Search

Abstract An accurate prediction of cardiovascular (CV) risk in patients with Axial Spondyloarthritis (axSpA) is a strong unmet need, as CV risk algorithms poorly perform in these subjects. The aim of this study was to establish whether the persistence of high C-reactive protein (CRP) and high disease activity may be considered predictive factors of CVD in axSpA. 295 patients without personal history of CVD, were consecutively enrolled in this study. To evaluate the relationship between CV events occurrence (fatal and non-fatal) and the persistence of increased CRP levels, ASDAS (Ankylosing Spondylitis Disease Activity Score) > 2.1, and BASDAI (Bath Ankylosing Spondylitis Disease Activity) > 4 during the follow-up, univariable and multivariable Cox Proportional Hazard Models have been performed. During follow-up (we analyzed 10-years retrospective data), 23 patients had a CV event. Multivariable Cox Proportional Hazard Models showed a strong association between CV event and the persistency of increased CRP levels (namely, percentage of visits in which CRP levels were increased) (HR = 1.03; 95%CI 1.015–1.045; p 2.1 (HR = 1.014, 95%CI 1.000–1.028, p = 0.047), and of BASDAI > 4 (HR 1.019, 95%CI 1.006–1.033, p = 0.006) during follow-up, after adjustment for age, sex, and diabetes. This study suggests that persistence of increased CRP levels and high disease activity may be considered biomarkers to identify those axSpA patients at higher risk of CVD. Innovative axSpA-specific CV risk score, including these variables, have to be developed.

Abstract We showed that the chemokine receptor C‐X‐C Motif Chemokine Receptor 2 (CXCR2) is essential for cartilage homeostasis. Here, we reveal that the CXCR2 ligand granulocyte chemotactic protein 2 (GCP‐2) was expressed, during embryonic development, within the prospective permanent articular cartilage, but not in the epiphyseal cartilage destined to be replaced by bone. GCP‐2 expression was retained in adult articular cartilage. GCP‐2 loss‐of‐function inhibited extracellular matrix production. GCP‐2 treatment promoted chondrogenesis in vitro and in human cartilage organoids implanted in nude mice in vivo. To exploit the chondrogenic activity of GCP‐2, we disrupted its chemotactic activity, by mutagenizing a glycosaminoglycan binding sequence, which we hypothesized to be required for the formation of a GCP‐2 haptotactic gradient on endothelia. This mutated version (GCP‐2‐T) had reduced capacity to induce transendothelial migration in vitro and in vivo, without affecting downstream receptor signaling through AKT, and chondrogenic activity. Intra‐articular adenoviral overexpression of GCP‐2‐T, but not wild‐type GCP‐2, reduced pain and cartilage loss in instability‐induced osteoarthritis in mice. We suggest that GCP‐2‐T may be used for disease modification in osteoarthritis.

Objectives Tocilizumab showed trends for improving skin fibrosis and prevented progression of lung fibrosis in systemic sclerosis (SSc) in randomised controlled clinical trials. We aimed to assess safety and effectiveness of tocilizumab in a real-life setting using the European Scleroderma Trial and Research (EUSTAR) database.Methods Patients with SSc fulfilling the American College of Rheumatology (ACR)/EULAR 2013 classification criteria, with baseline and follow-up visits at 12±3 months, receiving tocilizumab or standard of care as the control group, were selected. Propensity score matching was applied. Primary endpoints were the modified Rodnan skin score (mRSS) and FVC at 12±3 months compared between the groups. Secondary endpoints were the percentage of progressive/regressive patients for skin and lung at 12±3 months.Results Ninety-three patients with SSc treated with tocilizumab and 3180 patients with SSc with standard of care fulfilled the inclusion criteria. Comparison between groups did not show significant differences, but favoured tocilizumab across all predefined primary and secondary endpoints: mRSS was lower in the tocilizumab group (difference −1.0, 95% CI −3.7 to 1.8, p=0.48). Similarly, FVC % predicted was higher in the tocilizumab group (difference 1.5 (−6.1 to 9.1), p=0.70). The percentage of progressive/regressive patients favoured tocilizumab over controls. These results were robust regarding the sensitivity analyses. Safety analysis confirmed previously reported adverse event profiles.Conclusion Although this large, observational, controlled, real-life EUSTAR study did not show significant effectiveness of tocilizumab on skin and lung fibrosis, the consistency of direction of all predefined endpoints generates hypothesis for potential effectiveness in a broader SSc population.

