Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by a wide variability of clinical manifestations due to the potential involvement of several tissues and internal organs, with a relapsing and remitting course. Dysregulation of innate and adaptive immune systems, due to genetic, hormonal and environmental factors, may be responsible for a broad spectrum of clinical manifestations, affecting quality of life, morbidity and mortality. Bone involvement represents one of the most common cause of morbidity and disability in SLE. Particularly, an increased incidence of osteoporosis, avascular necrosis of bone and osteomyelitis has been observed in SLE patients compared to the general population. Moreover, due to the improvement in diagnosis and therapy, the survival of SLE patient has improved, increasing long-term morbidities, including osteoporosis and related fractures. This review aims to highlight bone manifestations in SLE patients, deepening underlying etiopathogenetic mechanisms, diagnostic tools and available treatment.
Calcium Pyrophosphate Crystal Deposition (CPPD) disease is characterized by the deposition of calcium pyrophosphate crystals in the cartilage. In most cases, it can manifest as a subclinical condition named chondrocalcinosis, often revealed by joint x-ray examination. In other cases, deposition can cause flares of arthritis, known as acute CPP crystal arthritis. In the last few years, many pathogenic pathways have been discovered. Interleukin-1 (IL-1) plays a key role in the pathogenesis of CPPD disease, both as a mediator of inflammatory response to crystals and as a promoter of damage to articular cartilage. In this review, we investigated the role of IL-1R inhibitor, such as Anakinra, as an alternative to the various therapeutic strategies for CPPD disease, especially among patients resistant to traditional treatment with NSAIDs, corticosteroids and colchicine.
A review of the available literature was performed in order to summarize the existing evidence between osteoblast dysfunction and clinical features in non-hereditary sclerosing bone diseases. It has been known that proliferation and migration of osteoblasts are concerted by soluble factors such as fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), transforming growth factor (TGF), bone morphogenetic protein (BMP) but also by signal transduction cascades such as Wnt signaling pathway. Protein kinases play also a leading role in triggering the activation of osteoblasts in this group of diseases. Post-zygotic changes in mitogen-activated protein kinase (MAPK) have been shown to be associated with sporadic cases of Melorheostosis. Serum levels of FGF and PDGF have been shown to be increased in myelofibrosis, although studies focusing on Sphingosine-1-phosphate receptor was shown to be strongly expressed in Paget disease of the bone, which may partially explain the osteoblastic hyperactivity during this condition. Pathophysiological mechanisms of osteoblasts in osteoblastic metastases have been studied much more thoroughly than in rare sclerosing syndromes: striking cellular mechanisms such as osteomimicry or complex intercellular signaling alterations have been described. Further research is needed to describe pathological mechanisms by which rare sclerosing non hereditary diseases lead to osteoblast dysfunction.
Background:Cardiovascular disease is the leading cause of morbidity and mortality worldwide. Myocardial calcifications have been related with cardiovascular diseases (CVD) such as focal wall motion abnormalities and arrhythmias. The impact of vascular calcifications is under investigation in order to define the risk of cardiovascular events. The relationship between cardiac calcification and systemic sclerosis (SSc) has not been investigated.Objectives:The aim of the study is to evaluate the frequency of different patterns of cardiac calcification in SSc patients, and to correlate them to other CVD risk factors.Methods:We analyzed thoracic-CT scanners of 35 SSc patients (88% female, aged 47,8 ys ±12,9, disease duration 12,8 ys ±9) to determine the location and extension of vascular and cardiac calcification. All recruited patients fulfilled the 2013 ACR-EULAR classification criteria for SSc. No one patients had renal failure, cardiomyopathy, myocarditis, history of cardiac surgery or radiotherapy.Results:We found myocardial vessels calcifications (MCv) in 37% SSc patients, aortic wall calcifications (ACw)in 60% SSc patients, cardiac valve calcifications (VC) in 28% SSc patient and heart wall calcifications (HCw) in 20%.The SSc patients with almost one calcification had older age (65±9,8 ys vs 50±8,8 ys; p=0,0001) and higher values of circulating NTproBNP (336,9±351,9 vs 144,2±107,8; p=0,04) compared to those without.In particular, the SSc patients with MCv had and uric acid (5,3 ±1,5 vs 4,1 ±1,3; p=0,05), higher rate of PAH (25% vs 0%; p=0,037), arrhythmia (38,5% vs 9%; p=0,036) and higher prevalence of CENP-B antibodies(46% vs 4%; p=0,01) compared to patients without MCv.Patients with HCw had lower C reactive protein (0,16 ±0,10 vs 0,7±0,7; p=0,008) compared to those without