary approach of each patient that was realized with the collaboration of other specialists (ophthalmologist, orthopedic, dermatologist, obstetric, psychologist). Conclusions In the era of biologic therapy there was an important improvement in a lot variables of the long-term outcome of JIA. One-hundred-eighty-seven (77.9%) patients were still in tight control, not only because of the continuation of the biological therapy but also because of the multidisciplinary care carried out even during remission. JIA often persists over the adulthood. The long term follow up and care of these patients has to be conducted by a rheumatologist expertized in JIA in collaboration with other specialists. Disclosure of Interest None declared

Background To date the evaluation of the disease activity and the monitoring of the therapeutic response of patients affected by Paget9s disease of bone is based only on clinical and hematological data. However, in clinical practice the management of these patients is still challenging. Previous angiographic and histological studies have revealed that the accelerated bone turnover is associated with an increased blood flow and hypervascularity, suggesting a role of high-resolution sonography with power-Doppler (PD) and color- Doppler (CD) in Paget9s disease. Our preliminary data demonstrated that this technique shows not only the alterations of the pagetic bone profile, but also the hypervascularization of the osteoperiosteal-layer, both at the diagnosis and during follow-up. Objectives To validate the PD technique as a useful tool not only for the diagnosis of Paget9s disease of bone but also for the evaluation of the disease activity and for the monitoring of the therapeutic response. Methods Forty-three consecutive patients affected by Paget9s disease of bone and treated with neridronate were followed up over the last ten years. Patients were classified in eight clinical patterns defined by the presence of bone alkaline phosphatase elevation over the normal range (BAP+), bone pagetic pain as visual analogue scale ≥30 (VAS+) and PD alterations of osteoperiosteal vascularization (PD+). Data were analyzed by Fisher exact test (two tails) to assess the associations between BAP+, VAS+ and PD+ at different times during follow up: before the start of the therapy, after the first, the second and the third neridronate cycle of therapy, and at the end of all cycles. Results At any time BAP+ and VAS+ were not associated. A trend of association between VAS+ and PD+ could be observed only after the first neridronate cycle. In contrast, the association between BAP+ and PD+ was statistically significant before the therapy, at the end of all cycles of therapy and after the second one, but not after the first one. Conclusions The lack of association between VAS+ and PD+ or BAP+ may be due to the difficulty of the patients in identifying and quantifying the pagetic pain, and suggests the weakness of the clinical criteria in defining the disease activity. Otherwise, PD technique proves to be a fast, reliable and not expensive tool, which is also very useful for monitoring/achieving better control of Paget9s disease of bone. References Adami S., et al. Italian guidelines for the diagnosis and treatment of Paget9s disease of bone. Reumatismo, 2007; 59(2):153–168. Singer F.R., et al. Paget9s Disease of Bone: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab, 2014; 99(12):4408–4422. Mastaglio C., et al. Characterization of Osteocortical-Periosteal Layers by High-Resolution Sonography Using a Doppler Technique in Paget9s Disease of Bone. JDMS, 2008; 24(3):136–144. Disclosure of Interest None declared

Dysbiosis has been described in systemic autoimmune diseases (SADs), including systemic lupus erythematosus (SLE), Sj&ouml, gren&rsquo, s syndrome (SjS), and primary anti-phosholipid syndrome (PAPS), however the biological implications of these associations are often elusive. Stool and plasma samples from 114 subjects, including in SLE (n = 27), SjS (n = 23), PAPs (n = 11) and undifferentiated connective tissue (UCTD, n = 26) patients, and geographically-matched healthy controls (HCs, n = 27), were collected for microbiome (16s rRNA gene sequencing) and metabolome (high-performance liquid chromatography coupled to mass spectrometry) analysis to identify shared characteristics across diseases. Out of 130 identified microbial genera, a subset of 29 bacteria was able to differentiate study groups (area under receiver operating characteristics (AUROC) = 0.730 &plusmn, 0.025). A fair classification was obtained with a subset of 41 metabolic peaks out of 254 (AUROC = 0.748 &plusmn, 0.021). In both models, HCs were well separated from SADs, while UCTD largely overlapped with the other diseases. In all of the SADs pro-tolerogenic bacteria were reduced, while pathobiont genera were increased. Metabolic alterations included two clusters comprised of: (a) members of the acylcarnitine family, positively correlating with a Prevotella-enriched cluster and negatively correlating with a butyrate-producing bacteria-enriched cluster, and (b) phospholipids, negatively correlating with butyrate-producing bacteria. These findings demonstrate a strong interaction between intestinal microbiota and metabolic function in patients with SADs.

Non-thrombotic hematologic manifestations of antiphospholipid syndrome (APS) comprise immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and immune neutropenia, at present not included in APS diagnostic criteria. These cytopenias have been largely reported in APS and share the same underlying pathogenic mechanism mediated by antibodies against blood cells. Thrombocytopenia (platelets

The past years have seen the publication of several studies on seronegative spondylarthritides (SpA) and cardiovascular risk as a result of new insights into the connection between inflammation and atherogenesis. Although the overall cardiovascular disease is a complex entity, chronic inflammation of SpA is known to contribute as an independent risk factor, and new therapies are aimed at reducing this persistent inflammatory status. This review provides an overview of the recent advances in understanding the role of the current therapeutic measures of SpA in preventing or accelerating cardiovascular risk.