Abstract Background Glucocorticoids (GC) modulate several regulators involved in the pathogenesis of bone changes in rheumatoid arthritis (RA). Trabecular bone score (TBS) allows the indirect assessment of bone quality. The aim of this study was to investigate the effects of GC on TBS and serum levels of bone turnover regulators in patients with recent-onset RA. Materials and methods Forty-seven subjects with recent-onset RA (

A growing body of evidence on the importance of vitamin D in immune modulation has increased the interest in its possible impact on the course of rheumatological diseases. The scope of our study is to assess if the presence of different statuses of vitamin D could interfere in the clinical subsets, in methotrexate monotherapy discontinuation, and biological drug (b-DMARDs) survival in psoriatic arthritis patients (PsA). We conducted a retrospective study on PsA patients and split them into three groups based on their vitamin D status: the group with 25(OH)D ≤ 20 ng/mL, the group with levels of 25(OH)D between 20 and 30 ng/mL, and the group with serum levels of 25(OH)D ≥ 30 ng/mL. All patients were required to fulfill the CASPAR criteria for psoriatic arthritis and to have the evaluation of vitamin D serum levels at baseline visit and at clinical follow-up visits. The exclusion criteria were ages less than 18 years old, the presence of HLA B27, and satisfaction of rheumatoid arthritis classification criteria (during the study time). Statistical significance was set at p ≤ 0.05. Furthermore, 570 patients with PsA were screened and 233 were recruited. A level of 25(OH)D ≤ 20 ng/mL was present in 39% of patients; levels of 25(OH)D between 20 and 30 ng/mL presented in 25% of patients; 65% of patients with sacroiliitis presented 25 (OH)D ≤ 20 ng/mL. Methotrexate monotherapy discontinuation for failure was higher in the group with 25 (OH)D ≤ 20 ng/mL (survival time: 92 ± 10.3 weeks vs. 141.9 ± 24.1 weeks vs. 160.1 ± 23.6 weeks; p = 0.02) with higher discontinuation risk (HR = 2.168, 95% CI 1.334, 3.522; p = 0.002) than those with 25(OH)D between 20 and 30 ng/mL and those with 25(OH)D ≥ 30 ng/mL. Significantly shorter survival of first b-DMARDs was assessed in the group with 25 (OH)D ≤ 20 ng/mL versus the other groups (133.6 ± 11 weeks vs. 204.8 ± 35.8 weeks vs. 298.9 ± 35.4; p = 0.028) (discontinuation risk 2.129, 95% CI 1.186, 3.821; p = 0.011). This study highlights significant differences in clinical presentation, in particular sacroiliac involvement and on drug survival (methotrexate and b-DMARDs) in PsA patients with vitamin D deficiency. Further prospective studies, including a larger sample of patients, are needed to validate these data and to assess if the supplementation of vitamin D could improve the b-DMARDs response in PsA patients.

Abstract Introduction The performance of seven cardiovascular (CV) risk algorithms is evaluated in a multicentric cohort of ankylosing spondylitis (AS) patients. Performance and calibration of traditional CV predictors have been compared with the novel paradigm of machine learning (ML). Methods A retrospective analysis of prospectively collected data from an AS cohort has been performed. The primary outcome was the first CV event. The discriminatory ability of the algorithms was evaluated using the area under the receiver operating characteristic (ROC) curve (AUC), which is like the concordance-statistic (c-statistic). Three ML techniques were considered to calculate the CV risk: support vector machine (SVM), random forest (RF), and k-nearest neighbor (KNN). Results Of 133 AS patients enrolled, 18 had a CV event. c-statistic scores of 0.71, 0.61, 0.66, 0.68, 0.66, 0.72, and 0.67 were found, respectively, for SCORE, CUORE, FRS, QRISK2, QRISK3, RRS, and ASSIGN. AUC values for the ML algorithms were: 0.70 for SVM, 0.73 for RF, and 0.64 for KNN. Feature analysis showed that C-reactive protein (CRP) has the highest importance, while SBP and hypertension treatment have lower importance. Conclusions All of the evaluated CV risk algorithms exhibit a poor discriminative ability, except for RRS and SCORE, which showed a fair performance. For the first time, we demonstrated that AS patients do not show the traditional ones used by CV scores and that the most important variable is CRP. The present study contributes to a deeper understanding of CV risk in AS, allowing the development of innovative CV risk patient-specific models.