HCw. No differences in the rate of heart and vascular complications of SSc were observed.The SSc patients with ACw had higher frequency of arrhythmia (33% vs 0%; p=0,016) and longer disease duration (15,5 y ±9,9 vs 8,8 ±5,8; p=0,03).The SSc patients with VC had higher rate of PAH (33%vs0%; p=0,003) and uric acid (6±0,5vs3,8±1,2 p=0,0001).Regression analysis excluded any association with gender, BMI, systemic arterial hypertension, steroid therapy, hypovitaminosis D or smoke habit. No cardiovascular event was recorded in one year of observation.Conclusion:All patterns of calcifications may be related mostly with the older age. Myocardial vessels calcifications have been found in a high percentage of SSc patients and in particular in those with PAH and positive for anti CENP-B. Furthermore, myocardial vessels calcifications could be associated to the higher occurrence of arrhythmia. More studied are needed to assess the importance of vascular calcification as a part of the vascular involvement in SSc.References:[1]John W. Nance Jr. MD. Myocardial calcifications: Pathophysiology, etiologies, differential diagnoses, and imaging findings. Journal of Cardiovascular Computed Tomography 9 (2015) 58 e 67.[2]Pagkopoulou E, Poutakidou M. Cardiovascular risk in systemic sclerosis: Micro- and Macro-vascular involvement. Indian J Rheumatol 2017;12, Suppl S1:211-7[3]Plastiras SC, Toumanidis ST. Systemic sclerosis: the heart of the matter. Hellenic J Cardiol. 2012;53(4):287–300.Disclosure of Interests:None declared
Background:Previous study evidenced a cross-reactivity between Sars-Cov-2 antibodies and autoimmune tissue antigen involved in connective tissue diseases, as nuclear antigen (NA), extractable nuclear antigen (ENA), histone and collagen (1). No study has been published about the titer of Sars-Cov-2 antibodies in non-infected patients with autoimmune disease.Objectives:To evaluate the titer of SARS-CoV-2 antibodies in non-COVID-19 patients and compare it between systemic sclerosis (SSc) patients and healthy controls (HC).Methods:A total of 58 patients with SSc (who fulfilled ACR/EULAR 2013 SSc classification criteria) and 18 HC were enrolled. Sera of all participants were collected, and SARS-CoV-2 antibodies (IgG and IgM) were evaluated by means ELISA. In all participants swabs for SARS-CoV-2 by real-time reverse-transcriptase-polymerase-chain-reaction assay were reported negative. Demographic, clinical, and autoimmune serological characteristics of SSc patients were recorded. The normal distribution was assessed using the Shapiro–Wilk’s test. Exclusion criteria was previous or actual Sars-Cov-2 infection. Comparisons between study groups of patients were evaluated by the Student’s t-test or Mann – Whitney U-test as appropriate. The differences between categorial variables were assessed by Pearson chi-square or Fisher’s exact test, as opportune. Statistical significance was set at p ≤ 0.05.Results:We observed significant differences between SSc patients and HC in serum levels of Sars-Cov-2 antibodies (IgG: 1,4±2,1 AU/ml vs 0,36±0,19 AU/ml respectively (p=0,001); and IgM: 2,5±3,1 AU/ml vs 0,8±0,7 AU/ml (p=0,022)). In 5 SSc patients was found titer of Sars-Cov-2 antibodies (IgG) exceeding the cut-off, but the control of swabs for SARS-CoV-2 by real-time reverse-transcriptase-polymerase-chain-reaction assay were negative. No significative differences in Sars-Cov-2 autoantibodies titer were found in subgroup of SSc patients with or without ILD or PAH, limited or diffuse skin subset, and different autoantibodies profile. Furthermore, antibodies titer was not associated with different drugs (steroid, methotrexate, mofetil-mycophenolate and bosentan) in use.Conclusion:A cross mimicking between Sars-Cov-2 antibodies and antinuclear antibodies or anti ENA could be hypothesized. Further studies are necessary to unravel the reliability of Sars-Cov-2 antibodies detection in autoimmune disease.References:[1]Vojdani, A., Vojdani, E., & Kharrazian, D. (2021). Reaction of human monoclonal antibodies to SARS-CoV-2 proteins with tissue antigens: Implications for autoimmune diseases. Frontiers in Immunology, 11, 3679Disclosure of Interests:None declared
: HCV is a global health problem affecting mainly the liver and often characterized by extrahepatic manifestions mediated by autoimmune reactions. Among these, arthritis and arthralgia are most frequent, as well as the presence of cryoglobulinemia that may induce vasculitis, and sicca syndrome. Thus, HCV appears to be a trigger for autoimmune response as demonstrated by the finding of autoantibody in a high percentage of serum of these patients. Therefore, it is important that clinicians recognize these autoimmune manifestations as symptoms due to an autoimmune activity triggered by HCV, in order to give the correct diagnosis and start an effective therapy strategy. Therefore, clinical examination, searching of markers of infection as well as autoantibody patterns should be performed to make a correct differential diagnosis. The treatment should be based on antiviral drugs associated to immunosuppressive drugs according to autoimmune manifestations.