Background Thrombosis of arteries in the central nervous system (CNS) represents the most frequent CNS manifestation and the most frequent arterial event in antiphospholipid syndrome (APS). Previous in vivo studies demonstrated that beta2 glycoprotein I (β2GPI) - the main antigenic target for anti-phospholipid antibodies (aPL) - does not localize in brain in resting conditions. However, β2GPI is detectable on the brain vascular endothelium in association with IgG and complement elements in immunized mice treated with lipopolysaccharide. These data suggest that after an appropriate second hit, β2GPI can play a critical role of in APS CNS damage, likely interacting with the complement system. To date, the pathophysiological functions of β2GPI in brain ischemic injury have not been investigated. Objectives To investigate the presence and the distribution of the activated form of β2GPI in the ischemic brain at different time points. Methods Eleven-week old male mice underwent focal cerebral ischemia induced by 609 transient middlecerebral artery occlusion (tMCAo), or sham-operation. Mice were sacrified at 909, 6h, 24h, 48h, 4d or 7d after tMCAo to obtain brains and plasma. The presence and time course of β2GPI deposition within the ischemic territory and its spatial distribution relative to blood vessels and brain cells were defined the by post mortem immunofluorescence and confocal microscopy. The activated β2GPI was detected by anti-beta2 glycoprotein I minibody (MBB2) – a human monoclonal IgG antibody targeting β2GPI domain I. Results β2GPI was present in the ischemic brain tissue starting from 909 after ischemic onset and was still detectable at 7d. β2GPI localized within blood vessels and in brain parenchyma at all times. Notably, at 24h β2GPI was mainly extravascular and colocalized with neurons (NeuN positive cells). Sham-operated mice showed only a faint signal for β2GPI. Conclusions β2GPI is present in its activated conformation in the brain vessels and tissue after experimental cerebral ischemia. It localizes on neurons in brain ischemic areas. These data suggest that an ischemic/inflammatory hit may up-regulate β2GPI tissue presence and may expose the N-terminal domain I of the molecule which is thougth to be the main target for pathogenic aPL. Disclosure of Interest None declared

Systemic sclerosis (SSc) is a connective tissue disorder characterized by tissue fibrosis affecting the skin and internal organs, fibroproliferative vasculopathy, and autoimmune activation. SSc still heralds a poor prognosis with significant morbidity and mortality. Early detection of organ involvement is critical as currently available treatments are most effective when started early. Many candidate biomarkers have been investigated in the past two decades. However, despite the enormous efforts, no accurate tool to predict the pattern of organ involvement and to assess disease activity has been yet identified. The N-terminal fragment of probrain natriuretic peptide (N-TproBNP) is a neurohormone released by ventricular myocytes in response to pressure overload. N-TproBNP is highly relevant for diagnosis, prognosis, and prediction of pulmonary arterial hypertension in SSc. Moreover, several studies support its potential benefit for cardiac assessment of scleroderma patients. Conversely, the role of N-TproBNP as surrogate marker of pulmonary fibrosis and skin involvement is much less clear. We provide an extensive review of the studies that have previously investigated the role of N-TproBNP as candidate biomarker in scleroderma manifestations, presenting also the findings of a recent study we conducted in a cohort of 87 SSc patients.

Background Systemic sclerosis (SSc) is an autoimmune condition characterized by polymorphic clinical presentations, high morbidity and mortality. It would be therefore valuable to identify biomarkers for diagnosis, prediction of organ involvement and disease subset. Objectives Aim of this study was to retrospectively assess the role of serum anti-IFI16 antibodies and NT-proBNP levels as candidate biomarkers in a cohort of scleroderma patients. Methods 100 SSc patients (49 with diffuse disease) were enrolled in this study; patients with PAH and renal insufficiency were excluded from NT-proBNP analysis. We investigated the relationship between the two candidate biomarkers and several scleroderma clinical manifestations (severe interstitial lung disease, cardiac involvement, digital ulcers, calcinosis, arthritis) and variables (age, disease duration, BP, Hb, mRSS, ESR, DLCO). Serum anti-IFI16 antibodies were detected by a home-made semi-quantitative ELISA, NT-proBNP levels were measured by the Roche immunoassay. Statistical analysis was performed using STATA 11. Results NT-proBNP was significantly increased in patients with heart involvement compared to those without (p=0.0003, 95%CI 57-232). A cut-off value of 130pg/mL gave a specificity of 70% and a sensibility of 74% to predict cardiac involvement (area under ROC curve 0.746; 95%CI 0.63-0.86), with a predictive negative value of 85%. Moreover, NT-proBNP levels>130pg/mL were strong predictors of heart involvement (OR 7). Not surprisingly, NT-proBNP levels were negatively correlated with LVEF (r=-0.266; p=0.002). Conversely, there was no association between anti-IFI16 antibodies and cardiac involvement (p=0.505). No other association was reported between the two candidate biomarkers and clinical manifestations of SSc. There was no significant difference between disease subsets in NT-proBNP levels (p=0.12) and anti-IFI16 antibodies titers (p=0.71). We report a significant association between NT-proBNP and age (r=0.315; p=0.003), disease duration (r=0.287; p=0.008), ESR (p=0.0086) and DLCO (r=-0.356; p=0.001) while anti-IFI16 antibodies were not significantly associated with any of the clinical variables. Conclusions Given the high negative predictive value, NT-proBNP may be a useful tool to identify scleroderma heart disease. SSc related cardiac involvement still heralds a poor prognosis, with 1% of annual mortality attributable to cardiac disease. Future studies are warranted to establish its role as surrogate biomarker. Disclosure of Interest None Declared