Abstract Background Adult-onset Still’s disease (AOSD) is a systemic inflammatory disorder of unknown aetiology usually affecting young adults. Interestingly, recent evidence from the juvenile counterpart of AOSD suggested the emergent high fatality rate of lung disease (LD) in these patients. In this work, we aimed to characterise LD in AOSD, to identify associated clinical features and predictive factors, and to describe long-term outcomes of the disease comparing patients with LD and those without. Methods A retrospective assessment of prospectively followed patients, from January 2001 to December 2019, was provided to describe the rate of LD in AOSD, associated clinical features and predictive factors, and long-term outcomes. Patients with AOSD, who were included in Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale (GIRRCS) cohort, were assessed. Results Out of 147 patients included in GIRRCS cohort, 18 (12.25%) patients were reported to be affected by LD, at the time of diagnosis of AOSD, who were characterised by older age, a higher prevalence of myalgia, of lymph node involvement, of pleuritis, and abdominal pain. Furthermore, patients with LD showed higher values of systemic score and ferritin. Among those clinical variables, older age and systemic score were also independently predictors of LD. Chest CT scans were also obtained, and the most common finding was the peripheral consolidations in 8 (44.4%) patients. Finally, a higher mortality rate, of 38.9%, was registered in patients with LD than others, since it was associated with a significant decreased survival rate. Conclusions The presence of LD could suggest an emergent cause of mortality in AOSD, as observed in juvenile counterpart recognising a further marker of severity and poor prognosis to be careful evaluated. Patients with LD were also characterised by some clinical features, higher values of systemic score and ferritin than the others, identifying a subset of patients mostly burdened by systemic signs and symptoms. Although specific designed future studies are needed to fully elucidate the significance of LD in AOSD, a more accurate evaluation and management of this feature could improve the long-term outcomes of these patients.

Musculoskeletal involvement is one of the most common manifestations of systemic lupus erythematosus (SLE), with a negative impact on both quality of life and overall prognosis. SLE arthritis can be classified into three different subtypes, with different prevalence and characteristic biomarkers and MRI findings. Identifying the pathogenetic mechanisms underlying musculoskeletal manifestations’ development is crucial to develop therapeutic strategies to suppress synovial inflammation, prevent erosions and deformities, and improve SLE patients’ quality of life. Hence, here we discuss the main pathogenetic mechanisms and therapeutic approaches of musculoskeletal manifestations of SLE from the 2022 International GISEA/OEG Symposium.

The association between estrogen receptor (ER) positive breast cancer (BC) and autoimmune disorders has been recently recognized. In particular exposure to aromatase inhibitors is associated with a significant increased risk of rheumatological autoimmune disorders. The purpose of this study was to investigate Sjogren syndrome (SjS) occurrence in patients with ER-positive BC. This is a prospective study analyzing 110 consecutive patients with ER-positive BC treated with anti-hormonal therapy. New 2016 American College of Rheumatology/European League against Rheumatism (ACR-EULAR) classification criteria were used to identify patients with SjS. Ultrasonography of salivary glands (SG) was used to screen patients with negative disease biomarkers, to candidate them to SGs biopsy. Sicca syndrome was detected in 51 patients (46%), whereas a true primary SjS was diagnosed in 11 patients (10%). Even if the evaluation of incidence and prevalence of primary SjS vary widely, to the best of our knowledge, the data from the present study emphasize a previously unsuspected high prevalence of defined pSjS that causes BC sicca symptoms complaints. Hypothesis, explanation of this link and even possible biases are discussed.

In this prospective observational study, data were collected from 34 rheumatology clinics in Italy in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) who started golimumab (GLM) as a second anti-TNFα drug. The primary objective was to evaluate the effectiveness of GLM after 6 months. Changes in quality of life using the EQ-5D-5L were also assessed. A total of 194 patients aged 53.2 ± 12 years started GLM as a second anti-TNF drug: 39 (20.1%) with RA, 91 (46.9%) with PsA and 64 (32.9%) with axSpA. After 6 months of GLM treatment, 68% of RA patients achieved low disease activity (LDA; DAS28-CRP ≤ 3.2), 31.9% of PsA patients achieved minimal disease activity and 32.5% of axSpA patients achieved LDA (ASDAS-CRP < 2.1). Good/moderate EULAR response was achieved in 61.9% and 73.8% of patients with RA and PsA, respectively, and 16% of axSpA patients achieved a 50% improvement in BASDAI. Across all indications, improvements in disease activity measures and EQ-5D-5L domains were observed over 6 months. The main reasons for GLM interruption were lack/loss of efficacy (7.2%) or adverse events (2%). This study confirms the effectiveness of GLM as a second-line anti-TNF for the treatment of RA, PsA and axSpA in a real-world setting in Italy.