Objectives: IL-17 modulates the synthesis of several molecules involved in the pathogenesis of Systemic Sclerosis (SSc). Vitamin D (1,25(OH)2D3) shows anti-fibrotic properties and it is able to affect the IL-17 production in several experimental conditions. The aim of this study is to assess the production of IL-17A and pro-fibrotic cytokines in peripheral blood mononuclear cells (PBMCs) from subjects with SSc in basal conditions and after treatment with 1,25(OH)2D3 and IL-17A neutralizing antibodies. Methods:The production of IL-17A and pro-fibrotic cytokines (TGFβ, CTGF and FGF2) in PBMCs obtained from 51 SSc patients and 31 healthy subjects was assessed both in basal conditions and in presence of anti-IL17A antibodies and several concentrations of 1,25(OH)2D3. The association of cytokines production with clinical disease characteristics and the in vitro effect of 1,25(OH)2D3 and IL-17A inhibition were assessed.Results: PBMCs from SSc subjects produced higher amount IL-17A, TGFβ, CTGF and FGF2 compared t o healthy controls. IL17, TGFβ, CTGF and FGF2 levels were higher in SSc patients with interstitial lung disease and digital ulcers, whereas IL-17A production was lower in patients with PAH. IL-17A inhibition reduced the production of FGF2, whereas enhanced the synthesis of TGFβ and CTGF. 1,25(OH)2D3 decreased the production of IL17A and pro-fibrotic cytokines in a dose-dependent manner. Conclusions: IL-17A is involved in the regulation of fibrogenesis in SSc, and could represent an intriguing potential therapeutic target, even if its role remains controversial. 1,25(OH)2D3 inhibits both IL-17A and pro-fibrotic cytokines, confirming its potential anti-fibrotic effect.
Background:Systemic Sclerosis (SSc) is a chronic rheumatic disease characterized by an autoimmune disorder with vasculopathy that leads to an excess in collagen and other extracellular matrix proteins deposition. This process results in progressive fibrotic and vascular damage of skin and visceral organs. According to observational studies conducted in last decades, mean survival of SSc patients had improved with significant changes in causes of death.Objectives:To assess the 10-years survival in a large Italian multicentre cohort of SSc patients in the last decade compared to previous periods published since the 1980s, and to identify features that can justify any change.Methods:We retrospectively analysed all medical records of our longitudinal SSc cohorts, fulfilling 1980 ARA and/or 2013 EULAR/ACR Classification Criteria, with a median (IQR) follow-up of 91.5 (51-120) months from 4 Scleroderma Units since January 2009. All clinical, laboratory and instrumental findings have been recorded and analysed. Survival rate was calculated with Kaplan-Meier curves and log-rank tests, and Cox proportional hazards models were used to identify any predictor. Then, observed SSc survival was compared to those previously published and to that expected in the general population, calculated using official data published on the website United Nation World Population Prospects (www.macrotrends.net/countries/ITA/italy/death-rate).Results:Of 912 SSc patients (91.6% female; mean (SD) age at first non-Raynaud symptom (RS) 51 (15.4) years; median (IQR) disease duration from non-RS 24 (0-84.7) months) diffuse cutaneous involvement was defined in 182 (20%) patients. Anti-centromere and anti-topoisomerase-I were detected in 390 (42.8%) and 302 (33.1%) patients, respectively, while 220 (24.1%) presented antibodies for other extractible nuclear antigens. Prevalent non-Raynaud manifestations were interstitial lung disease detected in 459 (50.3%), digital ulcers in 395 (43.3%) and oesophagopathy in 371 (40.7%) patients, respectively, while other gastrointestinal manifestations were reported in 234 (25.7%) patients. Chronic renal failure was observed in 61 (6.7%) patients and pulmonary arterial hypertension (PAH) was confirmed at right heart catheterization in 38 (4.2%) patients. Three hundred twenty-two (35.3%) patients received immunosuppressant, 215 (23.5%) assumed an endothelin receptor antagonist and/or a 5-phosphodiesterase inhibitor, and 72 (7.9%) were treated with a biologic agent. The global 10-years survival was 89.4%; female gender (HR 0.33, CI95% 0.17-0.67), diffuse cutaneous involvement (HR 2.14, CI95% 1.17-3.91), presence of pulmonary hypertension (HR 2.61, CI95%1.31-5.16) and older age at non-RS (HR 1.1, CI95% 1.06-1.12) affected survival. Furthermore, as compared to previous Italian studies, our cohort showed a significant improvement in rate (see Figure 1).Conclusion:Survival in SSc patients has improved in last 5 decades but still reduced compared to that expected in general population above all 5 years after diagnosis. Early diagnosis, with reduced renal involvement, along with better screening and innovative therapeutic strategies may explain these achievements.Figure 1.Ten-years survival in SSc patients since 2009 (left); comparison of survival across different Italian SSc cohorts (box: current analysis) (right).References:[1]Giordano M, et al. The Journal of Rheumatology. 1986; 13:911-916.[2]Ferri C, et al. Medicine. 2002; 81:139-53.[3]Vettori S, et al. Reumatismo. 2010; 62(3):202-209.[4]Ferri C, et al. Autoimmun Rev. 2014; 13(10):1026-34.Disclosure of Interests:None declared
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