Abstract Background Rheumatoid arthritis (RA) is associated with an increased risk of morbidity and mortality, when compared with general population, largely due to enhanced atherosclerotic disease. In this work, we aimed at assessing both occurrence and predictive factors of subclinical and clinical atherosclerosis in RA. Methods From January 1, 2015, to December 31, 2015, consecutive participants with RA, admitted to Italian Rheumatology Units, were assessed in the GIRRCS (Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale) cohort. After that, those participants were followed up in a 3-year, prospective, observational study, assessing the occurrence of subclinical and clinical atherosclerosis and possible predictive factors. McNemar test was employed to assess the changes in subclinical and clinical atherosclerosis, and regression analyses exploited the ORs for the occurrence of those comorbidities. Results We analysed 841 participants, mostly female (82.2%) and with median age of 60 years (range 21–90). The remission was achieved and maintained by 41.8% of participants during the follow-up. We observed an increased rate of subclinical atherosclerosis at the end of follow-up (139 vs 203 participants, p

Objective: Despite the well-established efficacy of methotrexate (MTX) in rheumatoid arthritis (RA), monotherapy is not sufficient in almost half of patients. The aim of this registry-based study was to detect possible predictive factors for the early failure of MTX as a first-line treatment in early RA patients. Materials and Methods: Five-hundred and ninety RA patients beginning MTX as the first-line treatment were included. Persistence on therapy was re-evaluated after 12 months. Baseline features of disease were evaluated by means of univariate Cox regression, and parameters significantly associated to the outcome were included in multivariate model. Results: One hundred and forty-nine patients (25.3%) failed MTX during the 1st year, for inefficacy in 43.6% and adverse events in 37.5% of cases, respectively. At univariate analysis, patients who discontinued or failed treatment showed lower mean age, higher prevalence of anti-citrullinated peptide antibodies (ACPAs), and higher number of tender/swollen joints. The dose of MTX was correlated with the efficacy and the tolerance of the drug. In particular, patients treated with 7.5 mg of MTX weekly showed a higher rate of discontinuation for inefficacy than adverse events, and the contrary was detected for higher doses. On multivariate analysis, age, ACPA, and number of tender joints were directly associated with MTX discontinuation or failure. Conclusions: More than 25% of RA patients treated with MTX as a first-line therapy failed treatment at 12 months. ACPA positivity, age, and number of tender joints were associated with early withdrawal of MTX in RA patients, while the dose of MTX was correlated to the efficacy and safety of the drug.

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.

Aim: Occasional findings of anti-cyclic-citrullinated-protein-antibodies (anti-CCP) were rarely observed in psoriatic arthritis (PsA). The aim of our study is to evaluate whether the presence of anti-CCP can determine different clinical subsets and influence methotrexate monotherapy survival, and biotechnological drug retention rate. Methods: We conducted a retrospective study on PsA patients. All patients were required to fulfill the CASPAR criteria for PsA, and to present juxta-articular osteo-proliferative signs at X-ray. The exclusion criteria were age less than 18 years old, satisfaction of rheumatoid arthritis classification criteria, and seropositivity for rheumatoid factor. Clinical characteristics, anti-CCP titer, drug survival and comorbidities information were recorded for each patient. Statistical significance was set at p ⩽ 0.05. Results: Of 407 patients with PsA screened 113 were recruited. Twelve patients were anti-CCP positive. Methotrexate monotherapy survival was shorter in patients with anti-CCP (150 ± 48.3 weeks versus 535.3 ± 65.3 weeks; p = 0.026) [discontinuation risk hazard ratio (HR) = 2.389, 95% confidence interval (CI) 1.043, 5.473; p = 0.039] than those without. Significant shorter survival of first-line biotechnological drugs (b-DMARDs) was observed in the anti-CCP positive group than in that without (102.05 ± 24.4 weeks versus 271.6 ± 41.7 weeks; p = 0.005) with higher discontinuation risk (HR = 3.230, 95% CI 1.299, 8.028; p = 0.012). A significant higher rate of multi-failure (more than second-line b-DMARDs) was found in anti-CCP positive patients than in those without (50% versus 14%, p = 0.035). Conclusion: Anti-CCP in PsA could be suggestive of more severe disease, with worse drug survival of both methotrexate monotherapy and first-line b-DMARDs, and higher chance to be b-DMARDs multi-failure. So, they can be considered for more intensive clinical management of these patients.

Pfeifer-Weber-Christian disease (PWCD) is a rare idiopathic disease characterized by lobular panniculitis of adipose tissue with systemic symptoms and multiple organ involvement. Even though the systemic involvement is rare, it is life-threatening and represent a treatment challenge for the clinicians. We report a case of PWCD characterized by hepatic, hematologic, and renal involvement, with good response to mofetil mycophenolate and prednisone treatment. A 47-year-old female presented several months’ history of painful subcutaneous nodules, fever and lymphadenopathy with recent appearing of microcytic hypochromic anemia, leucopenia with neutropenia, and increase in transaminase. Skin biopsy showed lobular panniculitis with lymph-histiocytic and neutrophilic infiltrates with necrosis of adipocytes. A combination therapy of corticosteroid with mofetil mycophenolate was effective. Moreover, we discuss the clinical manifestation and the therapeutic choices in PWCD, from classical immunosuppressive drugs to new biotechnological agents, and we provide a comprehensive review of the available literature.

Anti-hormonal therapies are used in the treatment of hormone dependent breast cancer. Their use may be complicated with the onset of arthralgia and autoimmune diseases. Recently a clinical relationship between oestrogen, anti-oestrogen therapy and rheumatic diseases has been reported in the literature, but, until now, experimental supporting data about the interacting biochemical pathways involved are still very limited. The understanding of this molecular link may provide important information to elucidate the relationship between autoimmunity and cancer mechanism and treatment. This review is intended to highlight the relationship between known common molecular mechanisms which explain this association and that probably need to be investigated in future studies.

ObjectiveTo assess the predictive role of ferritin and C-reactive protein (CRP) on occurrence of macrophage activation syndrome (MAS) and mortality in patients with adult onset Still's disease (AOSD), a rare and severe disease, included in the multicentre Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale (GIRRCS) cohort.MethodsThe predictive role, at the time of diagnosis, of serum levels of ferritin and CRP on occurrence of MAS and mortality, was evaluated by logistic regression analyses and receiver-operating characteristic (ROC) curves were built to identify patients at high risk of MAS and mortality, respectively.ResultsIn assessed 147 patients with AOSD, levels of ferritin were predictive of MAS (OR: 1.971; P: 0.002; CI 95%: 1.280-3.035). The ROC curve showed that the best cut-off for ferritin was 1225 ng/ml in predicting MAS (sensitivity 88%; specificity 57%). Levels of CRP were predictive of mortality in these patients (OR: 2.155; P: 0.007; CI 95%: 1.228-3.783). The ROC curve showed that the best cut-off for CRP was 68.7 mg/L in predicting mortality (sensitivity 80%; specificity of 65%).ConclusionsWe reported the predictive role of ferritin and CRP on MAS and mortality, respectively, in a large cohort of patients with AOSD, identifying subsets at higher risk of poor prognosis. Considering that the analysis of CRP and ferritin is widely available, these results could be readily transferable into clinical practice, thus improving the management of patients with AOSD.

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.

An increased risk of developing severe infections has been evidenced in rheumatic disease (RD) patients, and anti-COVID-19 vaccination is strictly recommended for RD patients. However, up to now, no data are available on safety, immunogenicity and efficacy of COVID-19 vaccinations in RD patients. The possible development of adverse events (AEs), including the flare-up of underlying RD, represents a matter of growing importance. The aim of our study is to assess, in RD patients, the safety profile of different types of approved vaccines and the possible influence of immunosuppressive therapies and clinical or demographic characteristics of RD patients on development of AEs. Participants (n = 185; 30.7%) received anti-COVID-19 vaccinations, 137 with autoimmune/chronic inflammatory RD (Au/cIn-RD) and 48 with nonautoimmune/chronic inflammatory RD (no-Au/cIn-RD). AEs were recorded in 42% of patients after the first dose of vaccine, and in 26% of patients after the second dose. The most common reported AEs after anti-COVID 19 vaccines were site injection pain (17%), headache (12%), fever (12%), myalgia (10%) and fatigue (10%). Relapses of the underlying Au/c-In-RD were recorded in 2.2% of patients after the first dose of vaccine. In Au/c-In-RD the risk of developing AEs after the first dose of vaccine was lower in older patients (OR = 0.95; p = 0.001), and in the group of patients with complete control of RD (OR: 0.2; p = 0.010). A lower percentage of AEs was observed in patients with complete control of their Au/cIn-RD (29%) compared to those with low (57%) or moderate-high disease activity (63%) (p = 0.002 and p = 0.006 respectively). In this study all types of COVID-19 vaccines in use in Italy seemed safe in RD patients. The results of this study might provide reassuring information for Au/cIn RD patients and clinicians and could strengthen the data on vaccine safety to guide the use of COVID-19 vaccines in Au/cIn-RD on immunosuppressive agents.

BackgroundThe inflammatory contribution to type 2 diabetes (T2D) has suggested new therapeutic targets using biologic drugs designed for rheumatoid arthritis (RA). On this basis, we aimed at investigating whether interleukin-1 (IL-1) inhibition with anakinra, a recombinant human IL-1 receptor antagonist, could improve both glycaemic and inflammatory parameters in participants with RA and T2D compared with tumour necrosis factor (TNF) inhibitors (TNFis).Methods and findingsThis study, designed as a multicentre, open-label, randomised controlled trial, enrolled participants, followed up for 6 months, with RA and T2D in 12 Italian rheumatologic units between 2013 and 2016. Participants were randomised to anakinra or to a TNFi (i.e., adalimumab, certolizumab pegol, etanercept, infliximab, or golimumab), and the primary end point was the change in percentage of glycated haemoglobin (HbA1c%) (EudraCT: 2012-005370-62 ClinicalTrial.gov: NCT02236481). In total, 41 participants with RA and T2D were randomised, and 39 eligible participants were treated (age 62.72 ± 9.97 years, 74.4% female sex). The majority of participants had seropositive RA disease (rheumatoid factor and/or anticyclic citrullinated peptide antibody [ACPA] 70.2%) with active disease (Disease Activity Score-28 [DAS28]: 5.54 ± 1.03; C-reactive protein 11.84 ± 9.67 mg/L, respectively). All participants had T2D (HbA1c%: 7.77 ± 0.70, fasting plasma glucose: 139.13 ± 42.17 mg). When all the enrolled participants reached 6 months of follow-up, the important crude difference in the main end point, confirmed by an unplanned ad interim analysis showing the significant effects of anakinra, which were not observed in the other group, led to the study being stopped for early benefit. Participants in the anakinra group had a significant reduction of HbA1c%, in an unadjusted linear mixed model, after 3 months (β: -0.85, p < 0.001, 95% CI -1.28 to -0.42) and 6 months (β: -1.05, p < 0.001, 95% CI -1.50 to -0.59). Similar results were observed adjusting the model for relevant RA and T2D clinical confounders (male sex, age, ACPA positivity, use of corticosteroids, RA duration, T2D duration, use of oral antidiabetic drug, body mass index [BMI]) after 3 months (β: -1.04, p < 0.001, 95% CI -1.52 to -0.55) and 6 months (β: -1.24, p < 0.001, 95% CI -1.75 to -0.72). Participants in the TNFi group had a nonsignificant slight decrease of HbA1c%. Assuming the success threshold to be HbA1c% ≤ 7, we considered an absolute risk reduction (ARR) = 0.42 (experimental event rate = 0.54, control event rate = 0.12); thus, we estimated, rounding up, a number needed to treat (NNT) = 3. Concerning RA, a progressive reduction of disease activity was observed in both groups. No severe adverse events, hypoglycaemic episodes, or deaths were observed. Urticarial lesions at the injection site led to discontinuation in 4 (18%) anakinra-treated participants. Additionally, we observed nonsevere infections, including influenza, nasopharyngitis, upper respiratory tract infection, urinary tract infection, and diarrhoea in both groups. Our study has some limitations, including open-label design and previously unplanned ad interim analysis, small size, lack of some laboratory evaluations, and ongoing use of other drugs.ConclusionsIn this study, we observed an apparent benefit of IL-1 inhibition in participants with RA and T2D, reaching the therapeutic targets of both diseases. Our results suggest the concept that IL-1 inhibition may be considered a targeted treatment for RA and T2D.Trial registrationThe trial is registered with EU Clinical Trials Register, EudraCT Number: 2012-005370-62 and with ClinicalTrial.gov, number NCT02236481.

Objective. To investigate the role of acetylsalicylic acid (ASA) in reducing the incidence of cardiovascular (CV) events in an Italian multicentre rheumatoid arthritis (RA) inception cohort. Methods. The clinical charts of RA patients consecutively admitted to 4 Italian centres for their 1st visit from November 1, 2000, to December 31, 2015, and followed up till December 2016 were retrospectively investigated for the incidence of CV events. Patients were subdivided into two groups, namely, ASA- and non-ASA-treated groups. The Kaplan–Meier curve and log-rank test were used to investigate differences in event-free survival. Cox regression analysis was carried out to identify factors associated with CV event occurrence. Results. Seven hundred forty-six consecutive RA patients were enrolled and followed up for a median of 5.6 years (range 2.9–8.9 years). The incidence rate (IR) of CV events was 8/1000 person-years (p-ys) in the overall cohort. The IR of CV events was significantly lower in the ASA-treated group with respect to the non-ASA-treated group (IR 1.7 vs. 11.8/1000 p-ys; p=0.0002). The CV event-free rate was longer in ASA-treated patients than in non-ASA-treated patients (log-rank test 12.8; p=0.0003). At multivariable analysis, arterial hypertension (HR 9.3) and hypercholesterolemia (HR 2.8) resulted to be positive predictors and ASA (HR 0.09) and hydroxychloroquine (HCQ) (HR 0.22) to be negative predictors. Conclusion. The IR of CV events in our Italian multicentre cohort was lower than that reported in other European and non-European cohorts. Low-dose ASA may have a role in the primary prophylaxis of CV events in RA patients.

Background: The improvement of muscular strength is a well-known extra-skeletal effect of Vitamin D. The aim of the study was to evaluate the effectiveness of the calcifediol supplementation compared to various cholecalciferol administration schedules in increasing 25(OH)D serum levels and improving muscular function. Methods: 107 post-menopausal women with hypovitaminosis D were assigned to receive Vitamin D supplementation according to four different regimens: colecalciferol single, monthly, or weekly oral dose and calcifediol weekly oral dose. Serum levels of 25(OH)D and muscular function of lower limbs (Sit-to-Stand test and Timed-Up-and-Go test) were evaluated at baseline and during 6 months follow-up. Results: Calcifediol and weekly cholecalciferol induced a greater and faster increase of serum 25(OH)D, compared to monthly or single-dose cholecalciferol administration. The 25(OH)D increase was associated with an improvement of muscle function of lower limbs. The larger increase of serum 25(OH)D observed with calcifediol and with weekly cholecalciferol was associated with a concomitant greater improvement of muscle strength. Conclusions: Supplementation with calcifediol is more effective and faster compared to cholecalciferol in increasing 25(OH)D serum levels and is associated with a greater improvement of muscular function, thus representing a therapeutic alternative for treatment of hypovitaminosis D.

A decline in bone mass leading to an increased fracture risk is a common feature of age-related bone changes. The mechanisms underlying bone senescence are very complex and implicate systemic and local factors and are the result of the combination of several changes occurring at the cellular, tissue and structural levels; they include alterations of bone cell differentiation and activity, oxidative stress, genetic damage and the altered responses of bone cells to various biological signals and to mechanical loading. The molecular mechanisms responsible for these changes remain greatly unclear and many data derived from in vitro or animal studies appear to be conflicting and heterogeneous, probably due to the different experimental approaches; nevertheless, understanding the main physio-pathological processes that cause bone senescence is essential for the development of new potential therapeutic options for treating age-related bone loss. This article reviews the current knowledge concerning the molecular mechanisms underlying the pathogenesis of age-related bone changes.

Carbamylation is a post-translational modification that mostly affects proteins with low turnover, such as dermal proteins. Carbamylated proteins accumulate in skin in an age-dependent manner, contributing to tissue alterations. As dermis is affected by systemic sclerosis (SSc) and anti-carbamylated protein antibodies (anti-CarP Ab) are found in SSc patients, we sought to evaluate the specificity of anti-CarP Ab and their relationship with clinical parameters reflecting skin involvement in SSc. This study investigated serum samples and clinical data from 124 patients with SSc. Anti-CarP Ab were affinity purified from pooled SSc sera, and their specificity was assessed by western blotting and ELISA with carbamylated proteins from two species (human and bovine albumin; human fibrinogen). Anti-CarP Ab were measured in SSc serum samples and in 41 healthy aged-matched individuals. Affinity-purified anti-CarP Ab recognized carbamylated epitopes irrespective of the protein type or species origin. Anti-CarP Ab levels inversely correlated with the modified Rodnan skin score (mRss) (Spearman's R = -0.32, p

Background. Referral centres for pulmonary hypertension will provide care by a multiprofessional team, which should as a minimum comprise: consultant physicians with a special interest in PH, clinical nurse specialist, radiologist, cardiologist with expertise in echocardiography. Aims. this study sought to determine whether the experience of the establishment of a clinic for pulmonary arterial hypertension, initially created only for the treatment and diagnosis of heart failure, may be considered positive. Methods. From 1 July 2008 to January 1, 2012 we evaluated 80 patients in our ambulatory dedicated to the diagnosis and treatment of PAH. All patients were performed to clinical evaluation, ECG, and echocardiography with estimation of the sPAP. Then we evaluated the functional capacity through cardiopulmonary exercise testing or six minute walking test (6MWT). RHC was required to confirm the diagnosis of pulmonary arterial hypertension. Results. 80 patients (mean age: 50.9 ± 18.68 years, 31 males) were evaluated in our center; the largest groups subjected to screening were thalassemia (21 subjects), rheumatologic patients (18 patients), respirators, suspected of “outof Proportion” (12 patients) and 4 patients with OSAS. 8 adult congenital heart patients. A diagnosis of PAH after right heart catheterization was possible in 25 cases. In particular, among patients with pulmonary arterial hypertension, 8 had a rheumatic etiology (systemic sclerosis), 2 postthromboembolic disease, 5 patients had congenital heart disease, 1 patient with HIV infection, 1 patient with thalassemia major, 1 chronic lymphocytic leukemia and 1 with myelodysplasia. Conclusions. The initial experience of our center and network within our hospital may be considered positive, because it permitted to patients easy access to hospital services, to undertake a comprehensive prognostic stratification and to recognize the early signs of worsening in subsequent tests.

A reduced bone mineral density (BMD) is observed in several rheumatic autoimmune diseases, including Systemic Sclerosis (SSc); nevertheless, data concerning the possible determinants of bone loss in this disease are not fully investigated. The aim of this study is to evaluate the relationship between BMD, body mass composition, skin sclerosis and serum Vitamin D levels in two subsets of SSc patients. 64 post-menopausal SSc patients, classified as limited cutaneous (lcSSc) or diffuse cutaneous (dcSSc) SSc, were studied. As control, 35 healthy post-menopausal women were recruited. Clinical parameters were evaluated, including the extent of skin involvement. BMD at lumbar spine, hip, femoral neck and body mass composition were determined by dual-energy X-ray absorptiometry. Serum calcium, phosphorus, alkaline phosphatase, urine pyridinium cross-links, intact parathyroid hormone and 25-hydroxyvitamin D (25OHD) were measured. BMD at spine, femoral neck and total hip was significantly lower in SSc patients compared to controls. In dcSSc subset, BMD at spine, femoral neck and total hip was significantly lower compared to lcSSc. No differences in both fat and lean mass were found in the three study groups even if patients with dcSSc showed a slightly lower total body mass compared to healthy controls. Total mineral content was significantly reduced in dSSc compared to both healthy subjects and lcSSc group. Hypovitaminosis D was observed both in healthy post-menopausal women and in SSc patients, but 25OHD levels were significantly lower in dcSSc compared to lcSSc and inversely correlated with the extent of skin thickness. These results support the hypothesis that the extent of skin involvement in SSc patients could be an important factor in determining low circulating levels of 25OHD, which in turn could play a significant role in the reduction of BMD and total mineral content.

Alterations in osteoblast growth, differentiation and activity play a role in the pathogenesis of several rheumatic diseases, such as rheumatoid arthritis, spondyloarthritides, osteoarthritis, and osteoporosis. In fact, in these rheumatic diseases, abnormal activity of Wnt signaling, receptor activator of nuclear factor-κB (RANK)-RANK ligand (RANKL)-osteoprotegerin (OPG) signaling, bone morphogenetic proteins (BMPs) pathway and other mechanisms have been described in osteoblasts. This review article is focused on current knowledge on the role of osteoblast dysregulation occurring in rheumatic diseases.

Biologic agents used in the treatment of rheumatoid arthritis (RA) are able to reduce both disease activity and radiographic progression of joint disease. These drugs are directed against several proinflammatory cytokines (TNFα, IL-6, and IL-1) which are involved both in the pathogenesis of chronic inflammation and progression of joint structural damage and in systemic and local bone loss typically observed in RA. However, the role of biologic drugs in preventing bone loss in clinical practice has not yet clearly assessed. Many clinical studies showed a trend to a positive effect of biologic agents in preventing systemic bone loss observed in RA. Although the suppression of inflammation is the main goal in the treatment of RA and the anti-inflammatory effects of biologic drugs exert a positive effect on bone metabolism, the exact relationship between the prevention of bone loss and control of inflammation has not been clearly established, and if the available biologic drugs against TNFα, IL-1, and IL-6 can exert their effect on systemic and local bone loss also through a direct mechanism on bone cell metabolism is still to be clearly defined.